NeuroNotesbook2013 4

Medical Neuroscience: 2013 Course Guide
There are two missions of the Medical Neuroscience course. The first is to prepare CMS
students for the USMLE Step 1 Exam. This course, together with Clinical Neuroscience and
portions of Anatomy, ECR, Embryology, Histology, Microbiology, Physiology, Pathology, and
Pharmacology courses will cover all the neuroscience-related material you are expected to
master for this first Board Exam (detailed below).
The other mission of Medical Neuroscience is to give you a firm understanding of the brain. No
matter what medical specialty you choose, understanding how your patient's brain works,
thinks, learns, feels, and repairs itself is going to be essential to your comprehensive care. The
value of neuroscience is obvious for students who end up in Neurology or Psychiatry. But even
those of you who choose family practice, pediatrics, or gastroenterology will benefit from a
thorough comprehension of the brain and its role in pain, movement, emotion, and cognition.
Simply put, it is your patients brain you will be communicating with when s/he steps into your
office; the brain that feels symptoms and interprets what's going on in the rest of the body.
This course represents the last chance in your formal education to learn basic neural science,
and we intend to bring you up-to-date, acquainting you with the latest research and
therapeutic advances that may someday be the mainstay of neurological and mental health.

National Board of Medical Examiners (NBME) Outline:
CNS-related topics
Topics covered in this Medical Neuroscience (either in part or in full) are highlighted. Other
topics were/will be covered in your Anatomy, Embryology, Physiology, Pharmacology,
Pathology, and Clinical Neuroscience courses.
NEUROSCIENCE
Biology of cells (signal transduction, muscle cells) 1%5%
Central/peripheral nervous system 95%99%
Normal processes 65%70%
Embryonic development 1%5%
Organ structure and function 50%55%
Spinal cord 5%10%
Brain stem 5%10%
Brain 5%10%
1
Sensory systems 5%10%
Motor systems 5%10%
Autonomic nervous systems 1%5%
Peripheral nerve 1%5%
Cell/tissue structure and function 5%10%
Repair, regeneration, and changes associated with stage of life 1%5%
Abnormal processes 25%30%
Infectious, inflammatory, immunologic disorders 1%5%
Traumatic/mechanical disorders 1%5%
Neoplastic disorders 1%5%
Metabolic/regulatory disorders 1%5%
Vascular disorders 1%5%
Systemic disorders 1%5%
Idiopathic disorders 1%5%
Congenital/metabolic disorders 1%5%
Degenerative disorders 1%5%
Paroxysmal disorders 1%5%
Disorders of the special senses 1%5%
Principles of therapeutics 1%5%
NEUROPATHOLOGY
Nutrition 1%5%
Infectious, inflammatory, immunologic disorders 20%25%
Traumatic/mechanical disorders 1%5%
Neoplastic disorders 20%25%
Vascular disorders 15%20%
Congenital/metabolic disorders 5%10%
Degenerative disorders 20%25%
PSYCHOPATHOLOGY/PSYCHOPHARMACOLOGY
Personality traits or coping style 1%5%
Psychopathologic disorders 70%75%
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Early-onset disorders 1%5%
Substance use disorders 10%15%
Schizophrenia 10%15%
Mood disorders 15%20%
Anxiety disorders 10%15%
Somatoform disorders 1%5%
Physical and sexual abuse 5%10%
Other disorders 1%5%
Psychopharmacologic agents 20%25%

Course Faculty
This course is taught primarily by the faculty of the Department of Neuroscience:

Lise Eliot, PhD Course Director and Associate Professor
Lise.Eliot@rosalindfranklin.edu, ext. 3416, Rm. 2.274
Marina Wolf, PhD Professor and Chair
Marina.Wolf@rosalindfranklin.edu, ext. 8659, Rm. 2.262
Marjorie Ariano, PhD Professor and Associate Dean of Undergraduate Studies
Marjorie.Ariano@rosalindfranklin.edu, ext. 3412, Rm. 1.330
Daniel Peterson, PhD Professor
Daniel.Peterson@rosalindfranklin.edu, ext. 3411, Rm. 1.381B
Anthony West, PhD Associate Professor
Anthony.West@rosalindfranklin.edu, ext. 8658, Rm. 2.217A
Beth Stutzmann, PhD Associate Professor
Grace.Stutzmann@rosalindfranklin.edu, ext. 8540, Rm. 2.216
Robert Marr, PhD Assistant Professor
Robert.Marr@rosalindfranklin.edu, ext. 8541, Rm. 2.212

Other participating faculty members:
Chris Brandon, PhD Associate Professor of Cell Biology & Anatomy
Michael Fennewald, PhD Associate Professor of Microbiology and Immunology
William Frost, PhD Professor and Chair of Cell Biology & Anatomy
Donald Waxler, MD Associate Professor of Radiology
Michael Welch, MB President & CEO of RFUMS, Professor of Neurology
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Office Hours
Faculty are happy to meet with you outside class time, but you might have trouble finding us in
our offices. Please call or email anytime to set up an appointment, even at short notice.

2013 Teaching Assistants
The following TAs will lead your 10 afternoon Neuroanatomy Small Group Sessions:

Cameron Araghi
Stan Bazarek
Dan Champeau
Melissa Logan
Anthony Purgianto
Andrew Scheyer
Catherine Thomas
Geeta Verma
Craig Werner
Pejman Zargarkalimi

Please check D2L for your group assignment before the first small group session, on April 4
th
.

D2L
Most information pertaining to the course will be available on our D2L site: PowerPoint
lectures and handouts, links to lecture videos, scheduling information, small group
assignments, quizzes, old exams, the answers and scores following each exam, and links to
other neuroscience & neurology sites of interest. Please note, however, the most faculty do not
check their D2L email, so please use rosalindfranklin.edu addresses when contacting any of us.

Lectures & Neuroanatomy Sessions
Most lectures take place in the morning and are held in Rhoades Auditorium. In addition, ten
afternoons are reserved for neuroanatomy instruction, which begins with a one-hour overview
at 1:00 p.m. in Rhoades Auditorium and continues in small group sessions at 2 or 3 pm
(depending on your group assignment).

Text Books
Two books are required for Medical Neuroscience. The first is: Neuroscience, 5
th
Ed, by Dale
Purves et al. (Sinauer, 2012). The second required book is: Neuroanatomy, An Atlas of
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Structure, Sections, and Systems, 8
th
Ed., by Duane E. Haines (2012). Both books have
accompanying web sites, and you are particularly encouraged to download the program that
accompanies Purves text: Sylvius4, An interactive atlas and visual glossary of human
neuroanatomy. Both books are available at the University Bookstore.
Although all the faculty will provide detailed Powerpoint notes on D2L, there are several
reasons why the text is useful: 1) because it is succinct and well-written; 2) because it gives a
coherent narrative flow to the entire course, tying together many different subjects in a way
that separate lecturers cannot achieve; 3) because it was edited, reviewed, and indexed,
making it a better source for both your current and future reference than lecture notes alone.
Most importantly, you should realize by this point in your education that it is very difficult to
gain a thorough understanding of a topic by studying just one source, such as lecture notes.
Reading increases your familiarity with important terms and is the best way to augment your
vocabulary. In past years, some students have had difficulty with terminology used in certain
exam questions, which assumed more versatility with the vocabulary than one would obtain
from verbatim memorization of the lecture notes. While students who have studied
neuroscience in the past may do very well without reading the text, it would be very difficult for
a student new to neuroscience to achieve an "A" in this course without completing the required
reading.
Some other recommended texts are:
1. Hal Blumenfeld, Neuroanatomy through Clinical Cases, 2
nd
Ed. (Sinauer, 2010): excellent
text that treats neuroanatomy in great depth and offers numerous clinical correlations
to aid your understanding of the basic pathways. Highly recommended for students
planning to continue in neurology, neurosurgery, or neuroradiology.
2. Eric Kandel et. al., Principles of Neural Science, 5
th
Ed. (McGraw-Hill, 2012): the
"Neuroscience Bible " or definitive source of recent knowledge in the field.
3. Mark Bear et al., Neuroscience: Exploring the Brain, 3
rd
Ed. (Lippincott, Williams &
Wilkins, 2007): another "user-friendly" text that covers experimental neuroscience in
somewhat greater detail than Purves.
4. Duane E. Haines, Fundamental Neuroscience for Basic and Clinical Applications, 3
rd
Ed.
(Churchill Livingstone, 2005): excellent clinically-oriented textbook by the author of our
required atlas; good source for a more detailed understanding of functional
neuroanatomy.

How to study the material in this course:
The faculty will use the lectures to: 1) give you an appreciation of the big picture of a
particular topic, and 2) to explain the more complex aspects of that topic. To adequately
present a topic, some lectures will provide more details than you will find in your text. Others
will present less detail than the text. To best integrate material from the text and lectures, we
recommend the following:
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1. Do a quick read of the Purves chapter that corresponds to the next lecture. DO NOT get
caught up in the details your first time through. Even if you do not understand
everything in this first reading, there is a type of learning called priming which will
help you. Studies show that once a subject has been presented with data (primed),
even if it is in a different context and not consciously registered, that information
facilitates later learning. Priming helps transfer information from short-term to long-
term memory. So prime yourself the night before each lecture.
2. Come to the lecture and take notes on the important points and complex details you
will not otherwise be able to remember.
3. Read the chapter a second time, focusing on the material presented in class.
4. Prepare your own study notes, to rehearse important details and make the material
"your own"that is, to synthesize the information you have learned from both the text
and lecture. This procedure will reinforce your understanding and also identify any gaps
in your knowledge that you may want to pursue with the lecturers.
While lengthy, this process will give you a much fuller understanding of neuroscience than
spending the same amount of time re-reading the Course Notes several times.

A note on Board Review books:
Many students find Neuroscience Board Review books a valuable adjunct to the other learning
materials in this course. If you plan on buying such a book before taking the Step 1 exam, you
should by all means purchase it now and use it in conjunction with your other assigned texts.
Please be aware, however, that none of these are considered definitive sources for this course
(i.e., support for exam challenges).

Neuroanatomy Labs
Your core training in neuroanatomy will take place in 10 afternoon sessions that cover the
material described in your Neuroanatomy Study Guide. All of these sessions will begin in
Rhoades Auditorium, with a one-hour slide show by one of the faculty, in which you are
introduced to the critical structures to learn that week. Following the lecture will be Discussion
Sessionssmall group meetings headed by our 10 TAs. The first session will accommodate half
the class and run from 2-3 pm; the second session will accommodate the other half and run
from 3-4 pm. Please check your group and room assignment on D2L.
The small group sessions will be focused on identifying the structures for that weeks lab, as
well as answering a series of Discussion Questions posed at the end of each chapter in your
Study Guide. To aid this process, your TA will bring different brain models to various sessions.
In addition to the 10 Neuroanatomy small group sessions, there will be three wet brain labs
sessions in the south end of the Gross Anatomy Lab where you will have the opportunity to
handle and study a variety of brain specimens. Each of these is held shortly before the last
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three exams, to help you review. Their dates are: April 3, April 26, and May 14. Group
assignments for these Wet Labs are posted on another accompanying D2L file. Please stick to
your assigned time; otherwise the lab will be too crowded and less valuable to all.
Note that cadaver brains pose a significant biosafety risk. You must wear a lab coat or other
dispensable, protective outer wear in these sessions. We will provide you with gloves and
goggles. DO NOT BRING FOOD OR DRINK INTO THE GROSS ANATOMY LABS.

Neurohistology Labs
In an effort to better integrate our curriculum, all neuroscience-related lecture material from
the Histology course has been moved into this course. ALL STUDENTS (including BMS) are
responsible for the material presented in the CNS Histology lecture (March 6), the Eye I & II
lectures (April 10), and the Auditory System (Ear) lecture (April 15). Material from these
lectures will be included in the Neuroscience multiple choice questions on your three exams.
However, MEDICAL STUDENTS ONLY are responsible for the Neurohistology labs that follow
each of these lectures (1-5 pm on March 6, April 11, and April 16). Material from these lab
sessions will be tested separately under Dr. Brandons discretion.
We are grateful for the assistance of the following members of the Dept. of Cell Biology and
Anatomy in teaching the Neurohistology Labs: Drs. Brandon, Frost, Haghighat and Vertel.

Optional Review Sessions
Dr. Eliot will hold five OPTIONAL review sessions, focusing on the neuroanatomy content of the
course. These one-hour sessions will be held in Rhoades Auditorium on the dates listed in your
Course Schedule and on the D2L Calendar.

Quizzes
Five extra-credit quizzes will be administered via D2L, containing a mixture of neuroanatomy
and lecture-based questions. The quizzes will be posted on D2L from Sunday at noon until
Monday at 10 pm, with answers posted by Tuesday evening. Each quiz is comprised of 10
multiple choice questions and you will have 60 minutes to complete it. You may work in
groups, but we expect that you will use each quiz as a legitimate learning exercise, and are on
your honor to not hand out the questions and answers to other students. Each quiz offers you
the opportunity to earn up to 0.25 extra credit point (for a potential 1.25 extra credit points, on
top of the 100 total exam points) and is intended to give you feedback on your mastery of the
material.

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Examinations
Four examinations are scheduled for this course. Each examination will have two parts: (1) a
lecture portion, using standard multiple-choice questions (A through E possible answers) based
on the morning lectures and clinical correlations; and (2) a neuroanatomy portion, using
extended multiple-choice questions (A through U possible answers) that require identifying
structures and their functions from drawings, photos, and micrographs of the brain. Note that
for the last exam (May 17) the neuroanatomy portion will be cumulative. Heres the schedule:
Date Time Covers # Questions % of Grade
March 15 1-4:30
pm
All lectures and labs from March 1
through March 12
18 lecture-based,
5 neuroanatomy
12.6
April 5 9 am to
noon
All lectures and labs from March 18
through March 22
19 lecture-based,
10 neuroanatomy
15.8
April 29 1-4:30
pm
All lectures and labs from April 10
through April 25
44 lecture-based,
22 neuroanatomy
36.1
May 17 9 am to
noon
All lectures from April 30 through May
10 and ALL 10 LABS (from March 1
through May 10)
38 lecture-based,
27 neuroanatomy
35.5
Examination procedure:
1) Report to the Auditorium, on time, bringing only #2 pencils and your CMS ID card.
Leave all other materials coats, baseball caps, notebooks, phones, etc. in your locker
or car. Seating assignments will be posted on the walls outside the entrance to
Rhoades. Students arriving more than 30 minutes after the exam begins will not be
allowed to take it.
2) Take care of all personal business before the examination. Restroom breaks are not
considered necessary during 3 hour exams.
3) Cell phones, i-Pods, i-Pads and other electronic devices are absolutely forbidden. They
are to be left in your backpack or locker or at home. Any student found with one of
these devices on his/her person during an exam will receive an automatic grade of Zero.
4) Questions to faculty or proctors are not permitted during the exam, except to correct
typographic or grammatical errors. Definitions and explanations are not permitted.
5) Once time is called, you must put your pencil down and may not bubble any more
answers to your Scantron form.
6) Your Scantron determines your definitive grade. Credit is not given for bubbling errors.
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Special Accommodations
Students with a documented learning difference will be accommodated in accordance with the
Americans with Disability Act and as described in the RFUMS Student Policies Handbook.
Please contact Dr. Eliot by March 6 with such requests.

Grading
Final letter grade assignments will be made based on a straight scale:
A = 89.5 100
B = 79.5 89.4
C = 69.5 79.4
Defer = 59.5 69.4 (initial grade will be reported as F but student is eligible for Retake Exam)
F = Below 59.5 (ineligible for Retake Exam; must enroll in a summer course or retake in 2014)
Exams will be curved based on the mean of the M1 class. If, on a particular exam, the mean
score for the M1s is > 80.0, then no adjustment will be made. If the mean score is < 80.0, then
it will be adjusted to 80.0 by adding the difference between 80.0 and the class mean to each
students score.
Please note that ours is a very diverse class, including M1, BMS, PMP and Clinical Psychology
students, and we cannot consider adjusting the curve for any single group.

Challenges to the Exam:
Students who believe that there is a mistake or more than one best answer on any exam
question may present their challenge by emailing Arslaan Arshed, the M1 Course Rep, within 24
hours of the end of the exam. Arslaan will organize and present all challenges to Dr. Eliot two
days after the exam. Decisions will be made and posted on D2L as promptly as possible.
Absences and Make-up/Re-take Examinations:
Absences from scheduled examinations are permissible only when authorized by the Office of
Student Affairs. There will be no make-up examination for students with excused absences
from Exam 9 or Exam 10. Instead, your final grade for the course will be determined by a
proportional weighting of Exam 9 or 10 and Exams 11 and 12. A student excused from both
Exams 9 and 10 must sit for the Make-up Exam. His or her final grade will be determined by a
proportional weighting of Exams 11, 12, and the Makeup Exam. A student who misses Exam 11
or Exam 12 must also sit for the Make-up Exam. His or her final grade will be determined by a
proportional weighting of Exams 9, 10, 11 or 12, and the Make-up Exam. Other absences will
be managed on a contingent basis.
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Students who receive "Defer" as their final course grade are eligible to sit for the Retake Exam
on May 28 or June 6, 2013. Whether taken as a Make-up or as a Retake exam, THIS EXAM IS
COMPREHENSIVE, COVERING ALL LECTURES AND ALL LAB MATERIAL.
There will be no adjustment to the mean on the Make-up/Retake Exam. An absolute score of
70% will be considered passing. If they pass the Retake Exam, students who originally received
a "Deferred" grade will receive a final course grade of "C." Failures of the Make-up/Retake
Exam will be reported as such to the Registrars office.
Students who receive an "F" in the course are not eligible to sit for the Retake Exam. They will
have to re-enroll in the course the following year or take an AAMC-approved summer
Neuroscience course at another medical school. In this situation, the original F will remain on
your transcript, supplemented with the letter grade (or P, if that course grades pass/fail)
received in the retake course. A passing grade (A, B, C or P) from an approved course at
another university will fulfill the Neuroscience requirement in either M1 or BMS program, but
will not be included in your GPA calculation at RFUMS.
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Day Date Time Room Reading Presenter
Fri 1Mar 11am Rhoades Intro.toBrainandBehavior 10-20, 717-720 Eliot
Fri 1Mar 1pm Rhoades Lab 1: Surface and Midsagittal Anatomy Eliot
Fri 1Mar 24pm Various Lab 1: Small Groups TAs
Wed 6Mar 8am Rhoades FunctionalPropertiesofNeuronsI 7797,102106 Wolf
Wed 6Mar 11am Rhoades CNSHistology 410 Brandon
Wed 6Mar 15pm LRC5067 CNSHistology(M1sonly) Faculty&TAs
Thu 7Mar 8am Rhoades FunctionalPropertiesofNeuronsII
Ch.7(skipboxes
7Aand7B) Wolf
Fri 8Mar 9am Rhoades CNSDevelopment&Regeneration Chs.22&25 Peterson
Quiz#1,coveringlecturesandlabsfrom3/1availablefromSun.3/10atnoontoMon.3/11at10pm
Mon 11Mar 9am Rhoades FunctionalPropertiesofNeuronsIII
Ch.6(skipbox6D)&
pp.169184(skipbox
8A) Wolf
Tue 12Mar 9am Rhoades FunctionalPropertiesofNeuronsIV SameasFPIII Wolf
Wed 13Mar 4pm Rhoades NeuroanatomyReview(OPTIONAL) Eliot
Fri 15Mar 14:30pmRhoades/E.PoComb.Exam9(Embryology,Anatomy,Histology,PhysiologyNeuro.)
Mon 18Mar 10am Rhoades BloodbrainBarrierandCSF 741-44 West
18Mar 11am Rhoades MeningesandCerebralHemorrhage 560-61, 570-73, 742 Peterson
18Mar 1pm Rhoades Lab 2: Cerebal Blood Supply 735-741 Peterson
24pm Various Lab 2: Small Groups TAs
Tue 19Mar 10am Rhoades CNSImaging 18-20, Haines pp2-4 Waxler
Thu 21Mar 10am Rhoades SomatosensorySystemI 207-22 Eliot
21Mar 11am Rhoades SomatosensorySystemII 233-41, 222-28, 664-7Eliot
Fri 22Mar 10am Rhoades Pain Chpt. 10 Eliot
22Mar 11am Rhoades CNSInfections Haines, p.56 Fennewald
22Mar 1pm Rhoades Lab 3: Somatosensory System Eliot
22Mar 2-4pm Various Lab 3: Small Groups TAs
Quiz#2,coveringlecturesandlabsfrom3/18thru3/22availablefromSun.3/24atnoontoMon.3/25at10pm
Wed 3Apr 1-5pm GrossLab Wet Lab #1: Small Groups Faculty&TAs
Thu 4Apr 1pm Rhoades NeuroanatomyReview(OPTIONAL) Eliot
Fri 5Apr 9am-12 Rhoa/HSB 1 Combined Exam 10 (Anatomy, Histology, Physiology, Neuroscience)
Week FIVE (wk 33)
Week SIX (wk 34)
Week FOUR (wk 32)
NEUROSCIENCE COURSE SCHEDULE 2013
Topic
WeekONE(wk29)
WeekTWO(wk30)
WeekTHREE(wk31)
11
Wed 10Apr 10am Rhoades EyeI 229247 Brandon
Wed 10Apr 11am Rhoades EyeII Brandon
Thu 11Apr 10am Rhoades VisualSystemI
Ch.1122938,242
56 Stutzmann
Thu 11Apr 11am Rhoades VisualSystemII Chpt.12 Stutzmann
Thu 11Apr 1pm5pmLRC5067 EyeHistology(M1sonly) Faculty&TAs
Fri 12Apr 11am Rhoades OculomotorSystem
43541.44950,
2589 Eliot
Fri 12Apr 1pm Rhoades Lab4:Vision Stutzmann
24pm Various Lab4:SmallGroups TAs
Quiz#3,coveringlecturesandlabsfrom4/10to4/12availablefromSun.4/14atnoontoMon.4/15at10pm
Mon 15Apr 10am Rhoades NeuralPlasticity Chpt.24,52527 Eliot
Mon 15Apr 11am Rhoades AuditorySystem(ear) 277291 Frost
Tue 16Apr 10am Rhoades ChemicalSenses Chpt.15 Wolf
Tue 16Apr 11am Rhoades AuditorySystem(CNS) 291301 Eliot
Tue 16Apr 1pm5pmLRC5067 EarHistology(M1sonly) Faculty&TAs
Wed 17Apr 4pm Rhoades NeuroanatomyReview(OPTIONAL) Eliot
Thu 18Apr 11am Rhoades VestibularSystem Chpt.14 Eliot
Fri 19Apr 1pm Rhoades Lab5:Auditory,Vestibular,Gustatory Eliot
Fri 19Apr 24pm Various Lab5:SmallGroups TAs
Mon 22Apr 10am Rhoades LowerMotorNeuronReflexes 1013,353367 West
Mon 22Apr 11am Rhoades DescendingMotorControl Chpt.17 West
Tue 23Apr 11am Rhoades Uppervs.LowerMotorNeuronDiseases 372373,395397West
Tue 23Apr 1pm Rhoades Lab6:PyramidalMotorSystem 817821 West
Tue 23Apr 24pm Various Lab6:SmallGroups TAs
Wed 24Apr 10am Rhoades VisceralMotorSystem Chpt.21 Ariano
Wed 24Apr 11am Rhoades Hainespp.4154 Ariano
Wed 24Apr 4pm Rhoades NeuroanatomyReview(OPTIONAL) Eliot
Thu 25Apr 10am Rhoades PeripheralNeuropathyandMS 59 Brandon
Thu 25Apr 11am Rhoades BrainstemAnatomy Ariano
Thu 25Apr 1pm Rhoades Lab7:BrainstemLesions Ariano
Thu 25Apr 24pm Various Lab7:SmallGroups TAs
Fri 26Apr 15pm GrossLab WetLab#2:SmallGroups Faculty&TAs
Mon 29Apr 1pm4:30 Rhoades/WCombinedExam11(Histology,Physiology,Neuroscience)
Tue 30Apr 10am Rhoades BasalGanglia Chpt.18 Ariano
Tue 30Apr 11am Rhoades Parkinson&HuntingtonDiseases Ariano
Wed 1May 11am Rhoades Cerebellum Chpt.19 Ariano
Wed 1May 1pm Rhoades Lab8:BasalGanglia&Cerebellum Ariano
Wed 1May 24pm Various Lab8:SmallGroups TAs
Thu 2May 10am Rhoades HigherCorticalFunctionI Chpt.26 Eliot
Thu 2May 11am Rhoades HigherCorticalFunctionII 67880,6878,69 Eliot
Fri 3May 11am Rhoades LanguageandAphasia Chpt.27 Eliot
Fri 3May 1pm Rhoades Lab9:CerebalCortex&Thalamus Eliot
WeekTEN(wk38)
WeekSEVEN(wk35)
Cranialnerves
WeekEIGHT(wk36)
WeekNINE(wk37)
Fri 3May 24pm Various Lab9:SmallGroups TAs

Tue 7May 11am Rhoades Stroke 735 Welch
Wed 8May 10am Rhoades Hypothalamus 45658 Eliot
Wed 8May 11am Rhoades SleepandWakefulness Chpt.28 Wolf
Wed 8May 4pm Rhoades NeuroanatomyReview(OPTIONAL) Eliot
Thu 9May 10am Rhoades LimbicSystem Cptr29 Marr
Thu 9May 11am Rhoades LearningandMemory 653667 Eliot
Fri 10May 9am Rhoades NeuralBasisMood/MemoryDisorders 713714 Marr
Fri 10May 10am12 Rhoades Schizophrenia/Dopamine/Reward West
Fri 10May 1pm HSB2.710 Lab10:LimbicSystem 73443 Peterson
Fri 10May 24pm Various Lab10:SmallGroups TAs
Tue 14May 10am12 Rhoades FunctionalAnatomyReview Eliot
Tue 14May 15pm GrossLab WetLab#3:SmallGroups Faculty&TAs
Fri 17May 9am12 Rhoa/Only CombinedExam12(PhysiologyandNeuroscience)
WeekELEVEN(wk39)
WeekTWELVE(wk40)
13
14
1-March-2013, 11 am
Dr. Lise Eliot
Introduction to the Introduction to the
Brain and Behavior Brain and Behavior
Lise Eliot, PhD
Medical Neuroscience
March 1, 2013
Organization of this course Organization of this course
Overview of CNS anatomy and
neuronal function
Sensory systems
2
Motor systems
Higher brain structures & function
Required Reading Required Reading
In addition to your Course Notes and
Neuroanatomy Study Guide, the following
texts are required:
1. Neuroscience, 5
th
Ed. by Dale
Purves et al (Sinauer 2012)
3
Purves et al. (Sinauer, 2012).
2. Neuroanatomy: An Atlas of
Structures, Sections, and Systems,
8
th
Ed., by Duane Haines
(Lippincott, Williams & Wilkins,
2012).
Both books are available at the University
Bookstore.
Supplemental reading Supplemental reading
Neuroanatomy Through
Clinical Cases, 2
nd
Ed.,
4
by Hal Blumenfeld MD,
PhD (Sinauer, 2010).
D2L D2L
Most information pertaining to this course will be posted on
the D2L site for Medical Neuroscience
Course Guide, including learning objectives, grading policy
and faculty contact info
Schedule (see also Calendar)
Lecture notes (ppt and pdf files)
5
Lecture notes (ppt and pdf files)
Neurohistology links
Lab overview ppts
Neuroanatomy Study Guide
Links to Neuroanatomy and Neurologic Exam learning sites
Five quizzes
Most lectures are posted as both ppt and pdf files.
Practice Pretest Practice Pretest
After youve successfully accessed D2L,
complete the Self-Evaluation Pretest, which
is found under the Quizzes icon.
Complete this quiz to the best of your current
6
ability, without looking up anything.
This Pretest will not be graded, but you are
encouraged to complete it promptly, to help
formulate your learning goals for the material
presented throughout the course. (It is
available until Thursday March 7 at midnight.)
15
1-March-2013, 11 am
Dr. Lise Eliot
Lab & Discussion Groups Lab & Discussion Groups
Neuroanatomy Discussion Groups (10 sessions).
Wet Brain Labs are scheduled shortly before the
last three exams: April 3, April 26, May 14.
Neurohistology Labs (M1s only):
7
gy ( y)
March 6 (CNS histo), April 11 (Eye), April 16
(Ear). BMS students are responsible only for
lecture material, not afternoon labs. Lab material
will be tested under Dr. Brandons discretion.
Group assignments will be posted on D2L under
General Course Information.
Optional review sessions Optional review sessions
I will hold OPTIONAL OPTIONAL NEUROANATOMY REVIEW
SESSIONS in Rhoades on the following dates:
Wed March 13 from 4-5 pm
8
Wed. March 13, from 4-5 pm
Thu. April 4, from 1-2 pm
Wed. April 17, from 4-5 pm
Wed. April 24, from 4-5 pm
Wed. May 8, from 4-5 pm
Exams and grading Exams and grading
Four exams, curved to a mean M1 score of 80%.
Five Quizzes will be given on D2L, each counting 0.25 extra
credit point above your final grade (out of 100 points); i.e.,
maximum total points = 101.25
Final letter grades are determined on a straight 70-80-90 scale.
9
Date Time Covers #Questions %of
Grade
March15 14:30
pm
AlllecturesandlabsfromMarch
1throughMarch12
18lecturebased,
5neuroanatomy
12.6
April5 9amto
noon
AlllecturesandlabsfromMarch
18throughMarch22
19lecturebased,
10neuroanatomy
15.8
April29 14:30
pm
AlllecturesandlabsfromApril
10throughApril25
44lecturebased,
22neuroanatomy
36.1
May17 9amto
noon
AlllecturesfromApril30through
May10andALL10LABS(from
March1throughMay10)
38lecturebased,
27neuroanatomy
35.5
Office hours Office hours
This course is taught by all faculty members of the
Dept. of Neuroscience (Drs. Ariano, Eliot, Marr,
Peterson, Stutzmann, West, Wolf) who are happy to
meet with you at any time.
Guest faculty include Drs Brandon and Frost (Cell
10
Guest faculty include Drs. Brandon and Frost (Cell
Biology & Anatomy), Fennewald (Microbiology),
Waxler (Radiology) and Welch (Neurology).
The best way to set up an appointment is by email email.
Faculty office numbers are listed in Course Guide.
Introduction to the CNS Introduction to the CNS
Todays Lecture Goals: Todays Lecture Goals:
To introduce you to the overall organization of the
nervous system, including the following topics:
Subdivisions of the CNS
11
Neural systems
Neural circuits
Note that everything covered today will be revisited in
greater depth before the end of the course.
Related reading in Purves: Chapter 1 (pp.10-20) and
Appendix (pp. 717-20).
Neural system Neural system
Refers to the collection of structures which
subserve a single behavioral function, and
may extend across both the CNS & PNS.
E l
13
Examples:
visual system
memory system
postural system
16
1-March-2013, 11 am
Dr. Lise Eliot
Nervous system Nervous system
12
The CNS The CNS
Levels:
1. cerebrum
(telencephalon)
2. diencephalon
3. midbrain
(mesencephalon)
4. cerebellum
5 pons
14
5. pons
6. medulla
7. spinal cord
(Purves A2)
17
1-March-2013, 11 am
Dr. Lise Eliot
Wheres the Lesion? Wheres the Lesion?
15 (Blumenfeld Fig. 2.25)
Functional Functional neuroimaging neuroimaging
((fMRI fMRI, PET, SPECT) , PET, SPECT)
16
In this fMRI experiment, the subject was slid into the scanner and then asked to move
first her left hand (activity shown in yellow and red) and then her right hand (activity
shown in green and blue). Active regions were then projected on a 3D rendering of the
brain, reconstructed from structural MRI. Such imaging is increasingly used to map
functionally important brain areas before neurosurgery. (Purves, Box 1B)
18
1-March-2013, 11 am
Dr. Lise Eliot
Functional MRI ( Functional MRI (fMRI fMRI) )
Unstimulated (resting in dark):
(Kandel, 19.21)
Stimulated (viewing checkerboard):
stimulated
i
17
(excess oxy-Hg)
minus
resting
fMRI works by a method called BOLD (blood oxygen level detection): When a particular
brain area is more active, its blood flow increases, and the ratio of oxy-Hg/deoxy-Hg
increases. Oxy-Hg produces more magnetic resonance than deoxy-Hg, so a comparison
of the two conditions reveals areas of greater cerebral blood flow.
Deep structures Deep structures
Underlying the cerebral
cortex are various levels of
deep structures that
participate in every neural
system and modify
everything the cortex does.
These include:
limbic structures (amygdala
& hippocampus)
20
& hippocampus)
basal ganglia
diencephalon (thalamus &
hypothalamus)
brainstem
19
1-March-2013, 11 am
Dr. Lise Eliot
CNS hierarchy CNS hierarchy
Old, but influential notion of triune brain
coined by neurologist Paul McClean.
The brain evolved, develops, and functions
in a hierarchical sequence:
Oldest level is reptilian brain (spinal
cord, brainstem, cerebellum) which
controls survival, reflexive and
automatic behavior.
Next level is paleo-mammalian brain,
corresponding to the limbic system; it
controls emotion, drive and motivation.
Highest level is neo-mammalian or
neocortex responsible for rational
21
neocortex, responsible for rational
thought, conscious experience,
voluntary action.
In fact, every neural system traverses all 3
levels and there is enormous feedback
between levels, even in the processing of
perception, memories, and emotions.
Still, the hierarchical concept is useful for
understanding brain-behavior relationships.
Anterior Anterior - - posterior organization posterior organization
The anterior brain (frontal lobes,
anterior thalamus, spinal cord) is , p )
responsible for action: generating
speech, movement, ideas and
emotional expression, initiating
responses, planning, problem-
solving, and decision-making.
The posterior brain (parietal,
occipital, posterior temporal lobes;
22
p p p
posterior thalamus, spinal cord) is
responsible for receiving and
interpreting information: sensation,
receptive language, awareness of
space and ones environment.
20
1-March-2013, 11 am
Dr. Lise Eliot
Laterality Laterality
Many aspects of behavior (perception,
movement, cognition, emotion) are
l li d t j t id f th CNS l localized to just one side of the CNS.
For example:
Sensation and movement largely
controlled by side of the brain opposite to
relevant side of the body.
Language is typically localized to the left
cerebral hemisphere; spatial perception to
cranial
nerves
23
cerebral hemisphere; spatial perception to
the right.
Sensory-motor lateralization requires
crossing or decussation of pathways
at defined levels of the neuraxis.
spinal
nerves
White matter White matter vs vs gray matter gray matter
White matter (WM) appears white in
unstained sections of brain or spinal cord
(black in Weil or Weigert stains or T2 MRI).
The white color reflects a high density of
m elinated a ons DTI (diff sion tensor
Lumbar spinal
cord sections
myelinated axons. DTI (diffusion tensor
imaging) exploits low water diffusivity out of
myelinated axons to map long WM tracts.
Gray matter (GM): regions of high neuronal
density, containing neuronal cell bodies, glia,
& neuropil (dendrites and synapses).
cord sections.
Top is a Nissl
stain, bottom
a Weigert
(myelin) stain.
DTI tractology
24
WM
GM
21
1-March-2013, 11 am
Dr. Lise Eliot
A neural circuit is a network of synaptically linked neurons that work in sequence to carry out a A neural circuit is a network of synaptically-linked neurons that work in sequence to carry out a
specific behavioral function. The knee jerk (myotatic; patellar) reflex circuit is one of the simplest
in the CNS and illustrates several features of CNS structure and function with which you should
already be familiar: the concept of a reflex, and the mechanisms of action potential generation
and propagation, inhibitory and excitatory synaptic transmission, neuromuscular transmission,
and muscular contraction.
The following events correspond to the numbers in the diagram:
1. The reflex is activated by hitting (stretching) the patellar tendon, which in turn stretches y g ( g) p ,
spindle receptors in the quadriceps (extensor) muscle, depolarizing them and triggering
action potentials that propagate along the sensory fiber into the dorsal horn of the spinal
cord at the L4 level.
2. Sensory neuron (afferent) action potentials trigger neurotransmitter release at two different
excitatory synapses: A) onto extensor motor neurons and B) onto inhibitory interneurons.
Both target cells increase their firing rate in response to the excitatory transmission. The
interneuron, in turn, releases neurotransmitter at its inhibitory synapse onto a flexor motor
neuron (C) neuron (C).
3. The extensor motor neuron conducts its action potentials out to the quadriceps muscle,
where it triggers extensor contraction (A); the flexor motor neuron, by contrast, fires less
vigorously after the stimulus and consequently decreases its excitation of the flexor muscle,
leading to its relaxation (B).
4. The combination of extensor contraction and flexor relaxation produces leg extension or
jerk.
The p rpose of this refle is to help maintain an pright stance in response to slight post ral The purpose of this reflex is to help maintain an upright stance in response to slight postural
disturbances. Clinically, it is also a good marker of sensory, motor, and spinal cord integrity at
the level of the 4th lumbar spinal cord.
22
1-March-2013, 11 am
Dr. Lise Eliot
Synaptic activity in the reflex Synaptic activity in the reflex
The sensory neuron (A)
synapses directly on the
extensor motor neuron,
producing a monosynaptic
EPSP (B) that depolarizes
this effector cell.
Sensory neuron firing (A)
also produces a
monosynaptic EPSP in the
inhibitory interneuron (C).
26
Activation of the inhibitory
neuron (not shown)
produces an IPSP in the
flexor motor neuron (D),
resulting in less excitation of
the antagonist muscle.
Spike activity during the Spike activity during the reflex reflex
Purves, Fig 1.8
27
Relativefiringfrequencyofactionpotentialsinneuronscontributingtothemyotatic reflex.
Eachspike,oractionpotentialisindicatedbyaverticalline.Notethefollowing:
1. theincreasedsensoryneuronfiringattheonsetofthereflex;
2. thelaterelevationoffiringrateintheextensormotorneuron&inhibitoryinterneuron;
3. thedecreaseintheflexormotorneuronsfiringrate,reflectinginputfromtheinhibitory
interneuron
23
1-March-2013, 11 am
Dr. Lise Eliot
Information enters the nervous system through afferent neurons or fibers; in this
case, the sensory neuron whose peripheral receptor sits in the quadriceps
muscle. Afferent refers to structures or tracts that carry information into the
central nervous system. So sensory neurons are all considered afferents. It is
also a relative term: for any two brain structures that are synaptically connected,
the afferent structure is the presynaptic one, which sends its axon to synapse on
the second structure.
Efferent refers to structures or tracts that carry information away from the brain or
spinal cord. Motor neurons are all efferents. In relative terms, efferent refers to
all of the synaptic targets of a given cell or brain nucleus.
The term interneuron is used to refer to any neuron that does not project over a
long distance, but whose axonal branches remain local, interconnecting other
neurons within a relatively small area of the brain. In this spinal cord example,
interneurons are neither sensory nor motor neurons, because they do not send
axons out the peripheral nerves. Interneurons are also distinguished from p p g
projection neurons whose axons traverse long distances within the CNS, such
as spinothalamic neurons that send information from the spinal cord to the
thalamus.
24
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34
NEUROHISTOLOGY
The Central Nervous System (CNS) comprises the brain and the spinal cord. The Peripheral Nervous System (PNS)
comprises all other nervous tissue, and serves to connect all other tissues and organs with the CNS. Functionally, the
nervous system is divided into a somatic component, which innervates those structures derived from embryological
somites (muscles, bones, skin), and an autonomic component, which innervates smooth muscle, cardiac muscle, and
glands (Figure 1).
1
2
1. OVERVIEW OF PERTINENT NERVOUS SYSTEM ANATOMY (Figure 2).
1.1. The Somatic Component. Information from peripheral receptors (in skin, muscle, etc.) is conducted toward the
CNS by afferent ("sensory") fibers within spinal nerves (from the body; Figure 3) or cranial nerves (from the head;
Figure 4). Sensory fibers from the body pass through dorsal root ganglia (spinal ganglia, sensory ganglia, DRG's),
and enter the dorsal horn of the spinal cord through individual dorsal roots (Figure 5). The cell bodies from which
these fibers originate reside within the DRG's. Certain of the cranial nerves have their own DRGlike ganglia adjacent to
the brainstem; these provide sensory input from the head.
Movement of skeletal muscle results from the activity of cells within the ventral horn of the gray matter of the spinal
cord; efferent ("motor", in this case) axons extend from these cells through ventral roots, then enter the same spinal
nerves as the sensory fibers, and finally synapse upon the skeletal muscle fibers (Figure 5).
3 4
1.2. The Autonomic Nervous System (Figure 6). The autonomic nervous system exerts control over the functions of
many organs and tissues in the body. Along with the endocrine system, it brings about fine internal adjustments
necessary for the maintenance of an optimal body environment (e.g. blood pH, temperature, gastric motility, etc.). The
autonomic nervous system innervates involuntary structures such as the heart, the smooth muscles, and the glands. It
NERVOUS TISSUE
NEUROHISTOLOGY 1
35
is divided into two parts, the sympathetic and the parasympathetic, both of which have afferent and efferent
components.
Afferent information (from the viscera, etc., to the spinal cord and brain) is carried by fibers that enter the spinal cord
through dorsal roots, as for the somatic system; the cell bodies that give rise to these fibers are located within the spinal
ganglia (Figure 5). Additional afferent information from the viscera is carried by several of the cranial nerves. The
visceral receptors include chemoreceptors, baroreceptors, and osmoreceptors. Pain receptors are present in
viscera, and certain types of stimuli, such as stretch, or lack of oxygen, may cause pain.
5 6
1.2.1. The Autonomic Sympathetic Component. Efferent sympathetic impulses (i.e. going from the spinal cord and
brain to the viscera) originate from neurons in the lateral horn of the gray matter of the thoracic and lumbar regions of
the spinal cord, and are relayed through synapses in sympathetic paravertebral or prevertebral ganglia (sympathetic
ganglia; Figure 7). Axons from neurons in these ganglia eventually terminate on or near visceral smooth muscle,
glands, etc.
The sympathetic system functions to prepare the body for an emergency. The heart rate increases, arterioles of the
skin and intestine constrict, those of skeletal muscle dilate, and the blood pressure increases. Blood is redistributed so
that it leaves the skin and GI tract and passes to the brain, heart, and skeletal muscle. In addition, the sympathetic
nerves dilate the pupils, inhibit smooth muscle of the bronchi, intestine, and bladder wall, and close the sphincters. The
hair stands on end, and sweating occurs (Figure 8).
7 8
1.2.2. The Autonomic Parasympathetic Component (Figure 6). The nerve cells of the parasympathetic part of the
autonomic nervous system are located in the brainstem, and in sacral segments of the spinal cord. Unlike sympathetic
ganglia, the ganglia of the parasympathetic system are located near (e.g. ciliary ganglion), or actually in (e.g. myenteric
plexus), the viscera they innervate.
The activities of the parasympathetic part of the nervous system are directed toward conserving and restoring energy
("vegetative" functions, such as digestion). The heart rate slows, pupils constrict, peristalsis and glandular activity
increase, sphincters open, and the bladder wall contracts (Figure 8).
NERVOUS TISSUE
NEUROHISTOLOGY 2
36
1.2.3. The Enteric Nervous System (Figure 9). The alimentary canal contains its own system of nervous elements that
control gut motility, secretion, etc.. These elements continue to function even when inputs from the CNS are cut; as a
result, this system is now considered to be a separate division of the ANS (although its actions are normally regulated
by both the sympathetic and parasympathetic divisions, as described above). This Enteric Nervous System comprises
two plexuses of ganglia and connecting fibers: Meissner's Plexus lies in the submucosal connective tissue, and
innvervates gland cells in the mucosa and submucosa, and the muscularis mucosa. Auerbach's Plexus regulates the
contractility of the outer muscle layers, which are involved in peristalsis.
9
10
1.2.4. Receptors and Effectors (Figure 10). All divisions of the nervous system must interact with the body to receive
afferent (sensory) information and to distribute efferent (motor) signals that influence various bodily structures. These
specialized regions and structures will be discussed in the appropriate sections below.
2. OVERVIEW OF NERVOUS SYSTEM EMBRYOLOGY.
11 12
The CNS is derived from ectoderm. The central portion of this ectoderm, the neurectoderm, forms the neural plate
(Figure 11). As the neural plate sinks into the underlying mesoderm, its lateral edges (the neural folds) become
elevated; these edges eventually fuse longitudinally, and the whole structure detaches from the overlying ectoderm, with
the resultant formation of a neural tube (Figure 12, Figure 13). As this happens, a column of ectodermal cells (neural
crest cells) forms, lying just deep to the neural folds. These cells also detach from the overlying ectoderm, and come to
lie on either side of the neural tube (Figure 13). The neurectoderm (neuroepithelium) differentiates into the
neurons, glia, and ependyma that form the brain and spinal cord (Figure 14).
NERVOUS TISSUE
NEUROHISTOLOGY 3
37
13 14
The neural crest gives rise to the following neural elements (Figure 15):
Sensory neurons of the cranial and spinal sensory ganglia. 1.
Postganglionic neurons of the sympathetic and parasympathetic ganglia. 2.
Supporting cells of the PNS (Schwann cells and satellite cells of the ganglia). 3.
The neural crest also gives rise to nonneural elements:
The cells of the pia mater and arachnoid mater. 1.
Some branchial cartilage and some cranial mesenchyme. 2.
Pigmentproducing cells of the skin and subcutaneous tissues (melanocytes). 3.
Chromaffin tissue (secretory cells of the adrenal medulla). 4.
15
16
Note that the CNS contains some elements derived from neural crest (e.g. the central axons of DRG cells that enter the
spinal cord), and that the PNS contains some elements derived from neuroepithelium (e.g. the axons of motorneurons
that enter spinal nerves) (Figure 16).
The epithelial origin of the CNS has two important consequences. First, the CNS contains no connective tissue
(except for that contributed by invaginating blood vessels); structures derived from neural crest, on the other hand, do
have connective tissue components. Second, the CNS is surrounded by a basal lamina. Individual neural components
of the PNS are also surrounded by basal laminae. The point at which the CNS and PNS meet is readily apparent in
histological preparations; incoming nerves have connective tissue, but white matter in the spinal cord does not (Figure
17).
NERVOUS TISSUE
NEUROHISTOLOGY 4
38
17 18
3. STRUCTURE OF CENTRAL NERVOUS SYSTEM ELEMENTS.
The CNS is comprised of two types of cells, neurons and glia (supporting cells).
3.1. Neurons.
The most significant functional characteristics of neurons, irritability (excitability) and conductivity, derive from the
presence of an excitable membrane. This provides the mechanism for communication among cells, and for the
transmission of nerve impulses over distances.
3.1.1. The "Typical" Neuron (Figure 18).
Different classes of neuron have widely different, characteristic morphologies (shapes and architectures), but all exhibit
dynamic polarization, which is the specialization of different parts of the cell into receptive sites, integrating sites,
an impulseinitiating site, and impulseconducting sites.
The expanded portion of the cell containing the nucleus is the cell soma. In H&E preparations, this is often the only
portion of the cell that can be seen. Other, highly specialized histological techniques, such as the Golgi method, reveal
one or more slender processes drawn out from the soma. These are of two types, axons and dendrites.
Dendrites branch from the soma in such a way that it is difficult to determine their exact point of origin. Dendrites
decrease in diameter, and branch more frequently, as they extend away from the soma. They provide the main
recipient zone of the neuron; processes from other neurons form specific contacts on these dendrites, at points called
synapses.
The axon arises from the neuronal soma, or, less frequently, from one of the cell's dendrites. Neurons have, at most,
one axon; a few neurons have no axon at all. The axon arises from a specialized region of the soma, the axon hillock,
which is the point of impulse generation (if the cell is of the type that generates an action potential). The axon hillock
narrows into an initial segment that is a few microns in length. The axon itself may be myelinated or unmyelinated,
may be very short (a few microns) or long (up to one meter), or any intermediate length. It may branch, forming
collaterals. The axon ends in synaptic terminals, which make contact with other neurons. The axon and synaptic
terminals are the main transmitting channels by which neurons affect each other. Note that not all neurons have axons
that are myelinated; generally, long axons are myelinated. Also note that not all neurons generate action potentials;
many only exhibit graded potentials.
19 20
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39
3.1.2. Fine Structure of Neurons (Figure 19).
The neuronal cell body (soma, which is the Greek word for 'body') generally contains a large and ovoid or spherical
nucleus with euchromatic chromatin; Barr bodies may be seen. The perinuclear cytoplasm has many ribosomes,
especially within stacks of RER; by LM, these stacks appear as very basophilic clumps called Nissl bodies; the RER
may extend a short distance into the dendrites (Figure 20). Not all neurons have prominent Nissl bodies; some are just
diffusely basophilic. A specialized region of the soma, the axon hillock, lacks Nissl substance altogether (see axons,
below). Neurons have a prominent Golgi complex, since neuronal cell bodies manufacture material (e.g. vesicles)
for release by the axon terminal. Neurons commonly contain lysosomes; insoluble residues of lysosomal activity may
accumulate to form lipofuscin granules, which are especially visible in neurons of sympathetic and dorsal root ganglia
(Figure 21). A few neurons contain melanin granules, especially within a brain region called the substantia nigra
(Figure 22). Cytoskeletal elements (microtubules and neurofilaments) abound; lightmicroscopic neurofibrillary
stains, which contain silver, turn these structures brown, revealing the shape of the cell and its processes (Figure 23,
left).
21 22
23 24
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40
Dendrites (Figure 24) are generally similar in fine structure to the soma; most of the synaptic input onto a neuron
(50100%) occurs onto its dendritic arbor. Dendrites may contain some Nissl substance (RER); many neurofilaments
and microtubules are present, running longitudinally (Figure 25; Figure 26); for this reason, dendrites are more visible
in silverstained preparations than by H&E (Figure 23). Specialized techniques, such as intracellular injection of visible
tracers, are necessary to reveal the entire structure of a neuron's dendritic arbor (Figure 27).
25
26
27 28
Dendritic spines are small specializations that occur on the denrites of some types of cells, such as the Purkinje cell of
the cerebellum (Figure 28). These structures serve to dramatically increase the dendritic surface area available for
synaptic input from other neurons (Figure 29). Spines may be "plastic", i.e. may change their shape or number in
response to experience (learning).
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41
29 30
Axons emerge from the axon hillock of the soma (Figure 30). In neurons with long axons, such as spinal cord motor
neurons, most of the volume of the neuron is contained within the axon (99.9%, in this case).
31
32
The axoplasm contains large numbers of microtubules and neurofilaments oriented longitudinally (Figure 31); these are
involved in axoplasmic transport (in both anterograde and retrograde directions; Figure 32) and in growth of the
axon during development and regeneration. The axon contains no ribosomes, and therefore no protein synthesis
occurs in the axon; proteins must be provided from the cell body by axon transport. The initial segment of the axon is
unmyelinated; the rest of the axon may or may not be myelinated. The conduction velocity of axons varies with their
diameter (larger = faster), and is greatly enhanced by the myelin sheath (Figure 33). Axons are most readily seen in
silverstained preparations, which show that the axon cylinder is the same diameter throughout its entire length (Figure
34); on this basis, it can be distinguished from dendrites, which are thicker as they emerge from the soma and get
slowly narrower. A neuron will never have more than one axon (a few retinal neurons have no axon); axons may
branch, however, often innervating many targets (Figure 35).
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42
33 34
Synapses are points of apposition between nerve cells which are specialized for the transmission of impulses from one
neuron to another. They have three basic components: 1) presynaptic membrane of the first neuron, with synaptic
vesicles in the cytoplasm close to the membrane; 2) synaptic cleft; 3) postsynaptic membrane of the second neuron
(Figure 36).
35
36
The pre and postsynaptic membranes appear thicker and more electrondense than membranes elsewhere
(Figure 37). The increased density is due to the presence of membrane proteins that 1) bring vesicles towards the
synapse, 2) anchor the presynaptic and postsynaptic membranes together, and 3) are postsynaptic receptors for the
neurotransmitter.
37
38
Depolarization of the axon terminal (carried from the cell body to the terminal by an action potential) causes a series
of ionic events that cause some synaptic vesicles to move towards the presynaptic membrane, bind to specific regions
NERVOUS TISSUE
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43
there, and eventually to fuse with the plasma membrane. Since synaptic vesicles are lipidbilayer structures, when they
fuse with the presynaptic membrane, their contents (neurotransmitter molecules) spill into the extracellular space within
the synaptic cleft (Figure 38, Figure 39). The transmitters then interact with specific receptors on the postsynaptic cell,
and cause it to respond. The fusion of synaptic vesicles causes the area of the presynaptic membrane to increase; this
extra membrane is then recycled by the formation of coated vesicles (Figure 40). The most common type of synaptic
vesicle is small (50nm), spherical, and clearcentered (Figure 37, Figure 41).
39
40
41 42
The most common type of synapse is one in which the presynaptic element is an axonal (synaptic) terminal, and the
postsynaptic element is a dendrite (Figure 42, Figure 43), although synapses often occur on other parts of the neuron.
Most neurons receive most of their synaptic input on their soma or dendritic arbor (Figure 44); such synapses can be
seen easily in silverstained material, usually as tiny black spots on the surface of a cell body or dendrite (Figure 45).
43
44
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44
45 46
3.1.3. Structural Classification of Neurons (Figure 46).
3.1.3.1. Unipolar. These are relatively rare; the best example is primary sensory (afferent) neurons, whose cell bodies
are in cranial or spinal afferent ganglia. These cells have a single process extending from the soma. This process then
bifurcates, with one branch extending into the peripheral nerve, and the other extending centrally, towards the spinal
cord. Both processes have the structure of axons, although the peripheral process is functionally a dendrite because it
is carrying (sensory) information towards the cell body.
3.1.3.2. Bipolar. These are also relatively rare. They are found in the retina, in vestibular and acoustic ganglia, and in
the olfactory epithelium of the nasal mucosa.
47
48
3.1.3.3. Multipolar. The soma of a multipolar neuron has more than one dendritic trunk; this is the commonest type of
central neuron, with a wide variety of subtypes. Subtypes may be defined according to the shape of the dendritic arbor
(e.g. pyramidal, Figure 47; stellate); pattern of axonal branching (e.g. "basket" cells, Figure 35); location (e.g. ventral
horn cells of the spinal cord); eponyms (e.g. Purkinje cells, Betz cells); or function (e.g. motor neurons). They are also
broadly classified into Golgi Type I and Golgi Type II cells. Type I neurons (projection neurons) are generally larger,
and project an axon from one brain region to another (e.g. spinal cord motor neurons; pyramidal cells of cortex); these
axons form the major tracts of the CNS. Type II neurons (interneurons) are generally smaller, and their axons project
locally, staying within a particular brain region. They are most often inhibitory.
3.1.4. Gross Organization of Cells and Fibers in the CNS.
In the CNS, neurons (and their dendrites, axons, and synapses) are concentrated in discrete areas collectively called
gray matter, while axons that run from one brain area to another travel in large bundles devoid of neurons, called white
matter. Gray matter may occur in thin sheets (e.g. cerebral cortex) or in rounded structures called nuclei (e.g. red
nucleus, solitary nucleus). In a section of fresh brain, gray matter appears gray (hence the name), and white matter
NERVOUS TISSUE
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45
white (Figure 48).
49
50
Sections stained with a lipid stain reverse that pattern, with the gray matter appearing white and the white matter
appearing black (Figure 49). With a cell body stain like H&E, gray matter appears relatively featureless at high
magnification (Figure 50, Figure 51), and diffusely blue at low magnification (Figure 52).
51
52
White matter appears white with H&E (Figure 52) and with silver (Figure 53). White matter contains no neuronal cell
bodies.
3.2. CNS Supporting Cells.
3.2.1. Neuroglia (Figure 54). These supporting cells outnumber neurons in the CNS by 10:1 to 50:1. In routine
histological preparations such as H&E, only their nuclei are visible (Figure 55); their cytoplasm contains only small
amounts of diffuse RER, and so they are not basophilic (i.e. glia do not contain Nissl bodies).
53 54
NERVOUS TISSUE
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46
3.2.1.1. Astrocytes are starshaped cells found in gray matter (protoplasmic astrocytes) and white matter (fibrous
astrocytes) (Figure 56). Astrocytic processes cover nonsynaptic neuronal surfaces. Astrocytic processes also
extend to, and surround, blood vessels. During development, astrocytes induce vascular endothelial cells to form the
bloodbrain barrier. Those astrocytes that are near brain surfaces extend processes to those surfaces, forming a
continuous covering around the brain, the glia limitans. In H&E preparations, only the nucleus of the astrocyte is visible
(Figure 57).
55 56
3.2.1.2. Oligodendrocytes (Figure 58) are responsible for the myelination of CNS axons, so they are especially
numerous in white matter. One oligo will form and maintain the myelin sheath of up to 50 axons. CNS myelin is similar
in structure to PNS myelin. CNS myelin is subject to autoimmune destruction (in Multiple Sclerosis), and to
developmental defects. In H&E preparations, only the nucleus of the oligodendrocyte is visible (Figure 57).
57 58
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47
3.2.1.3. Myelination. During myelination (Figure 59), a thin, flat cytoplasmic process from an oligodendrocyte
surrounds a section of an axon. It continues to wrap around, as many as 50100 times. The glial cytoplasm is squeezed
out, so that the inner and outer membranes come into contact; the result is a thick coat of glial plasma membrane
around the axon. The process is similar in the PNS, except that the myelinating cell is a Schwann cell rather than an
oligodendrocyte.
59
60
Two molecules function to hold the myelin sheath together. A specific proteolipid connects the outer membranes of
adjacent layers together; the inner and outer cytoplasmic portions of a specific layer are held together by bonds
between this same proteolipid and an intrinsic oligodendrocyte protein, myelin basic protein (Figure 60).
3.2.2. NonNeuroglial Supporting Cells.
3.2.2.1. Ependymal cells line the brain's ventricular spaces and the central canal of the spinal cord (Figure 61). Recall
that the CNS develops as a hollow tube; the remnants of this tube are lined with ependyma, a cuboidal epitheliumlike
tissue that is one cell thick. Ependymal cells have microvilli, and resemble astrocytes in their structure. Certain regions
of the ependyma, the choroid plexus, are vascular structures specialized for the secretion of cerebrospinal fluid
(CSF) into the brain ventricular spaces (Figure 62).
61 62
3.2.2.2. Microglia (Figure 63). These small cells are evenly distributed throughout gray and white matter. Under normal
conditions, microglia do not divide and do not show phagocytic activity, but they do transform into actively phagocytic
cells in response to CNS injury, functioning to clear away necrotic tissue. Most probably, microglia are actually
macrophages of mesodermal origin.
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48
63 64
4. STRUCTURE OF PERIPHERAL NERVOUS SYSTEM ELEMENTS.
PNS neurons have the same general characteristics as CNS neurons. We will concentrate on PNS supporting cells, of
which there are two types: Schwann cells ensheath the axons of peripheral nerve fibers; satellite cells ensheath the
cell bodies of neurons located in ganglia.
4.1. Peripheral Ganglia.
4.1.1. Dorsal root ganglia, and the sensory ganglia of some cranial nerves, have pseudounipolar neurons (Figure 64).
These neurons are heterogeneous in size; the size of the soma is roughly proportional to axon diameter, and this can
vary widely, from very small unmyelinated to large myelinated (see below). DRG neurons have no dendrites, and the
DRG contains no synapses. The soma of each DRG neuron is surrounded by a single layer of small, flattened cuboidal
cells, the satellite cells. Each surrounded neuron is itself surrounded by a basal lamina and loose CT, and the whole
ganglion is surrounded by a CT capsule that is continuous with the perineurium and epineurium of the associated nerve.
DRG cells often contain lipofuscin granules.
Note that all of the sensory information flowing in from the body (somatic and visceral), with the exception of
special senses, is carried by fibers of pseudounipolar neurons, and enters the spinal cord via the dorsal roots
(Figure 4).
4.1.2. Autonomic sympathetic ganglia (Figure 65) are present as swellings along the sympathetic chain. Autonomic
parasympathetic ganglia are present near, or within, the walls of organs innervated by the autonomic nervous system
(Figure 66). The multipolar neurons in these ganglia are more homogeneous in size than those in the DRG's. Also,
unlike the DRG, sympathetic ganglia are integrating centers with many synapses.
65 66
4.1.3. In the digestive system, enteric ganglia (formerly considered parasympathetic) are found in the submucosa (as
Meissner's plexus), and at the interface between the inner and outer layers of the muscularis externa (as Auerbach's
NERVOUS TISSUE
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49
plexus) (Figure 66, Figure 67).
67
68
4.2. Schwann Cells and Their Sheaths (Figure 68, Figure 69). Every PNS axon has a Schwann cell sheath. Those
axons greater than 1 micron in diameter are myelinated by Schwann cells, those smaller are ensheathed but
unmyelinated. In the PNS, one Schwann cell covers one internodal segment of one axon; in the CNS, one
oligodendrocyte covers one internodal segment of many (1050) axons.
All PNS sheaths, myelinated or unmyelinated, have the following general structure (innermost to outermost):
axon 1.
sheath (myelin or Schwann cell process) 2.
basal lamina 3.
CT layer #1 (ENDONEURIUM) 4.
CT layer #2 (PERINEURIUM) 5.
CT layer #3 (EPINEURIUM) 6.
Endoneurium lies around each individual myelinated axon or unmyelinated group of axons, perineurium lies around
each bundle of axons, and epineurium is a loose C.T. fascia that surrounds the entire nerve and blends in to the
surrounding C.T. All of these CT layers are formed by fibroblasts in the various layers (Figure 70).
69
70
4.2.1. Unmyelinated Peripheral Axons (Figure 71). One Schwann cell wraps a group of axons. One Schwann cell
may invest as many as 20 unmyelinated axons. The sheath of an unmyelinated axon does not have nodes of Ranvier,
as does a myelin sheath. A basal lamina surrounds the whole axon+sheath complex.
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50
71
72
4.2.2. Myelinated Peripheral Axons. PNS myelin is similar in structure to CNS myelin (Figure 72). The LM
appearance of myelin depends on the method of preparation. Preparation for HEstaining dissolves the lipid of the
myelin, leaving only a precipitated network of protein (called neurokeratin, but unrelated to the keratins) where the
myelin was before processing; nerves therefore looked motheaten and ragged (Figure 73). When nerves are treated
with osmium, the myelin lipid is retained and stains very darkly, while the axon itself is unstained; in contrast, silver
stains the cytoskeleton, so the axon cylinder is visible while the myelin is not (Figure 74).
73
74
The Node of Ranvier is the zone between adjacent myelinated segments on an axon (Figure 72, Figure 75). Since
the axon here is not insulated with myelin, ions can flow through the neuronal membrane at this point. The conductance
changes underlying the action potential can therefore jump from one node to the next, increasing the nerve's conduction
velocity (saltatory conduction; Figure 76).
NERVOUS TISSUE
NEUROHISTOLOGY 17
51
75
76
Peripheral nerves are mixed nerves, that is, they contain axons of many different sizes and degrees of myelination
(Figure 77), reflecting the fact that the nerve may be carrying sensory information from a wide variety of sensory
modalities, as well as motor information. The larger, myelinated axons (Type A or Group I) conduct impulses at the
highest rate, carrying information from muscle spindles, finetouch receptors, etc.. The small, unmyelinated axons
(Type C or Group IV) conduct slowly, carring information about pain and temperature (Figure 78).
77
78
4.3. Peripheral Terminations of Nerve Fibers.
4.3.1. Efferent Fibers.
4.3.1.1. Innervation of Skeletal Muscle. The neuromuscular junction is a specialized synapse in which the
presynaptic component is the ending (synaptic bouton) of a motoneuron in the spinal cord, and the postsynaptic
component is a skeletal muscle fiber. The synapse occupies a groove in the skeletal muscle (Figure 79). The axon
terminal, or endplate, is most visible when stained with silver (Figure 80).
NERVOUS TISSUE
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52
79 80
The postsynaptic membrane of the muscle has deep folds that extend into the muscle cell; the membrane of the folded
areas contains large numbers of neurotransmitter receptor molecules (Figure 81, Figure 82). Acetylcholine is the
neurotransmitter at this synapse. One motorneuron may innervate one or several individual muscle fibers, depending on
the degree of control required over the movement of the muscle. Oculomotor muscles, for example, have a 1:1 ratio of
axon to muscle fiber; in the muscles of the back, one axon innervates many muscle fibers.
81
82
4.3.1.2. Innervation of Smooth Muscle and Glands. Neurons innervating these structures release their transmitter
(norepinephrine, in the case of the sympathetic nervous system) into the general vicinity of a group of smooth muscle
cells or glands (Figure 83). This type of neurotransmission is slow and imprecise.
4.3.1.3. Hormonelike Innervation. The "presynaptic" sympathetic axon terminals of the adrenal medulla do not have
a discrete postsynaptic process or structure. Instead, these terminals release their transmitter, epinephrine, directly into
veins in the medulla. Certain CNS neurons of the hypothalamichypophysial axis release their hormones in a similar
manner (Figure 83, right).
83 84
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53
4.3.2. Afferent Fibers.
Receptors receive information about external stimuli from the body surface (exteroceptors), about joint position and
movement (proprioceptors), and about the state of the viscera and vasculature (interoceptors). In all cases, stimuli
are converted, or transduced, into voltage changes that are relayed to the CNS in the form of action potentials. Different
receptors exist for, and are named for, different modalities; thus there are thermoreceptors, mechanoreceptors,
chemoreceptors, and osmoreceptors. Morphologically, there are two basic types of receptor, encapsulated and
nonencapsulated endings. In the dermis of the skin, these various types of endings (free nerve endings,
encapsulated nerve endings, hair follicle afferents) form a network called the dermal plexus (Figure 84).
4.3.2.1. Free Nerve Endings. These are small terminal branches of afferent nerve fibers, ending in the CT of many
parts of the body (Figure 84, Figure 85). The axons are small in caliber, myelinated or unmyelinated (their terminal
regions are always bare), with slow conduction velocity, and may subserve temperature, pain, or touch. In skin, some
are associated with specialized epidermal cells (Merkel cells, Figure 85), or with hair follicles (Figure 84), but most end
without specialization.
85
86
4.3.2.2. Encapsulated Nerve Endings. Meissner's corpuscles are CT capsules, each containing several twisted,
unmyelinated afferent nerve processes embedded in nonneural cells of the capsule (Figure 86). They are located in
the dermal papillae of glabrous skin, where they subserve fine (twopoint discriminative) touch. Pacinian
corpuscles lie deeper in the skin, especially in the palms, soles, and digits, nipples, periosteum, mesentery, ligaments,
and external genitalia, where they respond to pressure (crude touch), vibration, and tension (Figure 87). They are
comprised of a single, unmyelinated afferent fiber that is surrounded by a multilamellar capsule 0.51mm in diameter.
Each layer of the capsule is made up of many flattened cells, and the layers are separated by fluid. Golgi tendon
organs are small bundles of tendon fibers enclosed in a lamellated capsule; free, nonmyelinated nerve endings
arborize around the tendon bundles. These receptors are stimulated by stretching of the tendon.
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54
87 88
4.3.3. The Neuromuscular Spindle (Figure 88).This structure contains a series of specialized, striated, intrafusal
muscle fibers that are innervated by myelinated fibers from spinal cord gamma motor neurons. The myelinated,
sensory nerves to a muscle spindle enter through the capsule and terminate near the equatorial region, then lose their
myelin and give rise to several branches that spiral around the muscle fibers. The whole terminal complex is called the
primary sensory ending of the spindle, and the parent fiber is a group Ia afferent fiber. Muscle spindles are found in
all human skeletal muscles.
4.4. NERVE DAMAGE
When a neuron's axon is cut, the distal portion degenerates (anterograde degeneration). Often, the postsynaptic
target degenerates as well (anterograde transneuronal degeneration). The cell body itself may degenerate
(retrograde degeneration). In the CNS, microglia transform into activated macrophages and scavenge the debris of
the axon and its associated myelin (Figure 89). Overall, CNS axons do not regenerate after being cut. In the PNS, in
contrast, a cut nerve can regrow if the severed ends are close enough to one another, or if the perineurium of the
severed ends is surgically reconnected. A PNS axon will regrow towards its target at a rate of ca. 1mm/day,
which is the same as the rate of slow axon transport (Figure 32). A nerve crush leaves the perineurium intact; in this
case peripheral axons will regenerate spontaneously, also at ca. 1mm/day.
89
90
5. THE MENINGES (Figure 90).
5.1. The Dura Mater (Latin for "tough mother") is a tough sheet of fibroelastic connective tissue made up of two layers.
In the cranium, the outermost layer is the periosteum of the skull, and is tightly applied to the inner, fibrous layer except
at certain specialized regions. In the spinal cord, on the other hand, the inner layer is separated from the periosteum of
the spinal canal by an epidural space. The dura is lined on its inner surface with a mesothelium.
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55
5.2. The Arachnoid Mater is a delicate, thin, avascular membrane that lines the dura. It is covered on both inner and
outer surfaces with an epithelium; connective tissue trabeculae extend from the inner surface of the arachnoid, across
the subarachnoid space, to the outer covering of the pial membrane. All of these surfaces are lined with a simple
squamous epithelium. Blood vessels passing to and from the brain course within the subarachnoid space, i.e. the
subarachnoid space is highly vascular. The arachnoid, like the dura, does not follow the surface of the brain into the
various folds, or sulci, but stretches across them.
5.3. The Pia Mater, unlike the arachnoid, covers the brain surface even into the deepest sulci; it follows and invests
blood vessels that penetrate into the brain. Its outer surface (which faces the subarachnoid space) is a simple
squamous epithelium; immediately below is an epipial layer of collagenous fibers, and deep to that is a layer of
reticular and elastic fibers, the intima pia, that is adherent to the glia limitans. The latter structure is formed by the
processes of astrocytes at the brain surface, and it is separated from the pial membrane by a basal lamina.
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NEUROHISTOLOGY 22
56
The meninges are a series of connective tissue layers that surround the brain; these layers
lie outside the basement membrane that surrounds the (epithelial) brain. Within the
cranium, the outermost meningeal layer (the dura mater) has two sublayers, the outermost
of which is actually the periosteum of the skull. There is normally no space between these
two layers (arrow and dotted line in lower-right picture). If the layers do separate (e.g. from
trauma-induced bleeding), then the resulting space is called epidural, i.e. "outside the dura".
57

periosteum of bone
In the spinal canal, an epidural space separates the dura mater
from the periosteum of the vertebral canal.
58

Blood vessels penetrate into the brain,
carrying connective tissue with them.
Epithelia are normally avascular, but the brain is very large and very metabolically active, so
it requires a very dense vascular supply. However, the capillaries are walled off from the
surrounding brain tissue by 1) their own basement membrane (dotted line), and 2) the
processes of astrocytic end-feet, which wrap completely around the blood vessels.
Together, these two layers comprise the blood-brain barrier. The space between the two
layers is called the Virchow-Robbin space, which plays a role in immune-system
dysfunctions that affect the brain.
Note the glia limitans, a layer formed at the outer surface of the brain by the foot processes
of astrocytes.
59

Cobblestone Lissencephaly - a mutation
that prevents formation of an intact
glia limitans
The glia limitans normally adheres to the overlying basement membrane via adhesive
protein complexes. Mutations in the genes coding for such adhesive proteins (e.g.
dystroglycan) prevent the glia limitans from forming properly during embryonic
development. In such cases, neurons migrate into the surrounding subarachnoid
connective tissue, resulting in severe malformation of the cerebral cortex. In one such
condition, Cobblestone Lissencephaly, sulci form incompletely, giving the surface of the
brain a cobblestone appearance. This condition manifests with severe mental retardation
and other severe effects (see your Embryology notes!).
60
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72
Dr. Daniel Peterson
March 8, 2013, 9:00
!
Development*and*Regenera0on*of*the*
Nervous*System*
Lecturer:*Dr.*Daniel*Peterson*
Objec0ves*to*Understand:*
Sequence*of*morphological*changes*
Regula0on*of*cell*dieren0a0on*
Regula0on*of*regional*specica0on*
Injury*to*mature*PNS*and*extent*of*regenera0on*
Injury*to*mature*CNS*and*limited*regenera0on*
Required*Reading*
Development*
Purves*et*al.,*Chp.*22*
Regenera0on*
Purves*et*al.,*Chp.*25*
This*reading*is*far*more*detailed*than*the*lecture*
notes:*you*will*be*responsible*for*the*level*of*detail*
provided*in*the*lecture*
Pay*aNen0on*to*the*Boxes*as*they*provide*useful*
and*relevant*informa0on*
73
Gastrulation is the major event transforming the initial sheet of cells into three
distinct cell layers known as the three germ layers: endoderm, mesoderm, and
ectoderm. This transformation happens by the ow of cells into a central location,
known as the primitive knot or pit (also called Hensens node), and its caudal
extension, the primitive streak. The ectoderm rostral to the primitive knot begins to
thicken and specialize to form the neural plate.!
!
The next major event to occur in the shaping of the embryo is the formation of the
neural tube in a process called neurulation. This event so dominates the appearance
of the embryo that at this stage it is called a neurula. The edges of the neural plate
fold upwards and eventually meet to form the neural tube. This is explained in more
detail in the next slide.!
!
The formation of the tube leaves openings at the rostral and caudal ends of the
neurula. These are called the anterior and posterior neuropores, respectively. In
normal development, both of these openings close by the rst month of gestation.
The lamina terminalis is the remnant of the anterior neuropore in the adult brain.
Failure of the anterior neuropore to close results in anencephaly. Failure of posterior
neuropore closure results in spina bida. Neural tube defects are the most common
cause of perinatal death. Folic acid deciency contributes to neural tube defects.!
Dr. Daniel Peterson
March 8, 2013, 9:00

74
Thickening, folding, and eventual closure of the neural plate produces the neural
tube. Although the neural tube walls are originally a single cell layer thick
(pseudostratied epithelium), they will soon expand by proliferation and migration to
form the CNS.!
!
The process of neural tube formation also isolates the adjacent paraxial mesoderm.
This subsequently segments to form the conspicuous somites. The midline portion of
the mesoderm that underlies the neural tube specializes to form the notochord. The
notochord plays an important role in inducing regional specication of the overlying
neural tube as will soon be discussed. The nucleus pulposus of the vertebral column
is the remnant of the notochord in the adult.!
!
At the lateral edges of the neural plate are a population of neuroectodermal cells that
end up on the most dorsal aspect of the neural tube when it closes, but are not part of
the neural tube itself. These are the neural crest cells that will form all of the
following based upon their migratory route:!
a) Schwann cells, b) adrenal medulla, c) skin pigment cells, d) intrinsic eye muscles,
and e) skeletal and connective tissues of the face!
!
The morphological changes of neurulation are mediated by changes in cell number
(proliferation), migration of those cells, and subsequent differentiation into different
cell fates. These process are regulated by a number of signaling molecules that will
be introduced later in this lecture.!
Dr. Daniel Peterson
March 8, 2013, 9:00

75
Dr. Daniel Peterson
March 8, 2013, 9:00
!
Vesicle'
Stages'
Prosencephalon!
- Telencephalon!
- Diencephalon!
!
Mesencephalon!
!
Rhombencephalon!
- Metencephalon!
- Myelencephalon!
!
Flexures!
- Cephalic!
- Pontine!
- Cervical!
Figure 22.3!
Adult'Deriva2ves'of'Embryonic'
Divisions'
76
Dr. Daniel Peterson
March 8, 2013, 9:00
!
Prenatal'Brain'Growth'
Prolifera2on'
Expanding'cell'
popula2on'
Migra2on'
GeBng'the'cells'to'
the'right'place'
Dieren2a2on'
Turning'the'cell'into''
the'right'kind'of'
neuron'or'glial'cell'
77
The neural tube starts out as a single layer of pseudostratied cells. Cells that are in contact
with the ventricular (apical) surface proliferate by undergoing repeated cell cycle (mitosis).
Although the cells foot remains tethered to the ventricular surface, there is a characteristic
migration of the nucleus and cell soma up to the pial surface during the S-phase (synthesis
phase) where DNA replication occurs. The nucleus then migrates down to the ventricular
surface before mitotic spindles form prior to nuclear and cell division.!
!
Cell division can occur in one of two ways. If the cleavage plane of cell division is vertical
to the apical surface, both of the resulting daughter cells are in contact with the apical
surface. Because they are receiving equivalent (symmetric) inuences, their fate
specication is also symmetric. Symmetric division expands the pool of proliferating cells.!
!
If the plane of cell cleavage is horizontal to the apical surface, then the inuence on the
daughter cells is no longer the same (asymmetric). The daughter cell that is not in contact
with the apical surface is not inuenced to retain the proliferative phenotype. As a result, it
begins to migrate away along the radial glia. Asymmetric division expands the pool of
migrating cells that subsequently differentiate into various types of neurons. Experimental
evidence indicates that the cell identity is established soon after cell division is completed. !
!
The balance between symmetric and asymmetric division determines the rate at which the
CNS is populated during development. Temporal and spatial differences in expansion
contribute to the overall size and composition of different CNS regions.!
!
Dr. Daniel Peterson
March 8, 2013, 9:00

78
In the case of the cerebral cortex, cells generated early in the process migrate toward the pial surface,
climbing along specialized radial glial cells as they go. As later-generated cells migrate outward, they
pass through the earlier population to add a new layer on the outside. Thus the latest cells generated
are in the most supercial parts of the cortex. Another way of saying this is that the cortex is formed
inside-out. See also Fig. 22.8 for an illustration of how this was determined using cell birthdate
labeling (also Box 22D).!
!
The process of cell generation and migration appears to be tightly regulated and vital to the correct
functioning of the CNS. For example, cell migration is disrupted in fetal alcohol syndrome, producing
severe functional decits. The process of migration is orchestrated by the expression of a number of
gene products including neuregulin, doublecortin (DCX) and Lis1 within migrating neuroblasts and
the expression of cell adhesion molecules by the radial glia. Expression of Reelin (RLN) serves as a
signpost to migrating neurons that it is time to exit radial migration. Dysregulation of migration can
produce irregular patches of cortical gyri (pachygyri) or, in extreme cases, an absence of gyri
(lissencephaly or smooth brain). See Fig. 22.13 for examples. Disruption of migration has also been
proposed as a neuroanatomical substrate of schizophrenia.!
!
Not all migration occurs radially. Recent work has determined that cortical interneurons arise from
proliferative centers along the ventricles, the lateral ganglionic eminence (LGE) and the medial
ganglionic eminence (MGE). Cells from these two regions migrate throughout the cerebral cortex.
See Box 22F for more information about this long-distance migration.!
Dr. Daniel Peterson
March 8, 2013, 9:00

79
A good example of environmental inuences governing cell fate has been provided
by research on neural crest cells (see earlier slide). Depending on the extracellular
factor this cell encounters, it can become different cells. This process is called
induction.!
!
How can the activation of cells be kept specic? One way to achieve this is for the
cell to have a window of opportunity to be inuenced. This capacity to be
inuenced is called competence. Therefore, induction only works if the cell has
competence to respond to that signal. As cells progress down the differentiation
lineage, their competence becomes progressively restricted, making them
unresponsive to inducing factors.!
!
Recent work has determined that there are a number of key signaling molecules
operating through several distinct pathways to regulate transcription and inuence
cell fate. Fig. 22.5 illustrates several of these major pathways. You should become
generally familiar with these ligand-receptor interactions and the signal transductions
pathways that they generate.!
Dr. Daniel Peterson
March 8, 2013, 9:00

80
As all cells in the CNS arise from common progenitor cells, there must be a
mechanism to drive cells down certain fate choice to produce the desired type of cell
in the right place at the right time. These fate decisions occur as a result of
transcription regulation and the balance of local environmental signals and
transcription factors determine which direction a cell goes. The top panels in this
gure illustrate the overall population inuences that move cell populations. Neural
induction occurs when expression of noggin and chordin have greater inuence than
bone morphogenetic proteins (BMPs) resulting in the specication of neuroectoderm.
Regional expression of other signals leads to specication of a dorsal and ventral
identity, a point that we will return to in a later slide. !
!
Once regional specication has occurred, it is still necessary to ne tune individual
cell fate between neurons and glia. Expression of notch will retain cells in an
uncommitted state. If proneural bHLH genes products predominate over notch
signals, then the cell will be instructed to adopt a neuronal fate. Subsequent
specication steps will then occur to inuence cell differentiation into a very specic
type of neuron.!
!
Neurons are generated rst. Cells that remain uncommitted during the neurogenic
period will subsequently have less exposure to the proneural bHLH gene products
and become more inuenced by notch and another molecule, neureglin (also seen in
post-commitment migrating neuroblasts) and inuenced to become astrocytes. Cells
exposed to the transcription factors Olig 1/2 and Nkx2.1 will be inuenced to become
oligodendrocytes. Cells which dont commit during this period are thought to persist
as primtive progenitor/stem cells. These cells may be subject to postnatal recruitment
for repair.!
!
Dr. Daniel Peterson
March 8, 2013, 9:00

81
The CNS starts out as a tube. To create the structures found in the mature CNS, it is
necessary to start segmenting the expanding tube into different identities. This starts
by specifying identities such as dorsal from ventral or rostral from caudal. !
!
Emerging research shows that these identities are determined by the expression of
various gene products. The local concentration of these factors and the balance of
their concentration against competing signals denes the boundaries in the
developing CNS. In the case of dorsal/ventral identity a gradient is established
between what is expressed dorsal and what is expressed ventral. Retinoic acid is
expressed dorsally that leads to expression of transcription factors that lead to
sensory neuron specication. Ventral expression is dominated by sonic hedgehog
(SHH) that directly inuences expression of transcription factors for motor neuron
fate. In intermediate regions, the lower expression gradients combine to repress
BMPs and Gli3 signaling, resulting in fate specication for interneurons. !
!
Dont memorize the transcription factors in the colored boxes- that is beyond the
level we can address in this course. However, the text and Boxes 22C and 22E
provide important illustrations as to how disruption of these inducing signals can lead
to serious birth defects. This information is clinically relevant and is likely to show
up on board style questions. This slide and the following slides discuss some of the
factors known to regulate regional identity within the CNS. Although the number of
factors and their interactions is complex, our current state of knowledge has probably
only scratched the surface. Increasing our knowledge of neuronal differentiation will
likely have important clinical benets, as therapeutic strategies to repair the CNS rely
heavily upon restoring developmental signals. !
Dr. Daniel Peterson
March 8, 2013, 9:00

82
The neural tube is originally quite similar, but subsequently undergoes regional
segmentation to produce the different functional levels of the spinal cord and the
different segments of the brainstem. Insight into how this is regulated came from
studying mutations in the fruit y, Drosophila melanogaster. Relating mutations in
specic genes to the developmental phenotype showed that regional expression
changes in a family of related genes was responsible for segmentation (see color-
coded schematic of the fruit y). The boundary between where two genes expressed
would become a morphological boundary in the adult. Because something similar
was split into adjacent boxes, this family of genes were called homeobox genes
(homeo is Greek for similar).!
!
The human analog of these homeobox genes are called Hox genes. As can be seen in
the color-coded representation of the human neural tube, differential expression of
the Hox genes determines the segmentation of the neural tube. There is some
evidence that autism and some forms of mental retardation may be linked to
mutations or polymorphisms of the Hox genes.!
!
Dont memorize the layout of the gene expression maps, that is beyond the level of
what you need to know. Box 22B provides a nice explanation of the role of
rostrocaudal identity in the positioning of cranial nerve nuclei.!
Dr. Daniel Peterson
March 8, 2013, 9:00

83
Dr. Daniel Peterson
March 8, 2013, 9:00
!
The$Mature$Nervous$System$is$Vulnerable$
Despite$bony$casing$and$protected$courses$of$
peripheral$nerves,$they$are$s=ll$subject$to$
damage$
Types$of$injury$
Mechanical:$crush,$cuts$(axotomy),$concussive$
Secondary$injury:$demyelina=on,$inamma=on$
Metabolic$injury:$stroke,$diabetes$
Neurotoxins:$heavy$metals,$some$viruses,$MPTP$
Neurodegenera=ve$diseases$
84
Axons in the PNS (A) extend for considerable distances and can be subject to injury by
compression (crush), hyperextension, or being cut. There is a typical response to this injury
as illustrated above. This gure is modied from Fig. 25.6, in your text.!
!
As shown in panel B, the cell body undergoes changes in response to axonal injury.
Because the cell body swells and the RER becomes dispersed, the reaction is termed
chromatolysis. The nucleus also becomes located to one side of the cell body (eccentrically
located nucleus). If the injury occurs too close to the soma and if there arent other intact
axonal collaterals to maintain viability, then the neuron will die. If the injury is some
distance down the axon, the neuron will survive and begin to express growth-related genes
necessary to initiate regeneration.!
!
Meanwhile, the axon downstream of the injury begins to degenerate in a process called
Wallerian degeneration (B). The Schwann cells around the axon also die and their myelin
is broken down and removed by scavenging macrophages. However, the basal lamina of
the Schwann cells remains intact and provides a critical guidance pathway for regeneration.!
!
Within one day of injury (panel C), Schwann cells proliferate and resume their position
around the old basal lamina. Through their expression of growth-promoting signals and
surface properties, they facilitate the progress of the regenerating axon back to its target.
Fig. 25.4 provides an interesting illustration of how this process was worked out early on.!
Dr. Daniel Peterson
March 8, 2013, 9:00

85
If nerve bers innervating skeletal muscle are cut, the distal axon will degenerate but the
post-synaptic acetylcholine receptors remain clustered at the synaptic site for several
weeks. The Schwann cells also remain providing a extracellular matrix substrate and guide
for axonal regeneration. The uorescence micrograph in panel C illustrates that the
reinnervation pattern substantially restores the neuromuscular synapse. Despite the success
of reinnervation in the PNS, there can be some imprecision with targeting. However, this
can often be remodeled over time to adequately restore sensation or function.!
Dr. Daniel Peterson
March 8, 2013, 9:00

86
Axonal injury can also occur in the CNS, most commonly in spinal cord injury (SCI). Most
SCI is found at C1-C2 or C4-C6 with head impact injuries (like diving accidents) or at T11-
L2 with workplace injuries. Injury can be direct to axonal pathways by crush or contusion
or secondary by cavitation of the spinal cord. There is very little regeneration following
CNS axon injury as illustrated above in gure 25.11 modied from page 574 of the text.!
!
Like seen in PNS axonal injury (B) the axon and supporting cells, the oligodendrocytes,
die. However unlike in the PNS, the myelin is not quickly cleared and its presence will
inhibit any attempts at regeneration. Furthermore, oligodendrocytes have no basal lamina,
so once they are gone, there is no ready pathway to guide any regeneration to the
appropriate target. Also unlike the PNS, central neurons do very little to reactivate growth
promoting signals.!
!
To add to these difculties (panel C), astrocytes respond to the site of injury and form a
dense network called a glial scar and appear to express additional inhibitory factors.
Whatever feeble regrowth is attempted by the neuron seems unable to get past this barrier.
Fig. 25.7 shows that the lack of growth can largely be attributed to differences between the
regenerative support of the PNS relative to the CNS.!
!
There is some hope for improving recovery from SCI. Recent evidence suggests that the
inhibitory signal of the myelin remnants, NoGo, can be blocked, enhancing regrowth (see
page 575). Other evidence suggests that expressing additional trophic factors past the glial
scar can draw regrowing axons through to the other side. Efforts are also underway to
replace oligodendrocytes with stem cells to support regenerating axons. !
Dr. Daniel Peterson
March 8, 2013, 9:00

87
Substantial research progress has been made in the last two decades demonstrating
that neurogenesis can persist in the adult mammalian brain, including the human
brain. Please read pages 577-583 for a concise summary of this progress. Although
adult neurogenesis appears to make a functional contribution to the circuitry of the
hippocampus and olfactory bulb, there is still little support for the extension of these
new neurons into adjacent regions in a fashion that could contribute to brain repair.
Nevertheless, many laboratories around the world are exploring the concept that such
new neurons can be coaxed to migrate out to regions of disease or injury or.
Alternatively, remnant stem cells in the brain can be activated and recruited for
repair.!
!
Such work is still in the early experimental phases, but is showing enough progress to
suggest that one day it may be possible to enhance repair on the CNS through
recruitment of endogenous neural stem cells. This type of personalized
regenerative medicine is advancing in many organ systems and may represent the
leading edge of a revolution in therapeutic approaches.!
Dr. Daniel Peterson
March 8, 2013, 9:00

88
Dr. Daniel Peterson
March 8, 2013, 9:00
!
Prospects)for)Restora-ve)Neurology)
Therapeu-c)strategies)to)restore)neuronal)func-on)apply)equally)to)acute)
injury)and)neurodegenera-ve)diseases)
Keeping)neurons)alive)
A)primary)goal)is)to)keep)neurons)alive)so)they)can)regenerate)
Most)work)has)focussed)on)supplemen-ng)the)brain)with)trophic)factors)using)gene)
therapy)
Controlling)outgrowth)environment)
Most)eort)is)focussing)on)understanding)the)developmental)regula-on)of)
outgrowth)in)hopes)that)this)can)shed)light)on)how)to)treat)the)injured)CNS)
Cell)replacement)therapyE)spare)parts?)
Many)cells)may)have)died)in)a)neurodegenera-ve)disease)before)the)pa-ent)is)
diagnosed.))Two)strategies)have)emerged)to)restore)func-on:)
Fetal)-ssue)graJing)to)restore)neurotransmiKer)levels)
Stem)cells)as)an)undieren-ated)replacement)cell)that)could)be)custom)tailored)
89
90
March 11, 2013
Dr. Marina Wolf
Functional properties of neurons III
March 11, 2013 (9 am)
N t itt P t I Neurotransmitters Part I
Function in normal brain
Introduction to their role in disease states
Reading (this is for both FPIII and FPIV):
Chapter 6 (skip box 6D) and pp.169-184 in
Chapter 8 (skip box 8A) Please do not worry Chapter 8 (skip box 8A). Please do not worry
about details not covered in my lecture notes.
Objectives (for Func Prop III & IV)
Distinguish between small molecule and peptide
neurotransmitters and understand the life cycle of neurotransmitters and understand the life cycle of
each
For each transmitter, know material presented in
lecture about synthesis, release, removal
mechanisms, receptor subtypes, and physiological
function
Understand role of glutamate receptors in LTP and Understand role of glutamate receptors in LTP and
excitotoxicity
Understand basic relationship of neurotransmitter
dysfunction to addiction, schizophrenia and
depression
Criteria for establishing that a substance
is a neurotransmitter
Synthesized by the neuron and
stored in nerve terminals
Released by depolarization in a
calcium-dependent manner
Produces postsynaptic changes by
binding to specific receptors
Mimics action of endogenously
released transmitter when
administered near the synapse administered near the synapse
Many neurotransmitters are termed
putative because all criteria are
not yet fulfilled
Two main groups of chemical transmitters
Small molecule transmitters (classical transmitters)
Acetylcholine y
Amino acids: Glutamate, aspartate, GABA, glycine
Monoamines (biogenic amines): dopamine,
norepinephrine, epinephrine, serotonin, histamine
Purines (ATP and adenosine)
Peptide transmitters
Short proteins usually 3-30 amino acid residues in
length
Over 100 peptides implicated as neurotransmitters
9
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112
The human brain requires an extraordinary degree of protection to survive the rigors
of everyday life. The bony skull provides the first level of protection. However,
other systems and mechanisms must prevent the brain from bumping against the
skull or simply collapsing under its own weight (~1500 g in air). Protection is
provided by cerebrospinal fluid (CSF) and the meninges (derived from greek word:
Meninx), a membranous canopy that suspends the brain within its bony vault.

March 18th , 2013
Dr. West
113
114

It is important to note that the CSF flows within the ventricular system and from the
ventricles into the brain where it baths neurons and glia. Thus, for the most part
(exceptions are discussed below), CSF produced in the ventricles can diffuse into
the brain parenchyma to fill the extracellular compartments that surround neurons
and glia.
115
Together with the meninges, the CSF provides structural and metabolic support.
These systems anchor the brain and provide bouyency so to protect against
concussion.
116
The above sagittal (A) and horizontal (B) views of the brain demonstrate the
approximate location of the ventricular system in relation to major brain regions.
Note that in both examples the ventricular system is superimposed on the cortical
surface to illustrate its approximate location with respect to cortical regions, but is
actually embedded in the core of the brain itself.
117
This diagram from Purves illustrates the location of major ventricular components
as they are associated with embryonic and adult brain compartments.
118
There are two lateral ventricles (LV), one in each hemisphere, which are separated
by the septum pellucidum (SP). The inset in the top left corner indicates the plane
in which the larger coronal section was cut. The inset in the top right corner is an
MRI of the whole head/brain at the level of the middle section. In this section, two
prominent basal ganglia structures are present, mainly the caudate nucleus (Cn)
which boarders the LV, and the putamen (Pt) which is separated from the Cn by the
internal capsule (IC).
119
This oblique section includes nuclei of the: 1) telencephalon such as the Cn, 2)
diencephalon such as the anterior (Ant), dorsomedial (DMn), ansd ventrolateral
(VLn) nuclei of the thalamus, and 3) mesencephalon such as the substantia nigra
(SN). Note that the intraventricular foramen (IF) can be seen to connect the LV
with the 3
rd
ventricle (3
rd
V) at this level.
120
This oblique section is cut at the level of the midbrain. The cerebral aquaduct (A)
which connects the 3
rd
and 4
th
ventricles, is positioned in the middle of this section
and surrounded by the periaquaductal grey (PAG). In addition to the SN, the red
nucleus (RN) is prominent, as are the cerebral peduncles (CP) which form the feet
of the midbrain.
121
The 4
th
ventricle (4
th
V) is found directly under the cerebellum in the brainstem.
Lying ventral to the 4
th
V are the reticular formation (Rf) and the pons. The
corticospinal (CS) tract is located in the ventral most region of this section.
122
The ventricles are lined with specialized glia cells called ependyma cells which do
not make tight junctions. These cells allow CSF to flow freely out of the ventricles
into the CNS extracellular space. In regions containing choroid plexus, the choroid
epithelial cells replace the ependyma, and introduce a barrier between the blood and
CSF in the ventricles. Indeed, it is this capillary-pia-choroid epithelium complex
that generates CSF in the ventricles.
123
This diagram from your text illustrates the course of CSF flow from its point of
production in the ventricles to its absorption from the subarachnoid space into the
superior sagittal sinus.
124
CSF leaves the ventricular system via 3 recesses in the 4
th
ventricle. The foramina
of Luschka (middle specimen) are located in the lateral aspects of the 4
th
ventricle.
The single foramen of Magendie is located in the medial aspect of the 4
th
ventricle
and can be seen best in the diagram of the ventricular system shown on the right.
125
Arachnoid granulations (villi) are one-way valves for absorption of CSF into dural
superior sagittal sinus.

126
Arachnoid granulations extend through tight cuffs in the meningeal dura.
Endothelial layer of dura reflected on the villus, leaving just a few arachnoid
cells exposed. Fluid flows through intercellular channels and through
transcellular vacuoles that originate at the basal membrane of the cell and
function as one-way valves. CSF pressure normally much higher than venous
pressure. If venous pressure is higher, flow slows or stops, so venous blood
never flows from sinus into subarachnoid space.
127
See above link for a video demonstrations of CSF flow through the ventricles and
subarachnoid space.
128
The lumbar puncture is an important procedure because it provides the clinician
with direct access to the subarachnoid space of the lumbar cistern. A hollow spinal
needle is introduced through the skin as shown in the above figure. The needle has
a stylus which occludes the lumen to prevent contamination of the CSF sample with
skin cells during the needle insertion. The procedure may be performed in the lying
or seated position. A manometer tube is used to measure CSF pressure which is
typically less than 20cm water in normal people. Drugs can also be introduced into
the subarachnoid space via this method.
129
The content of various ions (calcium, potassium, magnesium, chloride) is different
in CSF compared to plasma, suggesting that choroid plexus does more than just
filter the blood. The fact that CSF production is depressed by metabolic inhibitors
also argues that CSF is not just an ultrafiltrate of blood. Thus, CSF is an actively
secreted product whose composition is tightly regulated by specific transport
proteins.

130
Note that both CSF composition and fluid dynamics (CSF pressure) can be assessed
with the lumbar puncture technique.
131
132
133
134
135
136
Because the mature central nervous system is located within a closed container
with rigid walls, the usual result of hydrocephalus in adults is increased cranial
pressure. What happens to peripheral blood pressure?
Cerebral perfusion pressure = Mean arterial pressure - Intracranial pressure.
Blood pressure has to increase to compensate. What happens if intracranial
pressure increases such that the blood pressure cannot compensate? Cerebral blood
flow is reduced.

137
Other clinical manifestations include: Cushing's triad (hypertension, bradycardia,
irregular respiration).
The most catastrophic of the clinical effects of hydrocephalus are brain tissue
displacement or cerebral herniations. These occur because the cranium is divided
by rigid dural folds: The Falx cerebri and the tentorium cerebelli. Decerebration and
coma can occur due to compression of the midbrain as a result of focal expansion or
displacement of tissue surrounding the tentorium cerebelli.

138
Treatments for hydrocephalus include:
1) Elevate head to promote venous drainage
2) Elevate cerebral perfusion pressure to maintain cerebral blood flow (CPP=MAP-
ICP)
3) IV administration of mannitol and furosemide (diuretics).
4) Remove source of problem, e.g. tumor.
5) Implantation of shunt to allow CSF to drain directly into venous system (E.G.
jugular or subclavian) or the peritoneal cavity; this is most often done in infants.
6) Third ventriculostomy: endoscope is inserted into the third ventricle (via lateral
ventricle and foramen of monroe) and the floor is perforated allowing CSF to drain
into the interpeduncular cistern.

139
In addition to the need for structural or physical support, the central nervous system
requires that the chemical environment of nerve cells be controlled with great
precision in the face of ever changing concentrations of neurotransmitters,
metabolites, and blood-borne substances. This is provided by selective barriers
found within the brain called the blood-brain-barrier.
In order to maintain homeostasis for cells of the brain, there must be selective
communication between these compartments. Proper functioning of neuronal and
non-neuronal cells depends on very precise control of circulating ions,
neurotransmitters, hormones and other factors. Under normal conditions, a
complex array of anatomical and physiological systems are in place to regulate the
composition of these substances within the blood, brain and CSF compartments.
Disruption of these homeostatic systems under pathophysiological conditions can
have a devastating impact on brain function. BBB: refers to the anatomical and
physiological complex that limits the access of certain substances found in the
general circulation and extracellular fluid of the body to that of the brain (CNS).

140
In the early 1800s it was found that intravenous injection of a dye (Evans blue)
results in diffuse distribution of the dye to almost every organ and tissue, EXCEPT
the brain and spinal cord. This was first thought to be due to low affinity of the dye
for brain tissue. However, this was later found to NOT be the reason for the lack of
dye in the central nervous system. It turns out that the peripheral vessels have
several characteristics that make them leaky such as: 1) low resistance junctions, 2)
fenestra, and 3) pinocytosis.

141
There are ~100 billion capillaries in the human brain which total ~400 miles in
length. Thus, it is likely that every neuron is perfused by at least one blood vessel.
The endothelial cells of the BBB are distributed along the length of the vessel and
completely encircle the lumen. Astrocytic foot processes compress neighboring
endothelial cells together to form the tight junctions that are the physical basis of
the BBB. Astrocytic processes induce the morphological and functional (secrete
factors) features of the BBB. Note: The term luminal membrane of the capillary
endothelium refers to the blood side of the BBB. The term abluminal membrane
of the capillary endothelium refers to the brain side of the BBB.

142
The phrase small lipophilic molecules refers to fat loving compounds having
molecular weights < ~400-500 daltons. Numerous endogenous transport systems
exist within the BBB. These transporter systems are conduits to the brain for
endogenous chemicals and exogenous drugs used to treat brain disorders.

143
Only a small class of drugs (<2% of all small molecule drugs) with high lipid
solubility and low molecular mass (<400-500 daltons) cross the BBB (in the
absence of specific transport proteins). Because of these limitations, only a handful
of brain disorders can be treated with neuropsychopharmacological agents. Brain
diseases found to consistently respond to small molecule drugs include depression,
anxiety disorders, schizophrenia, Parkinsons disease, chronic pain, and epilepsy.

Parkinson's disease is treated with L-DOPA. L-DOPA is converted to dopamine via
the enzyme aromatic amino acid decarboxylase (AAAD). This enzyme is also
referred to as DOPA decarboxylase. Because AAAD is found in areas rich in DA
innervation (e.g. caudate/putamen, nucleus accumbens, olfactory cortex), L-DOPA
treatment will facilitate DA synthesis preferentially in these regions and alleviate
some of the motor symptoms of Parkinsons disease. Peripheral AAAD inhibitors
(do not cross the BBB) are often used in combination with L-DOPA (co-drugs) to
limit the effectiveness of peripheral metabolic enzymes and increase the transport of
L-DOPA into the brain.
144
To protect the CSF from peripheral blood-borne substances, the arachnoid
membrane and the epithelial cells covering the choroid plexus contain tight
junctions. In rare instances, certain compounds do manage to cross the choroid
plexus epithelial barrier. One example is the anti-AIDS drug azidothymidine
(AZT). Unfortunately, AZT penetration into the brain parenchyma is minimal. This
is because AZT is a substrate for a BBB active efflux pump which extrudes AZT out
of the CSF and back into the blood before it can enter brain tissue in significant
concentrations. This is another example of the BBB working against the clinician
and in effect, allowing the brain to serve as a sanctuary for the HIV virus. The
development of co-drugs with the ability to inhibit this active efflux pump could
increase the efficacy of AZT and other drugs for the treatment of AIDS.

145
Q: When there is such tight security kept on most of the brain, why would some
regions be allowed access to the periphery?

A: One primary purpose is to allow the brain to monitor physiological functions
(e.g.: electrolyte balance, fluid balance, detect toxins, modulate endocrine
processes) in the periphery.

CVOs are involved in Maintaining the stability of the internal milieu of the
organism. The neuroendocrine system also needs leaky vasculature to release
hormones and transmitters directly into the blood stream. The median eminence is
the raised area on the infundibulum of the hypothalamus at the floor of the third
ventricle of the brain. It is continuous with the infundibular stem or stalk of the
pituitary gland, and contains the primary capillary network of the hypophysial portal
system.

146
The ependymal cells lining the ventricles in regions adjacent to the Area
Postrema/CVO have developed specialized tight junctions. These specialized
ependymal cells are called TANYCYTES. Tanycytes prevent free exchange between
brain and CSF in these regions. Tanycytes processes interconnected by tight
junctions also form a barrier between the CVO and adjacent parts of the brain (e.g.
nucleus tractus solitarus, NTS).

147
148
149
This diagram from Blumenfeld summarizes the 3 main protective barriers in the
brain. The blood-brain barrier is a result of endothelial cells with tight junctions
which restrict the diffusion of substances from the blood into the brain parenchyma.
The blood-CSF barrier is a result of choroid epithelial cells with tight junctions
which restrict the diffusion of substances from the blood into the ventricles/CSF.
The brain-CSF barrier is a result of tanycytes with tight junctions which restrict the
diffusion of substances from the brain into the ventricles/CSF. Disruption of these
barriers by disease can result in compromised brain homeostasis as described above.
150
Dr. Daniel Peterson
March 18, 2013, 11:00
Meninges and Cerebral Hemorrhage
Lecturer- Dr. Daniel Peterson
Objectives to Understand:
The structure and function of each layer of the
cranial meninges
The major dural reflections and their functions
The structure and function of the dural sinuses
1
The structure and function of the dural sinuses
The relationship of the anatomy of the cranial
meninges to clinical problems
To discriminate effects of epidural vs. subdural
bleeding
Subarachnoid cisterns Subarachnoid cisterns
22
33
44
55
Blumenfeld, 5.12
1. Cisterna magna (largest)
2. Quadrigeminal cistern
3. Prepontine cistern
4. lnterpeduncular cistern
5. Chiasmatic cistern
6. Lumbar (most clinically relevant)
11
66
4
151
Dr. Daniel Peterson
March 18, 2013, 11:00
Dura mater
Latin for tough.
Envelops the entire brain and spinal cord Envelops the entire brain and spinal cord.
Composed of two layers around the brain and only one around the spinal cord:
Outer layer is called the periosteal layer (adherent to the skull). There is normally no space between the
skull and the dura, only the potential, epidural space. Bleeding into this space (typically, from trauma) is an
epidural hematoma.
The inner layer is called the meningeal layer (adherent to arachnoid).
The two layers are normally indistinguishable, except when they separate along the deepest fissures to form
the dural reflections. The cavity formed at the top of one of these, the falx cerebri, contains venous blood
and is called the superior sagittal sinus.
Single layer of dura wrapping the peripheral nerves called the epineurium.
Functions:
Protects the CNS by stabilizing it within in the skull and vertebral column.
Contains specialized cavities called dural sinuses that provide drainage for central venous blood back into
systemic circulation.
Arachnoid
Delicate cobweb-like substance enveloping all of brain and spinal cord.
Closely adherent to the inner layer of the dura (does not follow sulci)
The space between the arachnoid and the pia mater is the subarachnoid space.
Pi t Pia mater
Latin for tender.
Closely follows contours of gyri and sulci of the brain and spinal cord.
The pia and arachnoid together are known as the leptomeninges.
152
Dr. Daniel Peterson
March 18, 2013, 11:00
Subarachnoid space is bridged by connective tissue structures called trabeculae, weblike
structures that attach the arachnoid to the pia.
Subarachnoid space contains: blood vessels and CSF.
Because the subarachnoid space follows the gyri and sulci of the brain, it creates infolded
spaces called subarachnoid cisterns
153
Haines Table 4-1, 8th Ed.
6
Dural Reflections Dural Reflections
Cerebral Falx
Sellar Diaphragm
Cerebellar Cerebellar
Tentorium
7
Dural Reflections Dural Reflections
Tentorial Notch
8
Herniation syndromes Herniation syndromes yy
(Blumenfeld, 5.18)
(subdural hematoma in (subdural hematoma in
this example)
Categorized with respect to the tentorium cerebelli:
Above the tentorium = supratentorial; below = infratentorial. p
Transtentorial herniation pushes the uncus down past the tentorial
notch, putting pressure on midbrain structures.
9
1
5
4
Cerebral Venous Systems Ce eb a Ve ous Sys e s
Cerebral veins are
classified as superficial
or deep.
Superficial veins drain Superficial veins drain
primarily cortical
structures.
Deep veins drain
primarily subcortical
structures.
Superficial veins are
primarily found in the
subarachnoid space
Superior Sagittal Sinus
See also
subarachnoid space.
These veins puncture
through the dura and
lecture by
Dr. West
10
empty into the dural
venous sinuses.
10
Dural Venous Sinuses Dural Venous Sinuses
Superior Sagittal
Cerebral Falx
Superior Sagittal
Sinus
Inferior Sagittal
Sinus
Straight Sinus
Crista Galli
Confluence of
sinuses
g
Sellar Diaphragm
sinuses
Sellar Diaphragm
Great Cerebral Vein
Cerebellar
Tentorium
Haines D.E., Ed,
Fundamental Neuroscience
for Basic and Clinical for Basic and Clinical
Applications, 3rd ed.,
Churchill Livingstone, 2006
11
Superior Petrosal
Sinus
Transverse Sinus
Straight Sinus
Haines D.E., Ed,
for Basic and Clinical
Straight Sinus
Confluence of Sinuses
12
Dural Reflections and
Venous Sinuses
Superior
Sagittal Sinus
Cerebral Falx
g
Inferior
Sagittal
Sinus
Sellar
Diaphragm
Sinus
Transverse
Sinus
Cerebellar
T t i Tentorium
Cerebellar Falx
13
1
5
5
Dural Venous Sinuses
Cavernous
Dural Venous Sinuses
Cavernous
Sinus
Jugular Bulb
Sigmoid Sinus
Confluence of Confluence of
Sinuses
14
Dural Dural
Venous Ve ous
Sinuses
Haines Fig. 9-4
7th Ed.
15
16
Venous Sinuses
Superficial veins drain mainly Superficial veins drain mainly
into the superior sagittal sinus
and cavernous sinus.
Deep veins drain mainly into
the great cerebral vein of Galen
which is joined by the inferior j y
sagittal sinus to form the
straight sinus.
Ultimately nearly all venous
drainage from the brain
reaches the internal jugular j g
veins.
17
1
5
6
Cavernous Sinus Cavernous Sinus
Sellar Diaphragm
Cavernous Sinus
Internal Carotid A.
Anterior clinoid process
Optic Chiasm
Cavernous Sinus
Oculomotor N.
Trochlear N.
Ophthalmic N
Abducens N.
Pituitary Gland
Ophthalmic N.
Maxillary N.
Sphenoid Sinus
The internal carotid artery and CN III, IV, V, and VI all travel through the y , , , g
cavernous sinus- lesion to this area can produce unilateral headache,
opthalmoplegia, and forehead numbness (see lecture by Dr. West)
18
Clinical Note Clinical Note
Superior sagittal sinus
Supraorbital V.
Angular V.
Superior
Cavernous
Sinus
Ophthalmic V.
Facial V.
Inferior
Sigmoid sinus
Sinus
Transverse sinus
Infections from the face
and scalp can reach the
Ophthalmic V.
and scalp can reach the
cavernous sinus via the
connections with the
facial v. and its tributaries
and supraorbital and
Connection of
occipital sinus
t t b l and supraorbital and
supratrochlear veins.
to vertebral
venous plexus
19
Clinical Note
Di l i V i
Diploic veins are
connected to the
Clinical Note
Diploic Veins
connected to the
veins of the scalp
and the dural
venous sinuses
by way of their by way of their
connections to
emissary veins
which traverse
small foramina small foramina
through the skull.
This is another
way for external
infections to infections to
reach the interior
of the skull.
20
Clinical Note
Emissary V.
Scalp V.
Clinical Note
Diploic V.
Emissary veins
establish
connections
between veins of between veins of
the scalp and
diploic veins and
the dural venous
sinuses.
Superior Sagittal Sinus
sinuses.
21
1
5
7
Dr. Daniel Peterson
March 18, 2013, 11:00
Arachnoid granulations extend through tight cuffs in the meningeal dura.
Endothelial layer of dura reflected on the villus, leaving just a few arachnoid
cells exposed. Fluid flows through intercellular channels and through
transcellular vacuoles that originate at the basal membrane of the cell and
function as one-way valves. CSF pressure normally much higher than venous
pressure. If venous pressure is higher, flow slows or stops, so venous blood
never flows from sinus into subarachnoid space.
158
Arachnoid Villus Arachnoid Villus
Superior Sagittal
Sinus
CSF passes both through
the arachnoid cells (most)
and between them.
E d th li
Sinus
Endothelium
Periosteal Dura
Meningeal Dura
Pia
Arachnoid
Subarachnoid Space
Cerebral Falx
(meningeal dura)
Pia Subarachnoid Space
Haines D.E., Ed,
for Basic and Clinical for Basic and Clinical
22
Artery ( such as the middle meningeal a.)
Epidural Hematoma Skull
Periosteal dura
being forced
away from
attachment to
Dural Venous Sinus
Periosteal Dura
Meningeal Dura
attachment to
skull by arterial
blood
Meningeal Dura
Subdural Hematoma
Cerebral
Vein in SAS
Falx
Brain
Blood from vein forcing
its way between the
dural border cells of the
Haines D.E., Ed,
meningeal layer of the
dura
24
Epidural Hematoma
Epidural Hematoma Characteristics:
Haines Fig. 4-4
8th Ed.
- Lenticular shape that does not cross suture lines
- Localized and external to brain tissue
25
Subdural Hematoma
Subdural Hematoma Characteristics:
Haines Fig. 4-4
8th Ed.
- Thin and extensive
- Do cross suture lines
26
1
5
9
Dural Border Cells
Arachnoid Arachnoid
Artery in SAS
Subarachnoid Hemorrhage
Aneurysm ruptured into the SAS
Brain
Haines D.E., Ed,
27
Acute Subdural Hematoma (CT) Acute Subdural Hematoma (CT)
(Blumenfeld Case 5.2)
One year follow-up In Emergency Room One year follow up In Emergency Room
28
Summary of Cerebral Hemorrhages Su a y o Ce eb a e o ages
Epidural Hemorrhage
Between skull and periosteal dura Between skull and periosteal dura
Lenticular and confined within sutures
Does not bleed into subarachnoid or significantly displace
structures structures
Subdural Hemorrhage
Between meningeal dura and arachnoid barrier cells g
Forms thin crescent
Does not itself bleed into arachnoid space
C di l t t ( i d h i ti ) Can displace structures (compression and herniations)
Bleeding vessel with arachnoid space Bleeding vessel with arachnoid space
Diffuse blood extending into sulci and cisternae
Greater than 50% fatality with aneurysm
29
Intraparenchymal Hemorrhage
See later lecture on stroke by Dr. Welch
1
6
0
Dr. Daniel Peterson
March 18, 2013, 1:00

CNS$Blood$Supply$
Lecturer1$Dr.$Daniel$Peterson$
Objec<ves$to$Understand:$
Importance$of$blood$supply$to$the$CNS$
Major$arterial$supply$
Match$major$territories$with$arterial$supply$
Major$venous$drainage$
Diagnos<c$signicance$
Required$Reading$
Purves$et$al.$pp.$7351741$
See$also$recommended$text:$
Blumenfeld1$Neuroanatomy+Through+Clinical+Cases$$Chapter$
10$
Source$of$most$gures$in$handout$
Level$of$clinical$correla<on$is$in$excess$of$requirements$for$
this$course$
Some$gures$also$from$Siegel$and$Sapru$(in$library)$
See$also$Haines$atlas$(Chp.$9)$and$Neurosyllabus$
Clinical$correla<on$on$stroke$later$in$course$
161
Dr. Daniel Peterson
March 18, 2013, 1:00

CNS$Requirements$for$Vasculariza<on$
CNS$metabolic$demands$
CNS$receives$20%$of$res<ng$cardiac$output$
Brain$consumes$large$amounts$of$glucose$(about$20%$of$total)$and$oxygen$
Changes$in$glucose$and$oxygen$metabolism$and$in$local$blood$ow$rates$
used$in$live$imaging$of$CNS$func<on$
Interrupted$blood$ow1$Stroke$or$Cerebrovascular$Accident$(CVA)$
Analogy$of$major$roadway$construc<on$
Third$leading$cause$of$death;$Leading$cause$of$disability$in$US$
Stroke$refers$to$hemorrhagic$events$(bleeding)$or$ischemia$(interrup<on$of$
ow)$that$can$lead$to$an$area$of$infarc<on$(cell$death$resul<ng$from$
interrupted$blood$ow)$
Global$ischemia$from$cardiac$insuciency$
Embolic$infarct1$distant$blood$clot$lodges$in$CNS$artery$
Thrombo<c$infarct1$local$clot$oaen$at$atherosclero<c$site$
Diagnos<c$importance$
Ischemic$vs.$Hemorrhagic$Stroke$
162
Dr. Daniel Peterson
March 18, 2013, 1:00

Anterior$&$Posterior$Brain$Supply$
Angiogram1$Imaging$of$radio1opaque$contrast$dye$
injected$into$lea$internal$caro<d$
163
Dr. Daniel Peterson
March 18, 2013, 1:00

Internal$$
Caro<d$$
Angiogram$
Haines Fig. 9-1
8th Ed.
Posterior$
Arterial$
Supply1$
Lateral$View$
Haines Fig. 9-7
8th Ed.
164
Dr. Daniel Peterson
March 18, 2013, 1:00

Posterior$
Arterial$
Supply1$
Anterior$View$
Haines Fig. 9-8
8th Ed.
See also schematic in
Fig. 9-6C
Circle$of$Willis1$Base$of$Brain$
The Circle of Willis has
Five Arterial Components:
1) Posterior Cerebral
2) Posterior Communicating
3) Internal Carotid (that gives
rise to the posterior communicating,
anterior choroidal, anterior cerebral, and
middle cerebral arteries or PAAM)
4) Anterior Cerebral
5) Anterior Communicating
N.B. 1 arises from posterior flow through
the basilar artery
2 - 5 arise from anterior flow through the
internal carotid
(landmark!)
(landmark!)
165
Dr. Daniel Peterson
March 18, 2013, 1:00

The Circle of Willis Compensates for Blockages
Purves 1.20a!
Internal Carotid!
Anterior cerebral !
artery!
There is substantial anatomical variability in the Circle of Willis and
it is not patent (completely open) in all patients
Patients without a patent Circle of Willis have a greater probability of
morbidity following stroke.
MR$angiogram:$Circle$of$Willis$
(Blumenfeld, 4.18A; see also Haines atlas, Fig. 9-8)
166
Dr. Daniel Peterson
March 18, 2013, 1:00

Distribu<on$of$the$Anterior$Cerebral$Artery$(ACA)$
Fig. 4-2
In Siegel and Sapru
See also Haines Fig. 9-1 8th Ed.
Distribu<on$of$the$Posterior$Cerebral$Artery$(PCA)$
Fig. 4-4
In Siegel and Sapru
Haines Fig. 9-8B 8th Ed.
167
Dr. Daniel Peterson
March 18, 2013, 1:00

Distribu<on$of$the$Middle$Cerebral$Artery$(MCA)$
Fig. 4-3
In Siegel and Sapru
Lenticulostriate arteries emerge from MCA
See also Haines
Fig. 9-1 8th Ed.
Anatomy$of$Anterior$Cerebral$Artery1$ACA$and$
Posterior$Cerebral$Artery1$PCA$(another$view)$
168
Dr. Daniel Peterson
March 18, 2013, 1:00

Anatomy$of$the$Middle$Cerebral$Artery1$MCA$
(another$view)$
Supercial$Vascular$Territories$of$the$
Three$Cerebral$Arteries$
169
Dr. Daniel Peterson
March 18, 2013, 1:00

Anatomy$of$Arterial$Supply$to$Deep$
Cerebral$Structures$
Distribu<on$of$Arterial$Supply$to$Basal$
Ganglia$and$Thalamus$
170
Dr. Daniel Peterson
March 18, 2013, 1:00

Summary$of$Supercial$and$Deep$Vascular$Territories$
Watershed$Zones1$Regions$suscep<ble$to$the$
addi<ve$eect$of$ischemic$episodes$
171
Dr. Daniel Peterson
March 18, 2013, 1:00

Arteries$Supplying$the$Cerebellum$
SCA
AICA
PICA
*
* Supplies vestibular labyrinth
Vascular$Supply$to$Brainstem$
From Purves et al., p. 836
172
CNS IMAGING
DONALD WAXLER M D DONALD WAXLER, M.D.
DEPARTMENT OF RADIOLOGY
Related reading: Purves, pp. 18-20; Haines pp. 2-4
Further reading: Kandel, pp. 366-379; Blumenfeld, Ch. 4
NEURO IMAGING MODALITIES NEURO-IMAGING -- MODALITIES
1) CT & CTA
2) MR & MRA
3) US DOPPLER VASCULAR IMAGING
4) CONTRAST ANGIOGRAPHY
5) NM NEURO IMAGIING
6) NM CISTERNOGRAPHY
7) US NEONATAL SPINE IMAGING )
1
7
3
1
7
4
1
7
5
1
7
6
How MRI works
A strong magnetic field aligns all atomic nuclei in the body A radiofrequency (RF) pulse A strong magnetic field aligns all atomic nuclei in the body. A radiofrequency (RF) pulse,
tuned to the resonance frequency of protons (H
+
ions) is then applied in the direction of
interest (axial, coronal, etc.). When the pulse is turned off, the protons emit
a RF signal whose rate of decay depends
hydrogen nuclei
(no net dipole)
g y p
on the surrounding medium (e.g., fat,
water, bone). RF emissions are detected
by a receiver coil and deconvolved into a
two dimensional image two-dimensional image.
(Kandel 19.18)
1
7
7
Two types of MRI
(Blumenfeld, Fig 4.6)
T1-weighted image T2-weighted image
Proton relaxation from the excited state has two components a slow vertical Proton relaxation from the excited state has two components, a slow vertical
recovery (T1), along the axis of the magnetic field, and a faster horizontal recovery
(T2) along the plane perpendicular to the magnetic field. Depending on the RF
sequence chosen for scanning, either the T1 or the T2 signal will be stronger.
T1 vs. T2-weighted MR images
Tissue T1-weighted T2-weighted
Gray matter Gray Light gray
White matter White Dark gray g y
CSF Black White
Fat White Black Fat White Black
Air Black Black
Bone or calcification Black Black
Generally speaking T1 images look like unstained brain Generally speaking, T1 images look like unstained brain
sections, while T2 images look like myelin-stained sections.
1
7
8
MRI: Hydrocephalus
(Blumenfeld, Fig. 5.29)
hydrocephalus 8-mo follow-up
1
7
9
3D reconstructed brain (MR)
(Blumenfeld, 4.8)
MR angiogram: Circle of Willis
(Blumenfeld, 4.18A; see also Haines atlas, Ch. 8)
1
8
0
1
8
1
Invasive neuroangiography
A ld b ill id l d h d f d i h l i An old, but still widely-used method for detecting atherosclerotic
plaques and other vessel narrowings, aneurysms, and arteriovenous
malformations (AVMs).
Procedure: a catheter is inserted in the femoral artery under local
anesthesia and then threaded up through the aorta to the carotid or
vertebral arteries. Radio-opaque iodinated contrast material is then p q
injected and sequential x-ray images are taken in multiple planes.
(Blumenfeld, 4.9)
1
8
2
(Haines Fig 8 8B) (Haines Fig 8 8B)
Posterior cerebral angiogram
(Haines, Fig. 8.8B) (Haines, Fig. 8.8B)
PCA
Basilar
Superior
PICA
p
cerebellar
PICA
Vertebral
AICA
1
8
3
1
8
4
Functional imaging methods
PET PET
Positron emission tomography
Uses short-lived radionuclides (e.g.
15
O) to measure blood flow, glucose
t itt th bi h i l f i t t use, neurotransmitters or other biochemicals of interest.
Spatial resolution is about 4 mm. Temporal resolution is good, but cannot
retest same subject without reinjecting tracer. Limits scans per subject.
R di ti (th h d t) k thi i i t h i Radiation exposure (though modest) makes this an invasive technique.
SPECT
Single photon emission computerized tomography Single photon emission computerized tomography
Faster and more widely-available than PET. Similarly invasive, but
poorer spatial resolution & lack of quantitation limit research value.
fMRI fMRI
Non-invasive; more widely-available & better spatial resolution than PET.
Temporal resolution (a few seconds) limited by kinetics of blood flow; but
true for all functional imaging methods (Only EEG has ms resolution ) true for all functional imaging methods. (Only EEG has ms resolution.)
Magnetic resonance spectroscopy (MRS) for measuring neurochemicals.
Method of choice for research. Increasingly used for clinical purposes.
1
8
5
Functional MRI (fMRI)
U ti l t d ( ti i d k)
(Kandel, 19.21)
Unstimulated (resting in dark):
Stimulated (viewing checkerboard):
(excess oxy-Hg)
stimulated
minus
unstimulated (excess oxy Hg)
fMRI works by a method called BOLD (blood oxygen level detection): When
a particular brain area is more active, its blood flow increases, and the ratio of
oxy-Hg/deoxy-Hg increases. Oxy-Hg produces more magnetic resonance
than deoxy-Hg, so a comparison of the two conditions reveals areas of
greater cerebral blood flow. fMRI has better spatial resolution than PET.
fMRI during hand movement
Inside the scanner, patient was
asked to move first her left
hand (activity shown in yellow
and red) and then her right
hand (activity shown in green
and blue). Active regions were
then projected on a 3D t e p ojected o a 3
rendering of the brain,
reconstructed from structural
MRI imaging Such imaging is MRI imaging. Such imaging is
increasingly used to map
functionally important brain
b f areas before neurosurgery.
(Purves, p. 27)
Functional MRI (fMRI) Functional MRI (fMRI)
1
8
6
1
8
7
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Somatosensory Somatosensory System I: System I:
Receptors & Pathways Receptors & Pathways
1
Lise Eliot, PhD
March 21, 2013
Related reading: Purves pp. 189-201; 720-23
Lecture outline Lecture outline
1. Introduction to sensory systems
2. Functions and divisions of the somatosensory system
3. Receptors types
4. Mechanotransduction
2
5. Receptive fields and two-point discrimination
6. DRG neurons and the dorsal horn
7. Dermatomes
8. Dorsal column/medial lemniscus pathway
9. Anterolateral tract
10. Trigeminal system
Definition Definition
Somatosensory literally means bodily senses.
Responds to sensation from throughout the body:
skin, muscles, joints, and viscera
Processes information both subconsciously (reflexes
3
Processes information both subconsciously (reflexes,
some proprioception) and consciously (via cortex).
Two fundamental divisions:
Fine, discriminative touch, proprioception, and vibration
(dorsal column/medial lemniscus pathway)
Pain, temperature, and crude touch (spinothalamic
pathway of the anterolateral tract)
Stimulus properties Stimulus properties
Properties of individual receptors in every sensory system:
1. Modality (type of energy transduced): mechanical, chemical,
thermal, or electromagnetic (light)
2. Intensity (stimulus strength): coded by the number of action
potentials or a receptors characteristic threshold
3. Timing: coded by duration of action potential firing but
4
g y p g
adaptive properties of receptors also code dynamic properties
4. Location: each receptor has a distinct receptive field;
combining these creates somatotopy.
Other terms to know:
Transduction: converting energy from one modality to another
(ionic)
Receptor potential: voltage change produced by a receptors
adequate stimulus (analogous to an EPSP)
Stimulus magnitude is coded by Stimulus magnitude is coded by
afferent firing rate afferent firing rate
5
(Kandel 21-3
based on
Mountcastle et
al., 1966)
Somatosensory modalities Somatosensory modalities
Discriminative touch
Required for recognizing size, shape and texture
of objects and their movement across the skin
Proprioception
Dorsal
column/
medial
lemniscus
6
Sense of static position and movement of body
parts
Nociception
Signaling of tissue damage or chemical irritation.
Includes pain and itch
Temperature
Warmth and cold
lemniscus
Antero-
lateral
system
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Tactile sensitivity is greatest on glaborous (non-hairy) skin, which is located
on the fingertips, palms, lips, and soles of the feet. Hair follicle receptors
(i t) l t d i h i ki Th idl d ti d d t (inset) are located in hairy skin. They are rapidly-adapting and respond to
skin stroking. Their axons are myelinated and rapidly-conducting. A person
can feel movement of a single hair, but because the receptors adapt, the
perception stops before the displacement ends.
All other receptor types are found in both hairy and glaborous skin:
Encapsulated receptors mediate both touch and proprioception; capsu ated ecepto s ed ate bot touc a d p op ocept o ;
the capsule both amplifies and filters the stimulus.
Unencapsulated receptors are known as free nerve endings and
mediate pain and temperature. Free nerve endings are both more
numerous and widespread than encapsulated receptors.
There are four types of encapsulated receptors that provide the CNS
information abo t to ch press re ibration and c taneo s tension in information about touch, pressure, vibration, and cutaneous tension in
glaborous skin: the more superficially-located Meissner corpuscles and
Merkel disks, and the deeper Pacinian corpuscles and Ruffini endings.
All are low-threshold mechanoreceptors (fire action potentials to very weak
mechanical stimuli) and are innervated by larger, myelinated axons (A|
fibers).
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Meissners corpuscles are located just beneath the epidermis, interspersed among the dermal
papillae, to which they are mechanically coupled via collagen fibers. The nerve threads a tortuous
course between several layers of Schwann cells within a connective tissue capsule. This structure y p
makes them rapidly-adapting, because the lamellae gradually absorb the stretch during a
continuous stimulus, relieving pressure on the nerve ending. Meissners corpuscles are located
primarily in the fingers, palms and soles, and are the most numerous sensory receptors in the
hand. Because of their superficial location, they have punctate receptive fields and participate in
grip control and detecting the motion of objects across the skin.
Merkel disk receptors are clustered at the base of the papillary ridge in the basal layer of
epidermisthat is, close to the skin surface (like Meissners corpuscles). A small, semi-rigid
epithelial cell that surrounds the nerve terminal, this receptor is densely localized in the fingers,
toes, lips, and genitalia. They have the smallest receptive field of all the cutaneous receptors and
are important for fine tactile discrimination. However, unlike Meissners, they are slowly-adapting
and respond more to static object shape (edges, points, and curvature) than to dynamic stimuli.
Pacinian corpuscles are located in both viscera and skin, where their deep positioning gives them
larger, more diffuse receptive fields. They are the largest receptor, some 10 times larger than
Meissners corpuscles, but like them, are rapidly-adapting. That is, they respond to rapid
i d t ti b t t t d b th di i d d b ti ti indentation, but not steady pressure because the nerve ending is surrounded by connective tissue
lamellae that absorb constant stretch. This property makes both Meissner and Pacinian corpuscles
responsive to dynamic stimuli, such as stroking, rubbing, or the movement of objects across the
skin. Pacinian corpuscles are the most sensitive mechanoreceptors, responding to even minute
vibration or frictional displacement and are important for skilled tool use.
Ruffini endings are slowly-adapting receptors located at folds in the skin, in the palm and sites of
fingernail attachment, and in tendons and ligaments. The sensory axon branches among a bundle
of collagen fibrils that are connected to the dermis so stretching in the direction of the fibril of collagen fibrils that are connected to the dermis, so stretching in the direction of the fibril
depolarizes the nerve terminal. Their deep location confers a larger receptive field. Electrical
stimulation of Ruffini endings does not invoke a tactile perception, but grasping an object does
activate them. Ruffini endings act as stretch receptors of the skin, important for perceiving hand
position and the shape of objects held in the hand.
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Pacinian corpuscle
9
Merkel
Vibration Vibration
sensitivity sensitivity ((Kandel Kandel 23 23-- 8) 8)
Graphshowsneural
th h ld f d t ti
www.neuroexam.com, Clip 72
thresholdfordetecting
vibratorystimuli.
Meissner &Pacinian
corpusclesbothrespond,
butPacinian arefarmore
sensitive,andselectively
activatedbythetuning
10
forktest(128or256Hz)
inneurologicalexam.
Goodtestofdorsal
column/mediallemniscus
function.
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Dr. Eliot
Responsible for sense of bodily position and movement:
Static limb position sense
Kinesthesia (sense of limb movement)
Three types of mechanoreceptors:
muscle spindle receptors (muscle stretch), densely localized in fine
motor muscles, such as hand, neck, and extraocular , , ,
Golgi tendon organs (muscle force)
joint receptors (not shown), especially important for finger position
Employ fastest afferents (Ao), to drive fast reflexes.
Processed both consciously and subconsciously.
Unconscious proprioception is carried by the spinocerebellar tracts,
which are located in the lateral-most rim of the spinal cord and
terminate primarily in the ipsilateral cerebellum. In particular,
muscle spindles of the lower limb send their central afferent
projections to a column of neurons known as Clarkes nucleus,
which extends from spinal level C8 to L2 and is the origin of the
dorsal spinocerebellar tract.
Receptors in skin (Ruffini corpuscles) also contribute, and are especially
important for hand movements and fine facial expression. p p
Will be discussed further in motor section of course.
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Testing position sense (#73) Testing position sense (#73)
12
Primary afferent categories Primary afferent categories
(See also Purves Table 9.1) (See also Purves Table 9.1)
Fiber
class
Afferent
group

Myelin
Fiber
diameter
Conduction
velocity

Receptor type g p y y p yp
Ao Ia & Ib
+++
13-20
(m)
80-120
(m/sec)
Proprioreceptors
(muscle, tendon,
joint)
A| II
++
6-12 35-75
Mechanoreceptors
(skin, muscle,
viscera)
13
Ao III
+
1-5 5-30
Nociceptors,
thermoreceptors
C IV
-
0.2-1.5 0.5-2
Nociceptors,
thermoreceptors

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This figure shows the transduction mechanism in an encapsulated receptor,
such as a Pacinian corpuscle.
A. Ion channels are closed in the absence of a stimulus (left). Pressure
on the skin deforms the capsule, stretching the plasma membrane
(right). Stretch-activated channels are opened by this stimulus.
These are relatively non-selective channels, but the dominant ionic
movement is inward Na
+
flux, since its driving force is the greatest.
This inward current depolarizes the neuron.
B. Electrical response of the primary afferent neuron to stimuli of varying
strength Stronger pressure opens more ion channels increasing the strength. Stronger pressure opens more ion channels, increasing the
amount of depolarization. These sub-threshold responses are called
generator potentials or receptor potentials. With a strong enough
stimulus, the membrane potential exceeds threshold and an action
potential is generated that propagates into the spinal cord.
Despite differences in receptor cell structure, similar stretch-sensitive ion
channels are involved in mechanotransduction by other cutaneous channels are involved in mechanotransduction by other cutaneous
mechanoreceptors, muscle spindle receptors, and vestibular and cochlear
hair cells of the inner ear.
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Receptive fields Receptive fields
Mapped by inserting a
microelectrode into a nerve
and recording action
potentials evoked by skin
(Haines textbook, 17.3)
stimulus.
Receptive field size varies by
over an order of magnitude
across the body, reflecting
the spread of terminal fields
among different primary
afferent fibers.
More sensitive areas have
15
tighter terminal distribution,
higher receptor density and
smaller receptive fields.
To a first approximation,
receptive field size limits the
spatial resolution of
perception.
Testing 2 Testing 2- -point discrimination point discrimination
Patients
eyes should
be closed.
(Blumenfeld, neuroexam.com clip #74)
more
precise,
Kandel
25-5
16
Simultaneous detection of two punctate stimuli separated by minimal
distance. (In research, tested with precisely-spaced grooves or gratings.)
Best clinical test of fine tactile ability.
Important for perceiving object texture.
Though conveyed by dorsal column/medial lemniscus system, conscious
recognition of 2-point discrimination takes place in the cerebral cortex.
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Two Two--point discrimination point discrimination
Minimum distance between
two detectable stimuli.
(Purves 9.3)
Ranges from 2 to ~50 mm
in different body regions:
- Varies with receptive field
size.
- Correlated with receptor
density in superficial skin
17
density in superficial skin
(Meissners corpuscles &
Merkel disks).
- Central mechanisms also
contribute (e.g., lateral
inhibition).
Lateral inhibition Lateral inhibition
Most stimuli activate a wider area of
skin than we actually perceive.
I th i l d ( d hi h l ) In the spinal cord (and higher relays),
primary afferent fibers excite inhibitory
interneurons which depress activity in
projections from surrounding areas.
Because afferents at the center of the
stimulus are activated more strongly,
they will more potently inhibit their
i hb ll
18
neighbors, as well as overcome
inhibition by their neighbors.
Also known as surround inhibition.
Occurs similarly at many levels in the
visual system, where it functions to
sharpen visual contrast.
(Brodal 7.3)
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All sensory neurons are located in the PNS
Regardless of modality, all primary sensory neurons share certain
properties:
cell body in a DRG
bifurcating axon (pseudounipolar), with peripheral and central
branches that are together known as a primary afferent fiber
project into spinal cord
Sensory neurons in head and neck follow a similar plan, but cell
bodies lie in cranial nerve ganglia and project into the brain stem.
Differences among DRG modalities:
soma and axon diameter
peripheral receptor
degree of myelination
location of projection synapse
neurotransmitters
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Spinal cord gray matter is divided into ventral (anterior) and dorsal
(posterior) horns:
The dorsal horn receives sensory information that enters via the
dorsal roots.
The ventral horn contains the cell bodies of motor neurons that
project their axons out of the ventral roots and peripheral nerves to
control striated muscles.
Spinal cord white matter is divided into columns:
The dorsal columns carry mechanosensory information that is
ascending to the brainstem and cerebral cortex.
The ventral columns include both the anterolateral tract, which
carries ascending information about temperature and pain and
several descending motor pathways in the medial-ventral zone.
The lateral columns include the main descending pathways that
control voluntary movement (the corticospinal tract), as well as the
spinocerebellar tracts that send unconscious proprioceptive
information to the cerebellum.
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Spinal cord levels Spinal cord levels
As you ascend the spinal
cord, the proportion of
gray matter decreases gray matter decreases
and the proportion of
white matter increases.
Rostral levels include
sensory and motor tracts
connecting to the caudal
spinal cord.
22
Note lumbar and
cervical enlargements,
innervating the arms (C5 -
T1) and legs (L1 - S2/S3),
respectively.
(Purves A5)
Spinal Spinal
segments segments
S i l i l d Spinal spinal cord
segments are named
for the vertebral level at
which their nerves exit
the column.
31 spinal nerves:
8 cervical
23
8 cervical
12 thoracic
5 lumbar
5 sacral
1 coccygeal
(Purves A2)
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S i l t ti b d f i l th h th Spinal segmentation based on emergence of spinal nerves through the
intervertebral foramina.
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Dermatome defined as the area of skin innervated by dorsal root of a single spinal
segment.
Useful for localizing injury:
For example, sensory changes in distal forearm plus fifth finger indicates
injury to C8 and T1 dorsal roots.
Dermatomal boundaries are not as precise as these maps portray:
There is a lot of overlap among the nerves originating from adjacent dorsal
roots, such that injury to one dorsal root does not completely abolish
sensation in the associated body region.
There is also a great deal of inter-individual variability.
Dermatomes to know:
C2: back of head C6: lateral hand (thumb)
C7: middle finger C8: medial hand (pinkie)
T4: nipples T10: umbilicus
L4: kneecap S1: lateral foot
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Shingles (herpes zoster) Shingles (herpes zoster)
Shingles cases have been
useful for mapping
dermatomes: dermatomes:
Reactivation of dormant
herpes zoster (chicken pox)
virus in one dorsal root
ganglion which produces a
painful rash limited to one
dermatome.
26
This case involved the
ophthalmic division of the
trigeminal nerve (V
1
).
Haines textbook, Fig. 18.5.
Spinal Spinal
gray gray
matter matter
laminae laminae
27
Known as Rexed laminae for the Swedish anatomist who described them:
Dorsal horn = Layers I-VI
Ventral horn = Layers VII-IX
In general, thinner fibers (Ao and C) terminate in the most dorsal layers
(I, II, V) while thicker fibers (Ao and A|) synapse more ventrally (III-IX).
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Segregation of primary afferents Segregation of primary afferents
28
(Haines (textbook), 17.5)
Spinal cord: afferent somatotopy Spinal cord: afferent somatotopy
(Brodal 7.16)
29
(crude)
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Spinal cord injury Spinal cord injury
Understanding the different pathways of fine touch/vibration vs.
pain/temperature sensation is essential for diagnosing spinal cord
disease.
Three issues to discern based on sensory symptoms: Three issues to discern based on sensory symptoms:
1. Level: Which body parts are affected? Generally speaking,
loss of sensation will be at and below the level of the lesion.
2. Modality: Are discriminative touch and pain/temperature
equally affected? (indicates which pathways are involved)
3. Laterality: Which side of the body is affected? Unilateral
symptoms indicate unilateral damage, bilateral symptoms
i di t bil t l d ( l d lit diff h id )
30
indicate bilateral damage (unless modality differs on each side).
Lesion of dorsal columns results in chronic ipsilateral loss of tactile
discrimination, position sense, vibration sense, and object movement
perception.
Lesion of spinothalamic tract results in loss of pain and temperature
sensation on contralateral side (below the lesion).
Tabes dorsalis Tabes dorsalis
Lesion of the posterior spinal
cord resulting from tertiary
neurosyphilis.
Begins with dorsal root
degeneration, causing pain
and paresthesias: abnormal
sensations.
As degeneration spreads to dorsal columns, patients lose tactile
discrimination, position, and vibration sense below the level of the
lesion Loss of proprioception results in gait ataxia and hyporeflexia
31
lesion. Loss of proprioception results in gait ataxia and hyporeflexia.
Dorsal root degeneration also produces incontinence.
Similar syndrome can result from Vitamin B
12
deficiency, or from
traumatic injury, tumors, or multiple sclerosis affecting the same
region of the spinal cord. The general term for this set of clinical
findings is posterior cord syndrome.
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Sensory ataxia Sensory ataxia
Patient can stand unsupported
only with feet far apart and gaze
directed downward.
Gait is broad-based, with a
stamping action that ma imi es stamping action that maximizes
any residual conscious
proprioception.
Rombergs sign usually present
as well.
32 http://www.neuroexam.com/content.php?p=37
Ascending Ascending
projection projection
See also Sylvius See also Sylvius,
animated pathways
33
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First-order neurons are the receptors: cell body in DRG and
relay synapse in the dorsal column nuclei of the medulla: gracile relay synapse in the dorsal column nuclei of the medulla: gracile
& cuneate nuclei.
Second-order neurons in gracile & cuneate nuclei, cross the
midline of the medulla as the internal arcuate fibers, ascend as
the medial lemniscus, and synapse in the VPL of the thalamus.
Third-order neurons from VPL project through the posterior limb
of the internal capsule, to synapse in the primary somatosensory
cortex (S1), located in post-central gyrus.
Note the somatotopy.
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Pain and temperature information ascend in the spinothalamic
pathway of the anterolateral tract pathway of the anterolateral tract.
First-order neurons are the nociceptors and thermoreceptors:
cell body in DRG and synapse in the dorsal horn.
Second-order or, projection neurons, cross the midline
immediately, in the anterior white commissure, and then ascend
to the thalamus, where they synapse in VPL.
Third-order neurons project from VPL, through the posterior limb
of the internal capsule, to synapse in S1.
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Innervation of the face Innervation of the face
C3 dermatome innervates the neck.
C2 dermatome innervates posterior jaw and the
back of the head.
There is no dorsal root at C1.
Sensation in the face and top of the head carried
by 3 branches of the trigeminal nerve (three
twins; cranial nerve V):
I. Ophthalmic
II. Maxillary
III. Mandibular
(Blumenfeld 12 7))
36
(Blumenfeld 12.7))
Neurologic Exam, CN V sensory tests:
Test sensation over each branch using cotton wisp and pinprick; dermatomes
are more reliable over the center of the face, so test medial brow, nose & chin
before proceeding to lateral zones.
V1 carries afferent limb of corneal reflex (efferent = CN VII)
V3 carries afferent limb of jaw jerk reflex (efferent = motor branch of V)
Testing trigeminal sensation (#36) Testing trigeminal sensation (#36)
37
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CN V is the foremost sensory nerve of the face (but it also has a small efferent role).
Most trigeminal afferents have their cell bodies in the semilunar (also known as the
trigeminal) ganglion, which is analogous to the dorsal root ganglia that innervate the trigeminal) ganglion, which is analogous to the dorsal root ganglia that innervate the
lower body. One exception are proprioceptors (muscle spindles) that innervate the jaw
and some periodontal ligaments. These afferents are unusual in that their cell bodies sit
inside the midbrain, in the mesencephalic trigeminal nucleus.
The three sensory nuclei that receive fibers from CN5 are (in caudal-to-rostal order):
The long spinal trigeminal nucleus, where smaller fibers (Ao and C) involved in
pain and temperature form their synapses This nucleus which extends from the pain and temperature form their synapses. This nucleus, which extends from the
pons to C2, also receives some general sensory afferent (GSA) input from Cranial
Nerves VII, IX, and X.
The main or principal nucleus, located in the pons, where low-threshold
mechanoreceptors (A|) synapse. This is the primary nucleus involved in
processing discriminative touch from the face, including oral stereognosis (detecting
the property of objects in the mouth, such as food textures).
The mesencephalic nucleus, which contains the cell bodies of primary
proprioceptive afferents from the jaw and periodontal ligaments. These afferents
send their central projections to many targets, including the trigeminal motor
nucleus, where they form monosynaptic connections onto motor neurons involved
in the jaw jerk reflex.
Together, the three sensory nuclei are known as the nucleus of the spinal tract, which g , y p ,
constitutes the largest cranial nucleus and extends all the way from the midbrain to C2.
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From their respective trigeminal nuclei, both pathways send second- g y
order trigeminothalamic fibers across the midline to synapse in the
ventroposterior medial (VPM) nucleus of the thalamus.
Some texts use the term trigeminal leminscus to refer to the tract
carrying discriminative touch between the principal trigeminal nucleus
and VPM (by analogy to the medial lemniscus).
T i i th l i fib f th i l t i i l l Trigeminothalamic fibers from the spinal trigeminal nucleus carry
information about pain and temperature in the face.
From a strictly anatomical perspective, there are two trigeminothalamic
tracts, only one of which (the ventral trigeminothalamic tract) crosses the
midline. A smaller tract, the dorsal trigeminothalamic tract, projects
ipsilaterally from the main trigeminal nucleus to the ipsilateral VPM. You
are not responsible for knowing or identifying two pathways and should are not responsible for knowing or identifying two pathways, and should
regard the trigeminothalamic tract as primarily crossed.
211
212
Somatosensory Somatosensory System System Somatosensory Somatosensory System System
Part II: Cortex Part II: Cortex
Lise Eliot, PhD March 21, 2013
Lecture Topics:
I t d ti t th l d ti l t t Introduction to thalamus and cortical structure
Location and divisions of somatosensory cortex
Somatotopy Somatotopy
Cortical circuitry (input, output, and local processing)
Receptive fields & tactile perception
Assessing cortical somatosensory functions and lesions
Related reading: Purves, pp. 202-207, 588-89
What is cortex? What is cortex?
Thin outer layer of the
cerebral hemispheres cerebral hemispheres
Sheet of neuronal cell
bodies plus associated p
white matter
Neurons arranged in
layers (laminae)
Nissl-stained coronal
ti f k section of monkey
brain highlights the
difference between
laminar (cortex) and
nuclear (basal ganglia)
components of the
2
(Kandel 17.13)
components of the
cerebral hemispheres.
Phylogenetic Phylogenetic
ii
(Purves p. 590)
categories categories
Neocortex (new) comprising
some 90% of the human
b l h i h cerebral hemispheres:
Six distinct layers
2-4 mm in thickness 2 4 mm in thickness
10-20 billion neurons
Allocortex (other)
phylogenetically older:
Paleocortex (ancient) -
olfactory bulb and cortices & olfactory bulb and cortices &
some parahippocampal gyrus
Archicortex (old) -
hippocampus
3
hippocampus
3-4 distinct cell layers
Brodmanns Brodmanns areas areas
(Purves 26.2b)
German anatomist divided cortex
into 52 distinct regions based on
c to architect ral differences cyto-architectural differences.
Different histology corresponds to
different functions:
Sensory cortices have prominent
granule layers (esp. layer IV)
Motor cortices have meager g
layer IV, but prominent output
layer (V)
Association areas more
balanced
Primary somatosensory cortex:
Areas 3 1 & 2 extend from the Areas 3,1 & 2 extend from the
dorsal midline (longitudinal
fissure) down to the lateral
fissure.
4
Sometimes referred to as the
somatosensory strip.
2
1
3
Golgi Nissl Weigert
I
Neocortical layers Neocortical layers
I
II
Layer 1: Molecular (Plexiform)
Axons and dendrites of neurons in
III
Axons and dendrites of neurons in
deeper layers or other cortical
areas, but very few cell bodies
IV
Layer 2: External Granular
Small neurons (granule cells)
Layer 3: External Pyramidal
V
V
Layer 3: External Pyramidal
Smaller pyramidal cells
Layer 4: Internal Granular y
Granule cells, stellate cells and
other interneurons
L 5 I t l P id l
VI
Layer 5: Internal Pyramidal
Larger pyramidal cells
Layer 6: Multiform (Polymorphic) Layer 6: Multiform (Polymorphic)
Mixed cell population; blends into
white matter
Cell Categories Cell Categories
(Kandel 17.11)
Glial Neuron vs.
Projection
(pyramidal, Glu)
Interneuron
(non-pyramidal)
vs.
Excitatory
(Glutamate;
t ll t
Inhibitory
(GABA; e.g.
b k t ll )
vs.
e.g., stellate
cells)
basket cells)
6
SNP = spiny non-pyramidal, or stellate neuron
Input & output Input & output
Layer 1: Local cortical Layer 1: Local cortical
(horizontal) connections
Layer 2: Mixed input/output y p p
Layer 3: Longer-distance
cortico-cortico connections
Layer 4: Main input from
thalamus
Layer 5: Main subcortical
output (spinal cord,
brainstem basal ganglia) brainstem, basal ganglia)
Layer 6: Main output to
thalamus
7 (Siegel 26-4)
SS pathways SS pathways
First-order neurons are the
receptors: cell body in DRG receptors: cell body in DRG
and relay synapse in the
dorsal horn (anterolateral) or
dorsal column nuclei of the dorsal column nuclei of the
medulla (DC/ML system).
Second-order neurons Second order neurons
cross the midline (in spinal
cord, for anterolateral
system or medulla for system, or medulla, for
DC/ML system) and
synapse in the VPL nucleus
f th th l of the thalamus.
Third-order neurons project
to layer IV of primary
8
to layer IV of primary
somatosensory cortex (S1),
in the post-central gyrus.
2
1
4
Thalamus Thalamus
(Brodal 7.20; see also Purves 9.10)
Also known as the dorsal thalamus
Relays input from all the senses (except olfaction).
Like the cerebral cortex, the posterior thalamus is involved in sensation, the
anterior portion in motor & limbic function.
9
Sensory information from the body is relayed through the ventral (V) and posterior
(P) tier of its lateral (L) portion (=VPL). Sensory input from the face is relayed
through the medial zone of this ventro-posterior area (VPM).
Major thalamic nuclei Major thalamic nuclei
(b k k f f t f ) (bookmark for future reference)
Nucleus Major input Major output Function
Ventral posterior lateral
(VPL)
Medial lemniscus,
anterolateral tract
Primary somatosensory
cortex
Touch, position sense,
pain & temperature
Ventral posterior medial
(VPM)
Trigeminothalamic tract,
t l lit l
Primary somatosensory
t t t t
Touch, position, pain &
t t f f (VPM) rostral solitary nucleus cortex, gustatory cortex
(frontal operculum & insula)
temperature from face;
taste
Intralaminar Reticular formation, spinal
cord, hypothalamus
Limbic cortex & basal
ganglia
Arousal, motivation, affect
, yp g g
Lateral geniculate (LGN) Retina (optic tract) Primary visual cortex Vision
Medial geniculate (MGN) Inferior colliculus Primary auditory cortex Hearing
Pulvinar Superior colliculus,
extrastriate visual areas
Parietal, occipital, temporal
association areas
Sensory integration,
visual attention
Ventral anterior (VA) Basal ganglia (Gpi, SNr) Motorr premotor & diffuse Motor planning
Ventral lateral (VL) Cerebellum Motor & premotor cortex Motor planning & control
Anterior Hypothalamus &
hippocampus
Cingulate gyrus Learning, memory,
emotions
10
pp p
Medial dorsal Amygdala, olfactory cortex,
limbic basal ganglia
Prefrontal association areas Emotions, cognition and
learning
Corona radiata Corona radiata
(Carpenter 2.10)
11
Haines Haines Bonus D4 Bonus D4
lenticular
12
nucleus
2
1
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Primary somatosensory cortex (SI) lies in the postcentral gyrus and
includes Brodmanns areas 3a, 3b, 1, 2.
Evidence that SI is primary somatosensory cortex:
1. Receives dense input from area VP of thalamus.
2. Neurons are highly responsive to somatosensory stimuli, but
not to other sensory stimuli (low threshold, short latency).
3. Lesions abolish tactile discrimination (but not pain) in specific
body regions.
4. Electrical stimulation produces tingling or illusion of touch.
Secondary somatosensory cortex (SII) lies lateral and inferior to SI,
extending to the insular cortex and forming the superior bank of the
lateral sulcus. (For a better view of SII, see slide titled Cortical
circuitry.)
Posterior parietal cortex lies within the superior parietal lobule and is
composed of Brodmanns areas 5 and 7.
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Cortical Cortical
layers layers
Somatosensory cortex,
like all neocortex
(Kandel 23.6)
like all neocortex,
composed of 6
histologically distinct
layers of neurons.
Dendrites and axons of
principal neurons extend
through all layers of gray
matter; basis of
columnar organization
14
columnar organization.
Thalamic input synapses
on layer IV stellate
neurons.
Subcortical output from
layer V pyramidal
neurons.
Columnar Columnar
organization organization
(Siegel 26-11)
Within a column, all neurons
respond to same modality and
receptive field.
Cutaneous mechanoreceptor
input enters cortex in area 3b,
which further subdivides
16
columns by modality: slow
(e.g., Merkel) vs. rapidly-
adapting (Meissners.)
Note somatotopy of digits 1-3.
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Scalp electrodes capture summated post-synaptic potentials in the cortex,
f mainly from vertically-oriented large pyramidal cells whose tight clustering
facilitates spatial summation of the currents at the cortical surface.
Note the voltage deflection captured by the EEG electrodes. By convention:
upward deflections represent negative potentials when recording near
the synapse (current flow inward)
downward deflections represent positive potentials (when current flow
is outward because it is some distance from layer IV synapses).
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Most cortical mapping has been done by scientists using experimental ost co t ca app g as bee do e by sc e t sts us g e pe e ta
animals, although neurosurgeons also stimulate precise areas to identify
functional zones before removing tissue during brain surgery.
In this illustration, single-cell, or single-unit recording is used to map
sensory cortical areas that respond to stimulation of precise body sites.
By varying the type of stimulus, researchers can map not only receptive
fields b t also the precise modalit (e g lo threshold high threshold fields, but also the precise modality (e.g., low-threshold, high-threshold,
slowly-adapting, rapidly-adapting) that excites individual cortical neurons.
This example also illustrates the surround inhibition that is
characteristic of receptive fields in most sensory modalities: while
stimulation of the center of the field (light green area) triggers a robust
burst of spikes in this cortical neuron, stimulation of the surrounding zone p g
(dark green area) actually inhibits its firing, indicating that the afferent
input is shaped by inhibition from neighboring sensory neurons. (See
lateral inhibition slide in Somatosensory I lecture.)
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SI (as well as later cortical sites) contains a full map of the body, known as the
sensory homonculus:
Think of an acrobat with straight legs, bent over from the hip with arms dangling
down. Note, however, that the map is discontinuous between the hands and
fforehead.
The map is highly distorted: about 100X as much cortical area is devoted to one
square centimeter on the fingers as compared to the abdomen.
Distortion reflects differences in receptor density in different parts of body, but it is
also influenced by experiencea result of use-dependent plasticity.
Evidence for homonculus:
Stimulation of SI or SII during surgery produces itching, tingling,
numbness, etc. in specific region.
Also, Jacksonian seizures commonly involve tingling sensation that
migrates from one body part to another according to its position on the
somatosensory strip.
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Mouse Mouse-- monculus monculus
19
(Bear 12.20)
Cortical Cortical
circuitry circuitry
VPL/M of thalamus
connects mainly to
(Kandel 23-10)
Brodmanns area 3, with
minor projections to 1 & 2.
Different modalities enter
cortex at distinct points in
area 3.
Primary processing is in 3-
1-2 order, followed by
20
separate, parallel
projections to SII & area 5.
Receptive fields increase
in size as you move from
areas
3 1 2 5 7
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The somatosensory cortex is widely connected to other cortical and
subcortical brain areas contributing to the control of movement sensory subcortical brain areas, contributing to the control of movement, sensory
integration, and tactile memory. (Only some of these outputs are indicated
in the diagram.)
SI has extensive bidirectional connections with primary motor cortex,
contributing to the control of movement.
Descending fibers from somatosensory fields (not shown) actually
t b di fib ! E th id l t t ll outnumber ascending fibers! Even the pyramidal tract, generally
thought of as a motor pathway, is composed of a large minority of fibers
from somatosensory areas (esp. 3a). These descending pathways
presumably play a role in sensory filtering in the thalamus, brainstem,
and spinal cord.
Posterior parietal cortex: Area 5 (unimodal association cortex)
integrates mechanoreceptor and proprioceptive inputs to guide teg ates ec a o ecepto a d p op ocept e puts to gu de
movements. Area 7 (multimodal association cortex) integrates
somatosensory input with visual and auditory information to control
movement and spatial perception.
SII projects to the insula (located on previous slide), which in turn
sends fibers to the medial temporal lobe (amygdala and hippocampus);
this pathway is important for tactile memory and the emotional
i f t h d i experience of touch and pain.
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Tactile perception Tactile perception
Perception is a product of the entire population, not of
single neurons. At any instant, tactile awareness involves
i th fi i tt f ll th i comparing the firing pattern of all the neurons in
somatosensory cortex. (Analogous to visual perception,
where the brain takes individual pixels and converts
them into meaningful image perception.)
As you progress from 3-1-2-5-7, neurons respond to
progressively more abstract properties of a stimulus. So
while area 3 neurons respond to the precise location and
22
while area 3 neurons respond to the precise location and
modality of a stimulus, area 5 neurons begin integrating
tactile and proprioceptive information (which feeds into
motor planning centers), while area 7 neurons integrate
touch and vision to give a multi-sensory perception of
objects and to hand-eye coordination.
Integration Integration
No single receptor
signals all of the
ti f bj t
(Blumenfeld, p. 72)
properties of an object.
The actual perception
of objects in the hand
(stereognosis)
requires integration of
many receptors, and
testing stereognosis (#75)
23
takes place in cortex.
Haptics refers to the active exploration of objects through
touch. Involves the complex spatiotemporal pattern of
activity among many mechanoreceptors, as well as the
dynamic interaction between sensation and movement.
g g ( )
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Lesions of Lesions of somatosensory somatosensory cortex cortex
Depending on size, lesions in the anterior parietal cortex (i.e., SI or BA
3-1-2) can produce major contralateral deficits in all primary modalities:
joint position, 2-point discrimination, localized pain, temperature and
vibration and in complex recognition, such as stereognosis & visual-
tactile matching Such lesions may also distort hand movements tactile matching. Such lesions may also distort hand movements.
Affects all primary modalities, unlike lesion to dorsal columns/medial
lemniscus or anterolateral system.
Subregions of the body may be affected depending on the size and
cause of the lesion (e.g., leg alone, or face and upper extremity).
Associated deficits may include motor weakness, visual field deficits,
or aphasia, if adjacent cortical areas are affected.
24
p j
Isolated lesions in the posterior parietal cortex (areas 5 & 7; superior
parietal lobule) can produce more selective impairment of complex tactile
recognition. This pattern is called cortical sensory loss, and is
characterized by the relative sparing of primary modalities but difficulty
with tactile extinction on double stimultaneous stimulation, along with
astereognosis and agraphesthesia.
Other tests for cortical sensory loss Other tests for cortical sensory loss
Graphesthesia (#76): Tactile extinction (#77):
25
Patients eyes are closed, and
he/she is asked to identify
letters or numbers traced on
the palm or fingertip.
(Blumenfeld, p. 72)
If primary sensation is normal,
patient is touched simultaneously in
same spot on both sides of body
(with eyes closed). Inability to
detect stimulus on one side indicates
contralateral parietal lesion.
224
P i P i Pain Pain
Lise Eliot, PhD
March 22, 2013 ,
Related reading: Purves Chapter 10 (except Box C)
Lecture outline Lecture outline
Definition of pain and its clinical significance
Nociceptor and thermoreceptor properties
D l h l i Dorsal horn laminae
Referred pain p
Anterolateral and trigeminal pathways
Cortical pain processing
Hyperalgesia (sensitization) Hyperalgesia (sensitization)
Endogenous analgesia: Gate Control Theory
d t l d l ti i i t th
2
and central modulation via opiate pathways
Pain Pain
Clinically most important somatosensory modality
In most cases, a normal physiological response
that warns of injury or potential injury
Varies in duration:
Acute (minutes to hours) cute ( utes to ou s)
pin prick, paper cut
Prolonged or subacute (days to weeks) g ( y )
sunburn, sprain, backache
Chronic (> 3 months)
nerve damage, tumor growth, or other cause of pathologic,
disordered pain response
I hi hl bj ti
3
Is highly subjective
Pain severity Pain severity
To quantify the subjective experience, clinicians can ask patients to rank
their pain using scales on the right, for adults (top) and children (bottom).
4
Chronic pain is very common Chronic pain is very common p y p y
The World Health
Organization similarly
i h estimates the
worldwide prevalence
of chronic pain of chronic pain
between 20-30%.
5
Pain does not equal nociception Pain does not equal nociception
Nociception refers to the physiological detection of Nociception refers to the physiological detection of
noxious (damaging or potentially so) stimuli.
Pain is a psychological term: an unpleasant sensory p y g p y
and emotional experience.
Affective and cognitive factors (motivation, anxiety,
attention, and memory) modulate nociception.
Can have pain without nociceptor activation:
Neuropathic pain results from direct injury to CNS or
peripheral nerves (not necessarily nociceptors): e.g.,
phantom limb deafferentation thalamic pain and most phantom limb, deafferentation, thalamic pain, and most
commonly, neuralgia, which is an intense burning, shooting
or stabbing pain caused by irritation or damage to a nerve.
6
If a patient says s/hes in pain, it really hurts!
225
Nociceptors (and thermoreceptors) have no specialized endings--they are not
encapsulated.
Nociceptors are found at all levels of the skin and in all kinds of tissue (skin,
muscle, joints, internal organs, bone, blood vessels, heart), with the notable
exception of the brain itself.
Under normal circumstances, only nociceptors can cause a sensation of
pain. Stimuli that are below the threshold for nociceptor activation will not be
perceived as painful.
Nociceptors have larger receptive fields than low-threshold mechanoreceptors,
since the detection of pain is more important than its precise localization.
226
Types of nociceptors Types of nociceptors
1. High-threshold mechanoreceptors:
fast sharp pain fast, sharp pain
Ao fibers
(All other mechanoreceptorsMeissner, Merkel, ( p , ,
Pacinian, Ruffini & hair follicleare considered low
threshold by comparison)
Immediately-
2. Thermal nociceptors:
> 43
o
C = noxious heat (Ao fibers)
Immediately-
dangerous pain
(sharp and heat)
carried by
> 43
o
C = noxious heat (Ao fibers)
< 5
o
C = noxious cold (C fibers)
carried by
faster fibers.
3. Polymodal receptors (respond to inflammation):
temperature, chemical, and intense mechanical stimuli
8
slow burning pain
carried by C fibers
(Kandel 24.1; see
also Purves 10.2)
Nociception Nociception is slow is slow
Fast pain (sharp, prickly)
transmitted by high-threshold transmitted by high-threshold
mechanoreceptors (Ao fibers).
Slow pain (intense burning) Slow pain (intense, burning)
transmitted by polymodal C
fibers.
Part A shows that both pain
pathways are about an order of
it d l th l magnitude slower than low-
threshold mechanoreceptors
(A|) and proprioceptors (Ao). ( |) p p p ( )
Part B shows that you can
selectively block each type of
9
y yp
pain fiber with certain
anesthetics.
Primary afferent categories Primary afferent categories y g y g
10
Temperature perception Temperature perception
Four types of thermoreceptors:
Cold (nociceptor) fires at
temperatures below 5
o
C,
producing perception of producing perception of
cold pain.
Cool fires when skin temperature
falls below normal (34
o
C), with
maximal firing around 25
o
.
Warm non nociceptive thermoreceptor a
t
e
Warm non-nociceptive thermoreceptor
(blue curve) fires in proportion to
the amount of elevation above
normal skin temperature
n
t

f
i
r
i
n
g

r
a
normal skin temperature.
Hot (nociceptor, black curve) fires
only above about 43
o
C, the
A
f
f
e
r
e
n
11
y
point at which most people
perceive heat pain.
(Purves 10.1)
2
2
7
Between the two nociceptive extremes (5 to 43
o
C), ones overall sense of
t t i d d b th l ti ti it f d l t temperature is coded by the relative activity of warm and cool receptors.
For example, as the skin is cooled from 34
o
C to 25
o
C, warm receptors
reduce their firing rate, while cool receptors increase their firing rate. (This
is analogous to color perception, in which hue is encoded by the relative
firing rate of the three types of conesred, green, blue.)
Scientists have made great progress recently in identifying the ion channels
underlying temperature and pain perception One is the capsaicin underlying temperature and pain perception. One is the capsaicin
receptor (TRPV1), which is activated both by heat or by this ingredient from
hot chili peppers (which is why spicy foods feel hot in the mouth). Another
is the menthol receptor (TRPM8) which is activated by low temperatures
and chemicals such as menthol (which is perceived as cool). Yet another
channel, TRPV2, is expressed predominantly in Ao terminals and is
activated by very high temperatures.
In addition to the TRP family, nociceptor endings express a special, TTX-
insensitive sodium channel known as Nav1.7. Mutations in this channel
can make individuals insensitive to pain, a surprisingly dangerous
congenital condition.
As our understanding of nociceptive receptors evolves, such findings
promise to augment our arsenal of analgesics, which is still woefully
inadequate to treat pain in many patients.
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Dr. Lise Eliot
Spinal cord Spinal cord laminae laminae
Ao and C fibers enter the
dorsolateral tract or, zone of
Lissauer (white matter dorsal
to the dorsal horn) where they
ascend or descend for 1-2
segments before entering the
dorsal horn.
Unlike Ao and A| fibers,
which project directly to the
medulla, Ao and C fibers
i th d l h
13
synapse in the dorsal horn
onto 2nd order, projection
neurons.
C fibers synapse in layers I
(marginal zone) and II
(substantia gelatinosa). Ao
fibers synapse in layers I & V.
Projection fibers cross immediately Projection fibers cross immediately
14
Whats wrong with this picture?
229
Visceral pain is typically caused by inflammation and associated with other
discomfort (e.g., nausea, bloating).
Compared to somatic afferents visceral afferents constitute less than 10% of Compared to somatic afferents, visceral afferents constitute less than 10% of
total sensory input to the spinal cord, so visceral pain is not well-localized
and is commonly referred or confused with somatic pain.
The most common clinical example is angina: pain arising from heart muscle
that is not adequately perfused with blood. Referred to upper chest wall, with
radiation into left arm and hand.
Furthermore, visceral pain is transmitted by dorsal horn projection neurons , p y p j
(spinothalamic neurons) that also receive input regarding cutaneous pain.
(See next slide.) So its transmission is somewhat scrambled.
When a visceral pain is felt for the first time (such as a heart attack or kidney
stone), it is often interpreted as the more familiar sensation from skin or
musculoskeletal areas.
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Dr. Lise Eliot
Referred pain, contd. Referred pain, contd.
(Kandel 24.3)
16
Spinal cord Spinal cord
(Brodal 7.16)
17
(crude)
231
Pain and temperature information ascend in the spinothalamic
pathway of the anterolateral tract pathway of the anterolateral tract.
First-order neurons are the nociceptors and thermoreceptors:
cell body in DRG and synapse in the dorsal horn.
Second-order or, projection neurons, cross the midline
immediately, in the anterior white commissure, and then ascend
to the thalamus, where they synapse in VPL.
Third-order neurons project from VPL, through the posterior limb
of the internal capsule, to synapse in S1.
232
Pattern of dissociated sensory loss following spinal cord y g p
hemisection. In this example, it is at the left T10 spinal cord level.
Lose ipsilateral discriminative touch, but contralateral pain and
temperature sensation below the level of lesion.
There may also be a small wedge of complete ipsilateral sensory
loss at the level of the lesion, due to damage of the dorsal root.
Motor sign: weakness throughout left leg, due to lesion of left g g g,
corticospinal tract. This is the most obvious deficit to both patient
and examiner.
233
Face pain Face pain
(Brodal 16.20)
Pain and temperature Pain and temperature
afferents (Ao and C
fibers) from the face
enter the brainstem
through cranial
nerves V VII IX and nerves V, VII, IX, and
X, and descend in the
spinal trigeminal tract
to synapse in the
long spinal trigeminal
nucleus (which nucleus (which
extends from the
pons to C2).
20
Trigeminal neuralgia Trigeminal neuralgia g g g g
(tic (tic douloureux douloureux) )
Recurrent bouts of sharp, stabbing pain in
one or more branches of trigeminal nerve g
(usually maxillary or mandibular) on one
side of the face.
S h b l l t ti Such abnormal, unpleasant sensations
are known as dysesthesia or paresthesia
(burning, prickling, pins-and-needles).
Also see allodynia: unpleasant hypersensitivity to non-noxious stimuli
such as shaving, talking, or chewing.
More common after 50 years of age and in women.
May be caused by vascular compression of CN V.
21
Treated with anticonvulsant drugs such as carbamazepine or baclofen,
other agents and, if necessary, surgery.
Trigeminal Trigeminal gg
pain pain
th th pathway pathway
22
Medulla Medulla Medulla Medulla
Spinal trigeminal tract
and nucleus
Spinothalamic tract
Inferior olive
Medial lemniscus
23
2
3
4
Occlusion of PICA (or a smaller branch ) causes Wallenbergs syndrome a Occlusion of PICA (or a smaller branch ) causes Wallenberg s syndrome, a
complex set of deficits also known as Lateral Medullary syndrome. Signs include:
Contralateral loss of pain and temperature in body due to damage to 2
nd
order spinothalamic fibers in anterolateral system.
Ipsilateral loss of pain and temperature in face due to damage to primary
nociceptors in the spinal trigeminal nucleus and tract (2
nd
order pathway
decussates further caudally).
Di i i ti t h i t ff t d b di l l i i i t t Discriminative touch is not affected because medial lemniscus is intact.
Other deficits (dizziness, nystagmus, ataxia, hoarseness, difficulty
swallowing, loss of ipsilateral gag reflex) due to damage to vestibular nuclei,
inferior cerebellar peduncle, and nucleus ambiguus (motor nucleus of CNs
IX, X, XI).
Ipsilateral loss of taste, because of damage to solitary nucleus & tract.
Ipsilateral Horners syndrome (ptosis, miosis & anhydrosis; Purves p. 531)
Note that the medulla is perfused by three arteries:
1. PICA -- dorsolaterally
2. Anterior spinal artery -- medial
3. Vertebral artery -- territory in between
235
In addition to the primary spinothalamic (or, neospinothalamic)
tract, which terminates in VPL/M and mediates the discriminative tract, which terminates in VPL/M and mediates the discriminative
aspects of pain (e.g., location and intensity of a stimulus), the
anterolateral system carries several other projections responsible
for the more emotional (affective and arousal) experience of pain:
A paleospinothalamic tract, which terminates in the
midline and intralaminar thalamic nuclei. Unlike VPL/M
projections, which are somatotopically organized, the projections, which are somatotopically organized, the
intralaminar nuclei project diffusely to large areas of the
cerebral cortex.
A spinoreticular tract, which projects to the medullary-
pontine reticular formation, the brainstem arousal network
that coordinates emotional and autonomic responses in
both the brain and spinal cord. p
A spinomesencephalic tract, which terminates in both the
periaqueductal gray (PAG) and the parabrachial nucleus
of the midbrain. The PAG coordinates endogenous pain
control, and the parabrachial nucleus relays both ascending
pain information (to the amygdala and hypothalamus) and
descending pain control. g p
236
Thalamus Thalamus
(Brodal 7.20)
Thespinothalamic
tract and medial tractandmedial
lemniscus each
formsitsown
somatotopic map somatotopic map
inVPL.
However,the
thalamic
terminationofthe
anterolateral tract
ismoreextensive
thanthatofthe
medial lemniscus: mediallemniscus:
Toafirstapproximation, fast,sharp,welllocalizedpain (fromAo fibers)is
processedbyVPLandVPM.
26
Slower,dull,poorlylocalizedpain (Cfibers)iscarriedbyseparatespinothalamic
fiberswhichterminateinmidlineandintralaminar nuclei.
Cortical processing Cortical processing
Sharp, localized pain projected
in parallel with fine touch &
Affective & motivational aspects of pain
processed by the pain matrix, including:
proprioception.
Ascends from VPM & VPL
through the posterior limb of the
The anterior cingulate cortex, which
is part of the limbic system. fMRI
shows a strong correlation between
g p
internal capsule, entering S1 still
segregated from other
modalities.
anterior cingulate activity and
subjects subjective experience
(unpleasantness) of pain.
However, ablating S1 does not
abolish pain sensation, because
of parallel processing by several
The insular cortex, which integrates
the sensory, affective and cognitive
aspects of pain. Insular lesions
p p g y
other cortical sites.
produce asymbolia for pain, in which
patients can detect pain but are not
emotionally bothered by it.
The amygdala and hypothalamus,
which orchestrate autonomic
responses (fight or flight), participate
ACC
Ant.
I l
28
( g g )
in learning, and are central to all
emotional processing.
Insula
Pain perception is plastic Pain perception is plastic
Theperceptionofpaindoesnotsimplyinvolvea
momenttomomentanalysisofafferentnoxious
input,butratherinvolvesadynamicprocessthat
isinfluencedbytheeffectsofpastexperiences.
Sensorystimuliactonneuralsystemsthathave
beenmodifiedbypastinputs,andthebehavioral y p p ,
outputissignificantlyinfluencedbythememory
ofthesepriorevents.
Melzack etal.(2001),AnnalsoftheNYAcademyof
Sciences 933:15774
29
Sciences,933:157 74.
Hyperalgesia Hyperalgesia
Severeandpersistentinjury,whichcausesprolonged
activationofnociceptors,tendstosensitize them,
loweringtheirthresholdforexcitation.
Thisformofsensitizationisknownashyperalgesia: yp g
tissuethatisalreadydamaged(e.g.,bysunburn)is
muchmoresensitivetopain,providingaprotective
mechanismtoaidhealing.
Bothcentralandperipheralchangesinnociceptive p p g p
pathwaysareinvolved.
Explains why premedication is especially effective for
30
Explainswhypremedicationisespeciallyeffectivefor
blockingpostsurgicalpain.
2
3
7
Tissue damage sensitizes nociceptors by releasing an inflammatory soup
of chemicals (including bradykinin, serotonin, H
+
, prostaglandins,
nucleotides, NGF, and cytokines such as interleukin-1| and tumor necrosis
factor o [TNFo]) that potentiate TRPV1 (vanilloid) receptors and other
molecular targets.
For example, prostaglandins reduce nociceptors threshold by potentiating
a particular class of sodium channels.
Nociceptors themselves contribute to this effect by releasing substance P
and CGRP (calcitonin-gene-related peptide). These peptide
neurotransmitters cause vasodilation (leading to edema and inflammation)
and histamine release from mast cells. Histamine and edema also lower
nociceptors threshold, so this response, known as the axon reflex, causes
further hyperalgesia. yp g
The purpose of the extra pain is to protect the wound and the inflammatory
response promotes healing by guarding against infection.
Steroids, aspirin, and other NSAIDs are a useful treatment for hyperalgesia
because they inhibit the COX (cyclooxygenase) enzymes required for
prostaglandin synthesis (both peripherally and within the dorsal horn).
238
Central sensitization Central sensitization
Inadditiontoperipheralchanges,strongorprolongedpainfulstimulican p p g , g p g p
leadtochangesinpainprocessingatspinalandsupraspinal levels.Such
centralsensitization involvesmanymechanismsincluding:
StrongactivationofCfibersleadstoanNMDAdependent,LTPlike
enhancement oftheirconnectionsontospinalinterneurons,
increasing the flow of pain information to higher centers increasingtheflowofpaininformationtohighercenters.
AlthoughinitiatedbyCfiberactivation,thispotentiation appearsto
generalize to inputs from low threshold (A|) mechanoreceptors, generalizetoinputsfromlowthreshold(A|)mechanoreceptors,
reorganizingsynapsessuchthatstimulithatusedtobeinnocuous
nowactivatesecondorderpainprojectionneurons,producing
ll d i ( h ti li lik li ht t h b allodynia (wherestimulilikealighttouchorbreezearenow
experiencedaspainful).
Changes in GABA and 5 HT neurotransmission have also been
32
ChangesinGABAand5HTneurotransmissionhavealsobeen
implicatedintheincreasedflowofpaininformationinhyperalgesia.
Neuropathic pain Neuropathic pain p p p p
Sensitizationisanormalresponsetotissuedamage,andtypicallywanesas
h i h l h h i h h ld l thetissueheals,suchthatpainthresholdsreturntonormal.
However,whenafferentfibersorcentralpainpathwaysthemselvesare
damaged or when other psychosocial factors come into play sensitization damaged,orwhenotherpsychosocialfactorscomeintoplay,sensitization
likeprocessescanpersist,causingneuropathicpain achronic,intensely
painfulexperience resistanttoconventionalanalgesics.
Commoncausesarediabetes,shingles(postherpeticneuralgia),backorhip
problems,AIDS,chemotherapy,multiplesclerosis&stroke.
Thepainisoftendescribedasconstantburning,interruptedbyepisodesof
shooting,stabbing,orelectricshock.
Such sensitization helps explain the paradox of peripheral neuropathy where Suchsensitizationhelpsexplaintheparadoxof peripheralneuropathy,where
patientsmayexperienceseverepaincombinedwiththemarkeddiminution
ofothersensorymodalities.
33
Treatmenttypicallyrequiresmorethananalgesic&antiinflammatorydrugs
(e.g.,anticonvulsantsorantidepressants).
Endogenous analgesia Endogenous analgesia
Analgesiaistheoppositeofhyperalgesia.
E d l i h i di id l Endogenousanalgesiaoccurswhenindividuals
perceptionofpainisprofoundlyreduced bycertain
circumstances such as the stress of battle childbirth etc circumstances,suchasthestressofbattle,childbirth,etc.
Nociceptive transmissioncanbeblockedbymechanisms
initiatedinthespinalcordandhighercenters:
Gatecontroltheory y
Endogenousopiateanalgesia
34
Gate control theory Gate control theory
Pain transmission in the spinal Pain transmission in the spinal
cord is influenced by other
afferents:
Non-pain, A| fibers (or vibration)
activate inhibitory neurons that
reduce neurotransmission from
C fibers, decreasing firing in
pain projection pathway.
Neural basis of TENS analgesia Neural basis of TENS analgesia
(transcutaneous electrical nerve
stimulation): weak current
selectively activates larger (non- y g (
nociceptive) fibers.
Explains why holding your toe
temporarily reduces the pain of
35
temporarily reduces the pain of
stubbing it.
(Purves 10.8)
Endogenous analgesia Endogenous analgesia
Exogenousopiates (morphine)longknowntorelievepain.
Discoveryofendogenousopiates (peptideneurotransmittersand
hormonesincludingtheenkephalins,endorphins,anddynorphins)
and their receptors suggested intrinsic mechanisms may block pain andtheirreceptorssuggestedintrinsicmechanismsmayblockpain
transmissionundercertaincircumstances.
Opiod receptorsarehighlyconcentratedinthedorsalhorn, the p p g y ,
midbrainperiaqueductal gray(PAG), andotherbrainstemsitesthat
projectdowntothedorsalhorn.Stimulationatanyofthesesites
produces profound analgesia producesprofoundanalgesia.
Placebo,acupuncture,andstressinducedanalgesiaareallblocked
by the opiate antagonist naloxone bytheopiateantagonist,naloxone.
Similarly,theanalgesiceffectsofmarijuanaledtothediscoveryof
endocannabinoids,neurotransmittersfoundinboththePAGand
36
,
dorsalhornthatsuppressactivityinnociceptive pathwaysby
bindingCB
1
receptors.
239
Placebo means: I will please.
A physiological response to a pharmacologically inert remedy. p y g p p g y y
In one study, two-thirds of medical students given a fake sedative reported
feeling sleepy; many experienced side-effects and only 3 out of 56 reported
no appreciable effect.
In another study, Parkinsons patients exhibited decreased firing in the
subthalamic nucleus and less rigidity after placebo treatment.
Placebo are nearly as effective as fluoxetine (Prozac) in treating depression: Placebo are nearly as effective as fluoxetine (Prozac) in treating depression:
normalizes activity in same brain areas.
Placebos are well-known to work for analgesia (e.g., post-surgical pain),
where the effect is blocked by naloxone. Expectancy activates endogenous
pain control circuitry.
Hidden placebos are less effective than open ones: patient must be
consciously aware of treatment (frontal lobe activation) for placebo to work.
fMRI shows decreased activity in the pain matrix, especially the anterior
insular cortex and rostral anterior cingulate (RACing). This figure shows PET
imaging of -opoid receptor activation following placebo administration in
young adult males, suggesting the decreased activity (and analgesic
experience) is due to opioid release at these sites.
Recent research finds that individuals with certain personality traits (resilient,
altruistic straightforward non hostile) experience a stronger placebo altruistic, straightforward, non-hostile) experience a stronger placebo
response than others. [Pecina et al. (2012), doi: 10.1038/NPP.2012.227]
See Purves pp. 247-48.
240
Endogenous analgesia is orchestrated by the PAG, which integrates ascending
pain input with descending sensory, affective, and motivational influences to gate,
as necessary, the flow of pain information. The PAG:
receives ascending sensory input from the spinomesencephalic tract.
receives descending input from the hypothalamus, amygdala, and
somatosensory cortex.
connects to the dorsal horn via several pathways, one synapsing in the
serotonergic nucleus raphe magnus, and the second involving
noradrenergic neurons in the locus coeruleus.
Both descending pathways activate enkephalin-containing inhibitory
interneurons in the dorsal horn that presynaptically inhibit transmission between interneurons in the dorsal horn that presynaptically inhibit transmission between
nociceptive afferents and their spinothalamic projection neurons.
The PAG apparently also coordinates ascending pain control (e.g., blocking
activation of the pain matrix) but this circuitry is not as well understood.
241
242
Medical Neuro Medical Neuro Medical Neuro Medical Neuro
CNS i f i M CNS i f i M CNS infections: Men CNS infections: Men
Michael Fenn
oscience Course oscience Course oscience Course oscience Course
i i i & E h li i i i i & E h li i ningitis & Encephalitis ningitis & Encephalitis
newald Ph.D.
2
4
3
Objectives for Objectives for Objectives for Objectives for
B bl di i i h Be able to distinguish m
and recognize overlappin
B bl t di ti i h b Be able to distinguish be
meningitis
Be able to interpret CSF Be able to interpret CSF
them with clinical sympt
Do not worry about the i Do not worry about the i
their mode of transmissi
r this session: r this session: r this session: r this session:
i i i f h li i eningitis from encephalitis
ng symptom of both
t b t i l d i l etween bacterial and viral
findings and correlate findings and correlate
toms and signs
individual organisms or individual organisms or
on
2
4
4
Some Some Some Some
Pleocytosis: increased WBCs(w
Meningitis: inflammation of me
membranes covering the brain
i f i ( h l i f infection (there are also non-inf
covered here)
E h liti i fl ti f t Encephalitis: inflammation of t
are also non-infectious causes n
Meningoencephalitis: both of th Meningoencephalitis: both of th
terms terms terms terms
white blood cells) in the CSF
eninges, which are the
and spinal cord due to
f i hi h fectious causes which are not
th b i d t i f ti (th the brain due to infection (there
not covered here)
he above he above
2
4
5
MENINGITIS VERSUS ENCEPHALITIS
function is the important distinguishing f
i iti P ti t ith i iti meningitis. Patients with meningitis may
by headache, but their cerebral function r
abnormalities in brain function are comm
motor or sensory deficits altered behavio motor or sensory deficits, altered behavio
or movement disorders. Seizures and pos
alone and should not be construed as de
neurologic manifestations of encephalitis neurologic manifestations of encephalitis
paralysis, and paresthesias.
However, the distinction between the two
patients may have both a parenchymal an
features of both. The patient is usually la
encephalitis based upon which features p
meningoencephalitis is also a common te
The presence or absence of normal brain
feature between encephalitis and
b f t bl l th i di t t d be uncomfortable, lethargic, or distracted
remains normal. In encephalitis, however,
mon, including altered mental status,
or and personality changes and speech or and personality changes, and speech
stictal states can be seen with meningitis
efinitive evidence of encephalitis. Other
s can include hemiparesis, flaccid s can include hemiparesis, flaccid
o entities is frequently blurred since some q y
nd meningeal process with clinical
beled as having meningitis or
predominate in the illness although
erm which recognizes the overlap.
2
4
6
Menin Menin Menin Menin
Types of meningitis: cla
i l( i ) i viral(or aseptic) mening
Physical findings can di
d/ h li i two and/or encephalitis
information is needed.
i i f h CS Examination of the CSF
very important to distin
meningitis/encephalitis meningitis/encephalitis
ngitis ngitis ngitis ngitis
assically bacterial versus
i i gitis.
istinguish between these
b l l but almost always more
( b i l fl id) i F(cerebrospinal fluid) is
guish among the
diagnoses diagnoses.
2
4
7
Symptoms of a Symptoms of a
menin menin menin menin
Fever (bacterial inv
CSF) CSF)
Stiff neck (nuchal r
protective reflexes
of the subarachnoid of the subarachnoid
Brain dysfunction (
h d h i it bilit headache, irritabilit
obtundation)
Sometimes, rash or
acute bacterial acute bacterial
vasion of blood &
rigidity due to
from inflammation
d space) d space)
(nausea/vomiting,
t / it bilit ty/excitability;
r petechiae
2
4
8
249
Initial Symptoms Initial Symptoms
Bacterial (%)
Headache > 85 Headache > 85
Fever > 80
Meningismus >80
(Kernigs and Brudzinskis sign ( g g
Seizures ~ 30
Focal neurologic 10 35 Focal neurologic 10 35
Papilledema < 5
>85% have fever, headache, me
brain dysfunction such as com
s with meningitis s with meningitis
Viral (%)
50 90 50 90
88 100
~50(less in neonates)
ns and/or stiff neck))
14 18
??
?
eningismus, or some signs of
ma, confusion, delirium
2
5
0
focal neurological sign
meningitis/encephaliti meningitis/encephaliti
especially ocular and/
( i l 3 4 6 (cranial nerves 3, 4, 6
Deafness which can b
permanent permanent
This is often due to in
basal surface of the b
where the cranial nerv where the cranial nerv
ns common in
is is
/or facial palsies
6 d 7) 6 and 7)
be temporary or
nflammation of the
brain in meningitis
ves are exiting ves are exiting.
2
5
1
Kernig Kernig
(Vladimir Kernig, 1840 (Vladimir Kernig, 1840- -11
Limitation in passive
due to spasm of the h p
Basis: A protective re
pain of stretching inf pain of stretching inf
roots
g sign g sign
1917, Russian physician) 1917, Russian physician)
e extension at the knee
hamstrings g
eaction to prevent the
flamed sciatic nerve flamed sciatic nerve
2
5
2
Brudzins Brudzins Brudzins Brudzins
(Josef Brudzinski, 1874 (Josef Brudzinski, 1874- -11
Flexion at the knee
response to passive
Basis: Protective re
stretch of inflamed stretch of inflamed
(similar to Kernigs
May be more sensi
sitting position g p
skis sign skis sign ski s sign ski s sign
1917, Polish pediatrician) 1917, Polish pediatrician)
es and hips in
e flexion of the neck
eaction to prevent
d sciatic roots d sciatic roots
s sign)
itive if done in the
2
5
3
2
5
4
Normal eye exam
2
5
5
Papilledema
2
5
6
Examples of Examples of Examples of Examples of papilledema papilledema papilledema papilledema
2
5
7
Treatment algorithm for meningitis
Symptoms of
Check for papilledema and/or fo
Absent
Blood cultures, lumbar puncture
CSF consistent with bacterial meningitis
Give empiric antibiotics No m
No c
If cerebral edema seen on CT and meningitis is suspected
f meningitis
ocal neurologic deficits
Present
Obtain blood cultures
Empiric antibiotics
CT scan of head
mass lesion mass lesion present
cerebral edema
Alternative diagnosis
d, do blood cultures and empiric antibiotics
2
5
8
CSF findings in Patients w
Type Opening
Pressure
mmH20
Normal 50-180
Bacterial 200-500
Viral <250
with Meningitis
Leukocyte count
Cells/microliter-type yp
<5 Lymphocytes y p y
1000-5000 Neutrophils
50-1000 Lymphocytes
2
5
9
Type Glucose
mg/dL mg/dL
Normal 40-70
Bacterial <40
Viral >45
with Meningitis
Protein
mg/dL mg/dL
20-50
100-500
<200
2
6
0
Type Gram sta
Normal Negative g
Bacterial Positive:6
Viral Negative
with Meningitis
ain Culture
Negative g
60-90% Positive in
70-85%
Negative
2
6
1
CSF characteristics pr CSF characteristics pr
menin menin menin menin
Combination of the followin
bacterial meningitis
WBC counts >1000
Neutrophils predominating
Protein level > 200
Glucose level <40
CSF serum glucose ratio < g
redictive of bacterial redictive of bacterial
ng CSF values predicts g p
< 0.4
2
6
2
Why is bacteria Why is bacteria
devasta devasta devasta devasta
Increased permeability p y
barrier resulting from
response response
Brain edema from thre
vasogenic from increa
barrier permeability; c
products from inflamm
bacterial products; int bacterial products; int
obstruction of CSF flo
al meningitis so al meningitis so
ating? ating? ating? ating?
y of blood-brain y
inflammatory
ee mechanisms:
ased blood-brain-
cytotoxic from toxic
matory cells or
terstitial from terstitial from
ow
2
6
3
Bacterial meningiti Bacterial meningiti
I f ti d I f ti d Di Di
upper respiratory t upper respiratory t
dh i ili dh i ili
Infection and Infection and Disea Disea
adhesion pili adhesion pili
Bloodstream in Bloodstream in
Brain Brain--men men
is is-- --Course of Course of
tract tract colonization colonization
ases ases
nfection nfection- -sepsis sepsis
ingitis ingitis
2
6
4
Case 1: 60-year-old woman with fever, headdache, and nuchal rigidity
2
6
5
2
6
6
What is the What is the
1. Bacterial meningitis 1. Bacterial meningitis
2. Viral meningitis
3 Encephalitis 3. Encephalitis
4. Strep throat
5 Cellulitis 5. Cellulitis
6. Sinusitis
7 Otitis media
c
t
e
r
i
a
l

m
e
7. Otitis media
B
a
c
t
e
diagnosis? diagnosis?
8
0% 0% 0% 0% 0% 0% 0%
m
e
n
i
n
g
i
t
i
V
i
r
a
l

m
e
n
i
n
g
i
t
i
s
E
n
c
e
p
h
a
l
i
t
i
s
S
t
r
e
p

t
h
r
o
a
t
C
e
l
l
u
l
i
t
i
s
S
i
n
u
s
i
t
i
s
O
t
i
t
i
s

m
e
d
i
a
0% 0% 0% 0% 0% 0% 0%
V
2
6
7
Diagnosis: Acute Streptococcuus pneumoniae meningitis
2
6
8
Any further di Any further di Any further di Any further di
1 CT scan of head 1. CT scan of head
2. Blood cultures
3 Culture and sensitivities of 3. Culture and sensitivities of
CSF fluid
4 All of above 4. All of above
5. 1 and 2
6 2 and 3
C
6. 2 and 3
7. 1 and 3
iagnostic tests? iagnostic tests? iagnostic tests? iagnostic tests?
10
0% 0% 0% 0% 0% 0% 0%
C
T

s
c
a
n

o
f

h
e
a
d
B
l
o
o
d

c
u
l
t
u
r
e
s
l
t
u
r
e

a
n
d

s
e
n
s
i
t
i
v
i
t
.
.
A
l
l

o
f

a
b
o
v
e
1

a
n
d

2
2

a
n
d

3
1

a
n
d

3
C
u
l
t
u
2
6
9
Any further diagnostic tests at
Draw blood cultures, send sam
Treatment: ceftriaxone and va
known for S pneumoniae known for S. pneumoniae
t this point?
mple of CSF for culture
ancomycin until sensitivities are
2
7
0
END OF END OF CASE 1 CASE 1
2
7
1
MMI case 86:
This is a healthy 11 year old male who presents fo
despite treatment with acetaminophen and ibupro
t til f f th l t th d d h h d tactile fever for the last three days and has had m
was no history of trauma, but he has had recent U
is sent to the lab for tests when his mother notes t
going to the lab for tests, he develops shaking mo g g , p g
and he is taken to an emergency department via a
diazepam IV which promptly stops the seizure act
VS: T 38 6 P 136 R 15 (shallow) BP 108/65 oxy VS: T 38.6, P 136, R 15 (shallow), BP 108/65, oxy
unresponsive to voice commands and he has sha
trauma. His pupils are equal at 3 mm and reactive
noted. His oral mucosa is moist with no oral lesion
is regular. Lungs are clear with shallow aeration. H
perfusion are good. He has several bug bites on h
petechiae, or bruises. He has increased tone to th
is nonresponsive to voice commands but he with is nonresponsive to voice commands, but he with
movements or signs of posturing. His corneal refle
intact.
or persistent headaches for the last 4 days
ofen at home. He has had intermittent emesis and
i i l l i t k th l t 36 h Th minimal oral intake over the last 36 hours. There
URI symptoms 2 weeks ago. After evaluation, he
that he is more sleepy and unresponsive. While
ovements on the left side of his body. 911 is called y
ambulance. An IV is started and he is given
tivity.
ygen saturation 100% with mask Wt 40kg He is ygen saturation 100% with mask. Wt 40kg. He is
allow respirations. His head shows no signs of
e to light. No papilledema on funduscopic exam is
ns. His neck is supple without adenopathy. Heart y
His abdomen is normal. His pulses, color and
his extremities without signs of cellulitis,
he left side of his body and brisk reflexes L>R. He
draws to pain He exhibits no purposeful draws to pain. He exhibits no purposeful
ex, oculocephalic, and oculovestibular responses
2
7
2
He is given IV loading doses of fosphenytoin, acy
CBC, chemistry, and liver function studies. Urine a
h d CT ith t t t h id f i head CT without contrast shows no evidence of in
bleed. A lumbar puncture is done. Opening pressu
(65% segs, 26% lymphs, 9% mono), protein 95, g
CSF shows few WBCs, but no organisms seen. , g
clovir, and ceftriaxone. Lab studies show a normal
and serum toxicology screens are pending. A
t i l t i l l i t i l ntracranial mass, ventriculomegaly, or intracranial
ure is 100 mm H20. CSF analysis shows 58 WBC
glucose 40, 4th tube on hold. Gram stain of the
2
7
3
Does this patien
neurologica neurologica
1. Yes
2. No
nt have focal
l deficits?
7
l deficits?
0% 0%

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2
7
4
What is the most lik
1. Bacterial meningitis.
2 Vi l h liti 2. Viral encephalitis
3. Meningococcemia.
4 Typhoid fever 4. Typhoid fever
5. Leptospirosis
6. Bacterial sepsis p
kely diagnosis?
8
17% 17% 17% 17% 17% 17%
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What makes this mo
meningitis/encepha
mening mening
1. Age of the patient.
2. Presence of a grand mal g
seizure
3. Presence of nuchal rigidity
4. CSF findings of low WBCs
and near normal glucose
and protein and negative p g
gram stain.
5. Presence of focal
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ore likely to be viral
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gitis?
10
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What is the most What is the most
1 L C i 1. La Crosse virus
2. West nile virus
3. St. Louis enceph.
Virus.
4. Yellow fever.
5 Dengue fever 5. Dengue fever.
6. Western equine
i virus.
likely organism? likely organism?
8
17% 17% 17% 17% 17% 17%
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transmit
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2 Aerosol inhalation 2. Aerosol inhalation
3. Direct contact
4 E t 4. Exposure to
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t water
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isease likely isease likely
tted?
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THE THE END END
2
7
9
MMI case 32 Cunha Case 70: A 45-year-ol
History: A 45-year-old woman presents in Jul
associated with photophobia, sore throat, na
vomiting, and rash. There was no improvem
patients past medical history is unremarkabl patient s past medical history is unremarkabl
Physical exam: Temp. 38; pulse 99; respiratio
mild distress HEENT: pupils equally round mild distress. HEENT: pupils equally round,
normal, mild conjunctival injection; mild nuch
pharynx. Kernig and Brudzinski signs are ne
Abdomen: soft, nontender normal bowel sou ,
Neurologic: alert and oriented to person, plac
Lab: WBC 9500/microliter with normal differe
glucose 54 mg/dl; RBC 8/microliter; WBC 56
neutrophils, 11% monocytes. Gram stain of C
Urinalysis: normal
ld woman with fever and headache
ly with a 2-day history of severe headache
usea, and diarrhea. She denies fever, chills,
ent in her symptoms on analgesics. The
e and she has no known drug allergies e and she has no known drug allergies.
ons 18; blood pressure 100/60. General:
reactive to light and accomodation; fundi reactive to light and accomodation; fundi
hal rigidity; mild erythema of posterior
egative. No palpable lymphadenopathy.
nds. Extremities: no rashes or lesions.
ce and time; no focal deficits.
ential. Glucose: 88 mg/dl. CSF: clear,
6/microliter with 88% lymphocytes, 1%
CSF: numerous WBCs but no organisms.
2
8
0
What is the like What is the like
1 Strep throat 1. Strep throat
2. Leptospirosis
3 B t i l i iti 3. Bacterial meningitis
4. Viral or aseptic
meningitis
5. Tertiary syphilis y yp
ely diagnosis? ely diagnosis?
20% 20% 20% 20% 20%
8
20% 20% 20% 20% 20%

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8
1
Case 70: A 45-year-old woman with fever a
Diagnosis: Enteroviral aseptic meningitis
Aseptic or viral meningitis is a clinical syndro
non polio enteroviruses include groups A an non-polio enteroviruses, include groups A an
enteroviruses 68-71. These enteroviruses ar
infections ranging from mild to severe aseptic
The spectrum and severity of clinical disease The spectrum and severity of clinical disease
the affected individual, and the virulence of th
most commonly isolated from clinical specim
coxsackie B serotypes 1-5 and echovirus ser yp
enteroviruses account for 80-90% of all case
identified. Children and adults less than 40 y
What was the mode of transmissio
and headache
ome with short-term morbidity caused by the
d B coxsackieviruses echoviruses and d B coxsackieviruses, echoviruses, and
re able to cause a spectrum of CNS
c meningitis to encephalitis and myelitis.
e varies with age gender immune status of e varies with age, gender, immune status of
he enteroviral serotype. The enterviruses
mens from patients with aseptic meningitis are
rotypes 4,6,9,11,16, and 30. Non-polio yp , , , , , p
es of aseptic meningitis for which an agent is
years old are most commonly affected.
on of this virus?
2
8
2
What was the mo
i i transmission
1. Inhalation 1. Inhalation
2. Ingestion of
contaminated food or contaminated food or
water
3. Insect bite 3. Insect bite
4. Sexual contact
5 Direct contact with 5. Direct contact with
infected lesion on
other person other person
ost likely mode of
f hi i ? of this virus?
8
20% 20% 20% 20% 20%

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Case 70: A 45-year-old woman with fever a
Infection is acquired by the oral-fecal route. A
replicates and causes initially a mild and then replicates and causes initially a mild and then
are seeded, including the CNS, liver, lungs a
is antibody-mediated, and patients who are a
usually acquire infection perinatally) have mo usually acquire infection perinatally) have mo
and mortality. Aseptic meningitis has a benig
as a syndrome of meningeal irritation and CS
encephalitis or myelitis. p y
More than 75,000 cases of enteroviral asepti
year, particularly in the summer and fall mont
How does this disease typically pre
and headache
After the virus enters the GI tract, it
n a significant viremia Many organ systems n a significant viremia. Many organ systems
and heart. The ability to clear the enterovirus
agammaglobulinemic and neonates(who
ore severe illness with increased morbidity ore severe illness with increased morbidity
gn clinical course, and should be recognized
SF pleocytosis when there is no evidence of
ic meningitis are reported in the US every
ths. Seasonal outbreaks may occur.
esent?
2
8
4
The onset may be gradual or abrupt and is u
non-specific symptoms of a viral infection-fev
rash, cough, pharyngitis, diarrhea and myalg
headache, fever at 38-40
o
C, nuchal rigidity, a
i idit t i l 50% f ti t d rigidity presents in only 50% of patients and v
Brudzinski signs are present in only 30% of a
occuring in 5-10% of patients early in the cou
seizures in children complex seizures lethar seizures in children, complex seizures, lethar
neurologic symptoms resolve slowly and the
due to enteroviruses or other neurotropic viru
patients presenting with evidence of encepha patients presenting with evidence of encepha
other diagnoses to be considered include po
meningitis, acute HIV infection, or Lyme borr
fever and signs of meningeal irritation subsid g g
How would the diagnosis be confir
sually biphasic. Patients initially present with
ver, vomiting, anorexia, fine maculopapular
giawhich resolve. Two to ten days later,
and photophobia acutely develop. Nuchal
i f ild t K i d varies from mild to severe. Kernig and
adults. Focal neurologic findings are rare,
urse of the disease. They include febrile
rgy coma and movement disorders Focal rgy, coma and movement disorders. Focal
ir presence suggests encephalitis or myelitis
uses(e.g. HSV, arboviruses, and mumps). In
alitis petechial rash and muscle weakness alitis, petechial rash, and muscle weakness,
lio virus, partially treated bacterial
reliosis. In patients with aseptic meningitis,
de in about 3-7 days. y
rmed?
2
8
5
How would the diagn How would the diagn
1. Elisa test for viral antigen in 1. Elisa test for viral antigen in
CSF
2. Elisa test for viral antigen in
blood blood
3. Serology to look for
antibodies in blood.
4. Culture of virus in vitro
5. PCR
6 Either 4 or 5 6. Either 4 or 5.
7. Either 1 or 3
8. Either 2 or 3

E
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8
12% 12% 12% 12% 12% 12% 12% 12%
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The ability to culture enteroviruses from the C
the first week of onset of meningitis helps to the first week of onset of meningitis helps to
in cell culture is the gold standard for diagnos
PCR is much faster but is not always availab
How are the patients treated?
CSF, nasopharynx, throat and feces within
confirm the diagnosis Isolation of the virus confirm the diagnosis. Isolation of the virus
sis but may take 4-10 days. Detection by
ble.
2
8
7
How would this pa How would this pa
1 Ribavirin 1. Ribavirin
2. Acyclovir
3 C ft i 3. Ceftriaxone
4. Vancomycin
5. Gancylovir
6 Amantidine 6. Amantidine
7. Symptom support
atient be treated? atient be treated?
8
14% 14% 14% 14% 14% 14% 14%
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If the CSF results suggest aseptic meningitis
patients can be treated symptomatically. Ch
should be treated with antisera Neonates w should be treated with antisera. Neonates w
with antisera, maternal plasma, and exchang
The present patient exhibited mild meningitis The present patient exhibited mild meningitis
meningitis. Coxsackievirus grew from viral c
symptoms slowly resolved after 10 days with
s(CSF pleocytosis and negative Gram stain),
ildren or immunocompromised patients
with overwhelming sepsis have been treated with overwhelming sepsis have been treated
ge transfusions.
s Her CSF showed no evidence of bacterial s. Her CSF showed no evidence of bacterial
cultures of her throat and stool. Her
h symptomatic treatment.
2
8
9
THE THE END END
2
9
0
22-March-2013, 1 pm, Dr. Eliot

Somatosensory Lab Overview (3/22/13): all Haines 8
th
Ed. Fig #s

In addition to Lab 3 Powerpoint, which includes pathway diagrams and
NeuroExam videos, we will use the following from Haines & Neurosyllabus:

2.1(top) Spinal meninges, incl denticulate ligaments of the pia, arachnoid,
single dural layer merges with spinal nerve perineureal layer; real
epidural space; cervical dorsal roots, posterior spinal artery
2.2(top) DRG, dorsal columns, posterior median & intermed. fissures
6.1 Sacral section: gracile fasciculus, post. median fissure, ALS
6.2 L4 section: gracile fasciclus, dorsal root, Lissauers, ALS
6.3 T4 section: gracile & cuneate fascicles, Lissauers, ALS, posterior
intermediate sulcus begins at T6
6.4 C7 section: gracile & cuneate, ALS, anterior white commissure
[6.7shows internal capsule infarct & degeneration for this brain]
6.8 Medulla @ pyramidal decussation: gracile & cuneate fascicles &
nuclei, spinal trigeminal tract & nucleus (caudal part), ALS
2.31 Dorsal brainstem: gracile, cuneate & trigeminal tubercles=
tuberculum cinereum
6.9 Medulla @internal arcuate fibers: gracile & cuneate fascicles &
nuclei, spinal trigem tract & nucleus, medial lemniscus, ALS
6.11 Mid-medulla: ALS & medial lemniscus, spinal trigem nucleus & tract
& ventral trigeminothalamic tract
6.13 Pons-medulla junction:4
th
ventricle, ML rounding up, ALS hard to
see, but moving posterior, spinal trigem nucl & tract clear on left
6.20 Rostral pons: ALS, ML & trigeminothalamic tract, PAG
6.24 Midbrain @ superior colliculus: ALS & ML & trigeminothalamic tract,
PAG & cerebral aqueduct
5.6 Coronal slab & MRI: VPL & VPM, posterior limb & post-central gyrus
7.3 Stained hemi-horizontal: VPM, VPL & internal capsule; T2 inset

[Neurosyllabus 19.12 shows corona radiata; 5.19 shows paracentral lobule]

D4 (Bonus, online) internal capsule dissection
2.11 Lateral brain, showing superior parietal lobule
2.29 Midsagittal view: paracentral lobule (or Neurosyllabus 1.14)

291
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The Eye file:///Brandon/Today/eye/eye_lecture_with_figures_for_p...
1 of 18 02/26/2008 05:23 PM
THE EYE
Christopher Brandon
Reading: Gartner & Hiatt, Chapter 22
I. GROSS STRUCTURE OF THE EYE.
1
2
A. Tunics (Figure 1, Figure 2).
The eye is a spherical structure composed of three layers, or tunics. It functions as a sort of camera, by forming images of objects in the real world onto a layer of
photo-sensitive neurons (the retina) in the back of the eye; the resulting neural impulses are eventually relayed to visual centers in the brain.
The outermost layer, the sclera (fibrous tunic) corresponds to, and is continuous with, the dura of the CNS; it represents the posterior 5/6 of the globe.
The uvea (middle tunic) is a highly vascular layer that corresponds to the pia/arachnoid of the CNS; it consists of the choroid (posteriorly), the ciliary body (under the
corneo-scleral limbus), and the iris (anteriorly).
The innermost layer, the retina, has the same embryological origin as the CNS, and is anatomically continuous with the CNS. It consists of a photosensitive portion, the
neural retina, that lines the posterior 2/3 of the globe, and a non-photosensitive epithelial portion that covers the ciliary body and the posterior surface of the iris. Axons
from the retina leave the eye to form the optic nerve.
B. Chambers and Spaces in the Eyeball (Figure 3).
The fibrous and uveal layers are in close contact throughout most of the globe. These two layers separate at the iridocorneal angle (the junction of cornea and iris),
forming the anterior chamber, or aqueous compartment. The anterior chamber is formed by the inner surface of the cornea (anteriorly), the lens, iris, and base of ciliary
body (posteriorly), and the trabecular meshwork (circumferentially).
The posterior chamber is formed by the iris (anteriorly), the lens and zonule (posteriorly), and the ciliary processes (peripherally).
The vitreous chamber lies between the lens and the retina.
3 4
C. Path of Light Rays.
Light first traverses the cornea, then passes through the aqueous humor (anterior chamber), pupil, posterior chamber, lens, vitreous body, and all of the cellular layers of the
neural retina before striking the photoreceptors. When we look directly at an object (fixation), the image of that object falls directly on a specialized region of the retina
called the fovea, at the posterior of the globe.
D. Radius of Curvature of the Globe.
The globe is formed by the fusion of two spheres of unequal diameter. The sclera has a diameter of 12mm; the corneal diameter is 8mm. The point of intersection between
these two unequal spheres is a circular zone that surrounds the eye, the corneoscleral limbus (Figure 6).
E. Blood Supply of the Eye (Figure 3).
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Short and long posterior ciliary arteries; the former penetrate the sclera near the optic nerve, the latter on each side of the globe. The ciliary arteries provide blood
to the middle, uveal tunic; this, in turn, nourishes the avascular portion of the overlying retina by diffusion.
Anterior ciliary arteries penetrate the sclera just posterior to the corneoscleral limbus; they provide blood to the ciliary body and iris, which are also both uveal
regions.
Venous return is via vortex veins, which perforate the sclera, one for each quadrant of the eye.
The central retinal artery and central retinal vein enter the globe within the optic nerve, which passes through a perforated zone at the back of the eye, the lamina
cribrosa. These vessels pass through to the interior of the globe, then run laterally and spread out over the inner surface of the retina. Smaller branches then
penetrate the retina, nourishing its innermost half with a capillary plexus. The outer half of the retina is avascular and is nourished by diffusion from the underlying
choroid.
II. TUNICS OF THE EYE.
A. Fibrous Tunic.
A1. Sclera (Figure 4). This is a layer of dense fibrous connective tissue, 0.3-1mm thick, except where it thickens at the scleral spur. The sclera has a specialized area near
the posterior pole, the lamina cribrosa (Figure 5a, Figure 5b). This is a round, perforated zone, much like a sieve, through which ganglion cell axons leave the eye to form
the optic nerve.
5A 5B
A second specialized scleral zone is the Canal of Schlemm; this is a small tunnel lying just under the corneo-scleral limbus, running completely around the eye, forming a
ring-like structure (Figure 6, Figure 7). It functions to drain the fluid, aqueous humor, produced in the eye (see below).
6 7
A2. The cornea (Figure 8) has the greatest refractive (light-bending) power of any ocular structure; it is, therefore, the eye's principal lens. The cornea is
avascular; blood vessels would interfere with image formation. Its inner half is nourished by diffusion from the aqueous humor, while its outer half is nourished by tear fluid.
It has five histological layers:
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8 9
10
11
The epithelium (Figure 9, Figure 10) is stratified squamous, non-keratinized, 5-6 cell layers thick. It has many free nerve endings, and great regenerative power
due to mitosis in its basal layer.
The basement membrane of this epithelium is called Bowman's membrane (Figure 9); it is a structureless collagen membrane that ends at the limbus.
The body of the cornea forms 90% of the thickness of the cornea; it is formed of many lamellae of collagen fibrils, arranged at right-angles to each other, with
intervening fibroblasts (Figure 11). This structure allows the cornea to be rigid as well as transparent, and to have great light-refracting power.
Descemet's membrane (Figure 12) is the basement membrane of the corneal endothelium; it is continuous with the trabecular meshwork.
The endothelium (Figure 12) is a single layer of low cuboidal cells that transports nutrients from the aqueous humor to the cornea.
The corneo-scleral limbus (a region, not a histological layer) is well vascularized, and is about 1mm wide (Figure 6).
12
13
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B. Uveal (Vascular) Tunic.
B1. The choroid (Figure 13, Figure 14) is a spongy brown layer 0.1-0.3mm thick, with several component layers:
The vessel layer comprises many arteries and veins embedded in loose connective tissue with many melanocytes. The pigment serves to absorb light that has
passed through the retina and that might otherwise scatter back, reducing visual acuity (sharpness) and contrast.
The choriocapillaris is a layer of fenestrated capillaries. This layer extends anteriorly up to the ora serrata, and nourishes the outer, avascular half of the retina,
which lies directly upon it.
Bruch's membrane, the innermost layer of the choroid, is the basement membrane of the retinal pigment epithelium (Figure 14). Trauma may cause the retina and
the RPE to separate at this point; this is one form of retinal detachment, and will lead to retinal death if not surgically reversed. You will not be able to see this
membrane with LM, but you should know where it is.
14
15
B2. Ciliary Body.
The ciliary body attaches to the sclera at the scleral spur (anteriorly) (Figure 15, Figure 16). Viewed from the optic disk, it has radial ridges (ciliary processes) that are
highly vascular (Figure 17). It contains a large amount of smooth muscle (the ciliary muscle), arranged in an antero-posterior direction, and some elastic fibers and
melanocytes as well (Figure 18). A capillary bed lies just under the choroidal epithelium; this area produces aqueous humor and secretes it into the posterior chamber
(Figure 18) (see below).
16
17
The ciliary body is covered with a double layer of epithelium; one layer (the inner, i.e. closer to the interior of the globe) is continuous with the neural retina and is not
pigmented; the other layer (outer) is continuous with the retinal pigment epithelium, and is heavily pigmented (Figure 19). The outermost layer rests on a basement
membrane (a continuation of Bruch's membrane); another basement membrane covers the inner surface (between the epithelium and the vitreous body), and the apical
surfaces of these two epithelial layers lie against one another (because they started as a flat sheet that later folded onto itself - see Development, below).
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18 19
The epithelium extends forward to cover the posterior surface of the iris, reaching all the way to the pupil. It does NOT extend over the anterior surface, however, but
doubles back on itself (arrow, Figure 20, Figure 22). At this point, both epithelial layers are pigmented. The absence of an epithelial covering may lead to glaucoma (see
below).
20
21
22
23
B3. Iris.
Structure of the iris (Figure 21). The posterior portion of the iris derives from ectoderm, and is the double epithelium mentioned above (Figure 22); its anterior portion is
mesodermal (uveal). The anterior surface of the iris has no epithelial covering; instead, it has a relatively porous covering of specialized fibrobasts (Figure 23). Beneath
the surface is loose connective tissue with some pigmented cells (the number of these pigmented cells determines the color of the eye). Beneath this, in turn, is a layer of
blood vessels. The posterior surface is covered with two layers of cells, both of which are continuous with the ciliary epithelium; both of these layers are heavily pigmented.
Numerous myoepithelial cells derived from this epithelium form the dilator pupillae (Figure 24). Near the pupillary margin (i.e. the tip of the iris) lies a set of
circumferentially-arranged smooth muscle cells, the sphincter pupillae (Figure 25).
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24 25
Nervous Control of the Iris (Figure 26). The autonomic nervous system controls the diameter of the pupil. Sympathetic: The muscle cells comprising the dilator (above)
are oriented radially, like the spokes of a wheel, and therefore their contraction increases the diameter of the pupil; these cells receive their innervation from neurons in the
superior cervical ganglion. Parasympathetic: The pupillary sphincter is made up of smooth muscle cells oriented circumferentially near the pupil; their contraction
reduces the diameter of the pupil. These cells receive their innervation from neurons in the ciliary ganglion.
26 27
III. RETINAL DEVELOPMENT.
28
29
As the neural tube closes, the neural tube bulges out and forms two outpocketings called optic vesicles. Each vesicle grows laterally, but remains connected to the tube by
a stalk that will become the optic nerve (Figure 27). The vesicle collapses on itself, forming a double-layered cup; the innermost layer of this cup will become the retina,
while the outermost layer will become the retinal pigment epithelium. Because the vesicle is a single epithelial layer, it is surrounded by a basal lamina; when it collapses,
the apical surfaces of the two layers lie against one another, but very little holds them together (Figure 28). The basal lamina lies at the basal surface of the epithelium, and
will eventually end up partly on the inner surface of the retina (facing the vitreous chamber), and partly on the outer, basal surface of the retinal pigment epithelium (facing
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the choriocapillaris) (Figure 29). The absence of any connective tissue between the two layers of epithelium (which lie apex-to-apex; Figure 30) makes them vulnerable to
separation resulting from trauma to the eye.
The hyaloid artery supplies the developing eye, but degenerates once the globe has fully formed; its fragments remain in the adult eye and can cause problems (see
Vitreous Body, below).
30
31
IV. FLUID DYNAMICS OF THE EYE.
Aqueous humor fills the anterior and posterior chambers, being produced by the ciliary epithelium and capillaries within the ciliary processes. It is essentially an ultrafiltrate
of plasma, and is produced in the same way as CSF (it is very similar in composition to cerebrospinal fluid). Aqueous humor flows (Figure 31) from the ciliary processes
(Figure 32) into the posterior chamber, then through the pupil and into the anterior chamber (it may also percolate through the iris itself). The fluid is then reabsorbed by the
trabecular meshwork, from which it drains into the Canal of Schlemm within the sclera.
32
33
The trabecular meshwork is a spongy network through which aqueous humor percolates and finally drains into the Canal of Schlemm (Figure 33, Figure 34). The Canal
of Schlemm encircles the eye at the limbus (Figure 35). It drains into veins within the sclera.
34 35
Glaucoma. Aqueous humor is produced at a constant rate, and drainage usually matches production. This process maintains a significant level of internal pressure (usually
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10-20 mm of mercury), required to keep the eye in a fully spherical shape. If the ciliary body produces fluid at too high a rate, or if the drainage is blocked, then the pressure
within the eye (the intraocular pressure, or IOP) will increase. Because the globe is a sealed chamber, abnormally high internal pressure will reduce the amount of blood
flowing into the eye, eventually causing damage to the retina, and leading to blindness.
The most common cause of this condition is reduction of outward flow, caused by physical blockage of the trabecular meshwork by debris (pigment, cells or fibers
sloughed from the iris, pieces of the hyaline artery, etc.), much as hair would plug a shower drain. The leaching of material from the iris into the aqueous humor
probably results directly from the absence of an anterior epithelial covering on the iris. In this type of glaucoma, the iridocorneal angle is normal, so the condition is
called open-angle glaucoma.
[FYI: High intraocular pressure may also be caused by closed-angle glaucoma, which is often caused by trauma to the eye. Trauma can cause tearing of the delicate
trabecular meshwork, leading to the formation of a scar-like structure that pulls the iris and cornea closer together (reducing the angle between them, hence the name
'closed angle') and may obscure or collapse the meshwork altogether (Figure 36). Glaucoma may also result from overproduction of aqueous humor, a condition somewhat
analogous to high blood pressure; this form is common in people of African origin. In all forms of glaucoma, the high intraocular pressure is easily detected by routine
opthalmological examination; the high internal pressure forces the fibers of the optic disk outward, causing it to be more concave, a phenomenon known as "cupping" (this
may also result from thinning of the disk due to loss of axons from the optic nerve) (Figure 37).]
36
37
V. REFRACTIVE MEDIA.
A. Cornea. Light is refracted (bent) when it passes from a medium of low refractive index to a different medium with a higher refractive index. About 80% of the refractive
power of the eye resides in the cornea, since it represents an interface between two media of very different refractive indices (air and water). The structure of the cornea
was discussed above, in the section on "Fibrous Tunic".
B. Lens (Figure 38a, Figure 38b). The lens provides the remainder of the eye's refracting power; it contributes less than the cornea because it is essentially an aqueous
(cellular) structure surrounded by other aqueous regions (posterior chamber and vitreous chamber). However, it has the advantage that its shape can be changed by
muscular activity of the ciliary body, so its strength as a lens can be varied.
38a
38b
The lens (Figure 39a) develops from an epithelial sheet. The front part of the epithelium of the lens vesicle (the part facing the external world) remains as a thin sheet of low
cuboidal cells, the subcapsular epithelium (Figure 38b, Figure 39a, Figure 39b). The lens substance is made up of many lens fibers, which are hexagonal prisms that
lie parallel to the lens surface.
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39a
39b
The lens capsule that surrounds the lens is an elastic and collagenous membrane to which the suspensory (zonule) fibers attach (Figure 40); it is actually the basement
membrane of the original epithelial cells that formed the lens vesicle. Zonule fibers connect the lens to the ciliary processes that cover the ciliary body (Figure 40, Figure
41a).
40 41a
Cataract. With age, the osmotic balance of the lens fibers may change, causing them to become less transparent. The visual image then becomes hazy, and color
perception is diminished (Figure 41b, Figure 41c, Figure 41d). The condition can be corrected surgically, by removal of the cloudy lens and replacement with a plastic one.
Monet painted the same scene as a young man (Figure 41d, left panel) and, several decades later, after he developed cataracts (Figure 41d, right panel).
41b 41c
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41d
C. Vitreous body. This structure is a colorless, completely transparent gel that adheres to the retina, especially at the ora serrata and optic disk, and contains hyaluronic
acid and collagen fibrils, but very few cells. Remnants of the hyaline artery remain in the vitreous body throughout life; these are transparent, but they may refract light
under low-contrast illumination (looking at a white wall, or into the sky) and may then be seen as "floaters". They can present a problem for pilots, who, while flying, may
mistake them for something moving across their visual field.
D. Accomodation (Focusing). The eye's adjustments to form images of objects at different distances are called accomodation. Note that the eye, like the camera, forms
an image that is upside-down and backwards. Therefore, objects at the top of your visual field are focused on your inferior retina and are reversed left-to-right (Figure 42).
42
43a
D1. Mechanism of Accomodation (Figure 43a). When the eye (i.e. the ciliary muscle) is at rest, the lens is held in a somewhat flattened shape by tension from the zonule
fibers, which suspend it from the ciliary processes. The smooth muscle fibers in the ciliary muscle are oriented in the antero-posterior direction; as a result, contraction of the
ciliary muscle causes it to bulge inwards, towards the lens. This reduces tension on the zonule fibers, and allows the lens to assume its own, "relaxed", more-rounded
shape. When in this more spherical shape, the lens refracts light more strongly; this produces a stronger lens that can focus on nearby objects. When the ciliary muscle
relaxes, tension on the zonule fibers flattens the lens and makes it less refractive; in this configuration it will form a sharp image of a distant object. Therefore, active
contraction of the ciliary muscle leads to relaxation of the lens, and enables the eye to focus on close objects. The ciliary muscle is stimulated by parasympathetic
nerves, which therefore control focusing.
Emmetropia. In the normal eye (Figure 43b), the cornea plus the flattened lens act to form an image of distant objects exactly in the plane of the retina. When the lens
thickens, it becomes stronger, and the eye can then focus on close-by objects. This is the normal (emmetropic) condition.
43b
43c
D2. Disorders of Accomodation
Myopia. If the eye is too long (Figure 43c), then the in-focus image is formed in front of the retina, and the image formed on the retina is out of focus. This condition
can be corrected with a negative (reducing) lens of the proper strength. This condition is also called "near-sightedness".
Hypermetropia. If the eye is too short, then the in-focus image plane is actually behind the eye (Figure 43d), and the image formed on the retina is out of focus. This
condition can be corrected with a positive (magnifying) lens of the proper strength. This condition is also called "far-sightedness".
Presbyopia. The lens loses its elasticity with age. As a result, it can no longer assume the rounded shape needed for close focusing. Once an individual loses the
ability to focus at normal reading distance (0.3 - 0.5 meters, Figure 43e), which normally happens during the fifth decade of life, "reading glasses" can be used to
correct this condition; these are similar to the magnifying lenses used for far-sightedness.
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43d
43e
VI. RETINA.
A. Layers of the retina. The retina is a thin (200-375 microns) layer of CNS tissue that lines the inner surface of the posterior two-thirds of the eye (Figure 44). The neural
retina (optic retina) contains the actual light-sensitive elements of the eye (the photoreceptors), and extends anteriorly from the optic root to the ora serrata (Figure 45).
Anteriorly from the ora serrata, the retina continues as a non-neural layer that is not light-sensitive (i.e. the ciliary epithelium, described above). Classically, ten layers of
the retina have been defined; layers 2-10 comprise the neural retina, in which the cells and processes of the retina are segregated into discrete layers (Figure 46). You will
be responsible for the following layers:
44
45
LAYER 1: Retinal pigment epithelium (RPE). This is a layer of simple cuboidal epithelium (Figure 47) that rests on a basement membrane lying on the choroid (Bruch's
membrane, Figure 14); the cells contain melanin granules that serve to absorb stray light that has passed undetected through the photoreceptor layer. Processes from
these epithelial cells surround the outer segments of the photoreceptors, nourishing them by diffusion of nutrients, scavenging discarded photoreceptor outer segments, and
recycling the visual pigment. The most common type of retinal detachment involves separation of the retina from the RPE; as mentioned above, diabetes and mechanical
trauma are the most common causes of retinal detachment.
46 47
LAYER 2: Photoreceptor outer segments (Figure 47). The outer segments of photoreceptors are specialized for the absorption of light. Photoreceptor cells with
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rod-shaped outer segments (i.e. rods) are more sensitive, and are used for night vision; cells with conical outer segments (i.e. cones) are less sensitive, but can distinguish
different ranges of wavelengths, thereby permitting perception of color (see Photoreceptors, below).
***********************************************************************************
Material below is optional (Figure 46):
LAYER 3: Outer limiting membrane.
LAYER 4: Outer nuclear layer contains the cell bodies of the photoreceptor cells; axons extend from these cells in the vitreal (inner) direction.
LAYER 5: Within the outer plexiform layer, axon terminals from the photoreceptor cells interact with dendrites of bipolar and horizontal cells.
LAYER 6: The inner nuclear layer contains the somas of three neuronal cell types:
Bipolar cells, which receive input from the photoreceptor cells and transmit it to more vitreal layers.
Horizontal cells, which are interneurons found in the outer third of the inner nuclear layer.
Amacrine cells, which are interneurons found in the inner third of the inner nuclear layer.
LAYER 7: In the inner plexiform layer, processes from bipolar cells, amacrine cells, and ganglion cells interact synaptically.
end of optional section
*********************************************************************
LAYER 8: The ganglion cell layer (Figure 46) contains the cell bodies of ganglion cells.
LAYER 9: The optic nerve fiber layer (Figure 46) contains the axons of ganglion cells; these axons leave the retina at the optic disk, and form the optic nerve, which
projects to higher visual centers in the brain.
LAYER 10: The inner limiting membrane (Figure 46) is formed by the processes of retinal glial cells called Mller cells; processes from Mller cells span the entire
thickness of the retina. The innermost surface of the retina, which is formed largely by the end-foot processes of Mller cells, is covered by a basement membrane that is
part of the tenth layer (see Development, above, to understand how this B.M. got here). This basement membrane is important clinically because collagen fibers of the
vitreous attach to it; if they pull too strongly, they may cause retinal detachment.
B. Retinal function.
B1. Photoreceptors.
a. Photoreceptor structure.
When an image is formed on the retina, light energy is first absorbed by specialized neurons called photoreceptors, causing a change in their membrane potential and,
ultimately, a change in the amount of neurotransmitter that they release onto other retinal neurons. Thus, the photoreceptors convert, or transduce, light into a form
that can be transmitted by chemical (neurotransmitter) pathways; this process is called phototransduction.
48 49
The distal half of the photoreceptor (Figure 48, Figure 49) has a specialized region, the outer segment, that contains the biochemical apparatus for phototransduction. The
distal region of the outer segment is much enlarged, with many infoldings, called discs, of the plasma membrane that dramatically increase its the surface area. These discs
are oriented at right-angles to the path of light; this arrangement maximizes the chance that a photon of light will pass through the membrane and be detected. In addition, to
further increase sensitivity, outer segments are packed together at very high densities.
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b. Phototransduction.
50a
50b
The light-absorbing complex is dissolved in the plasma membrane of the discs. This complex contains a membrane protein, opsin, and a small molecule, retinal. Retinal
is a Vitamin A derivative. A photon of light strikes the complex and is absorbed by retinal, which changes its conformation (Figure 50a) and dissociates from the opsin.
This, in turn, causes a change in opsin's configuration that, through a second-messenger cascade, reduces the conductance of a sodium channel in the outer plasma
membrane of the outer segment (Figure 50b). Ultimately, this change causes the photoreceptor to hyperpolarize in response to light.
c. Visual acuity and color vision.
The vertebrate retina has two types of photoreceptors, rods and cones; the names relate to the shape of the outer segments (Figure 49). There is only one type of rod; it
can detect a broad range of visible light wavelengths in the green range, but, since there is only one type, it cannot distinguish among lights of different colors (Figure 51).
Rods are extremely sensitive to light, being able to detect a single photon. Because of this, rods are specialised for night vision (in fact, they do not function in bright
light). Human cones come in three types; each type can detect either red, green, or blue light, and all of them require bright light to function. They are also packed at very
high densities within the retina, so they provide a very high-resolution, fine-grained image. Therefore, cones are specialised for daylight, high-resolution color vision.
51
52
While rods and cones co-exist in most retinal regions (Figure 52), the rod:cone ratio varies across the retina. Cones are concentrated in the fovea of the retina (Figure
53); this area provides the image of the object we look directly at. They provide us with high-resolution color vision during the day. The peripheral retina provides us with
peripheral vision (outside the center of our visual field). Cone densities are much lower here, which means that our peripheral vision is largely color-blind. Rods are
absent from our foveal pit, which means that our central vision has low sensitivity; rods are absent from the fovea, but increase in number dramatically in the
peripheral retina, so that our peripheral retina is much more sensitive to dim light.
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53 54
[FYI: This is the reason that you cannot see a dim star on a dark night if you look directly at it - the image falls on relatively low-sensitivity cones, which simply can't see it.
Moving your eye slightly away from the star will make it appear, because the image falls on a retinal region that contains rods, which are sensitive enough to detect the star.]
[FYI: Rods cannot detect red light, whereas red cones can (Figure 51). Therefore, if you stay in a room lit only by deep-red light, your rods 'think' they are in the dark, and
therefore remain fully activated (they shut down in bright light). This means that military pilots can remain in a state of night-readiness, while still being able to see relatively
well, by staying in a room lit by deep-red light.]
Photoreceptors differ in their wavelength sensitivity because they contain different types of opsins; these various opsins make opsin-retinal complexes that differ in their
light-absorption maxima. Several different genes produce the several different types of opsins. All of these genes are located on the X chromosome; as a result, males are
much more susceptible to genetic deficits in color vision because they have only one copy of each gene (Figure 54). The most common deficit involves the
absence of a functional green opsin, which prevents the eye from distinguising red from green ("red-green color blindness"). Clinically, this can easily be detected with
colored diagrams called Ishihara plates (Figure 55a). A simple filter can be used to simulate color blindness (Figure 55b).
55a
55b
B2. Retinal pigment epithelium (RPE).
The photoreceptor's outer-segment discs are renewed constantly; new ones are made at the base of the outer segment, and older ones are shed at the tip. The discs are
phagocytized and digested by cells of the RPE, which have long, pigmented processes that surround the outer segments (Figure 56, Figure 57). In addition, the RPE
carries out part of the biochemical conversion of inactive retinal to active retinal, and Vitamin A to retinal. A genetic deficit in RPE function underlies the familial disease
Retinitis Pigmentosa; phagocytised discs accumulate without being digested, and the RPE eventually degenerates, causing death of the retina and leading to blindness.
56 57
308
15 of 18 02/26/2008 05:23 PM
B3. Ganglion cells (Figure 58).
The original light-induced hyperpolarization of the photoreceptor is conveyed synaptically across a series of retinal neurons (you will study these later). All of these neuronal
types modify the original signal in a variety of ways; eventually, the transduced information reaches the innermost layer of cells (i.e. closest to the vitreous), the ganglion
cells. The ganglion cell axons reach to the surface layer of the retina (nerve fiber layer), then run toward the optic disk, pass through the lamina cribrosa of the sclera, and
form the optic nerve. This heavily-myelinated nerve (cranial nerve II) projects into the cranium through the optic foramen, carrying visual information to higher brain regions.
58 59
C. Specialized areas of the retina.
C1. The fovea (fovea centralis) (Figure 59) is the region of the retina that is specialized for high-resolution, color vision. Here, the innermost retinal layers are
present, but have been displaced to the sides, away from the fovea (Figure 60). As a result, light has fewer layers to pass through (Figure 61), and is therefore scattered
less; this increases the sharpness of the image in this area. The higher primates (including man) have foveal retinas; most other animal species lack a fovea.
60
61
C2. The macula is a retinal region about 3mm in diameter that surrounds (and includes) the fovea, and that contains a yellow pigment (predominantly lipofuscin) (Figure
62). The pigment functions to absorb blue light, which would otherwise be scattered (which is what makes the sky blue); the scattered blue light would reduce image
sharpness.
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16 of 18 02/26/2008 05:23 PM
62 63
C3. Optic disk. At the optic disk (optic papilla), axons of ganglion cells gather and exit the eye (Figure 63), traveling through perforations in the sclera (the lamina
cribrosa) (Figure 64). No retinal neurons are found in this region, which is therefore called the "blind spot".
64
65a
Finding your blind spot (Figure 65a).
The retina cannot provide us with visual information about light falling on the optic disk, and yet we are not aware of the missing information, i.e. we do not see the
spot (Figure 65b). To identify your own blind spot, look at the dark 'plus' in the upper part of the diagram in Figure 65a with your left eye open and your right eye
closed. At the correct viewing distance, the image of the dark circle falls on your optic disk, and simply disappears.
[FYI: Our lack of awareness of the blind spot cannot be due simply to the fact that the images from our two eyes overlap and fill in the missing information, because
the blind spot does not appear in one eye even when we cover the other eye; in fact, the reasons are obscure, but psychophysical tests show that higher brain
centers "fill in" the missing information based on what they see in the surrounding areas. To demonstrate this to yourself, find your blind spot as above (Figure 65a),
then move down to the dark 'plus' in the lower part of the diagram. The gap in the line falls on your blind spot; your brain receives no information about what is in the
blind spot (it cannot know that the gap is there), so it "assumes" that the line is continuous across the spot, and you see an unbroken (but unreal) line.
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17 of 18 02/26/2008 05:23 PM
65b
66
Papilledema.
The optic nerve is NOT a peripheral nerve, but rather a tract within the CNS. This arrangement provides a very useful way to detect intracranial pressure that
is dangerously high. Because the sclera and dura are continuous, the underlying subarachnoid space around the brain is continuous with the corresponding
space under the sheath of the optic nerve (Figure 66). Because of this continuity, high pressure in the cranial cavity (due, e.g., to bleeding or to a tumor) will
result in high pressure around the optic nerve. At a high enough pressure, the central retinal vein will collapse, but the central retinal artery will remain open
(recall the differences in the structure of the walls of arteries and veins). Blood continues to enter the globe but cannot drain out; this causes fluid to be extruded into
the extracellular spaces of the optic nerve head and retina, causing them to swell. The normally-concave optic disk bulges inward, into the eye, becoming convex.
This condition, papilledema, is easily recognized on routine ophthalmological examination (Figure 67).
[Another consequence of the embryological origin of the retina: Because the retina is CNS tissue, diseases that affect the CNS also may affect the optic nerve. The
most common example is Multiple Sclerosis, an autoimmune disease in which CNS myelin is destroyed. Optic nerve inflammation and damage (and consequent
visual loss) is usually the first noticeable symptom of MS.]
67
68
D. Nourishment of the retina (Figure 3).
The inner half of the human retina is vascular, containing two capillary plexuses that derive from the central retinal artery. The retinal plexuses branch in the same plane
as the retina. The innermost plexus lies within the nerve fiber layer, and partially within the ganglion cell layer; the outer plexus runs in the outer plexiform layer. Diabetes
often leads to damage of these capillaries.
The outer half of the retina is avascular, receiving its nourishment by diffusion from the underlying choriocapillaris. Because of this arrangement, separation of the retina
from the RPE, or separation of the RPE from the choriocapillaris, cuts off the outer retina's normal supply of nutrients and oxygen, and very rapidly leads to
death of the separated region of retina. Separation may be caused by trauma (the tennis ball is a particularly effective agent for this), or by several systemic diseases
(e.g. diabetes).
The development of the retinal vascular capillary networks is disturbed in premature infants who are exposed to high oxygen levels within incubators (to alleviate
Respiratory Distress Syndrome, which, you should recall, is caused by inadequate production of pulmonary surfactant before 24 weeks of gestation). In response to the
high oxygen (hyperoxic) environment within the incubator, the retinal capillary networks do not develop (because they are not needed). Then, when the infant is returned to
room air, the change to a (relatively) hypoxic environment causes capillary development to be switched on; unfortunately, growth is often excessive
(hypervascularization), completely covering the inner surface of the retina, and leading to blindness (Retinopathy of Prematurity). Careful monitoring of oxygen levels
has reduced the incidence of this condition, which nonetheless remains clinically significant.
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18 of 18 02/26/2008 05:23 PM
VII. CONJUNCTIVA.
At the corneal margins, the epithelium of the anterior portion of the sclera (the bulbar conjunctiva) is continuous with the mucous membrane that lines the eyelids (the
palpebral conjunctiva) (Figure 68). This epithelium ranges from stratified squamous (at the corneal margin) to stratified cuboidal with mucous goblet cells. The underlying
stroma of the lamina propria is very loose, and rests on a cushion of intraorbital fat; this arrangement permits free rotation of the eyeball. This conjunctiva also functions to
seal off the orbit from the outside world. The goblet cell secretions become part of the tear fluid.
69
70
VIII. EYELIDS.
The inner surface of the eyelid contains ducts from several deep glands. Modified sebaceous glands (Meibomian glands) open on the free edge of the lid (Figure 69,
Figure 70); their oily secretion mixes with tear fluid and reduces the rate of evaporation of that fluid. Other modified sebaceous glands (Glands of Moll), as well as modified
sebaceous glands (Glands of Zeis) empty into the follicles of the eyelashes.
IX. LACRIMAL GLAND.
The lacrimal gland is a compound tubuloalveolar gland very similar to the parotid gland. It produces a serous secretion rich in the antibacterial enzyme lysozyme.
312
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353
15-April-2013, 10 am
Dr. Lise Eliot
Synapses are not fixed in strength: the magnitude of an EPSP or IPSP waxes
and wanes with the firing history of the synapse.
This figure shows several well-described types of short-term plasticity at the
neuromuscular junction, or endplate:
Facilitation (sometimes referred to as two-pulse or paired pulse
facilitation): repeated stimulation at high frequency increases the amount of
transmitter released, because excess calcium builds up in the presynaptic
terminal, increasing the number of vesicles released with subsequent action
potentials (rising phase of EPSP envelop) potentials (rising phase of EPSP envelop).
Depression: during prolonged high-frequency stimulation, synapses start
declining in strength (below their baseline magnitude; falling phase of EPSP
envelop). At the neuromuscular junction, this short-term depression is due to
the depletion of synaptic vesicles.
Post-tetanic potentiation (PTP): following prolonged stimulation, most
synapses show an increase in efficacy. PTP develops with a slight delay after synapses show an increase in efficacy. PTP develops with a slight delay after
stimulation, once the readily-releasable pool of synaptic vesicles has been
refilled, and lasts a few minutes in mammalian synapses. PTP is due to an
increase in intra-terminal calcium levels which activates Ca-dependent kinases
to increase the probability of vesicle release. Unlike LTP (which doesnt occur
at the neuromuscular junction), it decays with time.
The same forms of plasticity are found at synapses in the CNS, though an individual
synapse may tend to show more depression or facilitation (depending for example synapse may tend to show more depression or facilitation (depending, for example,
on its calcium buffering capacity, pool of releasable vesicles, and so on).
This type of plasticity is known as homosynaptic because it depends only on the
activity of the cells in the synapse itself; contrast with heterosynaptic plasticity...
354
15-April-2013, 10 am
Dr. Lise Eliot
Can be either short- or long-lasting. This figure shows an example of short-term
heterosynaptic modulation.
Presynaptic modulation (either excitatory or inhibitory) typically involves
axoaxonic synapses between a modulatory cell and the axon of another neuron,
not far from its synaptic release sites. Postsynaptic modulatory inputs are usually
onto the soma or dendrites of a neuron, and have the effect of increasing or
decreasing that cells response to synaptic input.
Generally speaking modulatory neurons produce slow (G-protein mediated) Generally speaking, modulatory neurons produce slow (G protein mediated)
responses that have very little effect on their targets membrane potential, but can
profoundly affect their fast synaptic transmission. (See Dr. Wolfs notes on
Neuromodulation.)
This figure shows one of the more common forms of short-term, heterosynaptic
plasticity: presynaptic inhibition. In this case, the modulatory neuron forms an
axoaxonic synapse on a presynaptic neuron, reducing the amount of
neurotransmitter it releases onto the postsynaptic neuron Electrical neurotransmitter it releases onto the postsynaptic neuron. Electrical
measurement in the cell body of the presynaptic neuron (Pre) shows no change
in the cells membrane potential, but the EPSP it produces in the postsynaptic
neuron is reduced immediately following activation of the inhibitory
neuromodulator. The mechanism involves presynaptic spike narrowing and
reduced calcium influx.
Presynaptic inhibition is commonly found among spinal cord afferents and is
known to participate in the gating of pain information known to participate in the gating of pain information.
355
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356
15-April-2013, 10 am
Dr. Lise Eliot
The best evidence that experience sculpts the brain through synaptic pruning comes
from some 50 years of research on the development of the visual cortex.
Studies initiated by David Hubel and Torsten Wiesel (for which they won the 1982
Nobel Prize in Physiology & Medicine) revealed dramatic changes in the structure of
the visual cortex as a function of the visual experience of infant cats or monkeys.
These micrographs show the visual cortex of two different monkeys, labeled to
differentiate the portion of cortex devoted to input from each of the two eyes. The
monkey reared with normal visual input shows an even division of input from the two monkey reared with normal visual input shows an even division of input from the two
eyes (the black and white labeled areas of the visual cortex are comparable in width),
whereas the monkey deprived of vision in one eye has very little of its visual cortex
devoted to processing vision from the deprived eye (dark stripes).
Note that these brain specimens were taken from adult animals, long after the period of
visual deprivation had ended. These experiments showed that anatomical
consequences of early visual deprivation are essentially permanent.
T h i l t di ti li i t l l b l (P 544) i Technical note: radioactive proline is a transneuronal label (Purves p. 544), meaning
it is taken up by one neuron, incorporated into some of its proteins, but also transported
to the end of its axons, which in this case project to the lateral geniculate nucleus of the
thalamus. There it is taken up by neurons that project to the visual cortex. Cortical
neurons similarly take up some of the label.
To refresh your understanding of ocular dominance columns, see Purves Fig. 12.13
357
15-April-2013, 10 am
Dr. Lise Eliot
Purves 24.5: Effect of early closure of one eye on the distribution of cortical
neurons driven by stimulation of either eye:
A. Distribution of the response properties of single neurons in primary visual
cortex (in all cortical layers except layer IV). Cells in group 1 were activated
exclusively by the contralateral eye; cells in group 7 exclusively by the
ipsilateral eye; and cells in intermediate groups were activated by both eyes
(binocularly-responsive), though to varying extents (i.e., group 4 cells were
activated equally by visual stimulation to either eye.) Exp = time when
experimental observations were made. In the normally-reared cat, most
cortical neurons are binocularly-responsive.
B. Electrophysiological responses in adult cat reared for the first 2.5 months of life
with its right eye closed. No neurons in left striate cortex respond to visual
stimulation of the eye right eye, nor are there any binocularly-responsive
neurons (e.g. groups 2-6). NR = cells that failed to respond to visual
stimulation of either eye. y
Comparable (or even longer) deprivation in adult cats has no effect on the
distribution of ocular response properties (see textbook Fig. 24.5C).
358
15-April-2013, 10 am
Dr. Lise Eliot
How does visual experience permanently shape the anatomy and physiology
f th i l t ? of the visual cortex?
The diagram on the left shows the general scheme of axonal maturation in the
connections between the visual thalamus (LGN) and layer IV of the visual
cortex, the thalamocortical or geniculocortical afferents. Early in development
(top), there is a lot of overlap in the terminal distribution zone of fibers carrying
visual input from each of the two eyes. With normal visual experience
(middle) these projections segregate forming distinct ocular dominance (middle), these projections segregate, forming distinct ocular dominance
columns, in which the electrical response to stimulation of one eye is much
stronger than to stimulation of the other. However, following monocular
deprivation (bottom), the terminals of thalamocortical afferents from the
deprived eye lose branches, ultimately innervating a smaller portion of the
cortex, while the terminals of afferents from the open eye expand their terminal
distribution, innervating a broader stripe of cortical territory.
The figure on the right shows the axons of real thalamocortical neurons in an
animal that was monocularly deprived for several weeks in early development.
Afferents carrying input from the closed eye have a smaller, less complex
terminal arbor than axons from the open eye, which sprout larger, more
complex terminal zones capable of forming a greater number of synapses in
layer IV. Axon arbor loss is evident with as little as one week of deprivation.
(Purves Fig. 24.8)
359
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15-April-2013, 10 am
Dr. Lise Eliot
Korean and Chinese immigrants were asked to identify ungrammatical phrases Korean and Chinese immigrants were asked to identify ungrammatical phrases.
Those who had arrived in the U.S. before 7 years of age performed as well as native-
born speakers. Grammatical skill then declined as a function of age of immigration,
reaching a plateau after 17 years. All of the subjects in this study were tested as
adults, and had lived here for at least 30 years, so their level of competence in
English had plateaued. In this test, subjects do not need to understand or be able to
state grammatical rules, only to decide whether or not a recorded sentence sounds
correct. Examples of the kind of sentences used to test grammatical fluency: correct. Examples of the kind of sentences used to test grammatical fluency:
The farmer buys two pig at the market. (missing plural -s)
The little boy is speak to a policeman. (missing -ing verb ending)
Yesterday the hunter shoots a deer. (wrong verb tense)
Tom is reading book in the bathtub. (missing definite article)
The man climbed the ladder up carefully. (misplaced preposition)
The data show that the critical period for language-learning begins to close
around age seven and ends by the end of puberty. Very similar results were obtained
in a study of first language acquisition. In this case, deaf subjects were tested for
grammatical competency in American Sign Language (ASL). Subjects varied in the
age at which they first learned ASL (depending on their age of enrollment at a school
for the deaf). )
361
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363
15-April-2013, 10 am
Dr. Lise Eliot
Purves 24.8: How visual experience shapes the developing visual cortex.
A cell in layer IV of primary visual cortex initially receives input (thalamocortical
synapses) from both eyes. In this case, the cell in a young animal receives two
inputs from the right eye and three from the left. Because each eye sees a
slightly different visual scene, the action potential patterns (vertical bars) of the
two sets of inputs are not identical. Inputs from the left outnumber inputs from
the right eye, and so they more effectively depolarize the postsynaptic neuron,
leading to NMDA-dependent LTP of all simultaneously-active (that is, left eye)
i t Ri ht i t b t t fi t f h ith th d i t l ft inputs. Right eye inputs, by contrast, fire out-of-phase with the dominant left
eye inputs; because their activity is not synchronized with postsynaptic
depolarization, their synapses undergo LTD,
After LTP is induced, long-term changes in synapses from the left eye include
the sprouting of additional synaptic terminals. By contrast, inputs from the right
eye eventually retract their weakened synapses, and are no longer capable of eye eventually retract their weakened synapses, and are no longer capable of
activating this particular layer IV neuron.
In strabismus, the child (or young animal) tends to close (squint) the weaker
eye, to prevent diplopia; squinting limits visual stimulation of the cortex from that
eye, allowing the stronger eye to win more of these synaptic battles. Patching
the stronger eye permits inputs from the weaker eye to dominate and retain their
ti f th LGN t th t connections from the LGN to the cortex.
364
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365
366
15-April-2013, 11am
Dr. William Frost
1
Lecture Content:
The structural components of the external, middle and internal ear
Unique features of the external ear
The physical role played by the middle ear ossicles
The function and structure of the Eustachian tube
The structural components of the cochlea
The structural components of the organ of Corti, and how it transduces sound into neural
activity
The different roles played by the inner and outer hair cells of the cochlea
Structure and function of the organs of vestibular sensation
367
15-April-2013, 11am
Dr. William Frost
2
The ear has three distinct parts: The external ear consists of the auricle, the external
auditory meatus and the tympanic membrane (eardrum). The middle ear is an air-filled
chamber containing the three ossicles -- the malleus, incus and stapes. The inner ear is
composed of the bony labyrinth (a hollowed-out cavity), and the membranous labyrinth,
which is suspended within the bony labyrinth and contains the auditory and vestibular
sensory structures.
368
15-April-2013, 11am
Dr. William Frost
Histology of the external ear:
The shape of the pinna is determined by an internal supporting structure of elastic
cartilage. Thin skin with hair follicles, sweat glands and sebaceous glands covers the
auricle. It has keratinized stratified squamous epithelium.
Function of the external ear:
Pinna and Concha: Gather and focus sound energy into the external auditory meatus and
on to the tympanum. Provide clues to the location of sounds, especially with respect to
elevation of the source
External auditory meatus: Selectively boosts sound pressure 30 to 100 times for
frequencies around 3 kHz
3
369
15-April-2013, 11am
Dr. William Frost
4
370
15-April-2013, 11am
Dr. William Frost
5
The external auditory meatus (upper left) is the canal that extends from the pinna to the
tympanic membrane. The meatus is lined with thin skin (keratinized stratified squamous
epithelium) containing hair follicles, sebaceous glands and ceruminous glands. Ceruminous
glands (arrow) are modified apocrine sweat glands that secrete a waxy material called
cerumen (earwax). The hairs and sticky wax help prevent foreign particles from
penetrating deeply into the ear.
371
15-April-2013, 11am
Dr. William Frost
6
372
15-April-2013, 11am
Dr. William Frost
7
The primary function of the middle ear is to convert sound waves arriving from the external
auditory meatus into amplified, mechanical vibrations that are transmitted to the cochlea
of the inner ear. This conversion is carried out by the 3 bones of the middle ear, the
malleus, incus and stapes. The lever action of the ossicles, plus the size change from the
tympanic membrane to the smaller oval window, results in a large amplification in sound
energy as it reaches the cochlea. The smallest muscle of the body, the stapedius muscle,
lies within the middle ear and acts with the tensor tympani muscle to attenuate movement
of the ossicles, protecting the inner ear from being damaged by excessive sound.
Lower left: a photograph of the tympanic membrane from the external auditory meatus,
through which can be seen the attached malleus. Lower middle and lower right: the 3
ossicles of the human ear. Upper right: Andreas Vesalius, who published the first
description of the malleus and incus in 1543.
373
15-April-2013, 11am
Dr. William Frost
8
The Eustachian, or auditory, tube (T) connects the middle ear to the nasopharynx. It
functions to allow equalization of the air pressure in the middle ear with the atmospheric
pressure. Normally collapsed, the tube opens during swallowing or yawning. The
cartilagenous tube walls (C) are lined with ciliated pseudostratified columnar epithelium.
This epithelium generates a mucus sheet that traps and moves bacteria toward the
nasopharynx, helping prevent infectious agents in the airway from reaching the middle ear.
Middle ear infections are most common in infants, whose Eustachian tubes are shorter and
oriented in a way that makes them less effective at preventing bacteria from reaching the
middle ear. The Eustachian tube was first formally described by Bartolommeo Eustachio in
1562.
374
15-April-2013, 11am
Dr. William Frost
With respect to the auditory function of the inner ear, the cochlea is the vital structure.
This is where the original sound generated, air conducted pressure waves are converted to
liquid conducted pressure waves and finally to neural impulses by the hair cells in the organ
of Corti in a process called mechanoelectrical transduction, with the hair cells being the
transducers.
9
375
15-April-2013, 11am
Dr. William Frost
10
The cochlea converts sound pressure waves generated by the ossicles acting against the
oval window into electrical activity in spiral ganglion neurons. The spiral structure of the
cochlea is evident when the encasing bony covering is chipped away (upper left + inset).
The cochlea consists of a spiral fluid-filled tube that everywhere along its length has 3
components, visible in cross-section (other 3 figs), termed the scala vestibuli, scala media
and scala tympani. The basilar membrane, which divides the scala media from the scala
tympani, is the location of the organ of Corti, where sensory transduction occurs.
376
15-April-2013, 11am
Dr. William Frost
11
The tectorial membrane (TM) that overlies the hair cells is seen in the upper left exposure
of the entire cochlea. The well-organized rows of hair cell stereocilia that normally press
against the tectorial membrane are revealed when the membrane is pulled aside (upper
right figure). A closer view reveals the single row of inner hair cells and three rows of outer
hair cells.
377
15-April-2013, 11am
Dr. William Frost
12
378
15-April-2013, 11am
Dr. William Frost
13
The organ of Corti functions as the sound receptor. It lies on the basilar membrane and is
composed of hair cells and supporting cells. The hair cells project stereocilia against the
tectorial membrane (TM). There are two types, the inner and outer hair cells. The inner
hair cells transduce sound into changes in membrane potential and thus into changes in
hair cell transmitter release. The microscopic anatomy of this structure was first described
in 1851 by Alfonso Corti.
379
15-April-2013, 11am
Dr. William Frost
Because the tectorial membrane (purple) is anchored only at one end, the hair cell
stereocilia embedded in it are rocked back and forth as the basilar membrane on which
they reside moves up and down in response to sound.
14
380
15-April-2013, 11am
Dr. William Frost
15
Hair cells in the cochlea and the vestibular structures function similarly in how they
operate. SEM views are shown above of vestibular and cochlear hair cell hair bundles.
Each bundle consists of a group of stereocilia, which are large microvilli filled with actin
filaments. The top cross section image was made through a single vestibular hair bundle.
When a stimulus bends the stereocilia in one direction, non-selective cation channels open
in the tips of the stereocilia that lead to depolarization of the hair cell and increased
transmitter release. Bending the other way leads to hyperpolarization and decreased
steady-state transmitter release. In the developmentally mature auditory system, hair cells
release transmitter in a continuously graded manner with membrane potential. Such
transmitter release without action potentials is an unusual feature in the nervous system.
The first neurons in the auditory system to display action potentials are the bipolar spiral
ganglion neurons, located in the cochlea, which carry information from the hair cells via
the VIIIth nerve to the brainstem.
These are examples of mechanically-gated ion channels. Tip links connecting the apical
ends of the stereocilia act to open the channels when stretched (right figures.) Due to the
ionic composition of the endolymph in the scala media produced by the stria vascularis, the
apical surfaces of these these hair cells display a potassium gradient that is reversed from
most other cells, leading to potassium entering rather than exiting the cell when the
channels open.
381
15-April-2013, 11am
Dr. William Frost
16
382
15-April-2013, 11am
Dr. William Frost
17
The stria vascularis is unusual in being an epithelium with capillaries. This specialized
epithelium maintains the special ionic composition of the endolymph in the scala media
that bathes the hair cells.
383
15-April-2013, 11am
Dr. William Frost
18
The movement of the stapes against the oval window produces pressure waves that travel
along the basilar membrane, causing it to move in a shearing fashion against the tectorial
membrane, stimulating the hair cell stereocilia. The structure of the 35mm long basilar
membrane is such that each frequency produces its maximum displacement at a different
location along its length (tonotopy.) Because each afferent neuron fiber innervates a single
locus along the basilar membrane, it responds best to one particular frequency. The group
of active auditory axons in the VIIIth nerve informs the brain of the exact frequency
composition of any complex sound.
384
15-April-2013, 11am
Dr. William Frost
19
385
15-April-2013, 11am
Dr. William Frost
20
In addition to its single row of inner hair cells, the basilar membrane has three rows of
outer hair cells (CB). These receptor cells are under efferent control from the brain, and in
addition they physically contract when electrically stimulated (right figure). Changes in
length of the outer hair cells is thought to enhance the sensitivity of the inner hair cells by
altering the sound-elicited shearing force experienced by the inner hair cell stereocilia
against the tectorial membrane.
Clinical relevance: otoacoustic emissions. Newborns are routinely tested for hearing
impairment using a device inserted into the ear canal that contains a small speaker and
sensitive microphone. If everything is functioning properly, a test sound pulse causes the
outer hair cells contract in response, which in turn elicits fluid movement in the organ of
Corti that vibrates the oval window, ossicles and tympanic membrane in reverse, producing
a tiny echo sound, an otoacoustic emission, that is picked up by the microphone. In
adults, spontaneous vibratory movements of the outer hair cells can sometimes produce
otoacoustic emissions loud enough to be audible to others.
386
15-April-2013, 11am
Dr. William Frost
21
Sound-elicited movements of the basilar membrane excite neurotransmitter release from
the inner hair cells onto the processes of bipolar neurons, whose cell bodies are located in
the spiral ganglion. This ganglion is located within the cochlea, inside its bony central axis,
the modiolus. The labels in the left picture indicate different portions of this continuous,
spiral-shaped ganglion. Axons emanating from the spiral ganglion neurons project in the
VIIIth nerve to the brainstem.
387
15-April-2013, 11am
Dr. William Frost
22
15,000 have been implanted worldwide.
Up to 24 electrodes, at different positions along the scala tympani, just beneath the
basilar membrane.
Device used to deconstruct sound and activate different electrodes in response to
different frequencies.
388
15-April-2013, 11am
Dr. William Frost
23
Can damage residual hair cells, so only used for profound hearing impairment.
389
15-April-2013, 11am
Dr. William Frost
24
The purpose of this study was to determine whether there is an optimal age, or critical
period, at which to provide cochlear implants to congenitally deaf children. The P1 latency
reflects the time taken for a sound at the ear to reach the cortex, as measured by scalp
electrodes. The P1 latency quickens as normal children age and their auditory pathways
mature (downward trajectory of blue band). Congenitally deaf children given cochlear
implants early enough (2-3 years; red boxes) can enter first grade with age-appropriate
language skills. Those receiving them a decade later are unable to achieve normal auditory
processing (green boxes.) This raises a dilemma for parents of deaf children, because the
decision to use or forgo the implant cannot wait until the child reaches the age of consent.
390
15-April-2013, 11am
Dr. William Frost
25
The vestibular apparatus contains two types of vestibular organs. The otolith organs,
consisting of the saccule and utricle, are specialized for detecting two types of stimuli:
static head tilt and linear acceleration. The saccule is oriented vertically, the utricle
horizontally, making them optimally sensitive to different stimuli. A device for selectively
stimulating the otolith organs (linear acceleration) is shown in the lower left figure. The
semicircular canals are specialized for detecting head turns. The canals are oriented in
three orthogonal planes with respect to one another. A device for selectively stimulating
the semicircular canals is shown in the lower right figure.
391
15-April-2013, 11am
Dr. William Frost
26
Light microscope views of the semicircular canals and the crista ampullaris of the canal
ampulla chamber.
392
15-April-2013, 11am
Dr. William Frost
27
Left: Light microscope view of a crista ampullaris. Right: The stereocilia projecting from its
surface can be seen in this SEM photograph, as well as the sensory epithelium containing
the hair cells (RC) and supporting cells (SC).
393
15-April-2013, 11am
Dr. William Frost
28
The otolith organs, the saccule and utricle, are located in two dilated regions of the
vestibule of the inner ear, near the ampullae of the semicircular canals. Internally, the
saccule and utricle are lined by simple cuboidal epithelium, but in each there is a small
region of highly specialized epithelium, the macula, containing hair cells. The otolith
organs are different in an important way from the semicircular canals. The hair cells in the
semicircular canals are especially sensitive to head turns, which produce the angular
acceleration needed to bend the cupula and therefore the stereocilia.
The otolith organs (upper figure), on the other hand, are sensitive to stationary head
position, and thus function as gravity receptors. This is because the stereocilia are
embedded in a gelatinous membrane that is covered with crystals of calcium carbonate
called otoconia. The otoconia make the otolithic membrane heavier than the structures
and fluids surrounding it. Thus, when the head tilts, gravity causes the membrane to shift
relative to the sensory epithelium. This acts to bend the stereocilia of the hair cells,
inducing a receptor potential that alters their transmitter release. A similar shift of the
otolithic membrane also occurs when the head undergoes linear acceleration, such as in an
elevator.
394
15-April-2013, 11am
Dr. William Frost
29
Left: The otolith organs are found in the immediate vicinity of the ampullae of the
semicircular canals, in the vestibule of the inner ear. Upper right: Macula of the utricle.
The stereocilia of the hair cells project into the otolithic membrane, which has visible
otoconia on its surface. Lower right: SEM view of the macular surface, after the otolithic
membrane has been removed during processing. The stereocilia bundles of individual hair
cells are visible among the otoconia.
395
15-April-2013, 11am
Dr. William Frost
30
Increasing magnification of one of our ear slides, ending up with a close-up view of an
otolith organ with otoconia on its surface.
396
15-April-2013, 11am
Dr. William Frost
31
Usefulness of having normally functioning otolith organs. Left: This mouse has normal
otoliths, and rights itself during a fall. Right: A mouse with defective otoliths is unable to
do so.
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420
18-April-2013
Dr. Lise Eliot
The Vestibular System
Lise Eliot, PhD April 18, 2013
Related reading: Chapter 14 (except Boxes B & D)
Outline:
1. Purpose of vestibular sensation
2. Semicircular canals & otolith organs
3. Hair cells and transduction mechanism
4. Primary afferents & the VIII
th
nerve
5 Vestibular nuclei & their connections 5. Vestibular nuclei & their connections
6. Cortical processing
7. Vestibular-ocular reflex (VOR)
8. Nystagmus
9. Clinical tests of vestibular function
10. Mnires disease & Benign paroxysmal positional vertigo (BPPV)
Vestibular functions
Underlies our sense of balance or equilibrium.
Senses both static position and movement of the head Senses both static position and movement of the head.
Stabilizes image on the retina, even if the head is
moving (VOR).
Triggers rapid postural adjustments to maintain balance
(vestibulospinal reflexes).
2
A good indicator of brainstem integrity, even in
comatose patients.
Disorders of equilibrium are common in neurology and
aging and indicate vestibular or cerebellar dysfunction.
421
18-April-2013
Dr. Lise Eliot
The membranous labyrinth is a dime-sized structure, located in the inner
ear and embedded in the bony labyrinth (a cavity inside the temporal bone
of the skull). It includes both the cochlea and vestibular apparatus. The
membranous labyrinth is bathed in perilymph, which is similar in composition
to CSF. It is filled with a very different fluid, endolymph, which more closely
resembles intracellular solutions (high K
+
and low Na
+
concentrations).
V tib l i f ti t th CNS i th tib l ti f th VIIIth Vestibular information enters the CNS via the vestibular portion of the VIIIth
nerve, which passes through the internal acoustic meatus (together with CN
VII) and enters the brainstem at the cerebellopontine angle.
422
18-April-2013
Dr. Lise Eliot
Note the following structures in the coronal MRI: Note the following structures in the coronal MRI:
Semicircular canal
Medulla
Pons
Interpeduncular fossa
Lateral ventricles & septum pellucidum
Superior temporal gyrus
Sylvian fissure
Note the following structures in the axial MRI:
Horizontal canal
Cochlea
8
th
nerve
Basilar artery
4
th
ventricle
Pons
cerebellum
423
18-April-2013
Dr. Lise Eliot
Disorder of the inner ear characterized by intermittent bouts of
tinnitus (ringing in the ear), sensorineural hearing loss, and vertigo
(sensation of turning in absence of any real rotation).
Generally unilateral.
Caused by overproduction or impaired drainage of endolymph (which
normally drains out of the endolympathic sac), leading to fluid build- normally drains out of the endolympathic sac), leading to fluid build
up and distortion of the membranous labyrinth. Histopathology also
shows damage to hair cells.
May lead to permanent hearing loss.
Incidence = about 1 new case for every 2000 individuals per year.
Onset usually in middle age. Etiology is unknown.
Spontaneous remission is common.
Treated using diuretics and symptomatic therapy (for nausea and
anxiety). May also resort to surgery or ototoxic drugs (e.g.,
gentamycin) to shunt or destroy part of the labyrinth.
424
18-April-2013
Dr. Lise Eliot
Five sensory structures
3 semicircular canals:
horizontal (lateral), anterior, and posterior
orthogonally oriented (all 90
o
angles) orthogonally-oriented (all 90
o
angles)
Dynamic sensitivity: respond to head turns (angular
acceleration) in all three dimensions
No information about static head position
2 otolith organs:
utricle (mostly horizontal orientation, so hair cells point up)
6
( y )
saccule (mostly vertical orientation, so hair cells point out)
Together respond to head movement in all directions.
Dynamic sensitivity (sense linear acceleration in 3D)
Static sensitivity (sense head position w.r.t. gravity)
Orientation of semicircular canals
7
425
18-April-2013
Dr. Lise Eliot
The vestibular apparati are oriented approximately 30
o
above the horizontal The vestibular apparati are oriented approximately 30
o
above the horizontal.
Because humans usually walk with our heads tilted forward by approximately this
angle, the horizontal canals (and utricle) mostly sit at in a plane parallel to the
ground and perpendicular to gravity. When testing function of the horizontal canals
(see Caloric slides), a clinician needs to tip a supine patients head forward by this
angle in order to put these canals in vertical alignment.
The different canals are responsive to the following movements:
The horizontal canals respond best to side-to-side head turns.
The anterior and posterior canals both respond to head tilts, either from
side-to-side or from front to back (dorsoventral).
The left and right vestibular apparati are both structural and functional mirror
images of each other, such that the following pairs respond in physiologically
opposite fashion to a given head turn: opposite fashion to a given head turn:
the left anterior & right posterior canals
the left posterior & right anterior canals
the left horizontal & right horizontal canals
In other words, any head movement that depolarizes hair cells in the left anterior
semicircular canal will hyperpolarize hair cells in the right posterior canal and semicircular canal will hyperpolarize hair cells in the right posterior canal, and
similarly for the other pairings.
426
18-April-2013
Dr. Lise Eliot
A i th dit t t d ti i th tib l As in the auditory system, sensory transduction in the vestibular
system is carried out by hair cells. In the semicircular ducts, hair
cells are embedded in an elevated epithelial structure, the crista
ampullaris, and project their cilia into the cupula, a gelatinous mass
that forms a barrier to endolymph flow along the canal.
The horizontal canals are sensitive to head turns. Because of fluid
inertia, a leftward head turn triggers a net rightward movement of
endolymph in both horizontal canals. (The hair cells and canal
move, but fluid does not, which bends stereocilia; part B.)
This displacement depolarizes hair cells in the left horizontal canal,
and hyperpolarizes those in the right canal.
Hair cells are active only during acceleration (and deceleration)
phase, and transmit this activity to afferent fibers, whose firing rate
is shown in part C There is no displacement in the semicircular is shown in part C. There is no displacement in the semicircular
canals during constant velocity head turning or with a static head
position change.
427
18-April-2013
Dr. Lise Eliot
Static head position and linear acceleration are detected by the two otolith
organs, whose sensory epithelium is known as the macula.
While ampullar hair cells (semicircular canals) are all oriented in the same
direction, macular hair cells are oriented in all directions. Their orientation is
organized with respect to a curved landmark, the striola, consisting of a
narrow trench of small otoconia (see next slide). Hair cells in the utricle are
positioned with their kinocilium closest to the striola, while those in the p ,
saccule are oriented with their kinocilium furthest from the striola. Because
of this curved layout, hair cells in each macula are sensitive to movement in
all directions, permitting each organ a more-or-less complete representation
of space.
Arrowheads indicate side of the hair cell at which the kinocilium is located for
each structure.
The utricular macula is oriented mostly horizontal; the saccular macula is The utricular macula is oriented mostly horizontal; the saccular macula is
oriented mostly vertical.
428
18-April-2013
Dr. Lise Eliot
Macular hair cells project their stereocilia into a gelatinous mass
crowned by the fibrous otolithic membrane. Embedded in this
membrane are small crystals of calcium carbonate known as otoconia,
or otoliths (Greek for ear stones; see scanning EM inset).
The otoconia increase the mass of the otolithic membrane, creating
additional leverage when the head tilts.
Otolith hair cells synapse onto primary afferent fibers, which increase
or decrease their firing rate during sustained changes in head position.
429
Displacement in utricule
(Purves 14.5)
Static
response response
Dynamic Dynamic
response
12
Benign paroxysmal
positional vertigo
(BPPV) ( )
www.dizziness-and-balance.com
Brief episodes of vertigo, lasting a few seconds, triggered by changes
in head position, such as getting out of bed, rolling over, or tipping the
head back to look up.
Accounts for ~20% of all vertigo cases; up to 50% in the elderly.
Cause thought to be dislocation of otoconia which may be triggered Cause thought to be dislocation of otoconia, which may be triggered
by infection, trauma, ear surgery, and even prolonged bed rest.
Detected with Dix-Hallpike maneuver (next slide).
13
Treatments include anti-vertigo medications (anti-cholinergics),
vestibular rehabilitation, and rarely, surgery.
Dix- Hallpike positioning test g
Examiner turns patients
head to one side and then
gently but quickly lowers
her back until head
extends over end of table extends over end of table.
Patient with BPPV will
exhibit nystagmus due to exhibit nystagmus due to
movement of free-floating
debris in the posterior
semicircular canal.
Blumenfeld NeuroExam video #43
14
Hair cells
Receptor cells of the vestibular Receptor cells of the vestibular
apparatus (and cochlea)
Specialized epithelia that Specialized epithelia that
transduce mechanical forces
into voltage changes
130,000 in vestibular apparatus
40-70 stereocilia tapering down 40 70 stereocilia tapering down
from the single kinocilium
In the ampullae of the semicircular canals, all hair cell bundles are p
oriented in the same direction. In the maculae of the utricle and
saccule, hair cells are oriented in relation to the curved striola, so
all directions are represented in both organs
15
all directions are represented in both organs.
Ototoxicity (auditory and vestibular)
Transduction channels are blocked by
i l id tibi ti (i l di aminoglycoside antibiotics (including
streptomycin, gentamicin, tobramycin) which
kill h i ll d l d t t can kill hair cells and lead to permanent
hearing loss and/or vestibular dysfunction.
Certain chemotherapeutic agents
(e g cisplatin) also have well known (e.g., cisplatin) also have well-known
ototoxic side effects.
16
Transduction mechanism
Receptor channels are located near the
stereocilia tips. Their threshold for opening is
endolymph
stereocilia tips. Their threshold for opening is
a mere + 0.3 nm of displacement and their
gating is extremely rapid--a few
microseconds--suggesting a direct
mechanism (i.e., no 2nd messenger).
Stereocilia deflection towards the kinocilium
opens non-selective cation channels,
perilymph
p
depolarizing cell. Deflection away closes
channels and hyperpolarizes the cell.
Transduction channels are active at rest.
Depolarization opens Ca
2+
channels and
leads to neurotransmitter release.
Hyperpolarization reduces release. Hyperpolarization reduces release.
Transmitter release is graded, meaning the
cell does not have to fire an action potential to
release vesicles Instead release varies with
Note:
Inward K
+
current is very
unusual, and attributable
hi h K i i f
17
release vesicles. Instead, release varies with
stereocilia position.
See also Purves Fig 13.8.
to high K
+
composition of
endolymph.
430
Direction coded by primary afferent Direction coded by primary afferent
fi i f fi i f firing frequency firing frequency
18
(Kandel 40.2)
Vestibulocochlear nerve
(Brodal 16 1)
The cell bodies of primary
afferents are located in the
(Brodal 16.1)
afferents are located in the
vestibular (or, Scarpas)
ganglion, at the base of the
internal auditory meatus.
The vast majority of these
fibers terminate in the
vestibular nuclei at the floor
(ventral side) of the fourth (ventral side) of the fourth
ventricle.
A small proportion of A small proportion of
primary afferent fibers
project directly to the
19
flocculonodular lobe of the
cerebellum.
Vestibular nuclei & connections
MLF MLF
(inferior vestibular nucleus)
20
(Brodal 16.16)
(Dorsal brainstem)
Vestibular nuclei
& projections contd & projections, contd
Vestibular nuclei extend from mid-
pons to mid-medulla.
All four nucleisuperior, lateral,
medial, and inferiorproject to the
ascending MLF and bidirectionally ascending MLF and bidirectionally,
through the inferior cerebellar
peduncle, to the cerebellum.
Lateral nucleus alone gives rise to
the lateral vestibulospinal tract.
Medial, superior, and inferior project
to descending MLF (medial
vestibulospinal tract), but most of its
21
p ),
fibers are from the medial nucleus.
(Nieuwenhuys p.136)
Spinal cord schematic
22
Sensory | Motor
431
18-April-2013
Dr. Lise Eliot
The vestibulospinal tracts are essential for balance and rapid postural
adjustments to sudden bodily displacement.
Medial VST (bilateral) originates primarily in the medial vestibular nucleus, and
is located in the descending MLF. It projects only to cervical levels, where it
participates in compensatory head movement reflexes (VCR). For example,
tripping activates the superior (anterior) canals, triggering reflexive activation of
head extensor muscles, pulling the head up.
Lateral VST (ipsilateral only) originates in the lateral vestibular nucleus. It
projects to all spinal levels, where it participates in fast postural adjustments in
antigravity muscles involving axial and proximal extensors (VSR). This is the
larger of the two vestibulospinal tracts.
Decerebrate rigidity is caused, in part, by unopposed action of lateral VST
f ll i b i t l i Hi h t ll i hibit th l t l following an upper brainstem lesion. Higher centers normally inhibit the lateral
vestibular nucleus, so when this inhibition is severed, the lateral VST strongly
activates extensors. (Dr. Ariano will discuss further in her lecture on lesions to
the motor system.)
Patients with bilateral damage to peripheral vestibular apparatus have difficulty
with head and postural stability, resulting in gait deviations. These balance
deficits become more pronounced in low light or when walking on uneven
surfaces, because vision and proprioception also contribute to balance.
Both pathways are influenced by the cerebellum.
432
18-April-2013
Dr. Lise Eliot
While most vestibular processing is subconscious, we are aware of our
bodys posture, balance, and motion.
Some of the MLF fibers from the lateral and superior vestibular nuclei
j t t ti f th t l t i l f th th l project to a portion of the ventral posterior nucleus of the thalamus
(near the somatosensory VPL).
Third-order neurons then project to a broad area of parietoinsular
cortex, bordering the face representation of SI and Brodmanns area 5,
and extending down into the posterior insula (connection is not shown).
Neurons in this area receive multisensory vestibular, visual, visceral
and proprioceptive inputs, contributing to an overall perception of body p p p p , g p p y
movement and orientation in extrapersonal space.
May be the locus of conscious dizziness or vertigo.
433
18-April-2013
Dr. Lise Eliot
Vestibulo- ocular reflex (VOR)
Adjusts eye position to counter changes in head position
(in all directions), to rapidly stabilize image on retina.
Always involves conjugate eye movements. y j g y
A.k.a., Dolls eye reflex
25
(Kandel 40.6)
Counterclockwise head
turning causes net
l k i t f
Horizontal
VOR
clockwise movement of
endolymph.
Hair cells in the left
horizontal canal are
deflected toward the
kinocilium (depolarized);
those in the right canal
are deflected away
26
(hyperpolarized).
VIII
th
nerve firing
increases on the left
side, decreases on the
right side, informing
CNS of head
movement.
434
18-April-2013
Dr. Lise Eliot
When the head moves left, both eyes move right.
Horizontal eye position is controlled by the balance of activity in the lateral and medial
rectus muscles. The lateral rectus is controlled by the abducens nucleus (CN VI) and
the medial rectus is controlled by the oculomotor nucleus (CN III).
These two muscles are reciprocally controlled: excitation of the left lateral rectus is
always accompanied by inhibition of the left medial rectus, and vice-versa.
The horizontal VOR acts on both excitatory and inhibitory circuits to maintain eye
position during head turns position during head turns.
Excitatory circuit: Leftward head turning depolarizes hair cells in the left horizontal
canal, increasing VIIIth nerve firing. In the left medial vestibular nucleus, this excitation
increases activity in neurons that project to the contralateral PPRF, which excites the
abducens nucleus, contracting the right lateral rectus. PPRF neurons also project via
the MLF to the oculomotor nucleus back on the left side, activating conjugate contraction
of the left medial rectus muscle. Both muscles trigger rightward eye movement.
Inhibitory circuit: The left medial vestibular nucleus also sends an inhibitory projection
to the ipsilateral PPRF nucleus, which deactivates left abducens neurons, decreasing
contraction of both the left lateral rectus and (via MLF connection to the right oculomotor
nucleus) the right medial rectus, also causing net rightward eye movement.
Hair cell hyperpolarization in the right horizontal canal has exactly the same effect on
oculomotor and abducens motor neuron activity for each eye (not shown). That is,
produces less excitation of the left lateral and right medial recti through the excitatory p g g y
circuit and disinhibits the right lateral and left medial recti through the inhibitory circuit.
435
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436
18-April-2013
Dr. Lise Eliot
To test the integrity of the vestibular system or to test eye movements in a To test the integrity of the vestibular system, or to test eye movements in a
comatose patient, one can use caloric stimulation.
Patient is supine, with head elevated about 30
o
. This puts horizontal canals in
approximately vertical orientation.
ALWAYS EXAMINE EXTERNAL CANAL WITH OTOSCOPE TO CHECK FOR
INJURY OR OBSTRUCTION.
Warm water (44
o
C) in ear triggers convection current in endolymph that mimics Warm water (44 C) in ear triggers convection current in endolymph that mimics
head turn to that side; cold water (30
o
C) does the opposite.
COLD water triggers slow eye movements toward irrigated side, so fast
phase is OPPOSITE.
WARM water triggers slow eye movements away from irrigated side, so fast
phase is SAME.
COWS (cold/opposite; warm/same)
Both treatments depicted here produce right nystagmus.
437
18-April-2013
Dr. Lise Eliot
In normal patients (1) cool water simulates a turn away from the irrigated side; In normal patients (1), cool water simulates a turn away from the irrigated side;
the vestibular apparatus thinks the subject is turning toward her left, triggering
slow rightward eye movements and a left fast reset (nystagmus). All eye
movements are reversed when the same ear is irrigated with warm water.
In comatose patients (with both cerebral hemispheres dysfunctional), there is no
saccadic reset. Nonetheless, if the brainstem is intact (condition 2), normal slow
movements are produced to either cool or warm irrigation.
In condition (3), cool irrigation triggers movement toward the irrigated ear (due to
decreased inhibition of the right lateral rectus). However, conjugate contraction of
the left medial rectus is destroyed by MLF damage, so the left eye does not move.
This syndrome, known as internuclear ophthalmoplegia, is common in Multiple
Sclerosis. If the patient were conscious, you would note that vergence
movements of the medial rectus are not affected, because the oculomotor
nucleus and nerve are still intact nucleus and nerve are still intact.
In condition (4), the vestibular nuclei or nerves are themselves lesioned, so there
is no VOR to either warm or cool irrigation on that side.
438
A Au ud di it to or ry y, , v ve es st ti ib bu ul la ar r & & g gu us st ta at to or ry y L La ab b O Ov ve er rv vi ie ew w ( (4 4/ /1 19 9/ /1 13 3) )

- Review lecture notes for each of these systems (April 16 & 18).

- Haines: see figures 8-51, 8-52 and 8-11 for overview of
pathways

- Follow with Haines figures 6.10, 6.11, 6.12, 6.15-6.17, 6.22-25
to track each system up through brainstem. Then 7.6, 7.7 to
show VPM and geniculates in stained thalamus

- Neurosyllabus: See figures 18.6, 7.11, 9.3, 9.19, 7.21, 7.19,
7.20, 18.10 for a few brainstem and cortical images of these
primary sensory areas

- Sylvius also has good views, especially in Sectional Anatomy
Auditory System, and Brainstem Sections (Ascending
sensory systems)

439
440
April 22, 2013
Dr. West

The lower motor neurons (LMN, -motor neuron, ventral horn cell) in the
brainstem and spinal cord innervate skeletal muscles to produce
movements. Our movements are guided by sensory stimulation of
receptors in the muscles and joints. We also have input from the visual,
vestibular and auditory systems to be able to make movements.
The sensory and motor systems are interconnected closely and sensory
input is translated by the motor system into muscular contractions to
produce movement programs, or behavior. Movements are based upon
coordination of simple reflexes, two of which will be demonstrated in this
lecture.
Another important function of the motor system is postural stabilization
of the skeleton so that voluntary (directed) movements can be performed.

441
April 22, 2013
Dr. West

Please review the anatomy of the spinal cord in your Haines Atlas (figures 2-
4, 6-1 through 6-5, 8-25 through 8-28) and in Purves chapters 1 and 16.
Remember that there are distinct characteristics for cervical, thoracic,
lumbar and sacral levels of the spinal cord. You will need to be comfortable
with these characteristics so you can identify spinal cord segments.
Information given in your Physiology class will add to the overview
provided in this lecture on skeletal muscle function and properties.
442
April 22, 2013
Dr. West

This schematic shows the major components of the motor system and how
they are related to accomplish movement. There are four principal centers:
spinal cord and brainstem networks (containing -motor neurons, also
called lower motor neurons [LMN] or ventral horn cells) that innervate
skeletal muscles. The -motor neurons may be either excited/inhibited by
descending systems from the motor cortex and brainstem (upper motor
neurons, UMN).
The UMN do not send axons peripherally to innervate the skeletal muscles,
but modify the activity of the spinal cord and brainstem LMN pools and
local circuit neurons (interneurons) of these two major motor system
components.
Two additional regions, the basal ganglia and the cerebellum modify the
UMN and LMN networks. The basal ganglia and cerebellum have no direct
contact with the LMN or interneurons in the brainstem and spinal cord, but
are necessary to achieve a coherent movement sequence. They are often
referred to as modulators of the motor program.

443
April 22, 2013
Dr. West

The white matter of the spinal cord, shown here to the left as dark fibers in
these myelin stained sections, contains ascending (sensory) and descending
(motor) tracts that connect the spinal cord with higher motor and sensory
centers of the brain. The ratio of white to gray matter varies in size and
shape over the rostral-caudal length of the spinal cord.
The -motor neurons that innervate the major muscle masses of the body
and limbs are found in the ventral part of the spinal gray matter, and can be
further subdivided into medial and lateral motor neuron pools on the basis
of whether they innervate proximal or distal muscles.
There is also a rich network of interneurons within the gray matter of the
spinal cord (one is shown in purple above). These neurons connect activity
across the cord by crossing through the mid-region, coordinate dorsal and
ventral components of the spinal cord and also integrate information
between the spinal cord segments.
444
April 22, 2013
Dr. West

All the LMN that innervate an individual skeletal muscle are part of the
motor neuron pool for that muscle. Motor neuron pools have distinct
longitudinal locations within the ventral portion of the spinal cord.
Illustrated here are the spinal cord locations for LMN innervating two
muscles of the lower leg, the gastrocnemius (distributed more laterally in
the spinal gray matter of the coronal section), and the soleus (somewhat
more medial location).
The LMN cell bodies have been labeled using retrograde transport of a dye
that was suffused over the surfaces of the muscles at the region where they
were innervated (the neuromuscular junction). Note that the motor neuron
pools extend through a number of spinal cord segments, (middle diagram)
for both muscles.
LMN pools are shown in the right diagram in a semi-transparent rendering
(we are looking through the dorsal portion of the spinal cord) so that you
can appreciate the rostral and caudal extent of these two motor neuron
pools.

445
April 22, 2013
Dr. West

Motor neurons that innervate flexor muscles are located more dorsally in the
ventral horn than motor neurons innervating extensors. This holds true in
both the cervical and lumbar enlargements of the spinal cord that provide
innervation to the arms and legs, respectively.
LMN innervating muscles of the axial skeleton (torso) are medial, while -
motor neurons innervating muscles of the arm, wrist and fingers proceed
progressively to the lateral edge of the gray matter in the ventral spinal cord.
This organizational scheme is called somatotypy. Interspersed with the
larger -motor neurons (named for their axon size and faster conduction
speed), are -motor neurons. The -motor neurons innervate muscle
spindles, a sensory receptor in the muscles (discussed later). These smaller
diameter -motor neurons also are organized somatotypically.
The intermediate zone of the spinal gray matter is the location of the cell
bodies of the interneurons of the cord. These local circuit neurons receive
information from the descending motor pathways, and integrate reflex
networks with volitional movement generation.

446
April 22, 2013
Dr. West

Local circuit neurons of the spinal cord can project extensively across many
segments and may terminate either bilaterally or ipsilaterally.
Medially located interneurons tend to give rise to bilateral projections in the
spinal cord (navy colored tracts), whereas laterally positioned interneurons
(lighter blue) tend to terminate ipsilaterally.
Interneurons that contact the medial regions of the spinal cord gray matter
control posture and link multiple segments of the cord to coordinate activity
of the arms, legs and torso.
Local circuit neurons that are positioned laterally in the intermediate zone
and contact lateral LMN pools are more involved in the fine control of
precise movements of the distal extremities. The axons of these interneurons
travel for fewer cord segments to integrate voluntary movements of the
fingers or toes.
447
April 22, 2013
Dr. West

The cell body of one -motor neuron in the monkey lumbar enlargement of
the spinal cord was impaled with an electrode filled with dye. This process
fills the LMN, its dendrites and its axon with the dye (this is called
electrophoresis). This type of experiment helps you appreciate the enormous
extent and complexity of the dendritic tree of the LMN.
The drawings in your text and in the lectures show simplified cell bodies
only, with the initial axon only of the -motor neurons. This over
simplification makes the extent of the local circuit networks seem trivial.
Imagine the density of ~1000 cell bodies and their dendrites that make up
the motor neuron pool of the soleus muscle in the lower leg!

448
April 22, 2013
Dr. West

The neuromuscular junction (NMJ) is where the -motor neuron axon
terminates on an individual muscle fiber cell. Please review lecture notes
from Physiology and Purves (pages 97-100) on the NMJ.
The axon bouton, or synaptic terminal ending of the -motor neuron
spreads out into a small plate-like structure with 40-50 individual boutons
where it makes contact with the muscle cell. These presynaptic terminal
plates are filled with vesicles containing ACh, which is released into the
synaptic cleft at the NMJ when the -motor neuron fires an action potential.
In normal circumstances, only one motor end plate innervates an individual
muscle cell. This relationship changes in some muscle diseases. When ACh
binds to its receptor in the NMJ it causes ion channels to open, the muscle
fiber depolarizes, calcium is mobilized and the actin and myosin cross-
bridges slide across one another to cause muscle contraction.
The accompanying image shows the axons of LMN as black-stringed
structures, and the expanded plate-like network of the synaptic termination
onto the skeletal muscle fibers at the NMJ. Also visible are the striations of
the skeletal muscle.
449
April 22, 2013
Dr. West

The LMN, its axon, and all the muscle fibers which that axon innervates are
a motor unit. Motor units respond in an all-or-nothing manner. This means
that when the LMN depolarizes and produces an action potential that
propagates down its axon, all the muscle fibers of its motor unit will
contract as one.
The motor unit is defined as the final common pathway through which all
muscle contraction (and thus movement) occurs. LMN have large,
myelinated axons that conduct action potentials rapidly to the skeletal
muscles. The muscle fibers of individual motor units are not located next to
one another, but are interspersed among muscle fibers incorporated into
other motor units, depicted on the right side of the illustration.
The number of muscle fibers innervated by a single -motor neuron is the
innervation ratio of that motor unit. The innervation ratio of each motor
unit determines the strength of contraction (force) that is possible to
generate in a particular muscle. Motor units innervating muscles controlling
rapid, precise movements requiring little strength (extraocular muscles of
the eye; intrinsic muscles of the hand) have small innervation ratios. This
allows for rapid and precise movements that do not have much force
generation. Motor units with large innervation ratios are often involved in
producing powerful contractions (gastrocnemius muscles during jumping).
450
April 22, 2013
Dr. West

The classifications of motor units are based upon the physiological and
biochemical profiles of the muscle fibers. Three basic motor unit types can
be recognized by:
the speed of the contraction following a single stimulus,
the amount of tension developed in response to multiple stimuli,
how long the tension can be maintained before the motor unit fatigues,
the complement of metabolic enzymes in the muscle fibers (shown in the
image on the right for MyoATPase as an index of cross bridge formation),
the type of cellular energy source preferred (aerobic or anaerobic).
Using this classification, three different types of motor units are described:
1) slow fibers -- S, 2) fast fatigable -- FF, and 3) fast fatigue-resistant -- FR.
Each of these three types of motor unit are mixed within most skeletal
muscles. The type of motor unit that predominates will determine the
physiological performance of a given muscle.
451
April 22, 2013
Dr. West

Comparison of the force (tension developed) and fatigue characteristics of the
three types of motor units is demonstrated here in response to stimulation.
These physiological responses adapt different types of motor units to specific
tasks. Skeletal muscles contain a mixture of the three different motor unit types,
but generally one type predominates and is a clue to the functions performed
by that muscle.
For example, the soleus muscle of the lower leg is largely involved in
maintaining posture. The soleus has an average of 180 muscle fibers for each
motor neuron. This is a medium innervation ratio. The motor units are
classified as slow type and the motor units are innervated by medium-sized
LMN.
On the other hand, the gastrocnemius muscle of the lower leg comes into action
during sudden, rapid changes in body position jumping, kicking a ball and
has an average of 1000-2000 muscle fibers in each motor unit. This is a large
innervation ratio. The predominant motor units in the gastrocnemius are fast-
fatigable, and the motor units are innervated by larger-diameter LMN.
What traits would be exhibited by motor units in the intrinsic muscles of the
hand?
452
April 22, 2013
Dr. West

If two motor neurons (MN) have the same density of ion channels in their
plasma membranes, the smaller of the two neurons will have fewer total
channels and a greater resistance to transmembrane current flow. This is
supported by Ohms Law, where voltage produced equals the current across
the membrane multiplied by the resistance of the membrane (V=IR). Thus, a
given amount of synaptic current will cause a greater membrane potential
change in the smaller neuron, making this cell fire more easily.
Small MN fire action potentials tonically. The response to a stimulus is
shown in the action potential trace to the left of the small MN; there is a
large EPSP that results in firing of the neuron for a given stimulus. This
information is conducted more slowly to a smaller number of muscle fibers,
and typically small MN have lower innervation ratios. This is shown by the
fewer number of axon branches at the NMJ. (Remember the soleus)
Large MN fire action potentials phasically. The response to a stimulus is
shown in the action potential trace to the right of the large MN it takes a
lot of synaptic drive to result in a burst of firing, which is then conducted
rapidly down the axon to a greater number of muscle fibers. Typically, large
MN have higher innervation ratios, and this is depicted as more numerous
axon branches at the NMJ. (Remember the gastrocnemius)
As the synaptic drive reaching the -motor neurons in the ventral horn
increases from segmental (spinal reflexes) and descending motor system
inputs, smaller sized LMN will reach threshold first, and other motor
neurons in the pool will be recruited in order of increasing cell body size.
This concept is termed the "size principle". See Box 16A in Purves (pg 359).
453
April 22, 2013
Dr. West

The amount of tension (force in grams) produced in whole muscles will change
with the LMN firing rate. A typical response to stimulation delivered at low (5 Hz)
stimulation frequency results in two successive muscle twitches. The motor unit
contracts, and then has sufficient time to relax before the next stimulus produces
another contraction. This gives a noticeable return to baseline between the
twitches, as seen in the left-most image.
When the frequency of LMN stimulation has increased to 20 Hz, the twitches
summate and there is not sufficient time to allow complete relaxation of the motor
unit before the next contraction occurs. This gives rise to a stair step rise in force
generated by the motor unit.
When the stimulus frequency of the motor neuron is increased to 80 Hz, an
unfused tetanus occurs. Individual motor unit twitches still can be distinguished,
but further summation is not observed.
When the frequency of the motor neuron stimulus has increased to 100 Hz, fused
tetanus is reached and no more force can be generated from this motor unit. In
fused tetanus, individual twitches of the motor unit are no longer detected and the
motor unit will fatigue when it has expended its cellular energy stores.
This frequency-dependent grading of muscle tension allows the resulting
movement to be performed smoothly with an appropriate amount of force.
*Note: the normal frequency range for human motor neurons is 5 to 60 Hz (thus fused
tetanus is not physiological).

454
April 22, 2013
Dr. West

The different components of a simple reflex arc are identified and explained in this
slide.
455
April 22, 2013
Dr. West

The muscle spindle is a complex kinesthetic receptor. The muscle spindle
receptor is located in parallel to the skeletal muscle fibers, which may also
be called extrafusal fibers.
The muscle spindle contains two types of afferents, which register dynamic
(group l) and static (group ll) aspects of muscle stretch. We will only
consider the larger, rapidly conducting type Ia afferent. The Ia afferents
encircle the equatorial region of the muscle spindle fibers (also known as
intrafusal fibers). When the muscle is stretched, the muscle spindle is
deformed at the central region, opening stretch-sensitive ion channels, and
action potentials are generated in the Ia afferent.
The Ia afferent is the starting point for the stretch reflex, a basic, hard-wired
circuit in the spinal cord that is important clinically.
Note: Stretch of the muscle is the adequate stimulus to produce a response from the
muscle spindle.

456
April 22, 2013
Dr. West

Testing the stretch reflex is a cornerstone in clinical assessment of patients.
The reflex is elicited by tapping the patellar tendon with a hammer (1). This
tap momentarily stretches the extensor muscles crossing the knee joint, and
this is sufficient to fire the Ia afferent. In the spinal cord, the Ia synapses
upon initial segments of dendrites and cell bodies of homonymous (2A,
same muscle in which the spindle receptor is located) and synergist
(muscles that have the same function across the joint as the homonymous
muscle) -motor neurons, and upon local circuit neurons (2B) in the spinal
cord. The firing of the Ia fibers during muscle stretching excites the -motor
neurons innervating the homonymous (3A) and synergist muscle.
The Ia fiber also activates Ia inhibitory spinal interneurons (2B) that will inhibit
the antagonist muscles -motor neurons (2C). Activation of the antagonist
LMN causes contraction in the antagonist muscle (3B), opposing the stretch.
The leg extension (4) that results from the tendon tap may be described as
brisk, normal, slow, or absent.
Thus, the stretch reflex produces activation of the homonymous (and
synergist) muscles and inhibits activity in the antagonist muscle. This dual
activity is termed reciprocal inhibition. The Ia fibers also rapidly adapt (stop
firing) when the muscle changes length and holds a new position.

457
April 22, 2013
Dr. West

When the muscle is actively contracted, as occurs in the antagonist hamstring
muscle following the tendon tap on the patella, the muscle spindle in the
contracting muscle goes slack, and is said to be unloaded. Recordings of Ia
afferent activity in the contracted extrafusal condition show a gap in the spindle
feedback response. Recall that the Ia afferent adapts rapidly, so it will resume its
baseline firing rate when the muscle ceases to contract.
However, the CNS does not like to lose information from any of its sensory
receptors. Thus to continue to generate activity in the muscle spindle, the -
motor system is stimulated in synchrony with the -motor neurons. This is
called coactivation, and in effect keeps the sensitivity of the central nuclear
region of the muscle spindle distended, and consequently, this maintains
continuous Ia afferent activity.
458
April 22, 2013
Dr. West

Muscle spindle sensitivity is affected by the gamma () motor system. The
-motor neurons innervate the intrafusal fibers at their striated, distal
endings (labeled -motor neuron end plate in the figure). When the distal
ends of the intrafusal fibers contract, they will stretch/deform the equatorial
region of the muscle spindle, activating stretch-sensitive ion channels and
setting off action potential discharges in the Ia afferent fiber.
The -motor neurons are intermingled throughout the LMN pool of -motor
neurons that supply the same skeletal muscle. The -motor neurons and the
-motor neurons are activated by the same peripheral and central motor
system inputs. This produces coactivation of the motor neurons so that
they respond in synchrony to information.

459
April 22, 2013
Dr. West

The result of stimulating the -MN system as the -MN causes muscle
contraction is shown here. The diagram on the left shows an unphysiological
condition where the -MN system has been inactivated (this was presented
previously).
The normal condition is demonstrated to the right, where coactivation
of both types of motor neurons has occurred. The Ia response becomes
filled in by contraction of the intrafusal fibers of the muscle spindle. The -
MN system controls the sensitivity of the muscle spindle so they can operate
efficiently regardless of the length of the homonymous skeletal muscle.
460
April 22, 2013
Dr. West

The Golgi tendon organ (GTO) is an encapsulated nerve ending, wrapped
within the collagen lattice of the muscles tendon at its insertion into the
bone. It is located at the muscle fiber junction with the tendon. The GTO is
not arranged in parallel to the extrafusal fibers like the muscle spindle, but
rather is arranged in-series with the skeletal muscle fibers.
When the muscle is passively stretched, most of the change in length occurs
in the muscle fibers because they are more elastic than the tendon fibrils.
This stimulus will fire the GTO afferent axon (Ib fiber). However, when the
tendon is deformed by active contraction of the muscle fibers, the GTO is
stimulated more readily and Ib firing is robust because most of the force is
acting on the tendon directly. This deformation of the tendon stimulates
mechanically sensitive ion channels in the nerve ending to initiate action
potentials in the Ib afferent.
The role of the GTO is to monitor the tension (contraction strength) in its
homonymous muscle. This receptor is important to maintain appropriate
muscle tone (discussed later).
The adequate stimulus for the GTO is deformation of the tendon by either
passive or active contraction of the muscle. The receptor is more responsive
to active contraction.
461
April 22, 2013
Dr. West

The wiring diagram for the reflex established by activation of the GTO is
illustrated. Contraction of the homonymous muscle activates its GTO and
initiates an action potential in the Ib fiber. The Ib activates interneurons that
will inhibit the LMN homonymous muscle this is called the Ib inhibitory
interneuron and lessens the muscles contraction.
At the same time, collaterals of the Ib fiber will activate excitatory
interneurons that will depolarize the LMN of the antagonist muscle. By
contracting the antagonist muscle, the GTO stimulation is diminished in the
original muscle.
This diagram also demonstrates points at which descending motor
pathways can alter the excitability of the local circuit neurons within the
intermediate zone of the spinal cord. These pathways will be discussed in
the next lecture, and are shown as green and black tracts, entering the
intermediate zone of the spinal cord from the lateral side.
462
April 22, 2013
Dr. West

The output from the muscle spindle, combined with other kinesthetic
receptors like the GTO, free nerve endings, and joint receptors, produces
appropriate feedback about muscle tension, length and speed of the change
in muscle length, to the central nervous system. If the intended movement
does not proceed as planned, then corrections (either positive or negative)
can be made to change the outcome. These adaptations of the movement
occur through integration in the cerebellum, to be discussed later in a motor
system lecture.

463
464
April 22, 2013
Dr. West

Reflexes rarely operate in isolation from the rest of the central nervous
system. Rather, they are continuously modulated by upper motor
neurons (UMN) activity to integrate ongoing sensations and process
environmental circumstances to create appropriate movements. UMN
have all of their parts dendrites, soma, axons and axon terminals
totally within the central nervous system. All UMN project upon LMN
of the brainstem and/or ventral horns of the spinal cord and can be
defined in specific pathways. We will examine six major descending
tracts that participate in motor control.

Corticospinal (CS)
Corticobulbar (CB)
Rubrospinal (RS)
Vestibulospinal (VS)
Medial Reticulospinal (MRtS)
Lateral Reticulospinal (LRtS)

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You should review the distributions and functions of the descending
pathways listed on the previous notes page.
The corticospinal tract (CS) is commonly used as the classic example of a
UMN. The neurons of origin are pyramidal-shaped cell bodies located
primarily in the pre- and post-central gyri in cortical layer 5. The axons
are extremely long, descending through all levels of the brain to
terminate throughout the spinal cord. Because of their extended
anatomical length, it is easy to damage the corticospinal axons along
their course. Interruption of the pathway may have devastating and
permanent affects on ones ability to produce crucial movements. We
will discuss this later in the motor system lectures.
The communication between the UMN and LMN allows the executive
motor centers of the brain to coordinate the activity of muscles so that
complex behaviors may be produced.

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This schematic is modified from the Purves text. It is a summary of the
descending pathways involved in coordinating LMN activity. Most UMN
that have their cell body locations in the cerebral cortex (blue) cross the
midline in the medulla at the pyramids. Thus damage to these UMN above
the level of the decussation in the medulla will affect movements on the
contralateral side of the body. Cortical UMN are focused on control of lateral
LMN pools and are critical for skilled movements of the digits.
UMN that have their cell body locations within the brainstem (gray) will
bilaterally influence the activity of LMN. This is shown as a double arrow in
this diagram. These descending brainstem systems principally control
activity in medial LMN pools and thus regulate posture and balance.
The anatomical location of these two types of descending UMN systems are
distinct and enable the differential control of the LMN pools of the ventral
horn of the spinal cord.
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April 22, 2013
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This diagram demonstrates the spinal organization of the descending UMN
pathways. The UMN from the cerebral cortex are crossed at the medullary
pyramid and travel to lateral LMN pools in the dorsolateral white matter
(funiculus) in the spinal cord. The pathway travels the entire length of the
spinal cord and preferentially modifies flexor LMN of the extremities (shown
as blue arrows). Activation of the motor pathways organized in the
descending tracts will influence movements of the hands (feet) and fingers
(toes).
UMN from the brainstem descend through the ventromedial funiculus of the
spinal cord. These tracts primarily target extensor LMN to the proximal
muscles and torso (illustrated as gray arrows). Activation of the motor
pathways located in the ventromedial tracts will influence posture and
balance because of controlling muscles of the torso and proximal extremity.
This organization provides clues to the types of motor behavior that are
influenced by pathways in these two systems.
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April 22, 2013
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The primary motor cortex (Brodmann's area 4, precentral gyrus) is organized
somatotopically and controls the execution of voluntary movement. Most
movements are controlled from the contralateral cortex because the corticospinal
tracts decussate at the medullary pyramid. Cortical motor planning and
sequencing activity begins in widespread areas including the premotor cortices
(Brodmanns area 6) and activity converges onto the pyramidal neurons in the
primary motor cortex, just prior to movement.
Most of the pyramidal neurons in the primary motor cortex influence small groups
of -motor neurons in the lateral pools of the spinal cord by indirect activation of
the interneurons in the intermediate zone. A small proportion of the primary motor
cortex pyramidal neurons have direct, monosynaptic activation (~10% are activated
directly) of the -motor neurons typically the ones that innervate the fingers.
This organization gives the primary motor cortex more precise control over motor
activity compared with any other cortical region. The force of muscle contraction
also is dictated by the firing rate of these cortical neurons.
A small percentage of the primary motor cortical UMN DO NOT DECUSSATE. This
pathway has a different distribution and will be discussed later.
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April 22, 2013
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The corticospinal pathway (CS) takes origin from many different cortical
regions and this is color-coded in this illustration from Blumenfeld. In
addition to the primary motor cortex, the premotor and supplementary
motor cortices, primary somatosensory cortex, and the parietal lobe all make
significant contributions to the corticospinal tract.
The supplemental and premotor cortices are both components of
Brodmanns area 6 and are connected reciprocally to one another. These two
area 6 sub-regions also provide connections to the primary motor cortex,
increasing the integration of information that occurs as a motor program is
planned and then finally executed by activity generated in area 4.
The lateral premotor area (orange) also receives inputs from the parietal
association region (Brodmann's areas 5,7), which as you recall is the sensory
association cortex. The primary motor area receives inputs from the primary
sensory region (Brodmann's areas 3,1,2) as well. Sensory inputs are
important to assist in sensory gating and somato-sensory integration.
Brodmanns areas 1-7 all contribute to CS origins!

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April 22, 2013
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As shown in this figure, the cytoarchitecture of the cerebral cortex has six
layers that can be distinguished using cellular histological stains, such as
Nissl (binds to RNA), as shown here. Approximately 35-50% of the
corticospinal tract fibers originate in cortical layers 5 and 6 of the primary
motor cortex. The neurons in cortical layer 5 include the giant pyramidal-
shaped Betz cells. The Betz neurons represent a small proportion of the axons
leaving the primary motor cortex but have the largest myelinated axons in the
corticospinal pathway, and thus conduct action potentials the fastest.
Other pyramidal neurons also exist in this cortical layer and give rise to
corticospinal UMN. Neurons in cortical layers 2 and 3 receive afferent inputs
mainly from the brainstem and other cortical areas (see Dr. Eliot's notes for
Somatosensory II).
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April 22, 2013
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The CS is crucial for our ability to perform precise, voluntary movements.
Studies examining the effects of electrical activation of various parts of the
cortex have shown that the body is mapped upon the surface of the motor
cortex, but there exists a disproportional representation of the hand, digits,
and tongue. This is referred to as the motor cortex homunculus. The
representation for the face, head, neck and tongue lies next to the Sylvian
(lateral) fissure, and UMN from this region of cortex generate the
corticobulbar (CB) tract.
Pyramidal neurons in one motor cortex hemisphere connect somatotopically
with the corresponding contralateral hemisphere. Inter-hemispheric
connections are most numerous between areas that represent the axial
muscles and proximal extremity areas. This organization facilitates side-to-
side coordination of postural muscles. There are no inter-hemispheric
connections for the cortical regions representing the distal extremities like
the fingers. This organization allows for greater independent movements in
the hands and feet.
There is also a precise somatotopic organization in the premotor areas,
which is similar to that observed in the primary motor cortex.

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April 22, 2013
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The comparison between the homunculi for sensory (left side) or motor (right side)
representations of the body is shown. While there are many similarities, there are
also distinct differences in the cortical space allocated to such regions as the gut
(sensory >> motor), genitalia (sensory >>> motor), pharynx (motor >> sensory) and
shoulder (motor >> sensory).

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April 22, 2013
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Mirror neurons were discovered about 15 years ago in macaque monkeys. These
neurons are located in the premotor cortex and fire when the animal acts, and also
when it sees someone else perform the identical action. Thus, the neuron mirrors
the behavior of another animal (or person) as if it was acting itself. This is depicted
in the top illustration, which shows the monkeys hand on the right, picking up
tidbits from the tray. The response of the mirror neuron is shown below the image.
The response of that same mirror neuron is also shown underneath the image that
reveals the experimenter's hand also picking up morsels on a tray. While not quite
as robust in its response, there is still a very highly correlated number of action
potentials that respond in the monkeys mirror neuron to the experimenter's
behavior.
The lower illustration shows that the monkeys mirror neuron does not fire when
the animal sees the experimenter holding a pair of pliers to pick up the tidbits on
the tray. In effect, if the task lacks salience, the mirror neuron will not exhibit a
corollary discharge.
Cognitive neuroscientists hypothesize that the mirror neuron system provides a
physiological mechanism for understanding the actions of other people, and
learning new skills by observation or imitation. It has also been proposed that
changes in function of the mirror neuron system may contribute to cognitive
disorders. This notion has been advanced especially for autism. This is still a
speculation.
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April 22, 2013
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Activation of mirror neurons is thought to simulate a cognitive
representation of an observed behavior in order to predict the salience of
an action and make an appropriate goal-directed response. Dysfunction
within these systems may underlie some of the neurological deficits
observed in autism. Functional MRI imaging experiments, like the one
presented in the 3-D figure here, show a loss of cooperation between
different brain areas, changes in the volume and the distribution of white
matter, but not a specific alteration in one area of the brain in individuals
with autism.
Part of the communication failure between brain regions could be due to
altered functioning in mirror neurons. The long fiber tracts that connect
to the mirror neurons are not as well organized, speculates Dr. Ralph-
Axel Mller (UCSD) who uses fMRI to study the brains of autistic and
control volunteers during the performance of cognitive tasks. The red
pseudo color shows active neurons in the two brains, while the blue arrow
is the site of mirror neurons in the human cerebrum.

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April 22, 2013
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These images show regions of increased cortical blood flow that can be
detected when an individual is given an instruction to touch the tips of their
index finger and thumb together (upper left) in a simple finger movement
trial.
The subject is next asked to touch each of the fingers of the hand in sequence
to their thumb (upper right, as demonstrated in class!). Notice that the area of
primary motor cortex that is involved in the execution of the movement
does not change, but the added complexity in planning and sequencing the
repetitive movement recruits an area of the supplemental motor region in
the premotor cortex.
Finally, the subject is asked to mentally rehearse the finger movements. Note
that only the supplemental area of the premotor cortex is activated.
The primary motor cortex executes skilled and accurate, repetitive
movements. The supplemental motor area of the premotor cortex is
concerned with mental ideation (internal cues), preparation and
programming the movement. The lateral premotor area is involved during
performance of movements needing directional guidance and anticipation
from sensory inputs (external cues).
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April 22, 2013
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The descending UMN motor pathways may be classified on the basis of their
location in the spinal cord white matter. They are grouped into ventromedial
or dorsolateral tracts, depending upon a number of features. While there are
many descending pathways, you will be responsible for the course and
function of six different UMN descending tracts and their subgroups, listed
above. Although each tract will be described separately, under normal
physiological conditions the pathways will never function alone.

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April 22, 2013
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Axons of the UMNs in the corticospinal tract descend in the posterior limb of the
internal capsule to the cerebral peduncles of the midbrain and through the pons,
where some axons send collaterals to the pontine nuclei. Others continue their
descent into the spinal cord and terminate at various segmental levels.
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April 22, 2013
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The organization of the internal capsule is depicted in this drawing from the text by
Blumenfeld. The orientation is in the horizontal plane. Three distinct regions of the
internal capsule can be defined:
Anterior limb: separates the caudate nucleus from other components of the basal
ganglia (putamen, GPe and GPi). Ascending sensory information is contained in a
middle portion in the anterior thalamic radiation, while descending information is
located on either side of the corticothalamic afferents in the frontopontine and other
corticofugal tracts.
Genu: is located at the turn or knee of the internal capsule, and is nearly exclusive
to the corticobulbar tract in its lateral area. Medial to the genu are continuations of
ascending sensory tracts from the thalamus to the cortex.
Posterior limb: separates the thalamus medially from the basal ganglia laterally.
The more medial components consist of ascending sensory information from the
thalamus in the superior thalamic radiation. In the lateral portions of the posterior
limb, caudal to the genu are located descending corticopontine fibers to the pontine
nuclei, other cortical descending tracts, and the corticospinal tract, organized by A =
arm, T = trunk, L = leg from rostral to caudal, respectively.
The auditory and optic radiations cross through the most caudal portion of the
posterior limb of the internal capsule, emanating from their geniculate nuclei in the
thalamus and headed to terminate in their primary cortices.
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(A) Corticospinal (CS) and corticobulbar (CB) fibers are organized
somatotopically in the posterior limb of the internal capsule. This
organization continues in the midbrain (B). In the midbrain, the CS and CB
tracts are ventrally located, and from the brain surface are visible as the
cerebral peduncles. The corticobulbar tract terminates in the brainstem at
the bulb or medulla, whereas the fibers innervating the leg, trunk and arms
continue to maintain somatotopical organization throughout their course
into the spinal cord, (C).
A helpful mnemonic: Leg is Lateral.
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April 22, 2013
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A small portion of the cortically-derived descending pathway ends in the
reticular formation and in cranial motor and sensory nuclei, disappearing
at the medulla (bulb). This portion is called the corticobulbar pathway,
and allows for willed movements of the head and neck, which are
innervated by the cranial nerves. Corticobulbar fibers make direct or
predominantly indirect connections (via interneurons in the reticular
formation) with all motor cranial nerves.
Most of these CB fibers innervate the LMN in the cranial nerve motor
nuclei in a bilateral manner. Noteworthy exceptions include the
contralateral innervation of the motor nucleus of cranial nerves VII (facial)
and XII (hypoglossal).
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April 22, 2013
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The corticospinal tract regulates the most discrete muscle contractions
via mono- and polysynaptic terminations upon -motor neuron pools
that control finger and toe movements. The lowest-threshold cortical
units innervate the most distal muscles. These same neurons decrease
their firing rate when strong, forceful gripping actions are required,
promoting strength generation over dexterity.
Rubrospinal neurons function analogously to corticospinal neurons,
but the rubrospinal tract innervates more proximal muscles of the
hand and wrist and terminates at upper thoracic/lower cervical spinal
cord.
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April 22, 2013
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The CS descending tract projects caudally as a distinct bundle and forms the
pyramid of the medulla oblongata. The pathway is often called the pyramidal
tract because of this anatomical course. Most fibers (85%) cross at the pyramidal
decussation, and become the large lateral corticospinal tract (LCS). This
descends through the entire spinal cord in the dorsolateral division.
A small part does not cross the midline, and becomes the ventral corticospinal
tract (VCS) that terminates bilaterally at upper thoracic levels of the cord. The
CS tract is the only pathway that passes directly, without synaptic interruption,
from the cerebral cortex to the -motor neurons in the spinal cord.

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April 22, 2013
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The RS pathway descends contralaterally from the red nucleus in the
midbrain and terminates at the distal part of the cervical regions of the
spinal cord, mostly within the intermediate zone. This tract is concerned
with control of muscles in the proximal limbs and also assists in
performance of complex well-learned, rote movements. Good examples of
movements thought to be controlled by the RS pathway are touch typing or
signing your name. The red nucleus receives a large input from the
cerebellum and integrates this important feedback information with the
movements generated by the RS.

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April 22, 2013
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Motor pathways exert control using multiple parallel pathways giving
redundancy to the system. Stronger sustained, forceful muscle contractions
are more associated with reticulospinal neurons which synapse densely
upon interneurons and -motor neuron pools innervating axial muscles and
the proximal extremities.
The vestibulospinal tract is unique because it is not subject to direct cortical
regulation. VS descends through the spinal cord and is important in
maintaining the posture and the center of gravity of the skeleton.
The ventral corticospinal tract is a made up of a minority of the pyramidal
tract fibers that do not decussate in the medulla and may play a role in the
regulation of proximal muscles involved in maintaining posture.

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April 22, 2013
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The vestibulospinal tracts (VS) integrate information from the semicircular
canals and the otolith organs of the inner ear to determine the appropriate
posture of the head and neck before, during and at the end of a movement.
VS neurons are particularly important for controlling posture via feedback
mechanisms that respond to postural disturbances. The pathways terminate
in the intermediate zone of the spinal cord, although some VS neurons
directly contact -motor neurons that innervate the proximal muscles of the
limbs. Fibers in the lateral VS tract are uncrossed (ipsilateral) and descend
the entire length of the spinal cord. Fibers in the medial VS tract project
bilaterally and terminate in the ventral horns of the cervical spinal cord.
These terminations are made predominately onto extensor motor neuron
pools and facilitate extensor motor tone.

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April 22, 2013
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The reticulospinal tracts (RtS) come from diverse and dispersed groups of neurons
in the brainstem tegmentum reticular formation. The descending course of RtS is
similar to the VS pathway. The reticular formation receives an enormous amount of
information from various brain centers and integrates the data to initiate
adjustments that stabilize posture prior to and during ongoing movements.
This pathway is particularly important for feedforward control of posture, a process
where muscle tone is modulated in anticipation of postural changes. A great
example of what this means in practical terms is the ability to get set to strike a
baseball with a bat, knowing that you will need to alter your posture and center of
gravity in response to where the baseball is aimed in the strike zone.
The medullary (lateral) RtS powerfully suppresses extensor spinal reflex activity.
The pontine (medial) RtS facilitates extensor spinal reflex activity.
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April 22, 2013
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You get set to strike a baseball in a particular stance. When the pitcher releases the
ball, you begin to swing your arms holding the bat so you can strike the ball. This
movement creates postural instability. There is a postural adjustment by your
muscles made so you do not fall over, but instead are still able to hit the baseball
solidly.

Some individuals can do this much better than others the more repetition of a
particular motor task (practice) the easier and more successful it will be to achieve a
desired outcome.
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April 22, 2013
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Most CS fibers (85%) cross at the pyramidal decussation, and become the large
lateral corticospinal tract (LCS) of the dorsolateral group of pathways. A small part
of this pathway does not cross the midline and is named the ventral corticospinal
tract (VCS). The VCS fibers terminate bilaterally at cervical and upper thoracic
levels of the spinal cord. The function of the VCS is not fully understood but may
play an role in the regulation of proximal muscles involved in maintaining posture
of the neck, shoulders and upper extremity.
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April 22, 2013
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Ventromedial Pathways
The primary role of ventromedial pathways is maintenance of posture.
These pathways influence the medial LMN pools controlling axial muscles.
These tracts diverge in the spinal cord and synapse with many local circuit
neurons. The ventromedial pathways make bilateral and ipsilateral
synapses. The lateral (RtS-L) and medial (RtS-M) reticulospinal and
lateral (VS-L) and medial (VS-M) vestibulospinal tracts belong to this
classification. The ventral corticospinal tract (VCS) is considered a
ventromedial pathway. Its function is not well defined in humans.

Dorsolateral Pathways
The dorsolateral pathways produce complex voluntary movements.
These pathways modify the lateral motor neuron pools innervating the
extremities. These tracts converge in their terminations and are largely
contralateral. The lateral corticospinal (LCS) and rubrospinal (RS) tracts
are part of this system.
Note: These systems are distinct from adjacent ascending sensory systems (i.e.,
anterolateral system).

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April 23, 2013
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1
Consider all of the elements of the nervous system that must be intact for the
simple reflex arc to function appropriately. In the example of the stretch
reflex, the muscle spindle must be intact, as well as the Ia afferent fiber. The
Ia axons travel in the peripheral nerve, while their cell bodies are located in
the dorsal root ganglion; if these are injured the reflex will not function. The
spinal cord and -motor neurons must be intact at the level where the dorsal
root enters. The ventral root and peripheral nerve carrying the axons of the
-motor neurons must be healthy, and the neuromuscular junction must be
functioning properly.
If any of these elements are damaged or destroyed, the simple spinal cord
stretch reflex will be less responsive than normal, or even absent. Correctly
using and interpreting the muscle stretch reflex is absolutely critical to the
neurological examination.
The stretch reflex is a cornerstone of neurology and also the history and
physical performed on any patient you examine. Moreover, the stretch reflex
is simple to assess with a reflex hammer and careful observation of the
patients response.

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2
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3
These are two photomicrographic images of neurons in the primary motor cortex
(Brodmanns area 4). The image on the left shows a green fluorescent label in a
small population of large-sized pyramidal neurons. These may be Betz cells (B in
subsequent drawings), however to fully determine that, the neuron would need to
be back filled from the spinal cord terminations to label the cell body in the motor
cortex. The blue stain is a counterstain for other cells in the gray matter of the cortex
similar to a Nissl stain to provide the cell density of the region.
The photo on the right uses bright field labeling of pyramidal neurons (horseradish
peroxidase, HRP) to illustrate the cell body, basal and apical dendrites, and a
number of tertiary processes arising from those structures. The axon of one large
pyramidal cell can be seen as a small caliber (it will be myelinated) process leaving
the gray matter of the primary motor cortex. No counter staining has been used in
this preparation.
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4
An UMN must be part of the motor system, but NOT project outside of the central
nervous system. The other CNS motor system components giving rise to UMN that
make direct connections with LMN of the brainstem and spinal cord are:

Cortex (pyramidal-shaped neurons in deeper layers of Brodmanns areas
1,2,3,4,5,6,7) corticospinal, corticobulbar tracts
Red nucleus rubrospinal tract
Reticular formation reticulospinal tracts
Vestibular nuclei vestibulospinal tracts
Colliculus/tectal nuclei tectospinal tract
Pedunculopontine nuclei (PPN, or the mesencephalic locomotor center)
Pathways that have been bolded will have been identified and discussed in
previous lectures.

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5
LMN death results in paralysis of the motor unit it innervates. If all of LMN to a
specific muscle die, that innervated muscle will be paralyzed and is called flaccid.
Typically however, only some of the LMN are affected, and the muscles response is
weakened. Muscle weakness is called paresis, or only a partial paralysis. When a
damaged motor axon does not regenerate, the muscle fibers it innervates will die
due because of disuse and the muscle will atrophy or lose its volume. This will
diminish the response of the stretch reflex a common diagnostic tool. In addition,
the muscle tone will be altered.
Denervated muscle fibers spontaneously contract at slow repetitive speeds, or
fibrillate. Because this is restricted to individual muscle cells it must be detected
using electromyography (EMG). Diseases may cause the LMN to generate
spontaneous action potentials that produce contraction of the motor unit. A visible
ripple or twitch due to motor unit contraction can be detected without a measuring
aid and this is termed a fasciculation. Fasiculations occur when the entire motor
unit contracts.
The combinations of symptoms that can be elicited clinically will assist in
diagnosing the type of disorder. This is crucial to determine whether the lesion
involves higher motor centers and the UMN, the LMN, the peripheral nerve, or the
muscle itself. The injury/disease may also affect a combination of these areas.
Paresis is a commonly used clinical term. We will define it as a weakness that is
due to loss of motor unit and muscle cell functioning. Affected muscles will show a
diminished response compared to that elicited in the same normal, healthy muscle,
typically compared to on the contralateral side of the body.
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6
Weakness is a critical functional consequence of LMN and UMN disease. A number
of terms are used clinically to describe the severity of the damage. Examples are
provided in this table to illustrate these concepts.
In the second portion of the table, the location of the weakness is presented. The
determination of lesion location is one of the most important tasks to acquire for
clinical diagnoses.
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7
Damage to the motor cortex or the axons of the corticospinal tract neurons
anywhere along their course, will demonstrate the hallmark symptoms above.
Because the system is topographically organized, the site of the lesion can be
determined. This is one of the most critical tasks for the clinician Where is the
damage located?
If the stretch reflex is elicited, the individual will exhibit a robust, brisk muscle
contraction, or hyper-reflexia. Clonus is a series of involuntary muscle
contractions due to sudden stretching of the muscle. Clonus causes large
motions that are usually initiated by rapidly flexing the foot upward
(dorsiflexion). It can be examined in any joint of the extremities but is easiest to
see in the ankle or wrist. Only sustained clonus (5 beats or more) is considered
abnormal.
The sign of Babinski is produced by running a sharp object along the sole of the
foot, from the heel to the toes. The abnormal response is for extension of the big
toe and fanning of the other toes. A later slide shows the movement.
Hypertonicity is an increase in muscle tone. This muscle stiffness is due to the
loss of the inhibitory influences exerted by the cortex on postural centers in the
brainstem (reticular formation, vestibular nuclei) as well as inertia, mechanical
joint properties and altered - and - motor neuron output.
Depending upon where the lesion is in UMN injury, there may also be loss of
fine movements of the fingers. This loss of fractionated movements frequently
occurs with lesions in the internal capsule or corticospinal tract. Loss of
fractionated movement cannot be recovered even with extensive rehabilitation.
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8
Clonus
Rapid series of rhythmic contractions,
elicited by stretch of the muscle. This
activity is caused by over-active stretch
reflexes and the loss of the inhibitory
input from the motor cortex.
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9
Tone is the resting level of tension in a muscle and may be elicited when the
examiner moves the limb through its range of motion. Tone is assessed
through feeling or sensing resistance as the examiner guides a joint through
passive range of motion. This resistance is caused by the combination of
inertia, mechanical properties of the joint, and output from the and motor
neurons. Hypertonicity may be indicative of an UMN lesion, which
disinhibits spinal motor neurons, increasing their output and resulting in
tonic excess firing of muscle fibers. Some examples of increased tone due to
UMN lesions are spastic tone and rigid tone.
Spastic tone: is due to corticospinal tract disease and varies with the speed of
movement. The examiner may have a difficult time perceiving spastic tone if
the joint is moved slowly through its range. If the movement is made quickly,
there will be a sudden increase in tone part way through the arc, causing a
catch or a block, as though the muscle hit an obstacle and just stopped.
Rigid tone: is due to a lesion involving the basal ganglia and/or their
connections. It is described as a diffuse increase in muscle tone to passive
range of motion. There is a constant level of muscle tone that affects both
agonist and antagonist muscles and is present equally from the beginning to
the end of a movement regardless of the speed of the movement. In
cogwheel rigidity, there is a jerky quality to the hypertonicity. As the
extremity is manipulated, it seems to give way in a series of small steps as if
the limb were attached to a heavy cogwheel or ratchet.
See Box 17E, page 397 in Purves.
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10
With the clasped knife phenomenon the examiner will encounter significant
resistance when attempting to passively flex the patients extended limb. (For
example, passively bending the patients elbow or passively bending the
patients extended knee.) This resistance is felt upon initial contact but, with
further examiner pressure, appears to melt away yielding motion into
flexion. Though traditionally thought to be due to autogenic inhibition (and
thus GTO activity) current theory is that clasped knife is due to stretch
excitation (muscle spindle activity) that eventually falls below threshold
resulting in muscle relaxation.
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11
The sign of Babinski will diagnose a lesion of the corticospinal (CS) tract.
When the plantar surface of the foot (the sole) is stroked firmly along the
path indicated by the dotted line, the normal response is shown to the left as
flexion of the foot and toes. The positive response is an extension of the big
toe and fanning of the toes, shown to the right. Consider whether this type
of response can be detected when -motor neuron damage is present.
Fibers of the CS tract are well isolated in the pyramids of the medulla and
can be damaged at this point. Following unilateral pyramidal knife cuts, a
monkey can move around normally. However the fingers cannot move
independently and the animal cannot pick up a morsel of food for some
time even though the hand can be used effectively for climbing. Gradually
over some weeks the monkey regains the ability to grasp objects with its
hand, but the movements are clumsy and consist of simultaneous flexion of
all fingers (like a scooping action).
The ability to move the fingers independently of each other, so-called
fractionated movement, never returns. The precision grip where the thumb
opposes the index finger is permanently lost. In humans with damage to the
motor cortex or the pyramidal tract (often a vascular insult within the
internal capsule), the most enduring deficit is an inability to perform
fractionated finger movements. Lesions of the internal capsule in humans
also produce other changes in muscle tone and reflexes that are not seen in
monkeys.

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12
Damage to the LMN cell body or its axon will produce characteristic symptoms.
The loss of the reflex arc through interruption of the circuit will result in
diminished or absent deep tendon reflexes when tested. This symptom is known as
hyporeflexia if some motor units are still intact. If there is complete absence of the
reflex, areflexia, the muscle is denervated completely.
Because the muscle has lost its innervation, it will be weak upon contraction
(paresis) or if all of the motor units in the muscle are denervated, the patient will
exhibit paralysis. This will produce loss of the muscles mass through atrophy due
to disuse of the muscle cells and motor units.
When muscles lack innervation, their cell membrane begins to deteriorate and the
excitability of the cells loses synchrony. At the level of an individual muscle cell,
these spontaneous contractions are termed fibrillations and are measured using the
EMG (electromyography). If an entire motor unit is affected, the patient and the
examiner will note fasiculations that are visible to the eye.
Because the damage occurs in the motor neurons, the sensory information is not
affected and this finding can be used to distinguish LMN disease from those issues
that interrupt the peripheral nerve or damage the muscles directly.
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April 23, 2013
Dr. West

13
1. Loss of innervation leads to paralysis of the motor unit or entire muscle.
2. Lack of use leads to atrophy of the motor unit/muscle (disuse atrophy).
3. Muscle tone is reduced because the effector limb or the target (muscle) is
damaged. This also occurs with interruption of the peripheral nerve.
4. Muscle cells become unstable because of loss of innervation and
randomly contract, generating fibrillations.
5. Entire motor units contract randomly due to damage of the LMN axon
resulting in fasiculations that can be felt and seen by the patient.
6. The loss of the efferent limb (LMN axon) of the reflex arc, or the effector
(muscle) interrupts the reflex arc, resulting in areflexia.
7. The afferent limb of the reflex also is involved in peripheral nerve injury,
and sensory loss occurs. This is a diagnostic distinction from the LMN
symptoms.

503
April 23, 2013
Dr. West

14
This table summarizes the differences in symptoms seen with lesions in the clinical
situations. These signs show the distinguishing symptoms between damage to the
UMN versus the LMN. These signs show the distinguish symptoms between
damage to the LMN or its ventral roots and issues with the peripheral nerve.
504
April 23, 2013
Dr. West

15

Decerebrate Rigidity
This situation presents as an increase in extensor muscle tone, caused by
transection of the brainstem rostral to the vestibular nuclei. This
transection denoted by the cut at "A" interrupts the cortical connections to
the reticular formation and their subsequent influence of the vestibular
nuclei and the reticular formation. These two areas, the reticular formation
and the vestibular nuclei give rise to the pathways that control postural tone
to axial (medial) motor neuron pools. Decerebrate posture occurs because of
the tonic VS and RtS stimulation of - and - motor neuron pools of extensor
muscle groups. The extensor muscles of the limbs and neck exhibit
hyperactivity and increased muscle tone.

Blumenfeld 3.5B
505
April 23, 2013
Dr. West

16
Decorticate Rigidity
This situation is seen as an increase in extensor muscle tone of the lower
extremities, while flexion occurs in the upper limbs. The decorticate posture occurs
when the brainstem is transected rostral to the level of the red nucleus (shown by
"B"). In this situation, only the direct corticospinal tract descending to the LMN
pools innervating more distal muscles of the extremities is interrupted from cortical
influence. Brainstem motor systems (VS, RtS and RS) are all intact and connect
with the spinal cord.

Blumenfeld 3.5A
506
April 23, 2013
Dr. West

17
Symptoms associated with loss of both UMN and LMN are seen in ALS; also called
Lou Gehrigs Disease after the famous NY Yankee 1
st
baseman [1925-1938] who was
afflicted with the disease and whose baseball jersey was the first EVER to be retired
from baseball see the web site, http://www.lougehrig.com/. In individuals who
have ALS, the intellect remains intact, so the person is aware of their deteriorating
condition. Some LMN are spared most notably autonomic neurons that control
sexual, bowel and bladder function. The extraocular muscles also are spared. LMN
that are not targeted by ALS have high levels of calcium binding proteins while
ALS-vulnerable LMN do not express these proteins. This suggests that vulnerable
motor neurons are less able to recover from increases in intracellular calcium
levels.
In the 10% of genetic cases (familial ALS), the cytosolic anti-oxidant enzyme SOD1
(copper/zinc super oxide dismutase) is mutated and the disease is inherited in an
autosomal dominant fashion. A rare autosomal recessive form of ALS is expressed
in juveniles and molecular analyses show that the protein alsin (GTPase regulator)
is mutated.
Disruptions in other proteins associated with hereditary forms of ALS suggest a
multi-gene disease. The basis for spontaneous ALS (~90% of cases) is unknown.
Purves provides a discussion of ALS in Box 16D, page 373.
MD Consult ALS : http://www.mdconsult.com/das/pdxmd/body/318651010-
3/0?type=med&eid=9-u1.0-_1_mt_1014439

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April 23, 2013
Dr. West

18
LMN traits: fasiculations, muscle biopsy results, EMG test results,
NCV (nerve conduction velocity) is normal

UMN traits: hyperreflexia, stiffness of limb muscles (hypertonicity),
oral motor signs, breathing problems

Both: left foot drop and hand weakness, speech problems, swallowing
difficulty
508
April 23, 2013
Dr. West

19
These brain sections have been stained using H&E. The normal motor
cortex shows six distinct layers, and the cell bodies of the large pyramidal
neurons are visible in layer V most of these give rise to the corticospinal
tract.
A section of the motor cortex from an individual who died from
complications associated with ALS is seen to the right. The six layers of
the neocortex can no longer be distinguished. The pyramidal neurons are
absent, resulting from degeneration of UMN as the disease progresses.
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April 23, 2013
Dr. West

20
510
April 23, 2013
Dr. West

21
Dystonia: occurs in any muscle group (except extraocular and
sphincter muscles); onset may be associated with specific voluntary
movements (e.g., writer's cramp). The movement(s) worsens with
anxiety, heightened emotions, and fatigue, but decrease with sleep
and relaxation. These symptoms result in sustained postural
changes and exhibit twisting and repetitive movements.

Ataxia: an unsteady, staggering and rolling gait, inability to
accurately reach a target, intention tremor, and associated with
cerebellar disease.

511
April 23, 2013
Dr. West

22
The diagnostic measures that are employed to assess deficits of the motor
system start with the least invasive first. The order of tests listed here would
be the logical sequence to follow to distinguish what type of lesion has
occurred in the patient.
Reflex assessment- Deep Tendon Reflexes (DTR) use a sharp tap to the
tendon to stretch the muscle
Sensory assessment stimulate mechanoreceptors to initiate sensation
EMG either surface or needle electrodes inserted into the muscle belly
measure the contractions of muscle fibers
Nerve conduction see Blumenfeld page 350, figure 9.9 for a clear
explanation of this procedure
Enzyme levels taken from the blood to screen for LDH, myosin kinase,
etc., as indications of general muscle damage
MRI imaging specific areas of the body to determine soft tissue damage
Muscle biopsy a small sample of muscle is taken (using a slender
needle) to get specific information on histology and enzymes in a designated
muscle

512
April 23, 2013
Dr. West

23
QUESTIONS:

Identify the type of disease (UMN, LMN, peripheral).
List the hallmark signs of diseases in this part of the
motor system.
What treatment would be administered?
What is the prognosis?

http://www.vhct.org/case399/index.htm
http://openlearn.open.ac.uk/file.php/2642/polio_case_study.pdf
513
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April 23, 2013
Dr. West

515
April 23, 2013
Dr. West
It is important for you to recognize named motor system pathways (there are 6 you
must know!) and how they descend through the neuraxis. Be aware of the
neighboring structures as this will help to diagnose where an injury or lesion has
occurred in the brain.
516
April 23, 2013
Dr. West
The lateral aspect of the brain is drawn on the left and it corresponds closely to the
fixed specimen to the right of the slide. The central sulcus divides the pre- and post-
central gyri, which correspond to the primary motor and sensory cortices,
respectively.
Note that the representation of the body can be distinguished at specific locations of
these cortical strips. This organizational pattern is known as the homunculus.
Functional control of muscles will be on the contralateral side of the body because
the corticospinal pathways are crossed at the medulla. The corticobulbar tract tends
to project bilaterally to cranial nerve motor nuclei.
517
April 23, 2013
Dr. West
The medial aspect of the brain is demonstrated here. The remainder of the lower
extremity of the body is mapped onto this portion of the cerebrum.
518
April 23, 2013
Dr. West
Brodmanns area subregions of the cortical contribution to the pyramidal
(corticospinal) tract are demonstrated. The drawing to the right shows the primary
perfusion zones of the MCA (middle cerebral artery). Recall how a stroke in this
principal artery will produce substantial deficits in patients motor and sensory.
519
April 23, 2013
Dr. West
The blood supply for the medial surface of the cortex is shown here and how it
perfuses the motor cortices. Note that there are watershed areas along the dorsal
aspect of the cerebrum that may also be perfused by branches of the MCA.
520
April 23, 2013
Dr. West
The different Brodmanns areas contributing to the origins of the corticospinal tract
are shown in these images from Blumenfeld. Extensive reciprocal connections occur
between the regions. This reciprocity contributes to widespread cortical
involvement in the planning and generation of movements in response to sensory
input from the environment.
521
April 23, 2013
Dr. West
The vascular supply to the entire corticospinal (CS) tract is shown to the left in this
drawing. The right side shows the levels of the neuraxis and the components of the
CS, with the regions of the body color coded for ease of understanding.
From rostral to caudal, the arteries are:
ACA
MCA
PCA
Anterior Spinal a.
Posterior Spinal a.
Vasocorona
522
April 23, 2013
Dr. West
This coronal section has been made at the level of the anterior nucleus of the
thalamus. The slight protrusion into the lateral ventricle made by this nucleus is
visible, with the white, myelinated mammillothalamic tract coming to terminate in
the structure. Be sure you can identify the mammillary bodies on the ventral
surface of the cerebrum, just dorsal to the basilar pons.
This section also shows the full development of the internal capsule
corona radiata leaving the cortical mantle
anterior limb separating the caudate and putamen
posterior limb separating the putamen, globus pallidus from the thalamus
523
April 23, 2013
Dr. West
The fixed brain section top is in the horizontal (axial) orientation. It is located at
the level of the genu of the internal capsule. In this orientation, it is possible to view
all three sections of the internal capsule (anterior, genu and posterior) and their
relationships to other structures. The basal ganglia and thalamus have been color
coded to help establish the boundaries they provide to the posterior limb.
The images below the fixed brain section are MRI scans (inversion recovery on the
left; T2-weighted on the right) are at the same plane. Remember that myelinated
tracts are black and CSF is white in the T-2 weighted images.
524
April 23, 2013
Dr. West
Another fixed brain slab, prepared in the horizontal (axial) orientation shows the
somatotopy of the posterior limb of the internal capsule. Note that the area that
carries descending fibers from the facial representation of the motor cortices is most
medial, and in closest proximity to the genu. The representations for the arm, trunk
and leg progress more laterally and caudally in the posterior limb.
Clinical comments: small lacunar strokes in the internal capsule may only impact a
portion of the bodys representation.
525
April 23, 2013
Dr. West
The functional organization of the cortical motor systems are shown in this slide,
modified from the Haines atlas. The corticobulbar (CB) tract is located more
medially in the crus cerebri than the corticospinal pathway. This pattern has
implications for the patient following damage to the blood supply or trauma in the
midbrain.
526
April 23, 2013
Dr. West
At a more caudal (distal) level of the midbrain, the cortical motor pathways still
maintain the same relationship CB is more medially located than the CS tract. The
somatotopy for the body (orange area) also stays constant, arm torso leg as one
proceeds from medial to lateral in the crus cerebri.
527
April 23, 2013
Dr. West
Anatomical organization of the pathways is still constant in the caudal midbrain.
Note that the fibers are more condensed as they descend through the brainstem.
This is due in part to the CB tract making terminal connections onto various cranial
nerve motor nuclei.
528
April 23, 2013
Dr. West
The CS tract is seen as a number of dispersed, myelinated tracts coursing through
the ventral aspect of the pons. It is interrupted by the transverse fibers of the ponto-
cerebellar system that makes up the middle cerebellar peduncle. The CB pathway is
no longer visible as a distinct system.
529
April 23, 2013
Dr. West
The corticospinal pathway maintains its ventral position throughout the pons,
surrounded by the transverse fibers that form the middle cerebellar peduncle
(MCP). Appreciate that rootlets from the facial nerve will travel just lateral to CS
fibers, and axons from the abducens nerve will pass through the fibers of the
corticospinal tract.
530
April 23, 2013
Dr. West
Appreciate that the CS pathway is more tightly condensed as it descends in the
pons.
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April 23, 2013
Dr. West
In the medulla, the CS tract forms the pyramid which is easily seen on the ventral
surface of the brainstem. The inferior olivary complex associated with the
cerebellum and discussed later is dorsolateral to the descending motor pathway.
532
April 23, 2013
Dr. West
About 90% of the CS tract crosses in the medullary pyramid and provides the
anatomical basis for motor expression on the contralateral side of the body from the
cortical origins. The 10% that remains uncrossed becomes the anterior corticospinal
tract. Note the locations of the RtS and RS pathways (color coded) in relation to the
spinal trigeminal nucleus.
533
April 23, 2013
Dr. West
The ventral surface of these whole brains demonstrates the prominent pyramids in
the medulla. On the right hand image one can see the actual crossing of the fibers at
the medullary surface.
534
April 23, 2013
Dr. West
The lateral view to the left shows the distribution of the spinal nerves. The brackets
refer to the location of the spinal nerves as they leave the intervertebral foramina.
These positions do not correspond exactly to the spinal cord segments. The image
on the right is a dorsal view, showing the major anatomical landmarks of the CNS,
spinal cord and cauda equina as the distal terminations.
535
April 23, 2013
Dr. West
This dissection shows the spinal cord, in situ with the peripheral nerves attached.
What level of the spinal cord is this? What is your reasoning for this decision?
536
April 23, 2013
Dr. West
The myelin-stained sections to the left show the four regions of the spinal cord. Be
sure that you can identify the level based upon:
Gray/white matter ratio
Gray matter shape
Presence/absence of fissures/sulci
Shape of the cord as a whole

537
April 23, 2013
Dr. West
The distribution of the major descending motor pathways are shown in this cervical
spinal cord section. The locations for these tracts may be organized into dorsolateral
or ventromedial. Recall the characteristics of the pathways in these two broad
categories.
538
April 23, 2013
Dr. West
Note that the anterior CS and the RS pathways are no longer present at this level of
the cord.
539
April 23, 2013
Dr. West
Note the change in white/gray matter ratio at this spinal cord level. What are the
small ovoid structures at the dorsolateral periphery of the cord section?
540
April 23, 2013
Dr. West
A major characteristic for sacral cord sections is the large amount of gray matter
compared to white matter. Why does this occur?
541
542
1
April 24, 2013
10 AM
Dr. Ariano
Visceral Nervous System
Autonomic and Enteric Innervation
Dr. Marjorie Ariano
Professor of Neuroscience
Associate Dean for Undergraduate Studies
BSB 1.330
Purves: Chapter 21
Thevisceralmotorsystemisalsoknownastheautonomicnervous system
anditcontrolsinvoluntarysmoothmuscleandcardiacmuscleactions.It
alsocontrolsimportantglands.Thebalanceofactivityinthissystem
maintainshomeostasisofthebody.
543
2
April 24, 2013
10 AM
Dr. Ariano
Learning Objectives
Describe the neural components of the
visceral motor system
Know the sympathetic circuitry and compare/
contrast it with the somatic system
Know the parasympathetic circuitry and
compare/contrast it to sympathetic circuits
Be able to describe the functional autonomic
innervation of the eye and the bladder
Define the anatomy and function of the enteric
nervous system
Identify the symptoms of Horners syndrome
Attheconclusionofthelecture,youshouldbeabletoachieveallofthese
learningobjectives.ReadPurvesChapter21toreenforcetheseconcepts.
544
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April 24, 2013
10 AM
Dr. Ariano
Autonomic Nervous System
Sympathetic
Preganglionic neurons
Postganglionic neurons
Parasympathetic
Cranial preganglionics
Sacral preganglionics
Enteric
Thevisceralorautonomicnervoussystemcontrolsinvoluntaryactionsof
smoothandcardiacmuscle,andsecretionsfromglands.Ithastwo
importantdivisions,thesympathetic (SNS)andparasympathetic (PNS)
components.Athirdunit,theenteric systemalsoisrecognizedand
functionssemiindependentlyfromthevisceralnervoussystem.The
entericnerveplexusandtheirinnervationarelocatedwithinthemuscle
layersinthegutwallandassistsinperistalsis.
IngeneraltheSNSmobilizesthebodyinthefightorflight response
whilethePNSisconcernedwithvegetativefunctions.Bothsystems
contributetothebodysabilitytoestablishandmaintainhomeostasis.
ThehypothalamusisthemajorCNScontrolcenterforthevisceralmotor
system,analogoustotheprimaryandsecondarymotorcorticesin the
oversightofthesomaticmotorsystem.
545
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April 24, 2013
10 AM
Dr. Ariano
Autonomic
Nervous
System
Sympathetic fibers
Parasympathetic fibers
Preganglionic
Preganglionic
Postganglionic
Postganglionic
Brainstem
C1
C8
T1
T12
L1
L2
S2
S1
S5
Intracranial vessel
Eye
Lacrimal gland
Parotid salivary gland
Sublingual &
submandibular
salivary glands
Lungs
Heart
Stomach,
Small intestine
Liver
Spleen
Adrenal
Kidney
Gut
Pancreas
Gut
Urinary bladder
Sex organs
Anoverviewofthesympathetic andparasympathetic divisionsofthe
visceralmotorsystemispresentedinthisdiagramandintable21.1(Purves).
Thetwosystemsworkinphysiologicaloppositiontooneanother, have
differentanatomicalorganization,andreleasedifferentneurotransmittersat
theirsynaptictargets.
TherostralintegratingCNScontrolcenterfortheautonomicsystemisthe
hypothalamus,locatedinthediencephalon.Descendingautonomicpathways
fromthehypothalamustothespinalcordusethreeprincipalpathways:1)the
dorsallongitudinalfasciculus,2)themammillotegmentaltract,and3)the
medialforebrainbundle.Thesetractsdescenduncrossedthroughthe
brainstem.
Thesympatheticneuronslocatedinthethoracicspinalcordaretermed
preganglionic neuronsandaredistributedinadistinctcellcolumnfromT1to
L2,inthelateralportionofthegraymatterknownastheintermediolateral
horn.
Thepreganglionicparasympatheticneuronlocationstendtobein comparable
lateralareasofthesacralspinalcordgraymatter.Therearedistinct
parasympatheticnucleiinthebrainstemthatmakeupthecranial portionof
thePNS.ThecentraldescendingPNSpathwaysarenotwelldefinedintheir
coursecomparedtothoseoftheSNS.
546
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April 24, 2013
10 AM
Dr. Ariano
Spinal Circuitry
Purves, fig 21.2A
Thoracic spinal cord
Sympathetic chain
ganglion
Dorsal root
ganglion
Sympathetic trunk
Visceral efferent fibers
White communicating White communicating ramus ramus
Peripheral nerve
Gray communicating Gray communicating ramus ramus
Prevertebral ganglion
To viscera
To blood vessels
and skin
TheorganizationoftheSNSpreganglionic andpostganglionic neuronsare
drawnhere.Preganglioniccholinergic neuroncellbodiesarelocatedinthe
intermediolateralhornofthespinalcordatT1L2levels.Themyelinated
preganglionic axonsleavethespinalcordintheventralroots,andareknown
aswhitecommunicatingrami becausemyeliniswhiteincolor.Thesewhite
rami enterthesympathetictrunk,whichrunsrostrally andcaudallynearthe
spinalcordbutoutsidethebonyvertebralcolumn,andthensynapseinvarious
sympatheticchainganglia.
ThesecondneuronintheSNScircuitislocatedinthesympatheticchain
gangliaandistermedthepostganglionicneuron. Itusestheneurotransmitter
norepinephrine.Theaxonsofthepostganglionicneuronsareunmyelinated,
andcalledgraycommunicatingrami.Axonsofthegraycommunicatingrami
travelintheperipheralnervestoinnervatetheirtargets(smoothmuscles,
glands).
AnotheranatomicalvariantofthisSNScircuithasthepreganglionic neurons
continuetothepostganglionic neuronslocatedinprevertebral ganglia.This
occursforsympatheticinnervationofthethorax,abdomen,andpelvis.The
prevertebral gangliahavespecificnames,suchastheceliacganglia,superior
andinferiormesentericganglia,andthesuperiorcervicalganglia.Theseare
showninTable21.1(Purves).
ThefinalsubsetofSNSpreganglionic nervesinnervatetheadrenalmedulla
(seeillustrationonpreviousdrawing).Theadrenalglandproducesthe
neurotransmitterepinephrine,whichisreleasedintotheperipheralcirculation.
AfferentSNSfeedbackreturnstotheCNSusingthesomaticnervoussystem
painandtemperaturefibers.
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April 24, 2013
10 AM
Dr. Ariano
SNS Somata
Purves, fig 21.2B
Spinal
cord
Intermediolateral
Cell column
T1-L2
Intermediolateral Intermediolateral
cell column cell column
Ventral horn
Lateral horn
Intermediate
gray zone
Dorsal horn
T1
L1
S1
Coc1
ThelocationoftheSNSpreganglionic neuronpoolisshowninthis
schematicofthevertebralcolumn.
Thethoracicspinalcordcrosssectionstotherightsidedemonstratethe
characteristicshapeofthespinalcordgraymatterinthethoraciccord
level,withthelateralgraymatterexpansionforthepreganglionicSNS
motorneuronsintheintermediolateralcellcolumn intermediolateralcellcolumn.
Notethemorecompactsizeoftheventralhornatthislevelofthespinal
cord,whichisduetofewernumbersofmotorneuronsthatonly
innervatethemusclesoftheaxialskeleton.
548
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April 24, 2013
10 AM
Dr. Ariano
Parallels in Organization
Somatic Somatic
Connections Connections
Autonomic Autonomic
Connections Connections
Somatic
afferents
Visceral
afferents
Skeletal
muscle
Smooth muscle,
Cardiac muscle,
glands
Hypothalamus
Thalamus
Sensorimotor Cortex
Cingulate Cortex
Ascending
Descending
Segmental
Ascending
Descending
Segmental
DCN
Thecircuitryandorganizationofthesomaticinnervation(left) andthe
autonomicsystem(right)aredifferent.Acomparisonismadeat thethoracic
spinalcordleveltodemonstratethetwosystems.
Bothsystemshavedescending descending corticalpathways,originatinginthe
primarysensorimotor(somatic)orcingulate(autonomic)cortices.The
descendingautonomicpathwayhasarelay(synapse)inthehypothalamus
beforedescendingtothespinalcordlowermotor(preganglionic) neurons.
LMNforeachsystemarecholinergicandhavemyelinatedaxonsthat
projectthroughtheventralrootstotheirtargetstructures.TheSNSsynapses
atanautonomicgangliaenroutetoinnervateitstargets(disynaptic
connection).Thesomaticsystemdirectlyinnervatesskeletalmuscletargets
(monosynaptic).
ThelocationoftheLMNforthesomaticsystemistheventralhorn.Thesite
ofthesympatheticLMN(preganglionicneurons)isinthespinalcord
intermediolateral horn,spanningT1throughL2spinalcordsegments.Both
typesofLMNuseAChastheirneurotransmitter.
Peripheralafferentinformationreturnstothespinalcordatthesegmental
level,somebifurcatetoparticipateinalocalcircuit localcircuit feedback(reflex).Other
afferentsdirectlyascend ascend tothedorsalcolumnnuclei(somatic)orto
hypothalamic(autonomic)nucleitosynapse.Someinputscontributetoboth
thesegmentalreflexesandascendingsystems.
549
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April 24, 2013
10 AM
Dr. Ariano
Efferent Comparisons
Skeletal muscle
(thorax)
Skeletal muscle
(tongue)
Autonomic ganglia
Thoracic
Spinal cord
SNS SNS
Caudal
Medulla
PNS PNS
Glands,
Smooth muscle
Glands,
Smooth muscle
Inferior
Olive
Pyramidal
tract
M
e
d
.

L
e
m
n
i
s
c
u
s
4
th
ventricle
Fasciculus
Gracilis
LCS
Theautonomicsystemisdrawnontheleftsideofeachsectionatthespinal
cordandbrainstem(medulla)levels.Thesomaticsystemisshown onthe
rightsideofeachsection.
Atthespinallevel,cholinergicpreganglionic cholinergicpreganglionic efferentsintheautonomic
systemaremyelinated,exitthroughtheventralrootsandsynapsewithin
autonomicganglia.Thepostganglionicfiber(dashedline)thentravels
variabledistancestoinnervatethetargetstructures,makingadisynaptic
circuit.Thesecondneuroninthecircuitusesnorepinephrine asatransmitter.
CholinergicLMN CholinergicLMN inthesomaticsystematthethoracicspinalcordlevel
projecttoaxialskeletalmusclesandinnervatetheirtargetsdirectly,makinga
circuitthatismonosynaptic.
Thedisynaptic andmonosynapticconventionisfollowedatthebrainstem
levelaswell.Cholinergic LMN cellbodiesarelocatedinthedorsalmedulla
alongthefloorofthe4
th
ventricle.Thevisceralnucleusinthiscaseisthe
dorsalmotornucleusofthevagusnerve,anditislateraltothesomatic
component,whichisthehypoglossalnucleus.Thedorsalmotornucleus
preganglionicneuron preganglionicneuron hasalongaxon,whilethepostganglionicneuron
(dashedline)liesnearthetargettissuetobeinnervated.Thedorsalmotor
nucleusofthevagusprovidesinnervationtotheheart,lungs,gut,etc.The
hypoglossalnucleus hypoglossalnucleus innervatestheskeletalmusclesofthetonguedirectly.
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April 24, 2013
10 AM
Dr. Ariano
A
C
B
Dorsal motor
nucleus of vagus
Dorsal motor
nucleus of vagus
Nucleus ambiguus Nucleus ambiguus
Edinger-
Westphal
nucleus
Edinger-
Westphal
nucleus
Purves, fig 21.3A
Midbrain
Pons
Medulla
Cranial
Parasympathetic
Nuclei
Salivatory
nuclei
Salivatory
nuclei
MCP MCP
SCP SCP
CN V
Sup
colliculus
Sup
colliculus
CN IV
Thalamus Thalamus
LGN
Caudate
Theparasympatheticdivisionofthevisceralmotorsystemismadeupof
neuronswithinthebrainstem(cranialpart)andthesacrallevelsofthe
spinalcord.Thecranialdivisionispresentedinthisdorsalviewofthe
brainstemshowingthefournucleithatgiverisetothecholinergic
preganglionicparasympatheticneurons.Thesenucleiarenamedfrom
rostraltocaudal:
EdingerWestphalnucleus(CNIII)
superiorandinferiorsalivatorynuclei (CNVIIandCNIX)
nucleusambiguus(CNIXandCNX)
dorsalmotornucleusofthevagusnerve(CNX)
EdingerWestphalprovidesinnervationtotheciliaryganglionoftheeye
viatheoculomotornerve.Itsactivationmediatesthepupillarylight
reflex.Thesalivatorynucleiinnervatethelacrimalandsalivaryglandsto
causetearandsalivaproductionandsecretion,respectively.Thenucleus
ambiguusinnervatesmucusglands,hasaroleincardiacinhibition,and
innervatesthestriatedmuscleofthepharynxandlarynxthatarederived
fromthebranchial arches.Thedorsalmotornucleusofthevagus
providesinnervationtotheheart,lungsandgutvisceraasfardistalas
thesplenicflexureoftheintestine.
SectionsatlevelslabeledA,B,andCshowtherelationshipofthesenuclei
incrosssectionandappearonthenextslide.
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A
C
B
CP
Red
nucleus
SN
Vestibular
nuclei
Pyramids
Inferior
Olive
Pyramids
Inferior
Olive
Brainstem
Sections
Edinger-Westphal
nucleus
Edinger-Westphal
nucleus
Oculomotor nerve (III)
Salivatory nuclei
Salivatory nuclei
Dorsal motor
nucleus of vagus
Dorsal motor
nucleus of vagus
Nucleus ambiguus
Nucleus ambiguus
Vagus nerve (X)
Modified from Purves, 21.3B
Midbrain
Upper
Medulla
Middle
Medulla
Facial nerve (VII) &
Glossopharyngeal
Nerve (IX)
PreganglionicPNSoutflowisfoundinthefollowingcranialnerves:
Oculomotor(III):tociliarymuscle[EdingerWestphalnucleus]
Facial(VII):tolacrimalandsalivaryglands[Superiorsalivatory
nucleus]
Glossopharyngeal(IX):toparotidsalivarygland,carotidbody,larynx
andpharynx[Inferiorsalivatorynucleus]
Vagus(X):toheart,lungsandviscera[DorsalmotornucleusofX;
Nucleusambiguus]
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Innervation of the Eye
Superior
Cervical
Ganglion
Superior
Cervical
Ganglion
Ciliary
ganglion
Ciliary
ganglion
CN 3
Levator
Palpebrae
Superioris
Iris
Pupil
Edinger-Wesphal
nucleus
Edinger-Wesphal
nucleus
Parasympathetic innervation Parasympathetic innervation
Sympathetic innervation Sympathetic innervation
Preganglionic fiber
Postganglionic fiber
Preganglionic fiber
Postganglionic fiber
Sympathetic: Axonsfrompreganglionicneurons(solidlines)attheT1
spinalcordlevelintheintermediolateralhornascendinthesympathetic
chaintothesuperiorcervicalganglionandsynapse.Postganglionicfibers
(dottedlines)aredistributedtotheradialsmoothmusclefibersoftheiris,
andwhenactivated,causepupillarydilation.Fibersalsoinnervateaportion
oftheeyelidmuscle(levator palpebrae superioris)thatwhenactivated,
causetheeyelidtoelevate(thedeerintheheadlights widesaucershaped
eyesasareactiontofear,istheperfectexample).
Parasympathetic: PreganglionicneuronsarelocatedintheEdinger
Westphalnucleusatthedorsalborderoftheoculomotornucleusinthe
midbrain.Preganglionicfibers(solidlines)aredistributedwithCNIIIand
synapseintheciliaryganglionneartheorbit.Postganglionicfibers(dotted
lines)theninnervatethecircular(sphincter)smoothmusclesoftheirisand
theciliarybody.Parasympatheticactivationcausesmiosis(constrictionof
thepupil)andrelaxationofthesuspensoryligamentsofthelens(thelens
becomesmoreconvex),andallowsgreaterlightrefraction.Thislatterisa
conditionthatismorefavorablefornearvision.Thesetworesponses,1)
constrictionofthepupiland2)makingthelensmoreconvexare includedin
theaccommodationreflex.
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From Purves, 21.3
Dorsal horn
Parasympathetic
preganglionic
neurons (S2-S4)
Parasympathetic
preganglionic
neurons (S2-S4)
Intermediate
gray zone
Ventral horn
Sacral
Parasympathetic
Somata
T1
L1
CoC1
S1
C1
Spinal cord
ThesacralcomponentofthePNSisshown.Cholinergicpreganglionic Cholinergicpreganglionic
sacralparasympatheticneurons sacralparasympatheticneurons arecontainedwithintheintermediatezone
ofthesacrallevelsofthespinalcord,andhavealateralpositioninthegray
matter.Themyelinatedaxonsoftheseneuronsprovideinnervationtothe
colon,distaltothesplenicflexure,therectum,thebladder,andthe
reproductiveorgans.
Theparasympatheticgangliainnervatedbythepreganglionicfibersare
locatedinorneartheorgansthattheytarget.Thismakesthepostganglionic
parasympatheticfibersrelativelyshort.Thepostganglionicparasympathetic
neuronsalsoreleaseAChontotheirtargets.
Theclassicterminologyusedtodescribetheparasympatheticfunctionsis:
restanddigest.
NOTE:MostorgansreceivedualSNSandPNSinnervation.The
exceptionsare:1)sweatglands,2)adrenalmedulla,3)piloerector muscles
oftheskin,and4)mostarterialbloodvessels,whichreceivesympathetic
innervationonly.
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Bladder Innervation
Purves, fig 21.10
Sympathetic preganglionic Sympathetic preganglionic
neurons (T10 neurons (T10- -L2) L2)
Postganglionic Postganglionic
Sympathetic Sympathetic
axons axons
Postganglionic Postganglionic
Parasympathetic Parasympathetic
axons axons
Urinary
bladder
Parasympathetic
ganglia
Sympathetic
ganglia
Parasympathetic Parasympathetic
preganglionic preganglionic
axons axons Parasympathetic Parasympathetic
preganglionic preganglionic
neurons (S2 neurons (S2- -S4) S4)
Voluntary
Innervation
Sympatheticefferents:T10L2spinalcordsegments oftheintermediolateralhorn
arethelocationforthecholinergicpreganglionicneuronsthatprovide
innervationtotheurinarybladder.Theiraxonstravelinthesympatheticchain
andsynapseintheinferiormesentericganglionandpelvicplexus.Postganglionic
fibers(norepinephrine;dottedline)reachtheurinarybladderthroughthe
hypogastric andpelvicnerves.Activationofthesympatheticfibersconstrictsthe
bloodvesselsofthebladderwall,closesthesphinctermuscleandprevents
micturition (urination).
Parasympatheticefferents:Preganglionicneurons(cholinergic)arelocatedinthe
lateralspinalcordgraymatterofS2S4.Axonstravelintheventralrootsandpass
throughthehypogastric plexustosynapseoncholinergicpostganglionicneurons
inthewallofthesmoothmuscleoftheurinarybladder.Activationofthe
parasympatheticsrelaxesthesphincterandencouragesmicturition (urination).
VisceralAfferents: Feedbackfromstretchreceptorsinthebladderwallenterthe
spinalcordatT10L2andalsoatS2S4.Theinformationistransmittedlocallyfor
reflexcontrolofthebladderandalsoascendstothebrainstemareasinvolvedin
bladdercontrol(periaqueductalgray;pontine micturitioncenter).
Somaticinnervation:Theexternalurethralsphincterhasstriatedmusclethatis
innervatedbymotorneuronsinspinalcordlevelsS2S4.Thisallowsvoluntary
controlofbladderemptying.
Incontinenceisaverymajormedicalissueinmanydiseasesandalsomay
becomecompromisedinaging.SeePurves470472offormoreinformation.
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Urinary Function
Modified from Blumenfeld 7-11
Urethral
afferents
Parasympathetics
Onufs nucleus
Sacral spinal cord
Descending tract to
sphincter and
detrusor nuclei
Bladder wall afferents
Urethral and
bladder afferents
(S2-S4)
Urethral and
bladder efferents
(S2-S4)
Sympathetics
Sacral
Motor
Nuclei
Pontine
Micturition
Center
Pontine
Micturition
Center
Cerebellar
Vermis
Cerebellar
Vermis
Basal
Ganglia
Basal
Ganglia
Frontal
Micturition
Inhibiting area
Frontal
Micturition
Inhibiting area
Sensorimotor
Sphincter
control area
Sensorimotor
Sphincter
control area
Normalbladder,bowelandsexualfunctionareenormouslyimportantto
thequalityoflife.Thenormalcontroloftheirfunctionrequirescomplex
interplayoftheautonomicandsomatosensorynervoussystemsdue tothe
combinedreflexiveandvoluntarycontroloftheseprocesses.
Thediagramaboveshowsthebasicelementstoemphasizehowtheprocess
ofbladdercontrolcanbeinterrupted.Sensoryinformationisconveyedon
S2S4afferentsandascendsusingbothanterolateralandposteriorcolumns
inthespinalcordtothepontine micturitioncenter.
Otherhigherlevelbrainareasthatshapetheappropriateresponsetostimuli
descendfromthefrontalmicturitioninhibitorycenterinthefrontalcortex,
rostraltothesupplementalmotorareaonthemedialaspectofthecerebrum.
Thebasalgangliaandcerebellumalsocontributetothemicturition
response.Asensorimotorsphinctercontrolareaintheparietalcortexhasan
importantroleinsensingthefullnessofthebladder.
VoluntaryefferentsarisefromanteriorhorncellsinS2S4spinalcord
segments calledOnufs nucleus andinnervatethesphinctermusclesof
thebladder.Thesacralparasympathetics(S2S4)andthesympathetic
neuronsfromT10toL1(intermediolateral cellcolumn)contribute
autonomiccontrolofmicturation.
Ingeneral,forlesionstoaffectthebladder(andbowelorsexualfunction),
thedamagemustbebilateral.
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Comparison of Autonomic Efferents
Parasympathetic
ganglion
Sympathetic
ganglion
Preganglionic
Parasympathetic
neuron
Preganglionic Preganglionic
Sympathetic Sympathetic
neuron neuron
CNS
ACh ACh ACh
NE NE
ACh ACh ACh
ACh ACh ACh
OrganizationaldifferencesbetweentheSNSandsacralPNSareshown.
Preganglionicneuronsforbothdivisionsarecholinergic(ACh).
Preganglionicaxonsaremyelinatedandsynapseinautonomicganglia.
TheSNSgangliaarenearthespinalcord(chainganglia,prevertebral
ganglia),whilethePNSgangliaarelocatednearthetargetstructurethatis
innervated.
PostganglionicSNSneuronshavelongaxonsandreleasenorepinephrine
(NE)attheirtargetstructure.PostganglionicPNSneuronshaveshortaxons
andreleaseACh attheirtarget.
PostganglionicneuronsineitherdivisionareNOTmyelinated.
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Enteric Motor System
Dorsal motor Dorsal motor
nucleus of vagus nucleus of vagus
GI Tract
Purves, fig 21.4A
Intrinsic neurons
of gut plexus
Intrinsic neurons
of gut plexus
Postganglionic
Parasympathetic
Neuron
Postganglionic
Parasympathetic
Neuron
Postganglionic
Sympathetic
Neuron
Postganglionic
Sympathetic
Neuron Prevertegral
ganglion
Preganglionic
SNS axon
Vagus nerve
Apopulationofneuronsareconcernedexclusivelywiththeinnervation
ofthegut.Theseneuronsareinaddition totheSNSandPNS
innervations,asshowninthedrawing.Thissystemistheentericmotor
systemandfunctionsindependentlyfromtheSNSandPNS.
Thecellbodiesoftheentericneuronsresideinthewallsofthegutandits
associatedorgansandreleaseanumberofdifferentneurotransmitters
(ACh,tachykinins,nitricoxide,VIP,opioids,ATP,amongothers).The
entericneuronshavecontroloverperistalsisandglandularsecretions
suchasbileanddigestiveenzymes.Auerbachs myenteric plexus and
Meissners submucosalplexus arethenamesoftheseneuralnetworks
andareillustratedonthenextslide.
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Peripheral Enteric Plexus
Meissners
Plexus
(submucosal)
Auerbachs
Plexus
(myenteric)
Purves, fig 21.4B
Circular muscle
layer
Mucosa
Longitudinal
Muscle layer
ThelocationofAuerbachs myenteric plexus andMeissners submucosal
plexus inthelayersofthegutwallareshown.
Auerbachs plexusisconcernedwithregulatingthemusclesofthegut
andperistalsis,whileMeissners plexusisconcernedwithchemical
monitoring(pHforexample)andglandularsecretions(mucous,
enzymes)toassistwithdigestion.
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A
B
Visceral
Afferents
Modified from Purves, 21.6
Glossopharyngeal
Nucleus of the
Solitary tract
Gustatory part Gustatory part
Visceral sensory Visceral sensory
MCP MCP MCP
SCP SCP SCP
CN V
Sup
colliculus
Sup Sup
colliculus colliculus
CN IV
Thalamus Thalamus Thalamus
LGN
Caudate
Visceral afferents
Vagus
2
nd
-order visceral
afferents
2
nd
-order visceral
afferents
Feedbackfromthevisceralmotorsystemiscrucial.TheafferentSNS
fiberstravelbacktotheCNSintheperipheralnervesasgeneralvisceral
andgeneralsomaticafferents.Theircellbodiesarelocatedinthedorsal
rootganglia.ThesacralPNSafferentsreturnwithothersomatic afferents
inperipheralnervesthatterminateatsacralspinalcordlevels,oruse
specificcranialnervesfortherostralcomponent.
ThisdiagramshowsthecranialafferentcomponentofthePNSinadorsal
viewofthebrainstem.Generalvisceralafferents(fromthecarotidbody,
baroreceptors,gut,heart,lungs)terminateinthecaudal,visceralpartof
thesolitarynucleus usingtheglossopharyngealand vaguscranialnerves.
Thesefiberstravelwithinthetractofthesolitarynucleustoreachtheir
finaldestinationinthebrainstem.
SectionsofthebrainstematA andB areshownincrosssectionsonthe
nextslidetoorientthenucleusofthesolitarytractwithotherbrainstem
structures.
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A
B
Pyramids Pyramids
Inferior
Olive
Inferior
Olive
Dorsal Column
Nuclei
Dorsal Column
Nuclei
Caudal medulla
Middle medulla
Solitary
tract
Solitary
tract
Nucleus of
Solitary tract
Nucleus of
Solitary tract
Glossopharyngeal
& Vagus nerves
Solitary
tract
Solitary
tract
Modified from Purves
Brainstem
Terminations
Thenucleusofthesolitarytractintegratesvisceralsensoryafferentsand
relaysthedatatothehypothalamus andothermotornucleiofthe
brainstemtegmentum(dorsalmotornucleusofthevagus,nucleus
ambiguus,etc).Thesevisceralafferentsformtheimportantsensory
feedbackforautonomicreflexesfromtheheart,lungs,gut,bladderand
bowel,andarepredominantlyunconscious.
Notethatthesolitarynucleussurroundsthetractasitcourses throughthe
brainstem.
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Horners Syndrome
Ipsilateral Pupillary
constriction (miosis)
Drooping Eyelid
(ptosis)
Apparent sinking
of the eyeball
(enophthalmos)
Purves, Box 21B
HornerssyndromeresultsfollowinganinterruptionoftheSNS.Itis
expressedipsilateral tothelesion.Thispicturedemonstratesthethree
mostobvioussymptoms:
ptosis
miosis
enophthalmos
Thepatientmayalsodemonstrateadryandflushedfaceonthesameside
asthedamage.Thisisduetolossofsympatheticinnervationto thesweat
glands(nosecretion)andbloodvessels(dilated).
Parasympatheticpathwaysarelocatedmoremediallyinthebrainstemand
aremorediffuse,thereforetheyarelessfrequentlyaffected.
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Horners Syndrome Circuitry
Purves, Box 21B
Thisdiagramshowsthedescendingsympatheticpathwaysfromthe
hypothalamustothespinalcord,followedbythepathwayfromthespinal
cordtoinnervatetheeye.Thecircuitis:neuron1,hypothalamustothe
ventrolateralmedullareticularformation;neuron2,reticularformationto
thepreganglionicSNSneuronsintheintermediolateral hornatcordlevel
T1T2;neuron3,preganglionicSNStraveltothesuperiorcervicalganglion;
neuron4,postganglionicneuronsfromthegangliontraveltoinnervatethe
eyeandheadandnecktargets.
ThesignsassociatedwithHornersSyndromeareipsilateraltothelesion
andmaybecausedbyinterruptionofthepathwaydrawnabove,atany atany
neuroninthecircuit neuroninthecircuit.Thesymptomsare:
Decreasedpupillarydiameter(miosis)
Droopyeyelid(ptosis)
Sinkingoftheeyeball(enophthalmos;aminorsymptom)
Decreasedsweating(skindrytothetouch)
Increasedskintemperature(bloodvesseldilation)
Flushing(reddeningduetoarterialdilation)ofthefaceandneck
TypicalcausesofHornerssyndromearetraumaticinjuryoftheheadand/or
neck,tumorsoftheapexofthelung,thyroidorcervicallymphnodes.The
presenceorabsenceofaccompanyingsymptomswilldistinguishwherethe
injurymaybelocatedinthecircuit.
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End Organs End Organs
(smooth muscle, cardiac muscle, and glands)
Autonomic Centers in
Brainstem tegmentum
Autonomic Centers in
Brainstem tegmentum
Hypothalamus
Hypothalamus
Cerebral Cortex
Cerebral Cortex
Preganglionic
Neurons in brainstem
and spinal cord
Nucleus of the
Solitary tract
Motor neurons in
Autonomic ganglia
Motor neurons in
Autonomic ganglia
Sensory
Ganglia
Sensory
Ganglia
Thalamus
Thalamus
Amygdala
Amygdala
Thisisasimplifiedoverviewofcentralcontrolofautonomicfunction.The
visceralmotorsystemhassomecorticalcontrolviathehypothalamus,
relatingemotionalexperiencestooutwardbehaviors(blushing,ashenface
tofear).Howevertheprimarycentralcontrollingregionforthevisceral
motorsystemisnotcortical,butthehypothalamus.However,thevisceral
motorsystemcontinuestofunctionevenifthereisinjuryordiseasethat
affectsthehypothalamus.
Theneurotransmittersofthevisceralmotorsystemareofcrucial
importanceinclinicalpracticeanddrugsthataffecttheautonomicsystem
areamongthemostwidelyusedinpharmacotherapies(bloodpressure
control,incontinence,sexualdysfunction!!).
BesureyouunderstandtheACh NEaxisintheautonomicnervous
system;thereareALWAYSquestionsregardingthefunctionsof
receptorsandinnervationofthevariousorgansonUSMLEboardexams
(andinNeurosciencetoo)!Seefigure21.1andTable21.1inPurves.
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1
Cranial Nerves
Functional Assessment
Purves, pages 722-728
Blumenfeld, pages 500-538
Thefunctionsofthecranialnervescanbeelicitedeasilywithouttheaidof
expensivetests.Usingafocusedlightsourceinaconsciouspatient,youmayask
themtoperformsimpletasksthatwillhelpyoudiagnosewheretheCNSdamageis
located.
Whileallcranialnervesshouldbetestedinthecompleteneurologicexam,onlyfive
nerves(7,9,10,11,and12)arediscussedhere.Theothershavebeencoveredin
previousNeurosciencelecturesandyoushouldreviewtheirfunctions,distribution
andthelocationsoftheircentralnuclei.
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2
Learning Objectives
Know functional assessments
and the central circuitry for:
Facial (CN VII)
Glossopharyngeal (CN IX)
Vagus (CN X)
Spinal Accessory (CN XI)
Hypoglossal (CN XII)
Thesecranialnervesareeasytotestwithsimpleprocedures.Youcangetavideoviewof
howtodothisonYouTube bysearchingforCranialNerveExam. Also,Blumenfelds
book(NeuroanatomythroughClinicalCases)hasanexcellentdiscussionofhowtoperform
theexamandtheclinicalsignificanceoffindingspp.5863.AlsocheckoutPurvesonpages
724725,TableA2andtheHainesAtlas,pp.4243Table32foracomprehensiveoverview
ofall12cranialnerves.
Thefirststepistoperformahistoryandphysicalexamofyour patient,andidentify
discrepanciesbetweenthetwosidesoftheheadandneck.Assess whichelementsare
controlledbyspecificcranialnerves,andthendecidehowtoexamineifthatfunctionis
intactbycomparingtheresponsesonbothsidesofthebody.
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Rapid Clinical Assessment
http://www.youtube.com/watch?v=eLzkgPkgkEo
Thisisashort(intime)videoonhowtoassesscranialnervefunctioninapatientwho
presentsintheemergencydepartment.Itisagreatlearningtoolandgivesthemostsalient
pointsthatyouneedtotestinaquickhistory.
Anotherpointtokeepinmindisthatitisveryeasytoassessthemotorfunctionsofthe
cranialnerves.Ittakessomewhatmorefinessetoexaminesensorydeficits.Alwaysbe
awareofyourlimitations,timeelementsanddonothesitatetoreferapatienttoa
specialist!
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4
Cranial Nerve Roots
Motor Motor
Mixed Mixed
Sensory Sensory
Modified from Purves A7
CN II, Optic CN II, Optic
CN III, Oculomotor CN III, Oculomotor
CN IV, Trochlear CN IV, Trochlear
CN V, Trigeminal motor
CN V, Trigeminal sensory
CN V, Trigeminal motor
CN V, Trigeminal sensory
CN VI, Abducens CN VI, Abducens
CN XI, Accessory CN XI, Accessory
CN X, Vagus CN X, Vagus
CN IX, Glossopharyngeal CN IX, Glossopharyngeal
CN VII, Facial CN VII, Facial
CN VIII,
Vestibulocochlear
CN VIII,
Vestibulocochlear
CN XII, Hypoglossal CN XII, Hypoglossal
Thisdiagramshowsthegrossbrainstemasviewedfromtheventralsurface.Thefunctions
of10ofthe12cranialnerves(CNI olfactoryandCNII opticaremissing)arecolor
coded.Inabroadclassification,cranialnervesareeithermotor,sensoryormixedmotor
andsensory.
Thepositionofthenervescanbeconnectedtothebrainstemregionsasfollows:
Midbraincranialnerves:oculomotorandtrochlear
Pontinecranialnerves:trigeminal
Pontomedullary junction:abducens,facialandvestibulocochlear
Medulla:glossopharyngeal,vagus,spinalaccessoryandhypoglossal
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Classification Scheme
CN V, VII, IX, X
Spinal nucleus
CN X
nucleus
ambiguus
CN X
Dorsal
motor of X
CN IX & X
nucleus
ambiguus
CN XI
Spinal
accessory
CN XII
Hypoglossal Medulla
CN V, VII, IX, X
Principal
nucleus
CN VII
Superior
salivatory
CN IX
Inferior
salivatory
CN V
Trigeminal
motor
CN VII
Facial
CN VI
Abducens Pons
CN V, VII
Mesencephalic
nucleus
CN III
Edinger-
Westphal
CN III
Oculomotor
CN IV
Trochlear
Midbrain
Special
Sensory
SSA
Special &
General
Visceral
SVA &
GVA
General
Sensory
GSA
General
Visceral
GVE
Branchial
(Special)
Visceral
SVE
General
Somatic
GSE
Location
CN VII, IX,
X
Solitary
nucleus
CN VIII
Vestibular
nuclei
Cochlear
nuclei
Modified from Purves Table 3, pp. 726
Thistabledrillsdown onthecranialnerves classificationschemeandthecolorcoding
shownintheheadersisusedthroughouttheslidesinthislecturetoaidinlearningthe
modalitiescarriedineach.Thebrainstemlocationforthenervesisshownstartingrostrally
inthemidbrain.Cranialnerves(CN)aremotor(efferent)orsensory(afferent).Thenerves
alsoareeithersomaticorvisceral.Afinalconsiderationiswhetherthenervesaregeneral
functionorincludespecialsenses,suchastaste,smell,vision,hearingorvestibularsenses.
Thesesixcombinationsdescribeallofthefunctionalcomponents ofthe12cranialnerves.
Puremotor(efferent)cranialnervesthatareanalogoustospinalcordmotorneuronsare
CNIII,CNIV,CNVIandCNXII.TheseareclassifiedasGSEandinnervatestriated
muscles.Cranialmotornervesinnervatingstriatedmusclesderivedfromthebranchial
archesembryologically,arecategorizedasspecialandvisceral(SVE).TheseareCNV
(motorpart),CNVII,CNIX,CNXandCNXI.Allofthesecranialnerveshaveother
modalitiesandsoareclassifiedasmixednerves.Thecranialnervesthatcarry
preganglionicparasympatheticfibersaregeneralandvisceral(GVE GVE).Theyareassociated
withnamednucleiwhoseaxonstravelinCNIII,CNVII,CNIXandCNX.
Puresensory(afferent)cranialnervesthatareanalogoustoperipheralnerveswith
peripheralganglioncellbodiesareCNV(sensory),CNVII,CNIXandCNX(GSA).The
specialfunctionoftasteisconsideredvisceralandisconveyed inCNVII,CNIXandCNX
(SVA).Theafferentfeedbackfromthepharynx,heart,lungsandgutarecarriedinCNIX
andCNXandareconsideredgeneralandvisceral(GVA).Thesolitarynucleusspansthe
ponsandthemedulla;therostralcomponentisgustatoryandreceivestasteafferents,the
caudalpartreceivesthevisceralafferents.Specialsensesofhearingandvestibular
componentsareconveyedbyCNVIII.Thevestibularandcochlearnucleispanthepons
andmedulla,sotheyaredrawnoverbothofthoseregionsinthe table.Theseare
consideredSSA.
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Cranial Nerve Nuclei
General somatic GSE
Branchial (special) visceral SVE
General visceral GVE
General somatic GSE
General somatic - GSA
General visceral GVA
Special visceral SVA
Special sensory - SSA
MOTOR or
EFFERENT
SENSORY or
AFFERENT
Thisdrawingshowsasemitransparentviewofthebrainstemviewedfromthedorsal
surface.Allofthenucleiofthecranialnervescanbevisualized.Thisslidetakesthesame
informationintheprevioustableandmakesit3Dtoassistinlearningthecranialnerves
classifications.Themotornucleiareshownontherightandthe sensorynucleiaredrawn
totheleft.Nucleiarecolorcodedbyfunction:
Component CranialNerves
Generalsomaticefferent GSE GSE III,IV,VIandXII
Generalvisceralefferent GVE GVE III,VII,IXandX
Special(branchial)visceralefferent SVE SVE V,VII,IX,XandXI
Generalsomaticsensory/afferent GSA GSA V,VII,IXandX
Specialvisceral/afferent SVA SVA I,VII,IXandX
Generalvisceralsensory/afferent GVA GVA IXandX
Specialsensoryafferent SSA SSA IIandVIII
Insomecasesdifferentbrainstemnucleicontributetoacranial nerve(CNVIIforexample);
alternativelythesamebrainstemnucleuscontributestomultiple cranialnerves(nucleus
ambiguusforexample).Again,reviewtheclinicaltestoffunctionstohelptodetermine
wherelesionsordamagemightbelocatedinapatient.
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Cross Sectional Organization
Efferent (Motor) Nuclei Afferent (Sensory) Nuclei
Sulcus Limitans
Pyramids
Pyramids
ICP
ICP
Inferior Olivary
Nucleus
Inferior Olivary
Nucleus
Branchial efferent
SVE
Branchial efferent
SVE
Visceral
efferent GVE
Visceral
efferent GVE
Somatic efferent
GSE
Somatic efferent
GSE
General somatic afferent
GSA
General somatic afferent
GSA
Special somatic afferent
SSA
Special somatic afferent
SSA
Special & General visceral afferent
SVA & GVA
Special & General visceral afferent
SVA & GVA
Theuniqueanatomyoftheheadandneckmakestheorganizationofcranialnervesensory
andmotorcategoriesmorecomplexthaninthespinalcord.
Asthefetusdevelops,thecranialnervenucleiareformedadjacenttotheventricular
system.Duringmaturation,threecolumnsofsensory(left)ormotor(right)nucleiform.
Thesefunctionalcolumnscoursethroughthebrainsteminaninterruptedmanner.
Thiscrosssectionofthemedullashowstheplacementofthesefunctionalcolumnsforthe
cranialnerves.Thesulcuslimitans separatesthesensory(lateral)andmotor(medial)nuclei
inthebrainstemandisshownastheblackandwhitedashedlines.
Sensoryvs motor
Somaticvs visceral
Generalvs special
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CN VII - Facial
SVE SVE facial nucleus facial nucleus
Muscles of facial expression
Stapedius, stylohyoid, digastric, platysma,
buccinator, occipitalis
GVE GVE salivatory nuclei salivatory nuclei
Lacrimal gland
Salivary glands
GSA GSA spinal nucleus of V spinal nucleus of V
External ear - pinna/neck area
SVA SVA rostral portion, solitary nucleus rostral portion, solitary nucleus
Taste from anterior 2/3 of the tongue
Thefacialnervecontrolsvoluntaryfacialexpression,productionoftearsandsaliva,taste
ontheanteriorportionofthetongue,andconveyssensationfromaverysmallareaofthe
externalear.
FacialexpressionsoccurwithactivityintheSpecialVisceralEfferent(SVE) SpecialVisceralEfferent(SVE) neurons
locatedinthefacialnucleusinthecaudalpons.Thestatusofthefacialmusclescanbe
examinedbyaskingthepatienttosmile,frown,puffouttheircheeks,pursetheirlips,
wrinkletheirforeheadetc,andnotingtheresponses.Motorinnervationoftheotherfacial
musclescanbetested,buttakesabitmoreskill.
Parasympathetic(GVE GVE)innervationcomesfromthesuperiorsalivatorynucleusinthepons
andinnervatesthelacrimalglandtoproduceandsecretetears,andsalivaryglandsto
produceandsecretesaliva.Themucosaofthenoseandthehardpalatealsoareinnervated
bytheparasympatheticaxonscarriedinCNVII.PatientswithdisruptionoftheGVEfibers
willcomplainofdrymouth andbeunabletoproducetears.
Averysmallareaofskinbehindtheearandthepinna conveygeneralsomaticafferents
(GSA) (GSA) inthefacialnerve.SpecialVisceralAfferent(SVA) SpecialVisceralAfferent(SVA) fortasteontheanteriortwo
thirdsofthetonguearecarriedonCNVII.
Thefacialnerveisvisibleontheventralsurfaceofthebrainstematthepontomedullary
junction,lateraltoCNVI.Thereareanumberofrootletsthatcanbedetected.
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Facial Nerve Distribution
SVE
GVE
GSA
SVA
SVE
GVE
GSA
SVA
Facial
Nucleus
Facial
Nucleus
S. Salivatory
Nucleus
S. Salivatory
Nucleus
Solitary
Nucleus
Solitary
Nucleus
Spinal
Trigeminal
nucleus
Spinal
Trigeminal
nucleus
Lacrimal
gland
Salivary
gland
Salivary
gland
Thissemitransparentdrawingshowsthedistributionsofthefourdifferentcomponentsof
thefacialnerve.Thefunctionsarecolorcodedtodemonstratethemodalitywhichis
conveyed.
TheSVE SVE motorportion,fromthefacialnucleus,isthelargestaxonbundleinthefacial
nerveanditisthemostmediallylocatedportionofCNVIIasitexitsfromthebrainstemat
thepontomedullary junction.ThefacialmotorfibersareSVEbecausethemusclesoffacial
expressiondevelopedfromthebranchialarches.
Keepinmindthatthiscranialnerveisconsideredmixedbecause itcontainsbothafferent
andefferentfibers.
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Central Distribution - Facial
Caudal
Pons
Corticospinal
Tract
CN VI
GSE
CN VI
GSE
CN VII
SVE
CN VII
SVE
Facial
Colliculus
Thisdrawingshowsacrosssectionofthecaudalpons thelocationofthesectioninthe
brainisshowninthesmallimageintheupperleftoftheslide.Thefacialnucleusislocated
inthemedialandventralportionofthecaudalpontine tegmentum.TheSVE SVE fibersexit
fromthenucleusdorsallyandmedially,andwraparoundthenucleusofCNVI(abducens;
GSE GSE).Thefacialaxonsformabumporcolliculusastheytravelaroundtheabducens
nucleus.Thiscolliculuscanbeseenonthefloorofthe4
th
ventricle.Thefacialnervethen
travelsventrallyandlaterallytoexitthebrainstematthepontomedullary junction,lateral
totherootofCNVI.
GVE GVE axonsleavethesuperiorsalivatorynucleusandproceedlaterallyandthenventrally,
joiningtheSVE SVE fibersofCNVII.TheSVA SVA fibersofthefacialnerve,bringthesensationof
tastefromtheanterior2/3ofthetongue.GSA GSA fromasmallareaoftheskinbehindtheear
lobeandpinna transmitsensation.Theseafferentaxonsterminateinthegustatoryportion
ofthenucleusofthesolitarytract orthespinaltrigeminalsystem,respectively.
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UMN vs LMN Facial Lesions
UMN
Corticobulbar
Damage
Contralateral
lower facial
paresis
LMN
Facial nucleus
or facial nerve
Damage
Ipsilateral
Facial
Hemiparesis
DistinguishingbetweenUMN(corticobulbartract)versusLMN(facialnucleusor
nerve)lesionsisshowninthisdrawing.Youwillbeobservingfacialasymmetryin
yourcranialnerveexaminationwhenyouaskyourpatienttoperformcertain
expressions.
UMNdamageresultsfrominsultstoeitherthecellbodiesinthe primarymotor
cortexregionrepresentingtheface,ortotheaxonsastheydescendthroughthe
internalcapsuletothefacialnucleusinthepons.Ifthecorticobulbarpathwayis
interruptedthepatientwillexhibitlossoffacialmuscletoneandlossoftheability
tocontractthelowerfaceonthesidecontralateral tothelesion.Theforehead
regionreceivesbilateralinnervation,andthepatientwillstillbeabletoraisetheir
eyebrowswhenaskedtodoso.However,theirsmilewillbeonesidedor
asymmetrical.Clinicalnoteofinterest:inmanycasesemotionallymotivated facial
movementsarestillpreservedinUMNlesions.
LMNdamageresultsfrominsultstoeitherthecellbodiesinthe facialnucleusor
anywherealongCNVIIaxonsastheyleavethenucleustoinnervatethemuscles.In
thissituationthepatientwillexhibitparalysisoffacialmusclestotheentirefaceon
thesideipsilateral tothelesion.Allactionsofthefacialmuscles,whethermotivatedby
voluntary,reflexoremotionalinputareaffected.
Ifthedamageistotheperipheralfacialnerve,therewillalso belossoftasteinthe
anteriorportionofthetongue whichmaybeassessed.
SeealsoPurvesBox17A,page379380forafurtherdiscussion.
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CN IX - Glossopharyngeal
SVE SVE nucleus ambiguus nucleus ambiguus
Stylopharyngeus
GVE GVE salivatory nucleus salivatory nucleus
Parotid salivary gland
GSA GSA spinal nucleus of V spinal nucleus of V
Posterior 1/3 of tongue
External ear
External surface of tympanic membrane
GVA GVA caudal solitary nucleus caudal solitary nucleus
Carotid body & carotid sinus
Oropharynx area
SVA SVA rostral solitary nucleus rostral solitary nucleus
Taste from posterior 1/3 of the tongue
Theglossopharyngealnerveisamixed(sensoryandmotor)nervethatcanbe
foundontheventrolateralsurfaceoftherostralmedulla.Itwasnamedduetoits
roleinsensationfortheposteriortongue(Lat.glossus)andpharynx.Itismost
readilytestedbyelicitingthegagreflex whichusestheSVE SVE innervationofthe
stylopharyngeus muscleastheefferentlimbofthereflexarc.TheGSA GSA fibersare
theafferentlimbofthisreflex.Thevagusnervealsoassistsinthegagreflex,so
testingforthisimportantreflexisnotapureCNIXfunction.
GVE GVE fibersarisefromtheinferiorsalivatorynucleusintheponsandprovide
parasympatheticinnervationtothesalivarygland.
OthercomponentsthatmaybetestedinCNIXaretheSVA SVA fiberswhichcarrytaste
sensationsfromtheposteriorthirdofthetongue.Theseafferentsendintherostral,
gustatorypartofthesolitarynucleusinthepons.
Feedbackfrombaroreceptors andchemoreceptors inthecarotidbodyconveythe
partialpressuresofO
2
/CO
2
inthebloodandarepartoftheGVA GVA portionofthe
glossopharyngealnerve.Theseterminateinthevisceral,caudalportionofthe
solitarynucleusinthemedulla.
Itisuncommontohaveanisolatedlesiontotheglossopharyngealnerve.However
itmaybedamagedincombinationwiththevagus(CNX),oratthelevelofthe
jugularforamen.
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Peripheral Distribution CN IX
SVE
GVE
GSA
GVA
SVA
SVE
GVE
GSA
GVA
SVA
Salivary
gland
Carotid
Body &
Sinus
Tongue
PeripheraldistributionsforthedifferentmodalitiesofCNIXaredemonstratedin
thiscolorcodedimage.Theglossopharyngealnerveexitsthebrainstemasthemost
rostralrootletsinthepostolivary sulcusofthemedullaandleavestheskull
throughthejugularforamen.
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Central Distribution CN IX
Wilson-Pauwels, fig. IX-2
Spinal tract Spinal tract
of V of V
Solitary nucleus Solitary nucleus
& tract & tract
Gustatory
Visceral
Gustatory
Visceral
Salivatory n.
n. Ambiguus
SVE
GVE
GSA
GVA
SVA
SVE
GVE
GSA
GVA
SVA
ThecentralcourseofCNIXinthemedullaisdepictedinthisdrawing.Notethat
thetasteafferents(SVA SVA)endintherostral,gustatoryportionofthesolitary
nucleus,whilechemoreceptivefeedback(GVA GVA)fromreceptorslocatedinthe
carotidbodyandcarotidsinusterminateinthecaudalportionofthissamenucleus.
Sensations(GSA GSA)fromthepinna andskinsurroundingthebackoftheear,aswell
astheposteriorpalateandposteriortongueterminateinthespinaltractofCNV
andthenrelaytotheVPMofthethalamus.
Efferentfibersarederivedfromtheinferiorsalivatorynucleus (parasympathetic,
GVE GVE)andthenucleusambiguus(branchialmotor,SVE SVE).
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CN X - Vagus
SVE SVE nucleus ambiguus nucleus ambiguus
Striated muscles of pharynx
Larynx
Tensor palati
Palatoglossus
GVE GVE dorsal motor nucleus of X dorsal motor nucleus of X
Smooth muscles and glands of pharynx, larynx, thoracic and
abdominal viscera, preganglionic parasympathetic neurons
GSA GSA spinal nucleus of spinal nucleus of V V
Skin at back of ear/neck
External acoustic meatus
External surface of tympanic membrane
Pharynx Gag reflex
GVA/SVA GVA/SVA solitary nucleus solitary nucleus
From larynx, pharynx, thoracic and abdominal viscera
Aortic arch stretch receptors
Chemoreceptors of aortic arch
Taste from base of the tongue
Thevagus(CNX)isthelargestcranialnerve,travelsthegreatestdistanceintheperiphery
andalsocontainsallmodalities,exceptGSE.Thevagusistypicallythoughtofasthesource
ofparasympatheticoutflow(GVE GVE)totheglandsandsmoothmuscleoftheviscera
innervatingthepharynx,larynx,heart,lungsandthedigestivesystemthroughthesplenic
flexure.
PurvesshowsbothnucleusambiguusandthedorsalmotornucleusofXprovide
parasympatheticcomponentstoCNX figure21.3,andexplanationonpages460461;
cardiovascularcontrol,page469;TableA3,andexplanationonpage726.
BlumenfeldonlyhasthedorsalmotornucleusofXtoprovideparasympathetic
componentstoCNX figure12.21,andexplanationonpages532533.
Thisillustratesthecomplexityofdistinguishingprecisefeaturesforsomecomponentsof
thecranialnerves,especiallytheglossopharyngealandthevagusnerves.
ForthepurposesofanyMedicalNeuroscienceexaminations,wewillusethe
conventionslistedbythePurvestextbook.
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Vagus LMN Lesion
Wilson-Pauwels, fig. X-3
Palate sags on the
affected side and the
uvula deviates to the
intact side.
ThevagusnervesharesinnervationofthepalatewithCNIX,and isimportantin
vocalization.Iftheperipheralvagusnerveisdamaged,themusclesofthesoftpalate
innervatedbythenucleusambiguus willnotcontract,andsothedamagedsidewill
droop.Whentheindividualwiththeunilateralperipheralnervedamageopenstheir
mouth,thisdifferenceinappearanceofthetwosidesofthesoftpalateisevident9image
above).Theuvulawilldeviatetotheintactsidewhenthepatientsaysah becausethose
musclescancontract,elevatingthesoftpalateontheintactside.
Damagetothevagusnervecanbeeasilyassessedbylisteningto thespeechofyourpatient.
Iftheirvoiceishoarse,thenthelarynxandvocalmuscleshave beenaffectedandCNXis
involved.
Clinicalnotes: Unilaterallesionofthevagusresultsinhoarsenessbecauseof paralysisof
theintrinsicmusclesofthelarynxononeside.Additionally,thepatientwillhavedifficulty
swallowingbecausethesoftpalatecannotbeelevatedadequately.Foodmaypassupinto
thenoseduetothelossofvagal function.Theseinjuriesordamagemayresultfromtrauma
totheneck,aorticaneurysm,metastaticcarcinomaintheparatracheal lymphnotes,or
surgicalproceduressuchascarotidendarterectomy orthyroidectomy.
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Peripheral Distribution Vagus
SVE
GVE
GSA
GVA
SVA
SVE
GVE
GSA
GVA
SVA
Tongue
Larynx
Aortic Arch
Receptors
Thevagusisamixednerve,containingbothmotorandsensoryfibers.SVE SVE neuronsinthe
nucleusambiguusinnervatepharyngealmuscles,thepalate,thelarynxandtheupper
portionoftheesophagus.Whenthevagusnervehasbeendamaged, manythingsgoawry.
Arelativelystraightforwardindicationofvagal nervetraumaishoarsenessofthevoice,
butotherchangesinhomeostasisalsowilloccur.
Ingeneral,vagal functionsaresubconsciousandprincipallyconcernedwithhomeostatic
functionsoftheheart,lungsandgut.Whenactivated,theGVE GVE parasympatheticfibers
fromthedorsalmotornucleusofXandasmallproportionfromthenucleusambiguus
(shownasthedottedlineabove),inducesrestanddigest behavior bronchiole
constriction,diminishedheartrate,increasedbloodflowtothe intestines,peristalsisand
gutsecretions.
GSA GSA returnsinformationtothespinalnucleusofVcarryingcutaneoussensationsfromthe
pharynx,larynx,meningesoftheposteriorfossa andasmallregionneartheexternal
auditorymeatus.
GVA GVA bringsinformationbackgeneralizedsensationsfromthedigestivetractandthoracic
visceratothevisceral,caudalportionofthesolitarynucleusinthemedulla.Alsoincluded
intheafferentinformationarestretchsensorsinthewallsoftheaorticarchtomonitor
bloodpressureandchemoreceptors intheaorticbodiesadjacenttotheaorticarch.
SVA SVA providestastesensationsfromtheposteriorpharynx,baseofthetongueandthe
epiglottis.Theseafferentsterminateintherostral,gustatoryportionofthenucleusofthe
solitarytractinthecaudalpons.
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A
B
Modified from Purves, 21.6
Glossopharyngeal
MCP
CN V
Sup
colliculus
Sup
colliculus
CN IV
Thalamus Thalamus Thalamus
LGN
Caudate
Visceral afferents Visceral afferents Visceral afferents
Vagus
Nucleus of the
Solitary tract
Gustatory portion Gustatory portion
Visceral portion Visceral portion
Feedbackforgeneralvisceralafferentandspecialvisceralafferentcategories
iscarriedonCNVII,IXandCNXtothenucleusofthesolitary tract.This
imageshowstheafferentcomponentsinadorsalviewofthebrainstem.
GVA GVA terminateinthecaudalpartofthesolitarynucleus usingthe
glossopharyngealand vaguscranialnerves;thisdivisionislocatedmore
caudallythanendingsforSVA SVA whichconveytaste. Rememberthat3nerves
providethesensationoftaste facial,glossopharyngealandvagus.
Theafferentfiberstravelwithinthesolitarytracttoreachtheirfinal
destinationinthenucleus.
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Cardiac
Innervation
Modified from Purves, fig 21-8
CN IX
CN X
Carotid
Body
Postganglionic
Sympathetic fibers
Postganglionic
Sympathetic fibers
Baroreceptor
afferents
Postganglionic
Paraympathetic
fibers
Postganglionic
Paraympathetic
fibers
Chemoreceptor
afferents
Nucleus of the
Solitary tract
Preganglionic
Sympathetic neurons
Preganglionic
Sympathetic neurons
T1
Dorsal Motor
Nucleus of X
Nucleus
Ambiguus
CardiacfunctioniscontrolledbyCNIX,CNXandthesympatheticdivisionofthevisceral
motorsystem.
Sensorymonitoringofthehomeostaticresponsesareconveyedbythebaroreceptorand
chemoreceptorafferentsinthecarotidbodyandaorticarchonCNIXandCNX,
respectively.Theafferentsterminateinthecaudal,visceralportionofthenucleusofthe
solitarytract.Thesolitarynucleusrelaystheaggregateinformationtothehypothalamus
andtherelevantautonomiccentersinthereticularformation.Theinformationisthen
relayedthroughtothecranialnervenuclei,completingthereflex.
Recallthatthepostganglionicsympatheticfiberswilltravelalongarteriestogettothe
heart.Thesefiberswillreleasenorepinephrinetospeedthebeatingoftheheart,whenthe
stimulusisappropriate.
NOTEMYADDITIONSTOTHEILLUSTRATION:Preganglionicparasympatheticoutflow
totheheartisgeneratedfromthedorsalmotornucleusofX.Thisnucleusisnearthe
midlineandislabeledabove.Thenucleusambiguus contributesGVE GVE parasympathetic
fiberstoCNXbutthemajorcontributionistoprovidespecialvisceralefferent(SVE SVE)
innervationtobranchialarchderivedmusclesofthelarynxandpharynx.
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CN XI Spinal Accessory
SVE SVE
Sternocleidomastoid
Trapezius
Thespinalaccessorynerveinnervatestwosuperficialmusclesof theneckandshoulder,the
sterno(cleido)mastoid andtheuppertrapezius.
TheLMNforCNXIarelocatedintherostralspinalcord,atlevelsC1andC2.Whenthe
accessorynerveisdamaged,patientswillbeunabletoshrugtheirshoulders(trapezius)
andhavedifficultyturningtheirhead(sternomastoid).
Clinicalnotes: Removalofthesuperficiallymphnodesoftheneckduringradicalsurgery
maydamagetheaccessorynervebecauseoftheircloseproximity. Paralysisofthetrapezius
andthesternomastoidmusclesproducesadownwardandlateralrotationofthescapula
andsomeshoulderdrop.Therealsoisweaknesswhenthepatientturnstheirheadtothe
sideopposite thelesion,andthisisparticularlynoticeablewhenperformedagainst
resistancesuppliedbytheexaminer.
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CN XII - Hypoglossal
GSE GSE
Intrinsic muscles of the tongue
XII
Thisisaverysimplecranialnerve,withitssolefunctiontoinnervatetheintrinsic
tonguemuscles.
Thehypoglossalnucleusislocatedinthefloorofthe4
th
ventricleinamedial
positionasseeninthismyelinstainedsection.Axonsfromthenucleusexit
ventrallyandpassjustlateraltothemediallemniscus.Theyexitattheventrolateral
sulcusbetweentheoliveandthepyramidasanumberofrootlets.
Whenthehypoglossalnerveisdamaged,themusclefiberswillatrophyandalso
fasciculatewithtime.Thislattereventcanbeseenasrippling overthesurfaceof
thetonguewhenitisprotruded,anduncoordinatedcontractionsofthetongue
muscleonthesideofthelesion.
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22
UMN vs LMN Lesions
Medulla
Thebalancedactionofthepairedgenioglossus muscles(youdonotneedtoknow
thenameforthisclass)inthetongueisrequiredtobeableto protrudethetongue
straightout.Ifonemuscleisinactive,theactionoftheintactmuscleisunopposed.
Thetonguewillthendeviatetowardthesideoftheparalyzedor inactivemuscle.
DamagetotheUMNmayresultinfasciculationswithoutatrophyofthetongue
musclesontheaffectedside.Thetonguewilldeviatetothesidecontralateral to
thelesion,asshowninthefigureontheleft.
LesionsordamagetotheLMNcellbodiesinthehypoglossalnucleusortothe
axonstravelingtoinnervatethetonguemuscles,willcauseatrophyCOMBINED
withfasciculations alsocalledflaccidparalysisontheipsilateral side.Thisis
drawnontherightsideoftheillustration.
586
Peripheral Neuropathy
and Multiple Sclerosis
Medical Neuroscience
Christopher Brandon,
Ph.D.
Overview of Peripheral Neuropathy
Definition
Incidence
Symptoms
Neurotrophins and muscle maintenance
Classification
Types
Other categories
PN with ANS involvement
Sensory neuronopathy
Painful neuropathies
Acquired neuropathies
Normal nerve structure
Appearance (LM) with various stains
Sheaths; the neurovascular bundle
Appearance (EM)
Classification of axons
Reaction to injury
Hereditary neuropathies
Acquired Neuropathies
Traumatic Neuropathy
Overview
Traumatic neuroma
Nerve transection
Morton's neuroma
Carpal tunnel syndrome
Wrist drop
Olfactory nerve damage
Inflammatory neuroma
Major types
Guillan-Barre
Electrodiagnostics
Acquired Neuropathies (cont'd)
Infectious neuroma
Major types
Leprosy
Diphtheria
Herpes zoster
Neoplastic
Toxic/Metabolic
Diabetes
Ulcers
Overview
Natural history
Mechanism of nerve damage
PKC in microvasculature complications
Vascular effects
Autonomic neuropathy
Overview
Loss of autonomic innervation
Sensorimotor neuropathy
Overview
Symptoms
Clinical signs
Loss of nervous innervation
Treatment
Management of Diabetic Peripheral
Neuropathy
587

A peripheral neuropathy is a disorder of the PNS, including:
cranial nerves (except the optic nerve)
spinal nerve roots (radiculopathy)
the dorsal root ganglia
peripheral nerve trunks and their terminal branches
the peripheral autonomic nervous system

Incidence: affects twenty million people in the U.S.
588

Symptoms
Somatic
numbness, burning sensation
tingling, and pricking sensations (paresthesia)
exaggerated sensitivity to touch
muscle weakness, wasting, paralysis

Autonomic
gland dysfunction, unable to sweat normally
unable to digest food easily,
unable to maintain safe BP levels
sexual dysfunction
breathing difficulties
organ dysfunction / failure

589

Muscle Wasting
Denervation of skeletal muscle causes
it to degenerate, or "waste".
wasting due to compression
of the brachial plexus.
Neurotrophins released by peripheral nerves bind to receptors on skeletal muscle cells.
Following denervation, the absence of neurotrophins leads to degeneration of the
muscle.
590

NEUROPATHIES
Acquired
Traumatic
Inflammatory
Infectious
Acquired Toxic/Metabolic
Neoplasms
Hereditary
HMSN-I, -II, -III

Neuropathies may be classified according to the region of the neuron that is affected.
Guillan-Barr syndrome, for example, involves destruction of peripheral myelin, and so is a
"myelinopathy". A tumor within a ganglion, on the other hand, would primarily destroy
neuronal cell bodies, and so would be a "neuronopathy".
591

Etiologies of Acquired Polyneuropathies
Metabolic or endocrine disorders

Diabetes mellitus
Renal disease
Vitamin deficiencies
(E, B1, B6, B12, niacin)
Alcoholism
Hormone disorders
Infectious
Herpes zoster
Leprosy, Lyme, HIV, sarcoid
Drugs or toxins
Vincristine
Immune-mediated
Guillain-Barr Syndrome
CIDP
Vasculitis
Connective tissue disease
Monoclonal gammopathies
Plexitis (brachial, lumbosacral)
Cancer related
lymphoma
Myeloma
carcinoma
Unknown etiology
"cryptogenic" sensory and

sensorimotor
592

longitudinal section of nerve (H&E) cross-section of nerve (H&E)
nerve (silver stain) nerve (myelin stain)
In normal histological preparations (Hematoxylin and Eosin, top two panels), axons are
lightly stained and myelin, having been extracted during preparation, is not visible at all.
Silver stains cytoskeletal proteins, so is the best choice for revealing axons (lower left
panel).
A lipid-reactive substance such as osmium (lower right panel) reveals the myelin sheath
as a circular profile around the unstained axon. Unmyelinated axons are not visible in
myelin stained preparations.
593

epineurium
outer
perineurial
sheath
axons
fibroblast
nuclei
fat
Schwann
cell nuclei
and outer
perineureal sheath
The perineurial sheath is particularly important in nerve regeneration; if it is intact (as in a
nerve crush), the nerve has a very good chance of regenerating. If a nerve is cut, suturing
the ends of the sheath together will significantly improve the chances for regrowth.
Diabetes and leprosy both involve significant damage to the epineurial and
perineurial sheaths of peripheral nerves.
594

A mixed nerve contains myelinated axons and unmyelinated axons,
and carries both sensory and motor information.
Schwann cell with
several unmyelinated
axons
Schwann cell with
one myelinated
axon
In the peripheral nervous system, myelin is produced by peripheral glia called Schwann
cells. Each Schwann cell myelinates one internodal segment of a single axon.
Unmyelinated axons are surrounded by the cytoplasmic processes of Schwann cells; a
single Schwann cell will generally surround several of these smaller axons. Even when
unmyelinated, therefore, axons in the peripheral nervous system are never bare.
The peripheral nerve contains axons but no neuronal cell bodies. The only cell bodies
present are those of Schwann cells and fibroblasts; the fibroblasts manufacture some of
the connective tissue that surrounds each axon and each bundle of axons (fascicle).
595

The myelin in a peripheral nerve
is manufactured by the Schwann
cell.
Unlike the oligodendrocyte of the
CNS, one Schwann cell myelinates
one internodal segment of a single
axon
Schwann cell
unmyelinated axons
596

A Simplified View of the PNS A Simplified View of the PNS
Motor Sensory Autonomic
Myelinated Myelinated Thinly
myelinated
Un- myelinated Thinly
myelinated
Un- myelinated
A A/ A C A C
Large
Muscle
control

Touch,
Vibration,
Position
perception
Cold
perception,
Pain

Warm
perception,
Pain
Heart Rate, Blood
Pressure, Sweating,
GI function
Small
100m/sec 0.5m/sec
Small fibers (1-5 m) - pain/temperature/autonomic pathways
Large fibers (10-20 m) - vibration/proprioception, motor

Almost all peripheral nerves have both small and large fibers
597

HOW NERVES REACT TO INJURY
regrowth
at 1mm/day
Muscle fibers cannot survive
unless they are innervated!
Muscle fibers have degenerated
during the time taken for nerve regrowth
Important note: under the proper conditions, peripheral nerves re-grow at
1mm/day. But, during this time, the denervated muscle will degenerate. If
significant time elapses before re-innervation, then the muscle may not
regenerate!
598

NEUROPATHY, Hereditary
Hereditary Motor and Sensory Neuropathy
(HMSN-I), a.k.a. Charcot-Marie-Tooth
Neuropathy (CMT).
HMSN-I molecular defect is in the gene for
P
o
, the principal myelin protein.
HMSN-II molecular defect is in an axonal
motor protein (defective cellular trafficking).
HMSN-III molecular defects in several myelin
proteins; most severe form of CMT (Djerine-
Sottas Disease).
pes cavus (high arch)
due to muscle wasting
wasting of
calf muscles
There are at least 30 different types of Charcot-Marie-Tooth disease (Hereditary Motor
Sensory Neuropathy), each involving a mutation in a different gene and affecting a different
aspect of nerve funtion. CMT1 is the most common group, and involves defective myelin
proteins.
599

Charcot-Marie-Tooth
disease, Type 2
Gap junctions are rare in adult

mammalian neurons but more
common in non-neural cells, e.g., glial cells (such as Schwann cells).
Mutation in one of the connexin genes expressed in Schwann cells causes Type 2
Charcot-Marie-Tooth disease, a hereditary, sex-linked progressive nerve disorder.
As a result of this mutation, connexin fails to form functional gap junction channels,
essential for flow of metabolites in Schwann cells. One consequence of this defect
is defective myelin.
600

NEUROPATHY, Traumatic
Laceration
Avulsion (tearing)
Carpal Tunnel syndrome
Traumatic (amputation) Neuroma
Saturday Night Palsy
The "funny bone" isn't so humerus
Morton's Neuroma
Radiculopathy
* The most common cause of injury to a nerve.
* Motor-vehicle accidents, falls, sports-related activities.
* Nerves may be partially or completely severed, crushed, compressed, stretched,
or partially or completely detached from the spinal cord.
* Broken or dislocated bones can compress adjacent nerves.
* "Slipped" disks can compress nerve fibers at the roots, i.e. where they emerge
from the spinal cord (causing a condition known as radiculopathy).
quiz: Why does a crush injury have the best chance for recovery?
601

TRAUMATIC (POST-AMPUTATION) NEUROMA
Regenerating axons and glia (Schwann Cells), but with no direction
Traumatic neuromas are growths that generally arise 1-12 months after a nerve transection;
they are not malignant. They most commonly occur after amputation of a limb, or in the
head and neck (e.g. after a tooth extraction, which severs a nerve), or the radial nerve and
brachial plexus.
602

MORTONS NEUROMA
Traumatic Compression
F>M
Interdigital
Intermetatarsal
MEDIAL Plantar Nerve
3
rd
COMMON digital branch
swelling
Mortons Neuromas most commonly occur in the 3
rd
common digital branch of the
MEDIAL plantar nerve, i.e., 3
rd
and 4
th
toe at the distal metatarsal level.
603

Carpal Tunnel Syndrome occurs
when the median nerve is squeezed
at the wrist by the carpal ligament
604

605

"Wrist drop" follows compression/damage to the radial nerve
when it gets pinched between the ends of a broken humerus.
606

11. Identify the encirled structure.
Almost any injury that involves bleeding will also involve nerve injury. This is because blood
vessels and nerves develop and run together, as neurovascular bundles. A typical
neurovascular bundle contains an artery (or arteriole) and its companion vein (or venule),
and a nerve.
607

The unusual path of axons of the olfactory tract makes them
vulnerable to damage from head trauma. The nerves(fila
olfactoria) may be sheared off (red arrows) by strong impact
to the head.
Inability to smell = anosmia.
Rapid decelleration of the head (as when it strikes the dashboard during an automobile
accident) can cause shearing and tearing (avulsion) of the axons of the olfactory nerve (fila
olfactoria) as they pass through the cribriform plate of the ethmoid bone. Because the torn
ends of the axons are displaced from one another, they cannot regrow. The result is
anosmia, a permanent loss of the sense of smell.
608

NEUROPATHY, Inflammatory
(autoimmune)
Guillain-Barr Syndrome Gangliosides GM1, GD1a
(GBS; AIDP)
Multifocal Motor Neuropathy Gangliosides GM1
(MMM)
Chronic Inflammatory Gangliosides; tubulin?
Demyelinating Neuropathy
(CIDP)
(CIDP is considered to be the chronic form of GBS;
GBS is also called Acute Inflammatory Demyelinating
Neuropathy, or AIDP)
Disease Self-Antigen
609

Guillain-Barr syndrome occurs 1-4 weeks after an
infection. The bacterium Campylobacter jejeni, and
the Epstein-Barr virus, have been implicated.
macrophage
digesting
myelin
segmental demyelination
axon destruction
neuronal death
Note: Lots of GBS at Great Lakes Naval Training Center!
The lipopolysaccharide coat of the bacterium Campylobacter is highly antigenic.
Occasionally, a Campylobacter infection can result in the production of anti-LPS antibodies
that happen to cross-react with the gangliosides of the host's peripheral myelin. This results
in a rapid autoimmune attack on nerves throughout the body.
610

Guillain-Barr (AIDP), Acute Inflammatory Demyelinating Polyneuropathy
leukocyte infiltration
in peripheral nerve
Clinical manifestations
The initial symptoms often consist of tingling and "pins and needles sensations" in the feet
and may be associated with dull low-back pain. by the time of presentation, which usually
occurs within hours or days after first symptoms, weakness has usually developed. The
weakness is usually most prominent in the legs, but the arms or cranial musculature may be
involved first. Tendon reflexes are lost early, even in regions where strength is retained.
Because the spinal roots are usually prominently involved, GBS can involve short nerves
(axial and intercostal as well as cranial nerves) as well as long ones. Weakness
progresses, with the low point reached within 30 days, and usually by 14 days. Progression
can be alarmingly rapid, so that critical functions such as respiration can be lost within a few
days or even a few hours.
The potential for respiratory insufficiency, as well as swallowing difficulty and autonomic
dysregulation, underlies the life-threatening nature of GBS. In the past, mortality was ca.
15%, but is now about 2%.
The major treatments are 1) plasmapheresis (exchange of the patient's plasma for an
albumin solution), which removes antibodies from the blood), and 2) infusion of high doses
of human immunoglobulin intravenously.
Patients generally recover well enough to walk after about 3 months.
611

NEUROPATHY, Infectious
Leprosy
Diphtheria
V/Z (Varicella/Zoster)
Lyme disease
HIV
612

Leprosy is caused by Mycobacterium
leprae. Granulomatous lesions (right)
kill peripheral nerves, leading to
auto-amputation.
infected,
inflamed
nerve
early tuberculoid lesion
Notice the inflammatory cells surrounding the nerve. The characteristic loss of digits is a
dramatic demonstration of the muscles' need for nervous innervation.
613

Corynebacterium diphtheriae causes a polyneuropathy in about 5% of patients
with Diphtheria. Like GBS, it may proceed to complete paralysis.
The polyneuropathy is caused by Diphtheria toxin, which has a direct toxic effect
on peripheral nerve. Lethal dose: 0.1 micrograms/kg (!).
Diphtheria
614

Herpes Zoster Infection
The Varicella/Zoster virus may infect
one or more dorsal root ganglia.
A herpetic eruption occurs in the area
supplied by the sensory nerve (left).
Pain usually subsides after a few weeks.
This is an example of an inflammatory,
sensory mononeuropathy; it is also a
radiculopathy (i.e. involves spinal roots).
(Herpes Zoster also causes chickenpox)
The varicella-zoster virus (VSV) causes chickenpox. After infecting an individual, the virus
can take up residence in sensory ganglia (DRGs). Occasionally, often in response to stress,
it becomes activated, and travels down the nerve towards the skin, where it forms blisters.
Note that the distribution of the rash parallels the distribution of the nerve, i.e. the rash
demonstrates the dermatome of the nerve.
615

NEUROPATHY, Neoplastic
Benign: Schwannoma
Malignant: Malignant Schwannoma
Note: all tumors of nerve are
tumors of Schwann cells
(because no neurons in nerves!)
616

NEUROPATHY, Toxic/Metabolic
Diabetes Mellitus
Vitamin deficiencies (B, E)
Vitamin B6 (pyridoxine) toxicity
Heavy metals (e.g. Lead, Arsenic, thallium)
Organic compounds
Antineoplastic drugs (cisplatin, taxol)

DIABETES
Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to
absolute insulin deficiency. This is usually due to autoimmune destruction of the pancreatic
beta cells (type 1A).
Type 2 diabetes is by far the most common type of diabetes, and is characterized by
variable degrees of insulin deficiency and resistance.
The high glucose levels resulting from this disease cause progressive, systemic nerve
damage.
B VITAMINS
617

THE B VITAMINS
THIAMINE (VITAMIN B1)
essential cofactor for carboxylation reactions
cofactor for normal carbohydrate energy metabolism

Thiamine deficiency
associated with alcoholism (Wernicke-Korsakoff psychosis)
early symptoms: loss of appetite, constipation, nausea
later symptoms: depression, peripheral neuropathy, unsteadiness, mental

confusion, ataxia, loss of eye coordination
PYRIDOXINE (VITAMIN B6)
cofactor in amino acid metabolism
cofactor in glycogen phosphorylase reaction
required for synthesis of serotonin, noradrenaline
required for synthesis of myelin components (sphingosine, sphingomyelin,

sphingolipids)
Pyridoxine deficiency
associated with alcoholism
early symptoms: irritability, nervousness, depression
later symptoms: peripheral neuropathy, convulsions, coma

618

34

Diabetic Complications Affect
Every Part of The Body
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease
Cardiovascular
Disease
Stroke
2 to 4 fold
increase in
cardiovascular
mortality
and stroke
Diabetic
Neuropathy
Leading cause of nontraumatic
lower extremity amputations
FYI ONLY:
Diabetic microvascular complications are most commonly manifested in the eyes,
kidneys, and nerves.
Diabetic retinopathy and diabetic macular edema: Diabetes is the leading cause of new
cases of blindness in adults between the ages of 20 and 74 years.

After 15 years of
diabetes, 2% of patients become blind and 10% develop severe visual disability.
Diabetic nephropathy: In end-stage renal disease, diabetes accounts for about 35% to
40% of new cases. People with diabetes make up the fastest-growing group of renal
dialysis and transplant recipients.
Diabetic neuropathy and amputations: Diabetes is the leading cause of nontraumatic
lower-extremity amputations, accounting for 50% of amputations in the United States.
About 60% to 70% of people with diabetes have some degree of diabetic nerve
damage.
There is also a high frequency of atherosclerosis (macrovascular disease) leading to
increased risk of stroke and/or heart attack.
Cardiovascular disease: People with diabetes are 2 to 4 times more likely to die from
heart disease than people without diabetes. Cardiovascular disease is responsible for
50% of diabetes-related deaths.
Stroke: A person with diabetes is 2 to 4 times more likely to suffer a stroke than a person
without diabetes.
619

BOTH demyelination AND a direct TOXIC
effect to peripheral nerves are seen in
diabetes, which is the MOST COMMON
cause of polyneuropathy.
The vasculitis (degeneration of blood
vessels), combined with sensory loss,
makes diabetic patients vulnerable to
severe ulcers (left).
axon undergoing
demyelination
620
36

Healthy Nerves and Blood
Vessels

Vasa
nervorum
Unmyelinated
nerve fiber
Myelinated nerve fiber
Occluded
vasa
nervorum
Damaged unmyelinated
nerve fiber
Damaged myelinated
nerve fiber
Nerves and Blood Vessels
Damaged by DPN
Diabetic Peripheral Neuropathy
Diabetes is a vessel disease...
2005 International Medical Press.
Patients with diabetic peripheral neuropathy experience diminished reflexes, and a
variety of sensory and motor deficits.
Examination of tissues from patients with diabetes reveals capillary damage,
neovascularization, and occlusion in the vasa nervorum.
Reduced blood supply to the neural tissue results in impairments in neurotransmission
that affects both sensory and motor conduction.
621

...that leads to destruction of nerves
A
B
C
.
A) Normal density of
epidermal nerve fibers (arrows)
in the back
(stained with silver)
B) Slightly reduced density
and abnormal nerve fiber
swellings in proximal thigh.

C) Complete absence of small
nerve fibers in calf.
622

Autonomic Neuropathy in DPN
(leading to Dysautonomia)
Heart rate abnormalities
Postural hypotension
Abnormal sweating
Gastroparesis
Neuropathic diarrhea
Impotence
Retrograde ejaculation
D
c
C
A
B
Normal
Diabetic
nerve fibers
Loss of Innervation of Sweat Glands (A,B)
and Hair Follicles (C,D)
623

Sensorimotor Neuropathy in Diabetes -
Clinical Signs
"glove"
"stocking"
Reduced or absent sensation to pain,

touch, cold, hot and vibration in a
stocking-glove distribution most
common signs of sensory neuropathy
Reduced or absent ankle reflexes,

muscle weakness, small-muscle
atrophy and prominence of the
metatarsal heads main signs of
motor neuropathy
624

Multiple Sclerosis -
Demyelination within the CNS
Can produce deficits in vision, strength, coordination,

speech, bladder control, sexual function, sensation, etc.
Affects both sexes, but women have 2-3x risk.
Affects young adults primarily.
Causes symptoms that vary greatly from individual to

individual, and from episode to episode.
Has an unpredictable course (but 50% of patients will

need help walking within 15 years after onset of the
disease).
At diagnosis, ~85% of people with MS present with a

relapsing form of the disease (i.e. active and inactive).
250,000 - 350,000 patients with MS in the USA.

625
41
A Case
A 35 year old white woman came to Neurology Clinic for evaluation of her
long-term neurological complaints.
She reports she has had many years of heat intolerance which will
precipitate a stumbling gait. She also relates that she has had intermittent
changes in her vision.
Two months prior to presentation, she got sick with a flu and her
neurological condition worsened. She could not hold objects in her hands,
had a significant tremor and severe exhaustion. She also had several bad
falls. Since that time she had noticed arthralgias on the right and
subsequently on the left side of her body.
She abruptly developed a right hemi-sensory deficit after several days of

work.
626
42
A Case Test Results
MRI scan revealed a multifocal white matter disease (increased T2 signal in

both cerebral hemispheres)
Spinal tap was also done which revealed oligoclonal bands (antibodies) in
CSF (reflects an autoimmune process)
Visual evoked response testing was abnormal with slowed conduction in

both optic nerves
627

Sclerotic plaques are often found in the
periventricular white matter, within the large
myelinated bundles that interconnect the
cerebral lobes, but can occur in any brain
region (e.g. optic nerve, above-right).
MS results from destruction of myelin
by an autoimmune mechanism
M
R
I
Gross brain
section
Sclerosis = ""any pathological thickening or hardening of tissue"
Lesions are located primarily in the white matter, although they may also occur in gray matter. They
can be anywhere in the brain or spinal cord. Lesions often accumulate in periventricular areas,
especially in the angle between the corpus callosum and the caudate (Wetterwinkel zone).
Lesions vary in size (<1mm to several cm), shape, and appearance. Lesions may show cystic
degeneration.
Lesions always follow venous blood vessels ("Dawson's fingers").
628

TWO FORMS OF MS
Cerebral
Physical deficits (sensory and motor)
Cognitive deficits
Mood disturbances (esp. depression)

Spinal cord
Physical deficits (sensory and motor)

often much more severe than with
the cerebral form
Pain
MRI showing
demyelinating
lesions in
spinal cord
629

myelinated axons in
normal white matter
demyelinated axons
lesion
sites
perivascular lymphocytes
venule
The hallmark of MS is the demyelinated plaque, a well-demarcated hypocellular area with loss of
myelin, and relative preservation of axons.
MS is thought to begin with an infection (viral?), to which the body responds by making antibodies.
In some individuals, one or more viral antigen resembles some part of Myelin Basic Protein (MBP),
an important protein contained within CNS myelin.
Years later, sensitized immune system cells, looking for the viral antigens, discover MBP and begin
attacking the myelin sheath and the oligodendrocytes that manufacture it.
Lymphocytes enter the CNS from the blood, accumulating around venules to form the characteristic
Dawson's fingers (lower-left micrograph).
In many cases, the axons are destroyed, leading to irreversible loss of function.
630

"Repair" myelin is usually very thin,
with reduced conduction velocity
normal
axons
remyelinated
axons
Demyelinated axons conduct action potentials at lower speeds, which
disrupts the normal functioning of neural circuitry.
In addition, unmyelinated axons are much more vulnerable to conduction
block, especially at high temperatures (which explains the worsening of
patients' symptoms when they get overheated).
Axons are often spared, although when completely demyelinated. Such
axons may be re-myelinated by surviving oligodendrocytes, although the
replacement myelin is thinner than normal; as a result, full conduction
velocity is never restored.
631

myelin
sheaths
Immunocytochemical localization
of MBP in oligodendrocytes
axon
The primary autoimmune target in MS
is myelin basic protein (yellow dots),
which functions to hold the layers of
myelin together.
.
.
.
.
.
.
EM of myelin.
Structural components of myelin sheath (30% protein, 70% lipid):
Myelin Basic Protein (MBP) - 30% of the structural protein in the membrane.
Proteolipid protein (PLP) - Makes up 50% of the protein in the membrane.
Myelin-associated glycoprotein (MAG).
Myelin/oligodendrocyte glycoprotein (MOG).

In experimental animals, immunization with any of these substances causes an
autoimmune condition (Experimental Autoimmune Encephalomyelitis) that mimics
MS.
632

EPIDEMIOLOGY
INFECTION
Strong evidence that a transmissible infectious agent starts the

autoimmune process, but no virus identified to-date. Campylobacter??
GENETIC SUSCEPTIBILITY
Risk of MS 20-20x for the sibling of a person with MS.
Much higher incidence in Scandinavians.

GEOGRAPHIC VARIATION I
Parallels distribution of Scandinavian genes (those doggone Vikings...)

GEOGRAPHIC VARIATION II
More light (or more fish oil)

--> more Vitamin D
--> lower MS incidence
Contagion - In the 1940s, British troops were stationed on the Faroe Islands,
where MS had not been observed until that time. In subsequent years, the resident
population experienced several years-long waves of MS, as might be expected if
the troops introduced an infectious agent.
Genetics - Increased incidence of MS in individuals with Scandinavian inheritance
is thought to relate to the presence of cell-surface markers unique to that
population. The worldwide distribution of MS closely parallels the distribution of
Scandinavian genes, spread during the years of Norse conquests (the "Viking
diaspora").
The high MS incidence in New Zealand reflects the settlement of that area by
individuals from Scotland (where MS rates are very high due to Scandinavian
inheritance).
Immune System Dysfunction - Vitamin D is an important regulator of the immune
system. Abnormally low levels of Vitamin D, due to low light levels (in, e.g.,
extreme northern climates), or to low consumption of fish oils, are strongly
correlated with increased MS susceptibility.
633

A Case
A 33 year-old female with a four-year history of
alcohol abuse was admitted to the hospital with
generalized ascending weakness and numbness
for three weeks. The patient denied flu-like or
gastrointestinal symptoms. A physical exam
revealed diminished power 3/5 of the extremities,
decreased sensation to pinprick, pain, and
temperature distally, areflexia, flaccid muscle
tone, dysphagia and a vital capacity (VC) of
900cc.
Diagnosis?
Treatment?
634
April 25, 2013
11 AM
Dr. Ariano
1
Brainstem Anatomy
Haines Atlas, Chapter 6
Structures to Identify
Know the location and function for
items listed in your Neuroanatomy
Study Guide on pages:
9-12 (Surface & Midsagittal structures)
43 (Somatosensory)
67 (Motor)
80-81 (Brainstem)
CN IV CN IV
Brainstem
Ventral aspect
Haines 2-20
Trigeminal n.
Optic n.
Pyramids
Hypoglossal n.
Facial n.
Abducens n.
Inferior Olive
Facial n.
Vestibulocochlear n.
Optic chiasm
Oculomotor n.
Pons Pons
Medulla Medulla
Cerebellum Cerebellum Pyramidal
decussation
Preolivary
sulcus
CN IV CN IV
635
April 25, 2013
11 AM
Dr. Ariano
2
Brainstem
Dorsal
aspect
Haines 2-31
Trochlear n.
Pons
Medulla
Midbrain
SC SC
IC IC
MGB MGB LGB LGB
Crus
cerebri
Crus
cerebri
MCP MCP
Posterior median sulcus
Cuneate
tubercle
Gracile
tubercle
Facial
colliculus
Dorsal Brainstem, transparent
Edinger-Westphal nucleus Edinger-Westphal nucleus
Oculomotor nucleus Oculomotor nucleus
Trochlear nucleus Trochlear nucleus
Superior colliculus
Inferior colliculus
Mesencephalic nucleus of V Mesencephalic nucleus of V
Principal sensory nucleus of V Principal sensory nucleus of V
Abducens nucleus Abducens nucleus
Vestibular nuclei Vestibular nuclei
Nucleus of solitary tract Nucleus of solitary tract
Nucleus of spinal tract of V Nucleus of spinal tract of V
SENSORY
MOTOR
Cochlear nuclei Cochlear nuclei
Facial nucleus Facial nucleus
Nucleus Ambiguus Nucleus Ambiguus
Hypoglossal Nucleus Hypoglossal Nucleus
Dorsal motor nucleus of X Dorsal motor nucleus of X
Salivatory nuclei Salivatory nuclei
Accessory nucleus Accessory nucleus
Trigeminal motor nucleus Trigeminal motor nucleus
Medulla Pons Midbrain
Orienting the Coronal Level
Find the ventricle in the section indicates dorsal direction
Locate the corticospinal/bulbar system ventrally
Medullary characteristic inferior olivary complex
Pontine characteristic middle cerebellar peduncle
Midbrain trait crus cerebri and lateral expansion for MGB
636
April 25, 2013
11 AM
Dr. Ariano
3
Know the function for
Tectum
Periaqueductal gray
Reticular formation (RF)
Medial geniculate
Lateral geniculate
Oculomotor nucleus and nerve
[Red Nucleus]
Medial lemniscus and spinothalamic tracts
[Substantia nigra]
[Cerebral peduncles]
MRI of Brainstem
http://www.med.harvard.edu/AANLIB/cases/caseNA/pb9.htm
T1-weighted
Gross Internal Areas
Tectum Tectum
B
a
s
i
s
B
a
s
i
s
Tegmentum Tegmentum B
a
s
i
s
B
a
s
i
s
Basis Basis
Tegmentum Tegmentum
Basis Basis
Tegmentum Tegmentum
637
April 25, 2013
11 AM
Dr. Ariano
4
Caudal Medulla
Haines 6-8
Pyramidal Pyramidal
decussation decussation
Spinal V
nucleus
Spinal V
nucleus
Gracile fasciculus
and nucleus
Gracile fasciculus
and nucleus
Cuneate fasciculus
and nucleus
Cuneate fasciculus
and nucleus
Myelin is stained black; nuclei are white
Anterolateral
system
Internal Capsule Stroke
Haines 6-7
Degenerated
Corticospinal tract
Degenerated
Corticospinal tract
Site of capsular
infarct
Site of capsular
infarct
Spinal cord
Medulla
Pons
Midbrain
Motor cortex
A
B
M
id
lin
e
Middle Medulla
Haines 6-11
Corticospinal
tract
Corticospinal
tract
ICP
MLF MLF
Inferior Olivary
Nuclear complex
Inferior Olivary
Nuclear complex
Medial
Lemniscus
Medial
Lemniscus
Solitary nucleus Solitary nucleus
and tract and tract
Spinal V Spinal V
tract tract
4
th
ventricle
Vestibular nuclei
*Anterolateral
System
* *
XII XII
638
April 25, 2013
11 AM
Dr. Ariano
5
Blood Supply, Caudal Brainstem
Anterior spinal artery
Posterior spinal artery
Vertebral artery
PICA
AICA
Vertebral & paramedian basilar
Medial lemniscus (ML)
Haines 6-14
Surface Views of Blood Vessels
Haines 2-33 Haines 2-19
Anterior spinal
artery
Posterior spinal
artery
Vertebral
artery
AICA
PICA
AICA PICA
Basilar
artery
Superior
cerebellar
artery
Ventral
Dorsal
Caudal Pons
Haines 6-13
4
th
Ventricle
Corticospinal Corticospinal
tract tract
SCP
MLF
Vestibular Vestibular
Nuclear complex Nuclear complex
Medial
Lemniscus
Medial
Lemniscus
* *Anterolateral Anterolateral
system system
Facial nerve Facial nerve
VI VI VI
Spinal V Spinal V
tract tract
ICP
* *
639
April 25, 2013
11 AM
Dr. Ariano
6
Middle Pons
Haines 6-17
SCP
MLF
Vestibular
Nuclear complex
Abducens
nerve
VI VI
Trigeminal
nerve
MCP
* *
CS CS CS *Anterolateral
System
Genu of
Facial
nerve
Facial nerve
Pons
Haines 6-20
Corticospinal
tract
SCP
MLF MLF Medial Medial
lemniscus lemniscus
Trigeminal Trigeminal
nerve nerve
MCP
PAG PAG
Trochlear nerve Trochlear nerve
Anterolateral Anterolateral
system system
Pontine Blood Supply
Haines 6-21
Basilar a. (paramedian)
AICA & Basilar (long circumferential)
Basilar (short circumferential)
SCA & Basilar (long circumferential)
640
April 25, 2013
11 AM
Dr. Ariano
7
Caudal Midbrain
C
r
u
s
c
e
r
e
b
r
i
MLF MLF
system system
IV IV IV
PAG PAG PAG
Inferior colliculi Inferior colliculi
Haines 6-23
Medial Medial
lemniscus lemniscus
Midbrain
C
r
u
s
C
r
u
s
c
e
r
e
b
r
i
c
e
r
e
b
r
i
MGN MGN
III III
system system
Superior Superior colliculi colliculi
PAG PAG PAG
Haines 6-25
ML ML
Pulvinar Pulvinar
MGN MGN
LGN LGN
Optic
tract
Optic
tract
ML
Midbrain & Diencephalon
Haines 6-30
3 3
r r
d d
v v
e e
n n
t t
r r
i i
c c
l l
e e
C
r
u
s
c
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r
e
b
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i
C
r
u
s
C
r
u
s
c
e
r
e
b
r
i
c
e
r
e
b
r
i
VPL VPL
Pulvinar Pulvinar Pulvinar
Pineal Pineal
VPM VPM
CM CM
Subthalamic Subthalamic
nucleus nucleus
641
April 25, 2013
11 AM
Dr. Ariano
8
Blood Supply, Midbrain
Haines 6-27
Basilar (paramedian)
Quadrigeminal & med post choroidal
Quadrigeminal (lateral) & med post choroidal
SCA & quadrigeminal
Thalamogeniculate
Surface Views of Blood Vessels
Haines 2-33 Haines 2-19
Basilar
artery
Superior
cerebellar
artery
Quadrigeminal
artery
Choroidal
arteries
Thalamogeniculate
arteries
MCA
Ventral
Dorsal
Spinal Cord Blood Supply
Haines 6-6
Anterior
Spinal artery
Posterior
Spinal artery
Arterial
Vasocorona
642
April 25, 2013
11 AM
Dr. Ariano
9
equivalent to Haines fig 6.4
Cervical Spinal Cord
Ventral horn Ventral horn
Dorsal
horn
Dorsal
horn
Intermediate
zone
Intermediate
zone
Anterolateral
system
Anterolateral
system
Anterior
Spinocerebellar
tract
Anterior
Spinocerebellar
tract
Posterior
Spinocerebellar
tract
Posterior
Spinocerebellar
tract
Gracile
fasciculus
Gracile
fasciculus
Cuneate
fasciculus
Cuneate
fasciculus
Lateral
Corticospinal
tract
Lateral
Corticospinal
tract
Haines fig 6.3
Thoracic Level
Anterolateral
system
Anterolateral
system
Anterior
Spinocerebellar
tract
Anterior
Spinocerebellar
tract
Posterior
Spinocerebellar
tract
Posterior
Spinocerebellar
tract
Gracile
fasciculus
Gracile
fasciculus
Lateral
Corticospinal
tract
Lateral
Corticospinal
tract
equivalent to Haines fig 6.2
Lumbar Level
Anterolateral
system
Anterolateral
system
Gracile
fasciculus
Gracile
fasciculus
Lateral
Corticospinal
tract
Lateral
Corticospinal
tract
643
April 25, 2013
11 AM
Dr. Ariano
10
Haines fig 6.1
Sacral Level
Anterolateral
system
Anterolateral
system
Gracile
fasciculus
Gracile
fasciculus
Lateral
Corticospinal
tract
Lateral
Corticospinal
tract
644
1
April 25, 2013
1 PM
Dr. Ariano
Brainstem Lesions
Theobjectiveofthislectureistohelpyoutodeterminewherethelocation
ofalesionmightbeinthebrainstem.Wewillsupposethatyoudonot
haveaccesstoexpensiveteststomakeyourdiagnosis.Thusyour
knowledgeofbrainstemanatomy,howtotesttheintegrityofreflexesand
cranialnervefunctions,willdefinethesiteofthedamageforyou.We
willfocusonafewsyndromesonly.Youwillberesponsiblefor
identifyingthebloodvesselsorothercausethatareassociated withthe
condition.
645
2
April 25, 2013
1 PM
Dr. Ariano
Learning Objectives
Be able to identify selected lesion sites and
probable causes based upon signs and
symptoms in:
Midbrain
Pons
Medulla
PotentialCausesofDamage:
Stroke
Trauma
Disease
Tumor
Virus(HIV,rabies,polio)
Neurodegeneration
646
3
April 25, 2013
1 PM
Dr. Ariano
Syndrome Outline Syndrome Outline
Paramedian Midbrain (Benedikts)
Medial Midbrain (Webers )
Parinauds
Medial Inferior Pontine
Lateral Inferior Pontine (AICA)
Locked-in
Medial Medullary
Lateral Medullary (Wallenberg or PICA)
Paramedian Midbrain (Benedikts)
Medial Midbrain (Webers )
Parinauds
Lateral Inferior Pontine (AICA)
Locked-in
Medial Medullary
Lateral Medullary (Wallenberg or PICA)
Midbrain Pons Medulla Midbrain Pons Medulla
Youshouldbeabletodistinguishthecharacteristicsymptomsassociated
witheachoftheseeightsyndromes.Thisknowledgeassociatesthe
functioningofneighboringstructureswithinthebrainstemwiththeirloss
duetostroke,traumaorotherdiseaseprocesses,andprovidesthelocation
oftheinjury.Thisisanexcellentwaytoremembertheneuroanatomyof
thebrainstem.
647
4
April 25, 2013
1 PM
Dr. Ariano
Arteries to Know Arteries to Know
Posterior Cerebral (PCA)
Basilar
Circumferential
Lateral pontine
Superior cerebellar (SCA)
Anterior inferior cerebellar (AICA)
Posterior inferior cerebellar (PICA)
Anterior spinal
So, just where is the lesion?
Ventral brainstem show UMN signs
No UMN signs, lesion must be lateral or dorsal
Assess cranial nerve status to determine rostral or
caudal level
Midbrain pupillary light reflex (CN III)
Inferior Pons facial expression, hearing (CN VII & VIII)
Medulla tongue and palate (CN IX, X, XI, XII)
648
5
April 25, 2013
1 PM
Dr. Ariano
Cranial Nerve Nuclei
How to establish rostral-caudal levels of damage
General somatic GSE
General somatic GSE
MOTOR or
EFFERENT
SENSORY or
AFFERENT
Thisdrawingshowsasemitransparentviewofthebrainstemviewedfromthe
dorsalsurface.Allofthenucleiofthecranialnervescanbevisualized.Thisslide
takesthesameinformationintheprevioustableandmakesit3Dtoassistin
learningthecranialnerves classifications.Themotornucleiareshownontheright
andthesensorynucleiaredrawntotheleft.Nucleiarecolorcodedbyfunction:
Component CranialNerves
Generalsomaticefferent GSE GSE III,IV,VIandXII
Generalvisceralefferent GVE GVE III,VII,IXandX
Special(branchial)visceralefferent SVE SVE V,VII,IX,XandXI
Generalsomaticsensory/afferent GSA GSA V,VII,IXandX
Specialvisceral/afferent SVA SVA I,VII,IXandX
Generalvisceralsensory/afferent GVA GVA IXandX
Specialsensoryafferent SSA SSA IIandVIII
Insomecasesdifferentbrainstemnucleicontributetoacranial nerve(CNVIIfor
example);alternativelythesamenucleuscontributestomultiple cranialnerves
(nucleusambiguusforexample).Again,reviewtheclinicaltestoffunctionstohelp
todeterminewherelesionsordamagemightbelocatedinapatient.
649
6
April 25, 2013
1 PM
Dr. Ariano
Sagittal Organization
Long
Tracts
Reticular Reticular
Formation Formation
Cerebellum
Midbrain
Pons
Medulla
tectum
4
th
Inferior
olive
Cerebral
aqueduct
Insagittalsection,onecanappreciatehowthelongmotorandsensory
tractsplusthereticularformation,traveltheextentofthecentralcoreof
thebrainstemtegmentum.Whiletheremaybesymptomsassociatedwith
damagetothesefeaturesofthebrainstem,theabilitytodistinguishthe
levelofinjuryisassessedbycranialnervefunction,whichwilldefinethe
rostrocaudal level(seepreviousslide).
Theventralanddorsalextentofabrainsteminjurymaybepartially
determinedbylossoffunctionsofthelongtracts especiallythe
corticospinalandcorticobulbarsystems.Damagetothelateralbrainstem
mayresultinHornerssyndromeandcanbehelpfulincomingtoa
diagnosis.
Damagetothereticularsystemusuallyresultsinlossofconsciousness.If
thedamageislocatedinthecaudalregions,itwillhaveserious
implicationsforlifesupportbecauseofthecardiacandrespiratory
controlcentersthatarelocatedwithinthisarea.
650
7
April 25, 2013
1 PM
Dr. Ariano
Respiratory Centers
Pons
Nucleus Nucleus
Solitarius Solitarius
Active during inspiration
Active during expiration
Modulate respiratory pattern
tonsil
Blumenfeld 14.16
Manybrainstemareascoordinatethecontrolbreathing.YouwillNOTBE
RESPONSIBLEforknowingthenamesofthesecenters!However,the critical
roleplayedbythenucleussolitarius thecardiorespiratorynucleus is
paramount,andalongwithitsotherfunctionsintaste,baroreceptorreflex,
andvisceralafferentsoftheautonomicnervoussystem,itisacritical
structuretounderstand.
Notetherelationshipofthecerebellartonsiltothesecrucialregions.When
thetonsilherniatesthroughtheforamenmagnumduetoincreased
intracranialpressure(perhapsfromacerebralhemorrhage),the
cardiorespiratorycentersandreticularformationareeasilyaffected.
651
8
April 25, 2013
1 PM
Dr. Ariano
Blumenfeld, 14.19
Midbrain
Pons
Medulla
Cerebellum
Ventral View
Surface Zones
Posterior Cerebral
Artery (PCA)
Posterior Cerebral
Artery (PCA)
Basilar A.
paramedian
Basilar A.
paramedian
Basilar A.
circumferential
Basilar A.
circumferential
SCA SCA
AICA AICA
PICA PICA
Vertebral, lateral Vertebral, lateral
Vertebral, paramedian & anterior spinal a Vertebral, paramedian & anterior spinal a
Theprincipalvascularterritoriesshownontheinferiorsurface ofthe
cerebrum,thecerebellumandtheventralbrainstemaredisplayed incolor
codesinthisimagefromBlumenfeld.Notethatmorethanonearterymay
perfuseaspecificsite andthereishighindividualvariabilityinthezones.
Figure14.20,page610611inBlumenfeldshowscrosssectionsofthe
brainstemformoredetail.
Knowledgeofthevascularterritorieshelpstolocalizethesite ofinjuryin
thebrainstemeventhoughthereisvariationamongindividuals.
652
9
April 25, 2013
1 PM
Dr. Ariano
Blood Supply
Superior
Cerebellar
Artery (SCA)
Posterior
Cerebral
Artery (PCA)
Basilar
Artery
AICA
PICA
Vertebral
Artery
Blumenfeld, 14.17B
Themajorcauseofinjuryinthebrainstemisduetostroke.Thisimage
showstheprincipalvesselsofthebrainstemfromthelateralviewpoint.
ThisimageisfromBlumenfeld,page608.
Youwillberesponsiblefortheseeightsyndromes:
ParamedianMidbrainsyndrome(Benediktssyndrome)
Weberssyndrome
Parinauds syndrome
MedialInferiorPontinesyndrome
LateralInferiorPontinesyndrome(AICAsyndrome)
LockedIn syndrome
LateralMedullarysyndrome(WallenbergorPICAsyndrome)
MedialMedullarysyndrome
653
10
April 25, 2013
1 PM
Dr. Ariano
Sectional Blood Supply
Penetrating Penetrating
Circumferential Circumferential
Arteries Arteries
Paramedian Paramedian
Penetrating Penetrating
Arteries Arteries
Short Short
Circumferential Circumferential
Arteries Arteries
Blumenfeld, 14.18
Thiscrosssectionalviewoftheponsdemonstratesthepenetratingarterial
supplyfromthebasilarartery.Theparamedianandshortcircumferential
arteriesprovidethebloodsupplytothebasisandtegmentumofthe
brainstem,whilethetectum isperfusedbypenetratingcircumferential
arteries,inpart.ThisimageisfromBlumenfeld,figure14.17, page609.
654
11
April 25, 2013
1 PM
Dr. Ariano
Midbrain Anatomy
Periaqueductal
grey
MGN
Medial lemniscus and
spinothalamic tract
(anterolateral system)
Oculomotor nucleus
and CN III
MLF
RF
Tectum (colliculi)
C
e
r
e
b
r
a
l

p
e
d
u
n
c
l
e
C
e
r
e
b
r
a
l

p
e
d
u
n
c
l
e
Red
nucleus
S
u
b
s
t
a
n
t
i
a

n
i
g
r
a
ST ST
ML ML
Thiscoronaldiagramshowsmajorstructuresinthemidbrain.Someof
thefunctionsoftheseelementswerecoveredinthefirstpartofthe
course,andareassociatedwithsensorymodalities,whileothers are
componentsofthemotorsystem.
Knowthefunctionfor
Tectum
Periaqueductalgray
Reticularformation(RF)
Medialgeniculate(MGN)
OculomotornucleusandcranialnerveIII
RedNucleus
Mediallemniscus
Spinothalamictracts
Substantianigra
MLF
Cerebralpeduncles
655
12
April 25, 2013
1 PM
Dr. Ariano
RF
Tectum (colliculi)
Red
nucleus
S
u
b
s
t
a
n
t
i
a

n
i
g
r
a
ST ST
ML ML
Paramedian Midbrain
Syndrome
Benedikts syndrome
Thissyndromeresultsfromocclusionorhemorrhageoftheparamedianmidbrain
branchesoftherostralbasilarartery ortheposteriorcerebralartery.Individuals
withthisvascularinsultexhibitthefollowingsymptoms:
Completeipsilateraloculomotornervepalsy(paralysis)
Ipsilateraleyeabductionanddepression
Ipsilateralptosis (droopingeyelid)
Ipsilateralfixedanddilatedpupil(completeinternal
ophthalmoplegia)
Contralateralhemiparesisofthelowerface(CN7),headturning/shoulder
elevation(CN11),tongue(CN12),andpalate(CN9andCN10),cannotshrug
thecontralateralshoulderorturntheheadeffectivelyawayfromthesideofthe
lesion(CN11).Duetocorticobulbardeficits
Cerebellarataxiawithdysmetria(rednucleus)
Contralateralhemiparesisoftrunk,armandlegduetocorticospinaltract
interruption
Iftheinjuryimpactsthedorsalportionsofthereticularformation,therewillbe
impairmentsinconsciousness.
656
13
April 25, 2013
1 PM
Dr. Ariano
Paramedian Midbrain
Hemorrhages
midbrain
pons
medulla
tectum
4
th
Inferior
olive
Cerebral
aqueduct
Thissagittalorientationprovidesaperspectiveofhowmuchofthe
rostrocaudalportionofthebrainstemcouldbeaffectedinthissyndrome,
andtohelpyour3Dvisualizationoftheinjury.
657
14
April 25, 2013
1 PM
Dr. Ariano
RF
Tectum (colliculi)
Red
nucleus
S
u
b
s
t
a
n
t
i
a

n
i
g
r
a
ST ST
ML ML
Medial Midbrain Syndrome
Webers syndrome
Thissyndromeresultsfromocclusionorhemorrhageoftheparamedianmidbrain
branchesoftherostralbasilarartery ortheposteriorcerebralartery.Individuals
withthisvascularinsulthavethefollowingsymptoms:
Completeipsilateraloculomotornerveparalysis(palsy)
Ipsilateraleyeabductionanddepression
Ipsilateralptosis (droopingeyelid)
Ipsilateralfixedanddilatedpupil(completeinternal
ophthalmoplegia)
Contralateralweaknessofthelowerface(CN7),tongue(CN12),head
turning/shoulderelevation(CN11)andpalate(CN9andCN10)dueto
corticobulbardeficitsinthecruscerebri
Contralateralhemiparesisofarmandlegbecauseofcorticospinaltract
damage
ThisisamoremodestinjuryzonethanthatseeninBenediktssyndrome,and
affectsthesamearterialsupply.Notethatthedistinctionbetweenthetwo
syndromesisthepresence/absenceofthecerebellarsignsdueto theinvolvement
oftherednucleus.Rememberthattherednucleusisoneofthemajortermination
sitesforcerebellaroutflowandgivesrisetotherubrospinaltractandtherubro
olivary tract.
658
15
April 25, 2013
1 PM
Dr. Ariano
Blood Supply, Midbrain
Modified from Haines 6-27
Basilar (paramedian) & PCA P1 segment
Quadrigeminal & med post choroidal
Quadrigeminal (lateral) & med post choroidal
SCA & quadrigeminal
659
16
April 25, 2013
1 PM
Dr. Ariano
RF
Tectum (colliculi)
Red
nucleus
S
u
b
s
t
a
n
t
i
a

n
i
g
r
a
ST ST
ML ML
Parinauds Syndrome
Symptoms
Paralysis of upward gaze (superior colliculi)
Hydrocephalus (occlusion of the cerebral
aqueduct)
Failure of eye movements (due to pressure
on CN III and CN IV)
Nystagmus (if the MLF becomes involved)
Cause: tumor of the pineal Cause: tumor of the pineal
or hydrocephalus or hydrocephalus
660
17
April 25, 2013
1 PM
Dr. Ariano
Caudal Pons
Anatomy
Vestibular nuclei
Nucleus & tract
of CN V
Medial lemniscus
Corticospinal
tract CN 6
MCP
DCN
CN 7 & 8 CN 7 & 8
MLF
Spinothalamic
tract
4th
Theprincipalcomponentsofthecaudalponsareillustratedincoronal
orientation.Besureyouarefamiliarwiththefunctionandlocationofthe
followingstructures:
MLF
Vestibularnuclei
Middlecerebellarpeduncle(MCP)
NucleusandtractofCNV(trigeminal)
CNVI(abducens),VII(facial),VIII(vestibuloacoustic)
Mediallemniscusandspinothalamictract
Corticospinal/corticobulbartracts
661
18
April 25, 2013
1 PM
Dr. Ariano
Syndrome
Vestibular nuclei
Nucleus & tract
of CN V
Medial lemniscus
Corticospinal
tract CN 6
MCP
CN 7 & 8
MLF
tectum
4
th
Inferior
olive
Cerebral
aqueduct
Midbrain
Pons
Medulla
Hemorrhage
662
19
April 25, 2013
1 PM
Dr. Ariano
Symptoms
Ipsilateral lateral rectus paralysis (CN VI)
Contralateral hemi-paresis of the trunk and
extremities (corticospinal tract)
Limb and gait ataxia (pontine nuclei)
Contralateral loss of proprioception,
discriminative tactile sensation, and vibration
sensation from the body (medial lemniscus)
Contralateral weakness in the muscles of the
lower face (CN VII) when corticobulbar is
affected, rostral to facial nucleus
Cause: occlusion or hemorrhage of basilar artery
-- paramedian branches
663
20
April 25, 2013
1 PM
Dr. Ariano
Vestibular nuclei
Nucleus & tract
of CN V
Medial lemniscus
Corticospinal
tract CN 6
MCP
CN 7 & 8
MLF
Lateral Inferior Pontine Syndrome
(AICA Syndrome)
Symptoms
Ipsilateral facial nerve paralysis
Loss of taste from the anterior 2/3 of tongue
Loss of the corneal and stapedial reflexes
Unilateral central nerve deafness
Nystagmus, nausea, vomiting, and vertigo
Ipsilateral loss of pain and temperature sensation
from the face
Cerebellar signs (ataxia, dysmetria,etc)
Contralateral loss of pain and temperature sensation
from the trunk and extremities
Horners syndrome -- ipsilateral
Cause: occlusion or hemorrhage of the
long circumferential branch of the basilar artery,
and/or AICA
664
21
April 25, 2013
1 PM
Dr. Ariano
Pontine Blood Supply
Haines 6-21
Basilar a. (paramedian)
AICA & Basilar (long circumferential)
Basilar (short circumferential)
SCA & Basilar (long circumferential)
665
22
April 25, 2013
1 PM
Dr. Ariano
Locked-In Syndrome
Vestibular nuclei
Nucleus & tract
of CN V
Medial lemniscus
Corticospinal
tract CN 6
MCP
CN 7 & 8
MLF
tectum
4
th
Inferior
olive
Cerebral
aqueduct
Midbrain
Pons
Medulla
Hemorrhage
666
23
April 25, 2013
1 PM
Dr. Ariano
Locked-In Syndrome
The syndrome consists of complete quadriplegia and bulbar and
facial paralysis due to complete interruption of both pyramidal tracts.
The bilateral lesion is usually in the basis of the pons, close to the
midbrain transition. Strong flexion of the upper extremity indicates
that the rubrospinal pathway is not affected by the strokes.
The patient is conscious but can make only vertical eye movements.
All other voluntary movements, including horizontal eye movements
are lost. The patient retains vertical eye movements because cortical
input to the vertical eye control center (the riMLF nucleus in the
midbrain tegmentum) is intact. But, horizontal eye movements are
lost, because these are controlled by the pontine PPRF. Since the
lesion spares the midbrain tegmentum, the patient retains
consciousness and can see, hear, and communicate by moving the
eyes up and down for yes and no. Thus, although the patient is
conscious and mentally intact, they are locked-in by complete
paralysis, including loss of control of the muscles of speech.
PathologyofLockedInSyndrome
Neurosyllabus 2-25
667
24
April 25, 2013
1 PM
Dr. Ariano
Medulla Anatomy
Corticospinal tract
Olivary nuclear
complex
Hypoglossal nucleus
Vagus nerve,
Motor n.,
N. Ambiguus
N. Solitarius
RF
MLF
Medial lemniscus
spinothalamic tract
Hypoglossal
nerve
Spinal Tract
of trigeminal nerve
Dorsal Motor Nucleus
of X
Thiscoronalsectionofthemedullaillustratesmajorstructures forwhich
youneedtoknowfunctions.Befamiliarwiththefollowing:
Hypoglossalnucleusandnerve(CN12)
MLF
DorsalmotornucleusofCN10
Nucleusambiguus
Solitarynucleus
Descendingsympatheticfibers(hypothalamicintermediolateralhorn
ofthoracicspinalcord).Note:thesefiberstravelinthelateral
tegmentum,buttheirlocationisimpreciselydefined.
Spinaltrigeminaltract
Mediallemniscusandspinothalamictract
Olivarynuclearcomplex
Corticospinaltract
668
25
April 25, 2013
1 PM
Dr. Ariano
Vagus nerve,
Motor n.,
N. Ambiguus
RF
Hypoglossal
nerve
Medial Medullary Syndrome
Symptoms
Contralateral hemiparesis of the trunk and
extremities
Contralateral loss of proprioception,
discriminative tactile sensation, and vibration
sensation from the trunk and extremities
Ipsilateral paralysis of the tongue with
fasiculations and atrophy
anterior spinal artery
669
26
April 25, 2013
1 PM
Dr. Ariano
RF
Hypoglossal
nerve
Lateral Medullary Syndrome
(Wallenberg)
tectum
4
th
Inferior
olive
Cerebral
aqueduct
Midbrain
Pons
Medulla
Hemorrhage
670
27
April 25, 2013
1 PM
Dr. Ariano
Symptoms
Ipsilateral Cerebellar signs
Nystagmus, nausea, vomiting and vertigo, ataxia, dysmetria
Ipsilateral N. ambiguus signs
laryngeal, pharyngeal and palatal paralysis
Loss of the gag reflex, hoarseness, uvula deviation
Contralateral loss of pain and temperature from the
trunk and extremities
Ipsilateral loss of pain and temperature from the face
Ipsilateral Horners syndrome
vertebral artery or one of its branches
like PICA
671
28
April 25, 2013
1 PM
Dr. Ariano
Blood Supply, Caudal Brainstem
Haines 6-14
Anterior spinal & Basilar arteries
Posterior spinal artery & vasocorona
Vertebral artery
PICA
AICA
Vertebral & paramedian basilar
Medial lemniscus (ML)
672
1
30 April 2013
10 AM
Dr. Ariano
Basal Ganglia
Purves: Chapter 18
Athoroughunderstandingofthecircuitryandchemistryofthebasalgangliais
usefulclinicallybecauseofthehighprevalenceofdisordersassociatedwiththis
systeminthegeneralpopulation.Theclinicianhashadtheabilityto
therapeuticallyattenuatethediseasesymptomsduetocontinuous discoveriesin
basicscienceresearch.
Therearefivenucleiwhichmakeupthebasalgangliasystem.Threestructuresare
subcortical andlinktotwoothernucleiintheventralthalamusandmidbrain.The
systemregulatesmovementthroughmodulatingtheactivityofuppermotor
neurons itdoesnotconnectdirectlywiththelowermotorneurons.When thereis
diseaseordamageofbasalgangliacircuitry,movementswillnot startorstop
smoothlyandthepatientwilldisplaycharacteristicsymptomsthatmaybe
detectedbysimpletests.
Theuseofganglia isahistoricalmisnomer,becausegangliaareaperipheral
nervoussystemstructure.However,wewillcontinuetousethisidentifier.Be
awarethatsometextbooksandyouratlascallsthissystemofstructuresthebasal
nuclei.
673
2
30 April 2013
10 AM
Dr. Ariano
Learning Objectives
Describe the circuit and location of the nuclei
Distinguish between the striatal projection pathways
Identify neurotransmitters of the circuits
Describe Extrapyramidal versus Pyramidal syndromes
Identify changes in the motor circuit with Parkinsons
disease (PD)
Know the mechanism of action of MPTP and how it
changed PD pharmacotherapy
Identify changes in the motor circuit with Huntingtons
disase
Know Tardive dyskinesia symptoms and their cause
674
3
30 April 2013
10 AM
Dr. Ariano
Basal Ganglia Anatomy
Basal Ganglia Anatomy
Subthalamic
nuclei
Subthalamic
nuclei
Globus
Pallidus
Globus
Pallidus
Putamen Putamen
Caudate Caudate
VA/VL thalamus VA/VL thalamus
Substantia Nigra
compacta
Substantia Nigra
compacta
Substantia nigra
reticulata
Substantia nigra
reticulata
Forebrain
Midbrain
Purves, fig 18.1
In
t
e
r
n
a
l
c
a
p
s
u
l
e
Thenucleiofthebasalgangliaare:
Caudatenucleus
Putamen
Globus Pallidus,externalsegment(GPe)
Globus Pallidus,internalsegment(GPi)
Subthalamic nucleus(STn)
Substantianigra(SN)
striatum
striatum
675
4
30 April 2013
10 AM
Dr. Ariano
Striatal
Afferents
Parietal and
Association
Cortex
Somatosensory
Cortex
Primary
Motor Cortex
Temporal
Cortex
Putamen Putamen
Caudate
nucleus
Caudate
nucleus
Internal Capsule
Crus cerebri
SNc SNc
Corticostriatal
Nigrostriatal
Corticostriatal
Nigrostriatal
Purves, fig 18.2
Inputstothebasalgangliacomefromthreeprincipalareasofthebrain:the
entirecorticalmantle(corticostriatal corticostriatal pathway),theintralaminarthalamus
(thalamocortical pathway,notshown)andthesubstantianigra,pars
compacta(nigrostriatal nigrostriatal pathway).Asmaller,lesswellunderstoodpathway
isgeneratedfromtheraphe nucleiinthebrainstem.
Thecorticostriatalandthalamostriatal pathwaysareexcitatory,using
glutamatefortheirneurotransmitter.Theseafferentsexcitethe principal
neuronsofthestriatum,designatedasmediumspinyneurons becauseof
theirsizeanddesign.Thenigrostriatalpathwayemploysdopamine which
isaneuromodulator tomodifytheexcitatoryafferentsarrivingfromthe
otherbrainareas.
Themediumspinyneuronsintegratetheinformation.Thedataisprocessed
throughanalogousbutdistinctparallelfunctionalcircuits.Inadditiontothe
commonlyknownmotorfunctions,thebasalgangliacontributeto
motivationandcognition.Thesearedescribedlaterinthelecture.
Wewillfocusonthemotorloop ofthebasalgangliaandexaminehow
differentdiseasestateschangetheinfluenceofthecircuitondownstream
uppermotorneuronsthatgetsexpressedinmovementgeneration.
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Intrinsic Circuits
SNr SNr
GPe GPI GPe GPI
Putamen Putamen
Caudate Caudate
MSN MSN
MSN MSN
ACh
interneuron
ACh
interneuron
Striatonigral
pathway
Striatopallidal
pathway
Modified from Purves, fig 18.3
MSN MSN
Dopamine
neurons
Dopamine
neurons
i
n
t
e
r
n
e
u
r
o
n
s
Corticostriatal Corticostriatal
neurons neurons
GPi/SNr
output
GPi/SNr
output
Thegateway tothebasalgangliaisthestriatum striatum (Caudate+ Putamen).The
striatumgeneratestwoefferentcircuitsstartingfromthem mediumsizeds spiny
n neurons(MSN MSN).TheMSNprojecttothetwosegmentsoftheglobuspallidus(GPe
andGPi)andtothesubstantianigrareticulata(SNr).Thisisshowntotheleft,
above(page401,Purves).Thelarge large sized sized interneurons interneurons produceAChandhave
beendrawnintothecaudateandputamennuclei.ThetwoMSNprojection
pathwaysarereferredtoasthestriatopallidalandstriatonigral,namedfromtheir
pointoforigintotheirterminationarea.
ThecellularsynapticrelationshipsoftheMSNareshowntotherightofthefigure.
Dopamine Dopamine (fromSNcneuronsinthemidbrain)hasamodulatory influenceonthe
massiveexcitatoryglutamateinnervationfromthecorticostriatalpyramidalcells corticostriatalpyramidalcells
andtheintralaminarthalamus(notshown).
ThereisconvergenceofinputontotheMSN.Theterminationsite ofglutamate
afferentsisontodendriticspineheads,whilethedopamineinputsynapsesupon
dendriticspinenecksoftheMSN.Thefunctionalsignificanceof thisisthat
dopaminewillchangetheamountofexcitatoryinfluence(ordrive)oftheglutamate
innervationuponMSNoutput.Thisbecomesimportantintheclinicaltreatmentof
basalgangliadiseases,discussedlater.
MSNalsoreceiveinputfromstriatalinterneurons(producingACh,GABAplus
numerousneuropeptides)andcollateralsfromotherMSN.Synapselocationsfor
theinterneuronsarealongMSNdendriticshafts.Sincetheseterminationsarecloser
tothesoma,theintegrationofsignalsandactivityonMSNoutputisdifferentthan
thecorticostriatalandnigrostriatalpathways.
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Spiny Dendrites
Axon
Medium Spiny Neuron
Soma
TheMSNrepresentsthevastmajorityofallneuronsinthestriatum.This
neuronusestheinhibitoryneurotransmitterGABA GABA.Twopopulationsofthe
MSNcanbedistinguishedbasedupontheirterminationsitesandthatthey
alsoproducedifferentneuropeptidesinadditiontoGABA:
1)enkephalin (enk)producingstriatopallidalneuronsareincorporatedinto
theindirect pathwayandterminateintheGPe.
2)substanceP (SP)containingstriatonigralneuronsareorganizedintothe
direct pathwayandendintheGPi/SNr.
Thetermsindirect anddirect pathwaysrefertohowmanysynapticrelays
existbetweenthestriatumandthebasalgangliaoutputnuclei,whichare
theGPi/SNr.Theindirectpathwayhastwosynapsesbeforeitarrivesat
GPi/SNr,whilethedirectpathwayismonosynaptictotheoutflow area.The
MSNprojectionsystemsareaffecteddifferentlyindiseasesofthebasal
ganglia.
Thisimageaboveisacameralucida drawingofahumanMSNafter
intracellularbiocytinfillingthatoccurredfollowingelectrophysiological
evaluationofthecellusingwholecellvoltageclampanalysis.Itwaskindly
providedbymycolleaguesatUCLA,Dr.MichaelLevineandDr.Carlos
Cepeda.
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Dr. Ariano
System
Efferents
Somatosensory
Cortex
Primary
Motor Cortex
Superior
colliculus
Putamen Putamen
Caudate
nucleus
Caudate
nucleus
Internal
Capsule
SNr SNr
Purves, fig 18.4A
Subthalamic
nucleus
Subthalamic
nucleus
Thalamus
(VA/VL)
Thalamus
(VA/VL)
Temporal
Lobe
Temporal
Lobe
Toreiterate,theMSNgeneratetwoprojections:1)SPstriatonigraldirectpathway
and2)enk striatopallidalindirectpathway.Thedirectpathwayismonosynapticto
theGPi/SNroutflownuclei.Theindirectpathwayhastwosynapticrelaystoreach
theGPi/SNroutflownuclei.Thereisasideloopintheindirectpathwayfromthe
GPetothesubthalamicnucleus(STn)andbackthatintegratesmoreinformation
intothiscircuit.Efferentdatafromthebasalgangliaproceedstothemotor
thalamus(VA/VL)andthesuperiorcolliculus.
Fromthemotorthalamus,thalamocorticalpathwaysprojecttothe primarymotor
andsensorycorticestoterminateonUMNwhichgiverisetothecorticospinaland
corticobulbartracts.Thiscompletesthebasalgangliamotorcircuitloop.The
informationfromthebasalgangliacontributestothesequencing andplanningof
movements.Thisrolemaybedemonstratedinindividualswhohave diseasesthat
impairbasalgangliafunction,discussedlater.
TheSNrisactuallypartoftheGPthatinearlydevelopmentbecomesseparatedbythe
formationoftheinternalcapsuleandthecerebralpeduncles.
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Dr. Ariano
Other Basal Ganglia Loops
Dorsolateral Dorsolateral
Prefrontal cortex Prefrontal cortex
Anterior cingulate, Anterior cingulate,
Orbital frontal cortex Orbital frontal cortex
Primary motor, Premotor Primary motor, Premotor
Supplementary motor Supplementary motor
cortices cortices
Motor Loop Oculomotor Loop Prefrontal Loop
Limbic &
Orbitofrontal Loops
S
t
r
i
a
t
u
m
T
h
a
l
a
m
u
s
P
a
l
l
i
d
u
m
C
o
r
t
i
c
a
l
i
n
p
u
t Motor, Motor,
Premotor, Premotor,
Somatosensory Somatosensory
Posterior Posterior
Parietal, Parietal,
Prefrontal Prefrontal
Dorsolateral Dorsolateral
Prefrontal Prefrontal
Amygdala, hippocampus, Amygdala, hippocampus,
orbitofrontal orbitofrontal, anterior , anterior
cingulate, temporal cingulate, temporal
Putamen Caudate
Anterior
Caudate
Nucleus
Accumbens
Lateral GP,
internal segment
GPi
SNr
GPi
SNr
Ventral
Pallidum
VA & VL
Mediodorsal
& VA
Mediodorsal
& VA
Mediodorsal
Frontal eye fields, Frontal eye fields,
Supplementary eye Supplementary eye
fields fields
Thebasalgangliacontributetootherbehaviorsbesidesmovement.Thisisdepicted
hereasparallelfunctionalloops.Thisshowstherangeofnonmotorbrainfunction
thatcanbeinfluencedbybasalgangliaactivity,orlossofthesefunctionsfrom
damage/disease.(BoxD,page414415inPurvesprovidesadiscussion).
Itisimportanttorememberthatthestartingpointforeachcircuitisthecortex,and
differentpartsofthecortexinitiateeachoftheseloops(colorcodedforeaseof
understanding).
Eachloopentersthebasalgangliathroughazoneinthestriatum,passesthrougha
partofthepallidum,andthenprojectsfromthebasalgangliatothethalamusasthe
finalrelaytoreturntothecortex.
Theanatomicalsimilaritiessuggeststhatnonmotorfunctionsmayberegulatedin
ananalogousmannertothewellunderstoodmotorloop.Forinstance,the
prefrontalloopmayadjustinitiationandterminationofcognitiveprocesseslike
planning,workingmemoryandattention.Thisprovidesapotentialexplanationfor
involvementofthebasalganglia,anddopamineinparticular,in diseasessuchas
parkinsonism(motorloop),schizophrenia(prefrontalloop),anddepressionand
chronicanxiety(limbicloop).Thisisanintensiveareaoftranslationalresearchand
illustrateshowbenchtobedside hasassistedindevelopingcoherent
pharmacotherapyformanybasalgangliarelateddiseases.
Activationofanyoftheseloopsmayoccursimultaneously.
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Dr. Ariano
Striatum
GPe
STn
SNc
GPi
SNr
Brain stem
Spinal cord
Functional
Circuit
Excitatory (glu) Excitatory (glu)
Inhibitory (GABA) Inhibitory (GABA)
enk enk enk SP SP SP
VA/VL
CM/PF CM/PF
Basal Ganglia
Outflow
Basal Ganglia
Outflow
cerebral cortex cerebral cortex
Striatopallidal
pathway
Striatonigral
pathway
ACh ACh
Theuseoftheboxcircuitdiagram torepresentthebasalgangliaconnectionsis
widelyemployedandisshownhere.Thisdiagramcontainsthesameinformation
asshownintheschematicdrawingsfromPurves(page406).Thecircuitabove
demonstratestheneurotransmittersproducedinbasalganglianeuronsandis
importantbecausethisdatahasformedthetreatmentrationaleforpatientswith
basalgangliadiseases.
Afferentscomefrom1)thecorticalmantle,especiallytheprimarymotorcortex
(corticostriatal),2)theintralaminarthalamus(thalamostriatal,CM/PF),and3)
thesubstantianigraparscompacta(nigrostriatal,SNc).Afferentsterminatein
thestriatum, whichinitiatesthebasalgangliacircuits.Rapheinputswhich use
serotoninarenotdrawnin(andyouwontberesponsibleforthem!).
Thebasalgangliaoutflow(GPi/SNr)terminatesinthemotorportionofthe
thalamus(VA/VL)andotherbrainregions(youwontberesponsiblefor
knowing!),whichprojectstothecortextofinallyinfluenceUMN.
Corticostriatal glutamate
Nigrostriatal dopamine
Striatopallidalandstriatonigral GABA plusenk orSP,respectively
Globuspallidus GABA
Subthalamicnucleus glutamate
Motorportionofthethalamus glutamate
Corticospinal/corticobulbar glutamate
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Dr. Ariano
Striatum
GPe
STn
SNc
GPi
SNr
Brain stem
Spinal cord
Direct Striatonigral Circuit
SP SP SP
VA/VL
CM/PF CM/PF
transient transient
tonic tonic
transient transient
transient transient
transient transient
Thedirect,striatonigralpathwayisshownhereinisolation.TheMSNdonot
havemuchspontaneousactivity.Theymustbeactivatedbytheexcitatorycortical
andthalamicinputs.Thisoccursinatransient manner theseneuronsbecome
activeduringmovementsandinplanningamovement.
Consequently,theGABA/SPneuronofthedirectstriatonigralpathway
transientlyinhibitsitsdownstreamtargetsintheGPi/SNroutputnuclei.Neurons
inGPi/SNraretonically active;theyspontaneouslyfire.Thetransientinhibition
fromthestriatonigralneuroninterruptsthisspontaneousfiring inGPi/SNr.This
resultsindisinhibitionoftheneuronsintheVA/VLthalamus.(Inhibitionofan
inhibitoryneuroniscalleddisinhibition).
Dopamineisaneuromodulator andisproducedbytheneuronsoftheSNc.The
nigrostriatalneuronsaretransientlyactive,andthusdopamineisreleased
sporadicallyinthestriatumtomodifytheactivityoftheMSN.Thedetermination
ofwhetherdopaminecausesexcitationorinhibitionatthestriatalsynapse
dependsuponthedensityandtypeofdopaminereceptorsontheMSN.
DopaminetendstobeexcitatorywhenitcontactsGABA/SPstriatonigralneurons,
throughitsD1typereceptor.
Theneteffectofactivityinthedirectstriatonigralpathwayistoincreasethedrive
ofthethalamocortical circuits,producingheightenedcortical(UMN)excitability.
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Dr. Ariano
Striatum
GPe
STn
SNc
GPi
SNr
Brain stem
Spinal cord
Indirect Striatopallidal Circuit
enk enk enk
VA/VL
CM/PF CM/PF
transient transient
tonic tonic
transient transient
transient transient
transient transient
tonic tonic
transient transient
Theindirect,striatopallidalpathwayisshownhereinisolation.Transient
activationofMSNoccursfromglutamatergiccorticostriatalandthalamostriatal
afferents.
Consequently,theGABA/enk neuronoftheindirectstriatopallidalpathway
transientlyinhibitsitsdownstreamtargetsintheGPe.GPe neuronsaretonically
active;theyspontaneouslyfire.Thetransientinhibitionfromthestriatopallidal
neuroninterruptsthisspontaneousfiring.Thisresultsindisinhibitionofthe
neuronsinthesubthalamus.(Inhibitionofaninhibitoryneuronisdisinhibition).
Thesubthalamic neurons(STn)aretransientlyactiveandexcitatory.They
interruptthetonicinhibitoryoutflowfromtheGPe neuron(arecurrentfeedback
loop),andtheyalsotransientlyactivatetheGPi/SNroutflownucleus.Thisalters
thepatternofinhibitionontheVA/VLofthethalamusasitclosesthecircuitback
tothecortex.
DopaminetendstobeinhibitorywhenitcontactsGABA/enk striatopallidal
neurons,throughitsD2typereceptor.
Theneteffectofactivityintheindirectstriatopallidalpathwayistodecreasethe
thalamocortical circuits,producinglesscortical(UMN)excitability.
Thereisanerrorinfigure18.7(and18.10)ofPurves,page406 (andonpage409).
ThelegenddoesnotdiscussthefeedbackloopofSTn backtoGPe.Therealsois
anerrorinthetext.GPe doesnothaveaprojectiontotheGPi itrelaysthrough
theSTn.
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Function Organization of
Striatal Pathways
+ +
- -
-
Direct
pathway
Direct
pathway
Indirect
pathway
Indirect
pathway
Striatum
GPi/SNr
VA/VL
Activation of
intended motor programs
Suppression of
competing motor
programs
Purves 18.8
Thetwoprojectionsystemsofthestriatumarefunctionalopposites attheir
downstreamtargets.Asisshowninthedrawing,activationofthedirectpathway
willhavethereverseoutcomeonneuronslocatedintheGPi/SNrbasalganglia
outputcomparedtotheindirectpathway.Thetwopathwaysalsoareorganizedin
acentersurroundfashion
Whenthedirectpathway isactivated,thenegativebasalgangliaoutflowthat
normallywouldinhibitthethalamusisdiminishedbecauseofdisinhibition.
BOTTOMLINE:activationofthedirectpathwaywillfacilitatethemotorprogram.
Whentheindirectpathway becomesactive,thethalamicinhibitionisincreased.
BOTTOMLINE:activationoftheindirectpathwaysuppressesthemotorprogram.
Itisthebalanceofactivityinthesetwostriatalprojectionsystemsthatdetermines
whenoutputfromthemotorthalamuswillbeinhibitoryorfacilitatetheintended
movements.Thedirectpathwayisorganizedsuchthatspecificfunctionalunitsin
theGPi/SNraretightlyregulated.Theinfluenceprovidedbythe indirectpathway
ismuchmorediffuseandactivatesabroaderrangeofneuralunits,asdrawnabove.
SeePurvespage407formorediscussion.
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Motor Syndromes
Pyramidal Tract Syndrome
Spasticity Spasticity
Paralysis/Paresis Paralysis/Paresis
Extrapyramidal Syndrome
Rigidity Rigidity
Involuntary movements Involuntary movements
Immobility without paralysis/paresis Immobility without paralysis/paresis
Thebasalgangliawerebelievedtobetheprimaryconstituentsofthe
extrapyramidalmotorsystem, baseduponclinicalfindings.Thissystem
wasthoughttocontrolmovementinparallel,butindependentfromthe
pyramidalmotorsystem, whichdescendsthroughthepyramidsofthe
medulla thecorticospinaltract.
Thus,twodifferentmotorsyndromesweredescribedclinically:1)the
pyramidaltractsyndrome characterizedbyspasticity andparalysis and2)
theextrapyramidalsyndrome characterizedbyinvoluntarymovements,
muscularrigidity,andimmobilitywithoutparalysis.Thissimple
dichotomyisnolongerconsideredasatisfactoryexplanationofmotor
dysfunctions.
Otherstructurescontributetodisturbancesinmovement(brainstem,red
nucleusandcerebellum),anddamagetothemcanproducesomeofthese
symptoms.Theextrapyramidal andpyramidal systemsdonotfunction
independentlyofeachother;nonethelessthisclinicaldistinctionisuseful.
Basalgangliadiseaseshavethreephysiologicalcharacteristics: 1)tremorand
otherinvoluntarymovements(hyperkinesis),2)changesinpostureand
muscletone(rigidity),and3)povertyandslownessofmovement
(hypokinesis).
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Parkinsons Disease
striatum
GPe
STn
SNc
GPi
SNr
VA/VL
Brain stem
Spinal cord
Striatopallidal
pathway
Striatonigral
pathway
Basal Ganglia
Outflow
Excitatory Excitatory
Inhibitory Inhibitory
enk
enk
SP
SP
ACh interneuron ACh interneuron
?
TheprimarydeficitinParkinsonsdisease(PD)isthelossofthedopamine
(DA)nigrostriatalcellbodiesintheSNcanddepletionoftheDAterminal
fieldinthestriatum.SymptomsofPDbecomeapparentfollowing ~80%loss
ofstriatal DAterminals.TheprevalenceofPDintheUSpopulationis>1%
forindividualsovertheageof55,andincreaseswithage.Thisisan
enormousfinancialandhealthburden.
LossofDAcausesanimbalanceinthefunctioningofthestriatalindirect
anddirectpathways.Theindirectpathwaybecomesmoreactive(heavier
inhibitoryarrowGABA/enk neuron),andtheoveralleffectinthecircuitis
thatlessinhibitionoccursintheGPi/SNrbasalgangliaoutputnuclei.
ThisisbecausethereisdisinhibitionattheSTnrelay.WhentheexcitatorySTn
neuronshaveamorepowerfulactivationontheGPi/SNr,thereis more
profoundinhibitionfromthebasalgangliatotheVA/VL.Thisincreased
inhibitionatVA/VLdiminishestheoutputofthethalamocortical pathway
andtheactivationofthecortexisreduced.ThisdecreasestheUMN
activationtotheLMN,resultingultimatelyinahypokinetic disorder.
ComparethisPDwiringdiagramwiththenormalmotorcircuitryofthe
basalgangliaonpreviousslidestofullyappreciatethechanges.
AlsoreadBox18AinPurves(p.410)formorediscussion.
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PD Physiology
Loss of DA modulation of corticostriatal inputs on the
MSN of the indirect projection pathway
Increased activity in MSN striatopallidal pathway,
causes more inhibition inhibition in the GPe
STn disinhibition causes more excitation excitation of GPi/SNr
basal ganglia outflow
GPi/SNr inhibits inhibits motor thalamus causing diminished
activity to the motor cortex
Reduction in normal thalamic reinforcement of the
cortex; produces a hypokinetic disorder
Thestatementsprovideanarrativedescriptionofwhathappensinthebasal
gangliacircuit.Thesignsandsymptomswillbediscussedinthe clinicalcorrelation
tofollow.
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Dr. Ariano
MPTP
HO
HO
HO
HO
CH
2
CH
CH
2
CH
COOH
COOH
NH
2
NH
2
Dopamine
Dopamine
N
N H
3
C
+
MPP
+
MAO-
In1982,anumberofdrugabusersintheirmidtwentiesdevelopedacutesignsand
symptomsofPDfollowinginjectionofapoorlymadesyntheticheroin.Thetoxic
contaminantinthesynthesiswas1methyl4phenyl1,2,3,6tetrahydropyridine
(MPTP).Whenthiscompoundwassubsequentlyinjectedintoexperimental
animals,itproducedthehallmarkfeaturesofPD.
InorderforMPTPtoproduceitseffects,thechemicalneedstobeconvertedtothe
highlytoxicMPP
+
ion bymonoamineoxidase B(MAO).Theoxidase enzymeis
foundinglialcellsthroughoutthebrain.TheMPP
+
ionisthentakenupbythehigh
affinityDAtransporterandconcentratedinthemitochondriaofSNcneurons.MPP
+
destroysthenigral neuronsbypoisoningthemitochondrialoxidationandredox
reactionsatcomplexIintherespiratorychain.
ThissuggestedthatinhibitorsoftheMAO enzymemightslowthedevelopment
ofthesymptomsofPD.ThecompoundLdeprenyl (Selegiline
TM
)isaMAO
inhibitor,andeffectivelyblocksthedevelopmentofPDsymptoms whengiven
priortoMPTPinfusioninanimals.Selegiline isnowusedincombinationwithL
DOPA(acotherapy)tomoreeffectivelytreatPDsymptomsinpatients.
TheneurochemicaldeficitinPDregardlessofetiologyislossoftheSNcDA
nigrostriatalinputtothestriatum.
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Huntingtons Disease
Striatum
GPe
STn
SNc
GPi
SNr
VA/VL
Brain stem
Spinal cord
Striatopallidal
pathway
Striatonigral
pathway
Basal Ganglia
Outflow
ACh interneuron
enk enk
SP
SP
?
Huntingtonsdisease(HD)isanautosomaldominantneurodegenerativedisorder
ofthebasalganglia.Itiscausedbyasinglepointmutationin onegeneontheshort
armofchromosome4.Theexpressionofthemutation anexpansionofglutamine
inthecodingregionoftheprotein causesprogressivedegenerationoftheMSN
andcorticostriatalpyramidalneurons(shownaslossofthecorticalneuronsand
fadingoftheGABA/enk MSNinthecircuit).
Theindirect,GABA/enk striatopallidalMSNdegenerateearlyintheprogressionof
HD.Thus,theearlysymptomsareduetochangesinbasalganglia outflowdueto
unopposeddirectGABA/SPstriatonigralMSNactivity.Themotorthalamus
becomesdisinhibited.Thereismorethalamicactivationtothemotorcortex.The
increasedUMNstimulationtothebrainstemandspinalcordLMNresultsina
hyperkineticmovementdisorder.
Asthediseasecontinuestoprogress,thedirectpathwaywillalsodie;bythispoint,
thepatientisseverelyaffectedbythedisease.
Box18BinPurves,page411providesmorediscussionandahistoricalperspective
onthediscoveryofthemutation.
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Dr. Ariano
HD Physiology
Striatopallidal pathway degenerates initially, causing
reduced excitation excitation from STn to GPi/SNr
Reduced inhibitory GABA outflow from the basal ganglia
GPi/SNr enhances thalamic excitation excitation of the motor
cortex
Increase in normal thalamic reinforcement of the cortex;
produces a hyperkinetic disorder
Thestatementsprovideanarrativedescriptionofwhathappensinthebasal
gangliacircuit.Thesignsandsymptomswillbediscussedinthe clinical
correlationtofollow.
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Dr. Ariano
Subthalamic
Nucleus
Subthalamic
Nucleus
Lacunar
Infarct
Lacunar
Infarct
Thalamocortical
fibers
GPi
GPe
VA/VL
VA/VL
Hemiballismus
Ballism,orballismus isawelldefineddyskinesiasthatisrare,butspectacular
whenitoccurs.ThenameisderivedfromtheGreekwordmeaningtothrow, and
themovementsofballism arehighinamplitude,violent,flingingorflailing,rapid
anddonothaveapattern.Theinvolvementofmoreproximalmusclesofthelimbs
usuallyisresponsibleforthethrowingorflingingnatureoftheextremities.
Thecauseistypicallyacerebrovascular accidentthatimpactsthesubthalamic
nucleusorthepathwaysleadingtoorfromtheSTn.Asmall,lacunar infarctismost
common,withsuddenonsetofsymptoms.Damageisexpressedcontralateraltothe
stroke.WHY?
Ballism isgenerallyunilateralandtermedhemiballismus. Occasionally,onlyone
limbisinvolved(monoballism);rarely,bothsides(biballism)orbothlegs(paraballism)
maybeaffected.Theneuropathologyisduetolesionsofthesubthalamic nucleus
thatreducethenormalexcitatorydrivefromSTn totheGPi/SNr.Thisreducesthe
inhibitoryoutputofthebasalgangliatotheVA/VL,andthisdisinhibitiongivesrise
toexcessiveexcitatorydrivetothecortex,whichisexpressedashyperkinetic
movements.
Themovementsareextremelydisablingtopatients,whodropthingsfromtheir
handsordamagecloselyplacedobjects.Selfinjuryiscommon,andexamination
oftenrevealsmultiplebruisesandabrasions.Additionalsignsandsymptoms
dependonthecause,location,andextentofthelesion.
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Dr. Ariano
Iatrogenic Changes
Produced by drug therapy treatments
Reversible in early stages
Become permanent with time
Commonly affect DA receptors
Tardive Dyskinesia is the classic
example
Aniatrogenicchangeisaninadvertent,adverseeffectofcomplicationthat
resultsfrommedicaltreatmentoradvice.
ThemostclassicexampleofthisdisorderisTardivedyskinesia.Tardivemeansa
sloworbelatedonset;dyskinesiaisadisorderedinvoluntarymovement.
Movementsarepatternedandmayaffectdifferentbodyparts.The disorderisoften
diagnosedasmentalillnessandconsequently,patientsaretreatedwith
antipsychoticsandneuroleptics.
Neuroleptics aredopaminereceptorantagonistswhichareprescribedforvarious
disorderslikeschizophreniaanddepression.Byblockingthedopaminereceptors
(D2receptorfamily),someindividualsdevelopreceptorsupersensitivity inthe
residualdopaminereceptorsdistributedthroughoutthebrain.Thesymptoms
associatedwithhypersensitivedopaminereceptorsaretheseabnormalinvoluntary
movements,similartothatseenwithHD.Theremedyistoremove theneuroleptic
treatmentbeforethealteredreceptorsbecomepermanentlychanged.
http://www.ninds.nih.gov/disorders/tardive/tardive.htm
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L-Dopa Induced Dyskinesias
The Scientist August 2008
Dyskinesiadenotesvariousinvoluntarymovementsthatcanaffect discretebody
partsorcanbecomegeneralizedandseverelydisabling.Theunderlyingchange
targetstheDAreceptorsinparticular recallthatthesereceptorsarepartofthe
superfamilyof7transmembrane spanningproteins.
AtleasthalfofallpatientstreatedwithLDOPAdevelopdyskinesias.UsingDA
receptoragonistslowerstheincidenceofdyskinesias.However,oncedyskinesias
havebecomeestablished,thesameinvoluntarymovementsoccuron every
administrationofDAmedication.Thissuggeststhattherearebasicchangesin
basalgangliafunctionandtheresponseofthecircuitstodrugtreatment.
Themajorfactorsthataffectdyskinesiainductionseemtobethetypeofdrugthatis
administered,themodeofdrugadministrationandtheextentofSNcDAcellloss.
LDOPAhasashortplasmahalflifeandisabsorbederraticallyfromthegut.This
producespeaksandtroughsinthecirculatinglevelsofLDOPA.
InearlystagesofPD,LDOPAisstoredinsurvivingnigrostriatalDAterminalsand
releasedgradually.However,astheterminalsdegenerateduetocontinued
progressionlossoftheSNcsynapses,theeffectivenessofLDOPAbecomesshorter
andmorecloselyreflectsitsplasmahalflife.TheexposureoftheincreasinglyDA
denervatedbasalgangliatothepulsatile plasmaLDOPAlevelsleadstodyskinesia
induction.Oncedyskinesiasareestablishedtheymaybeelicited byanyDA
replacementtherapy.
AnotherfindingisthatDAreceptorsbecomestructurallyaltered andoncethishas
occurred,dyskinesiascannotbereversed.
693
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Clinical Correlates
Diseases of the Basal Ganglia
http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm
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Ozzie Osbourne
Parkin Syndrome
Michael J. Fox Muhammad Ali Yassar Arafat
Adolf Hitler
Brian Grant Janet Reno
Deborah Kerr
Famous Faces of PD
Therearenopredispositionsforrace,genderorstatusinlife thebestcorrelateis
AGE.
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Lecture Objectives
Know the Signs & Symptoms of PD
Provide the rationale for PD Treatments
Identify the basal ganglia circuit changes
that occur in PD
Understand some of the translational
research being used for PD patients
Know the Signs & Symptoms of HD
Identify the basal ganglia circuit changes
that occur in HD
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Natural History of Neurodegenerative
Disorders
Preclinical Symptomatic
Diagnosis
N
e
u
r
o
n

F
u
n
c
t
i
o
n

N
e
u
r
o
n

F
u
n
c
t
i
o
n

Time
Science 302:830, 2003.
Clinical Symptoms
1
st
motor
symptoms
Thereisaprolongedphaseinneurodegenerativediseasesinwhich
neuronslosefunctionanddie(orangecurve),butthesymptoms
cannotbedetectedclinically(dottedline).DuringthePreclinical
phase,therapeuticinterventionsmayslowdowntheprogressionof
theneuronlossandmightdelaytheonsetofthefirstmotor
symptoms(inPDasanexample),IF itisknownwhatbiochemical
processestotarget.
FollowingtheappearanceofthecharacteristicPDmotorsymptoms
inthisexample,adiagnosiscanbemade.Asthediseaseprocess
continues,clinicalsymptomsbecomepronouncedandthepatient
becomessymptomaticforthedisorder.Neuronaldeathhasbecome
substantialbythistime(indicatedbytheblackarrowinthefigure)
andsinceneurogenesisislimited,repairorreversalofthedamagein
thecircuitsunderlyingthedisordercannotoccur.
l
o
s
s
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"Involuntary tremolous [sic] motion,
with lessened muscular power, in
parts not in action and even when
supported; with a propensity to bend
the trunk forewards, and to pass from
a walking to a running pace: the
senses and intellect being uninjured."
--- James Parkinson
An Essay on the Shaking Palsy (1817)
TheEnglishmanJamesParkinson(17551824)wasageologist,
paleontologist,politicalactivist,advocatingfortheunderprivilegedand
anoutspokencriticofthePittgovernment(theprimeministeratthe
time).ParkinsonalsowasasurgeoninLondonwithanactiveclinic
inheritedfromhisfather.Parkinsonfeltthatanyworthwhilephysician
shouldknowshorthand,andhewasadeptatitandmadecopiousnotes
ofhisclinicalobservations.Hewroteongoutandauthoredthe earliest
accountofperitonitisintheEnglishmedicalliterature.Hismostfamous
monographdescribedsixindividualswithsymptomsofparalysis
agitans. Some60yearslater,afamousFrenchneurologist,JeanMarie
Charcot(whopreciselyenumeratedthesymptomsofmultiplesclerosisin
1862),namedthisdisorderforthemanwhosocarefullydescribedits
sequelae.
JamesParkinsonalsodescribedthatinlateryearsthesepatientswith
shakingpalsymaybedelirious.Althoughmotorsymptomsepitomize
PD,othersignsarefrequentlycognitiveimpairmentsassociatedwith
executivefunctions.RetrospectivehistoriesofmostPDpatientsrecount
thatthecognitivechangesprecede themotorsymptomsbydecades.
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PD Pathophysiology
DA neuron degeneration in SNc; loss
of pigmented cells in primates
DA terminal loss in the striatum
Lewy body formation in SNc
Major protein inclusion is -synuclein
http://faculty.washington.edu/alexbert/MEDEX/Fall/pdnigra.jpg
PD Normal
Lewy Body
http://www.ppu.mrc.ac.uk/research/profiles/11/img/image_3.jpg
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Genetic factors
Free Radical theory
Neurotoxin hypothesis
Mitochondrial complex I defect
Possible Causes of PD
Inthelastsixdecades,distinctcausesofparkinsonismhavebeenidentified.While
thepathophysiologycanbedescribed,whatactuallycausestheDASNcneuronsto
diehasnotbeenidentified.Baseduponepidemiologicalstudies, threeprevalent
hypotheseshaveemergedandarebrieflysummarized.
TheFreeRadicalTheory (anditsvariations):Freeradicalsarehighlyreactiveand
induceoxidativedamagetoneighboringmolecules,extractingelectrons.The
principalsiteoffreeradicalgenerationisthemitochondrion,whereoxidative
phosphorylationoccursinassociationwithATPproduction.Levelsofbiochemical
markersforoxidativedamagehavebeendetectedinbrainsofindividualswhohad
PD.
TheNeurotoxinTheory (anditsvariations):MPTPistheclassicexample(seelater
slide),butthisalsoappliestoherbicidesandpesticideslikeparaquat androtenone.
Featuresincluderapidonsetandincreaseddiseasesusceptibilitywithage.These
neurotoxinsworkbybeingtransportedacrossthebloodbrainbarrier,andbeing
takenintotheDAneuronsthroughtheDAtransporter.Thetoxins become
concentratedinthemitochondria,itbindsandinhibitsthepartsoftheenzymatic
reactionsoftherespiratorychain.
TheMitochondrialDefectTheory (anditsvariations):Blockadebychemicals
(cyanide,CO,hydrogensulfide,nitricoxide),orthroughgeneticalterationof
mitochondrialfunctioningintherespiratorychainisthekeyevent.Mitochondrial
ATPsynthesisisimpairedortotallyabsent,andthecellularenergysourcesbecome
depleted,therebykillingtheneuron.
About10%ofPDcanbeattributedtomutationsinspecificgenes.
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Rest tremor
Bradykinesia
Hypokinesia
Rigidity
Postural instability
Festinating gait
Cognitive impairments
PD Symptoms
AdefinitivediagnosisofPDismadewhenatleast3ofthesecardinalsignsare
present.
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Risk Factors for PD
Older age
Caucasian race
Environmental
Occupational
Genetics
Themostimportantconsiderationisage theolderonebecomes,themoretherisk
increasesofdevelopingPD.
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Parkinsons Disease
striatum
GPe
STn
SNc
GPi
SNr
VA/VL
Brain stem
Spinal cord
Striatopallidal
pathway
Striatonigral
pathway
enk
enk
SP
SP
ACh interneuron
?
Basal Ganglia
Outflow
Basalgangliaafferents comefromthreemajorregions,1)thecorticalmantle,
especiallythemotorcortex,2)theintralaminarthalamus(CMPF, notshown),and
3)thesubstantianigraparscompacta(SNc).Afferentsterminateinthestriatum,
whichisthegatewaytothebasalganglia.
Therearetwostriatalprojectionpathways,theindirectstriatopallidal(makes
enkephalin,enk) andthedirectstriatonigral(makessubstanceP,SP) tracts.The
indirectpathwaymakesanumberofsynapticrelaysbeforereachingthebasal
gangliaoutflownuclei(GPi/SNr),whilethedirectpathwayterminates
monosynaptically inthisarea.
Thebasalgangliaoutflowterminatesinthemotorportionofthe thalamus(VA/VL)
returningtothecortextofinallyinfluenceLMNindirectlythroughthedescending
motorpathways.
Theneurotransmittersarewellknownandare:
Corticostriatal glutamate
Nigrostriatal dopamine
Striatopallidal&striatonigral GABA +enkephalinorSP
Globuspallidus GABA
Subthalamicnucleus glutamate
VA/VLandCMPFthalamus glutamate
Corticospinal glutamate
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Dopamine Biosynthesis
Tyrosine DOPA DA norepinephrine epinephrine
Tyrosine Hydroxylase
(TH)
*
*
COMT
Ubiquitously located in nearly all
cells, transfers a methyl group to
3-hydroxyl group on the ring.
MAO
On outer mitochondrial membrane, oxidatively
deaminates catecholamines. Drugs that interfere
with vesicular storage (reserpine) deplete DA.
HO
HO
HO
HO
CH
2
CH
CH
2
CH
COOH
COOH
NH
2
NH
2
Dopamineissynthesizedfromdietarytyrosine,usingthepathway shown.
ThecolorfulimagetotheupperrightisascanningmicroscopeimageofDA
(pseudocolored),andthewhitebiochemicalstructureontopisthatof
dopamine.
Dopamineisremovedfromthesynapsein3ways:
COMT=CatecholOmethyl transferase
MAO=Monoamineoxidase
Reuptakebythedopaminetransporterintothepresynapticterminal
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PD Therapy
L-DOPA, a DA precursor
DA receptor agonists
Selegiline (L-deprenyl), MAO-B enzyme
inhibitor
Transplantation of DA containing
substances to the striatum
Neurosurgical interventions in the motor
circuit to alleviate symptoms
TheprincipaltreatmentforPDistoreplacetheDAasitslevelsfallbecause
ofdegenerationofthecellbodiesintheSNc.Theeasiestwaytodothisisto
givetheDAprecursorLDOPAorallyandthisapproachprovidesthebest
patientcomplianceintakingthemedication.DAreceptoragonistsact
directlyattheMSNandcanbeusedasanalternativetreatmentinPD.DA
agonistbioavailabilityisnotaslongasLDOPA.UsingtheMAO inhibitor
Ldeprenyl (Selegiline)incombinationwithLDOPAallowsthenewly
synthesizedDAtoremaininthesynapticareaforalongertime, thus
improvingthedurationofdrugefficacy;alsoknownasitsbioavailability.
However,theusefulnessofthesetherapieschangeasthedisease progresses
andpatientsbecomelessresponsivetotreatment.Thereareseriousside
effectstousingDAreplacementtherapiesaswell.Noneofthese
interventionswillhalttheprogressofPD DAneuronsintheSNccontinue
todegenerate.Thusothermechanismsareunderinvestigationtohelp
alleviatethediseasesymptoms,orhalttheirprogression.
Twoothertreatments implantationofsubstances(stemcells,adrenalcells,
fetalmesencephalictransplants,DAreleasingpolymers)thatcan increase
striatal DAhavebeenusedwithlimitedsuccess;andneurosurgical
procedurestoalterthediseasedbasalgangliacircuitryhavebeenemployed.
Box18C(Purvespage412413)describestheuseofdeepbrainstimulationto
changetheelectricalactivityintheSTn,producingadifferent firingpattern
intheindirectpathwaythatcanyielddramaticresultsforsome patients
withPD.
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Familial PD Gene Targets
- Unknown
GIGYF2
Autosomal dominant
Park 11
- -
-
Susceptibility locus
Park 10
Lysosomal
dysfunction
P-type ATPase
ATP13A2
Autosomal recessive
Park 9
Multiple
pathways
Kinase
LRRK2
Autosomal dominant
Park 8
Oxidative stress Binds RNA?
DJ-1
Autosomal recessive
Park 7
Mitochondrial
dysfunction
Kinase
PINK1
Autosomal recessive
Park 6
UPS
dysfunction
Ubiquitin
hydrolase
UCHL1
Autosomal dominant
Park 5
- -
Unknown
Autosomal dominant
Park 3
UPS
dysfunction
Ubiquitin E3
ligase
Parkin
Autosomal recessive
Park 2
Protein
aggregation
Unknown
-synuclein
Autosomal dominant
Park 1 /4
Pathology Function Gene Inheritance Locus
AsmallpercentageofPDisinherited(<10%),andthegeneslistedhave
beenimplicated.Mutationsinthesegenesareautosomal,accountingfor
juvenileonsetPD(homozygousforPark6)aswellasformscommonto
olderadults.
MousemodelsofPDhavebeenproducedthatcarrytheseautosomal
mutations,andtherodentsexpressvariablephenotypes.This
translationalresearchiscontributingtotheunderstandingofthe
mechanismsunderlyingspontaneousPD.
Manyindividualswithspontaneous(idiopathic)PDalsoexpresssomeof
thesemutations,particularlytheLRRK2variants.
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Nonpharmacologic
Treatments
Stereotactic pallidotomy
Thalamotomy
Deep brain stimulation
Fetal tissue implants
Gene therapy
Jeffrey MacMillan for USN&WR
Incredible Voyage, NGS
Pallidotomy(GPi)byelectrocoagulative lesionanddestructionofthenucleus,
relievesrigidity/tremorbecauseinthebasalgangliacircuit,thislossoffunction
removestheexcessiveinhibitionofthalamocorticaltracts.
Thalamotomy (VA/VL)relievestremoronly,buthasnoeffectonothercardinal
featuresofPD.
DeepBrainStimulation(DBS)ofthesubthalamusbyanimplantablepulse
generatorhasbeenusedmorefrequentlyinthelastfewyearsbecause
stimulationisnotdestructiveofthebraintissuelikethetwocoagulative
proceduresabove.DBScanbeunilateralorbilateral,andthestimulusintensity
parameterscanbealteredovertime,providingaflexibilityinthetreatmentas
thediseaseprocessprogresses.
FetaltissueimplantsofDAproducingcellshavehadmixedresultswithsome
recoveryoffunction,howeverthetransplantedmaterialmay/many notsurvive
theprocedure.Additionallythereareethicalissuesofhowthe DAtissuesare
procured.
Genetherapyimplantsarecurrentlyunderinvestigationinanimalmodelsof
PD,buthavenotbeentriedinpatientswithPD(yet).Thisisatranslational
researchareawithintenseinvestigation.
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Blumenfeld 16.14
Left-Sided Pallidotomy
putamen
GP
III
pulvinar
R R L L
Blumenfeld 16.14
ThesearehorizontalT1weightedMRIscans,thatareadjacentsections,
progressingfromtheinferior(leftimage)tothesuperiorlevel (rightimage).
Thestereotaxicallyplacedlesionisvisibleintheleftglobuspallidus
(circumscribedbythedottedorangecircle),andislocatedalongtheventral
edgeofthenucleus.ThepatienthadadvancedPD,withasymmetrical
restingtremor,rigidity,bradykinesiaandgaitdifficultiesthatwere
sufficientlyseverethatthesurgerywasperformed.
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Copyright 2000 by the National Academy of Sciences
Phelps, Michael E. (2000) Proc. Natl. Acad. Sci. USA 97, 9226-9233
Brain Abnormalities in PD
TheseareimagesofapatientwithearlyPD(topseries)andaratmodelof
PD(lowerseries)thatinducedDASNcneurondestructionwithatoxin,6
hydroxydopamine(6OHDA).
(Upper)HorizontalplaneMRIshowedthattherewasnostructural
abnormalityinthebrainofthepatientwithPD.ThePETimageshowed
hypermetabolismofglucoseintheputamen(arrows)thatwasincreased
10%abovethenormalvalue.
Imagetotherightshowspresynapticsynthesisofdopaminedetectedby
labelingwith[F
18
]fluorodopa.Thiselucidatedanabnormalityinthe
dopaminesystem;70%reductionoccurred(arrows),comparedtocontrols.
Theimageofpostsynapticdopaminereceptors(farright)wasvisualized
withtheligand,[F
18
]fluoroethylspiperone(D2antagonist),andshowed15%
elevation(upregulation)ofthesereceptorsintheputamen(arrows).This
D2receptorchangeisanattempttocompensateforthelossofthe
presynapticdopamine.
(Lower) MicroPET imagesofa6OHDAunilaterallesioninaratmodelofPD
areshown.Ontheleftisanimageofpresynapticdopaminetransporter
bindingdeterminedusing[C
11
]WIN35425,andshowed60%lossonthe
lesionedside(arrow).Intherightimage,postsynapticDAreceptorswere
assessedusing[C
11
]raclopride(anotherD2antagonist)andshowed
compensatoryupregulationofthereceptors(arrow)inthestriatum.The
contralateralstriatumisusedasacontrol.
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Copyright 2000 by the National Academy of Sciences
Phelps, Michael E. (2000) Proc. Natl. Acad. Sci. USA 97, 9226-9233
Gene Therapy in PD
ImagingtheresultsofgenetherapytreatmentwithPETintheunilateralMPTP
monkeymodelofPDshowedrecoveryofDAbiochemicalfunctions. DAsynthesis
wasdeterminedwiththearomaticaminoaciddecarboxylase substrate,meta[F
18
]
fluorotyrosine.
(Left)Imageofnormaldopaminesynthesisinthecaudateandputamenofa
monkeybrain.(Center)ImageshowsunilateraldopamineMPTPinduceddeficit
(arrow)beforegenetherapy.(Right)Imageshowsrestorationofdopamine
synthesis(arrow)aftergenetherapyandsuggeststhatreplenishingthearomatic
aminoaciddecarboxylase usingthisapproachmayproveusefulinpatientswith
PD.
FigureiscourtesyofKBankiewicz,publishedinthecitedPhelpsarticle.The
referencefortheBankiewicz work:
Bankiewicz etal,LongtermclinicalimprovementinMPTPlesionedprimates
aftergenetherapywithAAVhAADC. Molec Therapy 14:564570,2006.
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Deep Brain Stimulation (DBS)
Patient Mickey Lawson points his finger while being prepared for
brain surgery at Emory University Hospital in Atlanta. The 63-year-
old picture framer from Lawrenceville, GA, will undergo deep brain
stimulation surgery to reduce the symptoms of his Parkinson's
disease.
U.S. News & World Report, L.P 2/20/06 edition on-line.
DBS Placement
From: Incredible Voyage: Exploring the Human Body, NGS
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19
Quality of Life
NEJM 366 (6): 511, 2012
February 9, 2012 issue
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Huntingtons Disease
The Other Basal Ganglia Disorder
Face of HD
www.workshoplive.com
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Charles Sabine
http://www.google.com/imgres?imgurl=http://moreintelligentlife.com/files/sabinehealth2.jpg&imgre
furl=http://moreintelligentlife.com/section/ideas
1%3Fpage%3D12&usg=__gr7oj6Wbyg0nO4P9PqV56Fz8fH4=&h=408&w=468&sz=75&hl=en&start=1
0&zoom=1&tbnid=5IMACan2tT35QM:&tbnh=112&tbnw=128&ei=BzFOT
nFK4OhsgLC98EW&prev=/search%3Fq%3Dcelebrities%2Bwith%2Bhuntington%2527s%2Bdisease%
2Bpictures%26um%3D1%26hl%3Den%26sa%3DN%26gbv%3D2%26tbm%3Disch&um=1&itbs=1
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What is HD?
Autosomal dominant, CAG triplet repeats
Basal ganglia neurodegeneration
About 40,000 individuals in US, more at risk
No cure No cure
The gene and its product have been identified
Function of normal huntingtin is unknown
Change caused by expanded polyglutamine is
unknown
http://www.ninds.nih.gov/disorders/huntington/huntington.htm
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HD Symptoms
Chorea
Hyperkinesia
Postural instability
Memory and cognitive difficulties
Metabolic abnormalities
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HD Neuropathology
www.sciam.com/dec2002
Normal HD Brain
Striatum Striatum
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HD Pathophysiology
Neural degeneration in cortex and striatum;
loss of the striatal projection neurons in a
defined order, enkephalin then SP, sparing
of ACh ACh interneurons
Expression of abnormal huntingtin huntingtin
protein accompanied by nuclear inclusions
ThediagnosisofHDmaybemadeusinggenetictestingforthepresenceof
themutation theexpansionoftheCAGcodonforglutamine.Additionally,
CATscanorMRIcanbeusedtodemonstrateenlargedlateralventriclesasa
directresultofstriatalneurondegeneration.Theoverlyingcortexalso
atrophiesinHDandhasasimilarappearancetobrainsfromindividuals
whodiedfromAlzheimersdisease.
Mutatedhuntingtinproteinisexpressedthroughoutthebrainand body,but
celldeathisrestrictedtothestriatalMSNandneuronsprojectingtothe
striatumfromthecortex.Huntingtincomplexeswithotherproteinsand
formsinclusionswithintheneuronalcytoplasmthataccumulateandare
transportedintothenucleusofthecellasthediseaseprogresses.
Itisnotknownyetwhetherthestriatalneuronshavethecapabilityto
retrogradelyinfluencethedegenerationofcorticostriatalneuronsorifthe
corticostriatalneuronsproducethedeathofthestriatalMSN.
Themechanism(s)underlyingmutanthuntingtinscapabilityforcausing
celldeathinthebrainisunknown.
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Causes of HD
Autosomal dominant disease, mutation located on
the short arm of chromosome 4
Polyglutamine expansion (CAG) causes
translation of an elongated huntingtin protein
Trinucleotide excess produces a sticky protein
that complexes with surrounding proteins and is
transported to the nucleus
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HD Therapy
Drug therapy to alleviate symptoms
Treatment of depression and suicide watch
Maintain caloric intake!
Genetic counseling of individuals at risk
Tetrabenezene for chorea in ambulatory HD
http://www.kumc.edu/hospital/huntingtons/index.html
Tetrabenazine istheonlysymptomatictreatmentthathasshownefficacyin
reducingchoreainambulatoryHDpatients
From:
JClin Invest.2011February1;121(2):476483.
Publishedonline2011February1.doi: 10.1172/JCI45364
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28
Huntingtons Disease
striatum
GPe
STn
SNc
GPi
SNr
VA/VL
Brain stem
Spinal cord
Indirect
pathway
Direct
pathway
Basal Ganglia
Outflow
ACh interneuron
InHuntingtonsdisease(HD)subsetsofneuronswithinthecortex
(responsibleforcognitivedeficits)andinthestriatalprojectionsystems
(givingrisetothemotorsymptoms)die.Thechangeinthebasalganglia
circuitryresultsinahyperkineticdisorder;thephysiologicaloppositeofPD.
HDisageneticdisordercausedbyasinglegenemutation,producingaCAG
expandedrepeatinthecodingregionofthegene.HDismuchrarerintheUS
populationthanPD.Approximately30,000individualshavebeendiagnosed
withHD,withanother150,000atriskforthedisorder.
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29
Dr. Nancy S. Wexler
President,
Hereditary Disease Foundation
The Venezuelan Study
Marjorie Guthrie
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The Venezuela Project
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Cerebellum
Chapter 19
Thecerebellummodifiesongoingmovements.Lesionsordiseaseof the
cerebellumwillproduceabnormalitiesinmovementsofthebodyandthe
eyes,affectbalanceandaltertheabilitytostopamovementat theintended
target.
ThecerebellumisnotpartoftheUMNsystem,butlikethebasal gangliaisa
satellite motorsystemintegrator.
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Learning Objectives
Describe the connections with motor system
Understand the functional circuit of the cerebellar
cortex
Define LTD and heterosynaptic motor plasticity
Describe cerebellar disease symptoms and how to
localize the damage
Identify the genetic defect for selected, inherited
cerebellar ataxias
Itisimportanttounderstandthekindofinformationthatisintegratedbythe
cerebellum.Knowingtheafferentconnectionstothecerebellumincombination
withtheinformationprocessingthatoccursbeforethatoutflowreachestheUMN
andLMNofthemotorsystemwillprovidethisinformation.
Thesynapticcircuit(andintrinsicneurons)ofthecerebellumareveryconsistent
throughoutthestructure.Thisfeaturehasmadeitpossibletodescribethe
underlyingchangesthatoccurasamotormemoryisacquired.Thismodelof
cerebellarsynapticplasticityhasprovidedafoundationfordescribinghowthe
nervoussystemestablishesmemoryinothertypesoflearning.
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Morphology & Functional Divisions
Three Anatomical Divisions
Anterior Lobe
Posterior Lobe
Flocculonodular Lobe
Functional divisions:
Cerebrocerebellum (motor planning)
Spinocerebellum (motor execution)
Vestibulocerebellum (posture and balance)
Deep Cerebellar Nuclei (DCN)
Dentate
Interposed
Fastigial
[Vestibular nuclei]
Primary fissure
Primary fissure
Thecerebellumisafistsizedstructurewithnumerous,smalltransverselyoriented
folia(smallgyri)thatconsistofanoutergraycorticalribbonandadeeperwhite,
myelinatedfiberarea.
Therearethreedistinctanatomicallobeswiththe(1)anteriorand(2)posterior
lobesseparatedbyadeep,primaryfissure.The(3)flocculonodular lobeisventral
tothemainbodyofthecerebellum,adjacenttothebrainstem.Thecerebellumis
attachedtothebrainstembythreepairedpedunclesorbridges.
Whilethethreelobesofthecerebellumareanatomicallydistinct,afunctional
classificationispreferredtodefinethestructure.Thefunctionalorganizationdoes
notcoincidepreciselywiththeanatomicallobes.Itisbaseduponthesourceofthe
inputs tothecerebellum.
Anothergraymatterregionislocateddeepintheheavilymyelinatedfibersgoing
toandfromthecerebellum.Thesestructuresarethedeepcerebellarnuclei(DCN).
BoththegraymatterofthecerebellarcortexandtheDCNreceiveafferentsfromthe
samesources.
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4
Brainstem Relationships
Caudate
Nucleus
Putamen
Midbrain
Internal Capsule
Thalamus
Cerebellar
hemisphere
Cerebellar
Peduncles
Superior
Middle
Inferior
Superior
Middle
Inferior
Deep Cerebellar
Nuclei (DCN)
Fastigal nucleus
Interposed nuclei
Dentate nucleus
Fastigal nucleus
Interposed nuclei
Dentate nucleus
Purves 19.1B
Vermis
* *
Theoverallanatomicalorganizationofthecerebellumisdemonstratedin
thissemitransparentdorsalviewfromthePurvestext.Therightcerebellar
hemispherehasbeenremovedtoshowtheunderlyingpedunclesthat
connectthecerebellumtothebrainstem.
The superiorcerebellarpeduncle (SCP SCP)isprincipallyanefferentpathway,
the middlecerebellarpeduncle (MCP MCP)isthelargestafferentsystemcoming
intothecerebellum,andtheinferiorcerebellarpeduncle(ICP ICP) isthe
smallestconnector,carryingbothafferentandefferentpathways.
TheindividualDCN arevisibleontheleftsideoftheillustration,withthe
largelateralexpansionofthecerebrocerebellumcoveringtheseimportant
relaycenters.TheDCNarefunctionallyorganizedandprovideinput/output
ofintegratedcerebellarinformation.
Cerebellartonsils formtheventromedialborderofeachlateralcerebellar
hemisphere itisjustvisibleinthisorientation,andmarkedbytheasterisk
(
* *
).Iftheintracranialpressureincreases,thetonsilsherniate downward,out
oftheposteriorfossaandthroughtheforamenmagnum.Compressionof
themedullocervical junctionbecauseoftonsilarherniationcauses
decerebraterigidity andrespiratory arrest.
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Cerebellar
Anatomy
(detached from
brainstem)
Cerebellar
cortex
Folia
Nodulus
Primary Fissure
Fourth
ventricle
SCP SCP
MCP MCP
ICP ICP
Purves 19.1C & D
MCP MCP
ICP ICP
Vermis
SCP SCP
Nodulus
Flocculus
Flocculus
Theanatomicalrelationshipsofthecerebellumareshownintheseimages.
Thecerebellumhasbeenremovedfromthebrainstemandthecutsurfaces
ofthethreepedunclesaredisplayedusingthesamecolorcoding asthe
previousslide.Noticehowtheflocculonodularlobeactuallywraps
underneath thesuperiorcerebellarpeduncle(SCP)andisjustnextto
wherethebrainstemwouldbeseparatedbytheCSFfilledspaceofthe4
th
ventricle.Theflocculusislateral,whilethenodulus isonthemidline.
Theparamediansagittalsection(lowerimage)showstheextensive
convolutionsoftheoverlyingcerebellarcorticalgraymatter.Thecerebellar
gyri arecalledfolia.Thewhitematterthatisdeeptothefoliacarries
informationfromtheDCNandthroughthesynapticcircuitinthe cerebellar
graymatterandfromthecerebellarcortexbacktotheDCN.
Theprimaryfissureseparatestheanteriorlobefromtheposteriorlobe.Itis
quitedeepandeasilyidentifiedingrossspecimensandalsoinslide
preparations.Theinteriorcoreofthecerebellumconsistsofmyelinated
fibers,anditiswithinthiswhitematterthatonecandetecttheDCN(not
shownhere).
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Purves 19.1A
Functional Classifications
Orientation: removed from
brainstem, then unrolled
and flattened. Viewed from
the superior aspect.
Spinocerebellum
Cerebrocerebellum
Vestibulocerebellum
Nodulus
Flocculus
Primary fissure
Thisillustrationshowsthefunctionalorganizationofthecerebellum:
Vestibulocerebellum correspondstotheflocculonodularlobe
(vestibularfunctions) receivesvestibularinputsandprojectsbacktothe
vestibularcomplex
Spinocerebellum correspondstothevermisandthetwoadjacent
paramedianstrips(postureandbalance;visualtracking;responsetovisual
andauditoryinputs) receivesspinocerebellar pathwaysplusauditoryand
visualcuesandprojectsbacktothereticularformationandsuperior
colliculus
Cerebrocerebellum encompassesthebulkofthelateralhemispheresof
thecerebellum(coordinationoffinemovements;planning;timing ofspeed
andtrajectories) inputsfromthemotor,premotorandsupplemental
motorcorticesandprojectsbacktotherednucleusandmotorthalamus
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Cerebellar Homunculus
Flocculus
Vestibulocerebellum
Nodulus
Spinocerebellum
Purves 19.4
Cerebrocerebellum
Primary fissure
Thesomatotopicmapsofthebodyappearonthisflattenedrenderingofthe
cerebellum,viewedfromthesuperioraspect.Notethatthesebodyimagesare
interruptedandthuscerebellarsomatotypicmapisnotaspreciseasseeninthe
somatosensory(UMN)homunculus.Therearetwodistinctregionsofbody
representation.Oneisalongthemidlinevermisintheanteriorlobe(rostraltothe
primaryfissure)andhasrepresentationofthetrunk/torso.Theheadwithauditory,
vestibularandvisualinputs,(afferentandefferent)ismappedjustcaudaltothe
primaryfissureinthefunctionalorganizationofthespinocerebellum.The
spinocerebellarregionsneighboringthevermiscontainrepresentationsofthe
appendicularskeleton(extremities)andlateralportionsofthehead.
Thevastmajorityofinformationenteringthespinocerebellum isassociatedwith
kinesthesia thesensoryfeedbackderivedfromthemusclespindles,Golgitendon
organs,jointreceptorsandfreenerveendings.Thesearecarriedintheanteriorand
posteriorspinocerebellar tracts,whicharefoundattheperipheryofthewhite
matterofthespinalcord.
Thevestibulocerebellum iscloselylinkedtothevestibularsystemandincorporates
theawarenessofgravity,angularaccelerationandposturalstabilityinthemotor
program.Itismappedtotheflocculonodular lobeandsomeregionsofthevermis
thatreceivemultiplesensorymodalities.
Notethatthelargeregionofthecerebrocerebellum doesnothaveapointtopoint
representationofsomatotypy.
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Cerebellum Cerebellum
Midline Midline
Pons
Pons Pons
Frontal-motor/
parietal cortices
Frontal Frontal- -motor/ motor/
parietal cortices parietal cortices
Spinal
cord
Spinal Spinal
cord cord
Vestibular
nucleus
nucleus nucleus
Principal Cerebellar Afferents
Purves, 19.3A
Pontine nuclei
ICP ICP ICP ICP
MCP MCP
Inferior
Olivary
Complex
Inferior Inferior
Olivary Olivary
Complex Complex
Majorinputstothecerebellumcomefromthemotorrelatedcorticesand
fromthebrainstemandspinalcord.Thedescendingcorticalinputsrelay
throughthepons,synapsinginthepontinenuclei.Axonsfromthepontine
nucleicrossthemidline intheMCP MCP andenterthecerebellum.The
informationisdistributedthroughoutthecontralateralcerebrocerebellum.
Sensoryinformationfromlowerextremitiesenterthecerebellumusingthe
ICP ICP,primarily.Muchofthisinformationisderivedfromthemuscle spindle,
GTOandjointreceptors allofthekinestheticinformationyoulearned
aboutpreviously.Informationfromthevestibularnucleusaboutbalance
andgravityalsoenterusingtheICP ICP.Aspecificafferentfiberoriginatesin
thecontralateralinferiorolivary complexandentersthroughtheICP ICP.
Thecerebellumalsoreceivesvisualandauditoryinformation,to helpin
producingcoherentmotorresponsesinvariousactivitiesthatmayseem
simplebutarequitecomplex.Trytothinkthroughtheexampleofsigning
yournameandhowthatmightbecoordinatedusingcerebellarfeedback
andfeedforwardinformation.
YouwillNOTBERESPONSIBLEforwhereandhowmanytimesthe
informationtravelingontheICP ICP(andSCP)cross!Youdoneedtoknowthat
cerebellarlesionspresentwithipsilateralsymptoms.
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Cerebellar
Afferents
Temporal Temporal
lobe lobe
Parietal lobe
Inferior Olive Inferior Olive
Pontine Nuclei
Vestibular Nuclei Vestibular Nuclei
Cerebral
Cortex
Frontal lobe
External
Cuneate Nucleus
External
Cuneate Nucleus
Dorsal Nucleus
of Clarke
Dorsal Nucleus
of Clarke
Purves 19.3B
Spinocerebellar inputs Spinocerebellar inputs
Cortico-
Pontocerebellar inputs
Cortico-
Pontocerebellar inputs
(ICP)
(MCP) (MCP)
Thisillustrationismorerepresentativeoftheanatomyofthecerebellar
afferentsthanthepreviousboxdiagram.Notethatthedescendingcortical
tractssynapseintheponsatthepontine nuclei.Thepontocerebellar fibers
crossthemidlineandformthemassiveMCP MCP.Thuscorticaldatais
distributedtothecontralateralcerebrocerebellumandisimportantfor
motorplanningandsequencing.
Theafferentsfromtheinferioroliveandthespinalcordalsotraversethe
ICP ICP. .Spinalcordinformation Spinalcordinformation terminatesinthespinocerebellum;
Olivocerebellar fibersspreadthroughoutthecerebellum.Thisafferent
systemwillbediscussedshortly.ThevestibularnucleialsoemploytheICP ICP
toenterthecerebellumandaredistributedtothevestibulocerebellum.
Notethatthereisredundancyofvestibularinformationtothevermisregion
ofthespinocerebellum thisdataisintegratedthroughthefastigialDCN.
Thisredundancyisacluetotheimportanceofthissensorymodalityinthe
productionofappropriateandsmoothmovementsalongwithmaintenance
ofpostureandbalance.
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IP3 Receptor
MAP-2
GFAP
IP3 Receptor
MAP-2
GFAP
Molecular
Layer
Granule cell
Layer
Blumenfeld, 15.6C
Purkinje
cell layer
Purkinje
cell layer
Thisisanactualfluorescencemicrographimageofthecerebellum(rat),produced
byDr.Andr ParentfromLavalUniversity(Quebec,Canada).Antiserathat
recognizetheinositol 1,4,5triphosphatereceptor(IP3)arelabeledingreen,andare
veryprominentwithinthedistinctivePurkinjecells.IP3receptorstainingisvisible
inPurkinjesomaandtheproximaldendritictree.
Microtubuleassociatedprotein2(MAP2)whichisamarkerofdendritic tubulin,is
labeledwithbluedye.Thisproteinisdistributedindendritesandotherprocesses
ofcerebellarinterneuronsinthedeeper,granulecelllayerfo thecorticalgray
matter.
Stainingfortheglialfibrillary acidicprotein(GFAP)isshowninredandlabelsglia
throughoutthecerebellarfolia.GFAPisespeciallyevidentinthegranulecelllayer
andthedeepwhitematteratthelowerrightoftheimage.Thismarkercanalsobe
seenasparallellinesinthemolecularlayer,stainingtheradialglialfibers(Bergman
glia).
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Cerebellar
Tissue
Cube
Granule cell
Parallel fibers
Purkinje
cell
Purkinje
cell
Mossy
fiber
Climbing fiber Climbing fiber
Purkinje cell layer Purkinje cell layer
Molecular
Layer
Granule cell
Layer
Golgi cell
Basket cell
Stellate
cell
*
Purves 19.9A
Acubeofcerebellarfoliaisshown.Thepial surfaceislocatedatthetopofthe
drawing.Onesurfaceisorientedintheparasagittalplaneofthecerebellum(seenat
thefrontleft).Theotherfaceofthecubeiscutparalleltothelongaxis,alongthe
pathofthefolia.Thecubehasbeenrotatedslightlytoillustratetherelationshipof
thecerebellarneuronsin2dimensions.
Theafferentsareclassifiedaseithermossy orclimbingfibers;thisalsodescribes
theirmicroanatomyinthecerebellum.
Mossyfibercircuits:areexcitatoryandterminateinaglomerulus(*)ontheGolgi
cellandtheexcitatory(glutamate)granulecell.Theglomerulus isthesynaptic
arrangementofamossyfiberafferent,theGolgicellandthegranulecell.Theaxon
ofthegranulecelltravelsperipherallytothemolecularlayerwhereitbifurcates
andbecomestheverynumerousparallelfibersofthecerebellum. Parallelfibers
excitethedistaldendritesofthePurkinjecells,Golgicells,Basketcells,andStellate
cells.ThesefourneurontypesalluseGABAastheirneurotransmitter.
Climbingfibercircuits:climb upthePurkinjecelldendritesandareexcitatory.
TheclimbingfibersariseONLYfromtheinferiorolivarynucleus.Eachclimbing
fibercontactsonlyafewneighboringPurkinjecells.
YOUWILLBERESPONSIBLEFORKNOWINGTHEAFFERENTFIBERSAND
THEIRSYNAPTICRELATIONSHIPS,THEGRANULECELLANDTHE
PURKINJECELL.
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Purkinje
cell
Purkinje
cell
Up Close and Personal
Golgi
cell
Parallel
fibers
Granule
cell
Mossy
fibers
glomerulus glomerulus
Dr. Jos Rafols,
Wayne State U.
Theseimagesarephotographsofhumancerebellarcortex,stained usinga
Golgiimpregnationtoshowthecomplexcytoarchitectureofindividual
neurons.TheoutstandingfeatureofthePurkinjecellisitsextensive
dendritictree.Whenthecerebellumisviewedinablockthatis inparallelto
thelongaxisofthefolia,thePurkinjecellbecomesalmosttwo dimensional
andtheparallelfibersarevisibleastheypassthroughitsdendritictree
(uppermiddle).
Thegranulecellneuronhasasmallcellbody,buttheterminalportionsof
itsdendritesareexpandedreceptiveregionsthatparticipatein thecerebellar
glomerulus(markedby8 8 pointstars pointstars,lowermiddle).TheGolgicell
interneuronalsoparticipatesinthecerebellarglomerulus,asdotheafferent
Mossyfibers.
Thelowerrightpanelisanelectronmicrographshowingthedensityof
packingoftheparallelfibersinthemolecularlayerofthecerebellum.Inthe
centralportionoftheimageisaPurkinjecelldendrite identifiedbyits
highdensityofmitochondria.
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Purves 19.9B
Mossy fibers
Climbing fiber
Granule cells
Purkinje cell
interneuron
Parallel fibers
DCN
Granular
layer
Deep
White
matter
Molecular
layer
Cerebellar
Afferents
Thesynapticcircuit ofthecerebellumandtherelationshipsofexcitatory
andinhibitoryconnectionsthroughthecortexandDCNareshown. This
circuitmoduleisrepeatedoverandoverthroughoutthecerebellumandis
identicalinitsconnectionsregardlessofthecerebellarareasampled.The
excitatorymossyandclimbingfibers havesynapsesinBOTHtheDCNand
thecerebellarsynapticcircuit.Theafferentsprovideinformationabout
bodyposition,thecenterofgravityandkinestheticdataofthe movementas
itisoccurring.
ConvergentinputstothePurkinjecellcomefromcerebellarinterneurons,
andotherPurkinjecells.Thisintegrationprovidesthebasisforcomparing
theevolvingmovementwiththesensoryfeedbackfromthekinesthetic
receptorstotheactionthatwasplanned.
ThePurkinjecelloutputtotheDCNgeneratesanerrorcorrectionsignal that
canmodifymovementsthathavealreadybeeninitiated.Climbingfibersprovide
thisbymodifyingthestrengthoftheparallelfiberinputstospecific
populationsofPurkinjecellsandthisformsalongheldtheoryofmotor
learning.ThisisshownlaterintheslidesandistermedHETEROSYNAPTIC
LongTermDepression (LTD).
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Synaptic
Circuit
Purves 19.10
Deep
excitatory
loop
Cortical
inhibitory
loop
Granular
layer
Deep
White
matter
Molecular
layer
DCN
DCN M
o
s
s
y

f
i
b
e
r
C
l
i
m
b
i
n
g

f
i
b
e
r
P
a
ra
lle
l fib
e
r
Purkinje cell Purkinje cell
Theflowofsynapticactivityinthecerebellumissimplifiedhere.Neuronsin
theDCNhaveanintrinsicfiringlevelthatistonic(alwaysactive).Excitatory
cerebellarafferentsspeedupthisintrinsicfiringfrequencywhenthey
becomeactivated(deepexcitatoryloop).Informationisconveyedfurther
intothecerebellarsynapticcircuitmoduletothegranulecells parallel
fiberstoactivatetheotherinhibitoryinterneuronsofthegray matter
(corticalinhibitoryloop).
Whenthemossyfibercircuitisactivated,asimplespike isgeneratedinthe
Purkinjecell.Whentheclimbingfibercircuitisactivated,acomplexspike is
producedthePurkinjecell.Thecomplexspikehasaprofoundeffectonthe
PurkinjecellandthedownstreamDCNfiringpattern.
ThePurkinjecellinhibitionisfinallyrelayedintotheDCN,butthe
inhibitionisdelayedduetointegrationoccurringoveranumber ofsynapses
inthecircuitmodule.ThusthetemporalactivityoftheDCNischanged a
newrhythmoccurs.Thisisdisplayedinelectrophysiologicaltracesin
Purvesfigure19.11.
Thesynapticplasticitydescribedherewasfirsthypothesizedby Dr.Masao
ItoatTokyoUniversity.Readmoreaboutthisonpages423426ofPurves,or
intheoriginalliterature.
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Parallel fiber Parallel fiber
Mossy
fiber
Climbing
fiber
Modified Synapse Modified Synapse
Purkinje Purkinje
cell cell
Heterosynaptic LTD Heterosynaptic LTD
Instruction
Instruction
Granule cell Granule cell
+
+
+
+ +
-
Mossyfiberinputtothecerebellumistoniccarryinginformationaboutthe
planned,andtheongoingmovement.Thisinformationistransferredtothe
cerebellarcortexthroughcontinuousactivityfromthegranulecellaxons
knownasparallelfibers.Whenanunanticipatedchangeoccursinthe
movementfromwhatwasintended,climbingfibersbecomephasically
active,andmossyfiberactivityisdepressedtransiently.
InputtoPurkinjecellsfromclimbingfibersisconsideredtobe themost
importantmechanismunderlyingmotorlearning.
Climbingfiberinputiscapableofcausinglonglastingchangesinthe
efficacyofparallelfibersynapsesatPurkinjecells.Thisistermeda
heterosynaptic heterosynaptic event.Achangeinactivityinonepathwayisproducedin
responsetoactivityinanotherpathway.Climbingfibersproducealong
termdepression(LTD LTD) intheweightingofparallelfibersynapses.The
cellularmechanismunderlyingthisisenhancedendocytosis ofAMPA
receptorsattheparallelfiberPurkinjecelldendritesynapse.
ReductioninefficacyoftheparallelfiberinputtothePurkinjecellswill
increasethefiringrateoftheDCN(lessimpactofthecerebellarcortical
inhibitoryloop).Studiesthatsupportthismechanismshowthat
pharmacologicalinactivationofthecerebellarcortexpreventsthe
heterosynapticLTD,andinturn,theexperimentalanimaldoesnotshow
behavioraladaptationormotorlearning.
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Cerebellar Afferents
Mossy fibers
excitatory
tonic activity
divergent distribution
end in the glomerulus
activate the granule
cell/parallel fibers
from all parts of
neuraxis
Climbing fibers
excitatory
phasic activity
focused distribution
climb up Purkinje cell
dendritic tree
complex spike generation
from the inferior olivary
nucleus
Theuniquecharacteristicsofthetwodifferentafferentfibertypesto
thecerebellumarehighlighted.KeepinmindthatEVERYcerebellar
synapticcircuitmodulereceivesbothkindsofinputs,regardlessofthe
locationsampledinthecerebellum.
EachmossyfiberandeveryclimbingfiberhasTWOsynaptictargets
inthecerebellum:1)DCNand2)anintrinsicneuronofthecerebellar
corticalgraymatter.
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Interposed
Fastigial
Interposed
Fastigial
Vestibular
Nuclei
Vestibular
Nuclei
Dentate
Dentate
Organization of Outputs
Cerebellar
cortex
Cerebro-
cerebellum
Cerebro-
cerebellum
Spino-
cerebellum
Spino-
cerebellum
Vestibulo-
cerebellum
Vestibulo-
cerebellum
DCN
Premotor cortex
Motor Planning
Motor cortex
Brainstem
Motor execution
LMN in Brainstem
Superior colliculus
LMN in spinal cord
Balance and Vestibulo-
ocular regulation
ThethreefunctionaldivisionsofthecerebellumrelaythroughspecificDCN.Itis
theDCN(oritsequivalentinthevestibularnuclei)thatwillthenprojecttoother
partsoftheCNSandconveycerebellarinformationtothemovement.
CerebrocerebellumDentatemotorthalamusand/orred
nucleusandfinallytothepremotorcortices
SpinocerebellumInterposedandFastigialUMN,superior
colliculusandreticularformation
VestibulocerebellumVestibularnucleiLMN
Thevestibulocerebellum isthemostancientofthedivisionsofthecerebellum.Its
Purkinjecellconnectionsaretothevestibularnucleidirectly, andthusthelatter
maybeconsideredfunctionally tobeaDCNequivalent.
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Cerebellar
Efferents
Purves 19.6B
VA/VL
Thalamus
DCN
DCN
Inferior Olive Inferior Olive
I
n
t
e
r
n
a
l

c
a
p
s
u
l
e
Primary motor
Premotor Cx
Thalamocortical
fibers
Rostrally-directed
efferents leave
the cerebellum on
the SCP to synapse in
the motor thalamus.
AS IT LEAVES, THE
SCP DECUSSATES.
Red Nucleus
SCP
SCP
InformationleavingthecerebellumpassesthroughtheappropriateDCN
beforeitwillinfluencethemotorsystem.Theoutputfromthecerebellar
cortexisthePurkinje cell.Allothercerebellarneuronsarelocalcircuit
neurons(interneurons)thatareintrinsictothestructure.
ThePurkinjecellfibersterminatetopographicallyintheappropriateDCN
(orvestibularnucleiiftheyareprojectingfromthevestibulocerebellum),
andalsogeneratecollateralstootherinterneuronsandneighboringPurkinje
cells.
ThemajorterminationsofDCNaxonsare1)rednucleus,2)motorthalamus,
3)reticularsystem,4)vestibularnucleiand5)superiorcolliculus.
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Cerebellar Efferents
(ascending tracts)
Modified from
Purves 19.6A
Midline
DCN
Dentate / Interposed
Primary Motor and
Premotor Cortices
Primary Motor and
Premotor Cortices
Cerebellar Cortex Cerebellar Cortex Cerebellar Cortex
Red Nucleus Red Red Nucleus Nucleus
SCP
SCP
Motor Thalamus
(VL)
Motor Thalamus Motor Thalamus
(VL) (VL)
TheoutflowfromthedentateandinterposedDCNtravelsrostrally toreachtheir
targets.ThesetractsusetheSCP SCP togettotheirdestinationsintherednucleus(from
theinterposed)andthemotorthalamus(fromthedentate).These pathwaysare
crossedastheyleavethecerebellum,andtheheavymyelinationofthesecerebellar
efferentsmakesanimposingdecussationoftheSCPinthedorsal tegmentumofthe
caudalmidbrainareaofthebrainstem.SeeHaines623Bfigure.
Cerebellarintegrationintherednucleuswillimpacttherubrospinaltract(RS),the
rubroolivary tract(synapsing ontotheclimbingfibersoftheinferiorolivary
nucleus),andtherubroreticular tract(terminatinginthereticularformation).You
onlyareresponsibleforknowingtheRStractanditsfunctioninthemotorsystem.
CerebellarintegrationinthemotorthalamuswillmodulateUMNoutputfrom
Brodmannsareas4,6and8.
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Cerebellar Efferent Pathways
(descending tracts)
Vestibular
nuclei
nuclei nuclei
LMN in medial motor pools Purves 19.7A
Superior
colliculus
Superior Superior
colliculus colliculus
Reticular
formation
Reticular Reticular
formation formation
DCN
(Fastigial)
DCN
(Fastigial)
Cerebellar Cerebellar
Cortex Cortex
Anterior-medial
white matter of
spinal cord
Anterior-medial
white matter of
spinal cord
ICP ICP ICP
Thisdiagramshowsthemajorefferentsfromthespinocerebellum andthe
vestibulocerebellum thatmodulatetheactivityofUMNinthebrainstem
(superiorcolliculus,reticularformationandvestibularnuclei).Purkinjecells
projectdirectlytothevestibularnuclei(rightsideofdiagram)fromthe
vestibulocerebellum.Thevermisalsohasvestibularfunctionsrepresented
andthatinformationpassesthroughtheDCN inthiscasethefastigial
nucleus.FastigialaxonstravelintheICP ICP toterminateinthesuperior
colliculusandreticularformation.
TheintegratedcerebellarinformationistransmittedtotheLMNinnervating
theaxialskeletonandlocatedinmedialmotorneuronpools,usingthe
tectospinal,reticulospinalandvestibulospinal tracts.Thesedescending
pathwaysinfluenceposture,balanceandstabilizationofthebodyinorder
tomovetheextremities.
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Normal
Start Finish
Cerebellar Disease
Intention Intention
Tremor Tremor
(dysmetria) (dysmetria)
Signs and Symptoms of Cerebellar
Lesions
Signs and Symptoms of Cerebellar
Lesions
Dystaxia Dystaxia -- loss of coordination of axial and
extremity muscles.
Dysmetria -- movement is not stopped in time
Dysarthria -- loss of speech coordination
Dysdiadochokinesia -- reduced ability to perform
rapidly alternating movements
Nystagmus -- loss of coordinated eye movements
Hypotonia -- cause is unclear
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Chronic Alcohol Abuse
Vermis (arrows) degenerates in the anterior lobe.
This individual showed ataxia when walking.
Purves 19.14
Notethesignificantatrophyofthecerebellarfoliainanindividualwho
sufferedfromalcoholism.StudiesshowthatPurkinjecellsofthe
anteriorlobeareparticularlysensitivetoalcoholanddegenerate.
Thechangesinthispartofthecerebellumproduceataxiainthe trunk
andabroadbasedgait.Thereissparingofthemotorcontrolinthe
upperextremitiesandfingers.
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Spinocerebellar Ataxia
Autosomal dominant, chromosome 22q14-qter Gaze-evoked nystagmus, seizures Mexican family of
Matsuura
Unknown Pure cerebellar Mexican-American
pedigree of Grewal
12p CAG expansion Chorea, seizures DRPLA
8q Head and hand tremor SCA-16
19 q Myoclonus SCA-14 (rare)
19q Mental retardation SCA-13 (rare)
5q CAG Head and hand tremor, akinesia SCA-12 (rare)
15q SCA-11
Chromosome 22q linked, pentanucleotide repeat Ataxia, seizures, primarily in Mexicans SCA-10 (5 families)
SCA-9
CTG repeat, 13q Horizontal nystagmus SCA-8
CAG repeat, 3p Macular degeneration, UMN SCA-7
CAG repeat, 19p (Ca
2+
channel) Downbeating nystagmus, positional vertigo SCA-6
Chromosome 11 Pure cerebellar SCA-5
Chromosome 16q Areflexia SCA-4 (17 families)
CAG repeat, 14q Gaze-evoked nystagmus, UMN SCA3 (MJD, 30-40%)
CAG repeat, 12q Diminished velocity saccades, areflexia SCA2 (6-15%)
CAG repeat, 6p Hypermetric saccades, UMN SCA-1 (3-15%)
Mutation Oculomotor findings SCA Type
ReviewBox19B(431432)inPurvestogetthehistoricalperspectiveon
geneticdiseasesofthecerebellum.Thisalsodemonstrateshowbasicand
clinicalsciencehavemergedtosolvehumanneurologicaldiseases.
Acommonfeatureofallofthecerebellarmutantmice,andmanypatients
withcerebellardiseaseisataxia.Thus,theyarereferredtoas
Spinocerebellar ataxia(SCA).
Thingstoconsider manyofthehumanmutationsexhibitexpansionsofa
tripletrepeat CAG.Rememberthatthisishowthemutationin
Huntingtonsdiseaseisexpressed.Manyoftheproteinsthataremutateddo
nothaveaknownfunction,butsomeareidentifiedasmembersof ion
channelproteins.
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Motor Anatomy II
Lab Introduction
Basal Ganglia & Cerebellum
Thislecturewillfamiliarizeyouwiththeanatomicalcomponents ofthebasal
gangliaandcerebellum.Youwilllearnthestructuresthataretheirneighbors,and
thereareslidesshowingthegeneralizedbloodsupplytoeachof thesemotor
systemcomponents.
LearningObjectives:
Knowtheanatomicalrelationshipsofthefivenucleiofthebasalganglia
incoronalorientation
inhorizontalorientation
UnderstandthegrosschangevisibleinPD
Identifythebloodsupplyofthebasalgangliaandsymptomsfollowingocclusion
orhemorrhageofthesevessels
Knowtheanatomicalrelationshipsofthecerebellum
Describetherelationshipsofthelobesofthecerebellumindifferentorientations
Identifythebloodsupplyofthecerebellumandsymptomsfollowingocclusionor
hemorrhageofthesevessels
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3D Model
Caudate
(head)
Caudate
(head)
Blumenfeld 16.1A
ventricles
Cerebellum Cerebellum
Nucleus
accumbens
Nucleus
accumbens
Amygdala Amygdala
Caudate
(Tail)
Caudate
(Tail)
Putamen
Putamen
Cellular bridges
Caudate
(body)
Caudate
(body)
This3dimensionalmodelshowstheCshapedstructureofthecaudatenucleus
anditsthreepartsastheyborderthelateralventriclewithinthecentralcoreofthe
cerebrum.
Notethatthecaudateislargestinsizeinitsmostrostralportion.Itiscalledthe
headofthenucleus.Thebodyofthecaudatenucleustravelsdorsally,then
caudally,andtheninferiorlyintheforebrain,andtapersintotheverysmalltail
(endregion).Thetailofthecaudatenucleusisdetectedonthe roofoftheinferior
hornofthelateralventricle.Lookforthesmalltailstructure intheexamplesthat
follow.
Theputamenismedial(andnotvisibleinthisview)totheCshapedcaudate
nucleusandconnectedtoitbycellularbridgesofmyelinatedaxons(fascicles).
Thesefasciclesgetseparatedasthedescendingcorticalfibersinthecoronaradiata
(seenextslide)coursetotheircaudaltargetsintheneuraxis, formingtheinternal
capsule.
Thenucleusaccumbensisventraltotheheadofthecaudatenucleusatitsmost
rostraldimension,whiletheamygdalaactuallyswells outfromthetailofthe
caudate.Boththenucleusaccumbensandamygdalaarepartofthe limbicsystem,
andnotassociatedwiththebasalgangliafunctionally.
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Caudate & Corona Radiata
UWIBA CAUDATE
Head Tail Body Head Tail Body
(Corticostriatal, Corticospinal, Corticobulbar)
TheCshapedcaudatenucleusinterruptsamassivecorticalefferent(corticofugal)
systemthatcanbedissectedbecauseitsaxonsareheavilymyelinated.This
structureisknownasthecoronaradiata(Latinforradiatingcrown)andcontributes
totheformationofthreepathways:
1) corticostriatal,
2) corticospinal,and
3) corticobulbar.
Othercorticofugal tracts thatconnecttheneocortextoothercorticalareasand
forebrainstructuresarealsopartofthecorona.
Thesethreenamedtractsarenotspecificallydefinedineitherthefixedbrain
dissectionontheleftorintheinkdrawingofthedissection,presentedtotheright
sideoftheimage.However,besureyouarecomfortablewiththe functionsofthe
threenamedpathways.
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Blood Supply
PCA
PCA
Anterior
choroidal
Anterior
choroidal
MCA
MCA
ACA
ACA
Anterior Limb,
Internal capsule
Internal capsule,
Genu
Posterior Limb,
Internal capsule
Optic
Radiations
Corona radiata
Modified from Blumenfeld, figure 10.8B
Themultiplevesselsengagedinprovidingthebloodsupplytothedeepstructures
ofthecerebrum,andthelongdescendingtractsaredrawn.Fourmajorarteries
supplythecoronaradiata:1)anteriorcerebralartery(ACA ACA),2)middlecerebral
artery(MCA MCA),3)anteriorchoroidalartery anteriorchoroidalartery,andposteriorcerebralartery(PCA PCA).
Thethreepartsoftheinternalcapsule(anteriorlimb,genu,posteriorlimb)are
perfusedbythreedifferentvessels.Thesymptomsassociatedwithdamagetothe
variouspartsoftheinternalcapsulecanbeusedtodeterminewhichbloodvessels
areaffected.Laterslidesofthebloodsupplywillpresentalternativeviewstoassist
inlearningthevasculature.
Seepage373inBlumenfeldformorediscussion.
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Horizontal view
http://library.med.utah.edu/WebPath/HISTHTML/NEURANAT/NEURANCA.html
Red nucleus Red nucleus
Substantia nigra Substantia nigra
ICA
ICA
ACA
ACA
MGN
MGN
LGN
LGN
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Thisisaventralhorizontalsectionofthewholebrain theclueisthatonlythe
midbrainandasmallportionofthetemporallobehavebeencutinthisbrainslice,
whiletherestofthecerebrumisintact.
Structuresthatsurroundtherednucleusandsubstantianigrain themidbrainare
thecruscerebri(cerebralpeduncles)ventrally,thatcontainthedescending
corticospinalandcorticobulbarUMNaxons.Thecruscerebriisvisibleonthe
ventralsurfaceofthemidbrain,rostraltotheexpandedpons(notseeninthisslide).
Dorsaltothemidbraintegmentumarethetwogeniculatenuclei(LGN,MGN);
structuresthatarepartofthethalamus.
Pigmentationinthedifferentbrainnucleiarecausedby:
rednucleus highconcentrationsofironandvascularization
substantianigra melanincontainedinDAneurons
LGN highlyvascularized,6layeredstructure
Theinternalcarotidartery(ICA)isevidentjustlateraltothe heavilymyelinated
optictract.ItwilldivideintotheMCAandstayinthelateral sulcus.Theanterior
cerebralartery(ACA)isvisiblerostraltotheopticchiasmbetweentheopticnerves.
Besurethatyouarecomfortablewithlandmarksthatwillhelpyoudistinguishthe
rostralfromthecaudalpolesofthebrainwhenpresentedwitha horizontalview.
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Ventral aspect
Striatum Striatum Globus pallidus Globus pallidus
Anterior commissure
Anterior commissure
Claustrum
Claustrum
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Thishorizontalbrainsectionislocatedmoredorsallythanthepreviousslide,and
showsthebasalganglianucleipositionedwithintheforebrain.Thestriatum striatum
(caudateandputamen)isoutlined.Medialtotheputamenarelocatedthetwo
portionsoftheglobus globuspallidus pallidus.
Neighboringstructuresforthecaudatenucleusarethelateralventricles recallthat
thecaudatealwaysbordersthelateralventriclethroughoutitscourse.Linkingthe
twosidesofthelimbicsystemrostrally istheanteriorcommissure,aheavily
myelinated(white)pathwaythatiscaudalandmedialtothecaudatenucleus.
Separatingthestriatumintothecaudateandtheputamenistheanteriorlimbofthe
internalcapsule.Theposteriorlimbislabeledandseparatesthebasalgangliafrom
thethalamus.Thefiberswithintheinternalcapsulearemyelinated.Theposterior
limboftheinternalcapsuleborderstheGPi,andmyelinatedfasciclesfromtheGPi
andGPearevisibleastheytravelperpendiculartothedescendingtracts.The
perpendicularfibersconnecttheglobuspallidustootherpartsofthenervous
system(canyounamethem?).
Thethinstripofgraymatterlateraltotheputamenistheclaustrum.Thewhite
matterthatismedialtotheclaustrumiscalledtheexternalcapsule,whilethewhite
matterthatseparatestheclaustrumfromtheinsularcortexiscalledtheextreme
capsule.Thesearelandmarkstohelporientyou.
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MRI Scan
Caudate Caudate
Putamen Putamen
GPe
Thalamus
Splenium
fornix fornix
STRIATUM
ThishorizontalMRIscan(T1weighted)islocatedmoredorsallythanthefixed
brainsectionshowninthepreviousslide.Thisdeterminationis madebecausethe
fornixisnowvisibleinthemostrostralpartofthelateralventricles,andtheatrium
ofthelateralventriclescanbeseenasaspacenexttothesplenium,andcaudalto
thethalamus.Thewhitematterstructuresthatappeartoconnect thespleniumto
thepulvinarnucleusofthethalamusarethecrusofthefornix. Thefornixis
travelingthroughtheventriclestogettoitstermination.Keep inmindthatthe
largepulvinarnucleusisthemostcaudalcomponentofthethalamus,bordering
thelateralventricle.
Thecaudatenucleus(headofthestructure)islargeandborders thelateralventricle
(itisthelateralwall)rostrally,whiletheanteriorlimboftheinternalcapsule
separatesthecaudatefromtheputamen.Thecaudateandputamennucleiare
togetherknownasthestriatum theybecomeseparatedearlyinembryonic
development.
MedialandcaudaltotheputamenistheGPe,seenontherightsideoftheimage
(whichistheleftsideoftheMRIscan!).
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Horizontal, fixed
Caudate
UWIBA
Putamen
ThishorizontalsectionoffixedbrainisyetmoredorsalthantheMRIimageinthe
previousslide.Notehowthethalamusismuchlargerinsize,positionedoneither
sideofthethirdventriclewhichisnowvisibleasathinslit, caudaltotheheavily
myelinatedfornix.
Theheadofthecaudateisseenrostrally,bulgingoutintothelateralventricle,and
thesmalltailofthecaudateislocatedalongtheinferiorhorn oftheventricle.The
putamenisdetectedonbothsides,buttheGPismoreventrallylocated,andthus
notseeninthissection.
Theentireinternalcapsuleisvisible.Theanteriorlimbseparatescaudatefrom
putamen;theposteriorlimbseparatestheputamenfromthethalamus.Theangled
areaoftheinternalcapsulethatisclosesttothemidlineiscalledthegenu orknee.
Itisthebendofthefibersoftheinternalcapsuleandiscomprisedofthe
corticobulbartract,outlinedinpurpleontheleftsideofthesample.SeeBlumenfeld
figure6.9,page223,formoreinformation.
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Horizontal Sections
Caudate & Putamen
Globus Pallidus
MRI, T1 weighted
In situ latex perfused
splenium splenium
ACA ACA
MCA MCA
Thesehorizontalsectionsreenforcetherelationshipsoftheforebrainnucleithat
comprisethebasalganglia.Thelargeststructuresarethecaudateandputamen,
formingthestriatum striatum.Thesenucleiareseparatedbytheanteriorlimboftheinternal
capsule.Medialtotheputamenarethetwopartsoftheglobus globuspallidus pallidus,which
literallymeanspaleglobe. ThisisbecausetheGPhasaroundedshapeandthere
aremyelinatedfasciclesthatpenetratethroughthenuclei,connectingtheGPwith
thestriatumascomponentsofthedirectandindirectpathways.Becausemyelinis
whiteincolor,thesemyelinatedbundlesgivetheGPapalerappearancethanthe
heavilyvascularizedstriatum.
Againrecalltherelationshipoftherostralheadofthecaudate nucleustothelateral
ventricle.
Remembertoothattheinternalcapsulecarriesdescendingmyelinatedfibersfrom
thecortex,ascendingfibersfromthethalamusandistopographicallyorganized.
ThisanatomicalrelationshipofthetractsispresentedinBlumenfeld,page223.
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MRI Imaging
Blumenfeld, figure 4.6
T1-weighted T2-weighted Proton density-
weighted
R R R L L L
Caudate Caudate Putamen Putamen
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ThesearetypicalMRIimagesofthebrainintheaxial(horizontalplane)that
illustratehowthedifferentcontrastparametersaltertheimage.Thescansare
alwaysorientedwiththerightside(R)totheleftasyouviewthescan.
AT1weightedMRIshowsmyelinatedstructuresaswhite,andcorrespondtothe
fatandwateroftheskinoverlyingtheskull.BoneandairareblackinMRIscans.
AT2weightedMRIhasmyelinatedstructuresinblack(lookatthecorpuscallosum
andopticradiations),fluidfilledspacesarewhite(lookattheventricles),andwill
providemorecontrasttotheinternalnucleiandgraymatterofthebrain
parenchyma.
Theprotondensityweightedimageontheright(firstecho)haslesscontrast
betweenthewhiteandgraymatterofthebrain.Inthistypeofscan,myelinisdark,
whilefluidiswhite.Theprotondensityweightedimageisusedforemphasizing
subtleabnormalitiesinthebrainparenchymaassociatedwithvariouspathology.
Here,youcandistinguishtheforebrainbasalganglianucleiand alsothecortical
gyri.
Thecaudatenucleusisdistinguishedeasily,regardlessoftheMRIweightedimage
becauseitprotrudesmediallyintothelateralventricleandiscapped rostrally by
thecorpuscallosum.Theputamenisdetectedjustlateralandcaudaltotheanterior
limboftheinternalcapsuleintheT2weightedimage.
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Coronal View
Caudate & Putamen Caudate & Putamen
Globus Pallidus
UWIBA
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insula insula
uncus uncus
amygdala amygdala
uncus uncus
insula insula
amygdala amygdala
TheT1weightedMRIinthecoronalplaneontheleftrevealsthecaudatenucleusat
thelateralborderofthelateralventricle bulgingintotheblackspacerepresented
bytheCSF.Whitematteriswhite(howconvenient!),sotheinternalcapsuleis
apparentseparatingtheputamenandglobuspallidusfromthecaudate.The
anteriorcommissurecanbeseenattheinferiorborderoftheGP,crossingthe
midlineandintersecting thetwocolumnsofthefornix,whichareheavily
myelinatedandthereforewhite.
Theformalinfixedbrainsliceontherighthandsideisnearthesamerostralcaudal
levelastheMRIscan.Again,notehowthecaudatenucleusisidentifiedatthe
lateralandinferiorborderofthelateralventricle.
Canyoudetermineiftheinternalcapsuleistheanteriororposteriorlimb?What
cluesdoyouusetomakethedecision?
Theinsularcortex,uncus andamygdalaarelabeledfororientation.
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III III
amygdala amygdala
Striatum Striatum
P
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hippocampus hippocampus
MCA MCA
Thiscoronalbrainslabshowsalloftheforebraincomponentsof thebasalganglia:
thecaudatenucleusisalongtheventricleandtheinternalcapsuleseparatesitfrom
itspartner,theputamen.Thestriatum islabeledontherightside.Medialtothe
putamenandinferiortotheinternalcapsulearethetwocomponentsoftheglobus
pallidus,GPe(morelateral)andGPi(medial).Wheretheinternalcapsuleseparates
theGPfromthethalamus(whichislocatedalongthemidline),itcanbecalledthe
posteriorlimb.Whentheinternalcapsuleseparatesthecaudateandputamen,itis
theanteriorlimb.
The3
rd
ventricle(labeledIII)issurroundedbythehypothalamuslaterallyand
inferiorly.Themostinferiorcomponentsarethemammillarybodies,whichare
visibleontheventralsurfaceofthebrain.Theamygdalaisseenclearlyasa
homogeneousgraynucleus,justlateraltotheuncus (notlabeled)ontheleftsideof
thebrain.Thehippocampusisvisibleontherighthandside,belowtheinferior
hornofthelateralventricle.Ithasconvolutedtexturetoit,andgivesrisetothe
fornix(thistractbeginsasthesubiculum).Thefornix,anotherCshapedstructure,
isseenasitproceedstoitsterminationarea,hangingdownventrallyatthecentral
borderofthelateralventriclesatthebaseoftheseptumpellucidum.
TheforamenofMunro,leadingfromthelateralventriclesintothe3
rd
ventricleis
detectedinthissample.
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GPi
GPi
GPe
GPe
MCA
MCA
External
capsule
Thisisthesamesampleasthepreviousslide,butprovidedata higher
magnification.TherelationshipsoftheputamentotheGPearemoreeasilyseen,
andthepalercolorofthepallidum,incomparisontotheputamenispossible.Note
thewhitemattertractthatbordersthelateraledgesoftheputameniscalledthe
externalcapsule.Thisseparatestheputamenfromtheclaustrum. Totheexternal
sideoftheclaustrumisanotherthinmyelinatedseparation,the extremecapsule.
Thiswhitematterintercedesbetweentheclaustrumandtheinsularcortex.
AbranchoftheMCAisvisiblewithinthelateralfissure,onthesurfaceofthe
insula.BranchesfromtheMCAwillperfusethesedeepstructuresofthebasal
ganglia,andarefrequentlythesiteofstrokes.
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Internal Capsule
Haines 4-5
Poster Limb
Internal Capsule
Crus Cerebri
Corticospinal tract
STn
SN
Thiscoronalsectionshowsthecourseoftheinternalcapsulethroughtheforebrain
andcaudallyintothepons.Notethattheposteriorlimb,separatingthebasal
gangliafromthethalamus,travelscaudallytobecomethecruscerebriinthe
midbrain.Inthemidbrain,thenucleusimmediatelydorsaltothe crusisthe
substantianigra,detectedeasilybyitsaccumulationofmelanin,whichisblack.Just
dorsaltothesubstantianigraisthesubthalamicnucleus(STn). Whatimportant
basalgangliapathwayrelaysthroughtheSTn?
Themyelinatedfibersofthecruscerebricanbeseenontheventralsurfaceofthe
brainasthecerebralpeduncles,justrostraltothepons.Thisveryadvantageous
coronalsliceshowsthatthedescendingfibersremainconfinedastheyenterthe
pons,asthecorticospinaltract.Reviewforyourselfwhathappensnextinthe
corticospinalsystem.
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Midbrain Components
Haines 5-31
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STn
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Caudate
ThisimagefromyourHainesatlasshowsthediencephalonandmidbrainfollowing
useofamyelinstain.Thecaudatenucleusisvisibleatthelateraledgeofthelateral
ventricleinthedorsalareaofthesection,andalsoontheroofoftheinferiorhorn
(youcanseeitontheleftsidetoo).Theputamenisvisibleas apalenucleus,similar
indensitytothecaudate.
Theglobuspallidus(GP)appearsdarkerthanthestriatumbecauseithas
myelinatedfasciclespenetratingthroughthenucleus.Inthiscoronalorientation
youcanappreciatetheproximityoftheSTnandtheSNtotheGPiofthebasal
ganglia.
Theinternalcapsuleisshowninitsentirety;theanteriorlimb separatescaudate
andputamen,theposteriorlimbdividesthethalamusfromtheputamenandGP,
thecruscerebriwrapsbeneath(ventral)totheSN.
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Arterial Supply, Coronal view
Blumenfeld 10.7 Blumenfeld 10.9A
Internal
carotid
PCA,
deep
branches
PCA,
deep
branches
Putamen
Caudate
Lenticulostriate
arteries
MCA
Ant. choroidal Ant. choroidal
PCA PCA
MCA,
inferior
MCA,
inferior
MCA,
deep
MCA,
deep
ACA ACA
Putamen
GPe
GPi
MCA,
superior
ThesetwofiguresfromBlumenfeldshowtheprincipalarteriesthatperfusethe
basalganglia.Ontheleftarethelenticulostriatearteries thatarebranchesfromthe
MCA.Thesearteriesaretheprimarysourceofbloodsupplytothestriatum,globus
pallidus,andinternalcapsule.
Strokesareprevalentinthelenticulostriatearteriesbecauseof1)thechangein
volumeandflowratefromthelargeMCAtothesmallerbranches, and2)because
ofthe90degreebendindirection.Themostprominentsignsofstroketotheregion
areUMNdamagesymptoms.Recallwhatthoseidentifyinghallmarks arefor
review.
Theimageontherightshowstheoverlapofthedifferentarterialsupplies,with
theirwatershedregions,colorcoded.Blumenfeldgivesanexcellentdescriptionof
symptomsassociatedwiththeterritoriesoftheACA,MCAandPCA inTable10.1,
page376377tohelpyoudigestthismaterial.
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Arterial Supply, Horizontal
Modified from Blumenfeld 10.9B
PCA,
deep
PCA,
deep
Ant. choroidal Ant. choroidal
PCA PCA
ACA ACA
MCA,
superior
MCA,
superior
MCA,
inferior
MCA,
inferior
MCA,
deep
MCA,
deep
ACA,
deep
Caudate Caudate
Putamen Putamen
GP GP
Anterior Limb
Internal capsule
Anterior Limb
Internal capsule
Posterior Limb
Internal capsule
Posterior Limb
Internal capsule
Thalamus Thalamus
ThisimagefromBlumenfeldshowstheperfusionpatternsofthearteriestothe
basalgangliainthehorizontalperspective.Recognitionofthesyndromesthat
resultfrominfarctsintheACA,MCAandPCAisacornerstoneof neurological
assessment.ReviewTable10.1inBlumenfeldtofamiliarizeyourselfwiththe
hallmarksymptoms.
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Arteries to Subcortical Nuclei
Modified from Blumenfeld 10.8A
Putamen
Ant.
choroidal
Ant.
choroidal
PCA PCA
ACA ACA
GPi
Basilar Basilar
MCA MCA
Lenticulostriate
arteries
Lenticulostriate
arteries
Caudate
Thalamus
Internal
carotid
Internal
carotid
Thisimagehasdissectedawayallofthecortexanddescendingfibertracts,leaving
onlythecentralcoreofthediencephalontomoreclearlydemonstratethearteries
thatperfusethebasalgangliaandthethalamus.
Again,allthreecerebralarteriessupplybloodtotheregion.Ofparticularnotefor
thebasalgangliaarethelenticulostriatearteries,derivedfromMCA(shownina
fawn fawn color),andtheanteriorchoroidalartery(inolive olive)anditsdeepbranches,
whichemanatefromtheACA.
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Cerebellum
Thisisarestatementfromtheopeningslide!
Thislecturewillfamiliarizeyouwiththeanatomicalcomponents ofthebasal
gangliaandcerebellum.Youwilllearnthestructuresthataretheirneighbors,and
thereareslidesshowingthegeneralizedbloodsupplytoeachof thesemotor
systemcomponents.
LearningObjectives:
Knowtheanatomicalrelationshipsofthefivenucleiofthebasalganglia
incoronalorientation
inhorizontalorientation
UnderstandthegrosschangevisibleinPD
Identifythebloodsupplyofthebasalgangliaandsymptomsfollowingocclusion
orhemorrhageofthesevessels
Knowtheanatomicalrelationshipsofthecerebellum
Describetherelationshipsofthelobesofthecerebellumindifferentorientations
Identifythebloodsupplyofthecerebellumandsymptomsfollowingocclusionor
hemorrhageofthesevessels
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Gross Brain
ThisisamostunusualdissectionshowingtheentireCNS.Thepositionofthe
cerebellumisatthemostcaudalandinferiorpartofthecerebrum,rostraltothe
spinalcord.Ongrossinspection,cerebellargyri aremuchsmallerthanthe
cerebrum,andthecerebellumhasonemajorsulcus,termedtheprimaryfissure.
Theventralneighborsofthecerebellumaretheponsandmedulla ofthebrainstem.
Thecerebellumisattachedtothebrainstembythreepairedpeduncles.
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MRI Scans
http://www.med.harvard.edu/aanlib/
Coronal Sagittal Axial
TheseT1weightedMRIscansshowthecerebelluminthe3differentplanes.Note
thatthecentralcoreofthecerebellumisheavilymyelinated,andthereforeiswhite
intheseimages.Theoverlyinggraymatterfoliaofthecerebellarcortexaremuch
smallerinsizethanthoseofthecerebralcortex.The4
th
ventricleisaprominent
landmarkinallorientations.
769
May 1, 2013
1 PM
Dr. Ariano
22
Ventral and lateral aspects
UWIBA
Flocculus (flocculonodular lobe)
Thesedissectionsshowthecerebellumwiththeattachedbrainstem.Ontheleftisa
ventralview,withtheflocculusatthelateralborderofthepontomedullary
junction.Thesampletotherightshowsalateralview,withthe flocculusagain
labeled.Whatmodalityisusedinthisfunctionalpartofthecerebellum?
Itispossibletoseetheconnectingpedunclefromtheponsinto thecerebellum
thisisthemiddlecerebellarpeduncle(MCP)carryingcerebropontocerebellar
fibers.Doyourecalltheinformationthatisbeingconveyedinthislargepathway?
Thecerebralpedunclesarevisiblerostraltothepons,andtheoptictracttraverses
overthesurfaceofthepeduncles.
770
May 1, 2013
1 PM
Dr. Ariano
23
Superior View
Primary
Fissure
Primary
Fissure
Hemisphere
Vermis
Haines 2-36A
Crus
Cerebri
SN
Thisimageshowsthecerebellumandbrainstem(ventral)thathavebeendetached
fromthecerebrum.Lookingdownonthecerebellum,theexpandedlateralarea
correspondstothehemisphere, encompassedbythebluepartialcircle.Themajor
functionalcomponentofthehemisphereisthecerebrocerebellum.Themidlineof
thecerebellumisdepressed,orpinched inwardandcorrespondstothevermis.
Canyourecallthefunctionofthevermis?
Theprimaryfissureseparatestheanteriorandposteriorlobesofthecerebellum.It
isaverydeepsulcus,andisbetterappreciatedinsagittalorientations.
Notethecloseproximityofthecolliculitothecerebellum.InParinauds syndrome,
atumordevelopsonthepinealglandandimpactsthecolliculi.Whatcerebellar
symptomswouldbenotedifthetumorislarge?
771
May 1, 2013
1 PM
Dr. Ariano
24
Midsagittal View
Tonsil Tonsil
Primary
Fissure
Primary
Fissure
Primary
Fissure
Primary
Fissure
Tonsil Tonsil
Thissagittalorientationofthecerebellumallowsyoutorecognizethe
distinguishinginternalfeatures thesmall,numerousrowsoffoliawithawhite
internalcomponent.Thisistermedthearborvitae becausethegrayandwhite
matterresembletheleafstructureofthisornamentalshrub.
Theprimaryfissureiseasilyvisible,asitsdepthspansnearly theentireexpanseof
thelobesofthecerebellumtothecentralwhitefibercore.
Appreciatethelocationofthetonsilofthecerebellum.Itmayherniatedown
throughtheforamenmagnumintheposteriorfossa oftheskullwhenthereis
increasedintracranialpressure.Thecompressionofthetonsiluponthebrainstem
maycauserespiratoryarrest,cardiacarrhythmias,lossofconsciousanddeath.
772
May 1, 2013
1 PM
Dr. Ariano
25
Inferior View
Vermis
Tonsil
Tonsil
Hemisphere
Haines 2-36B
Pons
Pyramid
ThisimagefromHainesshowsthecerebellumandbrainstem,asthoughwewere
lookingupatit thusaninferiorview.Onceagain,thelaterallyexpanded
hemisphereisnotedbythebluehemicircleandtheindentedvermisisalongthe
midline.
Thecluetowhatsurfaceofthecerebellumisbeingviewedisthatthetonsilsare
clearlyseenfromtheinferiorsurfaceoneithersideofthevermis.Youcan
appreciatetheirproximitytothebrainstem.Andalso,thebrainstemcutisbelow
thelevelofthepyramids,nearthejunctionwiththespinalcord.
TheprimaryfissureisNOTvisible,andneitheristheanteriorlobeofthe
cerebellum.
773
May 1, 2013
1 PM
Dr. Ariano
26
Dentate Deep Cerebellar Nucleus
Dentate
Dentate
Inferior Olive
Inferior Olive
Thisaxial(horizontal)crosssectionofthecerebellum,through itslargestpart,
clearlyshowsthemassoftheinteriorwhitematterofthestructure.Embedded
withinthewhitematterarethedeepcerebellarnuclei.Theonly onethatyoucan
clearlydistinguishduetoitsunusualshapeandsizeisthedentatenucleus.What
functionalcomponentofthecerebellumisrelayedthroughthisDCN?Whereare
thefiberscomingfrom,andwhatcelltypeofthecerebellarcortexsynapseshere?
[HINT:Theremaybemorethanoneneuronprojectingtothedentate!]
Notethesimilarityoftheinternalstructureofthedentatenucleustotheinferior
olivarycomplexinthemedulla.Recallthetypeofinformationthatisconveyed
fromtheinferiorolive,thepeduncleituses,andwhatitsactivationwillproduce.
774
May 1, 2013
1 PM
Dr. Ariano
27
Anterior view
brainstem removed
SCP
SCP
ICP
ICP
MCP
MCP
Nodulus
Tonsil
Flocculus
Haines 2-36C
Thisorientationofthecerebellumshowstheinternalsurfacethatisnexttothe
brainstem.Thethreepedunclesarecolorcoded,asinPurves,andconnectthe
cerebellumtotheneuraxis.Inthisperspective,thenodulus isvisible,onthe
midline,oncethebrainstemisremoved.Attachedtothenodulus istheflocculus
andtogethertheserepresentthevestibulocerebellum.WhatDCNisusedbythese
Purkinjecells?
Onceagain,thelocationofthecerebellartonsilcanbedistinguished,borderingthe
vermis,andatthemedialmarginofthestructure.
775
May 1, 2013
1 PM
Dr. Ariano
28
Blood Supply
Superior
Cerebellar
Artery (SCA)
AICA
PICA
Blumenfeld, 14.17B
ThisimagefromBlumenfelddemonstratesthesurfaceperfusionof thecerebellum.
The3majorarteriesarefromtheposteriorcirculationandare:
PICA:posteriorinferiorcerebellarartery
AICA:anteriorinferiorcerebellarartery
SCA:superiorcerebellarartery
Notethatwhenthereisastrokeordamagetothesevessels,therewilltypicallybe
brainstemsymptomsassociatedwithcerebellarsigns.Pleasereviewthebrainstem
lesionstohelplearnthismaterial.
776
May 1, 2013
1 PM
Dr. Ariano
29
Blood Supply
Superior and Dorsal aspect
Ventral aspect
Blumenfeld 15.12
PICA
AICA
SCA
Threearterialbranchesoftheposteriorcirculationsupplythecerebellum:PICA,
AICAandSCA.ThisdiagramfromBlumenfeldshowsthesurfacedistributionsof
thethreearteries.
Thedorsalviewisshowntotheleft,withthecerebrumremoved, butthe
diencephalonisstillattached.Theviewontherightshowstheventralsurfaceof
thecerebellumwiththebrainstemremoved.NotethatAICAperfusion
predominatesforthedeepstructureofthecerebellum,whilePICAandSCA
combinetoperfusethedorsalsurfaces.
Blumenfelddiscussestheprevalenceofstrokesinthecerebellar arteriesonpage
669,foryourinformation.
777
May 1, 2013
1 PM
Dr. Ariano
30
Internal Blood Perfusion
A
Blumenfeld 15.13
PICA
AICA
SCA
B C D
ThevascularterritoriesofPICA,AICAandSCAareshowninaxialsections
throughthecerebellum,frommostcaudal(A)torostral(D)levelsinthestructure.
InfarctsaremorecommoninPICAandSCAthaninAICAterritory. Patients
typicallypresentwithvertigo,nauseaandvomiting,horizontalnystagmus,limb
ataxia,andanunsteadygait.Headaches,whentheyoccur,maybe occipital,frontal,
orintheuppercervicalregions.
Rememberthatinfarctsinthelateralmedullaorponsmayproduceataxiabecause
oftheinvolvementofthecerebellarpeduncles,evenifthecerebellumisunaffected.
778
2-May-2013
Dr. Lise Eliot
Higher Cortical Function Higher Cortical Function
Lise Eliot, PhD May 2, 2013
Related reading: Purves Ch. 26 (& parts of Ch. 30)
Association areas of cortex
Agnosia and apraxia
Posterior parietal cortex: Attention
Temporal association areas: Recognition Temporal association areas: Recognition
Prefrontal cortex: Planning
Lateralization (pp. 615-16)
Sex differences (pp. 678-80, 687-88, 691-93)
Evolution of the Cerebral Cortex
(Bear 7.27; See also Purves 26.1)
Compared to other mammals, the human cerebral cortex does not
2
p ,
differ markedly in thickness (2-4 mm) or area devoted to primary
sensory & motor functions.
What does differ is: 1) the expansion of association areas, and
2) increased convolutions. Adding gyri and sulci dramatically
increases surface area, expanding many-fold the number of
columns (processing units) that can fit into a fixed cranial volume.
779
2-May-2013
Dr. Lise Eliot
The cerebral cortex is hierarchically structured. The first level of processing is in
primary sensory and motor cortices, which include:
Pre-central motor
Post-central somesthetic
Peri-calcarine visual
Superior temporal auditory
Piriform olfactory o o acto y
Insular gustatory
The next level of processing is in unimodal associate cortices, which include:
Premotor and supplemental motor areas (Motor association cortex)
Somatosensory association areas (parietal)
Visual association cortex (occipital & temporal)
Auditory association cortex (superior temporal gyrus) Auditory association cortex (superior temporal gyrus)
Finally, we get to heteromodal or multimodal association cortexareas that
neither receive direct sensory input nor send direct output to motor neurons and
process more than one form of sensation or behavior. These occupy a much larger
proportion of the human cerebral cortex than other mammals and comprise 4 zones:
Posterior parietal
Lateral temporal
Prefrontal
Limbic (cingulate; medial temporal, orbitofrontal)
780
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Referred to as the posterior parietal cortex because the anterior parietal
lobe (Brodmanns areas 3,1,2) is involved in primary somesthesia.
Integrates touch, visual, and auditory information to guide movements in
extrapersonal space.
Superior parietal lobule comprised of Brodmanns areas 5 & 7; inferior
parietal lobule comprised of area 40 (supramarginal gyrus) and area 39
(angular gyrus) (angular gyrus).
Area 5 (unimodal association area) translates somatosensory information
into goal-directed movements, such as object manipulation.
Area 7 (polymodal association area) is important for hand-eye
coordination, including the control of smooth pursuit eye movements.
Inferior parietal lobule integrates three senses and is involved in speech
perception and reading (on the dominant side) and spatial awareness (on perception and reading (on the dominant side) and spatial awareness (on
the non-dominant side).
Projects to premotor, cingulate, and prefrontal cortices, including frontal
eye fields (FEF).
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Dr. Lise Eliot
P ti t ith l i i t i i t l id tif bj t b t t Patient with lesion in posterior parietal area can identify an object, but cannot
reach out and pick it up.
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787
2-May-2013
Dr. Lise Eliot
These are just a few of the standard battery that neuropsychologists use to test for
frontal lobe injury or disease:
Wisconsin card sort task (WCST): patient is asked to sort a deck of cards
according to examiners response (Right or wrong, without explicitly stating
the rule. Tests ability to shift cognitive set. Frontal patients learn initial rule
(sorting by color, or number, or shape) normally, but perseverate when
examiner changes the rule examiner changes the rule.
Tower of London: subject must move balls from initial to goal arrangement
using as few moves as possible. Frontal patients use many more moves than
controls. Tests planning and sequencing.
Stroop test: examiner shows patient a card with a color word printed in a
different color (e.g., red, green, yellow). Subject is supposed to name the
color, not read the word, but frontal patients tend to do latter. Tests inhibition. co o , ot ead t e o d, but o ta pat e ts te d to do atte ests b t o
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789
2-May-2013
Dr. Lise Eliot
Part A shows the delayed-response task used to study working memory. In this
example, a monkey is shown two wells, one of which contains a reward. The wells
are then hidden for at least five seconds, after which, the screen is lifted and the
animal may uncover one well.
Animals with bilateral frontal lesions cannot remember location of the hidden food.
Parts B-D show electrophysiological recording from single neurons near the p y g g g
monkeys principal sulcus during a delayed response task. Cells fire during the
delay period (blue shading), but not during the cue or response phases, or when no
reward is present. Elevated firing rate in these neurons holds the memory of the
baited well.
The epicenter of this neural activity is Brodmanns area 46, sometimes referred to
as the dorsal convexity. (In monkeys, this area surrounds the principle sulcus
shown in the illustration, but the human brain does not have this sulcus.) Bilateral shown in the illustration, but the human brain does not have this sulcus.) Bilateral
lesions here degrade performance on delayed-response tasks. Conversely,
imaging studies with normal human subjects show it is activated during the same
kinds of tasks.
Depleting or blocking dopamine in the dorsolateral prefrontal cortex also interferes
with working memory. Dopaminergic input to prefrontal cortex originates in the
ventral tegmental area (VTA) of the midbrain, and is known as the meso-cortical
dopaminergic pathway dopaminergic pathway.
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Vision, touch, and kinesthesia are all relayed through the topographically- y g p g p y
organized corpus callosum:
Rostrum: orbitofrontal fibers
Genu: prefrontal fibers
Body: pericentral, parietal and temporal fibers
Splenium: occipital fibers from extrastriate regions
The anterior commissure interconnects the rostral temporal lobes, including
the amygdalas.
792
2-May-2013
Dr. Lise Eliot
Images projected to one side of the visual field will reach only the Images projected to one side of the visual field will reach only the
contralateral hemisphere in a split-brain patient.
Split-brain subject can only name the object if its projected to the right
visual field (left hemisphere). But he can match a left visual field
objecte.g., select a cube from a series of shapesusing his left (but
not his right) hand.
Similar results with tactual stimuli: A split-brain subject can name an
object only if feeling it with the right hand.
Clinical note: Can use similar tests to assess corpus callosum damage:
e.g., constructional ability (copying a drawing) is normally R hemisphere
dominant. A patient with a corpus callosum lesion can do it with his L
hand, but not R. Conversely, ideomotor praxis (comb your hair) is
controlled by the L hemisphere. A patient with a corpus callosum lesion
can do it with his R hand, but not L. Or, Tie your shoes with eyes y y
closed: tests for bimanual coordination, which is lost with a corpus
callosum lesion.
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796
3-May-2013, 11 am
Dr. Lise Eliot
Language and Aphasia Language and Aphasia Language and Aphasia Language and Aphasia
Lise Eliot PhD
1
Lise Eliot, PhD
3 May 2013
Reading: Purves Chapter 27
Outline Outline
1. What is language?
2. Neural basis & lateralization
3. Aphasia
4. Alexia and agraphia
2
5. Classic and updated neurological models
797
3-May-2013, 11 am
Dr. Lise Eliot
Language is unique to humans. It is defined as any system that uses abstract
symbols (words) to communicate thoughts between individuals. Of course, many
i l i t b lli i i t i ti ki d animals communicate--by calling, singing, stomping, snorting, squeaking, and
crying--but other species communication tends to be stereotyped, while human
language is infinitely creative. Even young children construct brand new
sentences all the time, combining words and phrases in ways they have never
heard before, but which will make sense to (almost) any other speaker. By
contrast, the few apes that have been taught sign language or other visual forms
of communication (using a symbol board) show only the most rudimentary
grammatical abilities and dont progress beyond the level of a young toddler grammatical abilities, and dont progress beyond the level of a young toddler.
Language is not synonymous with thinking. Although we often equate the two,
thinking can and often does take place without language. Animals, babies, and
people with aphasia (loss of language as a result of brain damage) are all capable
of reasoning, planning, remembering, imagining, and even communicating without
the use of language. (For example, even very young babies reason about object
properties, and are surprised to see physically impossible events.)
All human languages share a common structure, what the ground-breaking
linguist Noam Chomsky called Universal Grammar. Even sign language shares
many of the same grammatical properties as spoken languages, suggesting that
this structure is somehow innate to the human brain--as instinctive to our species
as walking or breathing.
798
3-May-2013, 11 am
Dr. Lise Eliot
There are just two basic components of language: words and rules. Words are
arbitrary. As Shakespeare wrote, A rose by any other name would smell as sweet.
They are simply an association between sound and meaning tacitly agreed upon by
everyone in the community of speakers They are memorized one by one everyone in the community of speakers. They are memorized, one by one,
beginning in the first year and continuing throughout life.
Grammar is the system of rules that specifies how we can combine these words.
There are just two basic tricks to grammar, each used to a different degree in all the
worlds languages:
Morphology:
rules for putting parts of words together to create new words with clear rules for putting parts of words together to create new words with clear
meaning
e.g., prenatal, postnatal; cry, crying, cried; emailing
Syntax:
rules for combining words into phrases and sentences
word order profoundly affects meaning
for example: Man bites dog vs. Dog bites man.
The English language depends more on syntax than morphology. But other
languages, notably German, depend heavily on morphology. (For example,
the word bildungsroman, which means a memoir describing ones
experience in travels and life that establishes the authors world view in early
life is virtually a sentence all its own).
Wh d ( b l ) l i t k l th h t lif ti l Whereas word (vocabulary) learning takes place throughout life, grammatical
learning is subject to a critical period.
799
3-May-2013, 11 am
Dr. Lise Eliot
SLI is a hereditary condition in which IQ, memory, and social skills are
unaffected, but reading and verbal skills are very poor. SLI is a subtype of
the general category of speech and language disorders, which affect up to
4% of the population, and includes autism. Such disorders are diagnosed
in children based on a significant delay in acquiring language milestones.
SLI runs in families and can be quite severe, affecting both the structure
and content of speech. Detailed analysis of one family with SLI identified a
dominant mutationin the FoxP2 geneassociated with the disorder and
subsequently found to affect verbal articulation and vocal learning. The
gene codes for a transcription factor and is expressed in corticostriatal
circuits involved in both human speech and songbird vocalization. In
songbirds, its expression is highest during developmental periods of highest
vocal learning. FoxP2 knockout mice show brain abnormalities and
reduced vocalizations as pups.
Conversely, Williams Syndrome is a form of mental retardation in which y, y
language is strikingly preserved...
800
3-May-2013, 11 am
Dr. Lise Eliot
Individuals with WS are not gifted with language--most are below average for
their age, and expressive language is about 2 years delayed in onset--but they are their age, and expressive language is about 2 years delayed in onset but they are
generally much better at language than individuals with Down syndrome (DS),
with comparable IQs. WS and DS subjects exhibit opposite cognitive profiles:
WS subjects perform well at verbal tasks (e.g. vocabulary, grammar, verbal
fluency--name as many animals as you can in 1 minute), but poorly at visual-
spatial skills (e.g., copying a drawing, detecting line orientation); conversely, DS
subjects are poor at language skills, but reasonably good at visual-spatial tasks.
WS subjects also perform close to normal at face recognition and are highly WS subjects also perform close to normal at face recognition and are highly
emotionally expressive; for instance, when telling a story, they use more affective
emphasis, interesting character voices, and exclamatory phrases (e.g.,
Gadzooks! or Lo and behold) than normal individuals of the same mental age.
Williams people are described as having endearing personalities--very loving,
trusting, and sensitive to others feelings. Many are also gifted at music. Indeed,
some researchers propose that WS is the polar opposite of autism, where
language social sensitivity and affective competence are impaired but spatial language, social sensitivity, and affective competence are impaired, but spatial
skills may be quite good. Recent research finds a correlation between reduced
size and connectivity of the anterior insula with the extent of personality difference
in individual WS subjects (http://www.pnas.org/content/109/14/E860.long).
The mutation involves the deletion of about 20 genes on Chromosome 7,
including the gene for elastin, which is now a marker for the disorder. It usually
occurs spontaneously, though individuals with WS have a 50% chance of passing
it t h ff i (It i d i t ) C d t t th d l ti i it on to each offspring. (It is dominant.) Can detect the deletion using
fluorescence in-situ hybridization (FISH) test for the elastin gene in white blood
cells. Two copies are normal; one copy indicates the disorder.
801
3-May-2013, 11 am
Dr. Lise Eliot
Language is located in the left hemisphere for the vast majority (97%) of the
population Even among left handed individuals some 75% have language localized population. Even among left-handed individuals, some 75% have language localized
to the left hemisphere. (Language dominance is determined with a Wada test--see
following.)
Especially strong evidence that the left hemisphere is genetically specialized for
language comes from the finding that the congenitally deaf also use their left
hemispheres to understand and produce sign language. This is surprising,
considering that it is the right hemisphere that participates more heavily in visual-
spatial processing, the modality in which sign language is perceived and produced.
So the fact that deaf individuals interpret and produce sign language with their left
hemispheres strongly supports the idea that language is innately programmed to
develop on this side of the brain.
The planum temporale, located in the posterior, superior temporal lobe, is larger
in the left hemisphere for most individuals. This asymmetry appears as early as 29
weeks gestation, suggesting it is genetically-determined. [Note the nearly two-fold weeks gestation, suggesting it is genetically determined. [Note the nearly two fold
difference in the left vs. right planum in infants in part B.]
Children who suffer damage to the left hemisphere can shift language to the right
hemisphere, but this plasticity declines steadily with age.
802
3-May-2013, 11 am
Dr. Lise Eliot
Used to locate the dominant hemisphere for language (e.g., before surgery).
A short-acting barbiturate or anesthetic is injected into one of the carotid
arteries (using a catheter, usually originating in the femoral artery) while the
seated patient raises both arms and begins counting.
When the injection is ipsilateral to language hemisphere, the contralateral
arm falls and counting is interrupted. (Arm position is monitored to insure
that the drug is reaching the brain.)
Injection into the carotid artery on the non dominant side has no effect on Injection into the carotid artery on the non-dominant side has no effect on
the counting task.
Also known as the sodium amytal test, for the barbiturate that is most
commonly used.
803
3-May-2013, 11 am
Dr. Lise Eliot
Right hemisphere communication Right hemisphere communication
While phonology, lexicon, and grammar are all
located in the left hemisphere the right hemisphere located in the left hemisphere, the right hemisphere
is important for prosody: the emotionality, melody,
stress, and intonation of language.
Damage to the right perisylvian region results in the
loss of these emotional elements of language,
known as aprosodia.
9
Right anterior lesions result in difficulty producing
appropriate intonation.
Right posterior lesions affect ones ability to
interpret the emotional tone in anothers speech.
Aphasia Aphasia
Loss of language due to dysfunction of the Dominant
cerebral hemisphere, and not a simple sensory or motor
deficit.
May affect speech, comprehension, or both.
Affects both spoken and written language.
NOT caused by impaired audition or articulation, global
confusion, arousal deficits, or psychiatric disorder.
=Distinct from dysarthria which is the inability to speak due to
10
Distinct from dysarthria, which is the inability to speak due to
weakness or incoordination of the tongue & face muscles
(although dysarthria may accompany aphasia).
=Must also rule out central or peripheral auditory deficits, where
reading and writing are preserved.
=Sometimes confused with schizophrenia, where speech can be
disordered and nonsensical.
804
3-May-2013, 11 am
Dr. Lise Eliot
In 1861 Paul Broca found speech controlled by specific area of frontal lobe.
Brocas aphasics are not able to distinguish sentences like Man bites dog and
Dog bites man. The frontal lobe is important for temporal sequencing, which is
what syntax requires.
Heres a case described by Howard Gardner (The Shattered Mind: The Person
after Brain Damage, 1974, pp. 60-61.)
'I am a sig. . .no. . .man. . .uh, well,. . .again.' These words were emitted
slowly, and with great effort. The sounds were not clearly articulated; each
syllable as uttered harshly, explosively, in a throaty voice. With practice, it
was possible to understand him, but at first I encountered considerable
difficulty in this 'Let me help you ' I interjected 'You were a signal ' 'A sig- difficulty in this. Let me help you, I interjected. You were a signal. . . A sig
nal man. . .right,' Ford completed my phrase triumphantly. 'Were you in the
Coast Guard?' 'No, er, yes, yes, . . .ship. . .Massachu. . .chusetts. .
.Coastguard . . .years.' He raised his hands twice, indicating the number
nineteen. 'Oh, you were in the Coast Guard for nineteen years.' 'Oh. . .boy. .
.right. . .right,' he replied. 'Why are you in the hospital, Mr. Ford?' Ford
looked at me strangely, as if to say, Isn't it patently obvious? He pointed to
his paralyzed arm and said, 'Arm no good,' then to his mouth and said, p y , g , ,
'Speech. . .can't say. . .talk, you see.'
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806
3-May-2013, 11 am
Dr. Lise Eliot
Phonemic paraphasias: substitution of erroneous word or
phoneme for intended word, (curl for girl; pish for fish)
Verbal or semantic paraphasias: difficulty selecting words to
accurately convey intended meaning (mistakes such as headman
for president; turner for key; ink for pen)
Boy, I'm sweating, I'm awful nervous, you know, once in a while I get
caught up, I can't get caught up, I can't mention the tarripoi, a month ago,
quite a little, I've done a lot well, I impose a lot, while, on the other hand,
you know what I mean, I have to run around, look it over, trebbin and all
that sort of stuff. Oh sure, go ahead, any old think you want. If I could I
would. Oh, I'm taking the word the wrong way to say, all of the barbers
here whenever they stop you it's going around and around, if you know
what I mean, that is tying and tying for repucer, repuceration, well, we were
t i th b t th t ld hil th ti it ith th b d trying the best that we could while another time it was with the beds over
there the same thing. . .
-- Howard Gardner, Ibid., p. 68
807
3-May-2013, 11 am
Dr. Lise Eliot
Also referred to as the Wernicke-Geshwind model, because it was elaborated
by Norman Geschwind in the 1960s, the classic neurological model of language
proposes the following structure/function relationships:
Speech is perceived by the auditory cortex and then shipped to Wernickes
area. Reading (or Braille) are also transferred to Wernickes area, except
the initial input comes from visual (or somatosensory) areas.
Wernickes area imparts meaning to words (spoken, written, or braille), or
composes words to express thoughts.
The arcuate fasciculus transmits ones mental composition from
Wernickes to Brocas areas.
Brocas area is a specialized motor planning center, which converts the
mental composition into an articulatory plan. It also controls grammar,
which basically involves sequencing words in the proper order.
Brocas plan is submitted to primary motor areas controlling the tongue,
lips, palate, larynx, and pharynx.
Writing (or typing) works the same way, except the plan is submitted to
motor areas controlling the hand and fingers.
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811
3-May-2013, 11 am
Dr. Lise Eliot
Recent functional imaging, neurophysiological, and lesion data provide
evidence for a more complex and distributed language processing circuit.
Important features of this revisionist model include:
A core implementation system, consisting of Brocas area (red),
Wernickes area (blue),the arcuate fasciculus, and portions of the
insular cortex and basal ganglia (not shown). This circuit analyzes
auditory signals and controls phonemic and grammatical construction
and articulation. (Fronto-striatal-thalamic circuits are involved in all and articulation. (Fronto striatal thalamic circuits are involved in all
complex behaviors.) The basic architecture underlying the mechanics
of language; permits repetition but not sufficient for fully meaningful
communication.
Mediational and conceptual systems that surround the core
implementation system, acting as a broker between other forms of
perception and thought and the motivation to express them verbally.
In sum, any sizeable lesion to the dominant hemisphere will have some
impact on language. The right hemisphere is also normally active during
language processing, and may (at least with large left hemisphere lesions)
aid aphasia recovery.
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6
823
7-May-2013, 11 am
Dr. Michael Welch
CPP= MAP ICP; CPP is mean arterial pressure (MAP) minus venous
pressure; Venous pressure is app. equal to intracranial pressure (ICP).
MAP= (SBP+2DBP)/3. Therefore:
CPP= (SBP+2DBP)/3 ICP
Venous pressure can be measured by putting a measuring transducer in a
central vein like the jugular vein. For more direct measurement of the
intracranial pressure, a transducer device can be placed on the dura or a
catheter is introduced into the lateral ventricles
CVR depends largely on blood vessel diameter
824
7-May-2013, 11 am
Dr. Michael Welch
Note that as perfusion pressure increases (mean arterial pressure 50 to 160) CBF
remains constant i.e. effective autoregulation. Belolw 50 mmHg flow falls near-
linearly with perfusion pressure and arterial diameter collapses accordingly. Above
160 mmHg flow increases (and can cause edema and hemorrhages) as the arterial
diameter balloons.
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7-May-2013, 11 am
Dr. Michael Welch
Cerebrovascular disease or stroke refers to the sudden onset of a neurological
deficit that is caused by either hemorrhage (hemorrhagic stroke) or cessation of deficit that is caused by either hemorrhage (hemorrhagic stroke) or cessation of
blood flow to a brain region (ischemic stroke). Ischemia is defined as a reduction in
the flow of oxygenated blood to an organ (e.g., the brain) due to obstruction of the
blood supply. Finally, infarction or infarct is permanent damage to a tissue or organ
caused by interruption of its blood supply.
Cerebrovascular events can be permanent as in ischemic stroke or transient
transient ischemic attacks. Worldwide, stroke is the second leading cause of death,
accounting for yearly 5 million stroke-deaths. Furthermore, one out of three strokes
is either fatal or severely disabling, and 1/6 patients with an initial stroke experience
S ( S) 0 000 a recurrent event in one year. In the United States (US), over 750,000 people
develop a stroke yearly, which translates into one stroke every 45 seconds. African-
Americans are more prone to strokes than Caucasians, and in recent years women
are as vulnerable as men are (Thom et al., Circulation 2006). Also, stroke remains
the number one cause of permanent disability and is the third leading cause of
death, accounting for approximately 160,000 yearly deaths. There has been a
steady decline in the stroke mortality rates (i.e., stroke deaths per 100,000
populations) in the US until the early 1990s. (Wolf PA, et al. Source: Wolf PA, et al.
In: Barnett HJM, et al (eds). Stroke. Pathophysiology, Diagnosis and Management. ( ) p y gy g g
New York, Churchill-Livingstone, 1992:3), but a consistent increase has been
observed since 1992. To date, the estimated annual total cost of stroke as an
illness is approximately 58 billion USD (Thom et al., Circulation 2006).
Eighty-five percent of all strokes are of the ischemic type and the remaining 15%
are hemorrhagic. Ischemic strokes are classified etiologically (i.e. by cause) and by
cerebral arterial territorial involvement.
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831
7-May-2013, 11 am
Dr. Michael Welch
Diagrammatic representation (left) of the territorial supply of ACA. Note the
small perpendicular arteries (arrows) that take off from the first and second
segments of ACA (medial lenticulostriate arteries) and MCA (lateral
lenticulostriate arteries) and dip into the deep substance of the brain.
Interruption of blood flow in such territories causes lacunes, which are small
deep ischemic strokes (arrow head on MRI image).
832
7-May-2013, 11 am
Dr. Michael Welch
T1 weighted MRI study showing a large area of infarction the middle cerebral
artery territory. Given the history of a recent heart attack and the total MCA
distribution stroke, the most likely cause is an embolus from the heart
833
7-May-2013, 11 am
Dr. Michael Welch
Posterior inferior cerebellar artery (PICA) territory stroke is the most
common large vessel infarct in the posterior circulation. AICA infract is
associated with dizziness and hearing loss because the internal auditory
artery is a branch of AICA. The basilar artery branches are: short
circumferential (short paramedian), intermediate circumferential, and long
circumferential (SCA, AICA)
834
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9
836
7-May-2013, 11 am
Dr. Michael Welch
Lacunes are small deep ischemic strokes in the territory of a perforating
cerebral artery
Cardiogenic strokes are caused by emboli that come from the heart
Others include conditions like substance abuse, systemic diseases, etc.
837
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7-May-2013, 11 am
Dr. Michael Welch
PMN leukocytes become activated and are recruited to the site of ischemic injury,
where they interact with platelets and endothelium. Upregulated P-selectin mediates
rolling and upregulated E-selectin and ICAM-1 mediates adherence of leukocytes
which form a complex with platelets and fibrin. These complexes might embolize
(white emboli) or in combination with red cells as red emboli.
839
7-May-2013, 11 am
Dr. Michael Welch
White cells are adherent to the endothelium (KCL) as the first phase of
inflammation. The cells are labeled for reactive oxygen species. The adherence can
be blocked by anti-oxidants (KCL+Lipoic Acid). The cartoon documants the stages
of white cell migration to the wall of the vessel beginning the process of
inflammation and eventually forming foam cells with LDL-Cholesterol in the early
stages of aterosclerotic plaque formation.
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7-May-2013, 11 am
Dr. Michael Welch
The left frame shows a perfusion image taken 7 hours after an acute MCA
occlusion. Note the complete MCA territory is involved. The ADC map (diffusion
imaging) reveals a small infarct in the frontal region but as time progresses brain
tissue in the total MCA territory is incorporated into the lesion. This illustrates that
there is considerable potentially salvageable tissue in the penumbra for a time after
the acute occlusion.
843
844
H h l H h l H h l H h l Hypothalamus Hypothalamus Hypothalamus Hypothalamus
Lise Eliot, PhD
May 8, 2013
Related Reading: Purves, pp. 456-58; Blumenfeld, pp. 792-800
1
Lecture outline Lecture outline Lecture outline Lecture outline
1. Hypothalamic functions
2. Anatomyy
3. Nuclei locations and functions
4. Hypothalamo-hypophyseal axis yp yp p y
5. Major pituitary hormones
6. Afferents 6 e e s
7. Efferents
8. Feeding & drinking 8. Feeding & drinking
9. Temperature
10 Sleep
2
10. Sleep
Hypothalamic Functions Hypothalamic Functions Hypothalamic Functions Hypothalamic Functions
The hypothalamus has four major roles, which you
can remember by the convenient mnemonic, HEAL
(see Blumenfeld, p. 792):
Homeostasis: orchestrates neurohormonal control over
hunger, thirst, temperature, stress, sleep, reproduction &
other behaviors
Endocrine: exerts master control, via the pituitary
Autonomic: central controller of both the sympathetic and
th ti t parasympathetic nervous systems
Limbic: an integral part of the emotion circuitry of the brain.
3
Homeostasis Homeostasis Homeostasis Homeostasis
4
Location Location Location Location
3D reconstruction of
hypothalamus hypothalamus
(in yellow).
The many nuclei of the The many nuclei of the
hypothalamus line the
walls of the anterior end
of the third ventricle.
5
Mid Mid--sagittal view sagittal view gg
anterior
commissure
hypothalamic
sulcus
commissure
lamina terminalis
mammillary
body
6
Haines 2-30: The hypothalamus sits in the lateral walls of the inferior third
ventricle, extending from the lamina terminalis to the hypothalamic sulcus.
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8-May-2013, 10 am
Dr. Lise Eliot
The hypothalamus can be divided into three (or sometimes, four) rostral-caudal zones
containing discrete nuclei with different functions The most anterior zone is subdivided containing discrete nuclei with different functions. The most anterior zone is subdivided
into the "preoptic region, which spills rostrally over the optic chiasm. Behind this sits the
"supraoptic region, which lies directly above the chiasm. (Unfortunately, the term
"anterior region is applied to each of these zones differently by Blumenfeld and Purves.
For the purpose of this course, we will consider both as subdivisions of the "anterior
hypothalamus.) The second zone, occupying most of the middle of the hypothalamus is
the "tuberal region, and the third is simply the "posterior hypothalamus.
The hypothalamus also contains different nuclei along the midline versus lateral zones:
s
The hypothalamus also contains different nuclei along the midline versus lateral zones:
Region Medial Area Lateral Area__________
1a. Preoptic Medial preoptic nucleus Lateral preoptic nucleus
(VLPO induces sleep)
1b Supraoptic Suprachiasmatic nucleus Supraoptic nucleus
Anterior nucleus Lateral nucleus
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Periventricular nucleus
2. Tuberal Dorsomedial nucleus Lateral nucleus
Ventromedial nucleus Tuberomammillary n. (TMN)
Arcuate nucleus (histamine arousal projection)
Periventricular nucleus
" A
3. Posterior Mammillary body Lateral nucleus
Posterior nucleus
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Dr. Lise Eliot
The most rostral level of the hypothalamus lies above and anterior to the optic
hi A th l d k i th t i i chiasm. Another landmark is the anterior commissure.
Cells of the lateral hypothalamus are interspersed with the longitudinally
running medial forebrain bundle (MFB), represented in these figures by the
black stippling. The MFB is a bidirectional pathway projecting from the
midbrain tegmentum, through the hypothalamus, to the forebrain septal area.
The medial preoptic hypothalamus (MPOA) plays a key role in temperature
regulation and in reproductive physiology and behavior ln the latter role it regulation, and in reproductive physiology and behavior. ln the latter role, it
controls the release of GnRH, contains a high density of estrogen receptors,
and is site of the best-described sexual dimorphism in the brain: a tiny
subnucleus, lNAH-3 (for "interstitial nucleus of the anterior hypothalamus) is
twice as large in men than in women. The analogous nucleus in rats (SDN-
POA) grows larger under the influence of prenatal testosterone (see Cortex ll
lecture).
Lateral preoptic and medial preoptic nuclei are rostral continuations of the
lateral and medial hypothalamic areas, respectively.
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Dr. Lise Eliot
The next level is the "supraoptic or "anterior level of the hypothalamus. (Note, however, that the
preoptic zone is also sometimes loosely described as residing in the "anterior hypothalamus ) preoptic zone is also sometimes loosely described as residing in the anterior hypothalamus. )
The nuclei and functions of the supraoptic hypothalamus include:
The suprachiasmatic nucleus (SCN) is a tiny nucleus, containing less than 10,000 neurons,
but acts as the body's "master clock, controlling circadian rhythms. lts free-running period
is about 25 hours, but it is entrained by light, locking it to actual day length. Visual input
comes directly from a small number of retinal ganglion cells that project through the optic
nerves and chiasm, straight into the SCN. (This makes it easy to remember, since the
SCN obviously sits immediately above the optic chiasm.) SCN neurons also express an y y p ) p
abundance of melatonin receptors; the nighttime rise in melatonin secretion by the pineal
gland helps to entrain the circadian clock. Some biological rhythms that are under SCN
control include daily fluctuations in temperature, blood pressure, metabolism, cortisol (and
most other hormone) secretion, and of course, arousal.
Large neurosecretory ("magnocellular) neurons in the supraoptic and the paraventricular
nuclei contain the 9-amino-acid hormones, oxytocin or vasopressin (antidiuretic hormone
[ADH]). These cells project their axons through the infundibulum into the posterior pituitary,
h th h l d l di id l d l th th where these hormones are released. lndividual neurons produce only one or the other
hormone, though both hormones are produced in both nuclei.
Vasopression functions to increase the reabsorption of water in the kidney, thereby
decreasing urine production.
Oxytocin triggers contraction of uterine and mammary smooth muscle, and is
important in parturition, milk ejection, and affiliative emotions.
The paraventricular nucleus is also a source of descending autonomic fibers The paraventricular nucleus is also a source of descending autonomic fibers.
The periventricular nucleus lines the walls of the third ventricle and produces releasing
factors that circulate in the portal system to control the anterior pituitary.
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Dr. Lise Eliot
The middle, or tuberal region of the hypothalamus lies directly above the , g yp y
pituitary and infundibulum. At this level, the medial zone becomes
subdivided into the dorsomedial and ventromedial nuclei, while the lateral
nucleus is continuous with both rostral and caudal levels. The dorsomedial
and ventromedial nuclei participate in many different hypothalamic functions
and receive input from limbic and visceral sensory structures (e.g., solitary
nucleus). Also present at this level is the arcuate nucleus, which sits in the
floor of the infundibular recess. Like the periventricular nucleus, the arcuate
nucleus releases factors into the hypophyseal portal system that promote or
inhibit the release of anterior pituitary hormones.
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8-May-2013, 10 am
Dr. Lise Eliot
The median eminence is one of the 7 CVOs (circumventricular organs) ( g )
that has a leaky vasculature. Axons from neurons in the arcuate,
periventricular, paraventricular and medial preoptic nuclei release their
various releasing and inhibitory factors here, which then enter the upper
capillary bed of the pituitary portal system and flow down to the anterior
pituitary.
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Dr. Lise Eliot
The mammillary bodies are the most distinguishing feature of the posterior The mammillary bodies are the most distinguishing feature of the posterior
hypothalamus. These nuclei do not interface with the pituitary and form
virtually no connections to other hypothalamic nuclei, but function as part of
the limbic system, receiving input from the hippocampus and sending output
to the anterior nucleus of the thalamus. Damage to the mammillary bodies
impairs memory in both human and non-human primates.
The lateral nucleus is present at all rostrocadual levels, including the
t i h th l lt f ti th t l t i f th idb i posterior hypothalamus. lt functions as the rostral extension of the midbrain
reticular formation, and is involved in arousal, attention, feeding, and
reproductive behaviors.
The posterior hypothalamus participates in heat conservation, by promoting
shivering and vasoconstriction. However, lesions to the posterior
hypothalamus eliminate all temperature regulation (a condition known as
poikilothermia) because it also contains fibers of passage from the anterior p ) p g
hypothalamus (which controls heat dissipation).
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Dr. Lise Eliot
The posterior pituitary, or neurohypophysis, is a neural structure, derived y y y
from an evagination of the floor of the embryonic ventricular system. lt does
not contain glandular cells, but the terminals of magnocellular neurons from
the paraventricular and supraoptic nuclei. These terminals secrete oxytocin
and vasopressin into the capillary bed of the posterior pituitary.
The anterior pituitary, or adenohypophysis, is derived from pharyngeal
ectoderm (Rathke's pouch) and contains glandular cells that secrete a variety
of hormones into the circulation lts secretion is controlled by small of hormones into the circulation. lts secretion is controlled by small
(parvocellular) hypothalamic neurons in several nuclei, including the arcuate,
medial preoptic, periventricular nuclei, and parvocellular portions of the
paraventricular nucleus. These neurons project to the median eminence,
where their releasing or inhibitory factors are secreted into the hypophyseal
portal system of fenestrated capillaries. These factors (all of which are
peptides, except for dopamine) diffuse out of the capillaries, and act on
secretory cells in the anterior pituitary to increase or decrease their release of secretory cells in the anterior pituitary to increase or decrease their release of
various hormones.
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Dr. Lise Eliot
Hypothalamic releasing & Hypothalamic releasing &
inhibiting factors inhibiting factors
(parvocellular secretions)
Somatostatin
Somatostatin
18
Blumenfeld
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Gonadotropin-
releasing hormone
(GnRH)
Pituitary hormones and their primary actions Pituitary hormones and their primary actions
19 Blumenfeld, 17.6
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Dr. Lise Eliot
Cortisol levels fluctuate with circadian rhythm: levels rise during
sleep, peak at waking, and then gradually decline through the day.
CRH is produced in the paraventricular nucleus.
Cortisol feedback inhibition of CRH release is impaired in clinical
depression. Hippocampal pyramidal neurons have high levels of
glucocorticoid receptors and project to the PVN to regulate CRH
production. In depression, the hippocampus is atrophied and this
negative feedback is impaired, leading to surplus CRH, ACTH, and
cortisol secretion. In addition, CRH neurons send branches to the
midbrain, where they inhibit dopamine- and serotonin-releasing
neurons, so excess CRH in depression may reduce levels of these
transmitters.
Dexamethasone suppression test thats used to test for Dexamethasone suppression test that s used to test for
hypercorticosolemia (Cushing disease) is also sometimes used in
diagnosing depression.
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Dr. Lise Eliot
Sensory input reaches the hypothalamus from various sites in the
brainstem, including the periaqueductal gray, the reticular formation, and
the solitary nucleus. Such input ascends in two pathways, the dorsal
longitudinal fasciculus, which travels, as its name implies, on the dorsal
side of the brainstem, close to the ventral wall of the 4
th
ventricle. Another
pathway providing ascending input to the hypothalamus is the medial
forebrain bundle (MFB), whose fibers continue rostrally within the lateral
nucleus of the hypothalamus itself. This pathway provides modulatory
i t f th i i i ll i th b i t t input from the various monoaminergic cell groups in the brainstem to
virtually all of the forebrain.
Another source of sensory input is the optic nerve, which contains a
small, but functionally important set of retinal ganglion cell axons that
project to the SCN.
The hypothalamus also receives wide input from various limbic structures.
The fornix conveys information from the hippocampus The stria The fornix conveys information from the hippocampus. The stria
terminalis travels near the floor of the lateral ventricle, nestled next to the
caudate, sending bidirectional information between the hypothalamus and
the amygdala. Another, shorter pathway connecting the amygdala and
the hypothalamus is the ventral amygdalofugal pathway. Other limbic
structures that project into the hypothalamus include the septal nuclei and
nearby ventral striatum, the orbitofrontal cortex, and other cortical areas.
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Dr. Lise Eliot
Hypothalamic output in many ways reciprocates its input. The fornix carries
h th l i ff t b k t th hi Th DLF MFB d hypothalamic efferents back to the hippocampus. The DLF, MFB and
mammillotegmental tracts carry output to various brainstem structures involved in
autonomic function. Both amygdalar pathways, the stria terminalis and the ventral
amygdalofugal pathway, carry bidirectional information between the hypothalamus
and the amygdala. Finally, the same cortical and medial forebrain areas, including
the septal nuclei and orbitofrontal cortex, receive hypothalamic output.
Of special clinical significance are descending projections (originating mainly in the
paraventricular nucleus) that influence the autonomic nervous system paraventricular nucleus) that influence the autonomic nervous system.
Hypothalamic efferents project to preganglionic sympathetic neurons in the
intermediolateral cell column of the thoracolumbar spinal cord that control various
functions, including pupillary dilation. Damage to this pathway anywhere along the
lateral brainstem or spinal cord above T2 causes a constricted, barely-responsive
pupil on the ipsilateral side. This miosis is one sign of Horners syndrome, which
also involves ptosis and loss of sweating on the affected side. (See Dr. Arianos
Visceral motor system lecture.)
Other hypothalamic output travels through the mammillothalamic tract. As its
name suggests, this pathway connects the mammillary bodies to the thalamus,
specifically, the anterior nucleus of the thalamus. The function of this pathway is
not well understood, although it is part of Papez circuit, or the limbic loop that
interconnects the cingulate gyrus, hippocampus, and hypothalamus and is thought
to participate in memory storage. Lesion of the mammillary bodies in monkeys
produces a memory impairment.
Last but not least are the two routes of hypothalmo pituitary output: direct neural Last, but not least, are the two routes of hypothalmo-pituitary output: direct neural
connections to the neurohypophysis, where hypothalamic neurons release oxytocin
and vasopression; and hormonal secretion into the hypophyseal portal system,
which carries hypothalamic releasing and inhibiting factors to the adenohypophysis
where they modulate the release of various pituitary hormones.
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Dr. Lise Eliot
Left: a special dissection revealing the lateral descending course of the p g g
fornix as it pierces the hypothalamus and eventually terminates in the right
mammillary body. The fornix divides the hypothalamus into medial and
lateral zones. lt provides bidirectional input between the hypothalamus and
the hippocampus, producing changes in endocrine and autonomic nervous
system activity as dictated by internal drives and emotional experience.
Also visible is the mammillothalamic tract, which connects the prominent
mammillary bodies to the anterior nucleus of the thalamus.
Right: diagram of same tracts, depicted in relation to major hypothalamic
nuclei and the pituitary gland, shown in its bony encasement.
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8-May-2013, 10 am
Dr. Lise Eliot
The lateral hypothalamus is an important feeding center in the brain;
l i t thi l l i b d i ht S f it lesions to this nucleus cause loss in body weight. Some of its neurons
secrete orexin, which acts elsewhere in the brain to increase feeding. The
lateral nucleus runs through all rostro-caudal levels of the hypothalamus,
and is continuous with the midbrain tegmentum.
The medial hypothalamus is an important satiety center; lesions to the
ventromedial nucleus result in overeating and obesity.
L i i ki d d b di i I bi d Ob i Leptin is a cytokine produced by adipose tissue. It binds to Ob receptors in
the arcuate nucleus, signaling the hypothalamus to orchestrate a series of
behavioral, metabolic, and neuroendocrine adaptations:
~ During nutrient abundance, leptin secretion is increased, leading to
decreased appetite and increased caloric disposal.
~ When nutrients are insufficient, leptin secretion declines, resulting in
increased appetite energy conservation behavioral arousal and increased appetite, energy conservation, behavioral arousal, and
metabolic adaptation.
Gut peptides, such as ghrelin and insulin also importantly influence appetite.
Ghrelin is an adipogenic hormone secreted by the empty stomach that
promotes appetite. Insulin is secreted during the mental anticipation of
meals and continues during food digestion and absorption. These
hormones, along with IGF1 (insulin-like growth factor 1) and GLP1
(glucagon like peptide 1) enter the brain and influence appetite and energy (glucagon-like peptide 1) enter the brain and influence appetite and energy
utilization through action on the hypothalamus and other limbic structures.
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The tuberomammillary nucleus , located in the posterior y
hypothalamus, contains the brain's only histaminergic neurons, which
project widely to the reticular formation as well as to the thalamus and
cortex. (See Dr. Wolf's "Functional Properties lV lecture.) These
neurons are active during the awake state, quiescent during sleep, and
form part of the ascending arousal system. (Anti-histamines cause
drowsiness.)
The lateral posterior hypothalamus produces orexins which are active The lateral posterior hypothalamus produces orexins, which are active
in the waking state. Orexin-producing neurons project widely to the
thalamus, the basal forebrain, the tuberomammillary nucleus, as well
as to cholinergic and adrenergic neurons in the rostral pontine reticular
formation.
The ventrolateral preoptic nucleus (VLPO) includes a nucleus that
produces GABA and is active during non-REM sleep. These neurons
i hibit b th t b ill d h li i i th inhibit both tuberomammillary neurons and cholinergic neurons in the
reticular formation.
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874
Dr. Marr
9-May-2013
The Limbic System
Required reading: Chapter 29, pgs. 647-667 of Purves
May 9
th
, 2013 [10am]
- Le lobe limbique Paul Broca, 1850
-Brain structures related to emotion which form a rim or
limbus around the corpus callosum and diencephalon.
- Involved in emotions, memory and more.
1
Dr. Marr
9-May-2013
Outline
Emotions
Location of major structures of the limbic system Location of major structures of the limbic system.
general associations.
Amygdala:
components, afferent / efferent connections.
functions.
fear conditioning.
Hi l F i Hippocampal Formation:
components, afferent / efferent connections.
functions.
Cortical regions of the limbic system.
Non-motor basal ganglia limbic loops.
Mesolimbic DA system Mesolimbic DA system.
Addiction.
Pathology affecting the limbic system.
2
Summary of major limbic associated pathways.
875
Note: Autonomic functions include heart rate, blood flow, piloerection, sweating, and
gastrointestinal motility. All associated with emotional states.
Box 29A: Evidence of separate systems for control of facial expressions.
- Patients with unilateral damage to pathways from motor cortex display facial motor
paresis.
can not voluntarily smile on the damaged side of the face but responds - can not voluntarily smile on the damaged side of the face but responds
normal (symmetrically) when expressing genuine amusement.
- Patients with unilateral damage to pathways from limbic / limbic associated areas
(descending projections from medial forebrain and hypothalamus) display emotional
motor paresis.
- can voluntarily smile symmetrically but can not raise the side of the mouth
controlled by the damaged pathway when expressing genuine emotion.
3
876
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More on LTP to come from Dr. Eliot (Learning and Memory, 5/9/13, 11am).
- The example shown in Fig. 8.8 is not the classical experiment where
strong induction from a CA3 neuron was used to induce depolarization in a CA1
neuron. In this example a weak stimulus from CA3 is paired with forced
depolarization of the CA1 neuron. As seen in Fig.8.8 this results in a sustained
strengthening of the connection between the weakly stimulated CA3 neuron and the
previously depolarized CA1 neuron such that subsequent stimulation from CA3
lt i h d EPSP f CA1 results in enhanced EPSP from CA1.
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however, this type of LTP is also found in the amygdala and is thought to mimic the
plasticity that occurs during fear conditioning.
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Water maze:
-Place rodent in water and allow time to search. If the hidden platform is not found,
place rodent on platform.
- Repeat this every day for several days. Over time the rodent will learn where the
platform is by using spatial cues in its environment. Therefore, the path length and
time to platform (latency) will drop.
- Hippocampal lesions degrade performance in this test Hippocampal lesions degrade performance in this test.
17
881
Note: The effects of lesions depend on the precise location of the lesion. Lesions
can produce a wide range of responses that are often contradictory. Probably due to
complexity of the frontal lobe, and the disruption of multiple subregions by lesions.
For example Phineas Gage suffered from emotional instability, however, frontal
lobotomies were once routinely performed to treat violent psychotic behavior.
18
882
Note that the major differences between the limbic loop and the motor loop is the
source of cortical inputs, the subregions of the striatum / pallidum receiving and
processing these inputs, the source of dopimanergic projections, and the thalamic
region involved (see Fig. 29.10 Pt.1 and BOX 18D).
Parallel loops:
-Motor circuits: voluntary movement initiation and termination Motor circuits: voluntary movement initiation and termination.
-Limbic circuits: alternate emotional motor system (autonomic) initiation and
termination.
- somatic and visceral motor expression.
19
883
In the VTA under basal conditions dopamine levels are low and released in small
bursts (tonic). However, when activated by reward dopamine is highly activated
(burst). These dopaminergic VTA projections target medium spiny neurons (MSN) in
the nucleus accumbens (NAc). This makes the MSN more responsive to coincident
excitatory cortical inputs. The end result of this is stimulation of the limbic forebrain
via thalamic inputs (Fig. 29.10 A).
20
884
VTA activity during associative learning
This system is subject to experience dependent plasticity or classical conditioning.
This is part of the normal function of the reward system.
Figure 29.12:
A) The VTA is activated when reward is presented to the monkey.
B) If the reward is paired with a cue and the association is learned, the VTA is now
activated by the cue and not the actual reward activated by the cue and not the actual reward.
C) If the reward is withheld there is a depression of VTA activity during the time the
reward should have been obtained.
This VTA circuit (see Fig. 29.10), leads to the promotion of behaviors directed at
obtaining rewards.
21
885
Addiction
Normal associative learning mediated by the limbic loop can be co-opted by chronic
use of drugs of abuse.
A common theme is that drugs of abuse alter neuromodulation in dopaminergic
circuits associated with associative learning and reinforcement (Fig. 29.11A).
In the addicted brain DA is altered and molecular changes occur that are
reminiscent of forms of learning.
Addicted individuals show reduced neural responses (NAc, VTA) to natural (less
potent) stimuli and elevated responses to drug associated stimuli.
Changes are persistent and irreversible (once an addict always an addict).
22
886
Dr. Marr
9-May-2013
Pathology Affecting the Limbic System
Seizure: An episode of abnormally synchronized and high-frequency firing of
Pathology Affecting the Limbic System
neurons in the brain that result in abnormal behavior or experience of the individual.
Blumenfeld pg. 790.
Seizure periods can be separated into ictal (during), postictal (immediately after),
and interictal (between) periods.
M di l t l l b tibl t i ti it T i ti i it Medial temporal lobes are susceptible to seizure activity. Tri-synaptic circuit.
Alzheimers disease: progressive neurodegenerative disorder effecting the elderly.
Neuronal pathology seen throughout the limbic system and cerebral cortex Neuronal pathology seen throughout the limbic system and cerebral cortex.
Lecture 5/10/12 (11am)
Korsakoffs Syndrome: Amnesia observed in chronic alcoholics Korsakoff s Syndrome: Amnesia observed in chronic alcoholics.
Vitamin B
1
deficiency. Degeneration in mammillary bodies and medial thalamus.
23
Dr. Marr
9-May-2013
Hi l F ti
Pathway
Structure
Structure
Hypothalamus Septal nuclei
Fornix
Major Limbic Pathways
Hippocampal Formation
Mammillary nucleus
Hypothalamus, Septal nuclei
Anterior thalamic nucleus
Fornix
Mammillothalamic tract
( f )
(part of Papez circuit)
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Cingulate gyrus
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Hippocampal Formation
Contralateral amygdala
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Amygdala
Anterior temporal cortex
Amygdala
Contralateral amygdala
Contralateral anterior temporal cort.
Hypothalamus
Anterior commissure
Stria terminalis
yg
Amygdala
yp
Septal Nuclei
Hypothalamus
Ventral amygdalofugal pathway
Amygdala, Hypothalamus,
Forebrain structures
Medial forebrain bundle
Brainstem nuclei
Entorhinal cortex
Medial temporal cortex,
A d l
Dentate gyrus granule cell layer
Perforant Pathway
Uncinate fasciculus
Orbitofrontal cortex
24
Amygdala
Orbitofrontal cortex
Note: Not an all inclusive list of all the targets of these pathways.Remember the fornix projects primarily to mammillary bodies.
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9-May-2013, 11am
Dr. Lise Eliot
Considerable research over the past 40 years has proven that memories are stored as
changes in synaptic strength throughout the brain.
In associative memory, two pathways converge in the nervous system, with the training
pathway influencing the strength of synapses in a second, stimulus or response pathway.
One of the best-studied examples is classical conditioning of the corneal reflex. In rabbits,
rodents, and humans, repeated pairings of a conditioned stimulus (CS) with an
unconditioned stimulus (US) induces a conditioned response (CR; eyeblink) to the CS alone. ( ) p ( ; y )
In this case, the animal heard the same, 1000 Hz tone as the CS, immediately preceding an
air puff to the eye (the US or training pathway). By itself, the air puff triggers reflexive
blinking. (Recall the circuit for the corneal reflex, involving CNs V and VII.) After a few
hundred CS-US pairings, however, the tone alone begins to trigger an eyeblink.
Connections between auditory and eyeblink pathways, while initially weak, have become
strengthened through repeated, simultaneous activation, such that auditory (VIIIth nerve)
input is now capable of triggering an eyeblink.
Th h i f thi ki d f i ti l i i th ht t i l H bbi The mechanism of this kind of associative learning is thought to involve Hebbian
strengthening of a weak auditory input (T stands for tone) to the blink reflex circuit.
Convergent activation of the CS and US pathways leads to simultaneous depolarization of
both the pre- and postsynaptic components of synapse T, triggering an NMDA-dependent
LTP or, long-term strengthening of this formerly weak synapse.
This diagram is highly simplified, and used to illustrate the general principle of an associative
learning mechanism. The actual locus of eyeblink plasticity is known to lie in the cerebellum,
and involves a somewhat different cellular mechanism and involves a somewhat different cellular mechanism.
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891
9-May-2013, 11am
Dr. Lise Eliot
Short (working) vs. long-term memory:
Capacity:
Short-term memory is limited in capacity (7-9 digits; where digit span is
defined as the number of items, numbers or words a person can
remember in a very brief stretch of time).
Long-term memory capacity is essentially unlimited.
Anatomical loci:
All parts of the nervous system participate in storing information, however, All parts of the nervous system participate in storing information, however,
with respect to conscious memories:
Attentional systems in the parietal and prefrontal lobes maintain
immediate and short-term memories, with the dorsolateral prefrontal
cortex, in particular, known to store working memories.
The medial temporal lobe is required for consolidation: the storage
or locking in of conscious, long-term memories.
Recent memories are stored in the neocortex but still depend on Recent memories are stored in the neocortex, but still depend on
medial temporal lobe structures.
Remote memories remain in the neocortex, but no longer depend on
the medial temporal lobe for their maintenance.
Storage mechanisms:
Short-term memories involve short-term plasticity of excitablility and
ti ffi ( d h l d l ti ) synaptic efficacy (e.g., second messengers, channel modulation).
Long-term memories involve changes in gene expression, protein
synthesis, and the physical structure of neurons (e.g., gain or loss of
presynaptic boutons, spines, dendritic branchesthe late changes Dr.
Wolf referred to in her lecture on synaptic plasticity).
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895
9-May-2013, 11am
Dr. Lise Eliot
At its simplest level, the hippocampus is composed of a tri-synaptic circuit, depicted t ts s p est e e , t e ppoca pus s co posed o a t sy apt c c cu t, dep cted
on the right of this diagram:
- The perforant path carries input to granule cells of the dentate gyrus;
- Dentate granule cells project to area CA3 via the mossy fiber pathway;
- CA3 pyramidal neurons project to CA1 via the Schaffer collateral pathway.
This circuit is unusual in that all of its primary connections are excitatory. The
hippocampus itself is a highly excitable structure. It has about the lowest threshold hippocampus itself is a highly excitable structure. It has about the lowest threshold
for seizure activity of any part of the brain, which is why medial temporal lobe epilepsy
is so common.
The hippocampus is also highly connected to many other parts of the brain (depicted
ahead). All inputs and outputs to the hippocampus are funneled through the
entorhinal cortex, which in turn is bidirectionally coupled to the parahippocampal and
perirhinal cortices.
All f th t t li i th di l t l l b d b th i i l All of these structures lie in the medial temporal lobe, and because there is a serial
flow of information through them, damage to any one can impair a persons memory
storage ability. Note, however, that the amnesia is generally not clinically evident
unless one suffers bilateral damage.
This diagram depicts only the cortical connections of the hippocampus. Recall that
the hippocampus is also extensively interconnected with other limbic and
diencephalic structures, including the amygdala, septal nuclei, anterior nucleus of the
thalamus, nucleus accumbens, hypothalamus, and mammillary bodies. Except for
the amygdala, all of these connections run through the fornix.
896
9-May-2013, 11am
Dr. Lise Eliot
Damage to many different brain areas has been linked to amnesia, suggesting a complex g y , gg g p
circuit for storing long-term explicit memories. Generally speaking, such lesions must be
bilateral to produce a full amnesic syndrome. Structures include:
In the medial temporal lobe:
Hippocampus
Entorhinal cortex:
Major input and output of hippocampus
Site of earliest pathological changes in Alzheimers disease Site of earliest pathological changes in Alzheimers disease
Perirhinal and parahippocampal cortices:
Input and output of entorhinal cortex
In the diencephalon:
Mediodorsal thalamus (slide 27; damaged in Korsakoffs syndrome):
Alcoholic psychosis caused by chronic thiamine (B1) deficiency
Severe anterograde and some retrograde amnesia Severe anterograde and some retrograde amnesia
Mammillary bodies (next slide):
Destruction produces moderate memory loss in monkeys
Also bilaterally degenerated in Korsakoffs syndrome; see Lab case 10.1
Mammillothalamic tract and anterior nucleus also damaged in cases of
diencephalic amnesia. (Case NA suffered damage to MD,
mammillothalamic tract and mammillary bodies.)
The basal forebrain (next slide):
Source of cholinergic input to much of the forebrain, including hippocampus;
acetylcholine is important for learning & memory.
Markedly degenerated in Alzheimers disease.
897
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2
8
907
908
Dopamine in Reward,
C iti d Cognition, and
Schizophrenia
Anthony R. West, Ph.D.
Associate Professor, Dept of Neuroscience
1
See also: Principles of Neural Science, Kandel et al.
The Chicago Medical School, Room 2.217A
Lecture Outline
1) Anatomy of dopamine systems in the brain
2) Function of distinct dopamine systems
3) Review of dopamine transmission
4) Dopamine hypothesis of schizophrenia
5) Brain abnormalities in schizophrenia
6) Frontal-subcortical circuit dysfunction in schizophrenia
7) Reconceptualization of the role of DA systems in
2
7) Reconceptualization of the role of DA systems in
schizophrenia
8) New targets for restoring cognition in schizophrenia
909
Arvid Carlsson was one of the first neuroscientists to study dopamine function.
Prior to Carlssons work in the 1950s, dopamine was believed to be simply a
precursor to another catecholaminergic neurotransmitter, noradrenaline. Carlsson
showed that dopamine is itself a neurotransmitter in the caudate/putamen
(collectively termed striatum). The above work reviewed in Science magazine in
2001, focused on studying the impact of levodopa (L-Dopa) on motor dysfunction
in rabbits that had been depleted of dopamine using the drug reserpine. His
discovery that L-DOPArestored DAlevels in the striatum and reversed discovery that L-DOPA restored DA levels in the striatum and reversed
parkinsonian-like motor deficits in the rabbit lead to the development of L-Dopa for
patients suffering from Parkinson's disease. He shared the Nobel Prize in Medicine
in 2001.
910
911
Dopamine biosynthesis
The primary pathology in Parkinson's Disease is that there is insufficient production
and release of dopamine. Dopamine is formed in the dopaminergic neurons in the
midbrain by the above pathway. The first step is biosynthesised by the enzyme
tyrosine 3-monooxygenase (which is more commonly referred to as tyrosine
hydroxylase (TH)). The activity of this enzyme is often depressed to as much as
10% of normal levels in Parkinson's Disease. The second step in the biosynthesis of
d i i di t d b th ti L i id d b l ( hi h dopamine is mediated by the enzyme aromatic L-amino acid decarboxylase (which
is more commonly referred to as dopa decarboxylase).
912
The MRI image in the top right of this slide shows a horizontal view of the human
substantia nigra. The bottom section is cut at the level of the rostral midbrain and
depicts the location of dopamine cell bodies (red dots) in the VTA (medial) and SN
pars compacta (lateral). The dopamine cells lie just above the cerebral peduncles
(stained black in this image).
913
The above images show the dopamine pathways in the sagittal plane. The figure on
the left from your text shows that most of the dopamine innervation originates from
cell clusters in the midbrain (e.g., VTA and SN) and projects rostrally to the striatum
and frontal cortical areas (PFC), and to some extent, other cortical regions. The
MRI on the right displays an overlay of the dopamine projections to the forebrain
and cortical centers.
914
915
This study reproduced from the Kandel textbook (Figure 43-8) shows PET images
of radiolabeled L-DOPA (
18
F-DOPA) uptake in the striatum of a normal subject
(left) and in an asymptomatic twin who has a sibling with PD (middle). In the
normal subject the radiolabeled L-DOPA is strongly taken up into the DA nerve
terminals in the striatum (most intense signal is colored white). Less radiolabeled
L-DOPA is taken up in the asymptomatic sibling (middle) compared to the control
subject. Moreover, the signal is greatly decreased in this same individual 5 years
later and following a diagnosis of PD The loss of dopamine terminals in the later and following a diagnosis of PD. The loss of dopamine terminals in the
striatum of this individual likely led to the onset of PD symptoms.
916
The remainder of this lecture will focus on the mesolimbic and mesocortical
dopamine systems and their role in reward and cognition, as well as their
dysfunction in schizophrenia.
917
918
Classic studies by neuropsychologist Wolfram Schultz have shown that dopamine
neurons are activated by novel rewarding stimuli. Schultz recorded from midbrain
dopamine neurons in conscious monkeys trained to perform an operant task in
which the pressing of a lever or key produced a rewarding food pellet. Upon the
first unexpected presentation of the food pellet, a short latency burst of neuronal
firing was observed in the dopamine cell. Once the monkey learned to associate the
lever with the food reward, the novelty wore off and the dopamine cell stopped
bursting upon delivery of the food Schultz concluded that dopamine neurons are bursting upon delivery of the food. Schultz concluded that dopamine neurons are
activated by novel, but not familiar, rewarding stimuli.
919
In a subsequent set of studies, Schultz examined whether dopamine neurons encode
reward (R) prediction in their firing patterns. In these studies the monkey was
trained to press a response bar when presented with a cue (e.g., light flash on
screen/conditioned stimulus (CS)) which predicted the delivery of a juice reward.
Interestingly, Schultz observed that a short latency burst of neuronal firing was
observed in the dopamine cell upon presentation of the cue that predicted the
delivery of the juice reward (histogram on top right), but not to the presentation of
the reward itself (remember that this is now an expected reward so the dopamine the reward itself (remember that this is now an expected reward so the dopamine
cell does fire to the reward presentation itself). Schultz also found that if the
predicted reward was omitted, there is a decrease in dopamine cell firing (middle
histogram). Lastly, if the monkey was shown a neutral stimulus that was never
paired with the reward, no response was seen in the dopamine cell (bottom
histogram). Schultz concluded that dopamine neurons report the prediction of
rewarding stimuli by firing immediately after appearance of the salient stimulus,
and also produce an error signal (e.g., decrease in tonic firing) when an expected
reward is not delivered. This is likely to teach the animal when to attend to
environmental cues and when to ignore them, in order to most efficiently extract
rewards (e.g., food, sex) from their environment. This phenomenon is also
important for reversal learning in situations where responding to a CS no longer
results in reward. Rather than wasting time with the CS, the animal can extinguish
responding and look for a different salient stimulus which reliably predicts reward. responding and look for a different salient stimulus which reliably predicts reward.
920
In more recent studies Schultz has shown that the magnitude of the predicted reward
is encoded by dopamine cells and reflected in the amplitude of burst firing in
response to a CS. As shown above, monkeys were trained to associate a visual
presentation of a symbol (CS) with a particular volume of juice (larger volumes
equate to more valuable rewards). A) Monkeys were found to spend more time
licking for juice when the expected value of the reward was great. B) Similarly, the
value of the reward predicted by the CS was correlated with the amplitude of the
burst response to the presentation of the CS (i e reward value is encoded in the burst response to the presentation of the CS (i.e., reward value is encoded in the
burst firing amplitude of the dopamine cell).
921
The man in the cartoon is clearly responding to the appetitive stimulus (the woman)
and attempting to produce a clever response to her monologue on dopamine
transmission. A more clever response on his part would be more likely to produce
robust burst firing in her mesolimbic dopamine system. And then she might pay
attention to him.
922
There are two major families of dopamine receptors (D1-like and D2-like) which
are composed of multiple dopamine receptor subtypes. The D1 and D5 receptor
subtypes belong to the D1 family, whereas the D2, D3, and D4 belong to the D2-like
family. These receptor families can be distinguished by their effects on second
messenger pathways (i.e., adenylyl cyclase-cAMP pathway) and agonists and
antagonist that bind to different receptor subtypes (see table above).
923
This figure from the Kandel text shows the presynaptic dopamine neuron and the
postsynaptic target cell in the cortex or striatum. The inset shows how dopamine
receptor subtypes might regulate pre- and post-synaptic function. For example, D2
and D3 receptors are found on dopamine terminals and function as autoreceptors to
control dopamine synthesis and release. This may occur through G-protein
mediated regulation of K+ and Ca++ availability. All five dopamine receptor
subtypes are found on the postsynaptic cell (although most cells only express
members of either the D1 or D2 receptor families-not both) As shown in this members of either the D1 or D2 receptor families-not both). As shown in this
diagram, D1/5 receptors activate adenylyl cyclase through stimulation of the Gs
protein, whereas D2/3/4 receptors inhibit adenylyl cyclase activity through
activation of the inhibitory Gi/o protein.
924
The above whole-cell current clamp recording studies demonstrate the effects of D1
receptor agonism on measures of striatal cell excitability. Studies show that bath
application of D1 receptor agonist (SKF 81297) can have both inhibitory (A) or
excitatory (B) effects on spikes evoked via depolarizing current injections into the
cell. Importantly, the nature of the effect is determined by the membrane potential
of the cell when exposed to dopamine D1 agonist. As shown in (A), when the cell is
in a hyperpolarized state (-82 mV), D1 receptor agonism inhibits current-evoked
spiking The opposite effect is observed in (B) when the D1 receptor agonist is spiking. The opposite effect is observed in (B) when the D1 receptor agonist is
applied while the cell is held at a depolarized membrane potential (-57 mV, i.e., an
increase in current-evoked spiking is observed). Thus, D1/5 receptor activation
appears to modulate membrane excitability and spiking in a state-dependent manner
(i.e., decreasing excitability when the cell is in a resting state, and increasing
excitability when the cell is in a activated depolarized state).
925
The above whole-cell voltage clamp recording studies demonstrate the effects of D2
receptor agonism on measures of striatal cell excitability. Studies show that bath
application of D2 receptor agonist (quinpirole) decreases the peak amount of barium
influx into the cell through calcium channels (A). A representative example of these
recordings is shown in (B). In these experiments the channels are triggered to open
by a step depolarization from resting membrane potential (-80 mV) to a depolarized
potential (-10 mV). D2 receptor agonism decreases the amplitude of this current as
compare to the control condition These studies indicate that D2 receptor activation compare to the control condition. These studies indicate that D2 receptor activation
can decrease cell excitability by decreasing Ca++ channel activity.
926
Studies by Drs. Arnsten and Golman-Rakic at Yale have shown that dopamine
regulates both neuronal firing activity in the prefrontal cortex (PFC) and working
memory tasks in a manner that depends on the level of D1 receptor stimulation.
They found that there is an inverted U function with regard to optimal
performance and D1 receptor enhanced cognition or performance on the working
memory task. In this model, low levels of dopamine D1 receptor stimulation does
not affect cell firing enough to facilitate memory performance. However, an
increase in signal to noise ratio with regard to cell firing is observed with increased increase in signal to noise ratio with regard to cell firing is observed with increased
dopamine D1 receptor stimulation (left). This increase in the tuning of cell firing
correlates with improvements in working memory (right). Interestingly, over-
stimulation of dopamine D1 receptors leads to both suppression of cell firing (left)
and working memory performance (right). These studies indicate that D1 receptor
stimulation within a critical range activates the PFC and mediates working memory
function. Too little or too much dopamine can compromise these executive
functions and are likely to underlie pathology observed in conditions such as PD,
ADHD and schizophrenia (too little D1 receptor activation in PFC) and stress and
psychosis (too much D1 receptor stimulation in PFC).
927
This diagram from the Kandel text demonstrates how pharmacological
manipulations of dopamine synthesis, release, reuptake, and receptor activation can
either produce or abolish psychotic symptoms associated with schizophrenia.
928
The dopamine hypothesis of
schizophrenia
The oldest and most influential hypothesis
(though now regarded as oversimplified) has
been the dopamine hypothesis: The p yp
symptoms of schizophrenia are due to
hyperactive dopamine
neurotransmission.
Based on two pharmacological cornerstones:
1) Drugs that increase dopamine
transmission (e.g., amphetamine, PCP)
can induce a state that is
indistinguishable from paranoid
schizophrenia
22
schizophrenia.
2) Drugs that are effective in treating
schizophrenia are dopamine receptor
blockers.
Morc han mcrc :cdaion lon_crm rcamcn
lcd o rcmi::ion oI p:_ohoio :_mpom:.
Schizophrenia is characterized by
psychotic episodes: positive symptoms
Striking abnormalities of the
psychotic episodes are called
positive symptoms because they positive symptoms because they
reflect the presence of
distinctively abnormal behaviors
(delusions/hallucinations).
Positive symptoms of psychosis
are not unique to schizophrenia;
also occur in affective disorders
d t t f t i d li i (
2
and states of toxic delirium (e.g.,
abuse of phencyclidine
PCP/angel dust).
Positive symptoms are usually
controlled by antipsychotic
drugs.
929
All classical antipsychotic drugs used in the clinic to treat psychosis in
schizophrenia are D2 receptor antagonists. These drugs have different binding
affinities for the D2 and other transmitter receptors (e.g., D1, 5HT, histamine, NE,
etc), however, both the therapeutic and motor side effects of these drugs correlate
with their affinity for D2-type receptors but not D1- or other subtypes of receptors
(plot on the right). This correlation strongly indicates that blockade of the D2
receptor is critical for decreasing psychotic behavior.
930
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While D2-like receptors are most concentrated in striatum and nucleus accumbens
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neuropsychopharmacologists is determining where these drugs act in the brain.
932
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933
This study examined the activational state of two different cortical regions during a
working memory task in patients with schizophrenia using fMRI. As shown in (A),
the inferior posterior PFC is activated normally during the working memory task
with both short and long delays in both control and schizophrenic subjects (graph on
right). However, as shown in (B), with long delays the dorsolateral PFC does not
activate appropriately in patients as compared to normal controls (graph on right).
934
Left: This longitudinal neuroimaging study examined grey matter loss over a 5 year
testing period in adolescent controls and patients with schizophrenia. As shown on
the left, some degree of grey matter loss is normally observed in controls (mostly
low levels indicated by the blue signal). However in schizophrenia (middle), highly
significant grey matter loss is observed across time in the temporal lobes, parietal
cortex and PFC. The brain images on the right show grey matter loss in
schizophrenia after subtraction of the normal loss observed in controls. Right:
consistent with neuroimaging studies postmortem studies report significant consistent with neuroimaging studies, postmortem studies report significant
decreases in dendritic spine density in the PFC of patients with schizophrenia as
compared with controls.
935
Because cortical output is organized in segregated and functionally unique parallel
diff b b d i d di h systems, different core symptoms can be observed across patients depending on the
degree that association, sensorimotor, and limbic cortical centers are compromised.
Below is a list of potential symptoms, can you link these symptoms to one or more
of these cortical-subcortical-cortical systems?
Positive symptoms: Abnormal perceptions and thinking
Negative symptoms: Lack of affect, motivation, pleasure seeking
Cognitive deficits: Impairments in attention, executive function, memory
Sensory abnormalities: Gating disturbances
Sensorimotor abnormalities: Eye tracking disturbances
Motor abnormalities: Posturing, impaired coordination
936
937
Post-mortem studies by Dr. Lewiss group at the University of Pittsburgh have
shown that the synaptic connectivity of the PFC is altered in schizophrenia,
suggesting a disturbance in neurodevelopment. In the normal PFC (left), a variety
of interneurons are thought to regulate the spike firing of pyramidal cells through
GABAergic inputs to the axon hillock, soma, and dendrites. In schizophrenia
(right), the interaction between the GABAergic fast-spiking interneurons (blue cells
labeled Ch for chandelier) and the glutamatergic pyramidal cells (green) is
abnormal largely due to a decrease in the GABAergic input to the axon hillock abnormal, largely due to a decrease in the GABAergic input to the axon hillock.
Thus, fewer terminals synapse onto the axon hillock and markers of GABA uptake
are decreased, suggestive of fewer release sites. Consistent with this, an
upregulation of postsynaptic GABA receptor expression is also observed. Markers
for these GABAergic interneurons (e.g., GAD67, parvalbumin (PV)) are also
decreased, suggesting loss of cell numbers. Together, these studies indicate that
interneuronal GABAergic regulation of pyramidal cell output is compromised in
schizophrenia.
938
Clinicians can monitor dopamine binding to D2 receptors in the caudate/putamen
and other brain regions in patients using neuroimaging techniques (e.g., SPECT
imaging). The patient is injected with a radioligand (IBF) that exhibits moderate
affinity for the D2 receptor (left). The ligand is concentrated (warm colors) in areas
of the brain such as the striatum that have the most D2 receptors (middle; i.e., the
ligand binds to D2 receptors). Because dopamine competes with the radioligand for
occupancy of the D2 receptors, displacement of the signal indicates an increase in
endogenous dopamine release (see next slide for example) The image on the right endogenous dopamine release (see next slide for example). The image on the right
shows an MRI of the figure in the middle so one can define regions of high
radioligand binding.
939
As described in the previous slide, in SPECT and PET studies an increase in
dopamine efflux (induced in this case by amphetamine) will be detected as a
decrease in the signal (less radioligand binding). In this study, patients were
observed to have greater signal attenuation (i.e., less raclopride binding) in the
striatum following amphetamine injection, indicating that their dopamine terminals
release more transmitter in response to this stimulus as compared to controls.
940
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Compromised dopamine transmission in schizophrenia is likely to be a result of
hypo-activation of the mesocortical dopamine system and hyper-activation of the
mesolimbic dopamine system. This results in decreased D1 receptor activation in
the PFC and increased D2 receptor activation in the nucleus accumbens and
striatum. These frontal cortical abnormalities in dopamine D1 receptor activation
lead to disrupted executive function in the PFC and loss of contextual processing
and memory disturbances (involves hippocampus-PFC interactions). These
subcortical abnormalities in dopamine D2 receptor activation lead to loss of filtering subcortical abnormalities in dopamine D2 receptor activation lead to loss of filtering
of cortical and thalamic input to the nucleus accumbens and striatum and abnormal
responses to stress and novelty that result from mesolimbic dopamine dysfunction.
Thus, this model predicts that drugs that restore dopamine signaling (e.g., D1
agonism, D2 antagonism) would be particularly effective antipsychotics.
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943
944
!
!
Students: The notes on the following pages are a bit cryptic as I had
prepared them for my own use as a checklist to make sure I told you
everything. !
!
!
Dr. Daniel Peterson
May 10, 2013, 1:00

945
Structures to Note:!
!
Note temporal lobes with only cortical structures!
!
Nucleus Accumbens!
!
Septum Pellucidum!
!
Diagonal Band (medial to Nacc)!
!
Insula (anterior)!
!
Cingulate gurus!
!
Cingulum!
Dr. Daniel Peterson
May 10, 2013, 1:00

946
!
Anterior Commissure!
!
Nucleus Basalis (ventral to AC)!
!
Optic Chiasm with supraoptic recess (rostral extent of hypothalamus)!
!
Uncus!
!
Amygdala!
!
Columns of Fornix!
Dr. Daniel Peterson
May 10, 2013, 1:00

947
!
Amygdala!
!
Third Ventricle!
!
Hypothalamus!
!
Anterior nucleus of the Thalamus !
Dr. Daniel Peterson
May 10, 2013, 1:00

948
!
Hippocampus!
!
Fornix!
!
Stria Terminalis and Terminal Vein!
!
Mammillary bodies (caudal extent of hypothalamus)!
!
Mammillothalamic Tract!
!
Anterior nucleus of Thalamus (in following section becomes
mediodorsal)!
Dr. Daniel Peterson
May 10, 2013, 1:00

949
!
Mediodorsal nucleus of the Thalamus!
Dr. Daniel Peterson
May 10, 2013, 1:00

950
Main Points:!
!
Hippocampal Organization!
!
Cortical connections through the entorhinal cortex!
!
Perforant pathway!
!
Fornix:!
!
Outow from the hippocampus and subiculum to septal nuclei and
hypothalamus and thalamus!
!
Inow to hippocampus from septal nuclei and diagonal band and from
commissural input!
Dr. Daniel Peterson
May 10, 2013, 1:00

951
Main Points:!
!
Distribution of Diagonal band efferents and afferents to medial septum!
!
Cortical projections to PFC !
!
Thalamic and hypothalamic projections!
Dr. Daniel Peterson
May 10, 2013, 1:00

952
Fornix!
!
General architecture!
!
Commissural bers!
!
Split distribution at the level of the anterior commissure:!
!- precommissural to septal nuclei!
!- postcommissural bers to anterior thalamus!
!- postcommissural columns to mammillary body!
!
Anterior commissure:!
!- rostral portion contains olfactory commissural bers!
!- caudal portion contains interhemispheric amygdalar
connections!
Dr. Daniel Peterson
May 10, 2013, 1:00

953
Dr. Daniel Peterson
May 10, 2013, 1:00
Haines 3.5 6th Ed.
Haines 3.2 6th Ed.
954
Ventral amygdalofugal pathway relays olfactory input processed by the
amygdala to the hypothalamus!
!
Amygdalar communication with the brainstem via the medial forebrain
bundle!
!
Stria terminalis as the fornix of the amygdala!
- reciprocal connections with hypothalamus and basal ganglia!
- connections with the bed nuclei of stria terminalis (in septal area) !
Terminal vein runs along stria and helps in location!
Dr. Daniel Peterson
May 10, 2013, 1:00

955
Dr. Daniel Peterson
May 10, 2013, 1:00

956

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Medical Neuroscience: 2013 Course Guide

Fri 3May 24pm Various Lab9:SmallGroups TAs

cranial nerves (except the optic nerve)

spinal nerve roots (radiculopathy)

the dorsal root ganglia

peripheral nerve trunks and their terminal branches

the peripheral autonomic nervous system

numbness, burning sensation

tingling, and pricking sensations (paresthesia)

exaggerated sensitivity to touch

muscle weakness, wasting, paralysis

gland dysfunction, unable to sweat normally

unable to digest food easily,

unable to maintain safe BP levels

organ dysfunction / failure

HMSN-I, -II, -III

Metabolic or endocrine disorders

Connective tissue disease

Plexitis (brachial, lumbosacral)

"cryptogenic" sensory and

Small fibers (1-5 m) - pain/temperature/autonomic pathways

Large fibers (10-20 m) - vibration/proprioception, motor

Gap junctions are rare in adult

Vitamin deficiencies (B, E)

Vitamin B6 (pyridoxine) toxicity

Heavy metals (e.g. Lead, Arsenic, thallium)

Antineoplastic drugs (cisplatin, taxol)

essential cofactor for carboxylation reactions

cofactor for normal carbohydrate energy metabolism

associated with alcoholism (Wernicke-Korsakoff psychosis)

early symptoms: loss of appetite, constipation, nausea

later symptoms: depression, peripheral neuropathy, unsteadiness, mental

cofactor in amino acid metabolism

cofactor in glycogen phosphorylase reaction

required for synthesis of serotonin, noradrenaline

required for synthesis of myelin components (sphingosine, sphingomyelin,

associated with alcoholism

early symptoms: irritability, nervousness, depression

later symptoms: peripheral neuropathy, convulsions, coma

Heart rate abnormalities

Reduced or absent sensation to pain,

Reduced or absent ankle reflexes,

Can produce deficits in vision, strength, coordination,

Affects both sexes, but women have 2-3x risk.

Affects young adults primarily.

Causes symptoms that vary greatly from individual to

Has an unpredictable course (but 50% of patients will

At diagnosis, ~85% of people with MS present with a

250,000 - 350,000 patients with MS in the USA.

She abruptly developed a right hemi-sensory deficit after several days of

MRI scan revealed a multifocal white matter disease (increased T2 signal in

Visual evoked response testing was abnormal with slowed conduction in

Physical deficits (sensory and motor)

Mood disturbances (esp. depression)

Physical deficits (sensory and motor)

Proteolipid protein (PLP) - Makes up 50% of the protein in the membrane.

Myelin-associated glycoprotein (MAG).

Myelin/oligodendrocyte glycoprotein (MOG).

Strong evidence that a transmissible infectious agent starts the

Risk of MS 20-20x for the sibling of a person with MS.

Much higher incidence in Scandinavians.

Parallels distribution of Scandinavian genes (those doggone Vikings...)