WINDOWS TO THE BRAIN

Robin A. Hurley, M.D., L. Anne Hayman, M.D., Katherine H. Taber, Ph.D.

Section Editors

The Brainstem: Anatomy, Assessment, and Clinical Syndromes

Robin A. Hurley, M.D., Laura A. Flashman, Ph.D., Tiffany W. Chow, M.D.,
Katherine H. Taber, Ph.D.

Cover and Figure 1. The internal

anatomy of the brainstem is pre-
sented in a simplified, color-coded
format.1–7 Cover. The approximate
locations and extents of nuclei that
are important sources for a partic-
ular neurotransmitter are color-
coded onto a sagittal magnetic res-
onance image. Figure 1. The
approximate locations and extent of
major tracts and nuclei are color-
coded onto simplified axial illustra-
tions of brainstem sections (left
panel). The most common pattern
of arterial territories is also pre-
sented (right panel). All illustra-
tions are oriented in the radio-
graphic perspective.

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 HURLEY et al.

Overview of Anatomy nerves III, IV, and part of V (sensory) are found in the

T he focus in neuropsychiatry is usually on the cor-

tical areas that subserve behavior, cognition, and
mood. It is essential to also understand the roles of the
midbrain. The ascending superior cerebellar peduncles
cross (decussate) in the caudal midbrain. Fibers enter
the red nucleus and also continue on to the thalamus.
brainstem for these functions. Of particular importance, Other key midbrain structures include the substantia
the brainstem is the source for the monoamine (norepi- nigra and ventral tegmental area (both dopamine-con-
nephrine [Figure 1, purple], dopamine [Figure 1, green], taining [green]), the pedunculopontine nucleus (acetyl-
and serotonin [Figure 1, yellow]) neurotransmitters that
project widely to modulate these circuits. The major
subdivisions of the brainstem (from rostral to caudal)
are the midbrain, pons, and medulla (Figure 1, left TABLE 1. Cranial Nerve Nuclei and Long Tracts
panel). The brainstem serves as a conduit for many Structure Symptoms
ascending and descending pathways (Table 1), contains CN III (Oculomotor) Ipsilesional eye looks down and
most cranial nerve nuclei (Figure 1, white, and Table 1), laterally
Upper lid droops (ptosis)
and is important for many key integrative functions. It Pupil is dilated and unresponsive to
contains the lower motor neurons for the muscles of the light
CN IV (Trochlear) May cause diplopia
head and does the initial processing of general afferent CN V (Trigeminal) Ipsilateral loss of sensation from
information concerning the head. The reticular forma- mandible (midbrain)
tion forms the central core of the brainstem (Figure 1, Ipsilateral loss of sensation from face
(upper pons)
area approximated with dashed red lines).1,2 It partici- Ipsilateral loss of pain and temperature
pates in a wide range of functions including control of from face (pons, medulla)
CN VI (Abducens) Ipsilateral lateral rectus palsy
movement, modulation of pain, autonomic reflexes, Eye looks medially
arousal, and consciousness. The vascular supply to the CN VII (Facial) Ipsilateral lower motor neuron facial
weakness
brainstem is primarily from the posterior cerebral ar- Ipsilateral loss of taste on anterior 2/3
tery and the vertebral-basilar system (Figure 1, right of tongue
panel).3 In general, the small arteries that penetrate and CN VIII Ipsilateral deafness (lower pons)
(Vestibulocochlear) Vertigo, nystagmus, vomiting
supply the brainstem arise directly from larger arteries.3 (medulla)
These regions are at high risk for ischemia because CN IX Ipsilateral decreased gag response
(Glossopharyngeal) Ipsilateral loss of taste on posterior 1/3
there is little or no interconnecting surface network to of tongue
provide collateral circulation. CN X (Vagus) Ipsilateral paralysis of larynx and soft
palate
The most rostral part of the brainstem is the mid- CN XII (Hypoglossal) Ipsilateral flaccid tongue weakness
brain. It is characterized by four bumps, the paired
Corticopontine tracts Transient ataxia and hypotonia
superior and inferior colliculi on its dorsal (posterior) Corticobulbar tract Contralateral hemiplegia
surface, and by the large cerebral peduncles (containing Corticospinal tract Contralateral hemiplegia
the descending corticospinal and corticopontine tracts) Medial lemniscus May cause contralateral loss of position
and vibration
on its ventral (anterior) surface. The nuclei for cranial Medial longitudinal Internuclear opthalmoplegia
fasiculus
Trigeminothalamic tract Ipsilateral loss of pain and temperature
Drs Taber and Hurley are affiliated with the Veterans Affairs Mid (dorsal) from face
Atlantic Mental Illness Research, Education, and Clinical Center, and Spinothalamic tract May cause contralateral loss of pain
the Research and Education Service Line at the W. G. Hefner Veterans (lateral) and temperature from body
Affairs Medical Center in Salisbury, N.C. Dr. Hurley is affiliated with Lateral lemniscus Bilateral partial deafness
the Departments of Psychiatry and Radiology at Wake Forest Uni- Middle cerebellar Ataxia and incoordination
versity School of Medicine in Winston-Salem, N.C., and the Men- peduncle
ninger Department of Psychiatry and Behavioral Sciences at Baylor Superior cerebellar Tremors
College of Medicine in Houston. Dr. Flashman is affiliated with Dart- peduncle
mouth Medical School in Lebanon, N.H. Dr. Chow is affiliated with Inferior cerebellar Ipsilateral ataxia
the Rotman Research Institute, University of Toronto in Toronto, peduncle
Ontario, Canada. Dr. Taber is affiliated with the Division of Biomed- Vestibulospinal tract Decerebrate posturing
ical Sciences at the Virginia College of Osteopathic Medicine in (lateral)
Blacksburg, Va., and the Department of Physical Medicine and Reha- Vestibulospinal tract Continuation of Medial longitudinal
bilitation at Baylor College of Medicine in Houston. Address corre- (medial) fasiculus
spondence to Dr. Robin Hurley, Hefner VA Medical Center, 1601
Brenner Ave., Salisbury, NC 28144; Robin.Hurley@va.gov (e-mail). Adapted from Hayman et al.3 and Marx and Thomke30
Copyright © 2010 American Psychiatric Publishing, Inc.

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THE BRAINSTEM
choline-containing [orange]) and the first of the raphe
nuclei (serotonin-containing [yellow]).
Caudal to the midbrain is the pons. The nuclei for
cranial nerves VI, VII, VIII, and part of V (motor) are
found in the pons. Here the corticopontine fibers (blue)
terminate in the pontine nuclei (gray). These nuclei give
rise to the pontocerebellar fibers that cross the midline
to form the middle cerebellar peduncle (blue). This area
is particularly vulnerable to injury in malnourished in-
dividuals, especially if there has been a rapid correction
of electrotype abnormalities.8 The classic symmetric ar-
eas of myelin disruption that characterize central pon-
tine myelinolysis are thought to result from osmotically
active factors expelled by the cells within gray matter
that are toxic to myelin. White matter adjacent to edem-
atous gray matter (like the crossing pontocerebellar fi-
bers intermingled with the pontine nuclei) is therefore
the most exposed. The ascending and descending fiber
tracts are compact white matter bundles and much less
affected. Lesions are also found in other gray matter
regions containing heavily myelinated fibers, such as
thalamus, basal ganglia, and cerebellum.
Caudal to the pons is the medulla, containing the
nuclei for cranial nerves IX, X, XI, XII and a portion of
V. Ascending spinocerebellar tracts form the inferior
cerebellar peduncle at this level. The ascending sensory
tracts from the body (posterior columns) terminate in
the posterior column nuclei (gracilis, cuneatus) in the
lower medulla. These nuclei are the origin of the spi-
nothalamic tracts that cross (sensory decussation) in the
lower medulla and ascend to form the medial lemniscus
(pink).
Neuropsychological Deficits
The common perception has long been that brainstem
injury results primarily in motor and cranial nerve def-
icits. More recent work has focused on the transient and
permanent cognitive deficits that can occur in conjunc-
tion with brainstem lesions. Individuals have been de-
scribed as being unable to return to their baseline levels
of functioning in daily life activities, even after physical
and neurological deficits have resolved.9 Although the
literature is somewhat limited, there have been several
case reports and case series examining cognitive func-
tioning in small cohorts of individuals with brainstem
insults.9 –13 The most frequently reported deficits fol-
lowing isolated brainstem lesions are impaired atten-
tion and executive functioning. These have been ob-
2 http://neuro.psychiatryonline.org
served across a variety of tests, including letter fluency
and category fluency, the Trail Making test, letter can-
cellation tests, various sorting tests (Weigl sorting test,
Modified Card Sorting Test), the Test of Every Day
Attention (visual elevator subtest), and the Stroop Color
and Word Test. Impaired naming ability also occurs
relatively frequently in individuals with brainstem in-
jury. Memory impairment has been reported much less
commonly, and sensory-perceptual deficits are not typ-
ically reported. Interestingly, one study noted declines
in general intellectual ability in approximately 50% of
children following resection of low-grade brainstem tu-
mors.14
Injury to the ventral pons can result in locked-in syn-
drome, characterized by paralysis of all four limbs and
mutism (paralytic).15 Using testing based on eye-coded
(yes/no) responding, several studies have examined
cognitive abilities in individuals with this condition. A
self-report survey study of patients (N⫽44) with
chronic locked-in syndrome indicated that six patients
(14%) reported impaired attention and 19% reported
memory difficulties.16 A recent study utilized neuro-
psychological testing in patients (N⫽9) with chronic
locked-in syndrome due to isolated brainstem injury.17
While cognitive functioning was generally preserved in
the group, individual-specific deficits included mental
calculation and problem solving, auditory and visual
recognition, and receptive language. In contrast, a case
report of two patients with chronic locked-in syndrome
found no cognitive deficits on neuropsychological as-
sessment.18 Similarly, a case series (N⫽10) reported that
locked-in patients can recover intact cognitive levels in
cases of pure brainstem lesions.19 Although the authors
of that study concluded that injuries to additional areas
of the brain were most likely responsible for reported
deficits in this population, other studies (as noted
above) have reported deficits in patients with isolated
brainstem insults.
In summary, the literature indicates a variety of cir-
cumscribed cognitive deficits may occur after brainstem
insults, and these do not always completely resolve.
The profile of deficits seen in well-studied individuals
implicates disruption of the frontal-subcortical system,
with specific impact on regions involved in attentional
and executive functioning. The brain areas that are pri-
marily associated with the performance of executive
functions are the prefrontal and the anterior cingulate
cortices.20,21 These areas are reciprocally interconnected
with the brainstem.22,23 The findings of pervasive atten-
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 HURLEY et al.

tional and executive impairment, with naming and re-
ceptive language deficits often present, serve to remind
us that specific cognitive abilities can be disrupted by
injury to areas remote from the cortical circuitry that is
primarily associated with these domains. The implica-
tions of these cognitive deficits are important. Several
studies examining functional outcome in rehabilitation
following stroke have shown that cognition, particu-
larly attention and executive abilities such as abstract
thinking, judgment, problem solving, short-term verbal
attention and memory, and comprehension can play an
important role in determining length of hospital stay
and in predicting functional status at time of dis-
charge.24 –28 Higher-order cognitive skills such as
awareness, accurate understanding of one’s impair-
ments, and the capacity to learn and generalize func-
tional skills also impact successful rehabilitation. Un-
fortunately, individuals who demonstrate significant
physical improvement may not make concomitant
gains in cognition and therefore may leave rehabilita-
tion with less functional independence and a greater
need for follow-up services.
Clinical Brainstem Syndromes
The clinician needs to be familiar with how neuroana-
tomical functional units cluster in the brainstem. These
can be summarized as cranial nerve nuclei; pigmented
nuclei (red nucleus, substantia nigra [“black nucleus”],
and locus ceruleus [“blue spot”]); and tracts (e.g., cor-
ticospinal, corticopontine, spinothalamic, spinocerebel-
lar) that pass through. When any two of these three
categories show impairment simultaneously, particu-
larly when there are alternating signs, the lesion is
likely to be within the brainstem. Thus, if the patient
has cranial nerve deficits (Table 1) accompanied by par-
kinsonism or cranial nerve deficits and a crossed corti-
cospinal neurological sign, the first place to localize the
lesion would be the brainstem. Lesion location can be
approximated (Table 2) by combining cranial nerve-
related symptoms (which provide rostral-caudal local-
ization) and long tract-related symptoms (which pro-
vide medial-lateral localization).29 There are multiple
named brainstem syndromes, most known by eponym
(Table 3).3,30 It has been noted that many of these are
seldom encountered in clinical practice. The combina-

TABLE 2. Key Structures and Symptoms for Brainstem Lesion Localization

Medial Injury Lateral Injury
Contralesional
Ipsilesional Symptoms Symptoms Ipsilesional Symptoms Contralesional Symptoms
Midbrain
Cranial nerve III (oculomotor): eye Corticospinal tract: Oculosympathetic tract: Horner’s Spinothalamic tracts: loss of pain
turned down and laterally; upper lid weakness (body) syndrome and temperature (body)
droops (ptosis); pupil is dilated and
unresponsive to light
Cranial nerve IV (trochlear): eye unable Medial lemniscus: loss
to look down when turned inward vibration and
(may cause diplopia) proprioception (body)
Medial longitudinal fasciculus:
internuclear ophthalmoplegia

Pons
Cranial nerve VI (abducens): eye looks
medially
Medial longitudinal fasciculus:
internuclear ophthalmoplegia
Corticospinal tract: Oculosympathetic tract: Horner’s Spinothalamic tracts: loss of pain
weakness (body) syndrome and temperature (body)
Medial lemniscus: loss Spinocerebellar tracts (inferior
vibration and cerebellar peduncle): ataxia
proprioception (body) (body)
Cranial nerve V (trigeminal-
sensory): loss of pain and
temperature (face)

Medulla
Cranial Nerve XII (hypoglossal): flaccid Corticospinal tract: Oculosympathetic tract: Horner’s Spinothalamic tracts: loss of pain
tongue weakness weakness (body) syndrome and temperature (body)
Medial longitudinal fasciculus: Medial lemniscus: loss Spinocerebellar tracts (inferior
internuclear ophthalmoplegia vibration and cerebellar peduncle: ataxia
proprioception (body) (body)

Adapted from Gates.29

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THE BRAINSTEM

tion of symptoms is the critical factor. Thus, the Weber,
Claude, Benedict, Nothnagel, and Parinaud syn-
dromes, all resulting from midbrain lesions, have oc-
ulomotor nerve palsy (CN III) in common. This gen-
erally causes diplopia on lateral gaze, but there could
also be disconjugate vertical gaze. Use of the Maddox
Rod and a penlight can help the clinician disentangle
the direction in which the eyes are disconjugate.31
The Millard-Gubler syndrome localizes to the pons
with its facial palsy (CN VII) and sometimes lateral
rectus palsy (CN VI, another way to achieve diplo-
pia). Avellis, Jackson, and Wallenberg syndromes
arise from medullary lesions that cause oropharyn-
geal deficits (CN IX-XII).32,33
The differential diagnosis for brainstem syndromes
can be fairly easy to remember. These are typically focal
lesions due to stroke, neoplasm, or multiple sclerosis.
Less common etiologies for brainstem syndromes
would include infectious diseases (especially some
meningitides that center on the base of the brain like
tuberculosis), vascular malformation, traumatic brain
injury, hyponatremia causing a central pontine myeli-
nolysis, and the neurodegenerative movement disor-
ders progressive supranuclear palsy (PSP) and multi-
system atrophy. Although not commonly considered a
brainstem syndrome, Parkinson’s disease almost al-
ways extends beyond the cardinal signs of parkinson-
ism (resting tremor, postural instability, akinesia, gait
changes) associated with degeneration of the substantia
nigra.34,35 Depression is highly prevalent among pa-
tients with Parkinson’s disease, at times manifesting as
a prodrome and certainly complicating disease man-
agement.36,37 Antidepressant effects of l-dopa and lack
of correlation of severities of depressive symptoms with
motor disability imply that depression in the Parkin-
son’s disease context results from the dopaminergic
deficit. Autonomic system impairments also impact
heavily on Parkinson’s disease quality of life, possibly
related to vagal neuropathy (lower pons).38 Parkinson’s
disease occurs in one of every 272 people in the popu-
lation, whereas multiple sclerosis occurs in one of every
700.
While most clinicians are familiar with the cardinal
signs of parkinsonism as described above, PSP is less

TABLE 3. Brainstem Syndromes

Syndrome Symptoms
Midbrain
Weber CN III palsy (ipsilesional); weakness and vertical gaze palsy (contralesional)
Claude CN III palsy (ipsilesional); ataxia, tremor and vertical gaze palsy (contralesional)
Benedict CN III palsy (ipsilesional); ataxia, tremor and weakness (contralesional)
Nothnagel CN III palsy (ipsilesional); ataxia and vertical gaze palsy (contralesional)
Parinaud Paralysis of upgaze, convergence-retraction nystagmus, lid retraction and light near dissociation
Pons
Raymond-Cestan Internuclear ophthalmoplegia (ipsilesional); ataxia and weakness (contralesional)
Raymond CN VI palsy (ipsilesional); weakness (contralesional)
Ataxic hemiparesis Weakness and ataxia (contralesional)
Millard-Gubler or CN VI and VII palsy (ipsilesional); weakness (contralesional)
Gubler
Foville CN VI and sometimes VII palsy (ipsilesional); weakness and sensory loss (contralesional)
Medulla
Wallenberg Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx and pharynx,
Horner’s (ipsilesional); loss of pain and temperature for body (contralesional)
Babinski-Nageotte Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx and pharynx,
Horner’s (ipsilesional); weakness and loss of pain and temperature for body (contralesional)
Cestan-Chenias Loss of pain and temperature for face, weakness of soft palate, larynx and pharynx, Horner’s
(ipsilesional); weakness and loss of pain and temperature for body (contralesional)
Reinhold Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx, pharynx and
tongue, Horner’s (ipsilesional); weakness and loss of touch, pain and temperature for body
(contralesional)
Avellis Weakness of soft palate, larynx, and pharynx (ipsilesional); weakness and loss of touch for
body (contralesional)
Vernet Weakness of palate, CN XI palsy, decreased taste posterior tongue (ipsilesional); weakness
(contralesional)
Jackson CN XII palsy, weakness of soft palate, larynx, and pharynx (ipsilesional); weakness
(contralesional)
Dejerine CN XII palsy (ipsilesional); hemiplegia and sometimes loss of position and vibration
(contralesional)

Adapted from Hayman et al.3 and Marx and Thomke30

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frequently seen, with a prevalence of 1 to 6.5 per
100,000.39 Most patients with PSP have an onset in the
7th decade of life. Reported male to female ratios range
from 1:1 to 4:6.40 Twenty percent of patients with PSP
present with the behavioral criteria for frontotemporal
dementia: insidious onset with gradual progression,
early decline in social interpersonal conduct, early im-
pairment in regulation of personal conduct, early emo-
tional blunting, and early loss of insight.41 The other
80% present with the motoric signs of PSP, most fre-
quently referred to as absence of vertical gaze. Clini-
cians may or may not find it helpful to consider PSP as
manifesting with a “leonine facies.” Some prefer to de-
scribe it as a surprised look, but this may be seen as an
angry stare by others. This feature is not included in the
diagnostic criteria for PSP. Instead, multiple unex-
plained falls and impairment of vertical gaze are re-
quired for probable PSP.42 When examining for vertical
oculomotor movements, the important features of the
vertical gaze are the latency and speed of the saccadic
movement.43 Abnormality can also be detected if the
patient needs to make corrections when they move the
gaze from one target to a second target in a vertical
direction. Patients with PSP may demonstrate increased
latency of saccades, slower speed, or “past pointing.” In
contrast, the patient who has normal changes to ex-
traocular movements due to aging will have some de-
creased range of motion on vertical gaze, but the sac-
cades should be intact. In addition, there is some
abnormality of horizontal gaze in PSP, in that the
square wave jerk can reflect decreased fixation. This is
thought to be due to dysfunction of burst cells in the
brainstem reticular formation.43 Patients with PSP may
show the atrophy of the midbrain in what is called a
“hummingbird” or “penguin” sign.44 A recent study by
Borroni et al.45 reports a correlation between an isoform
of cerebral spinal fluid tau levels and not only the di-
References
1. DeArmond SJ, Fusco MM, Dewey MM: Structure of the Hu-
man Brain: A Photographic Atlas. New York, Oxford Univer-
sity, 1989
2. Nolte J: The Human Brain. St Louis, Mosby, 2002
3. Hayman LA, Taber KH, Dubey N, et al: A functional atlas of
brain vascular territories, in Imaging of the Nervous System.
Edited by Latchaw RE, Kucharczyk J, Moseley ME. Philadel-
phia, Elsevier Mosby, 2005, pp 179 –197
4. Pahapill PA, Lozano AM: The pedunculopontine nucleus and
Parkinson’s disease. Brain 2000; 123:1767–1783
5. Hathout GM, Bhidayasiri R: Midbrain ataxia: an introduction
J Neuropsychiatry Clin Neurosci 22:1, Winter 2010
HURLEY et al.
agnosis of PSP but also the degree of atrophy in the
brainstem.
Cranial nerve deficits can be easy to recognize on
elemental neurological examination, but lesions to
substantia nigra, locus ceruleus or dorsal raphe may
be more insidious in their manifestations. As men-
tioned above, parkinsonism would be a clue that the
substantia nigra has been affected. There is also evi-
dence to support attention deficit/hyperactivity dis-
order arising from a lesion in the substantia nigra (as
well as from norepinephrine disturbance, see be-
low).46 Deficits in serotonin production by the dorsal
raphe have been associated with depression, suicid-
ality, psychosis, and frontotemporal dementia.47–49
Both serotonin and acetylcholine are important to the
function of the reticular activating system. Therefore
one might anticipate that sleep disturbances and de-
lirium could be related to a brainstem lesion involv-
ing the dorsal raphe.50 A lesion in the locus ceruleus
will reduce the production of norepinephrine. This is
associated with depressive symptoms, attention def-
icit/hyperactivity disorder, posttraumatic stress dis-
order, and hypotension.51–54 Apathy has been related
to all three of these neurotransmitters. Apathy has
been reported after pallido-nigral lesions55 and in a
patient population with neuro-Behçet disease, affect-
ing the brainstem and cranial nerves.56
In conclusion, a working knowledge of the brainstem
anatomy and physiology is essential for the assessment
of patients with symptoms of cranial nerve deficits,
motor, sensory, or cognitive/behavioral changes. Sum-
mary charts, color-coded maps, and tables are available
for clinicians who may not regularly assess patients
with brainstem injury. The inclusion of the brainstem in
discussions of the cognitive/emotion/behavior circuits
is necessary for a thorough review of brain function.
to the mesencephalic locomotor region and the pendunculo-
pontine nucleus. AJR Am J Roentgenol 2005; 184:953–956
6. Sasaki M, Shibata E, Tohyama K, et al: Monoamine neurons in
the human brain stem: anatomy, magnetic resonance imaging
findings, and clinical implications. Neuroreport 2008;
19:1649 –1654
7. Keren NI, Lozar CT, Harris KC, et al: In vivo mapping of the
human locus coeruleus. Neuroimage 2009; 47:1261–1267
8. Kumar S, Fowler M, Gonzalez-Toldeo E, et al: Central pontine
myelinolysis: an update. Neurol Res 2006; 28:360 –366
9. van Zandvoort M, de Haan E, van Gijn J, et al: Cognitive
http://neuro.psychiatryonline.org 5
THE BRAINSTEM
functioning in patients with a small infarct in the brainstem.
J Int Neuropsychol Soc 2003; 9:490 – 494
10. Crosson B, Trautt GM: Cortical functioning during recovery
from brainstem infarction: a case report. Int J Clin Neuropsy-
chol 1981; 2:3–7
11. Evyapan D, Kumral E: Pontine anosognosia for hemiplegia.
Neurology 1999; 53:647– 649
12. Garrard P, Bradshaw D, Jäger HR, et al: Cognitive dysfunction
after isolated brain stem insult: an underdiagnosed cause of
long-term morbidity. J Neurol Neurosurg Psychiatry 2002;
73:191–194
13. Hoffmann M, Schmitt F: Cognitive impairment in isolated
subtentorial stroke. Acta Neurol Scand 2004; 109:14 –24
14. Ris MD, Beebe DW, Armstrong FD, et al: Cognitive and adap-
tive outcome in extracerebellar low-grade tumors in children:
a report from the Children’s Oncology Group. J Clin Oncol
2008; 26:4765– 4770
15. Leon-Carrion J, van Eeckhout P, Dominguez-Morales MR: Re-
view of subject: the locked-in syndrome: a syndrome looking
for a therapy. Brain Inj 2002; 16:555–569
16. Leon-Carrion J, van Eeckhout P, Dominguez-Morales MR,
et al: The locked-in syndrome: a syndrome looking for a ther-
apy. Brain Inj 2002; 16:571–582
17. Rousseaux M, Castelnot E, Rigaux P, et al: Evidence of per-
sisting cognitive impairment in a case series of patients with
locked-in syndrome. J Neurol Neurosurg Psychiatry 2009; 80:
166 –170
18. Allain P, Joseph PA, Isambert JL, et al: Cognitive functions in
chronic locked-in syndrome: a report of two cases. Cortex
1998; 34:629 – 634
19. Schnakers C, Majerus S, Goldman S, et al: Cognitive function
in locked-in syndrome. J Neurol 2008; 255:323–330
20. Casey BJ, Trainor R, Giedd J, et al: The role of the anterior
cingulate in automatic and controlled processes: a develop-
mental neuroanatomical study. Dev Psychobiol 1997; 30:61– 69
21. Aron AR, Durston S, Eagle DM, et al: Converging evidence for
a fronto-basal-ganglia network for inhibitory control of action
and cognition. J Neurosci 2007; 27:11860 –11864
22. Allman JM, Hakeem A, Erwin JM, et al: The anterior cingulate
cortex: the evolution of an interface between emotion and
cognition. Ann N Y Acad Sci 2001; 935:107–117
23. Haber SN, Knutson B: The reward circuit: linking primate
anatomy and human imaging. Neuropsychopharmacology
2010; 35:4 –26
24. Anderson TP, Bourestom N, Greenberg FR, et al: Predictive
factors in stroke rehabilitation. Arch Phys Med Rehabil 1974;
55:545–553
25. Jongbloed L: Prediction of function after stroke: a critical re-
view. Stroke 1986; 17:765–776
26. Mysiw WJ, Beegan JG, Gatens PF: Prospective cognitive as-
sessment of stroke patients before inpatient rehabilitation: the
relationship of the Neurobehavioral Cognitive Examination to
functional improvement. Am J Phys Med Rehabil 1989; 68:
168 –717
27. Hier DB, Edelstein G: Deriving clinical prediction rules from
stroke outcome research. Stroke 1991; 22:1431–1436
28. Galski T, Bruno RL, Zorowitz R, et al: Predicting length of
stay, functional outcome, and aftercare in the rehabilitation of
stroke patients: the dominant role of higher-order cognition.
Stroke 1993; 24:1794 –1800
6 http://neuro.psychiatryonline.org
29. Gates P: The rule of 4 of the brainstem: a simplified method for
understanding brainstem anatomy and brainstem vascular
syndromes for the non-neurologist. Int Med J 2005; 35:263–266
30. Marx JJ, Thomke F: Classical crossed brainstem syndromes:
myth or reality? J Neurol 2009; 256:898 –903
31. Garber N: Evaluating diplopia with the Maddox Rod, Risley’s
prism, and red glass. J Ophthalmic Nurs Technol 1995; 14:
224 –228
32. Adams RD, Victor M: Diseases of the cranial nerves, in Prin-
ciples of Neurology, 4th ed. Edited by Adams RD, Victor M.
New York, McGraw-Hill Information Services Company,
Health Professions Division, 1989, p 1080
33. Wall M: Brainstem syndromes, in Neurology in Clinical Prac-
tice: Principles of Diagnosis and Management. Edited by
Bradley WG, Daroff RB, Fenichel GM, et al. Boston, Butter-
worth-Heinemann, 1991, pp 354 –361
34. Poewe W: Non-motor symptoms of Parkinson’s disease. Eur
Neurol 2008; 15:14 –20
35. Grinberg LT, Rueb U, Alho AT, et al: Brainstem pathology and
non-motor symptoms of PD. J Neurol Sci 2009 Sep 14. [Epub
ahead of print]
36. Chow TW, Cummings JL: Treatment of depression in the
patient with Parkinson’s disease. Clin Geriatrics 1998;
4:34 – 46
37. Lemke MR: Depressive symptoms in Parkinson’s disease. Eur
Neurol 2008; 15:21–25
38. Probst A, Bloch A, Tolnay M: New insights into the pathology
of Parkinson’s disease: does the peripheral autonomic system
become central? Eur Neurol 2008; 15:1– 4
39. Nath U, Ben-Shlomo Y, Thomson RG, et al: The prevalence of
progressive supranuclear palsy (Steele-Richardson-Olszewski
syndrome) in the UK. Brain 2001; 124:1438 –1449
40. Kaat LD, Boon AJ, Kamphorst W, et al: Frontal presentation
in progressive supranuclear palsy. Neurology 2007; 69:723–
729
41. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal
lobar degeneration: a consensus on clinical diagnostic criteria.
Neurology 1998; 51:1546 –1554
42. Litvan I, Agid Y, Calne D, et al: Clinical research criteria for
the diagnosis of progressive supranuclear palsy (Steele-Rich-
ardson-Olsezewski syndrome): report of the NINDS-SPSP in-
ternational workshop. Neurology 1996; 47:1–9
43. Leigh RJ, Riley DE: Eye movements in parkinsonism: it’s sac-
cadic speed that counts. Neurology 2000; 54:1018 –1019
44. Graber JJ, Staudinger R: Teaching neuroimages: “penguin” or
“hummingbird” sign and midbrain atrophy in progressive
supranuclear palsy. Neurology 2009; 72:e81
45. Borroni B, Malinverno M, Gardoni F, et al: Tau forms in CSF
as a reliable biomarker for progressive supranuclear palsy.
Neurology 2008; 71:1796 –1803
46. Oades RD: Dopamine-serotonin interactions in attention-def-
icit hyperactivity disorder (ADHD). Prog Brain Res 2008; 172:
543–565
47. Brown GL, Linnoila MI: CSF serotonin metabolite (5-HIAA)
studies in depression, impulsivity, and violence. J Clin Psy-
chiatry 1990; 51:31– 41
48. Burke WJ, Dewan V, Wengel SP, et al: The use of selective
serotonin reuptake inhibitors for depression and psychosis
complicating dementia. Int J Geriatr Psychiatry 1997; 12:519 –
525
J Neuropsychiatry Clin Neurosci 22:1, Winter 2010

49. Sjogren M, Minthon L, Passant U, et al: Decreased monoamine
metabolites in frontotemporal dementia and Alzheimer’s dis-
ease. Neurobiol Aging 1998; 19:379 –384
50. Mirsky AF, Duncan CC: Pathophysiology of mental illness: a
view from the fourth ventricle. Int J Psychophysiol 2005; 58:
162–178
51. Southwick SM, Paige S, Morgan CA, et al: Neurotransmitter
alterations in PTSD: catecholamines and serotonin. Semin Clin
Neuropsychiatry 1999; 4:242–248
52. Freeman R: Treatment of orthostatic hypotension. Semin Neu-
rol 2003; 23:435– 442
53. Kim CH, Waldman ID, Blakely RD, et al: Functional gene
J Neuropsychiatry Clin Neurosci 22:1, Winter 2010
HURLEY et al.
variation in the human norepinephrine transporter: associa-
tion with attention deficit hyperactivity disorder. Ann N Y
Acad Sci 2008; 1129:256 –260
54. Nutt DJ: Relationship of neurotransmitters to the symp-
toms of major depressive disorder. J Clin Psychiatry 2008;
69:4 –7
55. Adam J, Baulac M, Hauw J-J, et al: Behavioral symptoms after
pallido-nigral lesions: a clinico-pathological case. Neurocase
2008; 14:125–130
56. Oktem-Tanör O, Baykan-Kurt,B, Gurvit IH, et al: Neuropsy-
chological follow-up of 12 patients with neuro-Behcet disease.
J Neurol 1999; 246:113–119
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