Techniques in Cognitive

Neuroscience
Transcranial Magnetic Stimulation (TMS)

Dr. Roger Newport

Lecture Overview
Brief history of TMS and how it works

What can TMS add to Cognitive Neuroscience ?

What advantages are there for TMS over other brain-behavior techniques?
Lesion sudies
Direct cortical stimulation
Imaging
TMS

Design Considerations
TMS safety
Contraindications
Acceptable risks
Ethics
Coil shape
Depth and spatial resolution of stimulation
Coil Localisation
Control conditions
Stimulation techniques and effects
History of TMS and obligatory funny pictures

Merton &Morton (1980). Successful

Transcranial Electrical Stimulation

Magnusson &
dArsonval (1896/1911)
Thompson, 1910 Stevens, 1911
 Barker, 1984

Common rTMS machines

Magstim Dantec

Transcranial Magnetic
Stimulation allows the Safe,
Non-invasive and Painless
Stimulation of the Human
Brain Cortex. Cadwell
Electromagnetic Induction

Introduces disorder into a normally ordered system

Lecture Overview
Brief history of TMS and how it works

What can TMS add to Cognitive Neuroscience ?

What advantages are there for TMS over other brain-behavior techniques?
Lesion sudies
Direct cortical stimulation
Imaging
TMS
Other Brain-Behavior Techniques
Lesion Studies
Dependence of serendipity of nature or experimental models in animals
Single or few case studies
might be more than a single lesion
lesion may be larger than the brain area under study
Cognitive abilities may be globally impaired
Lesion can only be accurately defined post mortem
The damaged region cannot be reinstated to obtain control measures that
bracket the lesion-induced effect
Comparisons must be made to healthy controls; internal double dissociations
are not possible
Given brain plasticity, connections might be modified following lesions
Other Brain-Behavior Techniques

Cortical Stimulation
Invasive
Limited to the study of patients with brain
pathologies requiring neurosurgical
interventions
Stressful situation in the OR and medications
might condition subjects performance
Time constraints limit the experimental
paradigms
Retesting is not possible
Other Brain-Behavior Techniques

Neuroimaging (Brain Mapping)

Non-invasive identification of the

brain injury correlated with a given
behavior
Association of brain activity with
behavior - cannot rule out
epiphenomenon
Cannot demonstrate the necessity of
given region to function
Neuroimaging techniques are usually
only good either temporally or
spatially, not both (e.g. Pet & fMRI
lack temporal resolution, EEG lacks
spatial resolution)
Advantages of TMS in the Study of Brain-
Behavior Relations
Study of normal subjects eliminates the potential confounds of
additional brain lesions and pathological brain substrates
Acute studies minimize the possibility of plastic reorganization
of brain function
Repeated studies in the same subject
Study multiple subjects with the same experimental paradigm
Study the time course of network interactions
When combined with PET or fMRI, can build a picture of not
only which areas of brain are active in a task, but also the time at
which each one contributes to the task performance.

Study internal double dissociations and network interactions by targeting

different brain structures during single a task and disrupting the same cortical
area during different related tasks
Advantages of TMS: Virtual Patients
causal link between brain activity and behaviour
Braille Alexia
Real lesion TMS lesion

Cohen et al., 1997.

Occipital TMS
Hamilton et al., 2000. disrupts braille
Reported case of blind reading in early blind,
but not control
woman who lost ability to subjects
read braille following
bilateral occipital lesions Blue = sighted; Red = E blind
Advantages of TMS: Chronometry

Chronometry:
timing the
contribution of focal
brain activity to
behavior

Role of visual
cortex in tactile
information
processing in
early blind
subjects
Hamilton and Pascual-
Leone, 1998
Functional connectivity- relate behaviour to the
interaction between elements of a neural network

TMS to FEF - correlation between

TMS and CBF at
i) stimulation site
ii) distal regions consistent with
Paus et al. TMS/PET known anatomical connectivity of
monkey FEF
Mapping and modulation of neural plasticity
- rapid changes
Rapid plasticity - map changes in
cortical excitability using
TMS/MEPs during a learning task
(Pacual-Leone et al.)

Cohen and colleagues.

Modulation of cortical excitability
in deafferentation studies.
TMS of plastic hemisphere
increases neural response,
TMS of non-plastic hemisphere
downgrades neural response of
plastic hemisphere.
Serial Reaction Time Task
Mapping and modulation of neural plasticity
- slow changes
Amputee cortical excitability
Measure changes in motor
excitability in neurologic
disorders (e.g. PD, HD)
Braille reader took 10-day holiday from
reading. Size of finger representation
shrank dramatically until she returned
to work even time off over the
weekend quantitatively reduced finger
representation.
Other uses for TMS
Clinical - test speed, or existence of,
of corticospinal connections
(MS/stroke)
Therapy -rTMD has long term
effects on depression
Summary: What can TMS add to Cognitive
Neuroscience ?

Virtual Patients: causal link between brain activity

and behavior
Chronometry: timing the contribution of focal
brain activity to behavior
Functional connectivity: relate behavior to the
interaction between elements of a neural network
Map and modulate neural plasticity
Lecture Overview
Brief history of TMS and how it works

What can TMS add to Cognitive Neuroscience ?

What advantages are there for TMS over other brain-behavior techniques?
Lesion sudies
Direct cortical stimulation
Imaging
TMS

Design Considerations
TMS safety
Contraindications
Acceptable risks
Ethics
Coil shape
Depth and spatial resolution of stimulation
Coil Localisation
Control conditions
Stimulation techniques and effects
Safety
Seizure induction - Caused by spread of excitation. Single-pulse TMS
has produced seizures in patients, but not in normal subjects. rTMS has
caused seizures in patients and in normal volunteers. Visual and/or
EMG monitoring for afterdischarges as well as spreading excitation
may reduce risk.

Hearing loss - TMS produces loud click (90-130 dB) in the most
sensitive frequency range (27 kHz). rTMS = more sustained noise.
Reduced considerably with earplugs.

Heating of the brain - Theoretical power dissipation from TMS is few

milliwatts at 1 Hz, while the brain's metabolic power is 13 W

Engineering safety - TMS equipment operates at lethal voltages of up

to 4 kV. The maximum energy in the capacitor is about 500 J, equal to
dropping 100 kg from 50 cm on your feet. So dont put your tea on it.
Safety
Scalp burns from EEG electrodes - Mild scalp burns in subjects with
scalp electrodes can be easily avoided using, e.g., small low-
conductivity Ag/AgCl-pellet electrodes.

Effect on cognition - Slight trend toward better verbal memory,

improved delayed recall and better motor reaction time

Local neck pain and headaches - Related to stimulation of local

muscles and nerves, site and intensity dependant. Particularly
uncomfortable over fronto-temporal regions.

Effect on Mood in normals - Subtle changes in mood are site and

frequency dependant. High frequency rTMS of left frontal cortex
worsens mood. High frequency rTMS of right frontal cortex may
improve mood.
Safety
Follow published safety guidelines for rTMS

Maximum safe duration of single rTMS train at 110% MT

Frequency (Hz) Max. duration (s)

1 1800+
+ minimum inter-train
5 10 interval
10 5 e.g. at 20Hz @1.0-1.1
T leave >5s inter train
20 1.6
25 .84

Caution: Guidelines not perfect

Safety -Contraindications
Metallic hardware near coil
Pacemakers
implantable medical pumps
ventriculo-peritoneal shunts
(case studies with implanted brain stimulators and abdominal devices have not shown
complications)
History of seizures or history of epilepsy in first degree relative
Medicines which reduce seizure threshold
Subjects who are pregnant
(case studies have not shown complications)
History of serious head trauma
History of substance abuse
Stroke
Status after Brain Surgery
Other medical/neurologic conditions either associated with epilepsy or in whom a seizure
would be particularly hazardous (e.g. increased intracranial pressure)
Safety TMS Adult Safety Screen
Have you ever: had an adverse reaction to TMS?
Had a seizure?
Had an EEG?
Had a stroke?
Had a head injury(include neurosurgery)?
Do you have any metal in your head (outside of the mouth,) such as shrapnel, surgical
clips, or fragments from welding or metalwork? (Metal can be moved or heated by TMS)
Do you have any implanted devices such as cardiac pacemakers, medical pumps, or
intracardiac lines? (TMS may interfere with electronics and those with heart conditions are
at greater risk in event of seizure)
Do you suffer from frequent or severe headaches?
Have you ever had any other brain-related condition?
Have you ever had any illness that caused brain injury?
Are you taking any medications? (e.g. Tricyclic anti-depressants, neuroleptic agents, and
other drugs that lower the seizure threshold)

If you are a woman of childbearing age, are you sexually active, and if so, are you not using
a reliable method of birth control?

Does anyone in your family have epilepsy?

Do you need further explanation of TMS and its associated risks?
Ethics Guidelines
Informed Consent - disclosure of all significant risks, both
those known and those suspected possible
Potential Benefit must outweigh risk
Equal distribution of risk - Particularly vulnerable patient
populations should be avoided

Levels of Risk
Class I - Direct clinical benefit is expected, e.g. depression.
Level of acceptable risk (i.e. sz) is moderate
Class II - Potential, but unproven benefit, e.g. PD. Level
of acceptable risk is low.
Class III - No expected benefit. Will advance general
understanding. Requires stringent safety guidelines.
Practical
T
considerations
Coil shape

The geometry
of the coil
determines the
focality of the
magnetic field
and of the
induced current
- hence also of
the targeted
brain area.
Practical Considerations - stimulation depth
70x60 5mm

55x45 15mm
40x30 20mm
0 25mm

Cannot stimulate medial or sub-cortical areas

Caution!
All the figures quoted on the previous page are estimated.

Knowledge of the magnetic field induced by the coil is not

sufficient to know the induced current in the brain - and that is
very difficult to measure

The presumed intensity of TMS is usually based on motor threshold

But this assumes a uniform and constant threshold throughout cortex

It is possible that differences in brain anatomy may lead to inter-

individual differences in the substrates of TMS effects

Temporal effects depend on recovery rate of neural area

Further Caution! Spread of activation
and the path of least resistance
Coil localisation - hitting the right spot

Find functional effect

M1 - hand twitch (MEP)
V5 - moving phosphenes

Find anatomical landmark

inion/nasion-ear/ear vertex
EEG 10/20 system

Move a set distance along and

across (e.g. FEF = 2-4 cm anterior
and 2-4 cm lateral to hand area)
Coil localisation - hitting the right spot
But: not all brains are the same

Paus et al.

MRI co-registration
Functional and structural scan
Frameless
e.g. eye movement test from functional Stereotactic
and map onto structural, then co-reg System
v. expensive and laborious
Stimulation techniques and possible effects

- +
- +

Expected effect Connected effects Paradoxical effects

Single pulse Paired pulse Paired pulse

rTMS (low/high fr.)
Control Conditions

Real

Different hemisphere Different

effect or
no effect
Sham

Different site

Or interleave TMS with no TMS trials

Major advantages summary
Reversible lesions without plasticity changes
Repeatable
High spatial and temporal resolution
Can establish causal link between brain activation and behaviour
Can measure cortical plasticity
Can modulate cortical plasticity
Therapeutic benefits

Major limitations summary

Only regions on cortical surface can be stimulated
Can be unpleasant for subjects
Risks to subjects and esp. patients
Stringent ethics required (cant be used by some institutions)
Localisation uncertainty
Stimulation level uncertainty
 Suggested Readings
Walsh and Cowey (1998) Magnetic stimulation studies of visual cognition. Trends in Cognitive
Sciences 2(3), 103 -110
Vincent Walsh and Matthew Rushworth (1999) A primer of magnetic stimulation as a tool for
neuropsychology. Neuropsychologia 37, 125 - 135
Paus (1999) Imaging the brain before, during and after transcranial magnetic stimulation.
Neuropsychologia 37.
Paus et al. (1997) Transcranial magnetic stimulation during positron emission tomography: a new
method for studying connectivity of the human cerebral cortex. Journal of Neuroscience 17, 3178
- 3184.
Cohen, L.G. et al. (1997) Functional relevance of cross-modal plasticity in blind humans Nature
389, 180183
Pascual-Leone, Walsh and Rothwell. (2000) Transcranial magnetic stimulation in cognitive
neuroscience virtual lesion, chronometry, and functional
connectivity Current Opinion in Neurobiology 2000, 10:232237
Hamilton et al., (2000).. Alexia for Braille following bilateral occipital stroke in an early blind
woman. Neuroreport 11: 237-240, 2000
Hamilton and Pascual-Leone (1998). Cortical plasticity associated with Braille learning, Trends
in Cognitive Sciences, Volume 2, Issue 5, 1 May 1998, Pages 168-174
Eric M. Wassermann. (1998). Risk and safety of repetitive transcranial magnetic stimulation:
report and suggested guidelines from the International Workshop on the Safety of Repetitive
Transcranial Magnetic Stimulation, June 57, 1996 Electroencephalography and clinical
Neurophysiology 108 (1998) 116