1. Techniques in Cognitive Neuroscience
Transcranial Magnetic Stimulation (TMS)
Dr. Roger Newport

2. 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

3. History of TMS and obligatory funny pictures
Merton &Morton (1980). Successful Transcranial Electrical Stimulation
d’Arsonval (1896/1911)
Magnusson &
Stevens, 1911
Thompson, 1910

4. Barker, 1984
Common rTMS machines
Magstim
Dantec
Transcranial Magnetic Stimulation allows the Safe, Non-invasive and Painless Stimulation of the Human Brain Cortex.
Cadwell

5. Electromagnetic Induction
Introduces disorder into a normally ordered system

6. 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

7. 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

8. 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 subject’s performance
Time constraints limit the experimental paradigms
Retesting is not possible

9. 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)

10. 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

11. Advantages of TMS: Virtual Patients
causal link between brain activity and behaviour
Braille Alexia
Real lesion
TMS lesion
Cohen et al., Occipital TMS disrupts braille reading in early blind, but not control subjects
Hamilton et al., Reported case of blind woman who lost ability to read braille following bilateral occipital lesions
Blue = sighted; Red = E blind

12. 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

13. Functional connectivity- relate behaviour to the interaction between elements of a neural network
TMS
TMS to FEF - correlation between TMS and CBF at
i) stimulation site
ii) distal regions consistent with known anatomical connectivity of monkey FEF
Paus et al.
TMS/PET

14. 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

15. Mapping and modulation of neural plasticity - slow changes
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
Amputee cortical excitability
Measure changes in motor excitability in neurologic disorders (e.g. PD, HD)

16. 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

17. 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

18. 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 ( dB) in the most sensitive frequency range (2–7 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 don’t put your tea on it.

19. 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.

20. Safety Follow published safety guidelines for rTMS
Maximum safe duration of single rTMS train at 110% MT
Frequency (Hz)
Max. duration (s) 1
1800+ 5 10 20
1.6 25
.84
+ minimum inter-train interval
e.g. at T leave >5s inter train
Caution: Guidelines not perfect

21. 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)

22. 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?

23. Ethics Guidelines Levels of Risk
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.

24. Practical considerations
Coil shape T
The geometry of the coil determines the focality of the magnetic field and of the induced current - hence also of the targeted brain area.

25. Practical Considerations - stimulation depth
70x60
5mm
55x45
15mm
40x30
20mm
25mm
Cannot stimulate medial or sub-cortical areas

26. 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

27. Further Caution! Spread of activation
and the path of least resistance

28. 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)

29. Frameless Stereotactic System
Coil localisation - hitting the right spot
But: not all brains are the same
Paus et al.
MRI co-registration
Functional and structural scan
Frameless Stereotactic System
e.g. eye movement test from functional and map onto structural, then co-reg
v. expensive and laborious

30. - - Stimulation techniques and possible effects + Expected effect
Connected effects
Paradoxical effects
Single pulse
rTMS (low/high fr.)
Paired pulse
Paired pulse

31. Control Conditions Real Different hemisphere
Different effect or no effect
Sham
Different site
Or interleave TMS with no TMS trials

32. 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 (can’t be used by some institutions)
Localisation uncertainty
Stimulation level uncertainty

33. Suggested Readings
Walsh and Cowey (1998) Magnetic stimulation studies of visual cognition. Trends in Cognitive Sciences 2(3),
Vincent Walsh and Matthew Rushworth (1999) A primer of magnetic stimulation as a tool for neuropsychology. Neuropsychologia 37,
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,
Cohen, L.G. et al. (1997) Functional relevance of cross-modal plasticity in blind humans Nature 389, 180–183
Pascual-Leone, Walsh and Rothwell. (2000) Transcranial magnetic stimulation in cognitive
neuroscience – virtual lesion, chronometry, and functional
connectivity Current Opinion in Neurobiology 2000, 10:232–237
Hamilton et al., (2000).. Alexia for Braille following bilateral occipital stroke in an early blind woman. Neuroreport 11: , 2000
Hamilton and Pascual-Leone (1998). Cortical plasticity associated with Braille learning, Trends in Cognitive Sciences, Volume 2, Issue 5, 1 May 1998, Pages
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 5–7, 1996 Electroencephalography and clinical Neurophysiology 108 (1998) 1–16