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 sudiesDirect cortical stimulationImagingTMS

Design ConsiderationsTMS safetyContraindicationsAcceptable risksEthics Coil shapeDepth and spatial resolution of stimulationCoil LocalisationControl conditionsStimulation techniques and effects

d’Arsonval (1896/1911)Magnusson &Stevens, 1911Thompson, 1910

History of TMS and obligatory funny pictures

Merton &Morton (1980). Successful Transcranial Electrical Stimulation

Barker, 1984Barker, 1984

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

DantecMagstim

Common rTMS machines

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 sudiesDirect cortical stimulationImagingTMS

• 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 subject’s performance

– Time constraints limit the experimental paradigms

– Retesting is not possible

Other Brain-Behavior Techniques

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

Real lesion

Blue = sighted; Red = E blind

Cohen et al., 1997. Occipital TMS disrupts braille reading in early blind, but not control subjects

Hamilton et al., 2000. Reported case of blind woman who lost ability to read braille following bilateral occipital lesions

Advantages of TMS: Virtual Patientscausal link between brain activity and behaviour

TMS lesionBraille AlexiaBraille Alexia

Advantages of TMS: Chronometry

Role of “visual” Role of “visual” cortex in tactile cortex in tactile information information processing in processing in early blind early blind subjectssubjectsHamilton and Pascual-Leone, 1998

“Chronometry”: timing the contribution of focal brain activity to behavior

Paus et al.Paus et al. TMS/PET

TMS to FEF - correlation between TMS and CBF ati) stimulation site ii) distal regions consistent with known anatomical connectivity of monkey FEF

Functional connectivity- relate behaviour to the interaction between elements of a neural network

Mapping and modulation of neural plasticity - rapid changes

Serial Reaction Time Task

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.

Rapid plasticity - map changes in cortical excitability using TMS/MEPs during a learning task (Pacual-Leone et al.)

Other uses for TMSClinical - test speed, or existence of, of corticospinal connections (MS/stroke)

Therapy -rTMD has long term effects on depression

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.

Measure changes in motor excitability in neurologic disorders (e.g. PD, HD)

Mapping and modulation of neural plasticity - slow changes

Amputee cortical excitability

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 sudiesDirect cortical stimulationImagingTMS

Design ConsiderationsTMS safetyContraindicationsAcceptable risksEthics Coil shapeDepth and spatial resolution of stimulationCoil LocalisationControl conditionsStimulation 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 (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.

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.

+ minimum inter-train intervale.g. at 20Hz @1.0-1.1 T leave >5s inter train

Frequency (Hz) Max. duration (s)

1 1800+

5 10

10 5

20 1.6

25 .84

Maximum safe duration of single rTMS train at 110% MT

Follow published safety guidelines for rTMS

Caution: Guidelines not perfect

Safety

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)

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, surgicalclips, 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?

Safety TMS Adult Safety Screen

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.

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

The geometry of the coil determines the focality of the magnetic field and of the induced current - hence also of the targeted brain area.

TPractical considerations Coil shape

25mm

15mm20mm

70x60

55x4540x30

0

5mm

Practical Considerations - stimulation depth

Cannot stimulate medial or sub-cortical areas

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

It is possible that differences in brain anatomy may lead to inter-individual differences in the substrates of TMS effects

The presumed intensity of TMS is usually based on motor threshold

But this assumes a uniform and constant threshold throughout cortex

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

Temporal effects depend on recovery rate of neural area

Further Caution! Spread of activationand the path of least resistance

Find anatomical landmarkinion/nasion-ear/ear vertexEEG 10/20 system

Coil localisation - hitting the right spot

Move a set distance along and across (e.g. FEF = 2-4 cm anterior and 2-4 cm lateral to hand area)

Find functional effectM1 - hand twitch (MEP)V5 - moving phosphenes

But: not all brains are the same

Functional and structural scan

e.g. eye movement test from functional and map onto structural, then co-reg

v. expensive and laborious

MRI co-registration

Coil localisation - hitting the right spot

Frameless Stereotactic

System

Paus et al.

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Stimulation techniques and possible effects

Single pulserTMS (low/high fr.)

Paired pulse Paired pulse

Paradoxical effectsConnected effectsExpected effect

Real

Sham

Control Conditions

Different hemisphere

Different site

Different effect or no effect

Or interleave TMS with no TMS trials

Major limitations summaryOnly regions on cortical surface can be stimulatedCan be unpleasant for subjectsRisks to subjects and esp. patientsStringent ethics required (can’t be used by some institutions)Localisation uncertaintyStimulation level uncertainty

Major advantages summaryReversible lesions without plasticity changesRepeatableHigh spatial and temporal resolutionCan establish causal link between brain activation and behaviourCan measure cortical plasticityCan modulate cortical plasticityTherapeutic benefits

Suggested ReadingsWalsh and Cowey (1998) Magnetic stimulation studies of visual cognition. Trends in Cognitive Sciences 2(3), 103 -110Vincent Walsh and Matthew Rushworth (1999) A primer of magnetic stimulation as a tool for neuropsychology. Neuropsychologia 37, 125 - 135Paus (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, 180–183Pascual-Leone, Walsh and Rothwell. (2000) Transcranial magnetic stimulation in cognitiveneuroscience – virtual lesion, chronometry, and functionalconnectivity Current Opinion in Neurobiology 2000, 10:232–237Hamilton et al., (2000).. Alexia for Braille following bilateral occipital stroke in an early blind woman. Neuroreport 11: 237-240, 2000Hamilton 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 5–7, 1996 Electroencephalography and clinical Neurophysiology 108 (1998) 1–16