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

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 subject’s 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 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 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 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

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 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)

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 (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.

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 20Hz @1.0-1.1 T leave >5s inter train 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 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.

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.

Practical Considerations - stimulation depth 70x60 5mm 55x45 15mm 40x30 20mm 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)

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

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

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 (can’t 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, 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: 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 5–7, 1996 Electroencephalography and clinical Neurophysiology 108 (1998) 1–16