1. John Rothwell UCL Institute of Neurology, London, UK
Using brain stimulation methods to probe the physiology of motor control from cortex to cerebellum
John Rothwell
UCL Institute of Neurology, London, UK
John Rothwell IoN

2. First, some history!
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3. Transcranial methods of brain stimulation bypass the barrier of the scalp and skull
Nos 1, 2 and 7 are on the motor cortex
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4. Transcranial Stimulation of the Brain
Bartholow (1874): faradic stimulation of the brain of a patient exposed through a large ulcer on her scalp. Movements of contralateral body.
1900-present: neurosurgery (note sensory cortex)
Gualtierotti and Paterson (1954) attempt repetitive transcranial electrical stimulation of human cortex
Merton and Morton (1980): single electrical stimulation of motor and visual cortex.
Barker et al (1986): transcranial magnetic stimulation
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5. Experimental investigations into the functions of the human brain
Experimental investigations into the functions of the human brain. By Roberts Bartholow, M.D., Professor of Materia Medica and Therapeutics and of Clinical Medicine in the Medical College of Ohio; Physician to the Good Samaritan Hospital, etc
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7. Gualtierotti & Paterson (1954): repeated stimulation at 30Hz for 40s
Gualtierotti & Paterson (1954): repeated stimulation at 30Hz for 40s. Cathode right motor area, anode left motor area.

8. Merton (stimulated by RH Adrian) 1980:
Single high voltage pulse. Anode over right hand area.

9. I will end by demonstrating how failure of confidence and perseverance
can hold things up. I have here a device I built in
about 1947 to stimulate the brain through the scalp.
It consists of an old-fashioned gramophone motor
driving contacts which connect a condenser alternately
to a battery and then to the subject. We used
long trains of stimuli and large plate electrodes on
either side of the head. This was unsuccessful because
it became too painful before the voltage could be
turned up enough to make it effective. I now show
that using this original stimulator but with the right
sort of electrodes in the right place, and limiting the
number of stimuli to a few at high voltage, we could
have succeeded all those years ago in stimulating the
motor cortex
Merton, PA. Carmichael Lecture. J. Neurol. Neurosurg. Psychiatry 1981;44;

11. TMS is: Sylvanus P Thompson Phasic (like a peripheral nerve stimulus)
Not very focal
Does not penetrate deep into the brain
Sylvanus P Thompson
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12. “Figure 8” coils are more focal at point where the two loops overlap
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13. What gets activated in the cortex by TMS?
A brief electrical stimulus recruits neural elements in the following order:
Large diameter axons
Small diameter axons
Cell bodies (initial segment region)
So in the cortex we might stimulate
Axons of large diameter axons in the subcortical white matter.
Axons of neurones in the grey matter
Cell bodies in the grey matter
BUT where is the current strongest? At the surface?
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14. Modelling studies suggest that:
Currents are strong in gyral crowns (near the skull), particularly when the gyrus is oriented perpendicular to the induced electric field
This is why responses to TMS over primary motor cortex are largest and have lowest threshold if the coil induces current perpendicular to the gyrus
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15. Opitz et al
Individual brain: Fields induced on gyral crowns especially when coil is oriented perpendicular to gyrus (A)
(E) Using an anisotropic model of conductivity in grey/white matter, note that field is strong in white matter as well as in crown of gyrus. In white matter the nerve activating function will depend on orientation of the fibres to the field
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16. Modelling studies suggest that:
Unexpectedly, the anisotropic conductances in the white matter and the grey matter/white matter boundary make high induced electric fields in the subcortical white matter.
In the motor cortex white matter, the largest diameter axons are from giant Betz cells that travel in the corticospinal tract; the remainder are cortico-cortical axons
What is stimulated depends on the orientation of the fibres w.r.t. electric field and the relative proportions of each type of fibre….Betz cells are in a large minority!
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17. Modelling fields in precentral gyrus using anisotropic model
Modelling fields in precentral gyrus using anisotropic model. Note very high field strengths in white matter.
Fibres that are most likely to be activated by this are those that bend into the white matter from the grey matter.
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18. In motor cortex this causes:
Sites of activation are therefore in grey matter at gyral crown and subcortical white matter. In the latter the fibres activated preferentially will tend to bend into/out of the direction of the induced electric field
In motor cortex this causes:
Lowest threshold effects are inhibitory (is this grey matter??)
Next lowest threshold is I-wave activation (is this white matter??) with the precise set of inputs depending on the direction of induced current flow (I1 inputs with posterior-anterior induced current; I3 inputs with anterior-posterior induced current)
Higher threshold are axons of corticospinal neurones in White matter (D-inputs) (particularly if current is in latero-medial direction
Transcranial high voltage electrical stimulation leads preferentially to D-activation
John Rothwell IoN

19. Currents induced by standard “Magstim” 200 stimulator and coil:
NOTE threshold is different for each direction, lowest with PA, highest LM
PA induced (I1 waves)
AP induced (I3 waves)
LM induced (D waves)
Each direction preferentially activates different populations of cortical neurones. They have different effects on the brain!
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20. D
Anodal stimulation
AMT
+3%
+9%
Descending volleys from epidural space and EMGs in conscious human subject.
NB EMG recordings during active contraction to show shortest latency
Magnetic stimulation
AMT
+3% LM
+6%
+9%
AMT
+3% PA
+6%
+9%
+21%
+30%
20 uV
1 mV
5 ms
10 ms
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21. Membrane potential 0mV Threshold Active neurone Rest neurone I1 I2 I3
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22. Short interval intracortical inhibition (SICI)
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23. ICI showing descending volleys in epidural space and EMG responses
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24. TMS: inhibition after excitation
A single stimulus will excite neurones synchronously. In the cortex this often produces a short burst of rapid firing of cells, followed by a longer period of inhibition, rather like a “spike-wave” in epilepsy
This produces the “silent period” that follows the MEP (GABAb)
The net result of all this is that any processing in that area that is going on at the time the stimulus is given will be disrupted
Basis for “virtual lesion” studies
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25. Transient scotoma (“virtual lesion”) produced by stimulation over visual cortex (Amassian et al)
Very brief presentation of three dim letters on screen. Subjects identify the letters.
Give TMS to occiput after letters flashed
At correct timing subjects can no longer see anything
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26. TMS to motor cortex activates many outputs in addition to those in corticospinal tract that produce MEPs
These other projections can be visualised with other methods such as TMS/fMRI or TMS/EEG
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28. Brain activations obtained for a group analysis (9 subjects, P < 0
Brain activations obtained for a group analysis (9 subjects, P < 0.01, corrected) of responses to suprathreshold rTMS of the left PMd. (a) Sagittal (x=-40), coronal (y=-11), and transverse (z=55) view of activity in the left PMd. (b) Six transverse sections showing activity changes in the CMA, PMv, auditory cortex, caudate nucleus, left posterior temporal lobe, medial geniculate nucleus, and cerebellum. Activation maps are projected on a template brain (Montreal Neurological Institute, MNI)
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29. TMS and EEG Spread of activation from TMS stimulus over PMd
Ferarrelli et al (2010)
blue traces for waking, red traces for midazolam anaesthesia
“…might be possible to use TMS-EEG to assess consciousness during anesthesia and in pathological conditions, such as coma, vegetative state, and minimally conscious state”
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30. Recruitment of alpha EEG activity by 5 TMS pulses given at alpha frequency(10 Hz).
Note how the response to the initial 2 pulses is widespread, but at the last 3, is focussed at the site of stimulation, and gradually increases in magnitude
(Thut et al., 2011)
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31. After-effects of prolonged stimulation: synaptic plasticity
Occur after repetitive TMS protocols or after several minutes of continuous TDCS (or static magnet application)
Detected in motor (and visual) cortex by lasting (30min typical) effects on motor or visual thresholds as tested by single pulse TMS (MEPs, phosphenes)
Effects abolished by drugs that interfere with NMDA receptors
Thought to represent the early stages of synaptic plasticity leading to LTP/LTD at cortical synapses
Can interact with behavioural learning
John Rothwell IoN

32. Strengthening synaptic connections
Repeated activation of an existing synapse can increase its effectiveness
Long term potentiation (LTP)
stimulation here
Record here
Short period of repetitive stimulation

33. Evidence that an rTMS paradigm (iTBS) may produce after effects on cortex due to plasticity at cortical synapses (Huang et al, 2009)
TBS
Effects of theta burst stimulation on motor cortex are blocked by memantine, an NMDA receptor antagonist

34. Transcranial Direct Current Stimulation (TDCS)
Apply 1-2mA through large scalp electrodes for 5-20 min
Polarises neurones in cortex. No action potentials
Anodal TDCS tends to depolarise, cathodal to hyperpolarise
John Rothwell IoN

35. TDCS Physiology
Experiments on cat and rat cortex showed that DC polarisation of the cortical surface changed the firing rate of pyramidal neurones
Anodal (+) stimulation increased firing rates
Cathodal (-) stimulation decreased firing rates
Currents are of the order of 2.5 mA/cm2
Bindmann et al then found that the effects outlasted the DC stimulation by many minutes and hours
After-effects could build up over 30min or so when stimulation terminated
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36. Creutzfeld, Fromm & Kapp (1962). Cat cortex
Cathodal (outward)
Control
Anodal (inward)
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37. Surface anode will depolarise deep layers
Note that although Creutzfeld et al found anodal usually increased firing rates of motor cortical neurones, it sometimes decreased rates in neurones recorded from the bottom of a sulcus. Perhaps some of them are oriented in opposite direction w.r.t. the surface
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38. After-effects can last hours
But note this is with polarisation through recording electrode in grey matter
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39. TDCS in mouse M1 increases evoked LFPs and is blocked by NMDA receptor antagonist
Fritsch et al, 2011
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40. TDCS: mechanisms of long lasting effects?
Induction of 50 Hz LTP can be increased if depolarise during tetanus
Spike timing dependent plasticity can be increased by depolarising the post-synaptic cell
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41. TDCS: humans Very similar to the animal data:
Concurrent anodal TDCS increases MEPs evoked by TMS (presumably due to depolarisation of neurones by TDCS)
After-effects of TDCS seen as changes in MEP amplitude in 30min following TDCS
BUT much lower currents
But effects in human are very weak, only detectable with TMS.
Also in human the effects are very variable.
John Rothwell IoN

42. Realistic head modelling of currents in brain
(V/m)

43. Surface inflation – note fields at depths of sulci
Cortical interface
V/m
Normal component of E-field
A negative normal component means that current is flowing into the cortex.

44. Static magnets (10min) suppress MEPs for 20min
Large Magnet strength: 76kg
Small magnet: 23kg
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45. Pulsed ultrasound stimulation of deep brain structures
Tufail et al (2010)
Pulsed ultrasound stimulation of deep brain structures
(ultrasound can be focussed)
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