Using brain stimulation methods to probe the physiology of motor control from cortex to cerebellum
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Using brain stimulation methods to probe the physiology of motor control from cortex to cerebellum. John Rothwell UCL Institute of Neurology, London, UK. First, some history!. Transcranial methods of brain stimulation bypass the barrier of the scalp and skull.

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Using brain stimulation methods to probe the physiology of motor control from cortex to cerebellum

Using brain stimulation methods to probe the physiology of motorcontrol from cortex to cerebellum

John Rothwell

UCL Institute of Neurology, London, UK

John Rothwell IoN

John Rothwell IoN

Transcranial methods of brain stimulation bypass the barrier of the scalp and skull

Nos 1, 2 and 7 are on the motor cortex

John Rothwell IoN

Transcranial stimulation of the brain
Transcranial Stimulation of the Brain of the scalp and skull

  • 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

John Rothwell IoN

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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Gualtierotti brain. & Paterson (1954): repeated stimulation at 30Hz for 40s. Cathode right motor area, anode left motor area.

Merton (stimulated by RH Adrian) 1980: brain.

Single high voltage pulse. Anode over right hand area.

I will end by demonstrating brain.

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;861-870

TMS brain. is:

Phasic (like a peripheral nerve stimulus)

Not very focal

Does not penetrate deep into the brain

Sylvanus P Thompson

John Rothwell IoN

What gets activated in the cortex by tms
What gets activated in the cortex by TMS? loops overlap

  • 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?

John Rothwell IoN

  • Modelling studies suggest that: loops overlap

  • 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

John Rothwell IoN

Opitz loops overlap 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

John Rothwell IoN

  • Modelling studies suggest that: loops overlap

  • 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!

John Rothwell IoN

Modelling fields in loops overlapprecentralgyrus 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.

John Rothwell IoN

  • Sites of activation are therefore in grey matter at loops overlapgyral 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

Currents induced by standard “ loops overlapMagstim” 200 stimulator and coil:

NOTEthreshold 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!

John Rothwell IoN

D loops overlap

Anodal stimulation




Descending volleys from epidural space and EMGs in conscious human subject.

NB EMG recordings during active contraction to show shortest latency

Magnetic stimulation













20 uV

1 mV

10 ms

5 ms

John Rothwell IoN

Short interval intracortical inhibition (SICI) loops overlap

John Rothwell IoN

Tms inhibition after excitation
TMS: inhibition after excitation responses

  • 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

John Rothwell IoN

Transient responsesscotoma(“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

John Rothwell IoN

John Rothwell IoN

John Rothwell IoN those in corticospinal tract that produce MEPs

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)

John Rothwell IoN

TMS and EEG P < 0.01, corrected) of responses to suprathreshold rTMS of the left PMd.

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”

John Rothwell IoN

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)

John Rothwell IoN

After effects of prolonged stimulation synaptic plasticity
After-effects of prolonged stimulation: alpha frequency(10 Hz).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 abolishedby 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

Strengthening synaptic connections alpha frequency(10 Hz).

Repeated activation of an existing synapse can increase its effectiveness

Long term potentiation (LTP)

stimulation here

Record here

Short period of repetitive stimulation

Evidence that an alpha frequency(10 Hz).rTMS paradigm (iTBS) may produce after effects on cortex due to plasticity at cortical synapses (Huang et al, 2009)


Effects of theta burst stimulation on motor cortex are blocked by memantine, an NMDA receptor antagonist

Transcranial Direct Current Stimulation (TDCS) alpha frequency(10 Hz).

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

Tdcs physiology
TDCS Physiology alpha frequency(10 Hz).

  • 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

John Rothwell IoN

Creutzfeld alpha frequency(10 Hz)., Fromm & Kapp (1962). Cat cortex

Cathodal (outward)


Anodal (inward)

John Rothwell IoN

Surface anode will depolarise deep layers alpha frequency(10 Hz).

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

John Rothwell IoN

After-effects can last hours alpha frequency(10 Hz).

But note this is with polarisation through recording electrode in grey matter

John Rothwell IoN

TDCS in mouse M1 increases evoked LFPs and is blocked by NMDA receptor antagonist

Fritsch et al, 2011

John Rothwell IoN

Tdcs mechanisms of long lasting effects
TDCS: mechanisms of long lasting effects? NMDA receptor antagonist

  • 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

John Rothwell IoN

Tdcs humans
TDCS: humans NMDA receptor antagonist

  • 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

Realistic head modelling of currents in brain
Realistic head modelling of currents in brain NMDA receptor antagonist


Surface inflation note fields at depths of sulci
Surface inflation – note fields at depths of sulci NMDA receptor antagonist


Cortical interface

Normal componentofE-field

A negative normal component means that current is flowing into the cortex.

Static magnets (10min) suppress MEPs for 20min NMDA receptor antagonist

Large Magnet strength: 76kg

Small magnet: 23kg

John Rothwell IoN

Tufail NMDA receptor antagonist et al (2010)

Pulsed ultrasound stimulation of deep brain structures

(ultrasound can be focussed)

John Rothwell IoN