John RothwellUCL Institute of Neurology, London, UK

Using brain stimulation methods to probe the physiology of motor

control from cortex to cerebellum

John Rothwell IoN

First, some history!

John Rothwell IoN

John Rothwell IoN

Nos 1, 2 and 7 are on the motor cortex

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

John Rothwell IoN

Bartholow (1874): faradic stimulation of the brain of a patient exposed through a large ulcer on her scalp. Movements of contralateral body.

Transcranial Stimulation of the Brain

• 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

John Rothwell IoN

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

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

I will end by demonstratinghow failure of confidence and perseverancecan hold things up. I have here a device I built inabout 1947 to stimulate the brain through the scalp.It consists of an old-fashioned gramophone motordriving contacts which connect a condenser alternatelyto a battery and then to the subject. We usedlong trains of stimuli and large plate electrodes oneither side of the head. This was unsuccessful becauseit became too painful before the voltage could beturned up enough to make it effective. I now showthat using this original stimulator but with the rightsort of electrodes in the right place, and limiting thenumber of stimuli to a few at high voltage, we couldhave succeeded all those years ago in stimulating themotor cortex

Merton, PA. Carmichael Lecture. J. Neurol. Neurosurg. Psychiatry 1981;44;861-870

John Rothwell IoN

TMS is:Phasic (like a peripheral nerve stimulus)Not very focalDoes not penetrate deep into the brain

Sylvanus P Thompson

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“Figure 8” coils are more focal at point where the two loops overlap

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?

John Rothwell IoN

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

John Rothwell IoN

John Rothwell IoN

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

Opitz et al

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!

John Rothwell IoN

John Rothwell IoN

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.

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

John Rothwell IoN

PA induced (I1 waves)

AP induced (I3 waves)

LM induced (D waves)

Currents induced by standard “Magstim” 200 stimulator and coil:

NOTE threshold is different for each direction, lowest with PA, highest LM

Each direction preferentially activates different populations of cortical neurones. They have different effects on the brain!

John Rothwell IoN

Anodal stimulation

Magnetic stimulation

LM

PA

+3%

+9%

+3%

+6%+9%

+3%+6%

+9%

+21%

AMT

AMT

AMT

20 uV10 ms

1 mV

+30%

Descending volleys from epidural space and EMGs in conscious human subject.NB EMG recordings during active contraction to show shortest latency

5 ms

D

John Rothwell IoN

Short interval intracortical inhibition (SICI)

John Rothwell IoN

I1

I2

I3 I4C o n tro l

IS I 1 m s

IS I 2 m s

IS I 3 m s

IS I 4 m s

IS I 5 m s

C o n d i tio n in gs h o c k a lo n e

1 0 µ V5 m s

1 m V5 m s

ICI showing descending volleys in epidural space and EMG responses

John Rothwell IoN

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

John Rothwell IoN

Transient scotoma (“virtual lesion”) produced by stimulation over visual cortex (Amassian et al)

0 50 100 150 2000

1

2

3

subject 1subject2subject 3

Time of TMS after visual presentation(ms)

No

of c

orre

ct le

tters 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

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

John Rothwell IoN

John Rothwell IoN

John Rothwell IoN

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)

z=0 z=-5 z=-18

z=23z=43 z=18

t4.8>8

a

b

R L

John Rothwell IoN

TMS and EEGSpread of activation from TMS stimulus over PMdFerarrelli et al (2010)

“…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”

blue traces for waking, red traces for midazolam anaesthesia

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)

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

stimulation here

Record here

Short period of repetitive stimulation

Strengthening synaptic connections

Repeated activation of an existing synapse can increase its effectivenessLong term potentiation (LTP)

TBS

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

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

John Rothwell IoN

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

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 ratesCathodal (-) stimulation decreased firing ratesCurrents 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 hoursAfter-effects could build up over 30min or so when

stimulation terminated

John Rothwell IoN

John Rothwell IoN

Creutzfeld, Fromm & Kapp (1962). Cat cortex

Cathodal (outward)

Anodal (inward)

Control

John Rothwell IoN

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

John Rothwell IoN

After-effects can last hoursBut note this is with polarisation through recording electrode in grey matter

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

Fritsch et al, 2011

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

John Rothwell IoN

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 currentsBut 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

(V/m)

Surface inflation – note fields at depths of sulci

Cortical interface

Normal component of E-field

V/m

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

John Rothwell IoN

Static magnets (10min) suppress MEPs for 20min

Large Magnet strength: 76kgSmall magnet: 23kg

John Rothwell IoN

Tufail et al (2010)Pulsed ultrasound stimulation of deep brain structures(ultrasound can be focussed)