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

1. 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

2. First, some history! John Rothwell IoN

3. 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

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 John Rothwell IoN

5. 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

6. John Rothwell IoN

7. 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;861-870

11. TMS is: Phasic (like a peripheral nerve stimulus) Not very focal Does not penetrate deep into the brain Sylvanus P Thompson John Rothwell IoN

12. “Figure 8” coils are more focal at point where the two loops overlap John Rothwell IoN

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? John Rothwell IoN

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 John Rothwell IoN

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 John Rothwell IoN

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! John Rothwell IoN

17. Modelling fields in precentralgyrus 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

18. 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: 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

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 10 ms 5 ms John Rothwell IoN

21. Short interval intracortical inhibition (SICI) John Rothwell IoN

22. ICI showing descending volleys in epidural space and EMG responses John Rothwell IoN

23. 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

24. 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 John Rothwell IoN

25. 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

26. John Rothwell IoN

27. 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

28. 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” John Rothwell IoN

29. 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

30. 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 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

31. 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

32. 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

33. 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

34. 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 John Rothwell IoN

35. Creutzfeld, Fromm & Kapp (1962). Cat cortex Cathodal (outward) Control Anodal (inward) John Rothwell IoN

36. 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

37. After-effects can last hours But note this is with polarisation through recording electrode in grey matter John Rothwell IoN

38. TDCS in mouse M1 increases evoked LFPs and is blocked by NMDA receptor antagonist Fritsch et al, 2011 John Rothwell IoN

39. 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

40. 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

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

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

43. Static magnets (10min) suppress MEPs for 20min Large Magnet strength: 76kg Small magnet: 23kg John Rothwell IoN

44. Tufail et al (2010) Pulsed ultrasound stimulation of deep brain structures (ultrasound can be focussed) John Rothwell IoN