TMS in Clinical Practice Non-Standard Methods SILENT PERIOD: during voluntary contraction of the target muscle TMS evokes a MEP followed by a period of inhibition of the ongoing EMG activity The SP: - is expressed in msec and measured from the onset of MEP to the restart of a constant EMG activity (approximately >25% of pre-stimulus level) - gives information on GABA-mediated mechanisms controlling motor cortex excitability

Cortical Silent Period

Cortical Silent Period The SP evoked in the muscles of the upper limb originates largely from activation of cortical inhibitory interneurons, although spinal mechanisms are involved in the early part The SP recorded from the facial muscles originates solely in the cortex SP is longest in hand muscles and is shorter in proximal arm, leg muscles facial muscles diaphragm and anal sphincter In upper limb muscles, the SP can be evoked at lower stimulus intensities than the MEP SP duration is related to the intensity of stimulation but is not strongly related to the size of the preceding MEP nor to the levels of background EMG activity

Cortical Silent Period SP duration can be modulated by physiological phenomena that change cortical excitability, hyperventilation sleep deprivation muscle fatigue high-frequency rTMS. Pharmacological studies using benzodiazepines, selective agonists of the benzodiazepine receptor subtype BZ1, baclofen, tiagabine provided evidence that the SP reflects a long-lasting cortical inhibition mediated by GABAB receptors. Dopaminergic drugs lengthen the SP in normal subjects

Contralateral and Ipsilateral SPs A similar period of silence can be observed also in the ongoing EMG activity of the ipsilateral muscles. Such ipsilateral silent period probably originates from transcallosal inhibition

Il periodo silente “ipsilaterale” origina dall’attivazione di vie inibitorie transcallosali, per cui può essere utilizzato per misurare la conduzione attraverso il corpo calloso

TMS in Clinical Practice Non-Standard Methods 80-90% RMT 95% AMT 1 mV conditioning test PAIRED TMS: two magnetic stimuli can be delivered with: different intensity of stimuli variable interval between them (inter-stimulus intervals)

TMS in Clinical Practice Non-Standard Methods The test stimulus (suprathreshold) can be inhibited by a conditioning (subthreshold-80-90% RMT) stimulus given 1-5 msec before (INTRACORTICAL INHIBITION - SICI) or can be facilitated when the interval is longer than 7 msec (INTRACORTICAL FACILITATION - SICF) The conditioned test MEP is measured from peak-to-peak and expressed as a percentage of the unconditioned test MEP. Kujirai et al. 1993

Intracortical inhibition and facilitation These phenomena originate in the cortex from different neuronal populations: GABAA receptors mediate the enhancement of intracortical inhibition glutamatergic receptors mediate intracortical facilitation

Abbruzzese et al. 2002

Intracortical Inhibition and Facilitation GABAA-agonists: > ICI < ICF NMDA-antagonists: > ICI DA-agonists: > ICI DA-antagonists: < ICI > ICF GLU rec. SICF GABAA rec. SICI

GABA-A GABA-B SICI SP Hanajima et al. 1998 Werhahn et al. 1999

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GABAA receptor subtype specific enhancement of inhibition in human motor cortex: SICI is not mediated by the α1-subunit-bearing subtype of the GABAAR but by those bearing either the α2- or α3-subunit * * 15

Paired pulse transcranial magnetic stimulation at 10-25 ms ISIs ICF Paired pulse transcranial magnetic stimulation at 10-25 ms ISIs 16

Excitatory circuits activated by TMS 17

ISI= N20 + 2-8 ms Transcranial magnetic stimulation EMG recordings (FDI) Median nerve stimulation ISI= N20 + 2-8 ms 18

Short latency afferent inhibition 19

Short latency afferent inhibition Baseline After Scopolamine Test ISI=N20 latency + 3 ms 20

Gulledge AT, Stuart GJ. Cholinergic inhibition of neocortical pyramidal neurons. J Neurosci. 2005;25:10308-20

GABAA receptor subtype specific suppression of afferent inhibition in human motor cortex: α5-subunit ? * * * *

Inhibitory circuits activated by TMS 24

TMS-effetto intensità: curva dose-risposta del MEP SMAP 26

Input-Output Curves Cortical Maps Measure of the number and topographical representation of excitable sites