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Key points• Theta burst stimulation (TBS) protocols of repetitive transcranial magnetic stimulation (rTMS) have after-effects on excitability of motor areas thought to be due to LTP-and LTD-like processes at cortical synapses. TBS protocols have significant advantages over other rTMS techniques in time and intensities used.• Eyeblink classical conditioning (EBCC) is a form of associative motor learning in which paired presentation of a conditioned (CS) and unconditioned stimulus (US) leads to the production of a conditioned eyeblink response (CR). EBCC, with its heavy dependence on cerebellar function, is an ideal protocol with which to assess and potentially quantify the possible influence of TBS on the cerebellum.• We show that cerebellar TBS has clear effects on EBCC in humans, providing evidence that TBS can influence cerebellar function despite the low intensities of stimulation used and the anatomical constraints of the posterior fossa.Abstract Theta burst stimulation (TBS) protocols of repetitive transcranial magnetic stimulation (rTMS) have after-effects on excitability of motor areas thought to be due to LTP-and LTD-like processes at cortical synapses. The present experiments ask whether, despite the low intensities of stimulation used and the anatomy of the posterior fossa, TBS can also influence the cerebellum. Acquisition and retention of eyeblink classical conditioning (EBCC) was examined in 30 healthy volunteers after continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere.In subjects who received cerebellar cTBS, conditioned responses were fewer and their onsets were earlier (in the last half of the acquisition blocks) than those from control subjects. There was, however, no effect of cerebellar cTBS on the re-acquisition of EBCC in another session of EBCC 7-10 days later. There was also no effect of cerebellar cTBS on the re-acquisition of EBCC in subjects not naïve to EBCC when the stimulation was delivered immediately before a re-acquisition session. Control experiments verified that suppressive effects of cTBS on EBCC were not due to changes in motor cortical excitability or sensory disturbance caused by cTBS. Based on previous EBCC studies in various cerebellar pathologies, our data are compatible with the hypothesis that cerebellar cTBS has a focal cerebellar cortical effect, and are broadly in line with data from studies of EBCC in various animal models. These results confirm that cerebellar TBS has measurable effects on the function of the cerebellum, and indicate it is a useful non-invasive technique with which to explore cerebellar physiology and function in humans.

Eyeblink classical conditioning (EBCC) is a cerebellum-dependent paradigm of associative motor learning, and abnormal EBCC is a neurophysiological indicator of cerebellar dysfunction. We have previously demonstrated impaired EBCC in patients with primary dystonia, but it remains uncertain if this represents actual cerebellar pathology or reflects a functional cerebellar disruption. We examined this further by: (1) studying acquisition and retention of EBCC in a second session in eight patients with cervical dystonia (CD) who had a first session 7-10 days earlier; and (2) by investigating the potential of continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere to modify a first-ever EBCC session in 11 patients with CD. EBCC data of eight healthy controls previously studied were used for additional between-group comparisons. We observed an improvement of EBCC in a second session in patients with CD, which is in contrast to patients with proven cerebellar pathology who do not show further improvement of EBCC in additional sessions. We also found that cerebellar cTBS paradoxically normalized EBCC in patients with CD, while we previously showed that it disrupts EBCC in healthy volunteers. Combined, these two experiments are in keeping with a functional and reversible disruption of the cerebellum in dystonia, a phenomenon that is probably secondary to either cerebellar compensation or to cerebellar recruitment in the abnormal sensorimotor network.

Highly selective activation of the desired muscles for each movement and inhibition of adjacent muscles is attributed to surround inhibition (SI) which differentially modulates corticospinal excitability in active and surrounding muscles. Cerebellar brain inhibition (CBI) is another inhibitory neuronal network which is known to be active at rest and during tonic muscle contraction. The way in which CBI may be modulated at movement onset and its relationship with SI has not previously been investigated. We assessed motor evoked potential (MEP) size and CBI in first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles at rest and during a simple motor task where FDI was an active muscle and ADM was not involved in the movement (surround muscle). At onset of movement, MEP size in ADM was significantly suppressed, confirming the existence of SI. In contrast, CBI in both muscles was found to be significantly decreased at the onset of the movement. This was confirmed even after adjustments for changes in MEP size occurring due to onset of muscle activity in FDI and the effects of SI in ADM. Our findings fail to functionally link SI with CBI, but they do indicate a non-topographically specific modulation of CBI in association with initiation of voluntary movement.