Cerebellum to motor cortex paired associative stimulation induces bidirectional STDP-like plasticity in human motor cortex

Abstract

The cerebellum is crucially important for motor control and adaptation. Recent non-invasive brain stimulation studies have indicated the possibility to alter the excitability of the cerebellum and its projections to the contralateral motor cortex, with behavioral consequences on motor control and adaptation. Here we sought to induce bidirectional spike-timing dependent plasticity (STDP)-like modifications of motor cortex (M1) excitability by application of paired associative stimulation (PAS) in healthy subjects. Conditioning stimulation over the right lateral cerebellum (CB) preceded focal transcranial magnetic stimulation (TMS) of the left M1 hand area at an interstimulus interval of 2 ms (CB→M1 PAS2 ms), 6 ms (CB→M1 PAS6 ms) or 10 ms (CB→M1 PAS10 ms) or randomly alternating intervals of 2 and 10 ms (CB→M1 PASControl). Effects of PAS on M1 excitability were assessed by the motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cerebellar-motor cortex inhibition (CBI) in the first dorsal interosseous muscle of the right hand. CB→M1 PAS2 ms resulted in MEP potentiation, CB→M1 PAS6 ms and CB→M1 PAS10 ms in MEP depression, and CB→M1 PASControl in no change. The MEP changes lasted for 30–60 min after PAS. SICI and CBI decreased non-specifically after all PAS protocols, while ICF remained unaltered. The physiological mechanisms underlying these MEP changes are carefully discussed. Findings support the notion of bidirectional STDP-like plasticity in M1 mediated by associative stimulation of the cerebello-dentato-thalamo-cortical pathway and M1. Future studies may investigate the behavioral significance of this plasticity.

Anodal Direct Current Stimulation of the Cerebellum Reduces Cerebellar Brain Inhibition but Does Not Influence Afferent Input from the Hand or Face in Healthy Adults

“…In turn, less excitable Purkinje cells would disinhibit the dentate nucleus and reduce inhibition imposed upon M1, as we observed. Alternatively, there are both excitatory and inhibitory interneurons within M1 that are targets for cerebello-thalamo-cortical projections [43,45,46]. Anodal DCS may have directly excited the Purkinje cells themselves and reduced activity along the cerebello-thalamo-cortical pathway.…”

“…For CBI, the stimulus intensity to evoke 50 % MEPMAX was used as the test stimulus and was conditioned by TMS over the contralateral lateral cerebellum, using a figure-of-eight flat coil, 3 cm lateral and 1 cm inferior to the inion with the handle pointing up [43]. The conditioning stimulus (CS) intensity was set to 100 % of RMT of the FDI representation in contralateral M1, and the interstimulus interval (ISI) was set to 5 ms [43][44][45][46]. For SAI, cutaneous digital stimulation was applied to the index finger using wire ring electrodes with the cathode placed over the proximal, and anode over the distal, phalanx, respectively.…”

Applications of TMS to Study Brain Connectivity

“…ccPAS CB-M1 with precisely timed and repeated paired stimulation of CB and M1 at a very short ISI of 2ms increased M1 excitability whereas a slightly longer ISI of 6 or 10ms elicited a decrease in M1 excitability (Lu et al 2012). Interestingly, CBI-M1 connectivity decreased nonspecifically after all ccPAS CB-M1 protocols.…”

Non-invasive brain stimulation as a tool to study cerebellar-M1 interactions in humans

“…duration, intensity) as for plasticity protocols over M1. A separate group of plasticity paradigms involves cerebellar-M1 paired-associative stimulation (CB-M1 PAS) [19]. This paradigm is thought to induce spike-timing dependent plasticity (STDP), by repeatedly pairing (120 pairs at a frequency of 0.25 Hz) a cerebellar afferent input with M1 suprathreshold TMS at different intervals (2, 6 and 10 ms).…”