THE ROLE OF THE CEREBELLUM IN THE PATHOPHYSIOLOGY OF CORTICAL MYOCLONUS: INSIGHTS FROM NEUROPHYSIOLOGICAL INVESTIGATIONS

Cortical myoclonus (CM) is defined by the presence of giant SEP, enhanced long-latency reflex (LLR) (C-reflex) and jerk-locked back avaraging (JLBA), reflecting an increased sensorimotor excitability which is thought to be the cause of CM origin. In the first study, we demonstrate, however, that in more than half patients with a clinical diagnosis of CM, these techniques were not informative, mostly due to technical limitations. Moreover, according to our results, clinical-neurophysiological agreement for CM is generally quite low and electrophysiological criteria (JLBA, SEP, C-reflex) might have a lower diagnostic value compared to other neurophysiologic parameters with less powerful pathophysiological evidence (bursts duration, cranial-caudal progression, negative myoclonus). Interestingly, although SEP and C-reflex were commonly found concurrently abnormal in our study, the presence of all the three abnormalities in a single patient was very rare. This incongruity might be the consequence of different underlying mechanisms investigated by the three measures and suggests the possible involvement of several systems in CM pathophysiology. Indeed, neuropathological changes in patients with CM have most commonly been found in the cerebellum rather than in the suspected culprit, i.e. the sensorimotor cortex. It has been, in fact, hypothesised that the loss of the cerebellar inhibitory control over M1, via cerebello-thalamo-cortical connections, could be the cause of the increased sensorimotor cortical excitability seen in CM and consequently of the symptoms. In our unique case (second study) we propose that a decreased cerebellar drive from a left hypoplastic cerebellar hemisphere caused abnormalities in the mechanisms which regulate its control over the right M1, and that these, combined with abnormal somatosensory transmission, result in CM. In this case, our results pointed to a cortical origin of the myoclonus and suggest that a lack of cerebellar inhibitory control over sensorimotor areas is involved in its pathophysiology. This hypothesis was further investigated in a cohort of CM patients (third study), without cerebellar lesions. In this study, we aimed to reduce the enhanced sensorimotor excitability by increasing the inhibitory cerebellar output to M1, by means of cerebellar anodal tDCS. Nonetheless, the stimulation resulted in a facilitation, instead of inhibition, of the sensorimotor cortex excitability in CM patients. This paradoxical response was interpreted as an abnormal homeostatic plasticity within the sensorimotor cortex, likely driven by a dysfunction of the cerebellar inhibitory control over M1. In conclusion, the cerebellum certainly plays a role in the pathophysiology of CM, as demonstrated by our studies. It is possible that a deranged cerebellar output over M1 produces an abnormal homeostatic plasticity within the sensorimotor cortex, causing the well-known abnormal excitability in CM. These studies give insights on the pathophysiological mechanisms underlying CM and suggest new targets for its treatment.