Cortical Biomarkers in Huntington’s Disease: A Multicentric TMS-EEG Study

Elias P Casula, Santa Lucia Foundation, IRCCS, Rome, Italy.

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder with complete penetrance. Since the early stage, HD is characterized by a neurodegenerative process occurring first in the striatum and then in the cortex (Tabrizi et al., 2009). In particular, pathological changes are stronger over the motor cortex. Such neuronal loss are associated with the motor and cognitive symptoms characterizing HD. In light of this, the study of motor cortex excitability it is of critical importance in understanding the pathophysiology of HD (Orth et al., 2010). Here, we used a novel approach consisting in combining transcranial magnetic stimulation with concurrent electroencephalography (EEG). By simultaneously using the two techniques, is possible to directly probe the neurophysiological state of the stimulated area, and on its cortical connections. Materials and methods: 16 HD patients and 16 age-matched healthy volunteers (HV) were recruited. Clinical assessment of HD patients included the United Huntington’s Disease Rating Scale (UHDRS) and grip force assessment. Both HD patients and HV underwent a neurophysiological assessment consisting in 4 minutes of resting EEG (with eyes closed/open) and 2 sessions of TMS-EEG stimulating the primary motor cortex (M1) and the premotor cortex (PM). TMS-evoked activity was analyzed in time, space and oscillatory domain. Time-domain analysis revealed a strong reduction of later M1-TMS-evoked activity (150-250 ms after TMS; p = 0.018) in HD patients, compared to HV. Such effect was prominent over the site of stimulation (Monte Carlo p-value < 0.001). Oscillatory-domain analysis revealed a strong desynchronization of TMS-evoked response of HD patients in theta and alpha range. Analysis of associations between clinical and physiological measures revealed that mean inter-tap interval correlated positively with TMS-evoked activity amplitude and synchronization in the gamma frequency, i.e. the slower the rate of tapping the higher the degree of synchronization immediately after the TMS pulse (r=.615; p=.015). In HD, phase synchronisation in response to M1, but not PM, stimulation was lower than in controls in the theta and alpha band. This was associated with reduced M1 TMS-evoked activity and spectral EEG power, suggesting that in HD the ability of M1 to synchronise its activity in response to a strong stimulus is impaired. This could impact motor command and the ability to respond to more subtle, physiological inputs from other brain areas. In conclusion, we provide a cortical characterization of the pathophysiology of M1 in HD that could be a physiological basis for some key clinical features of the disease.