Background A better understanding of pathophysiological abnormalities in key cortico-subcortical pathways in Huntington’s disease (HD) will enhance our understanding of the causal relationships between the gene mutation and symptomatology during disease progression.

Aims Transcranial magnetic stimulation (TMS), with a paired-pulse paradigm, was used to assess cortical excitability and inhibition in eight individuals with early symptomatic HD (symp-HD; mean age=56.0 years), twelve individuals with premanifest HD (pre-HD; mean age=41.5 years), and eight healthy controls (mean age=43.1 years).

Methods Following TMS to left motor cortex, electromyographic (EMG) responses were recorded from the right abductor pollicis brevis muscle at rest. Amplitudes of motor-evoked potentials (MEPs), after paired-pulse stimulation, were compared to MEPs elicited by single pulses, and the degree of inhibition was calculated.

Results Resting motor threshold was significantly lower in pre-HD compared with symp-HD and controls, whereas symp-HD did not differ from controls. Symp-HD individuals had significantly reduced short-interval cortical inhibition (SICI) compared with pre-HD and controls, whereas pre-HD did not differ from controls. Further, investigation of the relationship between these electrophysiological indices and neurocognitive measures revealed that for pre-HD and symp-HD individuals, the degree of SICI was significantly correlated with finger tapping performance.

Conclusions These findings suggest very early pathophysiological changes during the premanifest stages of HD. In pre-HD, increased cortical excitability may be an early compensatory response to the neurodegenerative changes in cortico-striatal circuits. Our preliminary data suggest that TMS-EMG may be a sensitive tool for teasing apart the compensatory response observed during the premanifest stages of HD.