BACKGROUND: In Huntington's disease (HD), the cerebral cortex is involved early in the disease process. The study of cortical excitability can therefore contribute to understanding HD pathophysiology. METHODS: With transcranial magnetic stimulation (TMS) we examined motor cortex excitability in 8 premanifest HD gene carriers, 8 very early symptomatic HD patients, and 22 healthy control subjects. Electrophysiological measures were correlated with the clinical stage of HD to identify motor cortical dysfunction before overt clinical disease onset. RESULTS: Premanifest and early manifest HD patients had higher resting and active motor cortex thresholds than control subjects (p = .024). At rest, recruitment of motor evoked potentials was more gradual in both patient groups than in control subjects (p = .001). When active, recruitment and the duration of the cortical silent period were similar in all groups. There was a tendency for short interval intra-cortical inhibition to have a higher threshold in all patients taken together but not in each group separately. Short latency afferent inhibition (SAI) was reduced in early manifest patients compared with control subjects and premanifest patients (p <.001) and in contrast to all other measures was inversely associated with estimated time to onset (p = .013, adjusted R(2) = .32) and the Unified Huntington's Disease Rating Scale motor score (p = .001, adjusted R(2) = .5). A combination of age, CAG repeat length, and SAI strongly predicted the Unified Huntington's Disease Rating Scale motor score (p = .001, adjusted R(2) = .68). CONCLUSIONS: Our findings add to the evidence for early cortical involvement in HD possibly before HD signs appear.
