Abnormal motor cortex excitability in preclinical and very early Huntington's disease

Abstract

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.

Figure 1

cortico-spinal system excitability. A. MEP size (area) recorded from relaxed FDI after TMS shock to the M1 hand area with 110%, 125% or 150% of RMT. Patients recruitment slopes were flatter than those of controls (repeated measures ANOVA, interaction ‘intensity*group’, F_2,72=3.9, p=0.006). Post-hoc pairwise comparisons showed that the slope of both premanifest (0=0.013) and early manifest patients (p=0.017) was flatter than in controls whereas the slopes of both patient subgroups were similar. B-D. MEP size and CSP duration recorded from active FDI after TMS shock to the M1 hand area with 130%, 150% or 175% of AMT. MEP area (B), CSP duration (C) and the ratio of CSP duration and MEP area (D) are similar in controls and HD patients. Values are means ±SEM, n=16 for HD patients (n=8 premanifest, n=8 early manifest), n=22 for controls.

Figure 2

short intra-cortical inhibition. In controls and patients increasing intensity of the conditioning stimulus reduced the size of the conditioned MEP (amplitude) in a similar way. Values are means ±SEM, n=14 for HD patients, n=22 for controls.

Figure 3

short latency afferent inhibition. A. The SAI curve was flatter for manifest HD patients compared with controls or premanifest patients. B. Maximal SAI was greatest in controls followed by premanifest patients and early manifest patients (ANOVA, main effect of ‘group’, F_2,35=19.7, p<0.001,). Post-hoc pairwise comparisons revealed that controls and premanifest patients had more SAI than early manifest patients (*p<0.001). Values are means ±SEM, n=16 for HD patients (n=8 premanifest, n=8 early manifest), n=22 for controls.

Figure 4

backward stepwise regression analysis. There was a significant correlation of max SAI with predicted years to onset of symptoms (A) and with the UHDRS motor score (B). Data are from 16 Huntington patients.