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

Using transcranial magnetic stimulation (TMS) we examined motor cortex excitability in 8 premanifest HD gene carriers, 8 very early symptomatic HD patients and 22 healthy controls. Electrophysiological measures were correlated with the clinical stage of HD to identify motor cortical dysfunction prior to overt clinical disease onset.

Results

Premanifest and early manifest HD patients had higher resting and active motor cortex thresholds than controls (p=0.024). At rest, recruitment of motor evoked potentials was more gradual in both patient groups than in controls (p=0.001). When active, recruitment and the duration of the cortical silent period were similar in all groups. There was a tendency for short latency intra-cortical inhibition (SICI) 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 controls and premanifest patients (p<0.001) and in contrast to all other measures was inversely associated with predicted years to onset of HD signs (p=0.013, adjusted R2=0.32) and the UHDRS motor score (p=0.001, adjusted R2=0.5). A combination of age, CAG repeat length, and SAI strongly predicted the UHDRS motor score (p=0.001, adjusted R2=0.68).

Conclusions

Since reduced excitatory and inhibitory corticospinal thresholds and MEP recruitment in patients at rest do not correlate with symptom severity, they may be a consequence of carrying the HD mutation. In contrast, SAI correlated with the severity of motor signs and may reflect the disease state.

Background

Cognition is affected early in Huntington's disease, and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. We investigated whether there is evidence for abnormal synaptic plasticity using the human motor cortex-rTMS model, and if so, if there is any difference between premanifest HD gene carriers and very early manifest HD patients or any relationship with ratings of the severity of motor signs.

Methods

Fifteen HD gene carriers (7 premanifest, 8 very early manifest) and 14 control participants were given a continuous train of 100 bursts of theta burst stimulation (cTBS: three pulses at 50 Hz and 80% AMT repeated every 200ms). The size of the motor evoked potential was measured at regular intervals until 21 minutes after cTBS.

Results

HD gene carriers and controls responded differently to theta burst stimulation (F4.9,131.9=1.37, p=0.048) with controls having more inhibition than HD gene carriers (F1,27=13.3, p=0.001). Across all time points mean inhibition differed between the groups (F2,26=6.32, p=0.006); controls had more inhibition than either HD gene carrier subgroup (p=0.006 for premanifest and p=0.009 for early symptomatic) whereas there was no difference between premanifest and early symptomatic HD gene carriers. The measure of cortical plasticity was not associated with any clinical ratings (UHDRS motor score, estimate of age at onset).

Conclusions

Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD.

Dystonia is characterised by two main pathophysiological abnormalities: reduced excitability of inhibitory systems at many levels of the sensorimotor system, and increased plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short interval intracortical inhibition, SICI) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation, PAS) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.

Background

Dystonia is associated with impaired somatosensory ability. The electrophysiological method of repetitive transcranial magnetic stimulation (rTMS) can be used for non-invasive stimulation of the human cortex and can alter cortical excitability and associated behaviour. Among others, rTMS can alter/improve somatosensory discrimation abilities, as shown in healthy controls.

Methods

We applied 5Hz-rTMS over the left primary somatosensory cortex (S1) in 5 patients with right-sided writer's dystonia and 5 controls. We studied rTMS effects on tactile discrimination accuracy and concomitant rTMS-induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI).

Results

Prior to rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task-related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG.

Conclusion

Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG-S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task.