Motor cortex activation by transcranial magnetic stimulation in ataxia patients depends on the genetic defect

Abstract

In patients with degenerative ataxia, various abnormalities in motor cortex activation by transcranial magnetic stimulation (TMS) have been observed, including a reduction of intracortical facilitation and a lengthening of the silent period. However, the groups of patients examined in previous studies were heterogeneous, involving patients with autosomal-dominant and idiopathic cerebellar ataxia, and showing different clinical features. The aim of our present study was to investigate whether differences in motor cortex activation by TMS could be observed in genetically defined subtypes of degenerative ataxia. We examined six patients with Friedreich's ataxia, three patients with spinocerebellar ataxia (SCA) type 1, seven patients with SCA2, 12 patients with SCA3, nine patients with SCA6 and 14 healthy controls. In all subjects, motor threshold, central motor conduction time, cortical silent period after TMS, and intracortical inhibition and facilitation (as assessed by TMS using a paired pulses paradigm) were determined. Additionally, F wave amplitudes evoked by electrical peripheral nerve stimulation were measured. We found a significant reduction of intracortical facilitation in SCA2 and SCA3 patients. Furthermore, motor threshold was elevated in SCA1, central motor conduction time was lengthened in patients with Friedreich's ataxia and SCA1, and F wave amplitudes were enlarged in all the genetic subgroups except for SCA6. Silent period and intracortical inhibition did not differ between patients and controls. We conclude that changes of intracortical facilitation induced by TMS and other excitability parameters of the motor system are not a common phenomenon in degenerative ataxia, but are restricted to specific subtypes. This points to differences in the underlying pathophysiological processes in genetic subtypes of ataxia.

Heritability of Intracortical Inhibition and Facilitation

“…Interestingly, we have shown heritability of both ICF and ICI effects, whereas different genetic subtypes of ataxia only differed for changes in intracortical facilitation (Schwenkreis et al, 2002).…”

“…To date, there are no studies evaluating whether genetic heterogeneity contributes to the high interindividual variability of cortical excitability threshold levels, compared with the intersession-i.e., intraindividual-variability (Boroojerdi et al, 2000;Maeda et al, 2002;Wassermann, 2002;Orth et al, 2003). The basis of this phenotypic variability is not fully understood yet, although it is assumed that much of the difference among individuals and many of the quantitative traits are underpinned by genetic differences in gene expression (Myers et al, 2007); so far, few studies have directly evaluated the relationship between genetic factors and motor cortex activation, in relation to specific polymorphisms (Kleim et al, 2006;Cheeran et al, 2008) and genetic defects (Schwenkreis et al, 2002).…”

Electrophysiology in spinocerebellar ataxias: Spread of disease and characteristic findings

“…Recordings after paired pulse stimulation revealed reduced intracortical facilitation in SCA2 and SCA3, whereas SCA1 patients showed increased motor threshold. Silent period and intracortical inhibition were not altered in SCAs (16). Inhibitory effects were only impaired in patients with a lesion at cerebellar efferent or dentatothalamocortical pathways (17).…”

Regional patterns of cerebral glucose metabolism in spinocerebellar ataxia type 2, 3 and 6

“…By transcranial magnetic stimulation, abnormalities in motor cortex activation have also been observed in patients with SCA1, SCA2, SCA3, Friedreich ataxia [26], and SCA6 [6,18,26].…”