An investigation of cortical excitability in Huntington's disease using transcranial magnetic stimulation
Creators: name: Philpott, April Louise
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Huntington’s disease (HD) is a neurodegenerative disorder caused by a genetic mutation that is associated with pathological changes in cortico-subcortical pathways. Clinical onset typically occurs in middle adulthood, with an array of neuropathological, cognitive, psychiatric and motor signs evident during the “premanifest” disease stage. Despite increasing knowledge of the progressive structural, microstructural and gross functional brain changes of HD, obtained via magnetic resonance imaging for example, there is inadequate understanding of the pathophysiological changes in neural pathways underlying the disease. An alternative technique, transcranial magnetic stimulation (TMS) involves non-invasive brain stimulation to assess the functional integrity of neurons at a physiological level within targeted circuits. While TMS holds great promise, it has had only limited application in HD to date and mixed findings have resulted from methodological differences between studies. This thesis sought to address a number of unanswered questions in the literature, relating to the specific pathophysiological changes in excitatory and inhibitory neuronal function occurring in premanifest and symptomatic HD. Moreover, it investigated phenotypic heterogeneity amongst HD gene carriers via examination of the clinical, cognitive and psychiatric correlates of TMS measures and various genetic variants that may modulate disease progression. Sixteen premanifest, thirteen symptomatic HD participants and seventeen healthy controls were recruited. Participants underwent clinical, cognitive and psychiatric assessment, and provided saliva samples for genotyping. TMS was administered to the left primary motor and dorsolateral prefrontal cortices, and responses were measured through electroencephalography and peripheral electromyography. Various TMS protocols were included in order to comprehensively assess cortical excitability, inhibition and facilitation. A number of significant findings emerged from these investigations. Firstly, cortical inhibition measures were impaired in premanifest and symptomatic HD, and associated with biological disease burden and development of symptomology. Furthermore, TMS was able to differentiate between pathophysiological changes in specific intracortical inhibitory circuits at different disease stages. Secondly, intracortical inhibition showed significant sex differences, with less inhibition across all female participants (but no interaction with HD-related cortical inhibitory deficits). Thirdly, in combination with the HD mutation, additional genetic variants significantly modulated individual responses to TMS and the age at HD onset. One of these gene variants (rs11789969), coding for a neurotransmitter receptor within the inhibitory pathways affected by HD, was determined to be in the top 10% most deleterious variants genome-wide, and was therefore likely to have a direct functional impact on the gene product. Taken together, the findings of this thesis provide novel insights into pathophysiology in HD including new knowledge of the sequence of functional neurological changes that occur prior to, and shortly after, clinical onset. Based on the results, it is argued that intracortical inhibitory deficits, mediated by the inhibitory neurotransmitter GABA, may be a primary pathogenic outcome in HD. Building upon this line of research, it is suggested that future studies undertake longitudinal TMS investigations of motor and non-motor cortices with larger premanifest and symptomatic HD samples. This approach will assist in identifying TMS measures that may have utility as sensitive endophenotypic biomarkers in future clinical trials.