Electrophysiological premotor processing in Huntington's disease: an issue of functional connectivity
Creators: name: Turner, Lauren
Publisher: name: The Australian National University
Year: 2016
Subjects: HD
Huntington's disease
movement disorders
EEG
electroencephalography
motor
motor response potentials
MRP

description: Huntington’s disease is a neurodegenerative disease which presents with cognitive, motor and emotional-behavioural changes. Neural degeneration begins up to 20 years prior to symptom onset, arising initially in the striatum. Motor symptoms are a hallmark; disturbances occur due to disruption of crucial motor pathways through atrophy. However, these are not seen until much later in the disease. Such findings raise questions about the role internal processes play in maintenance of function, but little is known about functional motor connectivity during early stages. Electroencephalography is a sensitive measure of the integrity of neural process occurring prior to, and at, motor execution. This thesis explores the relationship between electrophysiological premotor/motor activation and structural integrity of critical neuroanatomy providing intra-hemispheric and inter-hemispheric connectivity – the striatum and corpus callosum. In the principal study, presymptomatic persons showed abnormal premotor activation (Contingent Negative Variation); greater relative activation across the premotor period, accompanied by normal motor potentials (Readiness Potential) and execution (response time). Aberrant premotor activation likely reflects disruption of critical inter-hemispheric circuitry such as fronto-striatal networks and the corpus callosum. Results implicated compensation in a context of early atrophy and/or an inability to regulate responses. Extending this hypothesis, Study Two examines the relationship between premotor electrophysiological activity and morphology of the striatum using magnetic resonance imaging. Structural integrity of the caudate and putamen was theorised to determine the fronto-striatal neuroanatomical circuits subserving electrophysiological responses. Quantification of volume/shape yielded structure and function associations in our combined sample: timing (latency) and consistency (relative activation/slope) of the premotor response was determined by degeneration, with greater atrophy predicting later and less consistent activation. This suggests compromise to motor pathways is progressive, and may first emerge as delayed, inefficient, and inconsistent electrophysiology. In Study Three, investigation was extended to the corpus callosum, which provides inter-hemispheric connectivity between primary and supplementary motor regions distinct from fronto-striatal pathways. It was proposed that atrophy to the corpus callosum (thinning) would disrupt both homotopic (e.g. parietal to frontal lobe) and heterotopic (e.g. left and right frontal lobe) circuits supporting premotor/motor connectivity. Raw correlations suggested compromise to mid- posterior (motor) and mid-anterior (frontal cortex/premotor/supplementary motor) affects premotor performance (extent and consistency of response). While results did not survive stringent FDR error corrections, they followed known anatomical relationships, suggesting functional motor connectivity and premotor processing are also determined by structural integrity of the corpus callosum. These findings are important in showing early, disease-related morphological changes to the striatum and corpus callosum do disrupt critical fronto-striatal and inter-hemispheric networks. Morphological changes accompanied by abnormal electrophysiological premotor activation support hypotheses of dysfunctional connectivity arising from atrophy to anatomical landmarks. Progression of circuit derangement may be mediated by secondary activation (e.g. supplementary motor areas, executive circuits) and typically indirect subcortical structures, which preserve function as connectivity with the primary motor area declines. Future studies using technology such as transcranial magnetic stimulation and diffusion tensor imaging may allow identification and stimulation of vulnerable and robust circuits respectively, potential intervention targets to preserve function and quality of life for longer.