title: Cortical inhibitory deficits in premanifest and early Huntington's disease.
abstract: Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington's disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short-interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long-interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype.
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC, Australia.
authors.forename: April L
authors.initials: AL
authors.lastname: Philpott
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC, Australia.
authors.forename: Tarrant D R
authors.initials: TDR
authors.lastname: Cummins
authors.affiliation: Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and the Alfred, Melbourne, VIC, Australia.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Bailey
authors.affiliation: Department of Neurology, Monash Medical Centre, Clayton, VIC, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Churchyard
authors.affiliation: Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and the Alfred, Melbourne, VIC, Australia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fitzgerald
authors.affiliation: School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC, Australia. Electronic address: nellie.georgiou-karistianis@monash.edu.
authors.forename: Nellie
authors.initials: N
authors.lastname: Georgiou-Karistianis
mesh_terms: D000328:Adult; D000368:Aged; D004576:Electromyography; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009433:Neural Inhibition / Q000502:physiology*; D062706:Prodromal Symptoms; D050781:Transcranial Magnetic Stimulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid
keywords: Cortical inhibition; Corticostriatal; GABA; Pathophysiological mechanism; Premanifest Huntington’s disease; Transcranial magnetic stimulation