RESUMEN
Huntington's disease (HD) affects GABA-mediated inhibitory circuitry in the cortex. As there is evidence that sex hormones affect GABAergic function, we investigated whether gender modulates GABA-related pathophysiological changes in HD. Fifteen premanifest HD, 11 symptomatic HD and 16 healthy control participants were assessed with paired-pulse transcranial magnetic stimulation applied to the primary motor cortex. Cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls. There was reduced inhibition in females overall, but no Group-by-Sex interaction. These findings suggest that sex hormones do not exert a direct influence on the mechanisms underpinning cortical inhibitory deficits in HD.
Asunto(s)
Enfermedad de Huntington/fisiopatología , Corteza Motora/fisiopatología , Inhibición Neural/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by motor, cognitive and neuropsychiatric symptoms. Recent research has established that individuals with HD display reduced discrimination of emotional facial expressions and impaired higher-order social cognitive skills, including 'theory of mind'. OBJECTIVE: This study aimed to further characterise the emotion evaluation and theory of mind deficits in HD in an ecologically-valid context, and determine their impact on socially-relevant functional abilities. METHODS: A sample of 17 HD participants and 24 healthy controls were assessed using The Awareness of Social Inference Test (TASIT), together with additional self- and informant rated measures of cognition, social communication, empathy and neuropsychiatric symptoms. RESULTS: Participants with HD showed significant difficulties in evaluating negative emotions, and understanding sincere, sarcastic and 'paradoxical sarcastic' statements, compared with controls. The ability to evaluate positive emotions was negatively correlated with behavioural problems, but no other clinical, behavioural or communication measures correlated significantly with TASIT subscales. CONCLUSIONS: These findings suggest that social cognitive difficulties in symptomatic HD may be underpinned by more generalised impairments, related to deciphering social exchanges, as opposed to a selective theory of mind deficit. Such difficulties have the potential to place significant strain on interpersonal relationships, and thus warrant thorough clinical assessment, using ecologically-valid tools, to promote early detection and development of person-centred interventions.
Asunto(s)
Síntomas Conductuales/etiología , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/psicología , Trastorno de la Conducta Social/etiología , Teoría de la Mente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración PsiquiátricaRESUMEN
Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials.
Asunto(s)
Enfermedad de Huntington/genética , Receptores de GABA-B/genética , Adulto , Edad de Inicio , Corteza Cerebral/fisiopatología , Estudios Transversales , Femenino , Estudios de Asociación Genética , Humanos , Enfermedad de Huntington/fisiopatología , Masculino , Persona de Mediana Edad , Plasticidad Neuronal , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D2/genética , Receptores de GABA-A/genética , Médula Espinal/fisiopatología , Estimulación Magnética TranscranealRESUMEN
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.
Asunto(s)
Enfermedad de Huntington/fisiopatología , Corteza Motora/fisiopatología , Inhibición Neural/fisiología , Estimulación Magnética Transcraneal , Ácido gamma-Aminobutírico/metabolismo , Adulto , Anciano , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síntomas ProdrómicosRESUMEN
Structural and functional magnetic resonance imaging modalities have been critical in advancing our understanding of the neuroanatomical and pathophysiological changes that emerge during the premanifest and symptomatic stages of Huntington's disease (HD). However, the relationship between underlying neuropathology and the motor, cognitive and behavioural changes associated with the disorder still remain poorly understood. Less conventional technologies, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), provide a unique opportunity to further investigate the causal relationships between targeted neural circuits and objective neurophysiological responses together with overt behaviours. In this review, we discuss previous successful applications of TMS in other neurological disorders and its prospective use in HD. We also address the added value of multimodal TMS techniques, such as TMS-EEG, in investigating the integrity of neural networks in non-motor regions in HD. We conclude that neurophysiological outcome measures are likely to contribute towards characterising further the trajectory of decline across functional domains in HD, enhance understanding of underlying neural mechanisms, and offer new avenues for elucidating sensitive endophenotypic biomarkers of disease progression.