Nair, A;
Razi, A;
Gregory, S;
Rutledge, RR;
Rees, G;
Tabrizi, SJ;
(2021)
Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington's disease.
Brain
10.1093/brain/awab367.
(In press).
Preview |
Text
awab367.pdf - Accepted Version Download (1MB) | Preview |
Abstract
The gating of movement depends on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways-the direct and indirect basal ganglia pathway. Both are complex and polysynaptic but the overall effect of activity within these pathways is thought to encourage and inhibit movement respectively. In Huntington's disease (HD), the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition giving rise to the characteristic motor features of the condition. But early HD is also associated with apathy, a loss of motivation and failure to engage in goal-directed movement. We hypothesised that in HD, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction respectively. We used spectral dynamic casual modelling of resting state fMRI data to model effective connectivity in a model of these cortico-striatal pathways. We tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal HD. Using an advanced approach at the group level by combining Parametric Empirical Bayes and Bayesian Model Reduction procedure to generate large number of competing models and compare them by using Bayesian model comparison. With this automated Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. Firstly, more severe motor signs in HD were associated with altered connectivity in the indirect pathway components of our model and, by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component. The empirical evidence we provide here is demonstrates that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of HD and may have important implications for therapeutics.
| Type: | Article |
|---|---|
| Title: | Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington's disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awab367 |
| Publisher version: | https://doi.org/10.1093/brain/awab367 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com. |
| Keywords: | Bayesian analysis, basal ganglia, huntington's disease, corpus striatum, ion channel gating, neostriatum, neurons, thalamus, apathy, functional magnetic resonance imaging, motor deficits, loss of motivation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10136776 |
Archive Staff Only
 |
View Item |
