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Akshay Nair

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2 papers

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YNICL Journal 2022 Journal Article

Timing of selective basal ganglia white matter loss in premanifest Huntington’s disease

Paul Zeun
Peter McColgan
Thijs Dhollander
Sarah Gregory
Eileanoir B. Johnson
Marina Papoutsi
Akshay Nair
Rachael I. Scahill

OBJECTIVES: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. METHODS: We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. RESULTS: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. CONCLUSIONS: Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.

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RLDM Conference 2019 Conference Abstract

Vigour as a diagnostic of apathy: sensitivity to opportunity costs of time pre- dicts action latencies

Akshay Nair
Ritwik K Niyogi
Sarah Tabrizi
Geraint Rees
Robb Rutledge

Choosing how fast to act is a critical component of goal-directed behaviour, and is impaired in a range of neurological (e. g. Huntington’s) and psychiatric disorders (e. g. major depression). Prolonged laten- cies of self-initiated behaviour are a hallmark of apathy, a common and disabling neuropsychiatric symptom. Understanding the computational basis of free operant action initiation may therefore lay the groundwork for better understanding apathy. Central to this is the opportunity cost of time (OCT). Slow responses deny participants benefits that might accrue from alternate activities, (they incur opportunity costs), which are greater when the rewards in the environment are larger. Here we demonstrate, with a novel behavioural task, that healthy participants adapt their choice of free operant action latencies rapidly in response to the OCT. Furthermore we demonstrate a strong relationship between sensitivity of action latencies to OCT and behavioural apathy scores (r = −0. 78, p < 0. 001). To better understand this relationship, we modelled task data using an average-reward reinforcement learning (RL) model at the heart of which is a trade-off between the OCT and the cost of vigour. By quantitatively fitting the latencies of responses, we show that highly apathetic participants are more sensitive to changes in OCT when compared to less apathetic par- ticipants. Furthermore the model captures changes in latency distributions in apathetic individuals. These results suggest that understanding the basis of OCT and the use of average-reward RL models may provide a novel theoretical framework for the investigation of apathy. This can provide new avenues for stratifying clinical populations with quantitative, precise diagnostics.

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