bioRxiv ScienceSearch

Biology subjects

Paliwal, S.

Publications and source records attributed to Paliwal, S..

2 recordsLinked to original sources

Subjective estimates of uncertainty and volatility during gambling predict impulsivity after subthalamic deep brain stimulation for Parkinson’s disease

1Subthalamic deep brain stimulation (STN-DBS) for Parkinsons disease may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether STN-DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, thirty-eight participants with Parkinsons disease played a virtual casino prior to subthalamic DBS (whilst on medication) and again, three-months postoperatively (whilst on stimulation). At the group level, there was a small but statistically significant postoperative decrease in impulsivity, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participants estimate of the tendency of the slot machines winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in persons with Parkinsons disease may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable.

neuroscience

Pharmacophore-driven Identification of N-Methyl-D-Receptor Antagonists as Potent Neuroprotective Agents Validated Using In-Vivo Studies

Alzheimers disease (AD), the most widespread cause of dementia is delineated by progressive cognitive impairment in the elderly people. During its progression, N-Methyl-D-Aspartate receptor antagonists are known to play a key role in the mechanisms of learning and memory. Extensive side effects alongside other effects on learning and memory have limited the therapeutic significance of various blockers and antagonists of the NMDA receptor. In this study, we identify potential compounds targeted against NMDA. In order to reveal the essential structural features for NMDA receptor, three-dimensional pharmacophore models are constructed based on a set of known NMDA inhibitors. This is followed by virtual screening which results in novel chemical compounds having the potential to inhibit NMDA. The lead compounds are then subjected to molecular docking and assessed by a scoring function, which results in two compounds with high Libdock scores. These compounds also show interactions with important residues at the active site. The compounds are shortlisted on the basis of high estimated activity, fit values, LibDock score, no violation to Lipinskis and availability for procuring.\n\nOf the shortlisted compounds, one compound satisfying the entire aforementioned criterion is further tested using in-vivo studies on mice with the help of an eight-arm radial maze. The pharmacophore-based virtual screening protocol presented in this study pave the way forward to address the unmet medical need of Alzheimer disease.

bioinformatics