Biology subjects

Gilbertson, T.

Publications and source records attributed to Gilbertson, T..

6 recordsLinked to original sources

bioRxiv2025

Focused ultrasound neuromodulation of mediodorsal thalamus disrupts decision flexibility during reward learning

When learning to find the most beneficial course of action, the prefrontal cortex guides decisions by comparing estimates of the relative value of the options available. Basic neuroscience studies in animals support the view that the thalamus can regulate this activity within and across the prefrontal cortex. We studied a group of patients (n=37) undergoing unilateral MR guided focused ultrasound for essential tremor, performing the restless bandit, a reward reinforcement learning task, immediately before and after thalamotomy. Thalamotomy significantly impaired the proportion of switch choices during the task without affecting overall performance. This effect was observed when the task was delivered to co-incide with maximal vasogenic thalamic oedema but not in a control group tested on the same day of their treatment. A reinforcement learning model fitted to the patients choices replicated the effect of thalamotomy when the model increased exploitation of the bandits learnt value estimate. This shift in the explore-exploit trade-off, manifesting as reduced choice flexibility, co-varied with the pattern of post-operative oedema extension into mediodorsal nucleus. These findings confirm a causal role of the thalamus and specifically the mediodorsal nucleus, in regulating the extent to which value estimates are used to guide decisions and learning from reward.

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bioRxiv2023

Impaired value-based decision-making in Parkinson's Disease Apathy

Apathy is a common and disabling complication of Parkinsons disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within pre-frontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, non-dopaminergic neuromodulators, influence decisions to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesised that Apathy in Parkinsons disease should be associated with a failure to adequately monitor and make adaptive choices when the rewarding outcome of decisions are uncertain. Using a 4-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinsons disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with Apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patients apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patients choices confirmed the apathy group made decisions that that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001). We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinsons disease, which was more marked in Apathy, but not predictive of their individual Apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated pre-frontal cortex to a similar degree to the age-matched controls. In contrast, Parkinsons patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinsons disease.

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bioRxiv2022

Pallidal neuromodulation of the explore/exploit trade-off in decision-making

Every decision that we make involves a conflict between exploiting our current knowledge of an actions value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit dilemma. To test this hypothesis, we examined the effects of neuromodulating the basal ganglias output nucleus, the globus pallidus interna, in patients who had undergone deep brain stimulation (DBS) for isolated dystonia. Neuromodulation enhanced the number of exploratory choices to the lower value option in a 2-armed bandit probabilistic reversal-learning task. Enhanced exploration was explained by a reduction in the rate of evidence accumulation (drift rate) in a reinforcement learning drift diffusion model. We estimated the functional connectivity profile between the stimulating DBS electrode and the rest of the brain using a normative functional connectome derived from heathy controls. Variation in the extent of neuromodulation induced exploration between patients was associated with functional connectivity from the stimulation electrode site to a distributed brain functional network. We conclude that the basal ganglias output nucleus, the globus pallidus interna, can adaptively modify decision choice when faced with the dilemma to explore or exploit.

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bioRxiv2020

Tonic dopamine, uncertainty and basal ganglia action selection.

To make optimal decisions in uncertain circumstances flexible adaption of behaviour is required; exploring alternatives when the best choice is unknown, exploiting what is known when that is best. Using a detailed computational model of the basal ganglia, we propose that switches between exploratory and exploitative decisions can be mediated by the interaction between tonic dopamine and cortical input to the basal ganglia. We show that a biologically detailed action selection circuit model of the basal ganglia, endowed with dopamine dependant striatal plasticity, can optimally solve the explore-exploit problem, estimating the true underlying state of a noisy Gaussian diffusion process. Critical to the models performance was a fluctuating level of tonic dopamine which increased under conditions of uncertainty. With an optimal range of tonic dopamine, explore-exploit decision making was mediated by the effects of tonic dopamine on the precision of the model action selection mechanism. Under conditions of uncertain reward pay-out, the models reduced selectivity allowed disinhibition of multiple alternative actions to be explored at random. Conversely, when uncertainly about reward pay-out was low, enhanced selectivity of the action selection circuit was enhanced, facilitating exploitation of the high value choice. When integrated with phasic dopamine dependant influences on cortico-striatal plasticity, the models performance was at the level of the Kalman filter which provides an optimal solution for the task. Our model provides an integrative account of the relationship between phasic and tonic dopamine and the action selection function of the basal ganglia and supports the idea that this subcortical neural circuit may have evolved to facilitate decision making in non-stationary reward environments, allowing a number of experimental predictions with relevance to abnormal decision making in neuropsychiatric and neurological disease.

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bioRxiv2019

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

Patients with dystonia caused by the mutated TOR1A gene exhibit a risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. We hypothesised this increased risk taking could be reproduced by a reinforcement learning model which included biologically realistic striatal plasticity learning rules. We aimed to test whether a specific combination of cortico-striatal plasticity abnormalities at D1 and D2 receptors could explain the abnormal behaviour. We found a model of cortico-striatal plasticity could generate simulated behaviour indistinguishable from patients only when both D1 and D2 plasticity was abnormally increased in opposite directions: specifically when D1 synaptic potentiation and D2 depotentiation were both increased. This result is consistent with previous observations in rodent models of cortico-striatal plasticity at D1 receptors, but contrasts with the pattern reported in vitro for D2 synapses. This suggests that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 synaptic plasticity that are not apparent in rodent models of this disease.

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bioRxiv2019

Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico-striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico-striatal synaptic plasticity contributes to abnormal reward-learning behavior in patients with focal dystonia. Forty patients and forty controls performed a reward-gain and loss-avoidance reversal learning task. Participants behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico-striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesised receptor specific abnormalities of cortico-striatal long term potentiation (LTP) and Long Term Depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post-reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patients motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patients behavior, suggesting excessive D2 cortico-striatal synaptic depotentiation could underpin biased reward learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioural correlate of D2 specific abnormalities in cortico-striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward-learning behavior in these patients.

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