The Effect Of The Dopamine Agonist Pramipexole On Measures Of Impulsivity In Young, Healthy Participants

Patients with Parkinson disease are prescribed dopamine agonists such as pramipexole to improve motor symptoms. Several studies have found that patients taking dopaminergic medication develop impulse control disorders. In contrast, other studies suggest that some behaviors become less impulsive with pramipexole. We evaluated the performance of 20 young, healthy participants who received pramipexole (0.5 mg) and 20 participants who received placebo, on the Go/No-Go, the Stop Signal Task, and the Balloon Analogue Risk Task. We found that the pramipexole group had more timed out Go trials on the Go/No-Go task than the placebo group, suggesting reduced motor impulsivity. There were no differences between the two groups’ performance on the other impulsivity tasks. This pattern of results is in line with the theory that impulsivity consists of a motor and a cognitive aspect, and that pramipexole might decrease motor, but not cognitive impulsivity

Cortical - Basal Ganglia Circuits: Control of Behaviour and Alcohol Misuse

Highly organised and differentiated neural circuits form and unite to link the cortex with the basal ganglia and thalamus to mediate movement, cognition and behaviour. Previous assertions that the basal ganglia primarily acted to filter cortical information to facilitate motor outputs only have since given way to an understanding of the basal ganglia as a relay and gating structure with functionally and structurally segregated inputs, functions and outputs. Thus, cortical – basal ganglia circuits can be segregated into three broadly separable functional domains mediating motor (primary and supplementary motor cortex (SMA) and putamen), cognitive (dorsolateral prefrontal cortex (dlPFC) and caudate), and limbic (ventromedial prefrontal cortex and ventral striatum (VS)) processes. In addition, cognitive and behavioural programs that pass through the cortical – basal ganglia circuitry can be subject to filtering by the subthalamic nucleus (STN), which receives direct projections from the cortex. This work first demonstrated the functional organisation of segregated intrinsic cortical – basal ganglia circuits in humans, alongside a detailed map of functional subzones within STN, a small and technically inaccessible midbrain structure. The behavioural relevance of the defined cortical – basal ganglia circuits was investigated by examining the cognitive constructs of impulsivity and compulsivity. Waiting impulsivity, a tendency towards rapid premature responses that has been associated with compulsive drug use, was associated with connectivity between limbic regions including subgenual anterior cingulate cortex, VS and STN. However, motor impulsivity, in the form of stopping ability, was associated with motoric regions including pre-SMA and STN. Compulsivity was captured as deficits in: reversal learning, implicating lateral orbitofrontal cortex; attentional shifting, implicating dlPFC; and habit learning, implicating SMA. Neural circuit changes were also examined in individuals with alcohol dependence and binge drinkers. Waiting impulsivity was elevated in both groups and the functional connectivity, microstructural integrity and anatomical connectivity of the neural circuit underlying waiting impulsivity were associated with problematic drinking behaviours in both groups. Together, this work establishes that discrete functional subzones of small subcortical regions can be differentiated in humans and that their behavioural correlates can be similarly mapped. The definition of intrinsic network architecture underlying a particular behaviour and the demonstration its disturbance in psychiatric groups will crucially inform the development of future diagnostic and therapeutic models

Action control in uncertain environments

A long-standing dichotomy in neuroscience pits automatic or reflexive drivers of behaviour against deliberate or reflective processes. In this thesis I explore how this concept applies to two stages of action control: decision-making and response inhibition. The first part of this thesis examines the decision-making process itself during which actions need to be selected that maximise rewards. Decisions arise through influences from model-free stimulus-response associations as well as model-based, goal-directed thought. Using a task that quantifies their respective contributions, I describe three studies that manipulate the balance of control between these two systems. I find that a pharmacological manipulation with levodopa increases model-based control without affecting model-free function; disruption of dorsolateral prefrontal cortex via magnetic stimulation disrupts model-based control; and direct current stimulation to the same prefrontal region has no effect on decision-making. I then examine how the intricate anatomy of frontostriatal circuits subserves reinforcement learning using functional, structural and diffusion magnetic resonance imaging (MRI). A second stage of action control discussed in this thesis is post-decision monitoring and adjustment of action. Specifically, I develop a response inhibition task that dissociates reactive, bottom-up inhibitory control from proactive, top-down forms of inhibition. Using functional MRI I show that, unlike the strong neural segregation in decision-making systems, neural mechanisms of reactive and proactive response inhibition overlap to a great extent in their frontostriatal circuitry. This leads to the hypothesis that neural decline, for 4 example in the context of ageing, might affect reactive and proactive control similarly. I test this in a large population study administered through a smartphone app. This shows that, against my prediction, reactive control reliably declines with age but proactive control shows no such decline. Furthermore, in line with data on gender differences in age-related neural degradation, reactive control in men declines faster with age than that of women

Neurocomputational models of corticostriatal interactions in action selection

Schema theory is a framework based on the idea that behaviour in many areas depends on abstractions over instances called schemas, which work in a cooperative or sequential fashion, but also compete with each other for activation. Cooper & Shallice (2000) provide an implementation of schema-theory with their model that simulates how routine actions works in healthy and neurologically-impaired populations. While schema theory is helpful in representing functional interactions in the action-perception cycle, it has no commitment to a specific neural implementation. Redgrave et al.’s (2001) model of the basal ganglia is, in principle, compatible with a device that regulates the competition among schemas, carrying out action selection. This thesis is mainly concerned with improving the neurobiological plausibility of the schema theoretic account of action selection without sacrificing its theoretical underpinning. We therefore start by combining an implementation of schema-theory with a reparametrised version of the original basal ganglia model, building the model from the ground up. The model simulates two widely used neuropsychological tasks, the Wisconsin Card Sorting Test (WCST), and the Brixton Task (BRX). In order to validate the model, we then present a study with 25 younger and 25 over-60 individuals performing the WCST and BRX, and we simulate their performance using the schema-theoretic basal ganglia model. Experimental results indicate a dissociation between loss of representation (present in older adults) and perseveration of response (absent in older adults) in the WCST, and the model fits adequately simulate these findings while grounding the interpretation of parameters to the neurobiology of aging. We subsequently present a further study with 50 participants, 14 of whom have an ADHD diagnosis, performing the WCST under an untimed and a timed condition, and we then use our model to fit response time. Results indicate that impulsivity traits, but not inattention ones, predict a slower tail of responses in the untimed task and an increased number of missed responses and variability across subtasks. Using the model, we show that these results can be produced by variation of a combination of two parameters representing basal ganglia activity and top-down excitation. We conclude with recommendations on how to improve and extend the model

Dopaminergic Modulation of Intertemporal Choice

The overall goal of the studies presented in this dissertation is to improve our understanding of dopamine (DA)-associated changes in intertemporal preferences. Understanding these DA-mediated relationships is essential to our understanding of the continuous dimensions of human functioning and the promise of the RDoC framework (U.S. Department of Health and Human Services, National Institutes of 2016). Study 1 in this dissertation investigates DAergic modulation of intertemporal choice in healthy adult participants using the DA D2-receptor antagonist haloperidol and state-of-the-art computational approaches to further decompose the decision-process. Study 2 takes behavioral testing beyond the lab into real-life environments and assesses the effects of addiction related environments on intertemporal preferences and model-based reinforcement learning in regular slot machine gamblers. In Study 3 we examine whether patients with Tourette Syndrome show aberrations in intertemporal choice. This is of particular interest because Tourette Syndrome is associated with reward sensitivity and disturbances in DA neurotransmission. In Study 4 we investigate short- and long-term stability of intertemporal preferences as a function of acute and chronic deep brain stimulation in a cohort of Obsessive-Compulsive Disorder patients