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2.  The Effect of Motivation on Movement: A Study of Bradykinesia in Parkinson’s Disease 
PLoS ONE  2012;7(10):e47138.
Bradykinesia is a cardinal feature of Parkinson’s disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes.
Methodology/Principal Findings
We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific.
We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes.
PMCID: PMC3471921  PMID: 23077557
3.  Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease 
Brain  2012;135(6):1871-1883.
The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson’s disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.
PMCID: PMC3359751  PMID: 22508958
Parkinson’s disease; learning; functional MRI; dopamine
4.  Dopamine, Affordance and Active Inference 
PLoS Computational Biology  2012;8(1):e1002327.
The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.
Author Summary
Dopamine is a neurotransmitter that has been implicated in a wide variety of cognitive and motor functions; it is depleted in Parkinson's disease, disrupted in schizophrenia and plays a central role in working memory, reinforcement learning and other cognitive functions. In this paper, we present a straightforward and neurophysiologically grounded explanation for the diversity of functions and pathologies that implicate dopamine. This explanation rests on a principled approach to the nature of action and perception called active inference. This approach suggests that (Bayes) optimal perception and consequent behaviour depends on representing uncertainty about states of the world in terms of the precision (inverse amplitude) of their random fluctuations. Crucially, this uncertainly can be encoded by the same postsynaptic gain of neurons that is modulated by dopamine. This means that changing the levels of dopamine changes the level of uncertainty about different representations. To substantiate this idea, we simulate dopamine depletion in a hierarchical sensorimotor network to show that a single function of dopamine (encoding precision in terms of postsynaptic gain) is not only sufficient to account for commonly observed behaviours following dopamine depletion but also provides a unifying perspective on many existing theories about dopamine.
PMCID: PMC3252266  PMID: 22241972
5.  Dopamine, Time, and Impulsivity in Humans 
Disordered dopamine neurotransmission is implicated in mediating impulsiveness across a range of behaviors and disorders including addiction, compulsive gambling, attention-deficit/hyperactivity disorder, and dopamine dysregulation syndrome. Whereas existing theories of dopamine function highlight mechanisms based on aberrant reward learning or behavioral disinhibition, they do not offer an adequate account of the pathological hypersensitivity to temporal delay that forms a crucial behavioral phenotype seen in these disorders. Here we provide evidence that a role for dopamine in controlling the relationship between the timing of future rewards and their subjective value can bridge this explanatory gap. Using an intertemporal choice task, we demonstrate that pharmacologically enhancing dopamine activity increases impulsivity by enhancing the diminutive influence of increasing delay on reward value (temporal discounting) and its corresponding neural representation in the striatum. This leads to a state of excessive discounting of temporally distant, relative to sooner, rewards. Thus our findings reveal a novel mechanism by which dopamine influences human decision-making that can account for behavioral aberrations associated with a hyperfunctioning dopamine system.
PMCID: PMC3059485  PMID: 20592211
6.  Experience and Choice Shape Expected Aversive Outcomes 
The value assigned to aversive events is susceptible to contextual influences. Here, we asked whether a change in the valuation of negative events is reflected in an altered neuronal representation of their expected aversive outcome. We show that experiencing an aversive event in the past, and choosing to experience it in the future, reduces its aversive value. This psychological change is mirrored in an altered neural representation of aversive value in the caudate nucleus, and anterior cingulate cortex (ACC). Our findings indicate that subcortical regions known to track expected value such as the caudate nucleus, together with anterior cingulate cortical regions implicated in emotional modulation, mediate a re-valuation in expectancies of aversive states. The results provide a striking example of a contextual sensitivity in how the brain ascribes value to events, in a manner that may foster resilience in the face of adversity.
PMCID: PMC2923025  PMID: 20610755
7.  Dopamine Enhances Expectation of Pleasure in Humans 
Current Biology  2009;19(24):2077-2080.
Human action is strongly influenced by expectations of pleasure. Making decisions, ranging from which products to buy to which job offer to accept, requires an estimation of how good (or bad) the likely outcomes will make us feel [1]. Yet, little is known about the biological basis of subjective estimations of future hedonic reactions. Here, we show that administration of a drug that enhances dopaminergic function (dihydroxy-L-phenylalanine; L-DOPA) during the imaginative construction of positive future life events subsequently enhances estimates of the hedonic pleasure to be derived from these same events. These findings provide the first direct evidence for the role of dopamine in the modulation of subjective hedonic expectations in humans.
PMCID: PMC2801060  PMID: 19913423
8.  Pneumonia 
BMJ : British Medical Journal  2006;332(7551):1213.
PMCID: PMC1463934  PMID: 16710006

Results 1-8 (8)