Tamara Shiner

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.

Dopamine, Affordance and Active Inference

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 Parkinsons 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.

Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease

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.

Dopamine Enhances Expectation of Pleasure in Humans

Summary 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.

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. 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 revaluation 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.

Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by paroxysms of dystonic, choreic, ballistic, or athetoid movements. Attacks usually commence during childhood or early adulthood, typically lasting a few seconds to a few minutes, and they can occur up to 100 times daily. Attacks usually respond to low-dose carbamazepine [1]. Mutations in PRRT2 have been identified as a cause of autosomal dominant PKD [2] and replicated in other studies [3-7]. It remains important to report the clinical characteristics of genetically defined families in order to fully describe the clinical syndrome, including the presence of additional associated features beyond the movement disorder. In a large Caucasian family with PKD (Fig. 1), a detailed neurological history and clinical examination were undertaken. Sanger sequencing of PRRT2 was performed. Three individuals have PKD alone, and three individuals have PKD and infantile convulsions (IC). Two individuals had isolated IC, whilst two other individuals had at least one adolescent seizure but no movement disorder. The age of onset for the movement disorder ranged between 3 and 30 years. Infantile convulsions occurred between the age of 6 and 12 months. In all cases, PKD attacks were choreic or dystonic in nature, lasting less than a minute, and responded well to carbamazepine. Attacks were provoked by sudden movements in all, with stress in II:10 and III:9. Four individuals were treated with low-dose carbamazepine and/or phenytoin for PKD/IC, which abolished symptoms of the movement disorder. Neurological examination was normal (Table 1). Fig. 1 Pedigree of Family 1. All individuals with symptoms of PKD, PKD and IC, or isolated IC were found to have a frameshift mutation in PRRT2 (c.649_650InsC p.P217fsX7) indicated by a plus symbol; individuals found not to have the mutation are indicated by ... Table 1 Clinical descriptions and genotyping results for family members Sanger sequencing of PRRT2 revealed the recognized pathogenic (c.649_650InsC p.P217fsX7) heterozygous mutation [2-7] in all eight clinically affected individuals as well as in three of the seven clinically unaffected individuals (Fig. 1). PRRT2 mutations are unlikely to be the cause of adolescent-onset seizures in this family, as individual III:12 did not carry the mutation. Non-penetrance was observed in three individuals. Migraine with aura, as classified using the International Headache Society diagnostic criteria [8], co-segregated in all but one individual with the p.P217fsX7 mutation, including in three individuals who do not have symptoms of IC/PKD, but was not observed in individuals who did not carry the p.P217fsX7 mutation. Visual aura (positive visual phenomena) was most frequently reported, other types of aura including expressive dysphasia, alexia and alien hand syndrome were also described. Migraine frequency ranged from twice a year to three times a month. Reported triggers included stress, sleep deprivation and exercise. Two individuals were treated with low-dose propranolol for several months, which reduced the frequency and severity of migraine attacks, but did not improve symptoms of the movement disorder. Previously reported linkage studies for this kindred (family 3, Spacey et al.) [9] generated LOD scores that were not significant for the analysis of PKD alone or PKD ± IC. We repeated linkage analysis using Merlin [10], assuming an autosomal dominant mode of inheritance with 80 % penetrance. LOD scores for the PRRT2 mutation and PKD/IC and the PRRT2 mutation and migraine with aura are 1.65 and 2.7, respectively. Several kindreds with hemiplegic migraine and PRRT2 mutations have recently been reported [11]. Migraine (with and without aura) is over-represented in individuals with PRRT2 mutations and clustering of migraine has been identified in small kindred’s harboring PRRT2 mutations [12] In this large family, migraine with aura segregates in a Mendelian fashion in nine of 10 individuals with the PRRT2 mutation, the remaining individual is still in adolescence and could still go onto develop migraine. Furthermore, it highlights that in some families, migraine with aura may be the predominant phenotype associated with PRRT2 mutations, which is important to bear in mind when determining whether a patient with PKD/IC has a positive family history, to enable appropriate genetic counseling and testing. The association of migraine with PRRT2 mutations raises the question of whether genetic variation in PRRT2 might play a role in susceptibility to ‘common’ migraine with aura.

Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. l-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinsons disease.

Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson’s Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson’s disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought.