Reward Learning Deficits Research Articles

Transdiagnostic inflexible learning dynamics explain deficits in depression and schizophrenia.

Deficits in reward learning are core symptoms across many mental disorders. Recent work suggests that such learning impairments arise by a diminished ability to use reward history to guide behaviour, but the neuro-computational mechanisms through which these impairments emerge remain unclear. Moreover, limited work has taken a transdiagnostic approach to investigate whether the psychological and neural mechanisms that give rise to learning deficits are shared across forms of psychopathology. To provide insight into this issue, we explored probabilistic reward learning in patients diagnosed with major depressive disorder (n = 33) or schizophrenia (n = 24) and 33 matched healthy controls by combining computational modelling and single-trial EEG regression. In our task, participants had to integrate the reward history of a stimulus to decide whether it is worthwhile to gamble on it. Adaptive learning in this task is achieved through dynamic learning rates that are maximal on the first encounters with a given stimulus and decay with increasing stimulus repetitions. Hence, over the course of learning, choice preferences would ideally stabilize and be less susceptible to misleading information. We show evidence of reduced learning dynamics, whereby both patient groups demonstrated hypersensitive learning (i.e. less decaying learning rates), rendering their choices more susceptible to misleading feedback. Moreover, there was a schizophrenia-specific approach bias and a depression-specific heightened sensitivity to disconfirmational feedback (factual losses and counterfactual wins). The inflexible learning in both patient groups was accompanied by altered neural processing, including no tracking of expected values in either patient group. Taken together, our results thus provide evidence that reduced trial-by-trial learning dynamics reflect a convergent deficit across depression and schizophrenia. Moreover, we identified disorder distinct learning deficits.

Reward and punishment learning deficits among bipolar disorder subtypes

BackgroundReward sensitivity is an essential dimension related to mood fluctuations in bipolar disorder (BD), but there is currently a debate around hypersensitivity or hyposensitivity hypotheses to reward in BD during remission, probably related to a heterogeneous population within the BD spectrum and a lack of reward bias evaluation. Here, we examine reward maximization vs. punishment avoidance learning within the BD spectrum during remission. MethodsPatients with BD-I (n = 45), BD-II (n = 34) and matched (n = 30) healthy controls (HC) were included. They performed an instrumental learning task designed to dissociate reward-based from punishment-based reinforcement learning. Computational modeling was used to identify the mechanisms underlying reinforcement learning performances. ResultsBehavioral results showed a significant reward learning deficit across BD subtypes compared to HC, captured at the computational level by a lower sensitivity to rewards compared to punishments in both BD subtypes. Computational modeling also revealed a higher choice randomness in BD-II compared to BD-I that reflected a tendency of BD-I to perform better during punishment avoidance learning than BD-II. LimitationsOur patients were not naive to antipsychotic treatment and were not euthymic (but in syndromic remission) according to the International Society for Bipolar Disorder definition. ConclusionsOur results are consistent with the reward hyposensitivity theory in BD. Computational modeling suggests distinct underlying mechanisms that produce similar observable behaviors, making it a useful tool for distinguishing how symptoms interact in BD versus other disorders. In the long run, a better understanding of these processes could contribute to better prevention and management of BD.

Early life stress in male mice blunts responsiveness in a translationally-relevant reward task

Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS—including childhood abuse, bullying, poverty, and trauma—are increasingly prevalent. Understanding the signs of ELS, including those associated with psychiatric illness, will enable improved treatment and prevention. Here, we developed a novel procedure to model human ELS in mice and identify translationally-relevant biomarkers of mood and anxiety disorders. We exposed male mice (C57BL/6 J) to an early-life (juvenile) chronic social defeat stress (jCSDS) and examined social interaction and responsivity to reward during adulthood. As expected, jCSDS-exposed mice showed a socially avoidant phenotype in open-field social interaction tests. However, sucrose preference tests failed to demonstrate ELS-induced reductions in choice for the sweetened solution, suggesting no effect on reward function. To explore whether other tasks might be more sensitive to changes in motivation, we tested the mice in the Probabilistic Reward Task (PRT), a procedure often used in humans to study reward learning deficits associated with depressive illness. In a touchscreen PRT variant that was reverse-translated to maximize alignment with the version used in human subjects, mice exposed to jCSDS displayed significant reductions in the tendency to develop response biases for the more richly-rewarded stimulus, a hallmark sign of anhedonia when observed in humans. Our findings suggest that translationally-relevant procedures that utilize the same endpoints across species may enable the development of improved model systems that more accurately predict outcomes in humans.

Effects of dopamine modulation on chronic stress-induced deficits in reward learning.

Anhedonia is characteristically preceded by chronic stress, likely involving downstream effects of glucocorticoid alterations on dopamine (DA) function. To elucidate the neural underpinnings of this interaction, we examined whether acute pharmacological modulation of DA alters reward learning after chronic mild stress (CMS). Forty-eight male Wistar rats were exposed to a 21-day CMS regime (n = 48 nostress controls) before completing the probabilistic reward task (PRT), a well-validated cross-species test of reward learning. We first examined whether stress-induced reward dysfunction could be restored by systemic injections of low-dose amisulpride (AMI), which increases DA transmission via D2-like autoreceptor blockade. Then, we investigated region-specific effects through bilateral infusions of quinpirole (QUIN), a D2-like receptor agonist, into either the nucleus accumbens core (NAcc) or medial prefrontal cortex (mPFC). Blunted reward learning in CMS animals was reversed by acute AMI administration, but this treatment did not alter reward learning in the no stress group. Elevated adrenal gland weight, a proxy for stress reactivity, predicted lower reward learning in the untreated CMS group. This effect was extinguished following AMI treatment. These findings might be attributed to significantly higher D2 receptor density in the NAcc of high stress reactive animals. To this end, NAcc QUIN infusions potentiated reward learning relative to mPFC QUIN infusions in CMS rats, but there was no effect in no stress control rats. Collectively, these findings suggest that DA modulation reverses stress-induced reward dysfunction, even among the most stress-reactive animals. The effect might depend on D2-like receptor activation in the mesolimbic system.

Targeted therapy of cognitive deficits in fragile X syndrome.

Breaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.

Childhood adversity and impaired reward processing: A meta-analysis

BackgroundChildhood adversity (CA) is associated with increased risk of psychopathology, and reward processing (RP) may be one of the underlying mechanisms. However, evidence on impaired RP in childhood adversity is theoretically and methodologically heterogeneous. ObjectiveTo provide a quantitative overview of studies on the relation between childhood adversity and RP assessed at the behavioral and subjective levels, and identify differences between studies that influence the effect size. Participants and settingTwenty-seven studies (overall N = 6801) were included. MethodsPeer-reviewed publications describing empirical studies on the relation between CA and behavioral and self-report measures of RP in humans were identified through systematic searches in six bibliographic databases. Effect sizes (r) were pooled using random-effects models. The potential moderator role of RP dimension, type of RP assessment, type of childhood adversity assessment, and age were examined. ResultsResults indicated a small, but consistent association between CA and impaired RP (r = 0.12; 95% CI: 0.07, 0.16), with medium heterogeneity (I2 = 62.43). The effect size was significantly larger (i.e., medium-sized) in studies that focused on reward learning rather than reward valuation and reward responsiveness; used cognitive tasks rather than self-report assessments of RP; and relied on official records rather than subjective reports of CA. There was evidence of publication bias, but overall effect size remained significant after imputation. ConclusionsThese results suggest that multidimensional RP impairments (e.g., deficits in reward learning, biased reward valuation) are a consistent marker of CA, and may represent mechanisms underlying the increased risk of psychopathology.

Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice.

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Investigation of reward learning and feedback sensitivity in non-clinical participants with a history of early life stress.

Early life stress (ELS) is an important risk factor for the development of depression. Impairments in reward learning and feedback sensitivity are suggested to be an intermediate phenotype in depression aetiology therefore we hypothesised that healthy adults with a history of ELS would exhibit reward processing deficits independent of any current depressive symptoms. We recruited 64 adults with high levels of ELS and no diagnosis of a current mental health disorder and 65 controls. Participants completed the probabilistic reversal learning task and probabilistic reward task followed by depression, anhedonia, social status, and stress scales. Participants with high levels of ELS showed decreased positive feedback sensitivity in the probabilistic reversal learning task compared to controls. High ELS participants also trended towards possessing a decreased model-free learning rate. This was coupled with a decreased learning ability in the acquisition phase of block 1 following the practice session. Neither group showed a reward induced response bias in the probabilistic reward task however high ELS participants exhibited decreased stimuli discrimination. Overall, these data suggest that healthy participants without a current mental health diagnosis but with high levels of ELS show deficits in positive feedback sensitivity and reward learning in the probabilistic reversal learning task that are distinct from depressed patients. These deficits may be relevant to increased depression vulnerability.

Computational Evidence of Altered Reward Learning in Remitted Major Depressive Disorder With a History of Psychomotor Symptoms

Reward processing deficits are common in current and remitted major depressive disorder (rMDD). Neurobiological substrates that implement reward-based learning (e.g., corticostriatal circuitry) are also implicated in psychomotor symptoms. Thus, psychomotor symptoms may relate to greater reward-learning deficits in rMDD. The present study sought to test whether reward-based learning is altered in rMDD with, versus without past psychomotor symptoms and controls.

Reward learning in unmedicated women with bulimia nervosa: A pilot investigation

Bulimia nervosa (BN) is characterized by recurrent engagement in eating disorder behaviors despite negative consequences, potentially reflecting aberrant stimulus-response or reward-learning processes. Indeed, frontostriatal circuitry involved in reward learning is altered in persons with BN and preliminary research suggests reward learning is impaired in persons with BN. Additional research on reward learning in BN and its association with eating disorder symptom expression is warranted to further the field's understanding of potential pathophysiological mechanisms of BN. To this end, the probabilistic reward learning task (PRLT) was administered to unmedicated women with BN (n = 15) and demographically matched psychiatrically healthy women (n = 18). Contrary to our hypotheses, results demonstrated that women with BN showed greater reward learning during the PRLT relative to healthy comparison women when covarying for symptoms of depression, social anxiety, and mania. Exploratory analyses showed that binge-eating frequency was inversely associated with reward learning in women with BN; however, results should be interpreted with caution due to the small sample size. Together, results suggest that women with BN do not have deficits in implicit reward learning. Given the preliminary nature of this investigation, larger-scale studies are needed to further examine reward learning in current BN and could compare reward learning using general (e.g., monetary) and disorder-specific (e.g., food) reinforcers. Further work is needed to confirm the inverse association between reward learning and binge eating.

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity. We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug. In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

Dissociable mechanisms underpinning effort-cost decision-making across the psychosis spectrum

Recent theoretical models propose that abnormal effort-cost decision-making (ECDM) likely has divergent underpinnings across mood and psychotic disorders. However, whether this same model applies to individuals across the psychosis spectrum, including individuals with affective psychosis, remains unclear. This study aimed to empirically test whether two component processes – working memory and reward learning – contribute to ECDM impairment across the psychosis spectrum. ECDM was assessed using the Effort Expenditure for Rewards Task in individuals with psychotic disorders (n = 190) and healthy controls (n = 52). Working memory was assessed using a Digit Sequencing Task and reward learning was assessed using a Probabilistic Reward Task. Relative to the control group, the psychosis group showed reduced willingness to expend effort for higher probability, higher value rewards. This effect was most pronounced in individuals with schizophrenia and schizoaffective disorder relative to individuals with psychotic bipolar disorder. Across the whole sample, better working memory but not reward learning predicted greater willingness to expend effort for higher probability rewards. However, the link between working memory and ECDM differed as a function of patient symptom profile. Specifically, working memory was only predictive of ECDM for individuals with less severe negative symptoms and minimal depressive symptoms. For individuals with more severe negative symptoms, poorer ECDM was instead predicted by deficits in reward learning. Although these findings reiterate the important link between working memory and ECDM in individuals with psychotic disorders, they also show that this link varies in accordance with the presence of prominent negative and depressive symptoms.

Diagnostic and dimensional evaluation of implicit reward learning in social anxiety disorder and major depression.

Increasing evidence supports the presence of an anhedonic endophenotype in major depressive disorder (MDD), characterized by impairments in various components of reward processing, particularly incentive motivation, effort-based decision making, and reward learning. In addition to its prominent role in MDD, reward processing dysregulation has been proposed as a transdiagnostic risk and/or maintenance factor for a range of other forms of psychopathology. Individuals with social anxiety disorder (SAD)-a condition that frequently co-occurs with MDD-demonstrate low trait positive affectivity and altered processing of rewards and positively valenced information. However, no studies to date have directly tested reward learning-the ability to modulate behavior in response to rewards-in this population. The current study evaluated reward learning in MDD, SAD, and healthy control subjects (N = 90) using a well-validated signal detection task. Given increasing data supporting transdiagnostic features of psychopathology, we also evaluated associations between anhedonia and task performance transdiagnostically in the patient sample. Contrary to expectations, results indicated no significant group differences in response bias in the full sample, suggesting no diagnostic differences in reward learning. However, dimensional analyses revealed that higher self-reported anhedonia (but not general distress or anxious arousal) was associated with worse reward learning in both the MDD and SAD groups explaining about 11% of the variance. Deficits in implicit reward learning are associated with anhedonia but not necessarily with major depressive disorder as a diagnosis, which supports the use of transdiagnostic approaches to understanding psychopathology.

Grant Report on Social Reward Learning in Schizophrenia †.

We report on the ongoing R21 project “Social Reward Learning in Schizophrenia”. Impairments in social cognition are a hallmark of schizophrenia. However, little work has been done on social reward learning deficits in schizophrenia. The overall goal of the project is to assess social reward learning in schizophrenia. A probabilistic reward learning (PRL) task is being used in the MRI scanner to evaluate reward learning to negative and positive social feedback. Monetary reward learning is used as a comparison to assess specificity. Behavioral outcomes and brain areas, included those involved in reward, are assessed in patients with schizophrenia or schizoaffective disorder and controls. It is also critical to determine whether decreased expected value (EV) of social stimuli and/or reward prediction error (RPE) learning underlie social reward learning deficits to inform potential treatment pathways. Our central hypothesis is that the pattern of social learning deficits is an extension of a more general reward learning impairment in schizophrenia and that social reward learning deficits critically contribute to deficits in social motivation and pleasure. We hypothesize that people with schizophrenia will show impaired behavioral social reward learning compared to controls, as well as decreased ventromedial prefrontal cortex (vmPFC) EV signaling at time of choice and decreased striatal RPE signaling at time of outcome, with potentially greater impairment to positive than negative feedback. The grant is in its second year. It is hoped that this innovative approach may lead to novel and more targeted treatment approaches for social cognitive impairments, using cognitive remediation and/or brain stimulation.

Reward and punishment learning in schizophrenia and bipolar disorder

Prior studies on reward learning deficits in psychiatric disorders have used probabilistic learning tasks, making it unclear whether impairment is due to the probabilistic nature of the task rather than reward processing. In this study, we tested probabilistic vs. deterministic reward and punishment learning in healthy controls and three patient groups: schizophrenia (SZ), psychotic bipolar disorder (BD), and nonpsychotic BD. Experimental results show that reward learning was impaired in patients with SZ and patients with psychotic BD in the probabilistic learning task compared to patients with nonpsychotic BD and healthy controls. In contrast, punishment learning in the probabilistic task was impaired in patients with nonpsychotic BD compared to the other patient groups and healthy controls. There were no significant differences among all groups in the deterministic learning task scores. We also found that Hamilton Depression Scale scores negatively correlated with probabilistic learning performance. Our data may suggest that reward learning impairment may be due to the nature of the task as well as subtype of BD.

A comparison of implicit and explicit reward learning in low risk alcohol users versus people who binge drink and people with alcohol dependence

Chronic alcohol use leads to specific neurobiological alterations in the dopaminergic brain reward system, which probably are leading to a reward deficiency syndrome in alcohol dependence. The purpose of our study was to examine the effects of such hypothesized neurobiological alterations on the behavioral level, and more precisely on the implicit and explicit reward learning. Alcohol users were classified as dependent drinkers (using the DSM-IV criteria), binge drinkers (using criteria of the USA National Institute on Alcohol Abuse and Alcoholism) or low-risk drinkers (following recommendations of the Scientific board of trustees of the German Health Ministry). The final sample (n = 94) consisted of 36 low-risk alcohol users, 37 binge drinkers and 21 abstinent alcohol dependent patients. Participants were administered a probabilistic implicit reward learning task and an explicit reward- and punishment-based trial-and-error-learning task. Alcohol dependent patients showed a lower performance in implicit and explicit reward learning than low risk drinkers. Binge drinkers learned less than low-risk drinkers in the implicit learning task. The results support the assumption that binge drinking and alcohol dependence are related to a chronic reward deficit. Binge drinking accompanied by implicit reward learning deficits could increase the risk for the development of an alcohol dependence.

Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age.

Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.

Relationship between effortful motivation and neurocognition in schizophrenia

Effortful motivation and reward valuation learning deficits are associated with negative symptoms and impaired cognition in schizophrenia (SZ) patients. Whereas clinical assessments of motivation and reward value typically rely upon clinician ratings or self-report scales, behavioral measures often confound these constructs. Simple reverse-translated behavioral tasks that independently quantify motivation and reward valuation—which could then be linked to cognition—may facilitate the development of pro-cognitive therapeutics by bridging the “preclinical-to-clinical” gap. This study determined whether novel behavioral measures of effortful motivation and reward valuation are associated with impaired cognition in SZ patients (n=36). Patients completed the Progressive Ratio Breakpoint task (PRBT; physical effort motivation) and the Probabilistic Learning Task (PLT; reward learning/valuation) in conjunction with the MATRICS Consensus Cognitive Battery (MCCB). SZ patients exhibited statistically significant deficits in global cognition and all individual MCCB subdomains. Significant correlations were observed between PRBT and MCCB global cognition (r=0.52), speed of processing (r=0.56) and attention vigilance (r=0.48) subdomains, but not with PLT or clinical symptoms. Results indicate that effort and reward learning deficits are dissociable targets that can improve our understanding of cognitive impairments associated among patients with SZ. More importantly, the results support the long-standing notion that the measurement of cognitive impairments in SZ is highly linked to a willingness to expend effort. The availability of a PRBT designed for use in both rodents and humans could improve our understanding of the nature of cognitive impairments in neuropsychiatric disorders and accelerate the development of novel pro-cognitive therapeutics.

Reward learning deficits in Parkinson's disease depend on depression.

Depression is one of the most common and debilitating non-motor symptoms of Parkinson's disease (PD). The neurocognitive mechanisms underlying depression in PD are unclear and treatment is often suboptimal. We investigated the role of striatal dopamine in reversal learning from reward and punishment by combining a controlled medication withdrawal procedure with functional magnetic resonance imaging in 22 non-depressed PD patients and 19 PD patients with past or present depression. PD patients with a depression (history) exhibited impaired reward v. punishment reversal learning as well as reduced reward v. punishment-related BOLD signal in the striatum (putamen) compared with non-depressed PD patients. No effects of dopaminergic medication were observed. The present findings demonstrate that impairments in reversal learning from reward v. punishment and associated striatal signalling depend on the presence of (a history of) depression in PD.