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Pizzagalli, Diego

Stress may promote the onset of psychopathology by disrupting reward processing. However, the extent to which stress impairs reward processing, rather than incentive processing more generally, is unclear. To evaluate the specificity of stress-induced reward processing disruption, 100 psychiatrically healthy females were administered a probabilistic stimulus selection task (PSST) that enabled comparison of sensitivity to reward-driven (Go) and punishment-driven (NoGo) learning under either “no stress” or “stress” (threat-of-shock) conditions. Cortisol samples and self-report measures were collected. Contrary to hypotheses, the groups did not differ significantly in task performance or cortisol reactivity. However, further analyses focusing only on individuals under “stress” who were high responders with regard to both cortisol reactivity and self-reported negative affect revealed reduced reward sensitivity relative to individuals tested in the “no stress” condition; importantly, these deficits were reward-specific. Overall, findings provide preliminary evidence that stress-reactive individuals show diminished sensitivity to reward, but not punishment, under stress. While such results highlight the possibility that stress-induced anhedonia might be an important mechanism linking stress to affective disorders, future studies are necessary to confirm this conjecture.

Background: Patients with psychosis spectrum disorders exhibit deficits in social and neurocognition, as well as hallmark abnormalities in motivation and reward processing. Aspects of reward processing may overlap behaviorally and neurobiologically with some elements of cognitive functioning, and abnormalities in these processes may share partially overlapping etiologies in patients. However, whether reward processing and cognition are associated across the psychoses and linked to state and trait clinical symptomatology is unclear. Method The present study examined associations between cognitive functioning, reward learning, and clinical symptomatology in a cross-diagnostic sample. Patients with schizophrenia (SZ; n = 37), bipolar I disorder with psychosis (BD; n = 42), and healthy controls (n = 29) were assessed for clinical symptoms (patients only), neurocognitive functioning using the MATRICS Battery (MCCB) and reward learning using the probabilistic reward task (PRT). Groups were compared on neurocognition and PRT response bias, and associations between PRT response bias and neurocognition or clinical symptoms were examined controlling for demographic variables and PRT task difficulty (discriminability). Results: Patients with SZ performed worse than controls on most measures of neurocognition; patients with BD exhibited deficits in some domains between the level of patients with SZ and controls. The SZ – but not BD – group exhibited deficits in social cognition compared to controls. Patients and controls did not differ on PRT response bias, but did differ on PRT discriminability. Better response bias across the sample was associated with poorer social cognition, but not neurocognition; conversely, discriminability was associated with neurocognition but not social cognition. Symptoms of psychosis, particularly negative symptoms, were associated with poorer response bias across patient groups. Discussion Reward learning was associated with symptoms of psychosis – in particular negative symptoms – across diagnoses, and was predictive of worse social cognition. Reward learning was not associated with neurocognitive performance, suggesting that, across patient groups, social cognition but not neurocognition may share common pathways with this aspect of reinforcement learning. Better understanding of how cognitive dysfunction and reward processing deficits relate to one another, to other key symptom dimensions (e.g., psychosis), and to diagnostic categories, may help clarify shared etiological pathways and guide efforts toward targeted treatment approaches.

Background: Childhood adversity increases the risk of psychopathology, but the neurobiological mechanisms underlying this vulnerability are not well-understood. In animal models, early adversity is associated with dysfunction in basal ganglia regions involved in reward processing, but this relationship has not been established in humans. Methods: Functional magnetic resonance imaging was used to examine basal ganglia responses to (a) cues signaling possible monetary rewards and losses, and (b) delivery of monetary gains and penalties, in 13 young adults who experienced maltreatment before age 14 and 31 non-maltreated controls. Results: Relative to controls, individuals exposed to childhood adversity reported elevated symptoms of anhedonia and depression, rated reward cues less positively, and displayed a weaker response to reward cues in the left globus pallidus. There were no group differences in right hemisphere basal ganglia response to reward cues, or in basal ganglia response to loss cues, no-incentive cues, gains, or penalties. Conclusions: Results indicate that childhood adversity in humans is associated with blunted subjective responses to reward-predicting cues as well as dysfunction in left basal ganglia regions implicated in reward-related learning and motivation. This dysfunction may serve as a diathesis that contributes to the multiple negative outcomes and psychopathologies associated with childhood adversity. The findings suggest that interventions that target motivation and goal-directed action may be useful for reducing the negative consequences of childhood adversity.

Background: Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms. Methods: Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history. Results: Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress. Conclusions: The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder.

During reinforcement learning, phasic modulations of activity in midbrain dopamine neurons are conveyed to the dorsal anterior cingulate Cortex (dACC) and basal ganglia (BG) and serve to guide adaptive responding. While the animal literature supports a role for the dACC in integrating reward history over time, most human electrophysiological Studies of dACC function have focused on responses to single positive and negative outcomes. The present electrophysiological study investigated the role of the dACC in probabilistic reward learning in healthy subjects using a task that required integration of reinforcement history over time. We recorded the feedback-related negativity (FRN) to reward feedback in subjects who developed a response bias toward a more frequently rewarded ("rich") stimulus ("learners") versus subjects who did not ("non-learners"). Compared to non-learners, learners showed more positive (i.e., smaller) FRNs and greater dACC activation upon receiving reward for correct identification of the rich stimulus. In addition, dACC activation and a bias to select the rich Stimulus were positively correlated. The same participants also completed a monetary incentive delay (MID) task administered during functional magnetic resonance imaging. Compared to non-learners, learners displayed stronger BG responses to reward in the MID task. These findings raise the possibility that learners in the probabilistic reinforcement task were characterized by stronger dACC and BG responses to rewarding outcomes. Furthermore, these results highlight the importance of the dACC to probabilistic reward learning in humans.

Background: Tobacco smoking, driven by the addictive properties of nicotine, is the most prevalent preventable cause of death in the Western world. Accumulated evidence suggests that nicotine may increase appetitive responding for nondrug incentives in the environment. Methods: To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled, crossover study of the effect of a single dose of transdermal nicotine on reward responsiveness in 30 psychiatrically healthy nonsmokers. A novel signal detection task in which correct responses were differentially rewarded in a 3:1 ratio was used to assess the extent to which participants modulated their behavior as a function of reward. Results: Despite expected adverse effects such as nausea, nicotine significantly increased response bias toward the more frequently rewarded condition, at the expense of accuracy, independent of effects on attention or overall vigilance. Additionally, response bias on placebo was greater in participants who received nicotine in the first session, indicating that an effect of nicotine on reward responsiveness or reward-based learning persisted for at least 1 week. Conclusions: These findings suggest that a single dose of nicotine enhances response to non-drug-related rewards in the environment, with lasting effects. This effect may contribute to reinforcement of early smoking behavior and development of nicotine dependence.

Background. Anhedonia and stress sensitivity have been identified as promising depressive phenotypes. Research suggests that stress-induced anhedonia is a possible mechanism underlying the association between stress and depression. The present proof-of-concept study assessed whether hedonic capacity and stress perception are heritable and whether their genetic and environmental contributions are shared. Method. Twenty monozygotic (MZ) and 15 dizygotic (DZ) twin pairs completed a probabilistic reward task that provides an objective behavioral measure of hedonic capacity (reward responsiveness) and completed several questionnaires including the Perceived Stress Scale (PSS). Bivariate Cholesky models were used to investigate whether covariation between (1) depressive symptoms and hedonic capacity, (2) depressive symptoms and perceived stress, and (3) perceived stress and hedonic capacity resulted from shared or residual genetic and environmental factors. Results. Additive genetic (A) and individual-specific environment (E) factors contributed to 46% and 54% of the variance in hedonic capacity, respectively. For perceived stress, 44% and 56%, of the variance was accounted for by A and E factors, respectively. The genetic correlation between depression and hedonic capacity was moderate (r(a)=0.29), whereas the correlation between depression and stress perception was large (r(a)=0.67). Genetic and environmental correlations between hedonic capacity and stress perception were large (r(a)=0.72 and r(e)= -0.43). Conclusions. The present study provides initial feasibility for using a twin approach to investigate genetic contributions of a laboratory-based anhedonic phenotype. Although these preliminary findings indicate that hedonic capacity and perceived stress are heritable, with substantial shared additive genetic contributions, replications in larger samples will be needed.

Incentive delay tasks implicate the striatum and medial frontal cortex in reward processing. However, prior studies delivered more rewards than penalties, possibly leading to unwanted differences in signal-to-noise ratio. Also, whether particular brain regions are specifically involved in anticipation or consumption is unclear. We used a task featuring balanced incentive delivery and an analytic strategy designed to identify activity specific to anticipation or consumption. Reaction time data in two independent samples (n = 13 and n = 8) confirmed motivated responding. Functional magnetic resonance imaging revealed regions activated by anticipation (anterior cingulate) versus consumption (orbital and medial frontal cortex). Ventral striatum was active during reward anticipation but not significantly more so than during consumption. Although the study features several methodological improvements and helps clarify the neural basis of incentive processing, replications in larger samples are needed.

Anhedonia, the reduced propensity to experience pleasure, is a promising endo-- phenotype and vulnerability factor for several psychiatric disorders, including depression and schizophrenia. In the present study, we used resting electroencephalography, functional magnetic resonance imaging, and volumetric analyses to probe putative associations between anhedonia and individual differences in key nodes of the brain's reward system in a non-clinical sample. We found that anhedonia, but not other symptoms of depression or anxiety, was correlated with reduced nucleus accumbens (NAcc) responses to rewards (gains in a monetary incentive delay task), reduced NAcc volume, and increased resting delta current density (i.e., decreased resting activity) in the rostral anterior cingulate cortex (rACC), an area previously implicated in positive subjective experience. In addition, NAcc reward responses were inversely associated with rACC resting delta activity, supporting the hypothesis that delta might be lawfully related to activity within the brain's reward circuit. Taken together, these results help elucidate the neural basis of anhedonia and strengthen the argument for anhedonia as an endophenotype for depression.

Preclinical studies suggest that stress exerts depressogenic effects by impairing hedonic capacity, in humans, however, the precise mechanisms linking stress and depression are largely unknown. As an initial step towards better understanding the association between stress and anhedonia, the present study tested, in two independent samples, whether individuals reporting elevated stress exhibit decreased hedonic capacity. The Perceived Stress Scale (PSS) measured the decree to which participants appraised their daily life as unpredictable, uncontrollable, and overwhelming. Hedonic capacity was objectively assessed using a signal-detection task based on a differential reinforcement schedule. Decreased reward responsiveness (i.e., the participants propensity to modulate behavior as a function of reward) was used as an operational measure of hedonic capacity. In both Study 1 (n = 88) and Study 2 (n = 80), participants with high PSS scores displayed blunted reward responsiveness and reported elevated anhedonic symptoms. Additionally, PSS scores predicted reduced reward responsiveness even after controlling for general distress and anxiety symptoms. These findings are consistent with preclinical data highlighting links between stress and anhedonia, and offer promising insights into potential mechanisms linking stress to depression.