Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression.

Importance: Major depressive disorder (MDD) is associated with deficits in representing reward prediction errors (RPEs), which are the difference between experienced and predicted reward. Reward prediction errors underlie learning of values in reinforcement learning models, are represented by phasic dopamine release, and are known to affect momentary mood. Objective: To combine functional neuroimaging, computational modeling, and smartphone-based large-scale data collection to test, in the absence of learning-related concerns, the hypothesis that depression attenuates the impact of RPEs. Design, Setting, and Participants: Functional magnetic resonance imaging (fMRI) data were collected on 32 individuals with moderate MDD and 20 control participants who performed a probabilistic reward task. A risky decision task with repeated happiness ratings as a measure of momentary mood was also tested in the laboratory in 74 participants and with a smartphone-based platform in 1833 participants. The study was conducted from November 20, 2012, to February 17, 2015. Main Outcomes and Measures: Blood oxygen level-dependent activity was measured in ventral striatum, a dopamine target area known to represent RPEs. Momentary mood was measured during risky decision making. Results: Of the 52 fMRI participants (mean [SD] age, 34.0 [9.1] years), 30 (58%) were women and 32 had MDD. Of the 74 participants in the laboratory risky decision task (mean age, 34.2 [10.3] years), 44 (59%) were women and 54 had MDD. Of the smartphone group, 543 (30%) had a depression history and 1290 (70%) had no depression history; 918 (50%) were women, and 593 (32%) were younger than 30 years. Contrary to previous results in reinforcement learning tasks, individuals with moderate depression showed intact RPE signals in ventral striatum (z = 3.16; P = .002) that did not differ significantly from controls (z = 0.91; P = .36). Symptom severity correlated with baseline mood parameters in laboratory (ρ = -0.54; P < 1 × 10-6) and smartphone (ρ = -0.30; P < 1 × 10-39) data. However, participants with depression showed an intact association between RPEs and happiness in a computational model of momentary mood dynamics (z = 4.55; P < .001) that was not attenuated compared with controls (z = -0.42; P = .67). Conclusions and Relevance: The neural and emotional impact of RPEs is intact in major depression. These results suggest that depression does not affect the expression of dopaminergic RPEs and that attenuated RPEs in previous reports may reflect downstream effects more closely related to aberrant behavior. The correlation between symptom severity and baseline mood parameters supports an association between depression and momentary mood fluctuations during cognitive tasks. These results demonstrate a potential for smartphones in large-scale computational phenotyping, which is a goal for computational psychiatry.

Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors.

BACKGROUND: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. OBJECTIVES: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors. METHODS: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity. RESULTS: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions. CONCLUSIONS: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.

Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder.

Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65±1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS-low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS-high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention.

Differential patterns of amygdala and ventral striatum activation predict gender-specific changes in sexual risk behavior.

Although the initiation of sexual behavior is common among adolescents and young adults, some individuals express this behavior in a manner that significantly increases their risk for negative outcomes including sexually transmitted infections. Based on accumulating evidence, we have hypothesized that increased sexual risk behavior reflects, in part, an imbalance between neural circuits mediating approach and avoidance in particular as manifest by relatively increased ventral striatum (VS) activity and relatively decreased amygdala activity. Here, we test our hypothesis using data from seventy 18- to 22-year-old university students participating in the Duke Neurogenetics Study. We found a significant three-way interaction between amygdala activation, VS activation, and gender predicting changes in the number of sexual partners over time. Although relatively increased VS activation predicted greater increases in sexual partners for both men and women, the effect in men was contingent on the presence of relatively decreased amygdala activation and the effect in women was contingent on the presence of relatively increased amygdala activation. These findings suggest unique gender differences in how complex interactions between neural circuit function contributing to approach and avoidance may be expressed as sexual risk behavior in young adults. As such, our findings have the potential to inform the development of novel, gender-specific strategies that may be more effective at curtailing sexual risk behavior.

Right prefrontal and ventral striatum interactions underlying impulsive choice and impulsive responding.

Although a multifaceted concept, many forms of impulsivity may originate from interactions between prefrontally-mediated cognitive control mechanisms and limbic, reward or incentive salience approach processes. We describe a novel task that combines reward and control processes to probe this putative interaction. The task involves elements of the monetary incentive delay task (Knutson et al., [2000]: Neuroimage 12:20-27) and the Go/No-Go task (Garavan et al., [1999]: Neuroimage 17:1820-1829) and requires human subjects to make fast responses to targets for financial reward but to occasionally inhibit responding when a NoGo signal rather than a target is presented. In elucidating the dynamic between reward anticipation and control we observed that successful inhibitions on monetary trials, relative to unsuccessful inhibitions, were associated, during the anticipation phase, with increased activation in the right inferior frontal gyrus (rIFG), decreased activity in the ventral striatum (VS), and altered functional connectivity between the two. Notably, this rIFG area had a small overlap but was largely distinct from an adjacent rIFG region that was active for the subsequent motor response inhibitions. Combined, the results suggest a role for adjacent regions of the rIFG in impulsive choice and in impulsive responding and identify a functional coupling between the rIFG and the VS.

BDNF Val66Met polymorphism influence on striatal blood-level-dependent response to monetary feedback depends on valence and agency.

Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of the striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether BDNF Val66Met polymorphism predicts VS activity. We found that BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.

Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking.

As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke-circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers.

Cerebral blood flow-based evidence for mechanisms of low- versus high-frequency transcutaneous electric acupoint stimulation analgesia: a perfusion fMRI study in humans.

Brain activities in response to acupuncture have been investigated in multiple studies; however, the neuromechanisms of low- and high-frequency transcutaneous electric acupoint stimulation (TEAS) analgesia are unclear. This work aimed to investigate how brain activity and the analgesic effect changed across 30-min low- versus high-frequency TEAS. Forty-six subjects received a 30-min 2, 100-Hz TEAS or mock TEAS (MTEAS) treatment on both behavior test and functional magnetic resonance imaging (fMRI) scan days. On the behavior test day, the pain thresholds and pain-related negative emotional feeling ratings were tested five times - at 4.5min before treatment, at 10, 20, and 30min during treatment and 4.5min after the treatment. On the fMRI scan day, to match the time-points in the behavioral testing session, the cerebral blood flow (CBF) signals were collected and incorporated with five independent runs before, during and after the treatment, each lasting 4.5min. The analgesic effect was observed in both the TEAS groups; the analgesic affect was not found in the MTEAS group. The effect started at 20min during the treatment and was maintained until the after-treatment states. In both TEAS groups, the regional CBF revealed a trend of early activation with later inhibition; also, a positive correlation between analgesia and the regional CBF change was observed in the anterior insula in the early stage, whereas a negative relationship was found in the parahippocampal gyrus in the later stage. The TEAS analgesia was specifically associated with the default mode network and other cortical regions in the 2-Hz TEAS group, ventral striatum and dorsal anterior cingulate cortex in the 100-Hz TEAS group, respectively. These findings suggest that the mechanisms of low- and high-frequency TEAS analgesia are distinct and partially overlapped, and they verify the treatment time as a notable factor for acupuncture studies.

Ventral striatum and the evaluation of memory retrieval strategies.

Adaptive memory retrieval requires mechanisms of cognitive control that facilitate the recovery of goal-relevant information. Frontoparietal systems are known to support control of memory retrieval. However, the mechanisms by which the brain acquires, evaluates, and adapts retrieval strategies remain unknown. Here, we provide evidence that ventral striatal activation tracks the success of a retrieval strategy and correlates with subsequent reliance on that strategy. Human participants were scanned with fMRI while performing a lexical decision task. A rule was provided that indicated the likely semantic category of a target word given the category of a preceding prime. Reliance on the rule improved decision-making, as estimated within a drift diffusion framework. Ventral striatal activation tracked the benefit that relying on the rule had on decision-making. Moreover, activation in ventral striatum correlated with a participant's subsequent reliance on the rule. Taken together, these results support a role for ventral striatum in learning and evaluating declarative retrieval strategies.

The neural correlates of regulating positive and negative emotions in medication-free major depression.

Depressive cognitive schemas play an important role in the emergence and persistence of major depressive disorder (MDD). The current study adapted emotion regulation techniques to reflect elements of cognitive behavioural therapy (CBT) and related psychotherapies to delineate neurocognitive abnormalities associated with modulating the negative cognitive style in MDD. Nineteen non-medicated patients with MDD and 19 matched controls reduced negative or enhanced positive feelings elicited by emotional scenes while undergoing functional magnetic resonance imaging. Although both groups showed significant emotion regulation success as measured by subjective ratings of affect, the controls were significantly better at modulating both negative and positive emotion. Both groups recruited regions of dorsolateral prefrontal cortex and ventrolateral prefrontal cortex (VLPFC) when regulating negative emotions. Only in controls was this accompanied by reduced activity in sensory cortices and amygdala. Similarly, both groups showed enhanced activity in VLPFC and ventral striatum when enhancing positive affect; however, only in controls was ventral striatum activity correlated with regulation efficacy. The results suggest that depression is associated with both a reduced capacity to achieve relief from negative affect despite recruitment of ventral and dorsal prefrontal cortical regions implicated in emotion regulation, coupled with a disconnect between activity in reward-related regions and subjective positive affect.