Learning attentional templates for value-based decision-making.

Attention filters sensory inputs to enhance task-relevant information. It is guided by an "attentional template" that represents the stimulus features that are currently relevant. To understand how the brain learns and uses templates, we trained monkeys to perform a visual search task that required them to repeatedly learn new attentional templates. Neural recordings found that templates were represented across the prefrontal and parietal cortex in a structured manner, such that perceptually neighboring templates had similar neural representations. When the task changed, a new attentional template was learned by incrementally shifting the template toward rewarded features. Finally, we found that attentional templates transformed stimulus features into a common value representation that allowed the same decision-making mechanisms to deploy attention, regardless of the identity of the template. Altogether, our results provide insight into the neural mechanisms by which the brain learns to control attention and how attention can be flexibly deployed across tasks.

Hippocampal neurons construct a map of an abstract value space.

The hippocampus is thought to encode a "cognitive map," a structural organization of knowledge about relationships in the world. Place cells, spatially selective hippocampal neurons that have been extensively studied in rodents, are one component of this map, describing the relative position of environmental features. However, whether this map extends to abstract, cognitive information remains unknown. Using the relative reward value of cues to define continuous "paths" through an abstract value space, we show that single neurons in primate hippocampus encode this space through value place fields, much like a rodent's place neurons encode paths through physical space. Value place fields remapped when cues changed but also became increasingly correlated across contexts, allowing maps to become generalized. Our findings help explain the critical contribution of the hippocampus to value-based decision-making, providing a mechanism by which knowledge of relationships in the world can be incorporated into reward predictions for guiding decisions.

Dissociable Contributions of Basolateral Amygdala and Ventrolateral Orbitofrontal Cortex to Flexible Learning Under Uncertainty.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

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.

Cortical Grey Matter Mediates Increases in Model-Based Control and Learning from Positive Feedback from Adolescence to Adulthood.

Cognition and brain structure undergo significant maturation from adolescence into adulthood. Model-based (MB) control is known to increase across development, which is mediated by cognitive abilities. Here, we asked two questions unaddressed in previous developmental studies. First, what are the brain structural correlates of age-related increases in MB control? Second, how are age-related increases in MB control from adolescence to adulthood influenced by motivational context? A human developmental sample (n = 103; age, 12-50, male/female, 55:48) completed structural MRI and an established task to capture MB control. The task was modified with respect to outcome valence by including (1) reward and punishment blocks to manipulate the motivational context and (2) an additional choice test to assess learning from positive versus negative feedback. After replicating that an age-dependent increase in MB control is mediated by cognitive abilities, we demonstrate first-time evidence that gray matter density (GMD) in the parietal cortex mediates the increase of MB control with age. Although motivational context did not relate to age-related changes in MB control, learning from positive feedback improved with age. Meanwhile, negative feedback learning showed no age effects. We present a first report that an age-related increase in positive feedback learning was mediated by reduced GMD in the parietal, medial, and dorsolateral prefrontal cortex. Our findings indicate that brain maturation, putatively reflected in lower GMD, in distinct and partially overlapping brain regions could lead to a more efficient brain organization and might thus be a key developmental step toward age-related increases in planning and value-based choice.SIGNIFICANCE STATEMENT Changes in model-based decision-making are paralleled by extensive maturation in cognition and brain structure across development. Still, to date the neuroanatomical underpinnings of these changes remain unclear. Here, we demonstrate for the first time that parietal GMD mediates age-dependent increases in model-based control. Age-related increases in positive feedback learning were mediated by reduced GMD in the parietal, medial, and dorsolateral prefrontal cortex. A manipulation of motivational context did not have an impact on age-related changes in model-based control. These findings highlight that brain maturation in distinct and overlapping cortical regions constitutes a key developmental step toward improved value-based choices.

Aberrant reward learning, but not negative reinforcement learning, is related to depressive symptoms: an attentional perspective.

BACKGROUND: Aberrant reward functioning is implicated in depression. While attention precedes behavior and guides higher-order cognitive processes, reward learning from an attentional perspective - the effects of prior reward-learning on subsequent attention allocation - has been mainly overlooked. METHODS: The present study explored the effects of reward-based attentional learning in depression using two separate, yet complimentary, studies. In study 1, participants with high (HD) and low (LD) levels of depression symptoms were trained to divert their gaze toward one type of stimuli over another using a novel gaze-contingent music reward paradigm - music played when fixating the desired stimulus type and stopped when gazing the alternate one. Attention allocation was assessed before, during, and following training. In study 2, using negative reinforcement, the same attention allocation pattern was trained while substituting the appetitive music reward for gazing the desired stimulus type with the removal of an aversive sound (i.e. white noise). RESULTS: In study 1 both groups showed the intended shift in attention allocation during training (online reward learning), while generalization of learning at post-training was only evident among LD participants. Conversely, in study 2 both groups showed post-training generalization. Results were maintained when introducing anxiety as a covariate, and when using a more powerful sensitivity analysis. Finally, HD participants showed higher learning speed than LD participants during initial online learning, but only when using negative, not positive, reinforcement. CONCLUSIONS: Deficient generalization of learning characterizes the attentional system of HD individuals, but only when using reward-based positive reinforcement, not negative reinforcement.

The effect of noninstrumental information on reward learning.

Investigations of information-seeking often highlight people's tendency to forgo financial reward in return for advance information about future outcomes. Most of these experiments use tasks in which reward contingencies are described to participants. The use of such descriptions leaves open the question of whether the opportunity to obtain such noninstrumental information influences people's ability to learn and represent the underlying reward structure of an experimental environment. In two experiments, participants completed a two-armed bandit task with monetary incentives where reward contingencies were learned via trial-by-trial experience. We find, akin to description-based tasks, that participants are willing to forgo financial reward to receive information about a delayed, unchangeable outcome. Crucially, however, there is little evidence this willingness to pay for information is driven by an inaccurate representation of the reward structure: participants' representations approximated the underlying reward structure regardless of the presence of advance noninstrumental information. The results extend previous conclusions regarding the intrinsic value of information to an experience-based domain and highlight challenges of probing participants' memories for experienced rewards.

Attention to Stimuli of Learned versus Innate Biological Value Relies on Separate Neural Systems.

The neural bases of attention, a set of neural processes that promote behavioral selection, is a subject of intense investigation. In humans, rewarded cues influence attention, even when those cues are irrelevant to the current task. Because the amygdala plays a role in reward processing, and the activity of amygdala neurons has been linked to spatial attention, we reasoned that the amygdala may be essential for attending to rewarded images. To test this possibility, we used an attentional capture task, which provides a quantitative measure of attentional bias. Specifically, we compared reaction times (RTs) of adult male rhesus monkeys with bilateral amygdala lesions and unoperated controls as they made a saccade away from a high- or low-value rewarded image to a peripheral target. We predicted that: (1) RTs will be longer for high- compared with low-value images, revealing attentional capture by rewarded stimuli; and (2) relative to controls, monkeys with amygdala lesions would exhibit shorter RT for high-value images. For comparison, we assessed the same groups of monkeys for attentional capture by images of predators and conspecifics, categories thought to have innate biological value. In performing the attentional capture task, all monkeys were slowed more by high-value relative to low-value rewarded images. Contrary to our prediction, amygdala lesions failed to disrupt this effect. When presented with images of predators and conspecifics, however, monkeys with amygdala lesions showed significantly diminished attentional capture relative to controls. Thus, separate neural pathways are responsible for allocating attention to stimuli with learned versus innate value.SIGNIFICANCE STATEMENT Valuable objects attract attention. The amygdala is known to contribute to reward processing and the encoding of object reward value. We therefore examined whether the amygdala is necessary for allocating attention to rewarded objects. For comparison, we assessed the amygdala's contribution to attending to objects with innate biological value: predators and conspecifics. We found that the macaque amygdala is necessary for directing attention to images with innate biological value, but not for directing attention to recently learned reward-predictive images. These findings indicate that the amygdala makes selective contributions to attending to valuable objects. The data are relevant to mental health disorders, such as social anxiety disorders and small animal phobias, that arise from biased attention to select categories of objects.

Encoding of Environmental Cues in Central Amygdala Neurons during Foraging.

To successfully forage in an environment filled with rewards and threats, animals need to rely on familiar structures of their environment that signal food availability. The central amygdala (CeA) is known to mediate a panoply of consummatory and defensive behaviors, yet how specific activity patterns within CeA subpopulations guide optimal choices is not completely understood. In a paradigm of appetitive conditioning in which mice freely forage for food across a continuum of cues, we found that two major subpopulations of CeA neurons, Somatostatin-positive (CeASst) and protein kinase Cδ-positive (CeAPKCδ) neurons, can assign motivational properties to environmental cues. Although the proportion of food responsive cells was higher within CeASst than CeAPKCδ neurons, only the activities of CeAPKCδ, but not CeASst, neurons were required for learning of contextual food cues. Our findings point to a model in which CeAPKCδ neurons may incorporate stimulus salience together with sensory features of the environment to encode memory of the goal location.SIGNIFICANCE STATEMENT The CeA has a very important role in the formation of memories that associate sensory information with aversive or rewarding representation. Here, we used a conditioned place preference paradigm, where freely moving mice learn to associate external cues with food availability, to investigate the roles of CeA neuron subpopulations. We found that CeASst and CeAPKCδ neurons encoded environmental cues during foraging but only the activities of CeAPKCδ neurons were required for learning of contextual food cues.

Anticipating social feedback involves basal forebrain and mesolimbic functional connectivity.

The mesolimbic system and basal forebrain (BF) are implicated in processing rewards and punishment, but their interplay and functional properties of subregions with respect to future social outcomes remain unclear. Therefore, this study investigated regional responses and interregional functional connectivity of the lateral (l), medial (m), and ventral (v) Substantia Nigra (SN), Nucleus Accumbens (NAcc), Nucleus basalis of Meynert (NBM), and Medial Septum/Diagonal Band (MS/DB) during reward and punishment anticipation in a social incentive delay task with neutral, positive, and negative feedback using high-resolution fMRI (1.5mm3). Neuroimaging data (n = 36 healthy humans) of the anticipation phase was analyzed using mass-univariate, functional connectivity, and multivariate-pattern analysis. As expected, participants responded faster when anticipating positive and negative compared to neutral social feedback. At the neural level, anticipating social information engaged valence-related and valence-unrelated functional connectivity patterns involving the BF and mesolimbic areas. Precisely, valence-related connectivity between the lSN and NBM was associated with anticipating neutral social feedback, while connectivity between the vSN and NBM was associated with anticipating positive social feedback. A more complex pattern was observed for anticipating negative social feedback, including connectivity between the lSN and MS/DB, lSN and NAcc, as well as mSN and NAcc. To conclude,  functional connectivity patterns of the BF and mesolimbic areas signal the anticipation of social feedback depending on their emotional valence. As such, our findings give novel insights into the underlying neural processes of social information processing.

Unconscious knowledge of rewards guides instrumental behaviors via conscious judgments.

The demonstration that unconscious learning supports instrumental behaviors (i.e., choosing the stimuli that lead to rewards) is central for the tenet that unconscious cognition sustains human adaptation. Recent studies, using reliable subliminal conditioning paradigms and improved awareness measurements have found evidence against unconscious knowledge sustaining accurate instrumental responses. The present preregistered study proposes a paradigm, in which unconscious processing is stimulated not by subliminally exposing the predictive (conditioned) stimuli, but by employing predictive regularities that are complex and difficult to detect consciously. Participants (N = 211) were exposed to letter strings that, unknown to them, were built from two complex artificial grammars: a "rewarded" or a "non-rewarded" grammar. On each trial, participants memorized a string, and subsequently had to discriminate the memorized string from a distractor. Correct discriminations were rewarded only when the identified string followed the rewarded grammar, but not when it followed the non-rewarded grammar. In a subsequent test phase, participants were presented with new strings from the rewarded and from the unrewarded grammar. Their task was now to directly choose the strings from the rewarded grammar, in order to collect more rewards. A trial-by-trial awareness measure revealed that participants accurately choose novel strings from the rewarded grammar when they had no conscious knowledge of the grammar. The awareness measure also showed that participants were accurate only when the unconsciously learned grammar led to conscious judgments. The present study shows that unconscious knowledge can guide instrumental responses, but only to the extent it supports conscious judgments.

Effects of predictive and incentive value manipulation on sign- and goal-tracking behavior.

When a neutral stimulus is repeatedly paired with an appetitive reward, two different types of conditioned approach responses may develop: a sign-tracking response directed toward the neutral cue, or a goal-tracking response directed toward the location of impending reward delivery. Sign-tracking responses have been postulated to result from attribution of incentive value to conditioned cues, while goal-tracking reflects the assignment of only predictive value to the cue. We therefore hypothesized that sign-tracking rats would be more sensitive to manipulations of incentive value, while goal-tracking rats would be more responsive to changes in the predictive value of the cue. We tested sign- and goal-tracking before and after devaluation of a food reward using lithium chloride, and tested whether either response could be learned under negative contingency conditions that precluded any serendipitous reinforcement of the behavior that might support instrumental learning. We also tested the effects of blocking the predictive value of a cue using simultaneous presentation of a pre-conditioned cue. We found that sign-tracking was sensitive to outcome devaluation, while goal-tracking was not. We also confirmed that both responses are Pavlovian because they can be learned under negative contingency conditions. Goal-tracking was almost completely blocked by a pre-conditioned cue, while sign-tracking was much less sensitive to such interference. These results indicate that sign- and goal-tracking may follow different rules of reinforcement learning and suggest a need to revise current models of associative learning to account for these differences.

Diminished prospective mental representations of reward mediate reward learning strategies among youth with internalizing symptoms.

BACKGROUND: Adolescent internalizing symptoms and trauma exposure have been linked with altered reward learning processes and decreased ventral striatal responses to rewarding cues. Recent computational work on decision-making highlights an important role for prospective representations of the imagined outcomes of different choices. This study tested whether internalizing symptoms and trauma exposure among youth impact the generation of prospective reward representations during decision-making and potentially mediate altered behavioral strategies during reward learning. METHODS: Sixty-one adolescent females with varying exposure to interpersonal violence exposure (n = 31 with histories of physical or sexual assault) and severity of internalizing symptoms completed a social reward learning task during fMRI. Multivariate pattern analyses (MVPA) were used to decode neural reward representations at the time of choice. RESULTS: MVPA demonstrated that rewarding outcomes could accurately be decoded within several large-scale distributed networks (e.g. frontoparietal and striatum networks), that these reward representations were reactivated prospectively at the time of choice in proportion to the expected probability of receiving reward, and that youth with behavioral strategies that favored exploiting high reward options demonstrated greater prospective generation of reward representations. Youth internalizing symptoms, but not trauma exposure characteristics, were negatively associated with both the behavioral strategy of exploiting high reward options as well as the prospective generation of reward representations in the striatum. CONCLUSIONS: These data suggest diminished prospective mental simulation of reward as a mechanism of altered reward learning strategies among youth with internalizing symptoms.

Reward history modulates visual attention in an avian model.

Attention can be biased towards previously reward-associated stimuli even when they are task-irrelevant and physically non-salient, although studies of reward-modulated attention have been largely limited to primate (including human and nonhuman) models. Birds have been shown to have the capacity to discriminate reward and spatial cues in a manner similar to primates, but whether reward history involuntarily affects their attention in the same way remains unclear. We adapted a spatial cueing paradigm with differential rewards to investigate how reward modulates the allocation of attention in peafowl (Pavo cristatus). The birds were required to locate and peck a target on a computer screen that was preceded by a high-value or low-value color cue that was uninformative with respect to the location of the upcoming target. All birds exhibited a validity effect (performance enhanced on valid compared to invalid cue), and an interaction effect between value and validity was evident at the group level, being particularly pronounced in the birds with the greatest amount of reward training. The time course of reward learning was conspicuously incremental, phenomenologically slower compared to primates. Our findings suggest a similar influence of reward history on attention across phylogeny despite a significant difference in neuroanatomy.

Pupillary response in reward processing in adults with major depressive disorder in remission.

OBJECTIVE: Major depressive disorder (MDD) is associated with impaired reward processing and reward learning. The literature is inconclusive regarding whether these impairments persist after remission. The current study examined reward processing during a probabilistic learning task in individuals in remission from MDD (n = 19) and never depressed healthy controls (n = 31) matched for age and sex. The outcome measures were pupil dilation (an indirect index of noradrenergic activity and arousal) and computational modeling parameters. METHOD: Participants completed two versions (facial/nonfacial feedback) of probabilistic reward learning task with changing contingencies. Pupil dilation was measured with a corneal reflection eye tracker. The hypotheses and analysis plan were preregistered. RESULT: Healthy controls had larger pupil dilation following losses than gains (p <.001), whereas no significant difference between outcomes was found in individuals with a history of MDD, resulting in an interaction between group and outcome (ß = 0.81, SE = 0.34, t = 2.37, p = .018). The rMDD group also achieved lower mean score at the last trial (t[46.77] = 2.12, p = .040) as well as a smaller proportion of correct choices (t[46.70] = 2.09, p = .041) compared with healthy controls. CONCLUSION: Impaired reward processing may persist after remission from MDD and could constitute a latent risk factor for relapse. Measuring pupil dilation in a reward learning task is a promising method for identifying reward processing abnormalities linked to MDD. The task is simple and noninvasive, which makes it feasible for clinical research.

Depression Severity Moderates Reward Learning Among Smokers with Current or Past Major Depressive Disorder in a Smoking Cessation Randomized Clinical Trial.

INTRODUCTION: Behavioral and pharmacological smoking cessation treatments are hypothesized to increase patients' reward learning to reduce craving. Identifying changes in reward learning processes that support effective tobacco dependence interventions among smokers who experience depression may guide patients towards efficient treatment strategies. The objective was to investigate the extent to which adult daily cigarette smokers with current or past major depressive disorder (MDD) learned to seek reward during 12 weeks of treatment combining behavioral activation and varenicline. We hypothesized that a decline in reward learning would be attenuated (least to most) in the following order: 1) Behavioral activation integrated with ST (BASC) + varenicline, 2) BASC + placebo, 3) Standard behavioral cessation treatment (ST) + varenicline, 4) ST + placebo. METHODS: We ran a Phase 4, placebo-controlled, randomized clinical trial with 300 participants receiving 12 weeks of one of four conditions across two urban medical centers. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI). Reward learning was ascertained at Weeks 1, 7, and 14 using the Probabilistic Reward Task (PRT), a laboratory task that uses an asymmetric reinforcement schedule to assess (a) learning to seek reward (response bias), (b) differentiate between stimuli, and (c) time to react to cues. RESULTS: There was a significant interaction of BDI group x PRT response bias. Response bias declined from Week 7 to 14 among participants with high baseline depression symptoms. The other two BDI groups showed no change in response bias. CONCLUSIONS: Controlling for baseline depression, participants showed a decrease in response bias from Week 1 to 14, and from Weeks 7 to 14. Treatment condition and abstinence status were unassociated with change in reward learning. IMPLICATIONS: Smokers who report greater depression severity show a decline in reward learning despite their participation in smoking cessation treatments, suggesting that depressed populations pose unique challenges with standard smoking cessation approaches.

Reinforcement learning profiles and negative symptoms across chronic and clinical high-risk phases of psychotic illness.

Negative symptoms are prominent in individuals with schizophrenia (SZ) and youth at clinical high-risk for psychosis (CHR). In SZ, negative symptoms are linked to reinforcement learning (RL) dysfunction; however, previous research suggests implicit RL remains intact. It is unknown whether implicit RL is preserved in the CHR phase where negative symptom mechanisms are unclear, knowledge of which may assist in developing early identification and prevention methods. Participants from two studies completed an implicit RL task: Study 1 included 53 SZ individuals and 54 healthy controls (HC); Study 2 included 26 CHR youth and 23 HCs. Bias trajectories reflecting implicit RL were compared between groups and correlations with negative symptoms were examined. Cluster analysis investigated RL profiles across the combined samples. Implicit RL was comparable between HC and their corresponding SZ and CHR groups. However, cluster analysis was able to parse performance heterogeneity across diagnostic boundaries into two distinct RL profiles: a Positive/Early Learning cluster (65% of participants) with positive bias scores increasing from the first to second task block, and a Negative/Late Learning cluster (35% of participants) with negative bias scores increasing from the second to third block. Clusters did not differ in the proportion of CHR vs. SZ cases; however, the Negative/Late Learning cluster had more severe negative symptoms. Although implicit RL is intact in CHR similar to SZ, distinct implicit RL phenotypic profiles with elevated negative symptoms were identified trans-phasically, suggesting distinct reward-processing mechanisms can contribute to negative symptoms independent of phases of illness.

Large-scale neural network computations and multivariate representations during approach-avoidance conflict decision-making.

Many real-world situations require navigating decisions for both reward and threat. While there has been significant progress in understanding mechanisms of decision-making and mediating neurocircuitry separately for reward and threat, there is limited understanding of situations where reward and threat contingencies compete to create approach-avoidance conflict (AAC). Here, we leverage computational learning models, independent component analysis (ICA), and multivariate pattern analysis (MVPA) approaches to understand decision-making during a novel task that embeds concurrent reward and threat learning and manipulates congruency between reward and threat probabilities. Computational modeling supported a modified reinforcement learning model where participants integrated reward and threat value into a combined total value according to an individually varying policy parameter, which was highly predictive of decisions to approach reward vs avoid threat during trials where the highest reward option was also the highest threat option (i.e., approach-avoidance conflict). ICA analyses demonstrated unique roles for salience, frontoparietal, medial prefrontal, and inferior frontal networks in differential encoding of reward vs threat prediction error and value signals. The left frontoparietal network uniquely encoded degree of conflict between reward and threat value at the time of choice. MVPA demonstrated that delivery of reward and threat could accurately be decoded within salience and inferior frontal networks, respectively, and that decisions to approach reward vs avoid threat were predicted by the relative degree to which these reward vs threat representations were active at the time of choice. This latter result suggests that navigating AAC decisions involves generating mental representations for possible decision outcomes, and relative activation of these representations may bias subsequent decision-making towards approaching reward or avoiding threat accordingly.

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 no stress 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.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. METHODS: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. RESULTS: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.