Using Drift Diffusion and RL Models to Disentangle Effects of Depression On Decision-Making vs. Learning in the Probabilistic Reward Task.

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these efforts by: (1) providing a more detailed analysis of standard PRT metrics-response bias and discriminability-to better understand how the task is performed; (2) analyzing the data with two computational models and providing psychometric analyses of both; and (3) determining whether response bias, discriminability, or model parameters predicted responses to treatment with placebo or the atypical antidepressant bupropion. Analysis of standard metrics replicated recent work by demonstrating a dependency between response bias and response time (RT), and by showing that reward totals in the PRT are governed by discriminability. Behavior was well-captured by the Hierarchical Drift Diffusion Model (HDDM), which models decision-making processes; the HDDM showed excellent internal consistency and acceptable retest reliability. A separate "belief" model reproduced the evolution of response bias over time better than the HDDM, but its psychometric properties were weaker. Finally, the predictive utility of the PRT was limited by small samples; nevertheless, depressed adults who responded to bupropion showed larger pre-treatment starting point biases in the HDDM than non-responders, indicating greater sensitivity to the PRT's asymmetric reinforcement contingencies. Together, these findings enhance our understanding of reward and decision-making mechanisms that are implicated in MDD and probed by the PRT.

Validating the Children's Depression Inventory-2: Results from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study.

Childhood-onset depression has adverse consequences that are sustained into adulthood, which increases the significance of detection in early childhood. The Children's Depression Inventory (CDI) is used globally in evaluating depressive symptom severity in adolescents, and its second version, the CDI-2, was developed by taking into account advances in childhood depression research. Prior research has reported inconsistencies in its factor structure across populations. In addition, the CDI-2 has not yet been empirically validated with Southeast Asian populations. This study sought to empirically validate the CDI-2's psychometric properties and evaluate its factorial structure with a Singaporean community sample of non-clinical respondents. A total sample of 730 Singaporean children aged between 8.5 and 10.5 years was used. Psychometric properties of the CDI-2, including internal consistency as well as convergent and discriminant validity, were assessed. Factor analyses were conducted to assess the developers' original two-factor structure for a Southeast Asian population. This two-factor structure was not supported in our sample. Instead, the data provided the best fit for a hierarchical two-factor structure with factors namely, socio-emotional problems and cognitive-behavioural problems. This finding suggests that socio-cultural and demographic elements influence interpretation of depressive symptoms and therefore the emerging factor structure of the construct under scrutiny. This study highlights the need to further examine the CDI-2 and ensure that its interpretation is culture-specific. More qualitative work could also bring to light the idiosyncratic understanding of depressive symptomatology, which would then guide culture-specific validation of the CDI-2.

Momentary gustative-olfactory sensitivity and tonic heart rate variability are independently associated with motivational behavior.

Deficits in motivational functioning including impairments in reward learning or reward sensitivity are common in psychiatric disorders characterized by anhedonia. Recently, anhedonic symptoms have been exacerbated by the pandemic caused by the Coronavirus disease 2019 (COVID-19) in the general population. The present study examined the putative associations between loss of smell (anosmia) and taste (ageusia) sensitivity, irrespective of COVID-19 infection, and anhedonia, measured by a signal-detection task probing the ability to modify behavior as a function of rewards (Probabilistic Reward Task; PRT). Tonic heart rate variability (HRV) was included in the model, due to its association with both smell and taste sensitivity as well as motivational functioning. The sample included 114 healthy individuals (81 females; mean age 22.2 years), who underwent a laboratory session in which dispositional traits, resting HRV and PRT performance were assessed, followed by a 4-days ecological momentary assessment to obtain daily measures of anosmia and ageusia. Lower levels of tonic HRV and lower momentary levels of smell and taste sensitivity were associated with impaired reward responsiveness and ability to shape future behavioral choices based on prior reinforcement experiences. Overall, the current results provide initial correlational evidence that could be fruitfully used to inform future experimental investigations aimed at elucidating the disruptive worldwide mental health consequences triggered by the pandemic.

Cognitive effort-based decision-making in major depressive disorder.

BACKGROUND: The association between major depressive disorder and motivation to invest cognitive effort for rewards is unclear. One reason might be that prior tasks of cognitive effort-based decision-making are limited by potential confounds such as physical effort and temporal delay discounting. METHODS: To address these interpretive challenges, we developed a new task - the Cognitive Effort Motivation Task - to assess one's willingness to exert cognitive effort for rewards. Cognitive effort was manipulated by varying the number of items (1, 2, 3, 4, 5) kept in spatial working memory. Twenty-six depressed patients and 44 healthy controls went through an extensive learning session where they experienced each possible effort level 10 times. They were then asked to make a series of choices between performing a fixed low-effort-low-reward or variable higher-effort-higher-reward option during the task. RESULTS: Both groups found the task more cognitively (but not physically) effortful when effort level increased, but they still achieved ⩾80% accuracy on each effort level during training and >95% overall accuracy during the actual task. Computational modelling revealed that a parabolic model best accounted for subjects' data, indicating that higher-effort levels had a greater impact on devaluing rewards than lower levels. These procedures also revealed that MDD patients discounted rewards more steeply by effort and were less willing to exert cognitive effort for rewards compared to healthy participants. CONCLUSIONS: These findings provide empirical evidence to show, without confounds of other variables, that depressed patients have impaired cognitive effort motivation compared to the general population.

A multi-pronged investigation of option generation using depression, PET and modafinil.

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

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.

Assessment of apathy in neurological patients using the Apathy Motivation Index caregiver version.

Apathy is a common, disabling neuropsychiatric syndrome that occurs across many brain disorders and may be associated with diminished motivation in behavioural, cognitive, emotional and social domains. Assessment is complicated by the variability of symptoms across apathy domains and self-report from patients, which can be misleading due to their lack of insight. Independent evaluation by clinicians also has limitations though if it has to be performed with limited time. Caregiver reports are a viable alternative, but current assessments for them either do not distinguish between different apathy domains or are interview-based and take long to administer. In this study, we developed a brief caregiver questionnaire version of the recently developed Apathy Motivation Index (AMI), which is a self-report tool. We confirmed three apathy factors in this new caregiver measure (AMI-CG) that were also present in the AMI: Behavioural Activation, Emotional Sensitivity and Social Motivation. Furthermore, we validated the scores against more extensive caregiver interviews using the established Lillle apathy rating scale as well as patient self-reports of apathy, measures of depression, anhedonia, cognition, activities of daily living and caregiver burden across four different neurological conditions: Parkinson's disease, Alzheimer's disease, subjective cognitive impairment and limbic encephalitis. The AMI-CG showed good internal reliability, external validity and diagnostic accuracy. It also uncovered cases of social apathy overlooked by traditional instruments. Crucially, patients who under-rated their apathy compared to informants were more likely to have difficulties performing everyday activities and to be a greater burden to caregivers. The findings provide evidence for a multidimensional conceptualization of apathy and an instrument for efficient detection of apathy based on caregiver reports for use in clinical practice.

Perseverative Cognition in the Positive Valence Systems: An Experimental and Ecological Investigation.

Perseverative cognition (PC) is a transdiagnostic risk factor that characterizes both hypo-motivational (e.g., depression) and hyper-motivational (e.g., addiction) disorders; however, it has been almost exclusively studied within the context of the negative valence systems. The present study aimed to fill this gap by combining laboratory-based, computational and ecological assessments. Healthy individuals performed the Probabilistic Reward Task (PRT) before and after the induction of PC or a waiting period. Computational modeling was applied to dissociate the effects of PC on reward sensitivity and learning rate. Afterwards, participants underwent a one-week ecological momentary assessment of daily PC occurrence, as well as anticipatory and consummatory reward-related behavior. Induction of PC led to increased response bias on the PRT compared to waiting, likely due to an increase in learning rate but not in reward sensitivity, as suggested by computational modeling. In daily-life, PC increased the discrepancy between expected and obtained rewards (i.e., prediction error). Current converging experimental and ecological evidence suggests that PC is associated with abnormalities in the functionality of positive valence systems. Given the role of PC in the prediction, maintenance, and recurrence of psychopathology, it would be clinically valuable to extend research on this topic beyond the negative valence systems.

Reward Functioning Abnormalities in Adolescents at High Familial Risk for Depressive Disorders.

BACKGROUND: A parental history of major depressive disorder (MDD) is an established risk factor for MDD in youth, and clarifying the mechanisms related to familial risk transmission is critical. Aberrant reward processing is a promising biomarker of MDD risk; accordingly, the aim of this study was to test behavioral measures of reward responsiveness and underlying frontostriatal resting activity in healthy adolescents both with (high-risk) and without (low-risk) a maternal history of MDD. METHODS: Low-risk and high-risk 12- to 14-year-old adolescents completed a probabilistic reward task (n = 74 low-risk, n = 27 high-risk) and a resting-state functional magnetic resonance imaging scan (n = 61 low-risk, n = 25 high-risk). Group differences in response bias toward reward and resting ventral striatal and medial prefrontal cortex (mPFC) fractional amplitude of low-frequency fluctuations (fALFFs) were examined. Computational modeling was applied to dissociate reward sensitivity from learning rate. RESULTS: High-risk adolescents showed a blunted response bias compared with low-risk adolescents. Computational modeling analyses revealed that relative to low-risk adolescents, high-risk adolescents exhibited reduced reward sensitivity but similar learning rate. Although there were no group differences in ventral striatal and mPFC fALFFs, groups differed in their relationships between mPFC fALFFs and response bias. Specifically, among high-risk adolescents, higher mPFC fALFFs correlated with a blunted response bias, whereas there was no fALFFs-response bias relationship among low-risk youths. CONCLUSIONS: High-risk adolescents exhibit reward functioning impairments, which are associated with mPFC fALFFs. The blunted response bias-mPFC fALFFs association may reflect an excessive mPFC-mediated suppression of reward-driven behavior, which may potentiate MDD risk.

Disentangling vulnerability, state and trait features of neurocognitive impairments in depression.

Depression is a debilitating disorder that often starts manifesting in early childhood and peaks in onset during adolescence. Neurocognitive impairments have emerged as clinically important characteristics of depression, but it remains controversial which domains specifically index pre-existing vulnerability, state-related or trait-related markers. Here, we disentangled these effects by analysing the Adolescent Brain Cognitive Development dataset (n = 4626). Using information of participants' current and past mental disorders, as well as family mental health history, we identified low-risk healthy (n = 2100), high-risk healthy (n = 2023), remitted depressed (n = 401) and currently depressed children (n = 102). Factor analysis of 11 cognitive variables was performed to elucidate latent structure and canonical correlation analyses conducted to probe regional brain volumes reliably associated with the cognitive factors. Bayesian model comparison of various a priori hypotheses differing in how low-risk healthy, high-risk healthy, remitted depressed and currently depressed children performed in various cognitive domains was performed. Factor analysis revealed three domains: language and reasoning, cognitive flexibility and memory recall. Deficits in language and reasoning ability, as well as in volumes of associated regions such as the middle temporal and superior frontal gyrus, represented state- and trait-related markers of depression but not pre-existing vulnerability. In contrast, there was no compelling evidence of impairments in other domains. These findings-although cross-sectional and specific to 9-10-year-old children-might have important clinical implications, suggesting that cognitive dysfunction may not be useful targets of preventive interventions. Depressed patients, even after remission, might also benefit from less commonly used treatments such as cognitive remediation therapy.

Pretreatment Reward Sensitivity and Frontostriatal Resting-State Functional Connectivity Are Associated With Response to Bupropion After Sertraline Nonresponse.

BACKGROUND: Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit are often switched to non-selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse. METHODS: In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline. RESULTS: Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample. CONCLUSIONS: Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care.

Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS).

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

Dopamine Modulates Dynamic Decision-Making during Foraging.

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by traveling elsewhere (background reward rate), to determine the opportunity cost of staying versus leaving. We hypothesized that dopamine specifically modulates the influence of background, but not foreground, reward information when making a dynamic comparison of these variables for optimal behavior. On a novel foraging task based on an ecological account of animal behavior (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background reward rates. In line with theoretical accounts, people's decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signaling the opportunity cost of rewards, not value per se. Using this ecologically derived framework, we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared.SIGNIFICANCE STATEMENT Many decisions, across economic, political, and social spheres, involve choices to "leave". Such decisions depend on a continuous comparison of a current location's value, with that of other locations you could move on to. However, how the brain makes such decisions is poorly understood. Here, we developed a computerized task, based around theories of how animals make decisions to move on when foraging for food. Healthy human participants had to decide when to leave collecting financial rewards in a location, and travel to collect rewards elsewhere. Using a pharmacological manipulation, we show that the activity of dopamine in the brain modulates decisions to move on, with people valuing other locations differently depending on their dopaminergic state.

Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Dopamine D2 receptor stimulation modulates the balance between ignoring and updating according to baseline working memory ability.

BACKGROUND: Working memory (WM) deficits in neuropsychiatric disorders have often been attributed to altered dopaminergic signalling. Specifically, D2 receptor stimulation is thought to affect the ease with which items can be gated into and out of WM. In addition, this effect has been hypothesised to vary according to baseline WM ability, a putative index of dopamine synthesis levels. Moreover, whether D2 stimulation affects WM vicariously through modulating relatively WM-free cognitive control processes has not been explored. AIMS: We examined the effect of administering a dopamine agonist on the ability to ignore or update information in WM. METHOD: A single dose of cabergoline (1 mg) was administered to healthy older adult humans in a within-subject, double-blind, placebo-controlled study. In addition, we obtained measures of baseline WM ability and relatively WM-free cognitive control (overcoming response conflict). RESULTS: Consistent with predictions, baseline WM ability significantly modulated the effect that drug administration had on the proficiency of ignoring and updating. High-WM individuals were relatively better at ignoring compared to updating after drug administration. Whereas the opposite occurred in low-WM individuals. Although the ability to overcome response conflict was not affected by cabergoline, a negative relationship between the effect the drug had on response conflict performance and ignoring was observed. Thus, both response conflict and ignoring are coupled to dopaminergic stimulation levels. CONCLUSIONS: Cumulatively, these results provide evidence that dopamine affects subcomponents of cognitive control in a diverse, antagonistic fashion and that the direction of these effects is dependent upon baseline WM.

Dopamine guides competition for cognitive control: Common effects of haloperidol on working memory and response conflict.

Several lines of evidence suggest that dopamine modulates working memory (the ability to faithfully maintain and efficiently manipulate information over time) but its specific role has not been fully defined. Nor is it clear whether any effects of dopamine are specific to memory processes or whether they reflect more general cognitive mechanisms that extend beyond the working memory domain. Here, we examine the effect of haloperidol, principally a dopamine D2 receptor antagonist, on the ability of humans to ignore distracting information or update working memory contents. We compare these effects to performance on an independent measure of cognitive control (response conflict) which has minimal memory requirements. Haloperidol did not selectively affect the ability to ignore or update, but instead reduced the overall quality of recall. In addition, it impaired the ability to overcome response conflict. The deleterious effect of haloperidol on response conflict was selectively associated with the negative effect of the drug on ignoring - but not updating - suggesting that dopamine affects protection of working memory contents and inhibition in response conflict through a common mechanism. These findings provide new insights into the role of dopamine D2 receptors on human cognition. They suggest that D2 receptor effects on protecting the memory contents from distraction might be related to a more general process that supports inhibitory control in contexts that do not require working memory.

Inflammation and dimensions of reward processing following exposure to the influenza vaccine.

BACKGROUND: Alterations in reward processing are a central feature of depression and may be influenced by inflammation. Indeed, inflammation is associated with deficits in reward-related processes in animal models and with dysregulation in reward-related neural circuitry in humans. However, the downstream behavioral manifestations of such impairments are rarely examined in humans. METHODS: The influenza vaccination was used to elicit a mild inflammatory response in 41 healthy young adults (age range: 18-22, 30 female). Participants provided blood samples and completed behavioral measures of three key aspects of reward-reward motivation, reward learning, and reward sensitivity-before and 1 day after receiving the influenza vaccine. RESULTS: The influenza vaccine led to mild but significant increases in circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (p < .001). Consistent with hypotheses, increases in IL-6 predicted lower reward motivation (p = .029). However, contrary to hypotheses, increases in IL-6 predicted increased performance on a reward learning task (p = .043) and were not associated with changes in reward sensitivity (p's > .288). CONCLUSIONS: These findings contribute to an emerging literature on the nuanced associations between inflammation and reward and demonstrate that even mild alterations in inflammation are associated with multiple facets of reward processing.

Differential impact of behavioral, social, and emotional apathy on Parkinson's disease.

Apathy is highly prevalent in Parkinson's disease. New findings suggest the syndrome is multifaceted. Here, we investigate whether all aspects of apathy are equally affected in Parkinson's disease and whether different dimensions of apathy were associated with depression and anhedonia. On the Apathy Motivation Index, while behavioral apathy and social apathy were elevated, emotional motivation was relatively preserved in Parkinson's disease, although a few patients did show impaired emotional sensitivity. Behavioral and social, but not emotional, apathy was associated with depression and anhedonia. These findings suggest aspects of motivation can be selectively impaired in Parkinson's disease and may have implications for guiding treatment.