Reward-related Ventral Striatum Research Articles

Exposure to community violence as a mechanism linking neighborhood socioeconomic disadvantage and neural responses to reward.

A growing literature links socioeconomic disadvantage and adversity to brain function, including disruptions in reward processing. Less research has examined exposure to community violence (ECV) as a specific adversity related to differences in reward-related brain activation, despite the prevalence of community violence exposure for those living in disadvantaged contexts. The current study tested whether ECV was associated with reward-related ventral striatum (VS) activation after accounting for familial factors associated with differences in reward-related activation (e.g. parenting and family income). Moreover, we tested whether ECV is a mechanism linking socioeconomic disadvantage to reward-related activation in the VS. We utilized data from 444 adolescent twins sampled from birth records and residing in neighborhoods with above-average levels of poverty. ECV was associated with greater reward-related VS activation, and the association remained after accounting for family-level markers of disadvantage. We identified an indirect pathway in which socioeconomic disadvantage predicted greater reward-related activation via greater ECV, over and above family-level adversity. These findings highlight the unique impact of community violence exposure on reward processing and provide a mechanism through which socioeconomic disadvantage may shape brain function.

Development and validation of an fMRI-informed EEG model of reward-related ventral striatum activation

Reward processing is essential for our mental-health and well-being. In the current study, we developed and validated a scalable, fMRI-informed EEG model for monitoring reward processing related to activation in the ventral-striatum (VS), a significant node in the brain's reward system. To develop this EEG-based model of VS-related activation, we collected simultaneous EEG/fMRI data from 17 healthy individuals while listening to individually-tailored pleasurable music – a highly rewarding stimulus known to engage the VS. Using these cross-modal data, we constructed a generic regression model for predicting the concurrently acquired Blood-Oxygen-Level-Dependent (BOLD) signal from the VS using spectro-temporal features from the EEG signal (termed hereby VS-related-Electrical Finger Print; VS-EFP). The performance of the extracted model was examined using a series of tests that were applied on the original dataset and, importantly, an external validation dataset collected from a different group of 14 healthy individuals who underwent the same EEG/FMRI procedure. Our results showed that the VS-EFP model, as measured by simultaneous EEG, predicted BOLD activation in the VS and additional functionally relevant regions to a greater extent than an EFP model derived from a different anatomical region. The developed VS-EFP was also modulated by musical pleasure and predictive of the VS-BOLD during a monetary reward task, further indicating its functional relevance. These findings provide compelling evidence for the feasibility of using EEG alone to model neural activation related to the VS, paving the way for future use of this scalable neural probing approach in neural monitoring and self-guided neuromodulation.

Mapping frontostriatal white matter tracts and their association with reward-related ventral striatum activation in adolescence

The ventral striatum (VS) is implicated in reward processing and motivation. Human and non-human primate studies demonstrate that the VS and prefrontal cortex (PFC), which comprise the frontostriatal circuit, interact to influence motivated behavior. However, there is a lack of research that precisely maps and quantifies VS–PFC white matter tracts. Moreover, no studies have linked frontostriatal white matter to VS activation. Using a multimodal neuroimaging approach with diffusion MRI (dMRI) and functional MRI (fMRI), the present study had two objectives: 1) to chart white matter tracts between the VS and specific PFC structures and 2) assess the association between the degree of VS–PFC white matter tract connectivity and VS activation in 187 adolescents. White matter connectivity was assessed with probabilistic tractography and functional activation was examined with two fMRI tasks (one task with social reward and another task using monetary reward). We found widespread but variable white matter connectivity between the VS and areas of the PFC, with the anterior insula and subgenual cingulate cortex demonstrating the greatest degree of connectivity with the VS. VS–PFC structural connectivity was related to functional activation in the VS though activation depended on the specific PFC region and reward task.

Reward‐ and threat‐related neural function associated with risk and presence of depression in adolescents: a study using a composite risk score in Brazil

Neuroimaging studies on adolescents at risk for depression have relied on a single risk factor and focused on adolescents in high-income countries. Using a composite risk score, this study aims to examine neural activity and connectivity associated with risk and presence of depression in adolescents in Brazil. Depression risk was defined with the Identifying Depression Early in Adolescence Risk Score (IDEA-RS), calculated using a prognostic model that included 11 socio-demographic risk factors. Adolescents recruited from schools in Porto Alegre were classified into a low-risk (i.e., low IDEA-RS and no lifetime depression), high-risk (i.e., high IDEA-RS and no lifetime depression), or clinically depressed group (i.e., high IDEA-RS and depression diagnosis). One hundred fifty adolescents underwent a functional MRI scan while completing a reward-related gambling and a threat-related face-matching task. We compared group differences in activity and connectivity of the ventral striatum (VS) and amygdala during the gambling and face-matching tasks, respectively, and group differences in whole-brain neural activity. Although there was no group difference in reward-related VS or threat-related amygdala activity, the depressed group showed elevated VS activity to punishment relative to high-risk adolescents. The whole-brain analysis found reduced reward-related activity in the lateral prefrontal cortex of patients and high-risk adolescents compared with low-risk adolescents. Compared with low-risk adolescents, high-risk and depressed adolescents showed reduced threat-related left amygdala connectivity with thalamus, superior temporal gyrus, inferior parietal gyrus, precentral gyrus, and supplementary motor area. We identified neural correlates associated with risk and presence of depression in a well-characterized sample of adolescents. These findings enhance knowledge of the neurobiological underpinnings of risk and presence of depression in Brazil. Future longitudinal studies are needed to examine whether the observed neural patterns of high-risk adolescents predict the development of depression.

Neuroticism and reward-related ventral striatum activity: Probing vulnerability to stress-related depression.

Elevated neuroticism may confer vulnerability to the depressogenic effects of stressful life events (SLEs). However, the mechanisms underlying this susceptibility remain poorly understood. Accumulating evidence suggests that stress-related disruptions in neural reward processing might undergird links between stress and depression. Using data from the Saint Louis Personality and Aging Network (SPAN) study and Duke Neurogenetics Study (DNS), we examined whether neuroticism moderates links between stressful life events (SLE) and depression as well as SLEs and ventral striatum (VS) response to reward. In the longitudinal SPAN sample (n = 971 older adults), SLEs prospectively predicted future depressive symptoms, especially among those reporting elevated neuroticism, even after accounting for prior depressive symptoms and previous SLE exposure (NxSLE interaction: p = .016, ΔR² = 0.003). Cross-sectional analyses of the DNS, a young adult college sample with neuroimaging data, replicated this interaction (n = 1,343: NxSLE interaction: p = .019, ΔR² = 0.003) and provided evidence that neuroticism moderates the association between SLEs and reward-related VS response (n = 1,195, NxSLE: p = .017, ΔR² = 0.0048). Blunted left VS response to reward was associated with a lifetime depression diagnosis, r = -0.07, p = .02, but not current depressive symptoms, r = -0.003, p = .93. These data suggest that neuroticism may promote vulnerability to stress-related depression and that sensitivity to stress-related reductions in VS response may be a potential neural mechanism underlying vulnerability to clinically significant depression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Apathy is not associated with reduced ventral striatal volume in patients with schizophrenia

BackgroundA growing body of neuroimaging research has revealed a relationship between blunted activation of the ventral striatum (VS) and apathy in schizophrenia. In contrast, the association between reduced striatal volume and apathy is less well established, while the relationship between VS function and structure in patients with schizophrenia remains an open question. Here, we aimed to replicate previous structural findings in a larger independent sample and to investigate the relationship between VS hypoactivation and VS volume. MethodsWe included brain structural magnetic resonance imaging (MRI) data from 60 patients with schizophrenia (SZ) that had shown an association of VS hypoactivation with apathy during reward anticipation and 58 healthy controls (HC). To improve replicability, we applied analytical methods employed in two previously published studies: Voxel-based morphometry and the Multiple Automatically Generated Templates (MAGeT) algorithm. VS and dorsal striatum (DS) volume were correlated with apathy correcting for age, gender and total brain volume. Additionally, left VS activity was correlated with left VS volume. ResultsWe failed to replicate the association between apathy and reduced VS volume and did not find a correlation with DS volume. Functional and structural left VS measures exhibited a trend-level correlation (rs = 0.248, p = 0.067, r2 = 0.06). ConclusionsOur present data suggests that functional and structural striatal neuroimaging correlates of apathy can occur independently. Replication of previous findings may have been limited by other factors (medication, illness duration, age) potentially related to striatal volume changes in SZ. Finally, associations between reward-related VS function and structure should be further explored.

ERRATUM: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. 222 unmedicated adults with MDD randomized to receive sertraline (n=110) or placebo (n=112) in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study completed demographic and clinical assessments, and pre-treatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on Week-8 depression levels (Fs≥9.67,ps≤0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower Week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pre-treatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pre-treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.Trial Registration:NCT01407094; http://clinicaltrials.gov/show/NCT01407094

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

Dopamine genetic risk is related to food addiction and body mass through reduced reward-related ventral striatum activity

The prevalence rate of obesity continues to rise in the U.S., but effective treatment options remain elusive resulting in increased emphasis on prevention. One such area of prevention research capitalizes on the relatively novel behavioral construct of food addiction, which has been implicated in obesity. Food addiction reflects an individual's propensity for compulsive eating despite negative consequences, and shares not only symptoms with both eating and substance use disorders but also genetic and neural correlates within neural reward-circuitry modulated by dopamine. Here, we examined associations between food addiction scores, body mass index (BMI), reward-related ventral striatum activity, and a polygenic score approximating dopamine signaling in 115 non-Hispanic Caucasian young adult university students. As predicted, polygenic dopamine scores were related to ventral striatum activity, which in turn was associated with higher food addiction scores. In addition, food addiction was related to BMI. An exploratory post-hoc path analysis further indicated that polygenic scores were indirectly related to both food addiction and BMI, in part, through ventral striatum activity. Collectively, our results provide evidence supporting the utility of food addiction in weight gain prevention research by establishing links with known risk-related neural and genetic biomarkers.

Trajectories of Alcohol Initiation and Use During Adolescence: The Role of Stress and Amygdala Reactivity

Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, little is known about developmental trajectories of alcohol use initiation and their putative biological and environmental correlates. Adolescents (N= 330) with high or low familial loading for depression were assessed annually for up to 6 years. Data were collected assessing affective symptoms, alcohol use, and stress at each assessment. Adolescents also participated in a functional magnetic resonance imaging protocol that included measurement of threat-related amygdala and reward-related ventral striatum activity. Latent class analyses identified 2 trajectories of alcohol use initiation. Early initiators (n= 32) reported greater baseline alcohol use and rate of change of use compared with late initiators and/or current abstainers (n= 298). Early initiators reported higher baseline levels of stressful life events (p= .001) and exhibited higher amygdala (p= .001) but not ventral striatum activity compared with late initiators. Early initiators were 15.3 times more likely to have a full drink (p< .0001), 9.1 times more likely to experience intoxication (p< .0001), and 6.7 times more likely to develop an alcohol use disorder by 19 years of age compared with late initiators (p= .003). Adolescents on a trajectory of early alcohol use initiation have higher levels of stress, have increased threat-related amygdala activity, are more likely to consume a full standard alcoholic drink, are more likely to experience early intoxication, and are at a heightened risk for the onset of an alcohol use disorder.

Prefrontal Executive Control Rescues Risk for Anxiety Associated with High Threat and Low Reward Brain Function.

Compared with neural biomarkers of risk for mental illness, little is known about biomarkers of resilience. We explore if greater executive control-related prefrontal activity may function as a resilience biomarker by "rescuing" risk associated with higher threat-related amygdala and lower reward-related ventral striatum activity. Functional MRI was used to assay baseline threat-related amygdala, reward-related ventral striatum, and executive control-related prefrontal activity in 120 young adult volunteers. Participants provided self-reported mood and anxiety ratings at baseline and follow-up. A moderation model revealed a significant three-way interaction wherein higher amygdala and lower ventral striatum activity predicted increases in anxiety in those with average or low but not high prefrontal activity. This effect was specific to anxiety, with the neural biomarkers explaining ~10% of the variance in change over time, above and beyond baseline symptoms, sex, age, IQ, presence or absence of DMS-IV diagnosis, and both early and recent stress. Our findings are consistent with the importance of top-down executive control in adaptive regulation of negative emotions, and highlight a unique combination of neural biomarkers that may identify at-risk individuals for whom the adoption of strategies to improve executive control of negative emotions may prove particularly beneficial.

Reward-Related Ventral Striatum Activity Buffers against the Experience of Depressive Symptoms Associated with Sleep Disturbances.

Sleep disturbances represent one risk factor for depression. Reward-related brain function, particularly the activity of the ventral striatum (VS), has been identified as a potential buffer against stress-related depression. We were therefore interested in testing whether reward-related VS activity would moderate the effect of sleep disturbances on depression in a large cohort of young adults. Data were available from 1129 university students (mean age 19.71 ± 1.25 years; 637 women) who completed a reward-related functional MRI task to assay VS activity and provided self-reports of sleep using the Pittsburgh Sleep Quality Index and symptoms of depression using a summation of the General Distress/Depression and Anhedonic Depression subscales of the Mood and Anxiety Symptoms Questionnaire-short form. Analyses revealed that as VS activity increased the association between sleep disturbances and depressive symptoms decreased. The interaction between sleep disturbances and VS activity was robust to the inclusion of sex, age, race/ethnicity, past or present clinical disorder, early and recent life stress, and anxiety symptoms, as well as the interactions between VS activity and early or recent life stress as covariates. We provide initial evidence that high reward-related VS activity may buffer against depressive symptoms associated with poor sleep. Our analyses help advance an emerging literature supporting the importance of individual differences in reward-related brain function as a potential biomarker of relative risk for depression.SIGNIFICANCE STATEMENT Sleep disturbances are a common risk factor for depression. An emerging literature suggests that reward-related activity of the ventral striatum (VS), a brain region critical for motivation and goal-directed behavior, may buffer against the effect of negative experiences on the development of depression. Using data from a large sample of 1129 university students we demonstrate that as reward-related VS activity increases, the link between sleep disturbances and depression decreases. This finding contributes to accumulating research demonstrating that reward-related brain function may be a useful biomarker of relative risk for depression in the context of negative experiences.

Reward-Related Ventral Striatum Activity Links Polygenic Risk for Attention-Deficit/Hyperactivity Disorder to Problematic Alcohol Use in Young Adulthood

BackgroundProblematic alcohol use in adolescence and adulthood is a common and often debilitating correlate of childhood attention-deficit/hyperactivity disorder (ADHD). Converging evidence suggests that ADHD and problematic alcohol use share a common additive genetic basis, which may be mechanistically related to reward-related brain function. In the current study, we examined whether polygenic risk for childhood ADHD is linked to problematic alcohol use in young adulthood through alterations in reward-related activity of the ventral striatum, a neural hub supporting appetitive behaviors and reinforcement learning. MethodsGenomic, neuroimaging, and self-report data were available for 404 non-Hispanic European American participants who completed the ongoing Duke Neurogenetics Study. Polygenic risk scores for childhood ADHD were calculated based on a genome-wide association study meta-analysis conducted by the Psychiatric Genomics Consortium and tested for association with reward-related ventral striatum activity, measured using a number-guessing functional magnetic resonance imaging paradigm, and self-reported problematic alcohol use. A mediational model tested whether ventral striatum activity indirectly links polygenic risk for ADHD to problematic alcohol use. ResultsDespite having no main effect on problematic alcohol use, polygenic risk for childhood ADHD was indirectly associated with problematic alcohol use through increased reward-related ventral striatum activity. ConclusionsIndividual differences in reward-related brain function may, at least in part, mechanistically link polygenic risk for childhood ADHD to problematic alcohol use.

PER1 rs3027172 Genotype Interacts with Early Life Stress to Predict Problematic Alcohol Use, but Not Reward-Related Ventral Striatum Activity.

Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.

A neuroscience perspective on sexual risk behavior in adolescence and emerging adulthood.

Late adolescence and emerging adulthood (specifically ages 15-24) represent a period of heightened sexual risk taking resulting in the greatest annual rates of sexually transmitted infections and unplanned pregnancies in the US population. Ongoing efforts to prevent such negative consequences are likely to benefit from a deepening of our understanding of biological mechanisms through which sexual risk taking emerges and biases decision making during this critical window. Here we present a neuroscience framework from which a mechanistic examination of sexual risk taking can be advanced. Specifically, we adapt the neurodevelopmental triadic model, which outlines how motivated behavior is governed by three systems: approach, avoidance, and regulation, to sexual decision making and subsequent risk behavior. We further propose a testable hypothesis of the triadic model, wherein relatively decreased threat-related amygdala reactivity and increased reward-related ventral striatum reactivity leads to sexual risk taking, which is particularly exaggerated during adolescence and young adulthood when there is an overexpression of dopaminergic neurons coupled with immature top-down prefrontal cortex regulation. We conclude by discussing how future research based on our adapted triadic model can inform ongoing efforts to improve intervention and prevention efforts.

Cumulative stress in childhood is associated with blunted reward-related brain activity in adulthood.

Early life stress (ELS) is strongly associated with negative outcomes in adulthood, including reduced motivation and increased negative mood. The mechanisms mediating these relations, however, are poorly understood. We examined the relation between exposure to ELS and reward-related brain activity, which is known to predict motivation and mood, at age 26, in a sample followed since kindergarten with annual assessments. Using functional neuroimaging, we assayed individual differences in the activity of the ventral striatum (VS) during the processing of monetary rewards associated with a simple card-guessing task, in a sample of 72 male participants. We examined associations between a cumulative measure of ELS exposure and VS activity in adulthood. We found that greater levels of cumulative stress during childhood and adolescence predicted lower reward-related VS activity in adulthood. Extending this general developmental pattern, we found that exposure to stress early in development (between kindergarten and grade 3) was significantly associated with variability in adult VS activity. Our results provide an important demonstration that cumulative life stress, especially during this childhood period, is associated with blunted reward-related VS activity in adulthood. These differences suggest neurobiological pathways through which a history of ELS may contribute to reduced motivation and increased negative mood.

Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms

BackgroundEmotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect. MethodsWe examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later. ResultsWe found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology. ConclusionsOur results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes.

Accounting for Dynamic Fluctuations across Time when Examining fMRI Test-Retest Reliability: Analysis of a Reward Paradigm in the EMBARC Study.

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs.