Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Association between reward-related functional connectivity and tri-level mood and anxiety symptoms.

Depression and anxiety are associated with abnormalities in brain regions that process rewards including the medial orbitofrontal cortex (mOFC), the ventral striatum (VS), and the amygdala. However, there are inconsistencies in these findings. This may be due to past reliance on categorical diagnoses that, while valuable, provide less precision than may be required to understand subtle neural changes associated with symptoms of depression and anxiety. In contrast, the tri-level model defines symptom dimensions that are common (General Distress) or relatively specific (Anhedonia-Apprehension, Fears) to depression and anxiety related disorders, which provide increased precision. In the current study, eligibility was assessed by quasi-orthogonal screening questionnaires measuring reward and threat sensitivity (Behavioral Activation Scale; Eysenck Personality Questionnaire-Neuroticism). These participants were assessed on tri-level symptom severity and completed the Monetary Incentive Delay task during fMRI scanning. VS-mOFC and VS-amygdala connectivity were estimated during reward anticipation and reward outcome. Heightened General Distress was associated with lower VS-mOFC connectivity during reward anticipation (b = -0.064, p = 0.021) and reward outcome (b = -0.102, p = 0.014). Heightened Anhedonia-Apprehension was associated with greater VS-amygdala connectivity during reward anticipation (b = 0.065, p = 0.004). The present work has important implications for understanding the coupling between the mOFC and vS and the amygdala and the vS during reward processing in the pathophysiology of mood and anxiety symptoms and for developing targeted behavioral, pharmacological, and neuromodulatory interventions to help manage these symptoms.

The Interplay between Reward-Relevant Life Events and Trait Reward Sensitivity in Neural Responses to Reward Cues.

The reward hypersensitivity model posits that trait reward hypersensitivity should elicit hyper/hypo approach motivation following exposure to recent life events that activate (goal-striving and goal-attainment) or deactivate (goal-failure) the reward system, respectively. To test these hypotheses, eighty-seven young adults with high (HRew) versus moderate (MRew) trait reward sensitivity reported frequency of life events via the Life Event Interview. Brain activation was assessed during the fMRI Monetary Incentive Delay task. Greater exposure to goal-striving events was associated with higher nucleus accumbens (NAc) reward anticipation among HRew participants and lower orbitofrontal cortex (OFC) reward anticipation among MRew participants. Greater exposure to goal-failure events was associated with higher NAc and OFC reward anticipation only among HRew participants. This study demonstrated different neural reward anticipation (but not outcome) following reward-relevant events for HRew versus MRew individuals. Trait reward sensitivity and reward-relevant life events may jointly modulate reward-related brain function, with implications for understanding psychopathology.

Risk for bipolar spectrum disorders associated with positive urgency and orbitofrontal cortical grey matter volume.

Bipolar spectrum disorders (BSDs) are associated with reward hypersensitivity, impulsivity, and structural abnormalities within the brain's reward system. Using a behavioral high-risk study design based on reward sensitivity, this paper had two primary objectives: 1) investigate whether elevated positive urgency, the tendency to act rashly when experiencing extreme positive affect, is a risk for or correlate of BSDs, and 2) examine the nature of the relationship between positive urgency and grey matter volume in fronto-striatal reward regions, among individuals at differential risk for BSD. Young adults (ages 18-28) screened to be moderately reward sensitive (MReward; N = 42), highly reward sensitive (HReward; N = 48), or highly reward sensitive with a lifetime BSD (HReward + BSD; N = 32) completed a structural MRI scan and the positive urgency subscale of the UPPS-P scale. Positive urgency scores varied with BSD risk (MReward < HReward < HReward + BSD; ps≤0.05), and positive urgency interacted with BSD risk group in predicting lateral OFC volume (p <.001). Specifically, the MReward group showed a negative relationship between positive urgency and lateral OFC volume. By contrast, there was no relationship between positive urgency and lateral OFC grey matter volume among the HReward and HReward + BSD groups. The results suggest that heightened trait positive urgency is a pre-existing vulnerability for BSD that worsens with illness onset, and there is a distinct relationship between positive urgency and lateral OFC volume among individuals at high versus low risk for BSD. These findings have implications for understanding the expression and development of impulsivity in BSDs.

Decreased reward-related brain function prospectively predicts increased substance use.

Substance use and addiction are prominent global health concerns and are associated with abnormalities in reward sensitivity. Reward sensitivity and approach motivation are supported by a fronto-striatal neural circuit including the orbitofrontal cortex (OFC), ventral striatum (VS), and dorsal striatum (DS). Although research highlights abnormalities in reward neural circuitry among individuals with problematic substance use, questions remain about whether such use arises from excessively high, or excessively low, reward sensitivity. This study examined whether reward-related brain function predicted subsequent substance use course. Participants were 79 right-handed individuals (Mage = 21.52, SD = 2.19 years), who completed a monetary incentive delay (MID) fMRI task, and follow-up measures assessing substance use frequency and impairment. The average duration of the follow-up period was 9.1 months. Regions-of-interest analyses focused on the reward anticipation phase of the MID. Decreased activation in the VS during reward anticipation predicted increased substance use frequency at follow-up. Decreased DS activation during reward anticipation predicted increased substance use frequency at follow-up, but this finding did not pass correction for multiple comparisons. Analyses adjusted for relevant covariates, including baseline substance use and the presence or absence of a lifetime substance use disorder prior to MRI scanning. Results support the reward hyposensitivity theory, suggesting that decreased reward-related brain function is a risk factor for increased substance use. Results have implications for understanding the pathophysiology of problematic substance use and highlight the importance of the fronto-striatal reward circuit in the development and maintenance of addiction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Category Congruence of Display-Only Products Influences Attention and Purchase Decisions.

In e-commerce settings, shoppers can navigate to product-specific pages on which they are asked to make yes-or-no decisions about buying a particular item. Beyond that target, there are often other products displayed on the page, such as those suggested by the retailers' recommendation systems, that can influence consumers' buying behavior. We propose that display items that come from the same category as the target product (matched) may enhance target purchase by increasing the attractiveness of the presented opportunity. Contrasting this, mismatched display items may reduce purchase by raising awareness of opportunity costs. Eye-tracking was used to explore this framework by examining how different types of displays influenced visual attention. Although target purchase rates were higher for products with matched vs. mismatched displays, there was no difference in fixation time for the target images. However, participants attended to mismatched display items for more time than they did for matched ones consistent with the hypothesized processes. In addition, increases in display attractiveness increased target purchase, but only for matched items, in line with supporting the target category. Given the importance of relative attention and information in determining the impact of display items, we replicated the overall purchase effect across varying amounts of available display information in a second behavioral study. This demonstration of robustness supports the translational relevance of these findings for application in industry.

Resting-State Functional Connectivity of the Central Executive Network Moderates the Relationship Between Neighborhood Violence and Proinflammatory Phenotype in Children.

BACKGROUND: Neighborhood violence increases children's risk for a variety of health problems. Yet, little is known about biological pathways involved or neural mechanisms that might render children more or less vulnerable. Here, we address these questions by considering whether neighborhood violence is associated with the expression of a proinflammatory phenotype and whether this relationship is moderated by resting-state functional connectivity (rsFC) of the central executive network (CEN). METHODS: The study involved 217 children (13.9 years old; 66.4% female; 36.9% Black; 30.9% Latinx), enrolled in eighth grade and reassessed 2 years later. At time 1, geocoding was used to estimate murder frequency in children's neighborhoods, and functional magnetic resonance imaging was used to characterize CEN rsFC. At both visits, children gave antecubital blood for ex vivo studies, where leukocytes were incubated with stimulators and inhibitors of inflammation, and cytokine production was measured. RESULTS: Consistent with our hypotheses, the relationship between neighborhood murder and inflammatory activity was moderated by CEN rsFC. Among children with lower rsFC, neighborhood violence covaried with a proinflammatory phenotype, reflected in larger cytokine responses to triggering stimuli and lower sensitivity to inhibitory agents. These associations were generally not apparent for children with higher rsFC, although occasionally they ran in the opposite direction. The same patterns were apparent 2 years later. CONCLUSIONS: These results advance the understanding of neighborhood violence and its relationship with processes involved in the initiation and resolution of inflammation. They also deepen understanding of variability in children's immunologic responses to stress and suggest that the CEN may be a neurobiological contributor to resilience.

Goal-striving tendencies moderate the relationship between reward-related brain function and peripheral inflammation.

Inflammation is associated with both lower and higher activity in brain regions that process rewarding stimuli. How can both low and high sensitivity to rewards be associated with higher inflammation? We propose that one potential mechanism underlying these apparently conflicting findings pertains to how people pursue goals in their environment. This prediction is based on evidence that both an inability to disengage from unattainable goals and low interest in and pursuit of important life goals are associated with poor health outcomes, including inflammation. Accordingly, this study examined the relationship between reward-related brain function and peripheral inflammation among individuals with different levels of ambitious goal-striving tendencies. Eighty-three participants completed an ambitious goal-striving tendency measure, an fMRI Monetary Incentive Delay task assessing orbitofrontal cortex (OFC) and nucleus accumbens (NAc) activation during reward anticipation and outcome, and a venous blood draw to assess the inflammatory biomarkers interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and C-reactive protein, from which we computed an inflammation composite score. We observed a reward anticipation by goal-striving interaction on inflammation, such that high OFC and NAc activation to reward anticipation (but not outcome) were associated with more inflammation, among high goal-striving individuals. By contrast, low NAc activation during reward anticipation (but not outcome) was associated with more inflammation, among low goal-striving individuals. The current study provides further evidence that both blunted and elevated reward function can be associated with inflammation. It also highlights the role that goal-striving tendencies may play in moderating the relationship between neural reward anticipation and inflammation.

Higher Peripheral Inflammatory Signaling Associated With Lower Resting-State Functional Brain Connectivity in Emotion Regulation and Central Executive Networks.

BACKGROUND: Researchers document bidirectional pathways linking peripheral inflammation and neural circuitries subserving emotion processing and regulation. To extend this work, we present results from two independent studies examining the relationship between inflammation and resting-state functional connectivity (rsFC), as measured by functional magnetic resonance imaging. METHODS: Study 1 involved 90 rural African American young adults, 25 years of age (52% female), and study 2 involved 82 urban African American youths, 13 to 14 years of age (66% female). Both studies measured circulating inflammatory biomarkers (C-reactive protein, interleukin 6, interleukin 10, tumor necrosis factor alpha), and the measures were averaged to form a composite. Study 2 also enumerated classical monocytes, a key leukocyte subpopulation involved in immune-to-brain signaling. All participants completed a resting-state functional magnetic resonance imaging scan. RESULTS: Consistent with our prediction, higher scores on the inflammatory composite were associated with lower rsFC within an emotion regulation network in study 1, controlling for sex. Study 2 replicated study 1, showing that higher scores on the inflammatory composite were associated with lower rsFC within the emotion regulation network, controlling for sex, age, and pubertal status, and found a similar pattern for rsFC within a central executive network. Study 2 also found that higher numbers of classical monocytes were associated with lower rsFC within both the emotion regulation and central executive networks. There was no relationship between rsFC in the anterior salience or default mode networks with inflammation in either study. CONCLUSIONS: With these findings, we document relationships between peripheral inflammation and rsFC within an emotion regulation and central executive network and replicate these associations with the emotion regulation network across two independent samples.

Functional connectivity in central executive network protects youth against cardiometabolic risks linked with neighborhood violence.

Although violent crime has declined in recent decades, it remains a recurring feature of daily life in some neighborhoods. Mounting evidence indicates that such violence has a long reach, which goes beyond family and friends of the victim and undermines the health of people in the surrounding community. However, like all forms of adversity, community violence elicits a heterogeneous response: Some remain healthy, but others deteriorate. Despite much scientific attention, the neural circuitries that contribute to differential adaptation remain poorly understood. Drawing on knowledge of the brain's intrinsic functional architecture, we predicted that individual differences in resting-state connectivity would explain variability in the strength of the association between neighborhood violence and cardiometabolic health. We enrolled 218 urban youth (age 12-14 years, 66% female; 65% black or Latino) and used geocoding to characterize their exposure to neighborhood murder over the past five years. Multiple aspects of cardiometabolic health were assessed, including obesity, insulin resistance, and metabolic syndrome. Functional MRI was used to quantify the connectivity of major intrinsic networks. Consistent with predictions, resting-state connectivity within the central executive network (CEN) emerged as a moderator of adaptation. Across six distinct outcomes, a higher neighborhood murder rate was associated with greater cardiometabolic risk, but this relationship was apparent only among youth who displayed lower CEN resting-state connectivity. By contrast, there was little evidence of moderation by the anterior salience and default mode networks. These findings advance basic and applied knowledge about adaptation by highlighting intrinsic CEN connectivity as a potential neurobiological contributor to resilience.