Concurrent and prospective associations of inflammatory signaling, specific depressive symptoms, and substance use in adolescence.

Substance use and depression frequently co-occur. Adolescence appears to be a vulnerable developmental period for increases in both substance use and depressive symptoms, often attributed to rapid maturation of reward and motivation systems. Another contributing factor could be inflammatory signaling, which has been associated with both substance use disorder and depression. Prior research indicates that an increase in inflammatory activity can cause physical and emotional malaise, which resembles depression, and the anhedonia and somatic symptoms could lead to substance use. This perspective that substance use is a type of self-medication in response to anhedonia and subjective experiencing of increased inflammatory physiology has not been investigated previously. To test these associations, we used path analysis to examine concurrent and prospective associations between three pro-inflammatory markers, specific depressive symptoms, and substance use frequency in a diverse sample of older adolescents. Participants completed repeated self-report measures of specific depressive symptoms (i.e., dysphoria, anhedonia, somatic concerns, negative cognitions, and functional difficulties) and substance use frequency. Blood was collected to quantify circulating levels of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). This analysis showed an indirect effect of IL-6 and TNF-α levels on future substance use, but only via functional difficulties. Substance use also predicted future functional difficulties. Only anhedonia directly predicted future substance use frequency. These findings help to more precisely identify pathways through which inflammatory physiology and specific depressive symptoms synergistically confer risk for substance use.

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.

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.

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.

Bipolar spectrum disorders are associated with increased gray matter volume in the medial orbitofrontal cortex and nucleus accumbens.

Objective: Elevated sensitivity to rewards prospectively predicts Bipolar Spectrum Disorder (BSD) onset; however, it is unclear whether volumetric abnormalities also reflect BSD risk. BSDs emerge when critical neurodevelopment in frontal and striatal regions occurs in sex-specific ways. The current paper examined the volume of frontal and striatal brain regions in both individuals with and at risk for a BSD with exploratory analyses examining sex-specificity. Methods: One hundred fourteen medication-free individuals ages 18-27 at low-risk for BSD (moderate-reward sensitivity; N = 37), at high-risk without a BSD (high-reward sensitivity; N = 47), or with a BSD (N = 30) completed a structural MRI scan of the brain. We examined group differences in gray matter volume in a priori medial orbitofrontal cortex (mOFC) and nucleus accumbens (NAcc) regions-of-interest. Results: The BSD group had enlarged frontostriatal volumes (mOFC, NAcc) compared to low individuals (d = 1.01). The mOFC volume in BSD was larger than low-risk (d = 1.01) and the high-risk groups (d = 0.74). This effect was driven by males with a BSD, who showed an enlarged mOFC compared to low (d = 1.01) and high-risk males (d = 0.74). Males with a BSD also showed a greater NAcc volume compared to males at low-risk (d = 0.49), but not high-risk males. Conclusions: An enlarged frontostriatal volume (averaged mOFC, NAcc) is associated with the presence of a BSD, while subvolumes (mOFC vs. NAcc) showed unique patterning in relation to risk. We report preliminary evidence that sex moderates frontostriatal volume in BSD, highlighting the need for larger longitudinal risk studies examining the role of sex-specific neurodevelopmental trajectories in emerging BSDs.

Mood symptoms and impairment due to substance use: A network perspective on comorbidity.

BACKGROUND: Mood disorders and problematic substance use co-occur and confer reciprocal risk for each other. Few studies use analytic approaches appropriate for testing whether specific features of one disorder confer risk for the other. METHODS: 445 participants (59.8% female, Mean age = 20.3 years) completed measures of depression and hypo/mania symptoms and substance use-related impairment; 330 had complete data at follow-up. Of these, 28% reported a history of depression, 4% of bipolar spectrum disorder, 11% of substance use disorder, and 55% reported substance-related impairment. Symptoms and domains of substance-related impairment were modeled in cross-sectional and cross-lagged panel network models. RESULTS: Impulsive and interpersonal impairment were most highly comorbid with mood symptoms. Suicidal ideation, sadness, decreased need for sleep, and guilt were the symptoms most highly comorbid with impairment. Interpersonal impairment due to substance use was the strongest cross-construct predictor of mood symptoms and suicidal ideation was most predictive of impairment. Social, intrapersonal, and physical impairment due to substance use were most predicted by previous mood symptoms and decreased need for sleep, guilt, and euphoria were most strongly predicted by past impairment. LIMITATIONS: Measures do not assess all mood symptoms, participants with low reward sensitivity were excluded, only self-report measures were used, and some variables were single-items. CONCLUSIONS: Components of these syndromes that confer cross-construct risk might not be the same components that are predicted by the other construct. The bidirectional relationship between mood symptoms and problematic substance use might be better conceptualized at the element, rather than diagnostic, level.

Neural reward circuit dysfunction as a risk factor for bipolar spectrum disorders and substance use disorders: A review and integration.

Bipolar spectrum disorders (BSDs) and substance use disorders (SUDs) are associated with neural reward dysfunction. However, it is unclear what pattern of neural reward function underlies pre-existing vulnerability to BSDs and SUDs, or whether neural reward function explains their high co-occurrence. The current paper provides an overview of the separate literatures on neural reward sensitivity in BSDs and SUDs. We provide a systematic review of 35 studies relevant to identifying neural reward function vulnerability to BSDs and SUDs. These studies include those examining neural reward processing on a monetary reward task with prospective designs predicting initial onset of SUDs, familial risk studies that examine unaffected offspring or first-degree relatives of family members with BSDs or SUDs, and studies that examine individuals with BSDs or SUDs who are not currently in an episode of the disorder. Findings from the review highlight that aberrant responding and connectivity across neural regions associated with reward and cognitive control confers risk for the development of BSDs and SUDs. Discussion focuses on limitations of the extant literature. We conclude with an integration and theoretical model for understanding how aberrant neural reward responding may constitute a vulnerability to the development of both BSDs and SUDs.

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).

The Role of Social Reward and Corticostriatal Connectivity in Substance Use.

This report describes an ongoing R03 grant that explores the links between trait reward sensitivity, substance use, and neural responses to social and nonsocial reward. Although previous research has shown that trait reward sensitivity and neural responses to reward are linked to substance use, whether this relationship is impacted by how people process social stimuli remains unclear. We are investigating these questions via a neuroimaging study with college-aged participants, using individual difference measures that examine the relation between substance use, social context, and trait reward sensitivity with tasks that measure reward anticipation, strategic behavior, social reward consumption, and the influence of social context on reward processing. We predict that substance use will be tied to distinct patterns of striatal dysfunction. Specifically, reward hyposensitive individuals will exhibit blunted striatal responses to social and non-social reward and enhanced connectivity with the orbitofrontal cortex; in contrast, reward hypersensitive individuals will exhibit enhanced striatal responses to social and non-social reward and blunted connectivity with the orbitofrontal cortex. We also will examine the relation between self-reported reward sensitivity, substance use, and striatal responses to social reward and social context. We predict that individuals reporting the highest levels of substance use will show exaggerated striatal responses to social reward and social context, independent of self-reported reward sensitivity. Examining corticostriatal responses to reward processing will help characterize the relation between reward sensitivity, social context and substance use while providing a foundation for understanding risk factors and isolating neurocognitive mechanisms that may be targeted to increase the efficacy of interventions.

Impulsivity and Behavior-Dependent Life Events Mediate the Relationship of Reward Sensitivity and Depression, but Not Hypomania, Among at-Risk Adolescents.

Both reward sensitivity and impulsivity are related to the development and course of bipolar spectrum disorders (BSDs) and have been implicated in other disorders and negative functional outcomes such as substance abuse, obesity, suicidal behaviors, and risk-taking. Furthermore, according to the transactional component of the Behavioral Approach System (BAS)/reward hypersensitivity theory of BSDs, people with reward hypersensitivity should experience more BAS-relevant events, and thus, are more vulnerable to mood symptoms and episodes via stress generation. Impulsivity may exacerbate stress generation in individuals at risk for BSDs based on exhibiting reward hypersensitivity. The current study examined whether impulsivity explained the generation of stress and subsequent mood symptoms beyond what is explained by reward sensitivity alone. Participants were 131 Moderate BAS and 216 High BAS sensitivity adolescents (M = 18.43 years, SD = 1.40), who completed baseline measures of reward sensitivity and impulsivity, as well as follow-up measures of life events and mood symptoms. Results from linear regression analyses indicated that higher baseline impulsivity predicted behavior-dependent, but not behavior-independent, life events. Furthermore, path analyses suggested that the effect of BAS group on depression symptoms at next follow-up was partly explained via the indirect effect of impulsivity and negative behavior-dependent life events. We did not find these effects for behavior-independent or positive-dependent events or for prediction of hypomanic symptoms. The findings suggest that impulsivity may account for stress generation of negative events that precede depression.

Relationship of recent stress to amygdala volume in depressed and healthy adults.

BACKGROUND: The amygdala is an integral part of the extrahypothalamic stress-response system, and its volume related to childhood trauma has been studied, but less is known of associations with recent stressful life events. Amygdala volume differences also have been studied in depression, with conflicting results. We hypothesized that effects of stress may be a confound for amygdala volumetric differences in the context of depression. METHODS: Right-handed participants (n=61) experiencing a major depressive episode during major depressive disorder (n=40) or bipolar depression (n=21) and healthy volunteers (n=60) underwent 1.5T magnetic resonance imaging (MRI). The amygdala perimeter was manually traced with an electronic mouse, based on anatomical landmarks on consecutive coronal slices, by raters blind to diagnosis. The effects of stress on amygdala volume were examined in linear regression models with self-reported physical/sexual abuse or highest category score on the St. Paul-Ramsey scale of stressful life events within the past 6 months as predictors, testing separately for age, sex, race, and depression status as covariates. RESULTS: Diagnostic groups did not differ significantly with respect to mean age (depressed, 37.8±11.8yrs; healthy, 34.9±13.8yrs) or proportion of males (depressed, 39%, healthy, 50%). We found no association between physical and/or sexual abuse history and amygdala volume. Life stress within the last six months, however, was associated with smaller left amygdala volume. The association between stress and amygdala volume did not differ by diagnostic group. LIMITATIONS: Most depressed patients were off medications for at least 2 weeks; however, this may not have been long enough to reverse effects of medications on amygdala structure. CONCLUSIONS: That life stress of relatively short duration was associated with amygdala size in the entire sample, while temporally distant life stress was not, suggests that amygdala volume changes may occur rapidly and reversibly, and independent of depression status.

Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome.

There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.