Higher substance use is associated with low executive control neural activity and higher inflammation.

Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.

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.

Neural changes in youth at high risk for bipolar disorder undergoing family-focused therapy or psychoeducation.

BACKGROUND: Patients with mood disorders may benefit from psychosocial interventions through changes in brain networks underlying emotion processing. In this study, we used functional magnetic resonance imaging (fMRI) to investigate treatment-related changes in emotion processing networks in youth at familial high risk for bipolar disorder (BD). METHODS: Youth, ages 9-17, were randomly assigned to family-focused therapy for high-risk youth (FFT-HR) or an active comparison treatment, Enhanced Care (EC). Before and after these 4-month treatments, participants underwent fMRI while viewing happy, fearful, and calm facial expressions. Twenty youth in FFT-HR and 20 in EC were included in analyses of pre- to post-treatment changes in activation across the whole brain. Significant clusters were assessed for correlation with mood symptom improvement. RESULTS: In the dorsolateral prefrontal cortex (DLPFC), activation increased from pre- to post-treatment in the FFT-HR group and decreased in the EC group. Insula activation decreased in the FFT-HR group and did not change in the EC group. Across both treatments, decreasing activation in the hippocampus and amygdala was correlated with pre- to post-treatment improvement in hypomania, while increasing activation in the DLPFC was correlated with pre- to post-treatment improvement in depression. DISCUSSION: Psychosocial treatment addresses abnormalities in emotion regulation networks in youth at high risk for BD. Increased prefrontal cortex activation suggests enhanced emotion regulation from pre- to post-treatment with FFT-HR. Improvements in family interactions may facilitate the development of prefrontal resources that provide protection against future mood episodes.

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.

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).

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.

Glutamate in Pediatric Obsessive-Compulsive Disorder and Response to Cognitive-Behavioral Therapy: Randomized Clinical Trial.

Cognitive-behavioral therapy (CBT) is effective for pediatric obsessive-compulsive disorder (OCD), but non-response is common. Brain glutamate (Glu) signaling may contribute to OCD pathophysiology and moderate CBT outcomes. We assessed whether Glu measured with magnetic resonance spectroscopy (MRS) was associated with OCD and/or CBT response. Youths aged 7-17 years with DSM-IV OCD and typically developing controls underwent 3 T proton echo-planar spectroscopic imaging (PEPSI) MRS scans of pregenual anterior cingulate cortex (pACC) and ventral posterior cingulate cortex (vPCC)-regions possibly affected by OCD-at baseline. Controls returned for re-scan after 8 weeks. OCD youth-in a randomized rater-blinded trial-were re-scanned after 12-14 weeks of CBT or after 8 weeks of minimal-contact waitlist; waitlist participants underwent a third scan after crossover to 12-14 weeks of CBT. Forty-nine children with OCD (mean age 12.2±2.9 years) and 29 controls (13.2±2.2 years) provided at least one MRS scan. At baseline, Glu did not differ significantly between OCD and controls in pACC or vPCC. Within controls, Glu was stable from scan-to-scan. Within OCD subjects, a treatment-by-scan interaction (p=0.034) was observed, driven by pACC Glu dropping 19.5% from scan-to-scan for patients randomized to CBT, with minor increases (3.8%) for waitlist participants. The combined OCD participants (CBT-only plus waitlist-CBT) also showed a 16.2% (p=0.004) post-CBT decrease in pACC Glu. In the combined OCD group, within vPCC, lower pre-CBT Glu predicted greater post-CBT improvement in symptoms (CY-BOCS; r=0.81, p=0.00025). Glu may be involved in the pathophysiology of OCD and may moderate response to CBT.

Graph-theoretical analysis of resting-state fMRI in pediatric obsessive-compulsive disorder.

BACKGROUND: fMRI graph theory reveals resting-state brain networks, but has never been used in pediatric OCD. METHODS: Whole-brain resting-state fMRI was acquired at 3T from 21 children with OCD and 20 age-matched healthy controls. BOLD connectivity was analyzed yielding global and local graph-theory metrics across 100 child-based functional nodes. We also compared local metrics between groups in frontopolar, supplementary motor, and sensorimotor cortices, regions implicated in recent neuroimaging and/or brain stimulation treatment studies in OCD. RESULTS: As in adults, the global metric small-worldness was significantly (P<0.05) lower in patients than controls, by 13.5% (%mean difference=100%X(OCD mean - control mean)/control mean). This suggests less efficient information transfer in patients. In addition, modularity was lower in OCD (15.1%, P<0.01), suggesting less granular - or differently organized - functional brain parcellation. Higher clustering coefficients (23.9-32.4%, P<0.05) were observed in patients in frontopolar, supplementary motor, sensorimotor, and cortices with lower betweenness centrality (-63.6%, P<0.01) at one frontopolar site. These findings are consistent with more locally intensive connectivity or less interaction with other brain regions at these sites. LIMITATIONS: Relatively large node size; relatively small sample size, comorbidities in some patients. CONCLUSIONS: Pediatric OCD patients demonstrate aberrant global and local resting-state network connectivity topologies compared to healthy children. Local results accord with recent views of OCD as a disorder with sensorimotor component.

Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders.

UNLABELLED: Adults with bipolar disorder (BD) and major depressive disorder (MDD) have higher circulating levels of proinflammatory cytokines than healthy controls. However, it is not known whether pediatric-onset patients with BD or MDD show increases in levels of inflammation or activation of nuclear factor kappa B (NF-κB), a key transcription factor in inflammatory signaling. Circulating levels of inflammatory cytokines, as well as spontaneous and stimulated levels of activated NF-κB in total peripheral blood mononuclear cells, monocytes and lymphocytes were measured in adolescents with BD (n=18), MDD (n=13), or no psychiatric history (n=20). Participants had a range of mood symptoms at time of testing. Adolescents with BD had significantly higher spontaneous levels of NF-κB in peripheral blood mononuclear cells, monocyte and lymphocyte populations, and higher plasma levels of IL-1ß than healthy controls. Following stimulation with recombinant human TNF-α, participants with BD and MDD both had greater increases in NF-κB in monocytes than controls. Further, greater stimulated increases of NF-κB in monocytes were associated with the current severity of depressive symptoms. The results are limited by the small sample and cross-sectional design. Interventions that target early immunological dysregulation should be examined in relation to long-term outcomes in youth with bipolar and depressive disorders. CLINICAL TRIAL REGISTRATION INFORMATION: Early Intervention for Youth at Risk for Bipolar Disorder, https://clinicaltrials.gov/ct2/show/NCT01483391.

Deficits in domains of social cognition in schizophrenia: a meta-analysis of the empirical evidence.

OBJECTIVE: Social cognition is strongly associated with functional outcome in schizophrenia, making it an important target for treatment. Our goal was to examine the average magnitude of differences between schizophrenia patients (SCs) and normal comparison (NCs) patients across multiple domains of social cognition recognized by the recent NIMH consensus statement: theory of mind (ToM), social perception, social knowledge, attributional bias, emotion perception, and emotion processing. METHOD: We conducted a meta-analysis of peer-reviewed studies of social cognition in schizophrenia, published between 1980 and November, 2011. RESULTS: 112 studies reporting results from 3908 SCs and 3570 NCs met our inclusion criteria. SCs performed worse than NCs across all domains, with large effects for social perception (g = 1.04), ToM (g = 0.96), emotion perception (g = 0.89), and emotion processing (g = 0.88). Regression analyses showed that statistically significant heterogeneity in effects within domains was not explained by age, education, or gender. Greater deficits in social and emotion perception were associated with inpatient status, and greater deficits in emotion processing were associated with longer illness duration. CONCLUSIONS: Despite the limitations of existing studies, including lack of standardization or psychometric validation of measures, the evidence for deficits across multiple social cognitive domains in schizophrenia is clear. Future research should examine the role of neurobiological and psychosocial factors in models linking various aspects of deficit in schizophrenia, including social cognition, in order to identify targets for intervention.