Reward and Immune Systems in Emotion (RISE) prospective longitudinal study: Protocol overview of an integrative reward-inflammation model of first onset of major depression in adolescence.

Background: Depression is associated with a reduced sensitivity to rewards and low reward-related brain function in cortico-striatal circuitry. A separate literature documents elevated peripheral inflammation in depression. Recently, integrated reward-inflammation models of depression have been proposed. These models draw on work indicating that peripheral inflammatory proteins access the brain, where they lower reward responsiveness. This blunted reward responsiveness is proposed to initiate unhealthy behaviors (substance use, poor diet), as well as sleep disruption and stress generation, which further heighten inflammation. Over time, dysregulation in reward responsiveness and immune signaling may synergize in a positive feedback loop, whereby dysregulation in each system exacerbates dysregulation in the other. Project RISE (Reward and Immune Systems in Emotion) provides a first systematic test of reward-immune dysregulation as a synergistic and dynamic vulnerability for first onset of major depressive disorder and increases in depressive symptoms during adolescence. Methods: This NIMH-funded R01 study is a 3-year prospective, longitudinal investigation of approximately 300 community adolescents from the broader Philadelphia area, United States of America. Eligible participants must be 13-16 years old, fluent in English, and without a prior major depressive disorder. They are being selected along the entire dimension of self-reported reward responsiveness, with oversampling at the low tail of the dimension in order to increase the likelihood of major depression onsets. At Time 1 (T1), T3, and T5, each a year apart, participants complete blood draws to quantify biomarkers of low-grade inflammation, self-report and behavioral measures of reward responsiveness, and fMRI scans of reward neural activity and functional connectivity. At T1-T5 (with T2 and T4 six months between the yearly sessions), participants also complete diagnostic interviews and measures of depressive symptoms, reward-relevant life events, and behaviors that increase inflammation. Adversity history is assessed at T1 only. Discussion: This study is an innovative integration of research on multi-organ systems involved in reward and inflammatory signaling in understanding first onset of major depression in adolescence. It has the potential to facilitate novel neuroimmune and behavioral interventions to treat, and ideally prevent, depression.

Residence in High-Crime Neighborhoods Moderates the Association Between Interleukin 6 and Social and Nonsocial Reward Brain Responses.

BACKGROUND: Residence in high-crime neighborhoods, especially in childhood, is linked to mental health issues later. Detecting distinct neurobiological processes underlying the effects of this environmental stressor may be critical to identifying prevention and intervention targets. This study examined the relationships of levels of a circulating inflammatory protein with social and monetary reward-related brain function among adolescents who lived in high- versus low-crime neighborhoods during childhood. METHODS: A total of 70 participants (mean age = 16.3 years; 57% female) completed measures of inflammatory markers, depression history, and health and 2 functional magnetic resonance imaging tasks assessing responsivity to monetary and social rewards. Multivariate linear regression tested whether individuals with higher interleukin 6, an inflammatory cytokine, who also lived in neighborhoods with higher crime had distinct orbitofrontal cortex and nucleus accumbens activation to monetary reward and social acceptance. RESULTS: For adolescents who lived in neighborhoods with more crime, higher interleukin 6 was associated with higher nucleus accumbens responses to social acceptance. We did not detect significant moderating effects of neighborhood crime rates on the associations of interleukin 6 with orbitofrontal cortex responses to social acceptance or orbitofrontal cortex/nucleus accumbens activation during monetary reward anticipation or outcome. These results were obtained before and after adjusting for neighborhood income and other covariates. We did not detect significant moderating effects of neighborhood income. CONCLUSIONS: High-threat residence environment and specific demands of the social context in childhood may have shaped the effect of peripheral immune activation on reward-related neural function in adolescence. The prevailing view that inflammation-associated behaviors are characterized by blunted responsiveness to reward may be oversimplistic.