Principal Investigators: Lauren Alloy & Robin Nusslock; Co-Investigators: Lauren Ellman, Gregory Miller & Thomas Olino

Grant: NIMH R01MH123473

Adolescence is an “age of risk” for the emergence of 1st onset of major depressive disorder (MD). Despite its prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to MD. Depression (Dep) is associated with a reduced sensitivity to rewards and low reward-related brain function in cortico-striatal circuitry. However, research has not yet tested whether chronically low reward responsivity (RR) or attenuated RR development during adolescence predicts 1st onset of MD. A separate literature documents elevated peripheral inflammation in Dep. Yet, research also has not examined whether chronically elevated inflammation or increases in inflammation during adolescence predicts 1st onset of MD. Further, research on inflammation and RR mostly has proceeded in parallel.

Recently, however, we and others have proposed neuroimmune network models of Dep. These models draw on work indicating that peripheral inflammatory mediators (e.g., cytokines) access the brain, where they lower RR. When dysregulated, this immune-to-brain signaling can lead to chronic and worsening low RR, which is reflected in dysphoria and anhedonia. This low RR 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 RR and immune signaling may synergize in a positive feedback loop, whereby dysregulation in each system exacerbates dysregulation in the other.

We propose that reward-immune dysregulation is a two-hit vulnerability for the 1st onset of MD and increases in Dep symptoms (Sxs) during adolescence. Moreover, childhood and adolescentadversity and recent stressors influence both RR and inflammation, and may set the foundation for reward-immune dysregulation. This proposal is the first systematic test of these hypotheses. We will use an innovative biobehavioral high-risk design to examine bidirectional relationships between peripheral inflammation and multiple indices and domains (monetary, social) of RR and their joint prediction of 1st onset of MD and increases in Dep Sxs, particularly anhedonia. Three hundred 14-15 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with no prior MD will be selected along the entire dimension of self-reported RR, with oversampling at the low tail of the dimension in order to increase the likelihood of MD onsets. At Time 1 (T1), T3, and T5, each a year apart, Ps will complete blood draws to quantify inflammation, self-report and behavioral measures of RR, and fMRI scans of reward neural activity and functional connectivity. At T1-T5 (with T2 and T4 6 mo. between the yearly sessions), Ps also will complete diagnostic interviews, and measures of Dep Sxs, reward-relevant life events, and behaviors that increase inflammation. Adversity history will be assessed at T1 only. This proposal is an innovative integration of research on reward and inflammatory signaling in understanding 1st onset of MD in adolescence. It has the potential to facilitate novel neuroimmune and behavioral interventions to treat, and ideally prevent, MD.

Principal Investigators: Lauren Alloy & Robin Nusslock; Co-Investigators: Jason Chein, Thomas Olino & Phyllis Zee

Grant: NIMH R01MH126911

Rates of depressive symptoms and diagnoses rise markedly between ages 15-18. Despite the scientific and public health significance, the mechanisms responsible for the adolescent surge in depression are not fully understood. Cognitive vulnerability – stress models have contributed importantly to our understanding of the increased incidence of depression in adolescence; however, these models do not adequately explain some of the somatic symptoms or incorporate biological stress mechanisms through which cognitive vulnerability evokes depression. A separate exciting body of research on immune correlates of depression has highlighted the role of proinflammatory pathways; yet, only some depressed individuals exhibit inflammation. This project provides a novel and compelling integration of the cognitive vulnerability – stress framework and the proinflammatory model of depression as applied to adolescence.

The research has the potential to solve puzzles and limitations faced by both models when considered separately. The findings may help to account for the full spectrum of depressive symptoms and identify cognitively vulnerable individuals as especially likely to evince signs of cytokine dysregulation and increased reactivity to stressful events. Moreover, it is known that early childhood adversity contributes to both the development of cognitive vulnerability and a proinflammatory bias. The primary goal is to determine the role of inflammatory states in combination with cognitive vulnerabilities, stress, and childhood adversity as contributors that underlie the rise in adolescent depression.

A multiwave, 4-year prospective study will be conducted with an existing, well-characterized community sample of 300 adolescents, including similar numbers of males and females and Caucasians and African-Americans, just reaching the critical age when the dramatic rise in depression begins. We will conduct yearly blood draws to assess proinflammatory and regulatory cytokines (a multicytokine array of 7 cytokines) and C-reactive protein (CRP), in parallel with ongoing assessments of life stress and depression and anxiety symptoms every 6 months. Cognitive vulnerabilities and depression and anxiety diagnoses will be obtained yearly, along with a history of childhood adversity in this unique cohort of urban adolescents. We also will examine interleukin-6 (IL-6) reactivity to an acute stressor (Trier Social Stress Test) to determine how individual variation in cognitive reactivity translates into increased IL-6 release.

This project fills a crucial knowledge gap about normal development of immunity in adolescence and its role in the dramatic rise in adolescent depression. It may lead to novel interventions for depression that target cognitive influences on cytokine responses to stress, as well as pharmacological manipulations of cytokines to address symptoms such as fatigue, anhedonia, and withdrawal.

Principal Investigator: Gene Brody; Co-Investigators: Steven Beach, Edith Chen, Katie Ehrlich, Steven Kogan, Gregory Miller & Robin Nusslock

Parent Grant: NIDA P50DA051361

Sub-Projects: RP1: 8117, RP2: 8121

The HARP Project is an NIH-funded P50 Center grant in collaboration with the Center for Family Research at the University of Georgia. It is designed to transform scientific understanding regarding the causes and prevention of addictive behaviors by investigating (a) the biological and neurocognitive contributors to addictive behaviors that drive many drug use and health disparities African Americans’ experience and (b) the potential of family-centered prevention programming to ameliorate the influence of growing up in chronically stressful contexts. Our neuroimmune network (NIN) model specifies stress-induced alterations in the transactions between peripheral inflammation and neurocognitive systems that subserve emotion regulation in the development of addictive behavior vulnerability. RP1 (Transitions) provides an in-depth assessment on neural activity and inflammation and comprises a “deep dive” into mechanistic hypotheses suggested by the NIN model through a two-wave study spanning 2.5 years of African American emerging adults, ages 18-20 at baseline. Data collection includes bioimaging of NIN-related neural systems, assay of peripheral inflammation, and measures of stress exposure and addictive behaviors. RP2 (Foundations) conducts a pioneering longitudinal, two-year experimental trial that includes baseline and follow-up assessments with fMRI, inflammatory, and behavioral data with 300 African American youth at age 11 and their primary caregivers. This study will be able to examine empirically the underlying biological mechanisms for the multi-level benefits of family-centered prevention programming. You can learn more about the projects here.

Principal Investigator: Joshua Schrock; Co-Investigators/Mentors: Brian Mustanski & Robin Nusslock

Grant: NIDA K01DA057143057143

Despite major advances in the treatment of HIV, people living with HIV (PLWH) experience greater burdens of multiple aging-related chronic diseases compared to people without HIV. Substance use, depression, and systemic inflammation are risk factors for aging-related chronic diseases and occur at higher rates among PLWH. Research is needed to identify factors that drive substance use, depression, and systemic inflammation among PLWH in young adulthood, at ages when chronic disease prevention is still feasible. The brain’s central executive network (CEN) plays a key role in exerting self-control, reappraising stressful stimuli, and managing intrusive thoughts. These skills are critical for managing negative emotions when facing stressful life circumstances. Lower CEN function may thus increase susceptibility to stress-related mental health outcomes, such as depression and substance use.

Among people living with HIV, greater substance use and depression may reduce adherence to antiretroviral therapy (ART). Reduced ART adherence may lead to greater systemic inflammation. Greater systemic inflammation may lead to lower CEN function. Lower CEN function, in turn, may further increase susceptibility to problematic substance use and depression. PLWH may therefore be at risk of falling into a vicious cycle of increased depressive symptoms, increased substance use, lower ART adherence, increased systemic inflammation, and reduced CEN function.

This project will test an integrated neuroimmune model of problematic substance use and depression in a sample of young adults living with HIV (n=246) who are enrolled in RADAR, a cohort study of sexual and gender minority youth assigned male at birth (e.g., gay and bisexual men, trans women, non-binary individuals). This project has considerable clinical importance because previous research suggests that CEN function can be improved through interventions such as cognitive training, meditation, and neuromodulation. Improving CEN function may therefore prove to be an important new component of HIV care plans aimed at reducing substance use, improving mental health, maximizing ART adherence, and reducing systemic inflammation among PLWH.

Principal Investigators: Michelle Craske, Susan Bookheimer, Richard Zinbarg & Robin Nusslock; Co-Investigators: Constance Hammen & Todd Parrish

The BrainMAPD Study examines the relationship between threat- and reward-related neural circuitries and symptom dimensions of anxiety and depression during the transition from adolescence to adulthood. In line with the Research Domain Criteria’s (RDoC) objective, BrainMAPD focuses on identifying new strategies for psychiatric classification based on observable dimensions and their corresponding neural circuitries. We have identified a tri-level model of symptom dimensions that includes a broad factor (General Distress) common to all anxiety and depressive symptoms, as well as factors of intermediate breadth (Fears, Anhedonia-Apprehension) that are more distinctive to subsets of anxious and depressive symptoms.

Existing research highlights dysregulation of a “threat-related” neural circuit encompassing the amygdala and subgenual portion of the anterior cingulate cortex in both anxiety and depression. Distinctions between anxiety and depression may be present in a “reward-related” neural circuit encompassing the ventral striatum and orbitofrontal cortex, which appears elevated in anxiety but reduced in depression. By studying both reward- and threat-related brain function, we address RDoC constructs of Positive Valence (reward sensitivity) as well as Negative Valence (threat sensitivity). We also examine whether neural profiles predict the course of symptoms, and conversely, whether symptom courses covary with changes in neural activation over 36 months. Taking a vulnerability-stress perspective, we are testing whether life-stress moderates the prospective associations between neural profiles and symptom trajectories. In addition, we are evaluating whether neural data possess predictive value above and beyond other indices of threat and reward sensitivity, including self-report, behavioral, and physiological measures.

BrainMAPD studies 18 to 19 year old college students from the University of California Los Angeles and Northwestern University. Self-report measures of threat and reward sensitivity were administered to select students who represent the full range on each dimension. Symptoms, impairment, and life stress were assessed at baseline, 12-months, 24 months, and 36 months, and fMRI scanning of threat- and reward-related brain function occured at baseline and 36 months.

Check out the BrainMAPD Wiki Page for measures summaries, data requests and access, current projects and other information and updates on the study.

Principal Investigator: Lauren Alloy; Co-Investigators: Jason Chein, Feroze Mohamed, Robin Nusslock & Lyn Abramson

Grant: R01MH077908

Adolescence is a developmental period involving both heightened reward sensitivity and risk for bipolar spectrum disorders (BSDs). Despite their prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to BSDs. Recent exciting research provides strong and consistent support for a Behavioral Approach System (BAS)/reward hypersensitivity theory of BSDs that shows great promise for elucidating and integrating the neurobiological, behavioral, and environmental mechanisms underlying risk along the bipolar spectrum. In addition, research on social and circadian rhythm models of BSDs is also very promising, but has proceeded independently of research on reward sensitivity. Yet, our recent work demonstrates influences of reward sensitivity on social rhythm disruption and mood symptoms, leading us to a novel integration of reward sensitivity and social rhythm dysregulation in this application.

The overarching goal of this proposal is to use an innovative biobehavioral high-risk design in adolescents to examine two interrelated processes that may help explain the association between reward hypersensitivity and BSDs: 1) heightened activation of a “reward-related” neural network involving the ventral striatum and orbitofrontal cortex; and 2) influences of reward sensitivity/activation on social rhythm disruption. We will continue to follow High and Moderate BAS/reward sensitive adolescents as they further age into the period of risk for BSDs with self-report and behavioral measures of reward sensitivity/processing, BAS-relevant cognitive styles, social rhythms, BAS-relevant and social rhythm disruption life events, and mood symptoms/ diagnoses. We also will conduct a new and novel neuroimaging study. We will compare High BAS adolescents who have developed BSD (HBAS+BSD), High BAS adolescents who have not yet exhibited, but are at risk for, BSD (HBAS), and Moderate BAS adolescents without BSD (MBAS) on reward-related brain activity and connectivity in response to the anticipation and receipt of monetary rewards in an fMRI study. In addition, we will examine the influence of reward sensitivity/activation and social rhythm dysregulation on mood symptoms in these same three groups of adolescents.