Search Grants — Free, No Account Required

National Institutes of Health

Silvio O. Conte Centers for Basic Neuroscience or Translational Mental Health Research

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Young adults’ simultaneous use of alcohol and marijuana/cannabis (SAM) is prevalent, increasing, and associated with heavy substance use and risk for substance-related harms. Scant research has focused on intervention programming for SAM use, and effects on use behaviors have been small to non-existent. Mobile app-based interventions are a promising option for delivering real-time intervention in moments of highest risk for young adult substance use. Given their ability to tailor based on features of a day (e.g., situations, motivations, mental health symptoms), app-based interventions are ideal for mitigating SAM-related harms. Mindfulness-based interventions (MBIs) and protective behavioral strategy (PBS) interventions are useful in distinct contexts, making them ideally suited for addressing individual determinants of SAM use in daily life. A micro-randomized trial (MRT) that randomizes the delivery of intervention content each day is the ideal, gold- standard approach for identifying whether and when distinct real-time intervention content is most effective. Toward our team’s ultimate goal of developing a novel app-based just-in-time intervention (JIT), we aim to conduct the first MRT with daily-level randomization to MBI, PBS, or no intervention among young adults who engage in SAM use. This R01 application has three aims: 1) To refine and co-curate with young adults digital MBI and PBS content to deploy in real time; 2) To conduct an MRT with daily level randomization (MBI, PBS, no intervention); and 3) To test time-varying moderators of intervention efficacy. We propose two studies within this R01, both with college- and non-college-attending young adults (ages 18-25) who report SAM use and frequent heavy episodic drinking and reside in Oregon or Washington. In Study 1 (n=1000), our team will gather quantitative and qualitative data on acceptability of MBI and PBS content (text, audio, visual) and ideas for improvement. In Study 2 (n=300), we will refine our intervention and then conduct an MRT in preparation for optimizing a future JIT. After completing a digital foundational module, participants will complete a brief daily diary for 45 days on behaviors that occurred the prior day, their current state, and planned behavior. Each day, participants will be randomized to 1 of 3 intervention conditions: MBI, PBS, or no intervention content. On each MBI and PBS intervention day, participants will receive unique intervention content 3 times (late morning, afternoon, early evening) to their mobile device. Our team will measure efficacy of the intervention on 3 same- day outcomes—substance-related harms, SAM use, and level of alcohol use—in addition to identifying features of days (e.g., an individual’s substance use motives) when distinct intervention content was more or less effective. Findings from this work will directly inform and prepare us to launch a JIT to deliver intervention content that changes in response to features of the day, meeting individuals in moments of greatest risk.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Suicide is a leading cause of death among adolescents, and rates of suicide in this age group have nearly doubled over the past two decades. However, our ability to predict and prevent suicidal thoughts and behaviors (STB) is limited, in part due to an emphasis on static, distal risk factors. Emerging research suggests that irregularities in sleep and circadian rhythms—systems which undergo marked change during adolescence— may be promising short-term predictors of suicide risk. However, prior studies have largely relied on retrospective self-report measures, long follow-up intervals, and have often overlooked the contribution of the circadian system, which collectively limits insight into the mechanisms underlying these dynamic processes that may increase suicide risk. This K23 project aims to address these gaps by leveraging intensive longitudinal methods, including actigraphy and collecting a biological indicator of endogenous circadian rhythms in a clinically acute adolescent sample. The proposed study will recruit 100 adolescents hospitalized for STB. During hospitalization, participants will continuously wear wrist actigraphs to measure objective sleep metrics (e.g., total sleep time, sleep onset latency) and provide continuous urine samples to estimate endogenous circadian timing using 6-sulfatoxymelatonin (aMT6s), a reliable indicator of circadian timing. Participants will also complete ecological momentary assessments (EMA) of suicidal ideation throughout their inpatient stay. STB will be reassessed at 1 and 3 months post-discharge, a period of heightened suicide risk. Three aims guide the project: (1) to test whether night-to-night variations in sleep predict next-day SI during hospitalization and STB after discharge; (2) to evaluate whether later circadian timing is associated with higher SI during hospitalization, increased risk for STB post-discharge, and shifts in the timing of SI toward later hours; and (3) to examine whether greater circadian misalignment—i.e., discrepancies between sleep behaviors and the biological clock—predicts increased STB both during hospitalization and after discharge. The proposed training plan complements the Candidate's research plan and will provide the Candidate with rigorous training in actigraphy, biological measurement of circadian rhythms, and advanced longitudinal data analysis. A team of leading scholars will provide expert mentorship in the assessment of adolescent suicide, sleep and circadian biology, and, intensive longitudinal methods, and biostatistics. The project is embedded in a rich, interdisciplinary research environment at Massachusetts General Hospital. By identifying modifiable, objective markers of short-term suicide risk, this research has the potential to advance predictive models and inform clinical interventions, particularly chronotherapeutic approaches. The proposed study will promote the Candidate's long-term goal of establishing an independent program of research focused on leveraging sleep and circadian science to improve youth mental health and reduce STB.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Epidemiological research suggests that up to 20% of adolescents have experienced at least one episode of major depressive disorder (MDD) in their lives and that rates of depression among this group are increasing. To address this, research is needed to identify modifiable risk factors that can be targeted to reduce risk of depression in this age group. There is growing evidence that sleep disturbance is both a symptom of, and risk factor for, depression in adolescents. Across studies, there is support for decreased sleep duration, worse sleep quality, delayed sleep timing, and decreased sleep regularity prospectively predicting depressive symptoms among adolescents. What remains unclear are the mechanisms by which sleep disruptions might increase depression risk in adolescents. One promising potential mechanism of risk is the impact on adolescents’ ability to inhibit attention to depression-relevant stimuli. Although no studies have tested this specifically, there is clear evidence that sleep disruption and depression risk are both associated with related constructs including higher levels of repetitive negative thinking and rumination, as well as biases in attention toward depression-relevant stimuli. The proposed study will provide a fine-grained examination of links between specific forms of sleep disruption, measured via actigraphy and self-report measures, and deficits in adolescents’ ability to inhibit attention to depression-relevant stimuli, directly assessed via steady-state visually evoked potentials (ssVEPS) derived from encephalography (EEG). Primary Aim 1 is to determine whether indices of sleep disruption (sleep duration, timing, quality, and regularity) are related to deficits in adolescents’ ability to inhibit attention to negative (depression-relevant) stimuli and predict depressive symptom trajectories across a two-month follow-up. Primary Aim 2 is to determine whether difficulty inhibiting attention to depression-relevant stimuli predicts prospective changes in adolescents’ depressive symptoms. A secondary aim of this study is to evaluate whether difficulty inhibiting attention to depression-relevant stimuli statistically mediates the relation between specific indices of sleep disruption (duration, timing, quality, regularity) and changes in depression over the follow-up. These research aims are complemented by a series of training goals designed to facilitate the applicant’s development into an independent researcher. These training goals are to (i) gain specialized training in adolescent sleep research, (ii) gain expertise in collecting, processing, and analyzing ssVEP data, and (iii) strengthen knowledge of statistical methods for analyzing multi-wave longitudinal data. Overall, this study will provide a fine-grained, multi-method examination of sleep disruption and adolescent depression risk focused on a core mechanism of risk hypothesized to be impacted by the changes in sleep that often occur during adolescence. This study will also provide the training necessary for the applicant to become an independent researcher focused on risk for depression in adolescents.

NHLBI - National Heart Lung and Blood Institute

Project Summary Abstract Childhood systemic lupus erythematosus (cSLE) is a chronic, inflammatory autoimmune disease that accounts for 10%-20% of all SLE diagnoses, and is associated with significant pain, fatigue, and cardiovascular morbidity. cSLE is more prevalent in non-Hispanic Black (Black) and Hispanic youth, who, in the U.S., have 80% heightened disease prevalence and are known to experience worse health outcomes, greater disease severity, and less access to care compared to non-Hispanic White (White) youth. Pain, fatigue, anxiety, and depression are interrelated and common in cSLE,and contribute to increased healthcare use and lower health-related quality of life (HRQoL). Our pilot findings in a diverse sample of youth with cSLE demonstrate associations between sleep health (duration, efficiency, regularity, sleepiness) and cSLE symptoms. Inadequate sleep duration, irregularity in sleep timing, poor sleep efficiency, as measured by actigraphy and symptoms of insomnia, predicted worse next day pain and were related to increased pain, fatigue, higher levels of anxiety and depressed mood, and lower HRQoL. Few studies have examined sleep in cSLE - highlighting a current research gap. In adults with lupus, poor sleep health is predictive of worse pain, fatigue, anxiety, and depression. Sleep is a modifiable behavior that is not routinely assessed in pediatric rheumatology care. Further, Black and Hispanic youth experience greater sleep health disparities, have increased risk for cSLE disease prevalence, potentially placing them at higher risk for worse cSLE symptoms. Black and Hispanic youth represent 40% of U.S. youth, underscoring the importance of focusing on these populations to address sleep health as an intervention target. Sociocultural factors such as family sleep beliefs and practices, family/social support, acculturation, stress, and socioeconomic status; and neighborhood characteristics such as social cohesion, economic disadvantage and safety are known resilience and/or risk factors associated with sleep health and HRQoL. Yet these social factors are understudied in youth with cSLE, and their contribution to sleep, fatigue, and mental health is poorly understood, which impedes effective intervention. We propose a mixed methods study that includes a multicenter cohort of 200 youth with cSLE, with a focus on recruiting Black and Hispanic youth, 13-to-17 years, and their parents recruited from 3 pediatric rheumatology centers in the U.S.; enriched with qualitative data on a subgroup of 30-36 youth-parent dyads to understand sociocultural beliefs and practices about sleep. cSLE represents a uniquely vulnerable group due to its combination of systemic inflammation, neurocognitive risk, high treatment burden, and disproportionate prevalence among Black and Hispanic youth. Findings will help clinicians prioritize screening and treatment for poor sleep health; alter clinical care in the management of cSLE to reduce symptoms; and inform a culturally tailored sleep intervention.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Depression affects millions of individuals worldwide, yet the treatments including transcranial magnetic stimulation (TMS), achieve only moderate success. While the exact mechanisms underlying the therapeutic effects of TMS remain unclear, they are in part attributed to the induction of neural plasticity. Notably, plasticity is most pronounced during non-rapid eye movement (NREM) sleep, particularly in slow-wave sleep (SWS), when synchronized oscillations between the cortex and thalamus may optimize neuroplastic changes. However, currently, TMS is administered in wake-state only. This research gap suggests a new frontier for TMS in depression - stimulating the brain during sleep rather than while awake. By timing TMS to coincide with critical neural events that promote plasticity and systems-level consolidation in NREM sleep, such as thalamocortical sleep spindles, we may enhance TMS efficacy to induce prefrontal plasticity for treating depression. I have developed an approach to deliver TMS during sleep, using automated systems for real-time detection of sleep stages, slow oscillations, and sleep spindles. My preliminary work has shown that intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) during NREM sleep produces more robust cortical changes than when applied during wakefulness and that spindle-guided iTBS further amplifies these plasticity effects. Building on this, I hypothesize that targeting the dorsolateral prefrontal cortex (dlPFC) with iTBS during NREM sleep will result in superior prefrontal plasticity, improving both brain function and behavior in depression. I will first test the effects of intracranial electrical iTBS of dlPFC during NREM sleep on brain activity in neurosurgical patients, using intracranial EEG (iEEG) to measure evoked responses and index plasticity (Aim 1). Next, I will focus on TMS-delivered dlPFC iTBS in depressed patients, using simultaneous TMS-EEG to measure noninvasive brain responses during NREM sleep and pre-sleep wakefulness conditions (Aim 2). Finally, I will investigate real-time sleep-spindle guided dlPFC iTBS in healthy individuals, hypothesizing that targeting events of spindles during SWS will induce even superior prefrontal plasticity and improvements in working memory (Aim 3). For training and professional development while pursuing these aims, I will rely on a mentoring team of world-class experts in invasive and noninvasive brain stimulation, depression, sleep and neural oscillations: Drs. Corey Keller, Josef Parvizi, and Andrea Goldstein-Piekarski, with Drs. György Buzsáki, and Manish Saggar as advisors. This work will deepen our understanding of the neural effects of TMS in the prefrontal cortex and its potential to enhance treatment outcomes in depression. Through this project, I will gain critical expertise in intracranial EEG, direct brain stimulation, pathophysiology of depression and learn how to design, recruit, and execute an independent clinical trial, all of which will prepare me to lead a future independent academic career in sleep-augmented brain stimulation therapies for psychiatric disorders.

NIMH - National Institute of Mental Health

Project Summary Obsessive compulsive disorder (OCD) affects approximately 2.2 million adults worldwide, with more than 200,000 cases and a socioeconomic impact exceeding $8 billion in the United States every year. Provisional FDA approval treats OCD by delivering deep brain stimulation (DBS). We propose that real opportunity lies in a vastly underused resource: the chronically implanted brain electrodes. To date, however, ambulatory intracranial electroencephalographic (iEEG) recordings from DBS leads have only been available under very specific conditions and without the benefit of synchronized disease-relevant behavioral monitoring to provide necessary context. The goal of this 5-year milestone-driven clinical trial proposal is to unlock the potential of DBS leads for continuous sensing of brain activity, enabling the real-time tracking of internal states linked to the full spectrum of motor and non-motor symptoms in OCD. Today, long-term continuous brain sensing is not feasible due to limitations in battery life, power delivery, and data transmission bandwidth in existing DBS systems. We aim to overcome these barriers by integrating new telemetry and wireless power solutions into an innovative wearable platform, SMART-DBS, that supports chronic streaming of neural signals along with physiological signals based on muscle activity, heart rate variability and accelerometry to provide additional symptom sensing. We will also collect validated symptom measures via patient-reported outcomes (e.g., digital scales), structured clinical instruments, and app-based logging. By aligning chronic brain recordings with subjective and objective measures of clinical symptoms in OCD, we will link brain states to clinical outcomes. This project develops innovative technologies to directly address the major challenges in brain-behavioral quantification and synchronization in order to enable a follow-up trial to treat OCD using adaptive, responsive DBS. Progress will also indirectly advance a range of next-generation clinical studies of the brain mechanisms of human behavior such as in Parkinsons, epilepsy, depression and other applications of DBS in ambulatory populations.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a leading cause of preventable liver-related morbidity and mortality, with hospitalizations for ALD increasing significantly in recent years. Many patients with ALD and active alcohol use disorder (AUD) are discharged from the hospital without receiving evidence-based behavioral interventions, despite hospitalization representing a teachable moment when patients may be more motivated to change. Psychosocial support in this setting is often limited by short inpatient stays, provider shortages, and workflow barriers. Novel digital health approaches are needed to increase access to structured, personalized behavioral support during hospitalization. This K23 Career Development Award proposal aims to assess the feasibility, usability, and clinical relevance of SOBER-VR, a virtual reality (VR) and artificial intelligence (AI)-powered digital therapeutic that delivers motivational interviewing (MI) to hospitalized patients with ALD and active alcohol use. SOBER-VR uses immersive VR to enhance emotional salience and a large language model (LLM)–driven conversational agent to simulate reflective, MI-consistent interactions. The intervention is brief (10–15 minutes), self-guided, and delivered using sanitized, standalone VR headsets with real-time support from trained staff. Using the NIH ORBIT Model for behavioral intervention development, this Phase Ib single-arm feasibility study will recruit 30 hospitalized patients with ALD and active alcohol use. Participants will use SOBER-VR during their inpatient stay and complete structured assessments post-discharge. The study will evaluate feasibility (recruitment, engagement, and retention), acceptability, usability, and safety of SOBER-VR. Preliminary signals of clinical impact, such as readiness to change, attitude to AUD treatment, among others, will also be explored. Specific Aims: • Aim 1: Develop a brief SOBER-VR-delivered intervention for inpatients with ALD • Aim 2: Evaluate the feasibility, usability, acceptability, and safety of brief therapy via SOBER-VR. • Aim 3: Conduct a pilot RCT to collect preliminary data assessing the feasibility and clinical impact of SOBER-VR vs. usual inpatient care in inpatients with ALD. This proposal directly aligns with the NIAAA’s mission to improve the prevention and treatment of alcohol-related problems through innovative, scalable, and patient-centered interventions. Findings will inform the refinement of SOBER-VR for a future multi-site R01 efficacy trial. The proposed mentored training plan will provide Dr. Yeo with expertise in qualitative research, implementation science, behavioral intervention development, and digital therapeutics to support his long-term goal of becoming an independent physician scientist advancing health services innovation in liver disease.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Parental anxiety is a well-known risk factor for youth anxiety during preadolescence, with social experiences contributing to this intergenerational transmission. Parental threat communication, including fearful and negative verbal and nonverbal expressions, is a potential social pathway linking parental anxiety with child anxiety. Our preliminary findings based on trait-based measures support this view, showing that parental threat communication links parental anxiety with children’s anxiety. However, two knowledge gaps remain: 1) whether parental anxiety extends to children's daily emotions in their real-life contexts as mediated via observed parental threat communication, and 2) which neural mechanisms underlie these associations. Parental threat communication can amplify children’s threat sensitivity by emphasizing the salience of threats, given evidence that parents can either buffer or amplify children’s neural responses to threats. Specifically, parents can facilitate children’s Error Monitoring, the brain’s ability to detect mistakes, typically indexed by the Error- Related Negativity (ERN) Event-Related Potential. Heightened error monitoring, particularly under stressful situations, is considered a potential biomarker of anxiety, as it correlates with levels of anxiety and predicts the onset of anxiety disorders. Our preliminary findings indicate that parental traits predict children’s error monitoring under social evaluation, and in young children, increased error monitoring in parental presence has been uniquely associated with anxiety. Although preadolescence is a critical time for the onset of anxiety problems, it is unknown if parental amplification of error monitoring is linked with children’s anxiety and daily emotions during this time. This project will examine (a) whether parental threat communication mediates the paths from parental anxiety to children’s anxiety and daily emotions, (b) whether parental threat communication mediates the link between parental anxiety and children’s error monitoring in parental presence, and (c) whether children’s error monitoring in parental presence is associated with anxiety, and daily emotions in real- life contexts. Children (ages 9 to 12, N = 140) and their parents will complete online questionnaires and participate in a lab visit. Parental threat communication will be observed during a modified TRIER social stress task. EEG will be recorded while children complete a Flanker task twice: in parental presence and alone. EEG data will be analyzed to compute parental modulation of children’s error monitoring. Following the lab visit, children will complete a 10-day Ecological Momentary Assessment (EMA) procedure to report their daily emotions. This study will make a significant contribution to understanding the parental behaviors and neural processes that link parental anxiety with children’s daily emotions, providing potential targets for family-based interventions. I will also receive in-depth training in (a) EMAs, (b) ERP and EEG time-frequency methods, (c) basic, translational, and affective clinical neuroscience, and (d) professional development in clinical research with youth and families to inform family-focused interventions.

NIMH - National Institute of Mental Health

ABSTRACT HIV stigma, poverty, and racism contribute to high rates of mental health problems and impede treatment for young sexually minoritized men (YSMM) living with or vulnerable to HIV. HIV stigma is associated with poorer HIV medication adherence, and worse mental health, including increased odds of suicidality for youth living with HIV. Inclusive, culturally, and contextually appropriate intersectional interventions can promote access to health services and prevent poor health outcomes including HIV transmission related behaviors. Our project, Social Contact-Based Brief Video Interventions To Reduce Stigma and ImproVe Engagement in HIV Prevention and Care and Mental Health Care for Youth Living with and Vulnerable to HIV (STRIVE), will evaluate the effectiveness and implementation of intersectionally-tailored brief videos to reduce public and internalized HIV stigma (BVHS). Throughout the project we will engage partners from the New York City Department of Health and Mental Hygiene (NYC DOHMH) (See LOS) as well as our Youth Advisory Board comprised of 5-8 individuals recruited from three existing Community Advisory Boards (CABS): the AIDS Clinical Trials Group (ACTG) CAB, the ongoing HIV Vaccine Trials Network (HVTN) of the Columbia Collaborative Clinical Trials Unit (Columbia CTU) (see Letter of Support (LOS)) and Columbia University HIV Center Consultants (See LOS). Individuals from these groups represent diverse racial backgrounds, adolescent and young adult age ranges, and lived experience with HIV and/or mental health challenges. In Aim 1 we collaborate with our YAB to adapt and then test the efficacy of BVHS to reduce public HIV stigma compared to a control using crowdsourcing platforms with pre/post/30-day follow-up assessments. In Aim 2 we test the efficacy of BVHS to reduce internalized stigma and increase linkage to HIV prevention, HIV care and mental health treatment among a subset of YSMM living with or vulnerable to HIV on social media. In Aim 3 we use a Consolidated Framework for Implementation Research (CFIR)-informed multi-method analytical plan in order to understand implementation outcomes (e.g., acceptability, feasibility) and inform scale up and dissemination (e.g., identifying key barriers). In Aim 4 we evaluate engagement and treatment-seeking behavior from the NY area dissemination of evidence-based BVHS via Instagram. Through STRIVE we will reduce HIV stigma, facilitated by emotional engagement and identification. This reduction in HIV stigma will mediate proximal outcomes by increasing HIV prevention, HIV care and mental health treatment-seeking among YSMM living with or vulnerable to HIV. This simple, intersectionally-tailored video intervention can potentially reduce duration of untreated HIV and mental health problems and alter public stigma about HIV.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Prior research has documented that social determinants of health such as neighborhood disadvantage and school context are associated with youth mental health3,7,10,11, with neighborhood effects on youth outcomes being mediated by parenting factors4. However, research on the role of these contextual factors in the trajectories of parenting and youth mental health and their relationships has been limited. Additionally, this prior work shows the importance of targeting parenting in family-focused preventive interventions in geographical areas with high contextual risk. While neighborhood economic disadvantage and subjective perceptions of neighborhood are associated with outcomes of preventive interventions32, 34, this prior work has used limited objective measures of social determinants of health, has had inconsistent longitudinal follow-up, focused on limited outcomes, and did not consider how social determinants of health influence intervention engagement. The proposed research will address these limitations with several aims: (1) Determine how neighborhood and educational risk and protective factors are related to youth mental health trajectories across childhood and adolescence and the role of parenting as a mediator between context and youth mental health trajectories, (2) Investigate whether neighborhood and educational risk and protective factors are associated with engagement in and response to the Family Check-Up, a family-focused preventive intervention, and (3) Determine whether findings from the first two aims differ based on urbanicity, race, or ethnicity. The results have implications for clinical practice and research in the development and dissemination of family-focused preventive interventions that promote positive family relationships and youth mental health for all families. The work addresses the NIMH Strategic Plan by aiming to examine trajectories of mental illness, strive for prevention, and advance services to strengthen public health. The proposed research and training plan, which will occur in a supportive, collegiate environment at Case Western Reserve University, will provide the researcher with critical training to support the transition to becoming an independent researcher in developmental psychopathology and prevention science. Specific training goals include (1) Develop a focused understanding of how neighborhood and educational social determinants of health influence parenting and youth mental health, focusing on how this perspective can inform development and dissemination of preventive interventions, (2) gain expertise in leveraging geocoded data to answer questions related to social determinants of health, family functioning, and intervention outcomes, and (3) master the use of complex quantitative methods to analyze longitudinal data. The applicant has assembled a mentorship team with an expertise in the areas which she plans to gain additional experience, and this team will provide superior guidance that will support her increasing independence as a researcher.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Social experiences are indispensable for mental health, and this is particularly important in younger populations where there is a developmental need for peer-peer social interactions. Atypical social experiences in the form of social isolation or deprivation became common during the COVID19 pandemic and have been particularly harmful for adolescent mental health. This can be seen with impaired age-specific social behaviors, like play in adolescent rats and investigation in adult rats. The poor social opportunity that arises from social deprivation alters brain function that contributes to adolescent vulnerabilities to social perturbations. The amygdala is a candidate brain region to investigate the impact of social deprivation on social development, as it is important for regulating social behavior and is sensitive to atypical social experiences. Adolescent amygdala maturation is epitomized by increases in inhibitory parvalbumin (PV) GABAergic tone and in activity evoked by the infralimbic region of the medial prefrontal cortex (IL). The adult basomedial amygdala (BMA) in particular receives dense inputs from the IL and is regulated by GABAergic neurons. Further, the adult BMA dynamically responds to social stimuli and is unique in that its activity directly correlates to the degree of social interaction. Our preliminary data show that BMA principal neuron activity regulates adolescent and adult social engagement. Within the BMA, we have identified IL inputs as a source of BMA principal neuron activation. This IL-evoked principal neuron activation is greater adolescents relative to adults, and the age-dependent reduction in IL-driven excitation is regulated by inhibitory GABAergic neurons in adults. However, it is unclear how social deprivation compromises unique developmental features of the BMA to subsequently impair social development. Our goal is to understand the initial effects of adolescent and adult social deprivation on BMA-driven changes in social behavior, as these initial changes will identify the adolescent-specific vulnerabilities when contrasted with adults. Our aims address a novel central hypothesis that social deprivation shapes BMA activity through reductions in principal neuron activity driven by the IL at both ages and reduction of PV activity in adults. This social deprivation-driven change to BMA activity impairs social interaction across ages. Our central hypothesis will be tested in three specific aims quantifying the contribution of excitation (Aim 1), PV activity (Aim 2), and the ILBMA pathway (Aim 3) to adult and adolescent social behavior and how this is neural circuitry is impacted by social deprivation. Each aim will use a combination of in vitro electrophysiology to mechanistically quantify BMA maturation, fiber photometry for functional changes in BMA activity time-locked to social investigation, and chemogenetics to understand the BMA regulation of adolescent and adult social behavior. The results from the proposed project are expected to create a novel framework through which social deprivation shapes BMA activation underlying adolescent and adult social dysfunction. This will identify distinguishing factors between ages that may contribute to age-specific mechanisms of social abnormalities and adolescent vulnerability to social perturbations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Social media use is associated with increased risk of psychopathology in adolescents, yet the underlying mechanisms linking social media use with mental illness are poorly understood. Social media use facilitates near constant peer evaluation and social feedback, which amplifies the potential for rejection sensitivity, the heightened physiological and emotional responses to social loss or rejection. Rejection sensitivity is of particular importance given that it is a transdiagnostic prodromal symptom of severe psychopathology (e.g., depression), that emerges during adolescence. Social media use engages social reward neural circuitry, which is altered in depression and modified by estradiol (E2), making it a promising neurophysiological candidate linking social media use and female adolescent depression. There is limited data on what makes an individual more sensitive to the impact of social media use, and what neurophysiological and psychological factors contribute to increased risk of depression linked to online experiences. To address this gap and extend the research in an innovative new direction, the primary objective of this project is to elucidate the social media characteristics (network features and positive/negative online experiences) and endocrine contexts in which online experiences have the largest impact on rejection sensitivity and depressive symptoms. We will focus on the perimenstrual window of the menstrual cycle as a vulnerable or “risky” context that contributes to disruptions in social reward neurophysiology, rejection sensitivity related to online experiences, and depressive symptoms in female adolescents. Two counterbalanced neurobehavioral testing sessions with EEG during perimenstrual E2 change and stable, mid-follicular E2 change will probe the cycle-related neurophysiological indices of social media- related reward responsiveness and how they relate to rejection sensitivity. Further, we will use data donation packages to code for online positive and negative experiences and conduct network analyses grounded in graph theory to characterize social media networks to determine the impact of network density (i.e., number of online connections), clustering, and communities (social groups), perceived and extracted online experiences on rejection sensitivity and depressive symptoms. This multimodal design will allow us to address the following specific aims: determine the extent to which rejection sensitivity is characterized by perceived social media experiences and neurophysiology of reward responsiveness, particularly during perimenstrual E2 change (Aim 1), and social media network characteristics (Aim 2), to determine how these measures may interact to predict depressive symptoms (Aim 3). Our central hypothesis is that greater rejection sensitivity will be associated with disrupted social reward responsiveness and greater perceived negative social media interactions, particularly during perimenstrual E2 change and in the context of high-density social media networks with fewer defined social groups. This research will help identify neurophysiological indices of social reward responsiveness and social media network characteristics that precipitate rejection sensitivity and susceptibility to depression.

NIMH - National Institute of Mental Health

ABSTRACT/PROJECT SUMMARY Anxiety is one of the most common and debilitating comorbidities with ADHD, affecting 57% of youth and 84% of adults, with particularly high rates in girls and women. Despite its widespread prevalence, this co-occurrence is often overlooked and poorly understood, contributing to worse mental health outcomes and greater economic costs than either condition alone. Social processes (i.e., social cognitions and relationships) appear to contribute to the emergence of anxiety in youth with ADHD, but extant work has most often relied on mother-reports in community samples, lacking a multi-informant perspective and consideration of how ADHD and anxiety co-occur across development or in clinical populations. These gaps hinder our ability to provide effective, timely interventions, leaving those at highest risk—especially girls and women—without the necessary support. There is also a notable lack of research on girls and women with ADHD and potential sex differences, despite growing identification of ADHD in girls and women, many of whom are identified with anxiety prior to diagnosis of ADHD. Aligned with Goal 2 of the NIH Strategic Plan (Examine Mental Illness Trajectories Across the Lifespan), this project will address these gaps using three existing datasets with large samples of girls and women. Aim 1 will use ongoing clinical cohort data from a specialized lifespan ADHD clinic to identify developmentally relevant social processes in the co-occurrence of ADHD and anxiety in children and adults, utilizing one of the most well- characterized and ecologically valid samples of girls and women with ADHD to date. Aim 2 will use data from two completed studies and one ongoing study to examine electroencephalography (EEG) measures of social processing as markers of ADHD and anxiety, as well as sex differences, in adolescents—a critical period for anxiety onset and heightened social sensitivity, particularly in girls. Findings will provide developmentally and sex-specific insights into altered social processing as a mechanism for co-occurring ADHD and anxiety, along with neural biomarkers during a critical risk period. With mentorship from experts in lifespan ADHD and sex differences (Babinski), EEG methods for assessing anxiety risk (Pérez-Edgar), measurement-based ADHD care in clinical settings (Waschbusch), and translational analytics/bioinformatics in clinical data (Tuan), this project is designed with an integrated training plan to provide the applicant with real-world clinical research experience, focusing on advanced data analytics to how altered social processing contributes to co-occurring ADHD and anxiety across the lifespan, alongside innovative EEG methods to identify neural markers of these processes. The exceptional mentorship team, coupled with the resources and infrastructure at Penn State College of Medicine, offers the optimal environment to support the applicant’s training goals, foster professional development, and promote growth as an independent ADHD researcher focused on identifying developmentally and sex-specific comorbidity risks in ecologically valid populations across development.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The social environment can be a source of stress. Social stress is normal, but when persistent, it causes oxidative stress in the brain, which contributes to a variety of mental health and neurodegenerative diseases. Mitochondria could mediate the link between the social environment and oxidative stress as they are a major source of reactive oxygen species (ROS) and play a role in stress adaptation. Previous research has focused on chronic social defeat stress and resulting elevation in glucocorticoid levels, which causes oxidative stress in specific brain regions. Androgens modulate many metabolic responses, yet despite their responsiveness to social stressors and relevance to many age-related diseases, the role of androgenic signaling in regulating oxidative challenges in a social context is understudied. My goal is to study how androgens and social stress influence the regulation of oxidative stress in the brain by leveraging the highly social cichlid fish Astatotilapia burtoni, a well-established model system for neurogenomics and integrated animal behavior. Male A. burtoni exist as two reversible phenotypes: dominant and subordinate. Dominant males aggressively defend a territory, have high androgen levels, large gonads, and mate with females, while subordinate males are nonterritorial and reproductively suppressed. Territorial defense is physically and cognitively demanding for dominant individuals, while subordinate males experience social suppression and intimidation from higher ranking individuals. Females engage in aggressive competition for shelter and form distinct dominance hierarchies when housed in all-female groups, allowing us to study the effect of distinct social stressors in high- and low-ranking individuals of both sexes. The overarching goal of this five-year proposal is to assess how competition-induced social stress combined with androgen receptor signaling influences the regulation of oxidative balance in the brain. In Research Direction 1, we will define the effect of social stress and androgen receptor signaling on oxidative stress and mitochondrial function across different parts of the brain. To this end, we will integrate social manipulations with androgen receptor pharmacology to study how distinct social and metabolic stressors across the dominance hierarchy influence the regulation of oxidative stress in the brain. In Research Direction 2, we will determine how social experience and androgen receptor signaling influence protection against an acute oxidative insult to the brain using a validated hypoxia-reoxygenation paradigm. Our integrative approach provides an opportunity to discover unanticipated cytoprotective mechanisms in the brain against both chronic and acute stressors. The proposed activities will allow me to develop a research program aimed at dissecting variable strategies used to cope with stressful experiences to maintain organismal homeostasis. My research program may lead to novel insights into intervention strategies or therapeutic targets that reduce oxidative stress and improve effective recovery from oxidative challenges.

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary/Abstract Psychological stress is an established contributor to bone and tooth loss and impaired bone growth. In the US, more than 50 million people currently experience bone loss while a similar number is afflicted by anxiety (40 million) and/or depressive disorders (16 million). Bone and tooth loss resulting from psychological stress has been observed in all age populations. A murine model of stress, repeated social defeat (RSD), recapitulates key physiological, immunological, and behavioral alterations in humans exposed to psychosocial stress such as bullying and loss of social status. RSD activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system to create a state in which primed, pro-inflammatory monocytes traffic from the bone marrow to the brain to generate neuroinflammation and anxiety-like behavior. In addition, RSD rapidly induces bone loss through increased activity of osteoclasts, and bone growth plate reduction. However, the precise mechanisms by which RSD influences bone have not been identified. Therefore, the overall goal of this project is to exploit a rodent model of psychological stress to better explore the relationships between immunological processes, mental and bone health. This will be accomplished in three Specific Aims. Aim 1 will examine the kinetics of bone loss and growth plate reduction in adolescent male and female mice following a period of RSD. Aim 2 will investigate a central role for osteoclast activation and chemokine (CXCL12) signaling in RSD-induced monocyte mobilization. Aim 3 will investigate mechanisms of RSD-induced growth plate reduction. Outcomes of this project will help achieve the long-term goal of developing more specific interventions to treat psychological stress-related disorders of skeletal physiology.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT This NIH K08 proposal describes a four-year career development training program in autism spectrum disorder (ASD) genomics research. With this research program, Dr. Mo will develop expertise in human genetics, analysis of next-generation sequencing data, and interpretation of somatic variants in non-neoplastic tissue. These skills complement Dr. Mo’s prior research and clinical training and ideally position her to transition to an independent investigator position studying somatic mutations in ASD. Dr. Mo’s mentor for this proposal is Dr. Christopher A. Walsh, a Professor of Neurology at Harvard Medical School, an HHMI Investigator at Boston Children’s Hospital, and a leader in the genetics of human neurological diseases. With over 25 years of mentorship experience, Dr. Walsh has an established track record of mentoring trainees to successful academic careers in biomedical research. Dr. Mo will be supported by a scientific advisory team and collaborators with complementary expertise in autism genetics, computational genomics, genotype-phenotype correlations of somatic mutations, and career mentorship. The institutional resources available at Boston Children’s Hospital, which is affiliated with Harvard Medical School, are world- class and provide an ideal environment to foster the development of a physician-scientist career. The primary scientific objective of the proposed research plan is to study the role of somatic (post- zygotic) variants in ASD. Dr. Mo’s central hypothesis is that somatic variants contribute to ASD risk. Dr. Mo provides pilot data indicating that somatic single nucleotide variants (sSNVs) are increased in gene exons in ASD probands compared to controls, particularly in highly constrained genes with loss-of-function intolerance. Furthermore, Dr. Mo shows that sSNVs in non-coding gene regulatory regions can be efficiently detected using ATAC-seq, which allows the detection of non-coding sSNVs in larger sample sizes than previously possible using whole genome sequencing. To achieve the research objective, a combination of whole exome sequencing, ATAC-seq, whole genome sequencing, amplicon sequencing, and computational analysis will be used. These strategies will systemically examine two independent, but related, aims: (1) the burden of sSNVs in functionally-relevant genes in ASD compared to neurotypical individuals; and (2) the distribution of sSNVs in non-coding gene regulatory regions in postmortem human brain neurons from ASD and neurotypical individuals. Findings from this study may improve our understanding of the genetic architecture and mechanisms of ASD as well as the genetic diagnosis of ASD in clinical practice.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Multiple sclerosis (MS) is a chronic and debilitating disease of the nervous system that has widespread effects, impacting physical and mental function. Among the most common symptoms experienced by people with MS (PwMS) are balance dysfunction and fatigue, rated as having the most profound negative impacts on quality of life. Although evidence suggests that fatigue and balance dysfunction are related, the specific mechanism that determines this relationship among PwMS is not known. However, evidence supports somatosensory impairment as a major contributor to balance dysfunction and fatigue among PwMS; we hypothesize that somatosensory impairments mediate increased attentional and physical demands that drive cognitive and physical fatigue, thereby increasing MS-related fatigue. The somatosensory system is vital to postural coordination because it is the most sensitive sensory modality to postural instability; thus, degraded or delayed somatosensory feedback leads to greater postural instability that must be counteracted by the neuromuscular system to maintain balance. We hypothesize that this requires increased motor output to prevent balance loss, increasing the physical load and consequently physical fatigue. Although somatosensory feedback is degraded among PwMS, we believe that compensatory mechanisms attempt to mitigate these effects; these include compensation by other sensory modalities (primarily vision), referred to as sensory reweighting, and greater attentional resources to maintain balance. We hypothesize that these compensations require additional cognitive resources that lead to increased cognitive fatigue. To test these hypotheses, we will systematically assess balance tasks that will increase the physical load, cognitive load and available sensory feedback to directly evaluate somatosensory impairment as a mediator of physical and cognitive fatigue, and balance dysfunction in PwMS. This study will leverage advances in wearable motion-tracking technologies to quantify postural sway dynamics, and portable functional near infrared spectroscopy to quantify changes in cortical blood flow indicative of changes in cortical activation. Thus, we will assess changes in the motor cortex related to physical load, the dorsolateral prefrontal cortex (which directs attentional resources to balance control) related to cognitive load, and the visual cortex to evaluate sensory reweighting. These measures, paired with subjective and objective assessment of fatigue, will provide new mechanistic insight into the role of somatosensory impairment in modulating balance dysfunction and fatigue. The expected outcomes of this research include: a new target for early therapeutic intervention that could mitigate MS-related fatigue and balance dysfunction, and improve quality of life among those with MS; and determination of potential differential impacts of somatosensory loss on balance and fatigue among nonprogressive and progressive MS subtypes—knowledge that could aid in identifying and tracking progression among those with MS.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Fragile X syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). It is caused by a CGG trinucleotide repeat expansion in the 5’-UTR of the FMR1 gene, leading to the loss of fragile X messenger ribonucleoprotein (FMRP), a key RNA-binding protein that regulates transcription, translation, and mRNA localization. The absence of FMRP results in profound translational dysregulation, impairing synaptic plasticity and disrupting neuronal circuits. While FMRP primarily functions as a translational repressor, its precise spatial and activity-dependent regulation in the brain remains poorly understood due to limitations of bulk and conventional transcriptomic methods. To address this critical gap, we will employ advanced spatial genomics technologies to construct the first high-resolution, single-cell map of translational regulation in the FXS mouse brain. In Aim 1, we will generate spatial transcriptomics and translatomics maps of FXS and control mouse brains using STARmap-PLUS and RIBOmap. These datasets will allow us to quantify the abundance and translation of FMRP-target mRNAs, non-targets, cell-type markers, and regional markers, revealing how loss of FMRP alters mRNA localization and translation at brain-region- and cell- type-specific levels. In Aim 2, we will investigate how synaptic activity modulates spatial mRNA translation by inducing activity-dependent long-term depression (LTD) in brain slices using a well-established protocol. This approach will provide the first direct link between synaptic stimulation and localized mRNA translation dynamics in FXS, offering novel insights into how synaptic dysfunction contributes to disease pathology. This study represents a significant technical and conceptual advance in FXS research, offering an unprecedented spatially resolved view of FMRP-mediated regulation at single-cell and subcellular levels. By uncovering activity- dependent translational dysregulation in FXS, our findings will generate critical mechanistic insights and inform novel therapeutic strategies targeting dysregulated local translation in neurodevelopmental disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The release of neurotransmitters at synapses occurs in three distinct modes: synchronous release, which is tightly coupled to an action potential (AP); asynchronous release, which lingers for hundreds of milliseconds after an AP; and spontaneous release, which happens independently of an AP. While our labs and others have begun uncovering the molecular machinery behind asynchronous release, major gaps remain – especially at the quantal level. This is largely because most of what we know about neurotransmitter release comes from electrophysiological studies, which lack direct spatial resolution. To address this problem, I will leverage the power of iGluSnFR3, a third-generation intensity-based Glutamate-Sensing Fluorescent Reporter, to directly visualize asynchronous release at the single-synapse level and dissect its molecular and physiological drivers. Aim 1 will determine if distinct molecular drivers of asynchronous release generate unique quantal and spatial phenotypes at the single synapse. First, I will further optimize iGluSnFR3 for reliable detection of quantal neurotransmitter release (subaim 1.1). My preliminary data demonstrates that iGluSnFR3 can detect quantal neurotransmission with single-synapse resolution. Subaim 1.2 will investigate how different extrinsic and physiological conditions can uniquely desynchronize neurotransmitter release. Although these conditions are often used interchangeably in the literature and assumed to have the same effect on facilitating asynchronous release, it remains unclear whether they influence release kinetics at the single-synapse level in the same way. My preliminary data shows that while these conditions increase the cumulative charge transfer of asynchronous release measured by electrophysiology, iGluSnFR3 imaging reveals striking differences at the single-synapse level. Finally, subaim 1.3 will investigate whether this desynchronization is organized within separate sub- domains of the same active zone. Aim 2 will test whether synaptotagmin-7 mediated asynchronous release regulates postsynaptic signaling (subaim 2.1) and plasticity thresholds (subaim 2.2). My preliminary data indicates that synaptotagmin-7 not only drives increased multivesicular release but also elevates postsynaptic calcium levels, leading to the activation of downstream target proteins. The overall hypothesis of my proposal is that asynchronous neurotransmission constitutes a distinct signaling pathway, separate from other modes of release, with unique regulatory mechanisms and functional consequences. Therefore, the completion of this project will further our understanding of the molecular mechanisms shaping neurotransmission and synaptic communication. Additionally, this F31 proposal, supported by a highly individualized mentoring plan and team, will help prepare me for my next career stage as I apply to psychiatry research-track residency programs, and, ultimately, to become an independently funded physician-scientist.

Administration for Children and Families - OFVPS

The purpose of the Specialized Services for Abused Parents and Their Children is to expand the capacity of family violence, domestic violence, and dating violence service programs and community-based programs to prevent future domestic violence. This is done by addressing the needs of children who have been exposed to family violence, domestic violence, or dating violence in an appropriate manner. Required activities include providing direct counseling; providing developmentally and age-appropriate services to victims and their children; providing advocacy on behalf of victims and their children; and supporting non-abusing parents in their roles as caregivers and in meeting social, emotional, and developmental needs of their children. Where appropriate, services may also work with a non-abusing parent and child together.Optional activities include providing early childhood development and mental health services; coordinating with and providing technical assistance to community-based organizations that serve victims or exposed children and providing additional services and referrals to services for children. These may include childcare, transportation, educational support, respite care, supervised visitation, or other necessary services.

Veterans Affairs Department

VA is announcing the availability of funds for suicide prevention grants under the Staff Sergeant Fox Suicide Prevention Grant Program (SSG Fox SPGP). The SSG Fox SPGP directs efforts to reduce Veteran suicide by awarding grants to community-based organizations to provide or coordinate the provision of primarily non-clinical suicide prevention services, including outreach and linkage to VA and community resources, to eligible individuals and their families. The SSG Fox SPGP furthers VA's public health approach to suicide prevention by combining community-based efforts with linkage to clinical care to prevent Veteran suicide for those inside and outside of VA health care. The goal of these grants is to reduce Veteran suicide risk by improving mental health status, well-being, financial stability, and social support for eligible individuals and their families.

NCCIH - National Center for Complementary and Integrative Health

Major Depressive Disorder (MDD) is a common mental health disorder that affects 8% of US adults, including more than 18% of young adults between the ages of 18 and 29. Decades of research indicate that music-based treatments are broadly effective against depression, but their impact remains tightly restricted by a shortage of trained practitioners and a lack of readily deployed standard protocols. Our overall objective here is to develop and test the feasibility of a new “Standardized Tunable Music Medicine for Depression” as one such protocol. STAMM-D integrates progress across music therapy, neuroscience, and technology within a compact, personalized, mobile health (mHealth) treatment protocol designed to leverage music’s core effects on emotion and reward against MDD’s core symptoms of low mood and anhedonia. Our hypothesis is that we can feasibly develop STAMM-D as an engaging mHealth intervention that will be attractive to a large proportion of young adults with MDD diagnoses (e.g., 75%), a disproportionately affected demographic that also exhibits peak engagement with music, listening for an average of four hours per day. Aim 1 is to develop STAMM-D around three specific innovations, each designed to address a key design principle derived from literature review. These innovations are: (1) “iso music” for mood elevation, adapted from industry wellness applications to MDD treatment; (2) a protocol for creating therapeutically-appropriate individually-tuned music playlists on the basis of a combination of patient-facing music preference interviews and modern music recommendation algorithms; and (3) easy-to-use digital “musical agency” controls that give listeners the power to modulate key musical features (e.g., tempo and spectrum), encouraging behavioral engagement towards affective synchronization. Aim 2 is to deploy STAMM-D alongside a therapeutically credible control condition (Relaxation Music; RM) in a small-scale feasibility trial (N=68) aimed at evaluating recruitment rates, retention rates, treatment fidelity, and acceptability, ahead of a follow-on efficacy trial. Feasibility trial protocol details (dosage, duration, outcomes, etc.) are thus designed to closely match those required to test STAMM-D’s capacity to effectively treat MDD in an appropriately powered and rigorously controlled future trial. Finally, trial operations are designed to generate as much data towards STAMM-D refinement as possible, deriving extensive quantitative and qualitative feedback directly from young adults with MDD (i.e., stakeholders). The significance of this work lies in developing and establishing STAMM-D as a first-in-kind musical treatment with the capacity to radically expand access to music-based treatment for depression. More broadly, we expect this work to outline a template for developing other standardized musical treatments at the intersection of music therapy, neuroscience, and technology—e.g., targeting anxiety and insomnia—thus making an important practical contribution to ongoing efforts to expand the role for music in medicine. Key Personnel include one interdisciplinary neuroscientist (PhD), one music therapist (MT-BC), an academic psychiatrist (MD), two clinical psychiatrists (MDs), and one biostatistician (PhD).

NIMH - National Institute of Mental Health

The absence of a clear understanding of mechanisms that drive the symptoms of schizophrenia represents a critical need, hindering our ability to develop effective interventions for this debilitating condition. Bayesian predictive learning offers a formal computational perspective on how the brain processes and integrates incoming sensory information to form higher-level beliefs about the world. Abnormal predictive learning has emerged as a key candidate mechanism to explain core features of schizophrenia, including auditory hallucinations and impaired cognition. Notably, abnormalities occurring at different levels of the predictive learning hierarchy (i.e., low-level sensory perception vs. high-level beliefs about the state of the world) may differ in terms of their stability and their relationships to specific illness features (e.g., auditory hallucinations, impaired cognition). Building upon promising preliminary data and in alignment with the NIMH Strategic Plan, we will use an innovative electroencephalography (EEG) paradigm to characterize specific neural abnormalities associated with aberrant predictive learning in schizophrenia and relationships with specific illness features over time. Ninety adults with schizophrenia, 60 of whom experience active auditory hallucinations at the baseline assessment, will complete an EEG assessment of auditory predictive learning three times over a six-month follow-up period. Thirty non-psychiatric comparison participants will be assessed at baseline only. Stability of the EEG predictive learning indices and associations with auditory hallucinations will be assessed over the follow-up period. Leveraging the specialized scientific expertise and the extraordinary clinical research and participant recruitment infrastructure available at the University of Manitoba and the strong domestic scientific leadership and Veteran representation available at the Minneapolis VA, we anticipate that the project will contribute to the health of the American public by identifying key biological markers and clarifying our understanding of the pathophysiology of this debilitating mental health condition in order to support the development of new treatments.