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NIMH - National Institute of Mental Health

SeeMe: A multimodal behavioral-electrophysiological tool for real-time detection of motor behavior in brain injury patients Abstract An obstacle in clinical and basic science consciousness research is the lack of quantitative techniques to assess the recovery of voluntary behavior. Standard techniques for consciousness detection depend on subjective assessment of voluntary behavior. These methods are slow, observer-dependent, and lack the temporal resolution to study brain circuits supporting consciousness. In Phase R61 of this proposal, SeeMe, a novel, objective, real-time tool, will be developed to detect voluntary behavior. This multi-modal tool is based on the measurement of face and hand movements to command in recovering traumatic brain injury (TBI) patients who may appear unresponsive. SeeMe detects early signs of low-amplitude voluntary behavior currently unseen by clinical examiners. These detected movements will be linked with neural recordings to interrogate underlying circuits supporting voluntary behavior. This tool will be made freely available to researchers interested in consciousness and more generally studying brain-behavior relationships. Phase R33 will use SeeMe to time- lock vagus nerve stimulation to voluntary behavior in recovering TBI patients, analogous to its FDA-approved use in stroke. This framework will be used to study the neural correlates of voluntary behavior in TBI patients. When complete, this project will deliver 1.) a novel objective tool for analyzing voluntary behavior, 2.) a computational framework for synchronizing behavior with brain activity, and 3.) a closed-loop stimulation system to develop future neuromodulatory therapeutic approaches to facilitate the return of motor behavior after injury.

NIMH - National Institute of Mental Health

While several studies have characterized myeloid cells as the primary central nervous system (CNS) HIV reservoirs on long-term suppressive antiretroviral therapy (ART), significant knowledge gaps remain in understanding the role of CD4+ T cells in CNS reservoir seeding, viral persistence, and neuropathogenesis. The characterization, and ultimate eradication, of HIV persistence and neuroinflammation remain key goals of HIV research and defining the roles of T cells and their interactions with CNS cell populations driving these processes are essential. In this application, we propose to leverage our validated nonhuman primate model of HIV neuropathogenesis and persistence, our experience defining early CNS seeding, and past studies of T cell sequestration, to determine the impact of blocking T cell circulation during acute SHIV infection on the establishment of durable brain reservoirs. Our model of CNS persistence uses TF SHIV.D.191859 (SHIV.D), a CCR5-tropic virus that efficiently replicates in both CD4+ T cells and macrophages, and consistently infects the CNS, causes neuroinflammation, and persists through ART via long-lived myeloid reservoirs. Genetically barcoded SHIV.D has been validated in persistence experiments, enabling tracking of clonotypes across tissues over time. Our recent studies of barcoded SHIV.D-infected, ART-treated NHP have shown early seeding of the brain that persists through durable ART. Our team has also demonstrated in ART-suppressed SIV-infected rhesus macaques (RMs) that a clinically approved immunomodulating therapy for multiple sclerosis, FTY720, results in rapid and near-complete redistribution of CD4+ T cells from blood into peripheral tissues, with minimal impact on blood monocytes. Thus, FTY720-induced inhibition of T cell, but not monocyte, migration will enable us to dissect the specific role of CD4+ T cells in trafficking of SHIV to the brain and establishing short- and long- term brain reservoirs. RMs will be infected with barcoded SHIV.D and then treated with FTY720 either 1 week prior to infection (Arm 1), or 7 days post-infection (Arm 2), or left untreated (Arm 3). ART will be administered 1- month post-infection, with half of the animals in each arm to undergo necropsy early at 1 month ART, or later at 6 months ART. Arm 4 animals will be infected and receive FTY720 only and be necropsied at study month 2 to compare the effects of FTY720 without ART. In these coordinated NHP studies, we will test our hypothesis that FTY720-mediated inhibition of T cell migration to the brain will prevent early seeding of SHIV brain reservoirs, will limit the size and diversity of the persistent CNS reservoir, and will reduce neuroinflammation on suppressive ART. Using an array of molecular, immunohistochemical, and single cell analyses, we will assess the impact of peripheral CD4+ T cell sequestration on early and late SHIV brain reservoir seeding, then characterize the impacts on neuroinflammation and neurodegeneration. These studies will provide valuable insight into the role of CD4+ T cells in CNS reservoir seeding, including their contribution compared to monocytes, the timing of the reservoir establishment, and their contribution to neuroinflammation.

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

PROJECT SUMMARY According to a recent report by the Centers for Disease Control and Prevention, 60% of U.S. adults have reportedly had at least one early adverse experience (e.g., physical, emotional, or sexual abuse) with nearly 40% having two or more early adverse experiences. Extensive work has been done to uncover the mechanisms that link early adversity to mental health problems with self-regulation consistently emerging as a key contender. Self-regulation is consistently and highly heritable with its development facilitated by both biological and environmental processes. Importantly, the transition from middle childhood to early adolescence marks a critical period of growth in self-regulation. Attachment theory suggests that parents play an integral role in its development through shaping both the genetics and the environment of the child. Studies on the role of parenting in the development of self-regulation to date examine a single level and time scale at a time failing to capture the complex, multilevel nature of children's experiences of parenting that span from moment-to- moment interactions to consistent parenting styles and interplay between them. Dynamic Systems Theory (DST) further highlights this limitation by emphasizing the importance of examining multiple levels of a system across different timescales to fully conceptualize the complex developmental processes at play. Thus, the overarching purpose of the proposed project is to better understand the development of self-regulation across phenotypic and genetic levels and different timescales using the Arizona Twin Project, a large longitudinal study of racially/ethnically and socioeconomically diverse twins, across middle childhood and the transition to adolescence. To accomplish this, the current project has proposed three aims. First, we will examine the effects of moment-to-moment parenting behaviors on self-regulation in middle childhood. Second, we will investigate the effect of parenting behaviors on self-regulation longitudinally across middle childhood and the transition to adolescence. Third, we will elucidate the shared genetic and environmental etiology of parenting behaviors and trait-level self-regulation across middle childhood and the transition to early adolescence. By the end of my doctoral education, I want to develop an extensive expertise on parenting and self-regulation, quantitative methodology, and science communication to ensure that I am prepared for a multifaceted tenure-track career at a rigorous, research focused academic institution. My training objectives include: 1) gain an in-depth understanding of the role of parenting in the development of self-regulation; 2) obtain advanced training in quantitative methodology with a focus on intensive and long-term longitudinal data; 3) extend academic writing and communication skills to translating scientific information for the public. By accomplishing these training objectives in tandem with the proposed project, I will lay the foundation for my future work focused on improving individual, familial, and societal well-being.

NINR - National Institute of Nursing Research

ABSTRACT Intimate partner violence (IPV) poses significant social and health challenges, particularly affecting immigrant women who confront increased risk and adverse consequences. Chinese immigrants, the largest Asian ethnic group in the U.S., with over 4 million individuals, have received limited focus in existing IPV research and intervention efforts, despite a high prevalence of IPV reaching nearly 21% within the past year. They face substantial barriers to accessing IPV and mental health services, due to sociocultural factors such as stigma or shame, limited English proficiency, isolation from mainstream American society, unfamiliarity with available resources, and limited availability of linguistically and culturally appropriate services. Moreover, IPV’s substantial and well-documented effects on mental health further exacerbate the challenges faced by this population of women. However, there is a lack of culturally appropriate interventions that address these barriers while improving their acceptability and accessibility to address the mental health needs of abused Chinese immigrant women. To fill this gap, our proposed community-partnered intervention, Self-Compassion, Health, and Empowerment (SHE), adapts a structured safety and empowerment intervention while uniquely incorporating mental health elements, including relaxation and self-compassion meditation, to address abused Chinese immigrant women’s mental health needs. Leveraging mobile health technology, our intervention seeks to overcome barriers such as geographic dispersal, stigma, and privacy concerns that often hinder access to support. Our pilot randomized controlled trial (RCT) with 50 abused Chinese immigrant women has shown the feasibility and acceptability of the mobile-based SHE intervention, which forms the basis for this proposal of a fully powered two-arm RCT. The primary aim of the study is to test the efficacy of the mobile-based SHE intervention in improving mental health among Chinese immigrant women experiencing IPV and co-occurring symptoms of depression, anxiety, or posttraumatic stress disorder (PTSD). We will recruit 364 Chinese immigrant women and randomize them 1:1 to the intervention or attention control group. The 6-week SHE intervention consists of one phone session on IPV safety and empowerment and five weekly relaxation/self-compassion sessions via text. The attention control group will receive 6 weekly nutrition and health sessions, matched in delivery mode, timing, and contact frequency. We will compare the two groups for primary outcomes of depression, anxiety, and PTSD symptoms and the secondary outcome of IPV from baseline to 6-week, 3-month, 6-month, and 12-month follow-ups. Our findings will provide evidence for the application of the mobile-based SHE intervention to support the mental health needs of abused Chinese immigrant women. Our approach is innovative, and there is a high potential for scaling up the intervention to improve access to IPV and mental health support among Chinese immigrant women experiencing IPV.

NIMH - National Institute of Mental Health

Project Summary Mood disorders in adolescence are prevalent, disabling, and associated with future chronicity and severity of mood problems in adulthood, making this a developmental period in which effective early intervention is especially important. A critical common ingredient of many interventions for adolescent mood disorders is inter- session monitoring of behaviors and mood; such monitoring is used by patients and practitioners to support case conceptualization, identify patient-specific maladaptive behaviors, and evaluate treatment outcomes. However, adherence to inter-session monitoring is low among adolescents, undermining intervention effectiveness. To optimize and support delivery of effective interventions for adolescent mood disorders, we are in need of novel, low-burden strategies for monitoring behavior and mood. The proposed study aims to address this urgent need by validating and translating a novel smartphone-based intervention monitoring approach (Sensor-Based Intervention Monitoring, SBIM). Aims will be tested in an adolescent sample (n=33, ages 13-19 years) engaged in interventions for mood disorders through the Helen and Arthur E. Johnson Depression Center or the Child and Family Clinic at the University of Colorado Anschutz Medical Campus. Study participants will complete a baseline evaluation followed by an eight-week period of SBIM using smartphones to collect native digital sensors (e.g., GPS, accelerometer, log data of screen use, app use, call/text activity, and ambient light/sound) and ecological momentary assessment (EMA) of mood symptoms. Daily behaviors are measured by extracting behavioral features from digital sensors, and include sensor-based measures of behavioral activation, impulsivity, physical activity, social withdrawal, sleep/circadian disturbances, and goal-directedness. SBIM Reports, providing inter- session monitoring information about patient-specific behaviors, mood, and behavioral predictors of mood, are delivered to clinicians and patients biweekly. Clinicians and patients report on acceptability, appropriateness, and feasibility of SBIM, and treatment outcomes, biweekly. Aim 1 centers on rigorously validating SBIM, testing the predictive accuracy of personalized models and comparing personalized to general models. Aim 2 evaluates feasibility, appropriateness, and acceptability of SBIM for both patients and clinical providers, and Aim 3 tests convergent validity of SBIM with standard treatment outcomes. Exploratory Aim 4 explores subgroups to compare differences in SBIM outcomes between interventions (behavioral, medication management), diagnoses (unipolar, bipolar) and as a function of sex, age, or pubertal stage. Ultimately, we aim that this work will develop and validate a novel monitoring tool and explore translation to the clinic, providing a foundation for research that scales and investigates SBIM outcomes.

NIH

This is a Veteran’s Administration Career Development Award 2 proposal for Jessica M. Ross, Ph.D. entitled “Sensory Entrained Transcranial Magnetic Brain Stimulation (seTMS) for Major Depression.” The goal of this project is to study phase-aligned TMS (i.e. brain wave synchronized TMS) in Veterans, to enhance personalized neuromodulation and clinical outcome for the 60-80% currently not achieving remission while not increasing cost and burden. To bring phase-aligned TMS to Veterans, the PI developed Sensory Entrained TMS (seTMS), a clinic-ready augmentation therapy. The seTMS protocol uses music to synchronize brain waves during TMS, to deliver precisely-timed TMS when the brain is maximally excitable. seTMS operates within the guidelines of currently FDA-cleared protocols, does not require EEG or phase estimation algorithms, and is affordable and accessible because it only requires headphones and plug-and-play software that is compatible with existing equipment. This work will be a thorough investigation of seTMS for effective VA clinical use. The current study aims to 1) apply pulses of seTMS to the dlPFC in Veterans and compare brain changes (target engagement in electroencephalography, EEG) to those from standard pulses of TMS; 2) apply seTMS to the dlPFC in Veterans with depression and compare target engagement to those from standard pulses of TMS; 3) treat MDD with an accelerated form of seTMS (se-aTBS) or standard a-TBS to compare symptom reduction and long-term target engagement (lasting brain changes). Symptoms will be measured using standard clinical scales, administered during the first visit (Day 0), during the last visit following TMS, and at 1-month post-treatment. These scales are the Montgomery-Åsberg Depression Rating Scale (primary) and Columbia Suicide Severity Rating Scale (secondary), and the standard scales collected routinely in the Palo Alto MIRECC Precision Neuromodulation Clinic: Patient Health Questionnaire (PHQ-9), the Brief Symptom Inventory 18 (BSI-18), PTSD Checklist for DSM-5 (PCL-5), Beck Scale for Suicidal Ideation (BSSI), Generalized Anxiety Disorder 7-item (GAD-7), and the 36-Item Short Form Survey (SF-36) Health Survey. The PHQ-9 and GAD-7 will also be given to the Veterans on each day of treatment (Days 1-4) after the last protocol of the day. Perceptual ratings of scalp feeling and pain will also be recorded to assess tolerability and feasibility in Veterans. The overarching research hypothesis is that seTMS will enhance prefrontal circuit changes in non-depressed and depressed Veterans and improve clinical outcomes when used for treating Major Depression (MDD) while being feasible for clinical use. The specific hypotheses are that 1) seTMS will enhance TMS-induced brain changes in Veterans and 2) Veterans with MDD and 3) the se-aTBS treatment protocol will lead to greater reduction of clinical symptoms than standard aTBS, and be feasible and tolerable, in Veterans with MDD. This CDA-2 award would allow Dr. Ross to gain proficiency in 1) theory and models of brain plasticity in Veteran clinical populations, 2) traditional and innovative clinical design, 3) adaptive and personalized TMS methodologies, and 4) professional development for a career at the VA. Training and research for the project will be conducted at both the VA Palo Alto Health Care System (VAPAHCS) as part of the Mental Illness Research, Education and Clinical Center (MIRECC) and Stanford University School of Medicine, in the Department of Psychiatry and Behavioral Sciences. Both sites offer excellent intellectual and physical resources to complete the proposed work. SeTMS is a novel intervention that harnesses principles of sensorimotor neuroscience and has the potential to increase the efficacy of FDA-cleared TMS protocols without increasing cost for Veterans with Depression.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Challenges in executive functioning (EF) are highly prevalent in autism; however, profiles of EF vary greatly. Challenges in both “cool,” logical skills, such as working memory and planning, and “hot,” state-dependent skills, such as inhibition and emotional regulation, have been implicated. For both non-autistic and autistic individuals, EF predicts a myriad of key functional outcomes including adaptive behavior, academic success, and mental health. There is burgeoning evidence that EF serves as an underlying mechanism for the development and maintenance of mental health outcomes as well as the heterogeneity inherent to autism. Mental health and EF represent (1) two key drivers of quality of life in autism, (2) are endorsed by autistic people as a high priority for research and intervention, and (3) are tangible and frequent targets of personalized intervention approaches. As such, understanding distinct profiles of EF, the developmental course of EF, and how EF challenges vary as a function of key variables such as sex and age is a promising step towards individualized, actionable intervention across the lifespan. Data driven approaches have been promoted in autism to understand heterogeneity across constellations of traits, yet extant work has not been sufficiently powered to examine the unique and intersecting impact of sex, age of diagnosis, and chronological age on EF. The proposed project will adopt a data driven approach (Latent Profile Analysis–LPA) to parse the heterogeneity of EF across development (4 to 25 years), spanning critical developmental periods where EF development is rapid. In Aim 1, we will use multi-group LPA to identify profiles of EF in a large sample (N = 724) of autistic and non-autistic individuals, equally split on sex and diagnosis. Profile modeling will be based on 5 subscales from a caregiver-reported EF measure (Behavior Rating Inventory of Executive Functioning). In Aim 2, we will determine how profiles of EF vary as a function of age, sex, and age of diagnosis in our autistic cohort. In Aim 3, we will conduct exploratory analysis to examine how EF profiles predict internalizing behaviors in both cohorts. We hypothesize 3 profiles will emerge in each cohort, with the following profiles in the autistic cohort: (A) challenges across all EF domains, (B) challenges in shifting, working memory, and planning, and (C) challenges in emotional regulation and inhibition. We anticipate our variables of interest, including age, sex, and age of diagnosis, will differentially predict profile membership in line with existing literature. Identifying these profiles can (1) inform educational and therapeutic approaches, (2) promote autonomy and well-being for autistic individuals, and (3) elucidate the mechanisms by which EF challenges contribute to mental health across key developmental windows. Training aims include advancing Ms. Russell’s understanding of EF and its relationship to clinical outcomes, enhancing her statistical skills by training in data-driven approaches, and expanding her experience working with data from autistic adults. These aims will support Ms. Russell establishing herself as an expert within the field of autism phenotyping.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The overarching scientific goal of this mentored career development award is to elucidate sex differences in striatal cholinergic (CINs) and parvalbumin-expressing fast spiking interneurons (FSIs). Interneuron disruption is implicated in many neuropsychiatric disorders, including several, such as Tourette Syndrome (TS) and autism, that show marked male-female differences in prevalence. Postmortem studies reveal deficits in both CINs and FSIs in TS. Recapitulating this abnormality in mice produces abnormal stereotyped grooming and social deficits, but only in males. A better understanding of how interneurons differ between sexes may provide insight into the causes of these disparities in prevalence and presentation. We have recently published a careful anatomical analysis documenting differences in interneuron number and distribution between male and female mice. Here, Dr. Meghan Van Zandt will characterize structural, functional, and molecular differences in striatal interneurons in males and female mice. Aim 1 will determine whether gonadal or genetic mechanisms underlie sexual dimorphism in striatal CIN and PV density and distribution that we have recently documented, using the four-core genotype mice; we hypothesize that hormonal/anatomical sex will determine interneuron properties. Aim 2 will examine anatomical and molecular properties of interneurons in males and females, using 3D reconstruction to compare morphology (2A), anterograde and retrograde synaptic tracing techniques to analyze interneuron networks (2B), and single-nucleus RNA seq to examine gene expression specific to both CINs and FSIs (2C); we hypothesize that interneurons in the dorsal striatum will exhibit stronger synaptic connectivity in females, compensating for their lower number. Aim 3 will analyze the population activity of striatal interneurons during spontaneous behaviors using fiber photometry in males and females, including analysis of females in different estrus phases. Dr. Van Zandt intends to pursue a career investigating sexual dimorphism in the pathophysiology of neuropsychiatric disease. This career development award will provide her with advanced training critical to her career goals, with mentorship and didactics in anatomical techniques, transcriptomic analysis, and fiber photometry. In addition, her senior mentorship team will support her development as an independent scientist, through ongoing training in writing, presentation, teaching, ethics, professionalism, and networking – and, in the later years of the award, through active support of her search for an independent research and teaching position. Together, this experimental and training plan will provide a strong foundation to prepare her for a career as an independent researcher and a mentor to young scientists in her own right.

NIMH - National Institute of Mental Health

Project Summary/Abstract This proposal focuses on the fundamental sex differences in the vulnerability to acute traumatic stress (ATS) and the role of the sex hormone estrogen, and signaling via sex-specific hippocampal receptors, in the enduring memory problems that follow ATS. It is now recognized that acute traumatic events (e.g., mass shooting, earthquakes) may provoke enduring disturbances of hippocampus-dependent memory, and that these problems are more common in women. We leverage robust preliminary data to probe why males, and females at different phases of the estrous cycle, differ in their vulnerabilities to ATS, what these differences are and the mechanisms that drive them. This information will provide important targets for promoting resilience to ATS. We find ATS causes memory disturbances in male (♂) and proestrous female (♀) but not estrous ♀ mice, and the deficits are long-lasting only in proestrous ♀. ♂ and ♀ differ in numerous measures, including in levels of hippocampal estrogens: ♂ and proestrous ♀, both vulnerable to ATS, have high levels of hippocampal estrogen compared with estrous ♀. Estrogen acts via several receptors (ERs) and its enduring effects are thought to result from interactions of ERα or Erβ with the chromatin. Leveraging robust preliminary data we will (1) Test whether ATS-induced memory disturbances require ERα in ♂ and, in contrast, Erβ in ♀ (Aim 1). (2) establish if sex- and Estrogen-level dependent vulnerability to ATS in ♂ and proestrous ♀ mice is a result of sex and hormone-dependent hippocampal chromatin states, which elicit distinct transcriptional programs upon exposure to ATS (Aim 2). (3) use focal conditional ER deletions to test whether the unique vulnerability of proestrous ♀ to persistent ATS-induced memory disturbances results from activation of distinct transcriptional targets of ERβ in ♀ hippocampus. Together, the expected discoveries will illuminate the mechanisms for the fundamental sex differences in vulnerability to enduring trauma-induced memory disturbances and will offer targets for mitigation.

NIMH - National Institute of Mental Health

Project Summary/Abstract The purpose of this project is to provide a train-the-trainer program in machine learning and emerging artificial intelligence (AI) technologies – such as generative AI and large language models – for early, mid-career, and senior scholars in the social and behavioral sciences. The rapid growth of available data, computing capacity, and powerful AI models has the potential to reshape how research is conducted in social science domains relevant to health, including population health, population dynamics, child and adolescent development, and health economics. Although machine learning and related methods have been used increasingly, their adoption in the social sciences is being outpaced by the development of emerging AI technologies, such as generative AI. Within the social sciences, pedagogy for emerging AI methods remains largely undeveloped, leaving a gap in formal training infrastructure. There is a pressing need for cutting-edge, scalable training programs that not only equip researchers to use these technologies but also establish replicable models for instruction across institutions grounded in novel pedagogical strategies. The proposed program consists of a series of 8-week, remote summer workshops designed to equip trainees to use machine learning and emerging AI technologies in their own research. The curriculum will be structured to prepare trainees to offer their own versions of the course, magnifying the program’s impact beyond its immediate participants. Trainees will not be expected to have prior programming experience. The course will build on our wealth of experience in developing remote data science training programs across the social and behavioral sciences. The course will begin with an introduction to the Python programming language, emphasizing a data science perspective. Participants will then explore advanced topics such as machine learning, large language models, and generative AI, with an emphasis on integrating these technologies into research workflows and building practical fluency in computational tools. Practical skills, such as use of the command line, version control, and cloud computing will also be covered. The workshops will take an active learning pedagogical approach, utilizing a flipped classroom that combines pre-recorded content with live sessions focused on coding exercises, applied examples, discussion, feedback, and formative assessment. Trainees will develop their own projects, with mentorship and consulting support from program staff, which will continue beyond the formal course period. Each course will also feature a slate of guest speakers discussing innovative health research that leverages machine learning to generate new knowledge. The program will culminate in an in-person conference where participants will meet, present their work, and build future collaborations. To facilitate trainees’ future use of these methods in both research and teaching, the project will openly disseminate all curricular and pedagogical materials, including syllabi, computational notebooks, videos, and lesson plans. Overall, this program will build a sustainable and resilient foundation for integrating emerging AI into social science research and teaching.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Suicide is a leading cause of death among adolescents, and the developmental period of adolescence often marks the first onset of suicidal thoughts and behavior. Suicidal thoughts fluctuate dynamically over brief periods of time (e.g., hour-to-hour, day-to-day), creating critical proximal windows to better understand suicide risk. Prominent theoretical models and empirical research on suicide have largely focused on adult samples and predicting suicide risk over the course of months, years, or lifetimes. However, limited research has examined dynamic, developmentally salient processes that underlie the occurrence of suicidal thoughts during adolescence. One such developmentally salient process is identity development, in particular, identity exploration. Identity exploration has been demonstrated to fluctuate daily and predict increases in negative mood. Identity exploration has traditionally been conceptualized as an offline process; however, social media use is nearly ubiquitous among adolescents, perhaps changing the medium through which identity exploration occurs. The unique features of social media, including the publicness of content and quantifiability of social feedback, may amplify the effects of social media identity exploration experiences on psychopathology in comparison to offline identity exploration. Although previous research has identified that negative social media identity exploration experiences (e.g., engaging with self-injury related content for the purpose of identity exploration) are associated with suicidal ideation cross-sectionally, there is a dearth of research examining proximal relationships between positive and negative social media identity exploration experiences and suicidal thoughts. Identity functioning is a transdiagnostic construct longitudinally linked to suicide risk and proximally associated with other forms of self-injury. Self-concept clarity is a dimension of identity functioning that develops during adolescence and may be particularly implicated in suicidal thoughts. Understanding the short-term associations between self-concept clarity and suicidal thoughts can provide another developmentally salient target for suicide prevention. Furthermore, examining the short-term, bidirectional feedback between self- concept clarity and social media identity exploration experiences and this feedback loop’s effect on suicidal thoughts can provide critical insight into how social media effects adolescent development and suicide risk in real time. The current study will use intensive longitudinal monitoring to understand the relationship between social media identity exploration experiences, self-concept clarity, and suicidal thoughts in a community sample of 70 adolescents ages 14-16 recruited from social media platforms and the community. Participants will respond to questions 4x/day for 28 days. The goal of this research is to understand the relationship between these developmentally salient processes and suicidal ideation as they unfold in real-time and provide critical targets for intervention to support adaptive adolescent development and prevent suicide.

SHRM Foundation

Supports workforce development, workplace inclusion, mental health at work, and programs advancing HR management excellence.

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.