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NIMH - National Institute of Mental Health

The onset of psychotic symptoms usually occurs in young people and 80% of those developing psychosis live in low and middle-income countries (LMICs). In LMICs, 90% of people with mental disorders are cared by families, and duration of UP is twice that in high-income countries (HICs). A longer duration of untreated psychosis (UP) is associated with poorer treatment response, high suicide rates, premature death, and greater disability and caregiver burden. No studies have examined Early Intervention Services (EIS) for young people in LMICs with new-onset, non-substance-induced, affective and non-affective UP. Coordinated Specialty Care [CSC] programs were developed in HICs to offer EIS that combines medication management and evidence- based psychosocial interventions to reduce duration of UP, symptoms, relapse, treatment discontinuation and hospitalization, and improve social and occupational functioning. Challenges to CSC programs' implementation in HICs ( e.g., inadequate community-based detection, high rates of disengagement, and scant infrastructure ) can be addressed through t echnology-based screening, community-based participatory services design, and enhanced mental health (MH) resources, all of which we are poised to apply in Mozambique, through our established partnerships, MH services infrastructure, and ongoing work. In Mozambique, the 4th poorest country in the world and with 40% of the 34 million inhabitants aged 15-24 years, psychotic disorders are the leading Since 2014, we have had a productive partnership among local and global researchers, the Mozambique Ministry of Health (MoH), providers, traditional healers, and community health committees at 64 rural primary care clinics. Together, we are implementing a novel patient-centered decision-support Mental Wellness Digital Platform (mWell) comprising (a) community-based detection with a brief, valid household screening tool, the Mental Wellness Tool (mwTool); (b) evidence-based care for common mental and substance use disorders, and suicide risk, (c) guidance for cause of inpatient admissions and the second reason for outpatient psychiatric care. diagnosis of severe mental disorders, and (d) psychotropic medication management. mWell also tracks implementation, services, and clinical outcomes. More than 1,200 community health workers (CHWs) and MH and primary care providers (PCPs) in Mozambique have adopted mWell as the new community MH “usual care” where care was absent. MH providers and PCPs use mWell's digitized diagnostic and medication decision aid to treat people with psychosis and to offer some rehabilitation services. Yet, a comprehensive evidence-based EIS program like a CSC does not exist. Our multi-sector partners in Mozambique have prioritized building capacity and integrating CSC interventions into mWell to develop and implement mWell-CSC country-wide. To respond to this critical mandate we will adapt CSC, create the digital decision-support platform mWell-CSC, develop strategies for implementation, and examine mWell-CSC implementation, services, and patient-level outcomes using a quasi-experimental design and mixed-methods evaluation to inform a future RCT.

NHLBI - National Heart Lung and Blood Institute

Project Summary Dr. Shah is a clinician-scientist with a focus on cardiovascular disease (CVD) heart-brain mechanisms and digital biomarkers, aiming to address the critical intersection between psychological stress and autonomic health. This K24 Mid-Career Investigator Award will support Dr. Shah in expanding research on sympathetic nervous system (SNS) activity and its role in both CVD risk and mental illness. This award will also provide resources to mentor junior clinical investigators and public health students in these areas. It will also provide Dr. Shah with the necessary training in advanced signal processing and analytics to work collaboratively with his various engineering collaborators. Dr. Shah has a strong record of mentoring trainees and contributing to cardiovascular research programs at Emory University, including the NHLBI-funded T32 training grant on cardiovascular health disparities. The mentorship component will focus on the design and execution of patient- oriented research projects in stress physiology and wearable technology, as well as on fostering independence in trainees pursuing careers in cardiovascular research. The study will leverage ongoing studies including Smart Health and Rehabilitation Technology (HEART) which will involve enrolling 300 veterans in cardiac rehabilitation and the Myocardial Infarction and Mental Stress 3 (MIMS3) cohort (R01 HL109413), which includes 306 post-myocardial infarction (MI) participants who underwent mental stress provocation with ECG monitoring and long-term follow-up. Specifically, Dr. Shah and his engineering collaborators will perform innovative analysis of the multi-channel ECG to examine periodic repolarization dynamics (PRD), a novel ECG-based biomarker of SNS activity that measures the low frequency spectral power of beat-to-beat changes in the spatial T-wave axis. The specific research aims of this project are: (1) to evaluate changes in PRD in response to mental stress and after therapeutic lifestyle modification; (2) to assess the association of PRD with mental health conditions, including depression and post-traumatic stress disorder (PTSD); and (3) to examine the relationship between PRD and long-term CVD outcomes, such as heart failure, myocardial infarction, and CVD-related mortality. This award will enable Dr. Shah to continue developing innovative research on digital biomarkers and autonomic health, while strengthening the mentorship pipeline for cardiovascular research. This will ultimately contribute to preventing adverse cardiovascular outcomes through both scientific discovery and the development of future investigators.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Overview. This K24 Mid-Career Patient-Oriented Investigator Award application proposes to support mentoring of junior investigators to apply implementation science to improve TB treatment outcomes and reduce long-term TB-associated disabilities among persons with and without HIV, with direct relevance to U.S. TB programs and high-risk populations. Candidate. Dr. Davis is a clinical epidemiologist and practicing pulmonary/critical care physician, Director of Educational Programs at the Yale Center for Methods in Implementation and Prevention Science (CMIPS), and Associate Professor of Epidemiology and Medicine at Yale University. His research develops and evaluates innovative strategies to improve TB diagnosis, treatment, and prevention in settings where HIV is co-prevalent. He conducts observational, mixed-methods, randomized, and quasi-experimental studies in the U.S. and internationally. Dr. Davis has been continuously NIH-funded since 2006 (F32, K23, and multiple R21, R01, and D43 awards) and has authored >170 peer-reviewed publications, including >60 as first or senior author. He has mentored >50 students, fellows, and junior faculty and served as the senior author on >40 trainee publications. His research on TB diagnostics and case-finding has advanced the field of implementation science, improved clinical and public health outcomes, and informed TB guidelines, policies, and practices endorsed by policymakers in the US and partner countries. He is committed to advancing implementation science by mentoring the next generation of global health investigators to improve the health of Americans in the U.S. and abroad. Mentoring Plan. Dr. Davis is PI of an NHLBI R01-funded, cluster-randomized implementation trial of TB adherence strategies and is Associate Director of a Fogarty D43 research training program. These roles provide a strong platform for recruiting and mentoring junior investigators in patient-oriented implementation research to improve short- and long-term TB treatment outcomes. Over the award period, he will provide structured career development and implementation science mentoring to 20 junior investigators and strengthen durable training pathways at US and partner institutions to build a cadre of researchers prepared to improve population health outcomes, reduce costs, and increase satisfaction. Research Plan. Dr. Davis will expand his research and mentoring program to address TB-related disabilities. He will introduce systematic screening for mental health conditions, respiratory impairment, and exercise intolerance among people with TB (with and without HIV) using validated instruments. He will adapt and pilot peer-facilitated rehabilitation strategies and evaluate their feasibility, acceptability, and appropriateness to inform future trials and implementation. This work will generate rigorous preliminary data and practical strategies to improve post-TB care through mentored research aligned with NIH priorities.

NCI - National Cancer Institute

Project Summary Sleep disturbances are highly prevalent among cancer survivors, with rates over 50% reported among breast, prostate, and colorectal cancer survivors.1-3 Sleep disturbances are associated with a range of negative effects on physical and mental health and quality of life.4 High rates of sleep medication use among survivors lead to a range of secondary harms (e.g., fractures, increased mortality).5-7 The underlying mechanisms of sleep disturbance among survivors are multifaceted with cancer and cancer treatment affecting the interplay between psychological (e.g., mood, cancer-related worry, beliefs about sleep), behavioral (e.g., sleep and activity), and physiological (e.g., increased inflammation) factors that influence sleep.8-11 Cognitive behavioral therapy for insomnia (CBT-I) is considered a first line treatment for the general population and survivors,12-17 but access to trained professionals is severely limited.18 Digital delivery of CBT-I (dCBT-I) using internet or mobile technologies has the potential to provide broader access at lower costs.19-21 There is a critical need to assess the efficacy of mobile dCBT-I that is designed for cancer survivors. Our Mi Sleep Coach app is the first to employ survivor-centered design features (e.g., unique human-digital agent interaction to extend the cancer care team, motivational interviewing to address perceived loss of control after cancer diagnosis, just-in-time behavioral activation to modify cancer treatment-related coping behaviors that may interfere with sleep) to deliver core CBT-I strategies. Pilot study results demonstrate high levels of program engagement, highly positive effects on insomnia, markedly reduced use of sleep medications, and specific associations between greater engagement with survivor-centered design features and better sleep. The purpose of this proposal is to rigorously assess the efficacy of the Mi Sleep Coach app. We propose a single-blinded RCT comparing Mi Sleep Coach app to a sleep education attention control app over a 7-week period with a 6-month follow-up. We will enroll a sample of 270 patients who have completed active treatment for breast, prostate or colorectal cancer in the NCI-funded National Clinical Trials Network. The primary outcome is insomnia severity. Secondary outcomes include reduction in the use of sleep medications and regulation of the neuroendocrine-inflammatory axis. Our research team, which has expertise in cancer clinical trials, sleep disorders, digital health, inflammatory markers, and biostatistics, is well positioned to pursue the following specific aims: Aim 1: Evaluate the efficacy of the Mi Sleep Coach app as compared to a sleep education control app to decrease insomnia as measured by the change in the Insomnia Severity Index (ISI). Aim 2: Evaluate the efficacy of the Mi Sleep Coach app as compared to a sleep education control app to decrease self-reported use of sleep medications from baseline to the end of intervention at 7 weeks. Aim 3: Examine mechanisms of intervention effect by assessing function of the neuro-endocrine-inflammatory axis as measured by the downregulation of pro-inflammatory gene expression.

Michigan Department of Health and Human Services

MDHHS funds nonprofits, local health departments, and community organizations providing public health, mental health, substance use treatment, child welfare, and social services to vulnerable Michigan residents.

NIEHS - National Institute of Environmental Health Sciences

PROPOSAL SUMMARY/ABSTRACT Global annual plastic production has grown significantly over the years, and plastic products are embedded in many facets of our daily lives. Microplastics (MPs) are small (< 500 mm) particles created during the breakdown of plastic materials. MPs are emerging as a significant environmental and public health risk due to their constant presence and consumption. Studies have shown that MPs consumed on a daily basis are known to distribute into multiple organ systems and illicit host-dependent responses, such as inflammation. MPs of various sizes are known to disrupt the intestinal barrier and promote tissue-dependent inflammation (e.g. neuroinflammation), leading to adverse events such as alterations in behavior linked by the gut-brain axis (GBA). In the current application, we propose conducting studies to determine how MP consumption impacts an animal model of inflammatory bowel disease (IBD). IBDs, such as ulcerative colitis (UC), refer to states of chronic inflammatory conditions in all or part of the gastrointestinal (GI) tract which results in increased intestinal permeability or “leaky gut”. IBDs such as UC are known to have extraintestinal manifestations (EIMs) such as alterations in mood or behavior, including development of depression. While growing research suggests that MP consumption can damage the GI barrier and distribute into various tissue/organ systems to promote inflammation, there are currently very few studies which focus on how MP consumption might impact an already weakened intestinal barrier due to colitis. The purpose of this application is to address this current unknown and generate preliminary data with the following specific aims: 1.) Assess depression-like behavior in a murine model of IBD after exposure to varied sizes of MPs; 2.) Develop a novel method for the quantification and visualization of MP localization in an IBD murine model. In order to complete these aims, this application proposes to test how consumption of MPs of varied sizes impact the dextran sodium sulfate (DSS) mouse model, a UC-like IBD animal model. In the first aim, we will test how MP consumption impacts colitis-associated depressive-like behavior and biomarkers of neuroinflammation. In the second aim, using the same model, we will next incorporate the use of tissue clearance and light sheet fluorescence microscopy (LSFM) to visualize and quantify biodistribution of MPs in various organs during an active colitis state. Results from these studies will help us better understand if MP consumption exacerbates colitis and colitis-related EIMs such as depression development and inflammation induced by deposition into other organs due to enhanced breakdown of the intestinal barrier.

NIMH - National Institute of Mental Health

Project Summary Schizophrenia (SZ), a major chronic psychiatric illness, is characterized by psychotic symptoms, negative symptoms (e.g., lack of motivation, social withdrawal), cognitive deficits, and impaired social and occupational functioning. Despite advances in understanding the illness, diagnosis still relies on psychiatric interviews and the exclusion of medical or substance-induced psychosis. Likewise, treatment response, typically taking several weeks, is assessed via interviews without reliable biomarkers to guide treatment decisions. This lack of clinically relevant biomarkers represents a significant gap in the field. MicroRNAs (miRNAs), small non-coding RNAs crucial for gene expression regulation, can target hundreds of messenger RNAs and have been implicated in complex diseases like schizophrenia. MiRNA dysregulation in schizophrenia has been demonstrated in genome-wide association studies, human post-mortem brain tissue analyses, and biological fluid studies. Most miRNA studies in biological fluids related to SZ have focused on miRNAs in blood, either as circulating free cell or within peripheral blood mononuclear cells. A new approach being tested in depression and other neurological illnesses involves measuring miRNAs contained in neural-derived extracellular vesicles (NDE) isolated from plasma. NDEs, isolated using brain-specific surface markers, carry an enriched cargo of brain-predominant miRNAs, offering a less invasive window into central nervous system processes. This study will investigate plasma NDE miRNAs as diagnostic and treatment response biomarkers in first-episode schizophrenia (FES) using two approaches. The first approach involves a mechanistic clinical trial with first- episode schizophrenia (FES) participants. This population was specifically chosen to minimize confounding effects associated with prolonged antipsychotic exposure and extended illness duration. Aim 1 will compare plasma NDE miRNA profiles between 80 acutely psychotic FES participants before initiation of controlled treatment and 80 healthy volunteers. Aim 2 will assess baseline and change scores of plasma NDE miRNAs as predictors of response to 12 weeks of controlled treatment with aripiprazole or risperidone. Our second approach will leverage our participation in the Psychiatric Biomarkers Network (PBN), a multi-site consortium focused on fluid biomarkers in psychosis spectrum disorders. We will analyze blood and cerebrospinal fluid (CSF) samples from 60 early-phase schizophrenia participants and 60 healthy volunteers from the PBN to validate our findings in an independent sample and correlate plasma NDE miRNAs with CSF extracellular vesicle miRNAs (Aim 3). This will assess the ability of NDE miRNAs to reflect central nervous system abnormalities as measured in CSF. Successful completion of these aims will provide preliminary evidence for the utility of plasma NDE miRNAs as biomarkers in schizophrenia, paving the way for future refinement, validation, and clinical implementation.

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

PROJECT SUMMARY Concussion and mental health are two significant public health problems disproportionately affecting youth. Con- cussions can severely impact developing brains and are potentially linked to mental health issues like anxiety, depression, and suicidality. Early detection of at-risk youth using artificial intelligence and machine learning (AI/ML) techniques is crucial for timely referrals and treatment. However, current AI/ML models often rely solely on structured electronic health records (EHR) data, neglecting other data types like unstructured clinical notes or wearable sensor data from nonclinical settings. Additionally, many models lack human-centered AI design principles, resulting in rapid abandonment by end-users during deployment. To address these gaps, we have assembled an interdisciplinary team to develop a multimodal AI-based data collection system, MindGuard (Aim 1), use MindGuard to collect multimodal nonclinical data from youth concussion patients aged 11-17 in home settings (Aim 2), develop and evaluate a risk prediction model for post-concussion mental health sequelae using large-scale EHR and MindGuard-collected small-scale nonclinical data (Aim 3), and create and evaluate a hu- man-centered AI system with an explainable risk prediction dashboard to support clinicians decision-making (Aim 4). Our long-term goal is to prevent mental health sequelae and aid concussion recovery in youth. We will use a large EHR dataset of approximately 20,000 youth concussion patients aged 11 to 17 from Nationwide Children’s Hospital (2013-2025). This dataset will be linked to unstructured clinical notes, SDoH, and small-scale multimodal nonclinical data collected prospectively using MindGuard. MindGuard includes data from wearable and smart speaker devices used by 150 youth concussion patients aged 11 to 17. We will use the linked full data to develop and evaluate an AI/ML predictive model for mental health sequelae post-concussion and create an interactive dashboard for clinicians. The main study outcomes will be measured as diagnoses of mental health disorders and self-harm. This project is significant as it addresses two major public health issues affecting youth. It is innovative in its use of wearable sensors, large language model (LLM)-based voice interactions, prospec- tively collected multimodal patient data, advanced AI/ML techniques, and an interactive decision support dash- board. The findings will have a substantial impact by facilitating early detection and timely treatment for at-risk youth to mitigate the risk of mental health sequelae among youth with concussion.

Minnesota Department of Human Services

MN DHS funds nonprofits, tribal nations, and community organizations providing mental health, substance use treatment, disability services, child welfare, economic assistance, and social services to vulnerable Minnesotans.

NIMH - National Institute of Mental Health

Project Summary Psychosocial stress in childhood is a prominent risk factor in the development, severity, and outcomes of internalizing disorders. Stress may impact pediatric mental health by disrupting homeostatic pathways, such as sleep and energy metabolism that can be indexed using mitochondrial biomarkers. Mitochondria, with broad roles in cellular energy and metabolic homeostasis, may contribute to stress-associated physiological wear and tear and serve as a target for intervention in children with internalizing disorders. Mitochondrial DNA (mtDNA) contains unique inflammatory and cell-signaling properties and is actively released as cell-free mtDNA (cf- mtDNA) in response to psychosocial stressors, promoting inflammation and oxidative damage. Levels of cf- mtDNA appear to fluctuate across days and throughout the day and may have a circadian rhythm. Importantly, pervasive disturbances in sleep are observed in both severe stress and mental health disorders and sleep impairment interferes with mitochondrial maintenance. Recent preclinical work indicates that sleep is required for homeostatic oxidative recovery of mitochondria and emerging clinical research demonstrates that circadian disruption is associated with dysregulation of cf-mtDNA. Taken together, this work suggests that stress- induced changes in mitochondrial signaling may contribute to physiological dysfunction and symptoms, potentially due in part to stress effects on sleep. Quantification of cf-mtDNA is now accessible through saliva and may hold promise as a robust biomarker of the dynamic effects of stress and behavior on psychiatric symptoms. The proposed study will recruit N=60 children ages 9-12 with internalizing disorders from a day hospital program. At the time of admission, children and caregivers will each provide baseline assessments of cumulative stress history, sleep disturbances and behavioral health symptoms over the past month, and assessment of a range of internalizing and externalizing symptoms. Following recruitment, children and caregivers will provide daily diary assessments of stress exposure, sleep, and symptoms, and salivary samples assessed for cf-mtDNA across two weeks. This study will 1) characterize baseline cross-sectional associations of levels of cf-mtDNA with cumulative early life stress, baseline sleep disturbances, and baseline internalizing symptom severity and 2) examine daily fluctuations of cf-mtDNA in association with daily stressors (type, severity, and timing), sleep (duration, timing, regularity and quality), and mental health symptoms. By investigating stress-associated mitochondrial processes and sleep in children with psychopathology, this study will yield clinically relevant information, consistent with NIMH Strategic Plan Strategy 2.2, to identify mechanisms of risk to guide the development of novel treatment targets for children with acute psychiatric pathology. Further, data from this study will be used to inform an R01 application investigating cf-mtDNA and additional mitochondrial indices and inflammatory targets in a larger, more definitive study of children with internalizing disorders.

NIMH - National Institute of Mental Health

The training and research plans described in this K23 Career Development Award will enable Dr. Kunmi Sobowale to achieve his long-term career goal of becoming an independently-funded investigator using mobile device technologies to facilitate screening, risk stratification, and personalized prevention and treatment for perinatal and infant mental health. To accomplish this goal, Dr. Sobowale aims to 1) Develop proficiency in the design of longitudinal studies and the statistical methods and skills to process and analyze intensive longitudinal data with a focus on mobile technologies; 2) Develop competence in signal processing and the methods of feature selection, and in particular the application of these methods to speech acoustic analysis; 3) Develop skills in research methods to assess the parent-child interaction and emotion regulation in early childhood. UCLA provides a rich environment for this training plan with a combination of didactic support and hands-on mentorship from leaders in depression neurobehavioral phenotyping, longitudinal study design and analysis, mobile health research, and child socioemotional development as well as the caregiver-child interaction in clinical and non-clinical populations. The training goals will be supported by and applied to the proposed research study. The objective of this longitudinal study of mother-infant dyads is to use mobile sensing devices (audio recorders and Bluetooth sensors) to enable daylong naturalistic assessment of the mother-child interaction. The focus will be mother-infant conversational turns, a key indicator of interaction quality, that are negatively affected by postpartum depression. The study will examine, in turn, how conversational turns affect child emotion regulation and, finally, will explore whether conversational turns are associated with mother-infant co-regulation and relationship quality. Aim 1 of this prospective longitudinal study investigates whether maternal postpartum depressive symptoms at 6 weeks are associated with conversational turn consistency at 3 and 6 months postpartum. Aim 2 examines whether conversational turn consistency at 3 and 6 months is associated with mother-reported child emotion regulation and whether it moderates the effectiveness of infant use of regulation strategies on distress (i.e., emotion regulation) during the still-face paradigm at 6 months postpartum. Aim 3 examines the association between conversational turn consistency at 3 and 6 months with observed mother-child co-regulation (mother-infant affect matches during the still-face paradigm) and mother-reported relationship quality at 6 months. This proposal is aligned with the National Institutes of Mental Health Strategic Objective to develop and assess novel mobile technology and digital health tools to enable objective measurement of behavior and intervention effects on symptom expression and functional outcomes in naturalistic environments. Ultimately, this sensor-based approach will facilitate large-scale assessment of the maternal-child interaction for screening and risk stratification and inform parent-child interventions for mother-infant dyads in the context of maternal postpartum depression.

NIMH - National Institute of Mental Health

Mobility is a well-recognized antecedent of HIV care disengagement in South Africa, but more research is needed to understand how different types and patterns of mobility impact HIV care continuity among marginalized populations like female sex workers (FSW), who experience suboptimal antiretroviral therapy (ART) adherence and viral load suppression. Emerging evidence indicates that everyday mobility, or day-to-day movements within a contained geographic area, may be a more prominent driver of HIV care discontinuity than cross-jurisdictional mobility (typically associated with internal migration) among FSW, but these mobility dynamics and their impacts on HIV self-management and treatment-seeking remain understudied. This four-year K01 Mentored Research Scientist Development Award will facilitate the multidisciplinary training and mentorship of Dr. Joseph G. Rosen (a social and behavioral HIV prevention scientist whose scholarship has historically focused on people who use drugs), facilitating his transition to independent research that develops and tests implementation strategies to optimize HIV care continuity among mobile and displaced populations. Under the primary mentorship of Dr. Susan Ramsey, a clinical psychologist with expertise in development and evaluation of HIV care engagement interventions, the K01 training proposal includes: (i) tailored co-mentorship and experiential learning with a cohesive, multidisciplinary team of seasoned HIV researchers with complementary expertise in mobility (Dr. Mark Lurie), spatial epidemiology (Dr. Thomas Stopka), ethnography (Dr. Jaclyn Hughto), intervention development and strategy specification (Dr. Sheree Schwartz), and FSW-tailored HIV treatment delivery (Dr. Harry Hausler); (ii) didactics, coursework, and directed readings in areas of transitional scholarship for Dr. Rosen, specifically mobility and HIV treatment; and (iii) mentored primary research in South Africa, propelling Dr. Rosen's pursuits to establish an independent, thriving program of interdisciplinary, mixed-methods HIV treatment research leveraging implementation science principles and methods from social epidemiology. The goal of the proposed K01 research is to characterize patterns of everyday mobility among FSW in South Africa and identify mobility-responsive implementation strategies enhancing their HIV care continuity. Specific aims are to: (1) characterize the spatial distribution of inter-venue mobility among FSW and their prospective association with indicators of HIV care disengagement; (2) identify patterns and drivers of day-to-day mobility, as well as their perceived impact on HIV care-seeking and self-management practices, among FSW; and (3) specify a package of implementation strategies that sustain ART adherence and enhance HIV care continuity in the context of mobility among FSW. By the conclusion of this K01, Dr. Rosen will be positioned to lead independent research testing mobility-responsive implementation strategies (identified and prioritized in the proposed K01) to optimize HIV care continuity among mobile FSW through a hybrid type I effectiveness-implementation, fractional factorial trial.

NIMH - National Institute of Mental Health

Project Summary/Abstract Depression is a leading global cause of disability in the United States and worldwide. Despite the availability of pharmacological and behavioral therapies, approximately 30% of individuals with depression remain treatment- resistant, in part due to persistent cognitive and emotional impairments. These deficits are thought to reflect disrupted interactions across prefrontal, temporal, and limbic brain regions, but the underlying neural mechanisms remain poorly understood. Prior stereotactic EEG (sEEG) studies from our group have shown that increased theta/alpha (4–15 Hz) power and altered frontotemporal connectivity during cognitive control differentiate individuals with and without depressive symptom history. However, it remains unclear whether emotion processing engages these same/overlapping networks, and whether biophysical model-based cognitive-emotion network features are associated with symptom severity. This proposal tests an overall hypothesis that dysregulated communication across fronto-temporo-limbic networks during simultaneous cognitive and emotional demands will distinguish between individuals with or without high (moderate to severe) depressive symptoms. To test this, we will examine large-scale neural dynamics underlying cognitive conflict and emotion processing using sEEG recordings from epilepsy patients with minimal to severe depression symptoms. In Aim 1a, we will assess whether individuals with high depressive symptoms demonstrate altered behavioral performance and fronto-temporo-limbic responses during a Multi-Source Interference Task (MSIT) with negative and neutral emotional distractors. In Aim 1b, we will use Jansen-Rit neural mass models within a Dynamic Causal Modeling (DCM) framework to estimate network interactions encoding cognitive conflict and emotional stimuli. In Aim 2, we will apply machine learning models trained on spectral, connectivity, and DCM-derived network features to determine their predictive validity for distinguishing between participants with and without high depression symptoms. Together, these aims are expected to identify biologically plausible mechanisms of cognitive-emotional dysfunction that map onto depression severity to inform future targeted interventions. The proposed fellowship training plan includes comprehensive mentorship from experts in neural engineering, computational modeling, and neuropsychiatry that will be crucial for developing an interdisciplinary skillset. Through the proposed training plan, the PI will gain expertise in advanced sEEG, biophysical modeling, and neural decoding techniques, as well as dedicated translational research training with external mentors. The PI, an MD/PhD student at the University of Cincinnati, will utilize outstanding institutional resources and mentorship to support their future career goal of advancing treatment for neuropsychiatric disorders as an independent physician-scientist.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Project Statement/Abstract. Adolescent alcohol use remains a major public health concern in the United States, with early initiation linked to long-term mental and physical health risks. Although overall prevalence has been declining in recent years, adolescents today engage in riskier patterns of alcohol consumption than before, including binge drinking and alcohol-induced blackouts. Peer relationships are a key influence on adolescent alcohol use. Adolescents both select peers with similar behaviors (peer selection) and are also influenced by their peers’ behaviors (peer influence). Social network analysis offers a powerful framework for examining these peer processes, but conceptual and methodological gaps remain in understanding how, when, and for whom they matter. Most existing studies rely on data collected in the 1990s and early 2000s, which do not account for the increasingly digital age and COVID-19 pandemic, both of which have shifted socialization. In addition, studies often assume that the effect of peer influence is constant across adolescence and overlook individual differences in network position or demographic characteristics like sex. This project will address those limitations using data from an NIH-funded, recently collected (2020-2024) longitudinal cohort study of high school students in Southern California. More than 3,000 students were surveyed once per semester throughout all of high school, resulting in eight waves of data on friendship nominations, alcohol use, and demographic characteristics. Retention exceeded 80% across all eight waves. These data provide a unique opportunity to model peer dynamics throughout high school as they relate to alcohol use. The project has three aims: 1) assess whether the association between peer alcohol exposure and individual use is moderated by an adolescent’s position in the network (i.e., centrality), 2) examine how alcohol use similarity contributes to the formation and dissolution of adolescent friendships and whether this differs by sex, and 3) determine when peer influence is most impactful during high school. This study will use lagged logistic regression models, temporal exponential random graph models, and time-varying effect modeling to test these three aims. This research will address key gaps in adolescent alcohol research by identifying who is most vulnerable to peer influence, how peer selection operates, and when prevention efforts may be most impactful. Findings will inform the development of network-based, developmentally timed prevention strategies and advance understanding of the social and developmental etiology of alcohol use. This project also offers a rigorous training platform in longitudinal network analysis and adolescent alcohol use, supporting the applicant’s development as an NIH-funded prevention scientist.

NIMH - National Institute of Mental Health

ABSTRACT Suicide is a critical public health issue and a leading cause of death in the United States. Individuals living with chronic pain face more than double the suicide risk compared to the general population. Despite this elevated risk, the mechanisms linking chronic pain to suicide remain unclear, and there are no established, targeted suicide prevention strategies for this growing and underserved population. The Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model offers an innovative framework for understanding suicide risk in the context of chronic pain. Originally developed to explain substance use vulnerability, CANUE posits that pain promotes maladaptive coping through negative reinforcement, and that cognitive-affective vulnerabilities—such as intolerance of uncertainty (IU) and anxiety sensitivity (AS)—amplify distress and motivate escape-based behaviors like suicide. IU reflects aversion to ambiguity, while AS reflects fear of anxiety- related bodily sensations. Both are theorized to heighten emotional reactivity to pain and fuel the desire for relief, including suicidal thoughts and urges. However, no study has directly tested this model in the context of chronic pain and suicide risk. The goal of this R21 study is to generate novel empirical data to determine how IU and AS interact to shape pain-related distress and momentary suicide risk using an innovative, multimodal research design. We will recruit 90 adults with chronic musculoskeletal pain and elevated suicide risk. Participants will complete a comprehensive laboratory session that includes validated self-report and behavioral tasks assessing IU, AS, and other CANUE-related factors, as well as quantitative sensory testing (QST) to assess pain sensitivity and affective responses to pain in a controlled setting. Immediately following the lab session, participants will complete a 21-day ecological momentary assessment (EMA) protocol, delivering a mix of time-based, random, and event-based mobile surveys to assess fluctuations in pain, pain-related affect, suicidal ideation, and escape- motivated thoughts in real time and natural environments. This combination of experimental and real-world methods will allow for the first rigorous test of whether IU and AS have unique and interactive effects on pain sensitivity, pain-related affect, and recent suicidal ideation in the lab (Aim 1), and whether they moderate the dynamic, moment-to-moment associations between pain, affect, and suicide risk in daily life (Aim 2). We hypothesize that participants with higher levels of IU and AS will report greater recent suicidal ideation severity and show greater pain-related negative affect in response to experimental pain. We also anticipate that IU and AS will moderate real-time links between pain and suicidal ideation in the natural environment. By leveraging laboratory and ecological data, this project represents a significant and innovative step forward in understanding the mechanisms underlying suicide risk in chronic pain. Findings will advance theoretical models of suicide and pave the way for more personalized, mechanistically informed prevention strategies for this high-risk and understudied population.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY There is a mental health crisis among graduate students, encompassing both mental illness and broader well-being issues. These challenges don’t disappear when graduate students enter the classroom, research lab, or their mentor’s office. The pressures of academia can exacerbate these issues. As a result, faculty mentors frequently interact with students experiencing psychological distress, either acutely in the moment or more chronically over time. However, faculty mentors are ill-equipped to navigate these mental health challenges. Most faculty mentors did not receive training about mental health or effective interventions during their graduate education. Furthermore, empirically supported faculty mentorship training focused on mental health among graduate students is virtually nonexistent. Thus, faculty mentors are left to navigate complex dynamics with their students without the necessary training to do so effectively. To address this gap, we propose a series of self-paced modules for mentors of graduate students: a foundational module on interpersonal responsiveness plus 6 additional modules in the mental health toolkit. These 6 toolkit modules will cover cognitive reframing, self-affirmation, mindful self-compassion, dialectical thinking, community building, and mental health crisis support. These modules are firmly grounded in existing research in psychology and relationship science about interpersonal interactions, mental health and well-being, and coping strategies. Our team is highly interdisciplinary, with expertise in psychology, relationship science, education, mentorship, experimental design, and assessment and evaluation. In addition, there are 3 advisory boards (content expertise advisory board, interdisciplinary faculty advisory board, interdisciplinary graduate student advisory board) of 5 members each, with members representing various disciplines, institutions, and geographic areas across the U.S. Thus, the modules will be grounded in the empirical literature, utilize the expertise of the PI and Co-Is, and also be guided by input from faculty mentors and graduate students across disciplines, institutions, and geographic areas in the U.S. First, we will develop the modules using a multi-step, iterative process. Next, we will pilot the modules and further refine the module materials. Then, we will conduct a randomized controlled trial (RCT) assessing the efficacy of the modules, disseminate the results, and disseminate the modules. Evidence-based training for mentors navigating mental health challenges among their graduate students is lacking. Thus, these modules will fill an important gap in higher education training and in the scientific literature on mentorship.

NIMH - National Institute of Mental Health

Contact PD/PI: lewis, elinor PROJECT SUMMARY Second generation antipsychotics (SGAs) are widely used clinical tools for the treatment of severe mental illness. However, their utility is highly variable, and they take weeks to become effective. The mechanisms behind this time course are not understood. SGAs are thought of as antagonists at the D2 dopamine receptor. Yet our recent work suggests that some SGAs function as arrestin-biased agonists at the less-characterized D3 dopamine receptor (D3R). Activation of the arrestin-3 pathway leads to degradation of D3R, potentially altering response to these drugs over time. I have generated preliminary data that shows mice grow tolerant to preclinical measures of SGA activity after chronic treatment of an arrestin-biased SGA. I hypothesize that D3R neurons are the locus of tolerance to select SGAs, and this tolerance is driven by decreased D3R membrane expression caused by arrestin-3 recruitment to D3R. I will use in vivo optical methods to assess changes in D3-neuron activity after chronic SGA treatment. I will also measure behavioral tolerance to SGA treatment in transgenic mice with altered abilities to degrade D3Rs and compare D3R levels using saturation binding and PET scans. This project will reveal mechanisms of tolerance to select SGAs at gross anatomy, cell- type, and protein levels. Project Summary/Abstract Page 6

NCCIH - National Center for Complementary and Integrative Health

Project Summary/Abstract Research: Fear activates the fight or flight stress-response, leading to rapid changes in behavior and physiological accommodations via the sympathetic nervous system. While the stress response facilitates survival from an acute threat, inappropriate activation or delayed termination after threats have passed can be maladaptive. Indeed, inappropriate sympathetic activation is a hallmark of psychiatric diseases such as post- traumatic stress disorder and major depressive disorder. Conversely, non-invasive brain modulation techniques such as transcranial direct current stimulation, which induces diverse physical and mental health benefits, may function in large part through its ability to mitigate the stress response. Together, this suggests that the neural circuits regulating the sympathetic nervous system could be an important therapeutic target. To map the central circuits regulating the adrenal gland, an essential effector of the fight-or-flight sympathetic response and the principal source of circulating epinephrine, I will use monosynaptic rabies. My preliminary data show that the adrenal medulla receives innervation not only from well-established hypothalamic nuclei, but also, surprisingly, from the motor cortex. The proposed project will expand upon this finding: In Aim 1) I will rigorously map the connections between the motor cortex and the adrenal gland and in Aim 2) I will investigate how these cortical neurons modulate epinephrine release and the physiological and behavioral response to stress. These aims will expand our understanding of this newly discovered neural circuit and its role underlying important mind-body interactions. Career development: This five-year research career development program will advance the career of a promising physician-scientist studying the neural circuits underlying mind-body connections as they relate to the physiological effects of stress. This proposal builds upon the candidate’s extensive background in molecular neuroscience and behavioral genetics, by promoting Dr. Greene’s acquisition of several necessary technical skills and extensive training to ensure that the candidate develops superb professional skills. The training goals are reflected in the expertise of the mentors (Dr. Andrés Bendesky and Dr. Rui Costa), tailored seminars and didactics, and the strong neuroscience training environment at Zuckerman Mind Brain and Behavior Institute. By completing the proposed studies and training plan, the candidate will acquire a unique and highly valued skill set that will support a successful transition to becoming an independent investigator.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Top-down signals from the prefrontal cortex have long been postulated to regulate hippocampal function as part of numerous cognitive and emotional processes, but the specific pathways mediating top-down control have been unclear. We have found a novel long-range GABAergic pathway from prefrontal cortex to hippocampus that represents a potential substrate for top-down control. Notably, this pathway seems to operate in an unusual manner: by inhibiting disinhibitory circuits. Our initial studies found that these prefrontal- hippocampal GABAergic projections can promote object exploration by enhancing hippocampal representations of object locations and associated network oscillations. However, two major questions remain unresolved. First, prefrontal GABAergic neurons which project to the hippocampus are heterogeneous and the significance of this is unknown. Second, the detailed circuit mechanisms through which long-range GABAergic projections from prefrontal cortex alter hippocampal information processing remain unclear. The goal of this project is to first and foremost, elucidate mechanisms through which long-range prefrontal-hippocampal projections shape computation in downstream circuits, and second, relate these to the heterogeneity of long- range GABAergic neurons. This project will specifically test our hypothesis that long-range GABAergic projections exert top-down control over the hippocampus by targeting disinhibitory microcircuits, thereby regulating how competing input regions recruit and entrain feedforward inhibition in the hippocampus. This could explain how hippocampal circuits switch between different information processing modes, each characterized by rhythmic synchronization with a different upstream region. Furthermore, we may identify different subtypes of long-range GABAergic neurons that each promote synchrony with a unique input region, elucidating organizational principles and functional implications for the heterogeneity of long-range GABAergic neurons.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Working memory allows past events to be transiently maintained in the brain so that it can be compared with ongoing experiences to drive behavior. This cognitive process has been shown to be severely impacted by the progression of many neuropsychiatric diseases and disorders. Thus, it is critical to understand the components of working memory to determine how normal mental function can be restored. Working memory must be selective to relevant stimuli and resistant to noise or irrelevant stimuli. It has been proposed that information is maintained through persistent activity at the single-cell or population level, either among local recurrently connected neurons or through long-range loops across multiple brain areas. Alternatively, it has been proposed that information could be maintained through activity-silent intracellular processes which are defined by specific genes and molecules. These theories are not necessarily mutually exclusive and may both be implemented in the nervous system. To achieve a comprehensive understanding of these mechanisms, it is necessary to investigate working memory across multiple biological scales spanning genes, cell types, local circuit dynamics, brain-wide communication, and behavior. Using a combination of multi-area two-photon calcium imaging, long-range anatomical tracing, cell-resolution optogenetic manipulation, and comprehensive spatial transcriptomic analysis, we will dissect working memory circuits as animals perform sensory-guided working memory tasks. In Aim 1, we will determine how specific stimuli are maintained in working memory by monitoring and perturbing local and long-range cortical activity to distinguish working memory maintenance from sensory-to-working-memory transformations. In Aim 2, we will determine the cellular and molecular mechanisms supporting local working memory by combining functional connectivity and gene expression measurements to distinguish their contributions to persistent activity and activity silent properties. Through this, we will determine the precise local and long-range dynamics that underlie working memory and the cellular and molecular properties that support these computations.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute on Drug Abuse and the National Institute of Mental Health, National Institutes of Health, is to solicit Research Project Grant (R01) applications from institutions/organizations that propose to identify chromosomal loci and/or genetic variation in genes and haplotypes that are associated with either increased or decreased vulnerability to, dependence on, and/or treatment response for addiction to stimulants (e.g., cocaine, amphetamine, caffeine), narcotics (e.g. opiates), nicotine, benzodiazepines, barbiturates, cannabis, hallucinogens, and/or multiple drugs of abuse and/or their associated mental co-morbidities (e.g., major depression, schizophrenia, bipolar disorder) in human beings or animal models. Similarly, there is interest in chromosomal loci and/or genetic variation in genes and haplotypes that are associated with differences in responses to treatment for addiction to drugs of abuse, and treatments for co-morbid disorders -Mechanism of Support. This FOA will utilize the NIH Research Project Grant R01 award mechanism. -Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

NIMH - National Institute of Mental Health

How networks of molecules persistently modify neuronal ensembles to store long-term memory is a fundamental question in neuroscience, relevant for disorders characterized by memory-like dysfunction of brain circuits. Whereas transient second messengers activate many kinases to briefly modify synaptic strength, the second messenger-independent, atypical PKC isoform, PKMz, is persistently active. Strong stimulation of synapses increases cellular PKMz through new synthesis; however, the kinase’s action maintains potentiation only at activated synapses. Our initial work on how PKMz selectively targets active synapses reveals PKMz does not act alone, but interacts continually with other molecules to maintain potentiation of specific synaptic connections. The postsynaptic scaffolding protein, KIBRA, genetically linked to human memory, forms persistent complexes with PKMz in LTP. Blocking their interaction reverses established LTP, without affecting unstimulated synaptic strength. The antagonists disrupt 1-month-old spatial memory, during which PKMz has been degraded and resynthesized. Thus, KIBRA acts as a persistent synaptic tag, anchoring PKMz to maintain LTP and memory despite protein turnover. PKCi/l compensates for PKMz loss in z-knockout mice and is also anchored at active synapses. Understanding this persistent synaptic tagging requires elucidating molecular networks that form and maintain potentiation at active synapses, and how this tagging modifies neuronal ensembles to store memory. Thus, Aim 1 is to identify the molecules establishing KIBRA-PKMz coupling at activated synapses. Multiple proteins interact with KIBRA, including the actin-associated protein dendrin and protein interacting with C-kinase (PICK1) that also binds both PKMz and AMPARs. Actin filaments and postsynaptic AMPARs increase in early-LTP. We will test whether dendrin and PICK1, together with other molecules identified by proteomic screening, accumulate KIBRA in early-LTP, which then anchors PKMz in establishing late-LTP. Aim 2 examines molecular networks maintaining KIBRA-PKMz complexes in LTP and memory. KIBRA stabilizes PKMz, and we will test if this stabilization and the persistent action of PKMz to strengthen synapses act in feedback pathways to perpetuate KIBRA-tagging in maintenance. We will use dual-eGRASP that persistently labels with fluorescent markers synapses activated in learning to examine KIBRA-PKMz coupling in activated synapses during spatial memory. Aim 3 investigates how KIBRA-PKMz persistent synaptic tagging expresses memory through modifications of place cell ensembles. Standard measures of place cell fields change only modestly as animals learn spatial information. Our recent optical recordings of hundreds of place cells reveal subpopulations of cells that form and maintain new cofiring relationships during spatial memory. Initial data show decoupling KIBRA-PKMz erases memory, and we will test if memory-related place cell ensembles and the spatial information they encode are also disrupted. Our 3 Aims will elucidate the molecular networks crucial for persistent synaptic tagging and so establish a basis for understanding disorders of memory.

NIMH - National Institute of Mental Health

Project Summary/Abstract Dopamine neurons in the ventral tegmental area (VTA) fire action potentials in complex patterns of tonic and phasic activity in response to environmental stimuli and during behavioral tasks. Transcriptomic, anatomical, and functional studies have established that VTA dopamine neurons can be divided into multiple subpopulations with variable gene expression, projection patterns, and response profiles. We recently completed a transcriptomic study that identified genetic markers for three distinct subpopulations of VTA dopamine neurons, and also found evidence for variability in ion channel gene expression between populations that correlated with differences in activity-dependent gene expression. However, much remains unknown regarding how specific genes encoding ion channels, receptors, transcription factors, or other signaling components contribute to the variability in baseline physiological properties observed across the VTA. Here we propose to combine slice electrophysiology recordings of VTA dopamine neurons with post-hoc single-cell sequencing analysis (i.e. patch-seq), which will allow us to directly correlate gene expression and physiological properties in order to identify candidate genes that may be key drivers of the variability between subpopulations. We also propose to validate and utilize a novel dual-recombinase CRISPR/Cas9 system for targeted gene mutagenesis in intersectional neuronal populations, which will provide a mechanism for testing gene function with unprecedented precision. We will use this approach to test the function of two candidate ion channel genes, the potassium channels Kcnh5 and Kcnh7, previously identified in our transcriptomic study as potential contributors to dopamine neuron action potential firing properties. We hypothesize that these genes are important for enabling rapid action potential firing in highly excitable dopamine neurons found in specific subpopulations. As a whole, with this proposal we aim to generate a valuable dataset linking gene expression in VTA dopamine neurons with physiology and subpopulation identification, as well as develop an intersectional gene mutagenesis strategy that can be used throughout the brain to precisely target neuronal subpopulations to test gene function. With this approach, we hope to facilitate future precision targeting of the dopamine system and dopamine-dependent behaviors.

NIMH - National Institute of Mental Health

PROJECT SUMMARY People experiencing major depression often decline their approach to rewards, to instead avoid threats (including irrelevant ones). Despite the prevalence of these costly behaviors featuring decision-making impairments, their underlying neurobiology is poorly defined. Here, I combine powerful mouse models to provide a multilevel characterization of approach and avoidance decisions linked to depression. Previous studies highlight specific areas within the corticostriatal-limbic system as signaling approach and avoidance expression. However, I propose to go beyond this limited approach by unbiasedly profiling neuronal activity in the whole brain of mice showing approach and avoidance decisional biases linked to depression-related phenotypes. Further, I propose to unbiasedly profile transcriptional patterns in key areas and to chemogenetically test the role of key cell types. I hypothesize that, in addition to proven areas, our results will reveal overlooked areas and cell types whose activity might be crucial in driving approach and avoidance biases linked to depression. Moreover, our transcriptional analyses will identify proven (i.e., ∆FOSB & CREB) and novel transcriptional regulators driving these biases. In Aim 1, I adapted a platform-mediated avoidance task, to profile approach and avoidance biases in mice exposed to chronic social defeat stress (CSDS), a model used to study depression-related pathology. I first demonstrated that mice susceptible to the CSDS, similar to depressed patients, show persistent avoidance to a cue previously announcing a shock threat, at the cost of missing rewards. In contrast, mice resilient to the CSDS quickly decrease their avoidance to maximize gaining rewards. To further characterize these behavioral biases, in Experiment 1.1, I use brain-wide immunostaining of cFOS as a proxy for correlated neuronal activity. Next, to leverage neuronal activity and gene expression patterns, in Experiment 1.2, I will use RNA-sequencing to transcriptionally profile areas whose activity most strongly correlated with approach and avoidance biases. Simultaneously, I will profile the nucleus accumbens, amygdala, and prefrontal cortex within the corticostriatal- limbic system, which have been proven to signal approach and avoidance and to be sensitive to the adverse consequences of stress. Next, in Experiment 1.3, I will perform chemogenetics, to test the causal role of key areas and cell types in biasing approach or avoidance decisions after CSDS. Capitalizing on this training, in the K00 phase, I will study in vivo temporospatial dynamics of decision-making circuits sensitive to stress, by combining behavior with calcium-imaging and computational modeling. The overall training and research plans outlined here will reveal novel insights into decision-making processes impacted by stress, and will greatly support my successful transition to a postdoctoral fellowship and subsequent scientific independence.