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NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIDA - National Institute on Drug Abuse

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Adolescence is associated with worsening anxiety, but the biological mechanism for this phenomenon is not understood. Much work has focused on how changes to social and cognitive processing during adolescence might contribute to anxiety symptoms. Very little work has investigated how pubertal changes to the body itself may contribute to worsening anxiety symptoms. Specifically, puberty is known to impact representation of the body in cortex. This in turn may impact the ability to identify and interpret interoceptive signals in a bottom-up manner, thereby exacerbating anxiety symptoms in vulnerable adolescents. Identification of novel neural targets and mechanisms associated with anxiety during adolescence can lead to interventions that reduce illness burden in adolescence and adulthood. Primary somatosensory (S1) and insular cortices are two potential neural substrates that are associated with cortical representation of the body, as well as interoceptive function. Both S1 and insular cortices show structural and functional shifts during puberty and are associated with anxiety symptoms in adults. The function of these regions during puberty and their relationship to anxiety symptoms has not been characterized. This functional magnetic resonance imaging (fMRI) study seeks to understand the neurofunctional correlates of body representation and interoceptive function and their relationship to anxiety symptoms during puberty. In this cross-sectional study, youth ages 11-15 (n=75) will complete assessments and self-reports of anxiety symptoms and pubertal development, as well as a magnetic resonance imagining (MRI) scan session. The MRI session will include an emotional cardiac interoceptive functional MRI task and a resting state scan. Participants will also complete an electrocardiogram task designed to assess interoceptive function, as well as a behavioral task designed to assess body representation, both outside of the scanner. We aim to understand the neural correlates of body representation during puberty and the relationship between interoceptive function/its neural substrates and physical symptoms of anxiety in adolescents. We also will explore the stability of these constructs over time and the predictive utility of the function of somatosensory and insular cortices for understanding anxiety symptoms. This study has the potential to identify novel targets for early intervention that could prevent or mitigate anxiety disorders in adolescence and adulthood.

NIMH - National Institute of Mental Health

Project Summary Strong, longstanding evidence points to important roles for the cerebellum in autism spectrum disorders (ASDs), yet cerebellar mechanisms remain understudied in ASDs compared to neocortical circuits. Anatomical and functional studies have pointed, in particular, to changes in the synapses of Purkinje cells, the sole output neurons of the cerebellum. Purkinje cells were reduced both in number and size in ASD cases, particularly in the cerebellar vermis and other sub-regions involved in cognition and emotional control. Genes localized to Purkinje cell synapses were down-regulated. Purkinje cell-specific conditional knockout mice for several ASD risk genes suggest direct effects of these cerebellar neurons on ASD-related behaviors and synaptic structure and function. However, cell type-specific transcriptional and epigenomic changes in the cerebellum of individuals with ASDs remain poorly characterized, and it is unknown whether the synaptic features identified in mouse models translate to the human condition. Here, we propose comprehensive multi-omic and synaptic imaging studies to address these knowledge gaps, utilizing a unique post-mortem brain tissue resource from the University of Maryland Baltimore Brain and Tissue Bank. We will generate single-nuclei multi-omic profiles of gene expression and chromatin accessibility in ~1.5 million cells from 100 ASD cases and 100 controls. In the same brain tissue samples, we will perform super-resolution confocal imaging to quantify the density, size, and nanostructure of Purkinje cell synapses. ~50% of the donors in our cohort will have known causal mutations, including multiple cases with tuberous sclerosis complex (TSC), Rett syndrome, and Fragile X syndrome, enabling us to define shared vs. unique features of ASDs with mutations in different genes. Key findings will be validated in a mouse model of TSC, Tsc1 conditional knockout mice, enabling us to determine which transcriptomic and synaptic phenotypes arise from the direct effect of this mutation in Purkinje cells.

NIMH - National Institute of Mental Health

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation methodology FDA- approved for treatment of major depressive disorder (MDD). While rTMS achieves higher antidepressant efficacy than conventional treatments, reported response and remission rates are highly variable across cohorts. To reduce this variability and enhance overall remission rates, an understanding of the biological mechanisms behind rTMS’s antidepressant efficacy is needed. Recent studies have identified that rTMS works through a common biological mechanism even across multiple neurological disorders being treated: reduction of neuroinflammation, specifically, reduction in microglia activation. This is particularly relevant for MDD, as increased neuroinflammation is well-documented, on average, in groups of patients with MDD, and microglia are reported to be the cells responsible for this neuroinflammation. We and others have shown that people with MDD exhibit a range of neuroinflammation and that only those with high neuroinflammation have an antidepressant response to anti-inflammatory treatment. Taken together, this suggests that the mechanism of action of rTMS may be through the reduction of neuroinflammation (specifically, microglia density) and that the reported heterogeneity in response to rTMS may be due to the heterogeneity of neuroinflammation in MDD itself. We seek to probe this in the proposed high-risk, high-reward proof-of-concept study in n = 10 treatment- seeking participants with MDD, who will undergo rTMS as part of their standard of care – this is not a clinical trial: Aim 1. Explore the relationship between rTMS-associated reductions in depression severity and reductions in microglial density, as measured by microglia-specific [11C]PS13 positron emission tomography (PET) tracer. We expect microglia density to decrease following rTMS based on published animal literature reporting a ~23% reduction in microglia after TMS. Data from our current study examining participants with MDD receiving anti-inflammatory medication suggest that reductions in depression severity will be correlated with this reduction in neuroinflammation. Aim 2. Explore the relationship between pretreatment microglia density as measured by [11C]PS13 PET and antidepressant response to rTMS. Data from our current study suggest that greater pretreatment neuroinflammation will be associated with better response to rTMS. This high-risk, high-reward R21 will be the first study to assess rTMS’s effects on microglia in patients with MDD, advancing our understanding of its mechanism of action, providing proof of concept to support future larger studies, and stimulating the development of both novel neuroinflammation-specific therapeutics and future improvements in rTMS protocols.

NIMH - National Institute of Mental Health

Title: R-loop-induced CGG contraction as a therapeutic approach for Fragile X syndrome PROJECT SUMMARY Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder and one of the most common monogenic causes of inherited intellectual disability and autism spectrum disorders (ASD). FXS has a higher incidence among males (~1:3000) than females (~1:6000). Approximately 60% of FXS individuals demonstrate autistic features, 86% have an anxiety disorder, and almost all exhibit cognitive, motor, and developmental delays. Disease-modifying treatments have been of major pharmaceutical interest. Clinical trials have largely targeted pathways downstream of FMR1 or alternative pathways to modulate disease phenotype, such as arbaclofen and metabotropic glutamate receptor 5 (mGluR5) antagonists, with a phosphodiesterase-4D (PDE4D) allosteric inhibitor recently shown to improve cognitive function. However, because FMRP — the gene product of FMR1 — has many functions in the brain, the molecular, synaptic, and circuit dysfunctions seen in FXS may not be easily corrected by targeting a single downstream or parallel pathway. Despite intensive efforts to better understand the etiology, there remains a dearth of disease-specific treatments. It is now known that restoring FMR1 expression can at least partially rescue FXS phenotypes. Towards this goal, we recently identified a new approach that corrects the underlying genetic defect by reactivating the silenced FMR1. By investigating conditions favorable to FMR1 reactivation, we found that two compounds (“2i”) — a MEK and a BRAF inhibitor — could fully turn back on FMR1 in cellular models. We traced the mechanism to 2i-mediated DNA demethylation and formation of site-specific R-loops that then recruit endogenous DNA repair mechanisms to excise the CGG repeat. We went on to demonstrate that the CGG contraction and gene reactivation could be recapitulated by driving site-specific R-loop formation using dCas9 and an FMR1-specific gRNA. These discoveries lead to a model in which R-loops induce a positive feedback cycle comprising DNA demethylation, de novo FMR1 transcription, and reinforcement of R-loops at the CGG repeat — which in turn drive recruitment of endogenous DNA repair mechanisms to remove the aberrant RNA:DNA structure. Excision of the long CGG repeat then enables the reactivation of FMR1. We observed that repeat contraction is specific to FMR1 and fully restores production of FMRP protein. Our study thereby identifies a novel and potential method of treating FXS. In the proposed research, we aim to obtain proof-of-concept that R-loops form and induce contraction of the CGG repeat in post-mitotic neurons and that the contraction can lead to FMR1 reactivation in a human 3D disease model for FXS. If successful for FXS, the R-loop approach could be a potential therapeutic for other tandem repeat disorders as well.

NIDCR - National Institute of Dental and Craniofacial Research

PROJECT SUMMARY/ABSTRACT The US faces a mental health crisis; nearly 83 million Americans experience mental illness, but fewer than 50% of these individuals accessed past year mental health services. There is a critical need for highly disseminable, potent mental health interventions. Standalone digital interventions offer promise for improving clinical outcomes at scale; however, efficacy of these interventions to date is modest, likely due in part to insufficient personalization to patient heterogeneity and to momentary changes in mental health symptoms. The present study seeks to rapidly improve the efficacy of precision psychiatry digital health interventions by developing real-world, person-centered maintenance models for psychopathology using ecological (i.e., in patient’s daily lives) data and dynamic systems modeling. Dynamic systems modeling of repeated time series data yielded by ecological momentary assessment (EMA) and smartphone sensors will be used to evaluate the individual and interactive effects of empirical maintenance factors to understand each individual’s maintenance system for psychopathology in their daily life. Just-in-time adaptive interventions (JITAIs) are prompts delivered in-the-moment via smartphone at identified instances of risk for maladaptive behaviors. Although often evaluated in aggregate across months, JITAIs could be conceptualized as ecological quasi-experiments that induce use of specific therapeutic skills at observable times. Accordingly, this study will use micro-randomized (in which the content of the JITAI is randomly assigned in the moment) JITAIs delivered at times of elevated risk for maladaptive behavior based on the individual’s developed dynamic system to evaluate the effects and mechanisms of specific therapeutic skills on outcomes of interest, to provide granular insight into treatment mechanisms. Eating disorders are the ideal population in which to test proof-of-concept for these methods to improve efficacy of precision psychiatry digital interventions, as they are characterized by easily measurable maladaptive behaviors (i.e., dietary restriction, binge eating, compensatory behaviors), are maintained by a complex intersection of biological, psychology, and social factors, and their frontline treatment, enhanced cognitive behavioral therapy (CBT-E), is primarily comprised of behavioral skills. The aims are: 1) test the hypothesis that person-centered dynamic models will describe risk for dietary restriction, binge eating, add compensatory behaviors with ≥ 60% average goodness-of-fit, 2) test hypothesized effects and mechanisms of CBT-E skills on eating disorder behaviors and primary maintenance factors using JITAIs, and 3) characterize feasibility and acceptability of the standalone JITAIs. The study will enroll N = 170 adults with eating disorders who will complete four months of ecological data collection and receive JITAIs to use CBT-E skills at times of elevated risk for 10 weeks of the data collection period. The study will set the stage for future randomized controlled trail to evaluate the optimized, standalone JITAI system, which will have the potential to substantially improve access to evidence-based mental healthcare.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Fetal Alcohol Spectrum Disorder (FASD) is a lifelong and highly consequential condition affecting up to 1 in 20 children in the U.S. Despite the availability of evidence-based treatment options, only a very small minority of pregnant women meeting criteria for an alcohol use disorder receives treatment; and of those not receiving treatment, 95% do not feel that they need it. Screening and brief intervention approaches (SBIRT) are designed to reach this non-treatment seeking majority and are widely recommended for use in pregnancy. However, although SBIRT is predicated on small effects that have a meaningful public health impact when delivered at scale, decades of research have shown that (1) its effects are smaller than once hoped, and (2) it is challenging to implement in busy healthcare settings. In response, we have extensively studied digital SBIRT approaches (e-SBIRT), with promising results regarding efficacy—particularly when pairing e-SBIRT with digital “dose” enhancers such as text messages and booster sessions. Unfortunately, implementation challenges have persisted despite the greatly reduced effort needed to implement e-SBIRT in prenatal care settings. Continued innovation is urgently needed. We propose two enhancements designed to increase e- SBIRT scalability and impact. First, we will improve scalability by testing e-SBIRT delivery within a whole- health pregnancy checkup and feedback model addressing a range of protective and risk factors, such as sleep, prenatal care adherence, mental health, and nutrition, in addition to alcohol. This adaptation will reduce stigma and increase perceived relevance among patients as well as clinic staff. Although allocating disproportionate time to alcohol, this approach will also allow delivery of content addressing factors known to contribute to alcohol use, such as depression. Second, we will improve impact by augmenting individual-level e-SBIRT with an engaging intervention to help family members, friends, and/or partners—selected by the pregnant participant—to effectively support the pregnant participant’s health in all areas, including alcohol. In the R61 phase, Aim 1 will use mixed methods to develop e-SBIRT multi, a user-centered, multi-level, and multi-target screening and brief intervention for pregnant participants and their key support network. R61 phase Aim 2 will evaluate e-SBIRT multi feasibility and acceptability in a single-arm trial. If e-SBIRT multi meets a priori benchmarks/milestones, R33 phase Aim 3 will test it against enhanced treatment as usual in a confirmatory two-arm randomized clinical trial (N = 326 pregnant women plus support participants). R33 phase Aim 4 of this hybrid type 1 trial will evaluate implementation outcomes among healthcare professionals, clinic staff, pregnant participants, and support network participants. This project will develop and rigorously evaluate two enhancements with the potential to increase brief intervention acceptability and impact while retaining the high-reach advantages of e-SBIRT. It represents an important step toward re-imagining SBIRT to achieve the goal of a true public health impact on FASD.

NIMH - National Institute of Mental Health

Project Summary/Abstract Amid an unprecedented youth mental health crisis, adolescents and young adults (AYA) have the most barriers to receiving mental healthcare. While digital tools are a scalable and accessible way to provide timely mental health screening and referral options, these tools have failed to engage AYA in their daily lives. This failure is driven by multiple factors, including a lack of: 1) understanding of implementation determinants for digital tools in community spaces; and 2) partnership with AYA, their caregivers, and support staff who work in key community settings where AYA spend their time. Consistent with the NIMH Strategic Plan and National Advisory Mental Health Council report, the goal of this R34 proposal is to target AYA engagement in the design and implementation of a digital low-intensity treatment for AYA in Chicago Park District (CPkD) Teen Programming. The CPkD is the largest park district in the country, and more than 40,000 youth are served daily across all 77 Chicago neighborhoods. This project harnesses on a partnership with CPkD and is grounded in the Accelerated Creation-to-Sustainment (ACTS) Model to guide the development of a technology (the “CPkD D-LITe”), as well as its service and implementation plans for CPkD sites. Aim 1 follows the first phase of the ACTS Model, Create. Human-centered design and community-engaged research methodologies will be used to collaborate with the existing CPkD Youth Advisory Board and Teen Programming participants, caregivers of AYA served by CPkD, and CPkD staff. Design activities will focus on targeting mechanisms that are believed to influence engagement: 1) individual-level barriers to care; 2) leveraging spaces where youth spend their time, including assessing determinants in these spaces; and 3) elevating key player input throughout design. The products of Aim 1 will include: an initial version of the “CPkD D-LITe” that demonstrates usability and acceptability by key players, a service protocol for integration of the “CPkD D-LITe” and potential higher clinical needs reported by AYA as a result of using the tool, and an implementation blueprint for integration into CPkD programming. Additionally, extended usability testing will pilot all trial activities to be conducted in Aim 2. In Aim 2, the second phase of the ACTS Model, Trial, will be followed by conducting a pilot randomized controlled trial in CPkD sites using an Optimization, Effectiveness, and Implementation trial methodology. The “CPkD D-LITe” will be compared to a control condition (digital workbook) across a pragmatic, rollout implementation trial. Primary outcomes include acceptability and feasibility, along with reductions of individual levels to mental healthcare, DMH use, and, secondarily, clinical outcomes (anxiety, depression). Optimization activities will occur across the trial period. In sum, the naturalistic approach of this work addresses multiple barriers to real-world digital tool engagement failures for AYA. It will provide key insights into engagement strategies, adaptations, and both service and implementation practices that will support AYA in community settings, both broadly and in a future R01 proposal.

NIMH - National Institute of Mental Health

This application proposes extensive community engagement activities to adapt and pilot test an evidence-based intervention to improve employment outcomes for young adults experiencing early psychosis in Uganda called Individual Placement and Support (IPS). Psychosis usually starts during adolescence and young adulthood, a critical developmental period, and, despite its relatively low prevalence, accounts for a disproportionate number of global disability and level of caregiver burden. People with severe mental disorders, including psychosis, are seven times more likely to be unemployed than those without a disorder. While treatment for acute episodes is important, post-acute interventions are crucial for long term recovery and improved clinical and functional outcomes. Our research has demonstrated that Ugandan youth experiencing psychosis are eager to work and complete their education, yet there are no placement or support services like IPS available to them. Because IPS has never been systematically implemented in a low- and middle-income country (LMIC) in Africa, we anticipate that adaptations will be necessary to fit the local cultural, economic, and social context. Thus, we propose a systematic process of community engagement to adapt and pilot test IPS in the newly established early psychosis services in Kampala. Aim 1. We will engage with the community to identify barriers to and facilitators of IPS implementation in Uganda. We will conduct 45 qualitative interviews and focus group discussions with young people diagnosed with early psychosis and their relatives, potential employers, local alternative healers, mental health providers, and policymakers. Aim 2. Using Aim 1 findings, we will adapt IPS to the local context by conducting a multi-day workshop with 15 key stakeholders, featuring IPS demonstrations followed by surveys and group discussions. Based on this, an adapted IPS-Uganda draft will be developed and iteratively reviewed. After integrating all feedback, we will finalize the IPS manual and create a training scheme for personnel delivering the intervention during the trial. Aim 3. We will evaluate the potential methodology for a randomized controlled trial (RCT) and pilot test the adapted IPS intervention among 60 Ugandan patients experiencing early psychosis. We will conduct a pilot RCT to examine the feasibility, costs and acceptability of IPS. Participants will be randomized to receive IPS or treatment as usual. The follow-up period will be twelve months. This proposal is a collaboration between teams in Uganda and New York to address the pressing need to increase access to post-acute evidence-based recovery-oriented interventions that improve the lives people experiencing psychosis in LMICs. This project will lay the foundation for a larger trial in the future.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Over 1.4 million individuals in the United States are diagnosed with Lewy Body Dementia (LBD), the second most common type of degenerative dementia after Alzheimer's disease (AD). LBD results in early impairments in cognitive abilities, along with bothersome neuropsychological and bodily symptoms such as visual hallucinations, parkinsonism, dysautonomia, and sleep disorders. Up to 80% of individuals with LBD receive care from family members, with nearly half of the caregivers' experiencing depression. Web-based and telehealth interventions for caregivers of individuals with dementia are promising solutions for reducing caregiver depression, paralleling the potential of traditional in-person approaches. Yet, most of the interventions generalize across all dementia forms without adaptations for LBD's distinct challenges. Accessibility of existing digital interventions is also limited by internet bandwidth and lower digital literacy in caregiving populations, perpetuating inequity and leaving them underserved. Our project aims to test the effectiveness of a fully asynchronous, low bandwidth, text-based psychoeducational online intervention tailored specifically for caregivers of individuals with LBD (VOCALE LBD). This intervention engages caregivers in moderated peer-to-peer discussions focused on LBD caregiving and problem-solving skills over an eight-week period. In a pilot study, the intervention showed promising results in reducing depressive symptoms among fifty-four LBD family caregivers age 68±10. Clinicians also uniformly agreed that the intervention is impactful, acceptable, and well-aligned with their strategic priorities, but they suggested strengthening its pragmatic potential by introducing practical measurements of the intervention's progress. We propose a two-arm randomized controlled trial (RCT) comparing VOCALE LBD to the standard of care (SOC) among 220 caregivers nationwide, recruited using Lewy Body Dementia Association (LBDA) outreach. The primary outcome will be depressive symptoms at eight weeks post-enrollment. Secondary outcomes will include sustained effects on depressive symptoms at six months, and exploratory outcomes will assess caregiving burden, stress, social support, and loneliness. Additionally, we will evaluate the mechanisms influencing the intervention's effects, focusing on caregiver empowerment and problem-solving, and explore pragmatic approaches for monitoring the intervention's effectiveness through user engagement and user-generated data. Our project is aligned with national priorities to effectively leverage digital and telehealth solutions for caregivers of people with Alzheimer's Disease and Related Dementias (ADRD). We aim to create an evidence- based, equitable, and accessible solution for LBD caregivers, ensuring practical application and intervention fidelity. If successful, this project will lay a foundation for the next stage effectiveness research in clinics and community organizations.

National Institutes of Health

Purpose. This Funding Opportunity Announcement (FOA) issued by the National Institute of Nursing Research (NINR), National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Alcohol, Alcoholism, and Alcohol Abuse (NIAAA), National Cancer Institute (NCI), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), solicits Research Project Grant (R01) applications from institutions/organizations that propose to conduct research to reduce health disparities among minority and underserved children. Specifically, this initiative focuses on ethnic and racial minority children and underserved populations of children such as: children from low literacy, rural and low-income populations, geographically isolated children, hearing and visually impaired children, physically or mentally disabled children, children of migrant workers, children from immigrant and refugee families, and language minority children. Specific targeted areas of research include biobehavioral studies that incorporate multiple factors that influence child health disparities such as biological (e.g., genetics, cellular, organ systems), lifestyle factors, environmental (physical and family environments), social (e.g., peer influences), economic, institutional, and cultural and family influences; studies that target the specific health promotion needs of children with a known illness and/or disability; and studies that test and evaluate the cost effectiveness of health promotion interventions conducted in nontraditional settings

National Institutes of Health

Purpose. This Funding Opportunity Announcement (FOA) issued by the National Institute of Nursing Research (NINR), National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Alcohol, Alcoholism, and Alcohol Abuse (NIAAA), National Cancer Institute (NCI), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), solicits Exploratory/Developmental Grant (R21) applications from institutions/organizations that propose to conduct research to reduce health disparities among minority and underserved children. Specifically, this initiative focuses on ethnic and racial minority children and underserved populations of children such as: children from low literacy, rural and low-income populations, geographically isolated children, hearing and visually impaired children, physically or mentally disabled children, children of migrant workers, children from immigrant and refugee families, and language minority children. Specific targeted areas of research include biobehavioral studies that incorporate multiple factors that influence child health disparities such as biological (e.g., genetics, cellular, organ systems), lifestyle factors, environmental (physical and family environments), social (e.g., peer influences), economic, institutional, and cultural and family influences; studies that target the specific health promotion needs of children with a known illness and/or disability; and studies that test and evaluate the cost effectiveness of health promotion interventions conducted in nontraditional settings.

NIMH - National Institute of Mental Health

Project Summary Autistic youth are at far higher risk for depression than their neurotypical peers, and depression symptoms have significant negative impacts on functioning and quality of life of autistic young people. Despite great need, there are currently no evidence-based interventions for depression in autistic youth. Informed by my reviews on depression in autistic individuals, I developed and piloted a manualized behavioral activation (BA) treatment for depression in autistic adolescents in a single-arm or open trial (n = 15), supported by funding from American Psychological Foundation. Notably, autistic youth depression symptoms significantly improved pre-treatment to post-treatment and 1-month follow-up. To further the aforementioned pilot work, this study will iteratively refine our previously developed BA treatment based on comprehensive feedback from vested community members and test the refined intervention in an initial randomized controlled trial (RCT) versus an enhanced treatment as usual (TAU) control condition; we will conduct this research project in partnership with a community advisory board comprised of autistic youth, caregivers of autistic youth, and autistic-serving mental health providers to ensure the treatment protocol is aligned with community needs and values. To refine BA treatment, we will seek feedback on previously developed BA manual/materials through a series of focus groups (3 groups comprised of caregivers, 3 groups comprised of providers) and individual interviews with autistic youth (12-17 years old) with depression. Following each round of individual interviews/focus groups, we will refine BA manual/materials (iterative revision). Subsequently, we will evaluate effects of refined BA intervention in an RCT versus enhanced TAU control condition; 60 autistic adolescents (12-17 years old) with clinically significant depression symptoms will be randomized. We will compare change in depression symptoms from pre- treatment to post-treatment and 1-month follow-up across groups. We will additionally examine change in engagement in enjoyable and values-aligned activities (or construct of BA) as a mechanism of action of reduction of depression after BA relative to TAU. We hypothesize that autistic youth in the manualized BA condition will exhibit greater depression symptom reduction than autistic youth in enhanced TAU, and increased enjoyable/values-aligned activities will mediate treatment response. Furthermore, we will investigate feasibility and acceptability of refined BA treatment. We will examine BA treatment session attendance, and we predict that ≥80% of participants randomized to BA will attend all sessions. Adolescents and caregivers will complete post-treatment acceptability/satisfaction surveys and qualitative interviews; and we hypothesize that manualized BA intervention will be rated as feasible, acceptable, and useful. The proposed research project, in addition to the proposed training plan, will logically connect my previous research experience to a future R01 submission of a fully-powered multisite RCT of manualized BA treatment and provide critical skills required for my transition to research independence in the field of community-engaged autism clinical trial research.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Lifelong mental and physical health are seeded during infancy, with parent-infant interactions playing a pivotal role. Despite the critical importance of these early relationships, the neural circuits underlying infant-specific social behaviors remain largely unexplored. This project aims to elucidate these fundamental mechanisms by focusing on a population of somatostatin-expressing neurons in the infant mouse zona incerta (ZISST neurons) that we have identified as crucial for modulating infant responses to maternal presence. Based on our preliminary findings, we posit that ZISST neurons serve as an integrative brain node for the central representation of maternal presence (to be tested in Aim 1), which engages dedicated downstream neural circuits (to be tested in Aim 2) to guide maternal-dependent behavioral responses in the infant (to be tested in Aim 3). Specifically, aim 1 will determine the activity dynamics of ZISST neurons in preweaning mice in response to various maternal behaviors using fiber photometry and single-unit recordings. This will provide detailed insights into how maternal care modulates ZISST neuron activity at both the population and single-cell levels. Aim 2 will establish the functional connectivity of preweaning ZISST neurons and their recruitment by maternal presence through whole-brain mapping and projection-specific recordings. We will perform functional whole-brain mapping of activated (Fos+) neurons in infants under different conditions and use projection-specific expression of jGCaMP7s and fiber photometry to identify circuits that respond to maternal presence. These results will uncover target neural circuits from ZISST neurons that mediate the effects of maternal presence on infant social responses. Finally, aim 3 will leverage newly developed odor learning assays for preweaning mice to test the role of ZISST neurons in mediating the effects of maternal presence on different forms of aversive learning in infants, which rely on diverse sensory and central circuits. By testing the role of ZISST neurons in modulating aversive odor learning using both exteroceptive and interoceptive unconditioned stimuli, this aim will provide critical insights into how ZISST neurons influence learning processes that depend on maternal influence. Utilizing cutting-edge techniques in behavioral analysis, in vivo neural recordings, and neural circuit manipulation, this research will provide a comprehensive understanding of the physiological and anatomical mechanisms by which ZISST neurons mediate infant social behaviors. These insights could inform strategies to enhance early developmental outcomes and mitigate social and developmental disorders, ultimately contributing to improved mental and physical health across the lifespan.

NIMH - National Institute of Mental Health

Abstract Serotonin regulates a variety of complex behaviors in both mammals and invertebrates including sleep. The extracellular serotonin level available for signaling to post-synaptic receptors determines the activity of most, if not all underlying circuits. The plasma membrane Serotonin Transporter (SERT) is responsible for reuptake of serotonin after exocytotic release and therefore represents the primary mechanism for regulating extracellular serotonin levels. To date, the mechanisms by a which a decrease in SERT activity and the subsequent increase in extracellular serotonin alters circuit function and behavior remain poorly understood. Drosophila represents a powerful model to address this issue, but the requisite genetic tools have remained underdeveloped. We have addressed this issue by generating new tagged and/or mutant alleles of the Drosophila Serotonin Transporter (dSERT) and a subset of serotonin receptors. In Aim 1 we will use these lines to explore potential heterogeneities in the pathways by which dSERT regulates sleep and determine whether loss of dSERT activity during development can influence adult sleep. Both issues have broad translational relevance. In Aim 2 we will map for the first time, the location of serotonergic autoreceptors in the fly. We will then determine whether a serotonergic autoreceptor we have identified regulates sleep. In Aim 3 we will probe specific subsets of post-synaptic neurons in the mushroom bodies for potential changes in gene expression. We will use genetic tools that surpass the level of detail available in mammalian systems. These data will provide fundamental information about the mechanisms by which SERT can influence a translationally relevant behavior. We speculate that the principles we uncover will be relevant to both sleep as well as other complex behaviors regulated by serotonin and SERT.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Drug overdose accounts for approximately one-fifth of all pregnancy-associated deaths (the majority involving opioids) and drug-related foster care placements for infants have quadrupled over the past decade. Pregnant and parenting women with opioid use disorder (OUD) too often experience shame and stigma; punitive responses to prenatal substance use drive pregnant women away from care, creating major obstacles to receiving life-saving medications and engaging in treatment. To address the growing number of infants affected by prenatal substance exposure, the federal reauthorization of the Child Abuse Prevention and Treatment Act (CAPTA) requires a “Plan of Safe Care” (POSC) for parent-infant dyads affected by prenatal substance use at delivery. However, state implementation efforts have been varied, and few states have fully addressed all CAPTA requirements. Current approaches to meeting the POSC requirement, which rely on a static document created at delivery, do not provide adequate support for families struggling with custody issues and substance-related stigmas. The proposed study aims to adapt and evaluate the Family Care Planning (FCP) intervention, which implements longitudinal, transdisciplinary, and family-centered teleconference meetings to bring mothers together with their clinical, community, and child welfare teams to engage in facilitated, respectful treatment planning discussions. In the R61 Phase, we will refine and standardize protocols for the FCP approach using participatory co-design principles, incorporating input from early clinical adopters, mothers, community supports, and child welfare workers (Aim 1). We will also pilot test the FCP intervention to assess feasibility, fidelity, and acceptability (Aim 2). In the R33 Phase, we will conduct a stepped-wedge cluster randomized control clinical trial using a Hybrid Type 1 Effectiveness – Implementation study design with 312 parent-infant dyads. This phase will evaluate the effectiveness of FCP, implemented longitudinally over six months in the postpartum period, to increase maternal OUD treatment engagement and rates of family preservation. Additionally, we will explore the extent to which FCP improves substance use recovery, postpartum overdose rates, maternal self-efficacy, maternal mental health, and well-child care adherence. We will also explore measures of interpersonal (participants) and interagency (clinical-child welfare) trust. Finally, we will use the RE-AIM implementation framework and mixed methods to assess the extent to which FCP implementation is associated with effectiveness outcomes (Aim 4). Findings from this study are expected to have significant implications for addressing the effects of maternal substance use in the postpartum year.

NIDA - National Institute on Drug Abuse

Maternal morbidity and mortality is a growing public health crisis in the United States that disproportionately impacts pregnant and postpartum Native Americans (Native mothers) and, subsequently, their children and families. In Utah, the leading causes of maternal death are related to substance use, substance use disorder (SU/SUD), and mental health conditions, with many considered preventable. In response, the University of Utah has partnered with the Confederated Tribes of the Goshute Reservation to develop, implement, and evaluate CEREMONY, a perinatal clinical program for Native mothers with SU/SUD. CEREMONY is rooted in cultural practices and addresses additional structural and social barriers to engagement in care and recovery. Relationships strongly influence health behaviors and outcomes, and this is acutely pertinent for Native Americans whose traditional values and family structures emphasize community healing and kinship. However, there is a critical gap in our understanding of the social networks of Native mothers, which have not been previously well-characterized or studied, and how these networks might be important to recovery from SU/SUD. Longitudinal research on the evolution of social networks in Native mothers navigating SU/SUD could inform the development and guide the improvement of effective interventions. Through this project, I will: 1) characterize the social networks of Native mothers participating in a culturally integrated perinatal SU/SUD program, thereby enhancing my social network analysis skills; 2) assess the relationship between social network characteristics and SU/SUD and perinatal program outcomes, and 3) explore Native mothers’ perceptions of their social networks and how their networks impact their health behaviors and outcomes, further developing my qualitative and mixed methods skills. The completion of the aims outlined in this proposal will both contribute to a critical knowledge gap and provide me with an important research skill set in SU/SUD and maternal health research. Rigorous training in mixed methods design, social network analysis, qualitative methods, and biostatistics will accelerate my transition to a tenure-line independent investigator. My training plan was developed in collaboration with my Co-Sponsors to achieve the following goals: 1) form clinically relevant hypotheses and design rigorous experiments to test them, 2) develop skills in mixed methods design and social network analysis, 3) strengthen my skills in scientific writing and communication, 4) develop and demonstrate mentorship and leadership skills, and 5) maintain and strengthen clinical skills to better understand the clinical significance of my research. My interdisciplinary team of mentors will provide extensive guidance to achieve these goals, thus facilitating my progression into an independent physician-scientist researcher and leader. This fellowship will help me, a rising Eastern Shoshone physician-scientist, develop the skills required to conduct reciprocal, ethical research that honors Tribal sovereignty, knowledge, and traditions as essential tools for addressing health disparities.

NIMH - National Institute of Mental Health

PROJECT SUMMARY One of the brain’s most remarkable abilities is its capacity to learn and adapt continuously throughout life. This capacity relies on balancing two competing demands: keeping context- and task-specific details distinct while also integrating shared structure across experiences to enable generalization. However, we still do not fully understand how the brain concurrently manages these demands, largely due to the lack of tasks designed for studying them together. We propose that memory replay—the reactivation of brain activity patterns in the absence of overt task demand—support continual learning in the brain by reorganizing neural representations to fulfill these demands. Although past research has identified evidence of replay across animals and humans, its role in learning and behavior remain unclear. To address these gaps, we have developed a new experimental design that examines examines how the brain manages to keep task-specific details separate while also extracting common patterns during continual learning. We will also explore how memory replay enables the brain to strike this balance. Our approach tests two main hypotheses: first, that the brain forms representations that segregate context- and task- specific information while abstracting shared structure across tasks; and second, that replay supports continual learning by helping to orthogonalize and abstract task representations. In our study, participants will first learn simple, one-step transitions before planning longer action sequences across three different graphs, all while their brain activity is recorded using magnetoencephalography (MEG). This design will allow us to assess how well participants retain details specific to the individual graphs and extract a hidden, abstract structure common to all of them. We will analyze both behavior and neural patterns to understand how the brain manages these dual demands, and we will compare human behavior and neural representations with that of neural network models optimized for the same tasks. We will also use advanced MEG decoding techniques to track replay events during both rest and active task phases, examining how these events shape behavior and task representations. Complementary measures, such as eye-tracking, will help us explore how different physiological states influence replay dynamics. By combining behavioral testing, neuroimaging, and computational modeling, this study aims to provide new insights into how the brain continually adapts to changing environments. The findings will deepen our fundamental understanding of human learning and memory, and guide future efforts to enhance cognitive function in educational, clinical, and aging settings.

NIMH - National Institute of Mental Health

Project Summary The proposed project addresses the need for reliable, privacy-preserving real-world evidence (RWE) on the potential mental health effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Although preliminary evidence suggests neuropsychiatric benefits, current observational studies are hindered by confounding, exposure misclassification, and institutional data-sharing barriers. These challenges are especially relevant in mental health research, where treatment timing and adherence are often uncertain. Aim 1 will develop a one- shot, lossless federated target trial emulation (TTE) framework that produces pooled-equivalent causal estimates using summary data. The model will integrate sequential trial emulation to address immortal time bias, likelihood- based exposure correction, and calibration via negative control outcomes. Summary statistics will be computed locally and securely aggregated in a single communication round. Aim 2 will evaluate the framework using de- identified EHR data from Ividence and UTSW and deliver a prototype R package. The package will include tools for data preprocessing, federated estimation, and visualization, supporting scalable and reproducible use across sites. Feasibility will be assessed based on analytic performance, system usability, and concordance with benchmark evidence. This project will deliver a scalable, privacy-compliant solution for multi-site causal inference using EHR data. It will advance the generation of RWE for mental health drug repurposing and establish a foundation for future clinical research and commercialization.

NIMH - National Institute of Mental Health

Recent advances in human genetics defined hundreds of causal variants for Autism Spectrum Disorder (ASD) and other neurodevelopmental disorders (NDDs). However, substantial effort is now required to identify downstream disease processes and guide development of interventions. One such new NOD gene is ZNF292: mutations were recently associated with ASD and other NDDs in humans, but ZNF292 requirements for brain development and consequences of pathogenic mutation have not been studied in any animal or human cellular model. Here, we propose a comprehensive mechanistic investigation of ZNF292, using both established cuttingedge workflows and innovative new approaches to study the consequences of both deficiency and pathogenic mutation at the molecular, cellular, structural, and functional and behavioral circuit levels. We use two complementary experimental systems, mouse models and human pluripotent stem cell (hPSC)-derived neurons, to define ZNF292 requirements for neurodevelopment. We focus initially on hPSC models carrying six pathogenic ZNF292 variants identified in patients with ASD, intellectual disability, and other NOD clinical phenotypes (e.g., microcephaly, epilepsy), and comparison with hPSC lines with constitutive or inducible ZNF292 deficiency. Our preliminary work has already demonstrated shared disruptions of neurodevelopment, transcriptional regulation, and neuronal network function stemming from either ZNF292 deficiency or pathogenic mutation in these models. We also developed conditional and non-conditional mouse knockout models of ZNF292 deficiency and demonstrated that these exhibit NOD-relevant circuit disruptions and, accordingly, altered behavior. Further, we developed cutting-edge tools for temporally controlled reversal of ZNF292 deficiency in our hPSC models, enabling us to investigate the effects of restoring ZNF292 gene function either during development or in mature neurons. Related landmark experiments profoundly changed our understanding of other NDDs by demonstrating that a substantial proportion of chronic NOD phenotypes were reversible, thus spurring the development of therapeutics based on either restoring gene expression or reversing its chronic consequences for neuronal function. In complementary efforts, we continue to model additional cases in this rapidly expanding patient population, linking NOD clinical phenotypes to shared, reversible endophenotypes related to altered neuronal network function. Based upon our preliminary data, we hypothesize that impaired circuit and neuronal network function stemming from chronic reduction of ZNF292 activity contributes substantially to NDDs in this patient population. These deficits may be tractable for molecular or pharmacological treatment to develop interventions. Therefore, together, the experiments performed here will elucidate requirements for and mechanisms by which ZNF292 normally controls brain development and function, will determine how these are disrupted by pathogenic ZNF292 mutation, and could also chart a course towards ZNF292-targeted therapies.