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NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This proposal will address the critical need for evidence-based transdiagnostic sleep interventions for autistic adolescents and young adults (AYA). Autistic AYA frequently report a multitude of pervasive sleep and circadian problems, including difficulties initiating and maintaining sleep, excessive sleepiness, delayed phase, and irregular sleep–wake schedules. These sleep and circadian problems often occur in unison rather as isolated problems, and contribute to the onset, worsening, and continuation of mental health disorders. This project will adapt and pilot the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C), an effective sleep intervention, so that its content and delivery are effective and sustainable for autistic AYA. Aim 1 is to iteratively adapt as needed and pilot TranS-C for autistic AYA (12-25 yrs). Preliminary data, iterative pilot testing with autistic AYA (N=15-24), and input from an advisory panel of autistic AYA (N=4), caregivers (N=4), medical providers (N=2), and behavioral health clinicians (N=2) will guide needed adaptations. Assessments for Aim 1 include multidimensional sleep health (MSH) (actigraphy, self-report measures), as well as implementation science outcomes (feasibility, acceptability, engagement, and fidelity). Aim 2 is to conduct a pilot randomized trial of the adapted TranS-C to examine intervention efficacy, as well as feasibility, acceptability, engagement and fidelity. Autistic AYA (12-25 yrs) (N=90) will be randomly assigned to the adapted TranS-C, traditional TranS-C, or a wait-list control, with assessments of multidimensional sleep health (MSH) (actigraphy, self-report measures), as well as self-report measures of anxiety, depression, emotion regulation, social functioning, and suicidal ideation and behavior, at pretreatment, posttreatment, and 3-month follow-up. Aim 3 is to evaluate hypothesized mediational processes that may explain relationship between sleep and circadian problems and mental health outcomes in autistic AYA. The resources and expertise of the assembled research team of interdisciplinary researchers will provide an outstanding context to successfully execute this project. This project will also provide necessary data for Dr. Lenker’s future R01 submission of a large-scale effectiveness trial of a transdiagnostic sleep intervention trial for autistic AYA. This project aligns with NIMH’s priorities, as it focuses on assessing and treating sleep and circadian problems within a multidimensional and transdiagnostic context to better understand underlying mechanisms related to mental health, as well as optimizing patient-centered treatment options for autistic individuals.

NIMH - National Institute of Mental Health

PROJECT SUMMARY To inform the origin and treatment of mental health and neurological disorders, there is a need to access specific cell types of the brain and determine how their interactions produce cognition, affect, and behavior. The long- term goal of this project is to understand the biology of an understudied cell type, semilunar granule cells (SLGC), in hippocampus-dependent processes. The dentate gyrus (DG) is a “gate” to the hippocampus. The principal cells of the DG, Granule Cells (GC), broadly excite CA3 pyramidal cells, which in turn excite CA1 pyramidal cells. Therefore, tight control of GC activity prevents hippocampal hyperexcitability that could impair memory and produce seizures. It is thus critical to understand how this gate functions, to determine how GC activity is constrained. In this proposal, the central goal is to develop tools to test the hypothesis that SLGCs function in vivo to limit GC activity. Based upon literature from ex vivo slice work, it has been determined that, in response to excitatory input, SLGCs fire persistently and activate interneurons to inhibit GCs. Thus, SLGCs are poised in the circuit to limit GC activity, but this model has gone untested. Whereas the in vivo roles of GCs are well defined thanks to genetic tools for their specific access, a barrier to progress has been a lack of tools that grant experimental access to SLGCs in vivo. This project pursues methods for recombinase expression in SLGCs of the mouse in vivo and the implementation of these tools to test the hypothesis that SLGCS constrain GC activity. To pursue this objective, 2 Aims are pursued. In Aim 1, strategies for recombinase expression in SLGCs of the mouse will be optimized. Aim 1 will be achieved through two independent strategies. The recombinase Cre is broadly utilized, e.g. Cre-on viral tools or conditional knockout of floxed alleles. In Aim 1, a tamoxifen-Inducible strategy Cre in SLGCs will be optimized. The approach is to characterize at least three promising mouse lines. However, SLGCs and GCs are spatially intermingled and have a high degree of transcriptional similarity, so a single gene approach may not succeed. Therefore, the second strategy of Aim 1 is an Intersectional method to achieve action of the alternative recombinase Flp in SLGCs. The approach is to utilize virus mediated expression of Flp, the expression and activity of which is gated by the SLGC selective expression of two different genes. By either strategy, this project will yield the first methods to selectively access SLGCs in vivo. Aim 2 is to determine if SLGC prevent GC hyperactivity in vivo. The strategy is to utilize recombinase mediated silencing of SLGCs and determine the impacts upon GC physiology and upon hippocampal circuit function using varied ex vivo and in vivo electrophysiology, imaging, and behavioral assays. This project will facilitate studies of the cell and circuit basis of learning and memory and will inform models of hippocampal development and pathologies, serving NIMH Goal 1 to Define the Brain Mechanisms Underlying Complex Behaviors.

NIA - National Institute on Aging

PROJECT SUMMARY The rapid aging of the global population presents a significant societal challenge, with an increasing number of older adults experiencing chronic diseases that compromise their health-span despite advances in medical technologies. This paradox results in substantial economic burdens due to lost productivity and healthcare expenditures. To address this, there is a critical need for strategies that enhance health-span, enabling older adults to maintain functional abilities, independence, and quality of life. The proposed Translational Gerontology and Geroscience (TG2) Training Program at the University of Alabama at Birmingham (UAB) aims to develop the next generation of interdisciplinary, aging-focused scientists. This program will support 5 predoctoral and 3 postdoctoral trainees; providing them with collaborative, interdisciplinary mentoring and comprehensive research training. The goal is to inspire and develop dedicated, motivated, and well-trained scientists capable of tackling society’s big challenges in the field of aging. TG2 will emphasize bidirectional training to create an interdisciplinary experience that addresses physical, mental, and social aspects of health necessary for healthy aging. The program will leverage an exceptionally rich institutional environment that offers a robust infrastructure in aging research, including NIA P30 awards for an Alzheimer’s Disease Research Center, Nathan Shock Center in the Basic Biology of Aging, and Resource Center for Minority Aging Research; as well as one of four McKnight Brain Institutes sites and a VA Geriatric Research, Education, and Clinical Center (GRECC). The program integrates 40+ faculty from five UAB Schools and Colleges (Medicine, Arts & Sciences, Nursing, Optometry, Health Professions) and includes established, independent investigators with strong mentoring history as well as rising stars in the aging field who will be part of our Mentoring on Mentoring Program. Together the trainee, mentor, and a Translational Mentoring Team will craft an individual development plan that includes coursework, laboratory and clinical research, professional development programs, workshops, presentations locally and at national meetings, and training in the responsible conduct of research. Overall, the program will build and develop a multidisciplinary cohort of scholars that will support, learn from, and challenge one another to think critically about how to address the complex challenges of aging and how to develop successful careers in gerontology and geroscience.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT The proposed Translational Neuroscience Training for Clinicians (TNTC) T32 program leverages the breadth and depth of the Boston clinical and neuroscience community to provide outstanding postdoctoral research training for clinician-scientists. Our program addresses a pressing need in the psychiatry research workforce: strengthening the pipeline for clinically trained individuals to enter translational neuroscience research careers. We are well-positioned to address this important gap, with access to both a talented pool of trainees from outstanding psychiatry residency and psychology internship programs, as well as an expansive network of basic, translational, and clinical investigators across Harvard and its affiliates. Program faculty members are seasoned investigators and mentors based at the MGH Department of Psychiatry or the Broad Institute, and each has independent funding as part of a multidisciplinary research portfolio. We are requesting support for a total of five postdoctoral fellows, who will each be co-mentored by one clinical and one translational/basic scientist. Two to three new trainees, either psychiatrists or psychologists who have recently completed their clinical training, will enter the program each year and receive a maximum of three years of support. Trainees will receive cross-disciplinary mentorship that spans two of four research “hubs,” consisting of (1) the numerous clinical research programs within the MGH Department of Psychiatry, (2) the Martinos Center for Biomedical Imaging, (3) the MGH Psychiatric and Neurodevelopmental Genetics Unit, and (4) the Stanley Center of the Broad Institute. Leveraging vast datasets from across these programs, trainees will develop mentored research projects that bridge the domains of clinical research, brain imaging, genomics, animal models, and cell/molecular biology through forward and/or reverse translation. Specialized didactic training encompasses these domains and general issues in translational research, including biostatistics, ethics, scientific writing, and career planning, in preparation for career development awards or other independent funding applications to be submitted during the fellowship period. Our trainees will, therefore, enter the fellowship period with a deep, first-hand knowledge of unmet clinical needs in psychiatry; they will graduate with a foundation of cutting-edge tools to address these needs over their careers. We have an accomplished and experienced faculty in terms of scientific expertise and methodology who have enthusiastically participated in primary mentorship and teaching in our didactic program. This T32 program will provide a strong, longitudinal mentored research experience for fellows, guided by program faculty, to foster critical scientific contributions and enhance the career development of trainees, supporting their transition to productive, independent careers in academic medicine.

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

Summary: The negative effects trauma exposure, such as those that promote PTSD, can be passed to offspring. While the environment in which affected parents raise their offspring clearly plays a role, a significant genetic component also exists. However, some of this genetic influence, typically revealed by twin studies, may stem from epigenetic inheritance; as implied by studies in male rodents, where trauma-specific changes in sperm miRNA content can lead to trauma-specific behavioral changes in all offspring. Evidence for epigenetic inheritance in humans is mainly epidemiological, but recent studies have revealed stress-induced sperm miRNA changes consistent with this idea. For example, we found that men with high Adverse Childhood Experiences (ACEs), whose children can be negatively affected, show reduced sperm levels of miR-34/449 family members; mirroring findings in mice exposed to chronic social instability (CSI) stress across generations. In mice, these sperm miRNA changes persist in preimplantation embryos post-fertilization, altering early embryonic gene expression that leads to elevated anxiety and impaired sociability in female offspring as well as reduced levels of sperm miR-34/449 in males. Our new data driving this proposal reveals another example. The degree of men’s exposure to adult trauma, as assessed by the Trauma History Questionnaire (THQ), which measures PTSD risk, correlates with the levels of miRNAs 532, 361, 375, and 491 in their sperm. The highest THQ scores are associated with 4- to 130-fold increases in these levels. In contrast, these miRNA changes do not correlate with ACE scores and miR-34/449 does not correlate with THQ score. Notably, miRNAs-532 and 375 are two of the 9 sperm miRNAs whose enhanced levels in male mice mediate how chronic variable (CV) stress leads to a suppressed HPA axis response in offspring, a trait linked to mental health disorders. This proposal investigates how elevated levels of sperm miRNAs-532,361,375 and 491 in men with high THQ scores might affect their offspring using the mouse model that previously demonstrated how elevated levels of sperm miRNAs transmit the stress-related effects of paternal CV stress across generations. Aim 1 tests how injecting THQ-associated miRNAs, at levels found in sperm of men exposed to high levels of trauma, into mouse zygotes affects the phenotypes of resulting offspring. Aim 2 will begin to reveal how these injected miRNAs lead to phenotypic changes revealed in Aim 1 by i) identifying gene expression changes induced by them in mouse blastocysts, and ii) looking for similarities to those occurring in discarded blastocysts from IVF procedures using men’s sperm with elevated THQ associated miRNAs derived from an ongoing, independently funded project. This study has the potential to: a) provide strong support for using mouse models to understand epigenetic inheritance in humans; and b) drive future research showing that a significant portion of inherited susceptibility to mental health disorders arises from epigenetic inheritance, and how to reverse it before fatherhood.

NIMH - National Institute of Mental Health

Project Summary/Abstract Post-traumatic stress disorder, or PTSD, is a mental health condition that develops following exposure to traumatic events. In the United States, it affects approximately 5-10% of the general population. Although multiple treatments are available, a significant gap persists in the current understanding of the underlying mechanisms and objective predictors (i.e., treatment-related biomarkers) of the treatments for PTSD. Our study aims to develop a framework, called “Trauma Recovery via EEG and Actigraphy Tracking” or TREAT, to address this gap. TREAT utilizes advanced neurophysiology and imaging technologies, including conventional, portable, and dry EEG, as well as actigraphy-based sleep pattern monitoring, to track the physiological and electrophysiological brain-based changes modulated by Written Exposure Therapy (WET), a robust and scalable treatment paradigm. Comparing pre- versus post-treatment EEG and sleep data, Aim1 will identify clinically relevant biomarkers of WET. This aim is to pinpoint the key EEG channels that are most responsive to WET, thereby providing insight into the spatial effect of WET in PTSD. It will also pinpoint key EEG and sleep biomarkers associated with symptom reduction, providing objective measures to track WET outcomes. Aim2 will longitudinally track neurophysiological and sleep-related markers to identify a critical time point when the shift in EEG/sleep markers begins during WET. Creating a temporal map of the WET effect on EEG and sleep enables clinicians to optimize treatment duration and intensity for each individual patient in the future. Finally, Aim3 will provide models that predict WET outcome only based on baseline EEG and sleep markers, supporting personalized treatment selection and avoiding ineffective interventions in the future. This aim will determine which baseline EEG channels, EEG biomarkers, and sleep markers predict treatment outcomes prior to the initiation of therapy. Finally, it will identify subgroups of patients (i.e., biotypes) characterized by distinct EEG and sleep profiles at baseline, which will enable the prediction of treatment response and advance personalized intervention strategies. By drawing on expertise from clinicians, therapists, biostatisticians, engineers, and computational neuroscientists, this project will establish TREAT as a comprehensive biomarker identification framework for PTSD treatment and potentially for other neuropsychiatric conditions.

NCI - National Cancer Institute

ABSTRACT Cigarette smoking is the leading preventable cause of premature cancer-related mortality in the US. Quitting smoking lowers cancer risk, improves mental health, and can increase life expectancy by 10 years. Women are less successful in their attempts to quit smoking and their rates of quitting are lower than that of men. Women experience greater smoking-related disease and increased risk of mortality from smoking. Women face distinct challenges which can impede smoking cessation. One particularly important factor is psychological trauma. Women have a greater prevalence of trauma exposure and are three times more likely to experience post- traumatic stress disorder compared to men. Trauma is a significant risk factor for smoking initiation and is associated with lower quit rates and increased cancer risk in women. However, no national studies have examined the impact of trauma on difficulty with tobacco cessation in women. Further, though the use of trauma- informed approaches has improved treatment engagement and outcomes for patients with alcohol and other substance use, studies have not evaluated trauma-informed approaches to tobacco cessation in women. The proposed training and research plan for this K08 application will enable Dr. Anita Hargrave to obtain the necessary skills to achieve her career goal of becoming an independent NIH-funded clinician-investigator leveraging expertise in advanced statistical analyses, implementation science, and clinical trials to improve tobacco cessation and women’s cancer prevention using trauma-informed approaches. With a highly experienced mentorship team and a thorough training plan, Dr. Hargrave will build on her prior experience in trauma and cancer-related research to obtain mastery in using nationally representative survey data, applying implementation science behavior change theory, and conducting a pilot randomized controlled trial. This training will complement and facilitate the completion of her research aims: (1) assess challenges to successful tobacco cessation among women with and without trauma histories using a national survey; (2) conduct a formative evaluation using an implementation framework to adapt an evidence-based tobacco cessation intervention by incorporating trauma-informed approaches; (3) determine the feasibility and acceptability of the novel trauma- informed tobacco cessation intervention in a 12-month pilot randomized controlled trial (RCT). The proposed research will inform the development of an R01 application to evaluate the trauma-informed tobacco cessation intervention in a full-scale RCT, with the goal of improving tobacco cessation and cancer prevention for women with histories of trauma.

Office of Juvenile Justice and Delinquency Prevention

Grants to federally recognized tribes for juvenile justice, delinquency prevention, and mental health programs for tribal youth.

NIMH - National Institute of Mental Health

Trichotillomania (TTM) is a chronic and impairing obsessive-compulsive and related disorder that involves repetitively pulling one’s hair, causing visible hair loss. TTM in youth and emerging adults is associated with shame, low self-esteem, academic and social impairment, and comorbid anxiety and depression. Despite the substantial morbidity associated with this condition, existing treatments have clear limitations. There are no known effective medications. Frontline psychotherapy is habit reversal training (HRT), a simple behavior therapy with modest efficacy and durability, perhaps due to its lack of focus on core emotional and cognitive experiences (e.g., shame, perfectionism) that maintain and exacerbate hairpulling. HRT is also extremely difficult to access, due to a scarcity of trained clinicians, high costs of specialty care, and logistics of receiving care (e.g., needing appointment times after school hours) - barriers which disproportionately affect young people. Indeed, less than one-fifth of youth with TTM receive frontline care. To address critical care gaps in this undertreated specialty population, and in line with NIMH Strategic Goal 4 to improve the efficiency, effectiveness, and reach of mental health services, we seek to develop TrichTok, a novel digital self-help TTM treatment for adolescents and emerging adults that (1) is specifically designed with and for adolescents and emerging adults, (2) is delivered in brief TikTok-style videos, to be scalable, accessible, and engaging for teens, (3) incorporates coach-moderated peer support, to further address shame and isolation that affect youth with TTM, and (4) builds on HRT to also incorporate novel cognitive skills that target mindset shifts around shame and perfectionism, for greater efficacy. Initial pilot data from clinician and teen end-user stakeholders provides very strong support for the idea as important, innovative, and feasible, and underscores the value of adapting the program’s design and content specifically for young people with TTM. To accomplish objectives, we will build a functional beta version of the program via iterative user-centered design and development in collaboration with 10 licensed clinicians with expertise in adolescent TTM and 10 adolescents and emerging adults with TTM (Aim 1). Next, we will test the program’s feasibility, usability, and acceptability in 30 adolescents and emerging adults with TTM nationally, via an open pilot trial. Results will be evaluated against pre-registered success criteria. Our team consists of developers, designers, and people with lived experience who created the HabitAware online community and device (a smartwatch that passively detects hairpulling and supports HRT, developed under R43MH114773) and NIH-funded psychologists with expertise in research and treatment of TTM across the lifespan. If we achieve success criteria, we will seek Phase II funding to validate TrichTok’s efficacy and potential for commercialization via a randomized controlled trial as a next step. If successful, this proposal will uniquely result in a relatable, engaging, and novel intervention for adolescent TTM that can dramatically enhance access to care and effectiveness of care.

TX Veterans Commission

Grants for veteran employment services, mental health programs, and housing assistance.

UJA-Federation of New York

One of the largest local philanthropies in the world. Funds poverty relief, aging services, mental health, education, and community strengthening in New York.

NIMH - National Institute of Mental Health

Background: Depression is a serious mental disorder, with treatment selection largely relying on trial and error, often prolonging patients' suffering. The increased availability of electronic health records (EHRs) and advancements in AI offer new opportunities to address this clinical challenge. However, current EHR-based approaches have shortcomings: a. they underutilize information in unstructured data that could be important for outcome prediction and confounding adjustments; b. they lack accuracy in cohort definition and treatment response assessments; c. they omit genomic information, which is known to affect treatment response; and d. they are not aware of uncertainties arising from the fitness of assumptions required to produce reliable predictions, potentially providing misleading estimates. In addition, genetic tests currently available are limited to select genetic variations, failing to utilize information from the full genome. Research: We propose to address these limitations by crafting advanced AI models for predicting differential antidepressant treatment responses, leveraging the latest developments in natural language processing (NLP), predictive modeling, causal inference, and the inclusion of both EHR and genomic data. Aim 1 will involve developing a large language model-based, human-in-the-loop active learning framework to identify an incident-user cohort started on antidepressants for depression, assess treatment responses, and extract key depression-related information from clinical notes. Aim 2 will develop uncertainty-aware, EHR-based prediction models for differential antidepressant responses, accounting for cases where a patient-antidepressant pairing falls outside the training data and for residual confounding. Aim 3 will combine EHR and three classes of genomic predictors for response prediction: genome-wide and pathway-specific polygenic risk scores, and variations associated with cytochrome P450 enzymes. This effort will enhance our understanding of integrating EHR and genomic data to predict personalized treatment responses, paving the way for future comprehensive systems. Candidate's Career Development, Goals, and Environment: The research objectives and the candidate's career development will be facilitated by the abundant resources at Massachusetts General Hospital and Harvard Medical School, as well as formal training and mentorship in (G1) advanced clinical NLP, (G2) integration and analysis of large-scale EHR and genomic data, (G3) ‘causal machine learning’ and its uncertainty assessments, and (G4) grantsmanship, leadership, effective collaborations, and research management. The mentorship team comprises Mentor Dr. Jordan Smoller, a leader in precision psychiatry and clinical predictive analytics; Co-Mentor Dr. Tianxi Cai, an authority in bioinformatics and healthcare predictive modeling; and Consultants Dr. Timothy Miller, an expert in NLP and AI, Dr. Issa Dahabreh, a specialist in causal inference, and Dr. Tian Ge, a renowned statistician and geneticist. This award will equip the candidate with the advanced skillset to become an independent researcher in precision psychiatry.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The UNDERSTAND project aims to develop and evaluate an innovative mobile health system designed to support young adults dealing with comorbid Major Depressive Disorder (MDD), Social Anxiety Disorder (SAD), Generalized Anxiety Disorder (GAD), and other anxiety-related conditions. These mental health conditions are highly prevalent, frequently co-occur, and lead to significant functional impairment in social, academic, and daily life settings. Traditional therapeutic approaches, such as Cognitive Behavioral Therapy (CBT) and Dialectical Behavior Therapy (DBT), have demonstrated efficacy in clinical settings but often fail to provide real-time, context-sensitive support during the daily interactions and triggers that exacerbate these symptoms. The overarching goal of UNDERSTAND is to address this critical gap by leveraging mobile and wearable sensors, machine learning models, and Large Language Models (LLMs) to deliver Just-In-Time Adaptive Interventions (JITAI) based on DBT principles. Grounded in transdiagnostic theory, the system targets shared mechanisms such as emotional dysregulation, cognitive distortions, and interpersonal challenges across MDD, SAD, GAD, and related disorders. It will unobtrusively monitor physiological and socio-behavioral indicators such as heart rate variability, speech patterns, and body posture, which are correlated with symptoms across these emotional disorders. In moments of heightened emotional distress, the system will deliver tailored interventions in real-time, helping individuals manage their anxiety, depressive symptoms, and other triggers during challenging situations. The project has three specific aims: (1) to develop and validate predictive models using sensor data to detect emotional distress in real-time across a range of anxiety and depressive triggers, (2) to design and implement personalized, LLM-driven interventions that provide DBT-based guidance through mobile and wearable devices, and (3) to evaluate the feasibility and user experience of the system through iterative co-design with young adults and DBT-trained clinical psychologists. If successful, this project represents a paradigm shift in mental health care by moving from clinic-based, reactive treatments to proactive, real-time interventions that can be seamlessly integrated into daily life. The system has the potential to improve mental health outcomes, reduce the long-term burden of untreated comorbid emotional disorders, and advance the field of mobile health technology by providing scalable, technology-driven solutions for managing complex mental health conditions in naturalistic environments.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT ABSTRACT For most people, alcohol use generally peaks before age 25 years and then decreases. For some, however, alcohol use increases throughout adulthood, leading to alcohol use disorder (AUD) and many adverse mental and physical health consequences. Understanding who develops persistent AUD can inform intervention models for AUD and its consequences. Antisocial behavior (ASB) and other substance use disorders (SUDs) are often comorbid with AUD and are associated with more AUD persistence and worse psychosocial functioning among those with AUD. Three key study design features make the proposed project well- positioned to advance the science of AUD and co-occurring ASB and other SUDs. First, studies of AUD, other SUDs, and ASB are often limited by the low prevalence of these behaviors. We propose a new assessment of a highly affected longitudinal sample of 559 participants now in mid-adulthood who have high rates of AUD (67%), ASB (50% arrested), and other SUDs (cannabis = 44%, amphetamine = 16%, cocaine = 16%, opioid = 8%). Second, longitudinal data are critical to understanding when alcohol use is a cause, as opposed to a consequence, of poorer functioning (e.g., psychiatric symptoms, including ASB and other SUDs). The data collected in the proposed project would comprise the fourth assessment wave of these participants (spanning adolescence and mid-adulthood), allowing us to assess the mental and physical health effects of persistent AUD and whether other SUDs and ASB exacerbate such effects. Third, alternative explanations must be considered to understand AUD’s effects fully. We propose a sibling-comparison design that controls familial confounds while testing AUD's potential causes and consequences. Specifically, this project will combine data from the proposed participants with data from their siblings, who have been assessed in parallel with our proposed participants at three prior waves and are currently being assessed for a fourth wave in another project. Leveraging these study design characteristics, we propose to examine two common theoretical models that can help understand the nature and timing of risk/protective factors for AUD and co-occurring ASB and other SUDs. The first is that ASB and other SUDs cause or worsen AUD, or vice versa (Aim 1). The second is that AUD, ASB, and other SUDs are explained by pre-existing risk/protective factors, such as early-life risk factors (e.g., stressful environment, education), personality (e.g., impulsivity), and neurocognitive functioning (Aim 2). A final strength of this project is the inclusion of individuals who are underrepresented in alcohol research, including 36% women and 31% previously incarcerated. These sample characteristics will greatly increase the generalizability of findings from the proposed work and support our ability to examine sex differences in the causes and consequences of persistent AUD (Aim 3).

NIMH - National Institute of Mental Health

PROJECT SUMMARY The Developmental Origins of Health and Disease framework has illuminated that maternal factors during pregnancy, such as exposure to elevated stress, increase children’s risk of mental health problems, via prenatal and postnatal mechanisms. Thus, there is a critical public health imperative to conduct research in this area to understand and ultimately prevent the development of psychopathology. Fetal exposure to elevated maternal inflammation during pregnancy (PMI) increases risk for child psychopathology via placental mechanisms, however, evidence from animal and human models suggests that heightened PMI may also disrupt maternal parenting behaviors. Via a phenomenon called “sickness behaviors,” high levels of inflammation can cause social withdrawal, depression-like feelings, and problems understanding social situations. Although social withdrawal and depressive tendencies may be potentially adaptive, energy- conserving responses that facilitate fighting an infection, affective and social difficulties may impair parents’ ability to recognize and respond optimally to their baby’s signals. Critically, the direct and indirect associations among PMI, parenting, and child mental health have not yet been tested in humans. In this proposal, I will fill critical training gaps in prenatal immune biology, advanced longitudinal statistical modeling, and multidisciplinary intervention research to test 3 Aims. First, I will leverage my primary mentor’s deeply-phenotyped, sociodemographically diverse longitudinal pregnancy cohort of mother-child pairs (n = 1303) to test the novel hypothesis that parenting partially accounts for positive associations between PMI and childhood mental health problems (Aims 1 and 2). Mentored training and findings will inform a pilot intervention study in which I partner with a well-established clinical research program to bridge Aims 1-2 findings with applied solutions (Aim 3). This program delivers an evidence-based intervention targeting traumatic stress exposure (Perinatal Child-Parent Psychotherapy) to pregnant Latina women. In this study, I will collect repeated measures of PMI as well as observations of parenting and infant behavior (n = 20). Preliminary findings from associations among intervention-related changes in PMI, parenting, and infant behavior will validate the mechanism tested in Aims 1 and 2 and lay the groundwork for a follow-on R-34 intervention study testing effects of prenatal psychological intervention on PMI, parenting, and child mental health. Investigating associations between PMI, parenting, and child mental health will elucidate the etiology and maintenance of child psychopathology, as well as mechanisms for targeting prenatal prevention and postnatal intervention. Addressing these potential determinants and solutions are public health and NIMH priorities. Mentored training from this K23 proposal will support my transition to an independent interdisciplinary clinical science career investigating and preventing the intergenerational transmission of stress and psychopathology.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Electroconvulsive therapy (ECT) is a highly effective treatment for severe treatment-refractory depression and other conditions, in which carefully titrated electrical stimulation elicits brief, generalized seizures to change the brain to improve symptoms. An abundance of longitudinal MRI studies report robust and replicable brain plasticity after ECT, including increased hippocampal gray matter. However, it remains unclear how or why seizures are therapeutic in this context. Epilepsy research has demonstrated that seizure activity progresses through different brain regions and networks. Initial detection of seizure activity often occurs in a specific brain region (e.g., in medial temporal lobe), which can propagate locally, and in some cases spread via highly coordinated thalamo- cortical activity during generalization. Endogenous processes terminate the seizure, involving regions like anterior thalamus, basal ganglia, and cerebellum. A similar process appears to occur in ECT targeting temporal lobes, where electrical current initiates seizure activity in seizure-genic regions of medial temporal lobe (MTL), progressing to generalized seizure activity. Some seizure-network nodes have been implicated in antidepressant response to ECT, including parts of the hippocampus and thalamus. However, many seizure-network nodes are understudied in both ECT and epilepsy research in humans, because they are not included in standard MRI atlases (e.g., piriform cortex, substantia nigra, cerebellar nuclei) or due to limited spatial resolution in other neuroimaging techniques (e.g., coarse spatial resolution in molecular imaging, difficulty resolving deep structures in scalp EEG, limited number and position of pre-surgical recording electrodes in intracranial EEG). Thus, a precise, comprehensive understanding of seizure-network connectivity both in therapeutic seizure in ECT and pathological seizure in epilepsy remains elusive. The proposed studies will leverage pre-existing multi-modal MRI datasets to provide fundamental, mechanistic knowledge of entire seizure-network function before and after therapeutic and pathological seizure. The overall goal is to understand how seizure-network nodes interact in typical states and after therapeutic and pathological seizure, and to use that mechanistic knowledge to improve the administration of ECT, by using pre-treatment brain state to predict susceptibility and response to seizure therapy and by manipulating stimulus dose to influence the putative site of seizure initiation. Beyond improving the administration of ECT, the proposed studies have the potential to inform new neuromodulation strategies for depression, epilepsy, and other disorders, and to further knowledge of brain network function.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Psychedelics have shown strong potential to improve multiple difficult-to-treat mental health conditions. Defining and measuring post-acute psychedelic-related adverse effects (AEs) is a necessary step toward enhancing the safety of psychedelic interventions, developing strategies to reduce likelihood of persisting AEs, and for developing treatments for persisting AEs when they occur. Persisting AEs of psychedelics, recognized in scientific literature, are poorly captured by existing assessments. This K23 will validate a measure of post- psychedelic AEs, characterize AE profiles liked with persisting impairment, and develop consensus-based strategies for prevention and treatment of post-acute psychedelic AEs. Candidate: Dr. Palitsky is a clinical psychologist with a strong background investigating determinants of differential response to interventions, acquired through doctoral training and a postdoctoral fellowship. An Assistant Professor at Emory University School of Medicine, his career aim is to lead a R01-funded program of research that enhances the safety of multicomponent psychiatric interventions including, but not limited to, psychedelics. Training: Dr. Palitsky’s career goals require additional training in psychedelic-assisted therapy development, clinical trials, biostatistics including structural equation modeling and psychometrics, and translational impact and scientific leadership to inform standards and policy. Accordingly, this K23 leverages multidisciplinary training in Emory’s departments of Psychiatry, Health Sciences, and Ethics, alongside individualized curricula using extramural resources tailored to his needs. Training includes formal coursework, individualized training with mentors, and structured career development support. Mentoring: An exceptional team of investigators committed to mentoring Dr. Palitsky include: Primary mentor Dr. Barbara Rothbaum, PhD, who has expertise in psychotherapy development and psychedelic-assisted therapies, and co-mentors with expertise in clinical trials and psychopharmacology (Dr. Boadie Dunlop, MD), biostatistics (Dr. Job Chen, PhD), and translational impact and scientific leadership (Dr. Charles Raison, MD). A significant contributor, Dr. Todd Korthuis, MD, will give expert oversight on Delphi methodology and recruitment for population health research. Research: Leveraging existing studies and established partnerships with psychedelics safety research stakeholders, this project will validate a preliminary measure post-acute psychedelic AEs initially developed by the PI (N = 940); characterize persisting AE profiles using a longitudinal study (N = 400, 6 waves in 1 year); and produce consensus on primary and secondary prevention strategies using a Delphi study (N = 25). Products include 7 planned manuscripts, a living protocol for psychedelic AE measurement, and an R34 and R01 submitted by the applicant. Environment: The candidate receives strong institutional support from the Department of Psychiatry and Behavioral Sciences. The training environment includes multiple Emory collaborative health institutes and Emory’s Mood and Anxiety Disorders Clinic, the site for the applicant’s planned R34 and R01.

NIMH - National Institute of Mental Health

Project Summary: Schizophrenia Spectrum Disorders (SSD) are severe, chronic psychiatric conditions that impair cognitive functioning and sensorimotor coordination, affecting approximately 3.5% of the population. While existing treatments primarily address positive symptoms, negative symptoms, and cognitive impairments remain largely unresponsive to current interventions. Cognitive deficits, often more debilitating than positive symptoms, serve as significant predictors of long-term disability and diminished quality of life. Consequently, there is an urgent need for new approaches targeting cognitive dysfunction in SSD. Recent studies underscore the cerebellum’s involvement in cognitive functions such as attention and memory, which are disrupted in SSD. Traditionally linked to motor control, the cerebellum also plays a crucial role in cognitive processing, emotional regulation, and social behavior. However, its precise contribution to SSD remains poorly understood. This study seeks to bridge this gap by examining the cerebellum’s role in SSD through multimodal neuroimaging techniques, including resting-state functional MRI (rsfMRI), diffusion MRI (dMRI), and multi-echo gradient (mGRE) imaging. The research will compare young adults with early-stage SSD to healthy controls, investigating how cerebellar abnormalities contribute to cognitive deficits and identifying potential biomarkers for early intervention. By focusing on early-stage SSD, this study aims to identify biomarkers associated with cerebellar dysfunction in individuals with schizophrenia, laying the groundwork for future diagnostic tools and targeted treatments. The fellowship will provide advanced training in neuroimaging, data analysis, and clinical applications under the mentorship of Dr. Mariana Lazar, equipping the researcher with the expertise needed to become an independent investigator in the field. The potential impact of this research is substantial, offering novel insights into the cerebellum’s role in early-stage SSD and paving the way for innovative treatments to enhance cognitive outcomes and overall quality of life for individuals affected by the disorder.

NIMH - National Institute of Mental Health

Project Summary Uncertainty-related cognitive dysfunctions are central to anxiety disorders, behavioral addictions, attention- deficit hyperactivity disorder, and schizophrenia, yet remain poorly understood. Anxious individuals, for example, are highly intolerant of uncertain situations, while those with gambling addictions often seek uncertainty, leading to loss-chasing behaviors. These diverse clinical presentations may stem from a fundamental computational challenge: the brain must simultaneously distinguish between two types of uncertainty—moment-to-moment stochasticity of observations and environmental volatility (how quickly underlying causes change)—that require opposite learning strategies. Previous work has focused on one factor or the other, but in reality, both volatility and stochasticity are unknown and potentially changing. Importantly, while they both increase experienced noise, they require opposite behavioral responses, making their dissociation both critical and computationally difficult and prone to systematic errors. Our recent work provides a computational framework for how the brain solves this challenge and how this process breaks down in psychiatric illness. In a large-scale neuroimaging program spanning three aims, we combine behavior, computational modeling, simultaneous fMRI-pupillometry, and causal arousal manipulation to elucidate neural mechanisms processing uncertainty while systematically manipulating both volatility and stochasticity across different outcome types. We will test specific hypotheses about the neurocomputational mechanisms of uncertainty processing (Aim 1), determine whether they are causally linked to arousal mediated by the locus coeruleus–norepinephrine system (Aim 2), and examine how these processes differ across outcome types (Aim 3), providing a mechanistic foundation for understanding uncertainty-related symptoms across psychiatric disorders.

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

PROJECT SUMMARY The psychosocial functioning of youth in our society is currently the cause for widespread concern. By middle childhood, ~20% of children have behavior problems. To address growing concerns about the psychosocial functioning of our youth and consequences for society, the scientific community is interested in the earliest developmental origins of these problems. Stress during gestation and early childhood is a critical determinant of poor bio-psychosocial competence. However, the pronounced heterogeneity of outcomes among early life stress-exposed children makes it difficult to determine when, for whom, and how children are affected. Gaining such knowledge is the long-term goal of our research. This project leverages our previous R01- funded project (NICHD grants # R01HD085990, R01HD100469) that is following a cohort of 374 mother-child dyads oversampled for life stress, with data collection starting at gestation week 15 until age 6. We conducted a granular assessment of pregnancy stress (measured weekly by maternal report), as well as a frequent (every 3 month) assessment of early childhood stress with the goal of understanding critical periods when stress derails later childhood biopsychosocial functioning. The overall objective of this project is to examine when, for whom, and how prenatal and early childhood stress shape biopsychosocial development in middle childhood. Middle childhood is a developmental period in which much of the self-regulation developed in early childhood is consolidated and is highly predictive of functioning in adolescence and adulthood. Specifically, in Aim 1 we will determine when stress during the prenatal and early childhood periods and the interaction of this timing influences 5 salient domains of biopsychosocial competence in middle childhood (internalizing/ externalizing behaviors, stress reactivity, social/academic competence). In Aim 2, we will identify for whom by examining subgroup differences (i.e., sex and supportive contexts) in effects of the timing stress on middle childhood outcomes. Finally, in Aim 3, we will examine which domains of early childhood psychobiological regulation mediate the effects of early life stress. We will use advanced confirmatory data analytic methods to address these questions, as well as machine learning to follow-up our hypothesis testing by leveraging all data to identify which effects among when, for whom, and how are most salient. This project is innovative in its multimethod approach (e.g. observation, biomarkers of stress, lab tasks), its granular assessment of prenatal and early childhood stress, and the novel statistical approaches used to determine which epochs of stress are most relevant for biopsychosocial competence. This highly significant research will be the first longitudinal, prospective, multi-method study of how differential timing of early life stress influences the development of biopsychosocial competence in middle childhood. Thus, this study is critical in developing data-informed, targeted interventions for early-life stress to address the alarming mental health crisis among our youth.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Abstract The bed nucleus of the stria terminalis (BNST) plays a pivotal role in processing emotional information and is linked to key brain regions relevant to mental health and alcohol use disorders (AUD). Despite decades of foundational studies emphasizing BNST's significance in anxiety, stress, and addiction, these studies have primarily been cross-sectional, often relying on small datasets comprising only a few dozen individuals. Both negative affect (anxiety and depression) and problematic drinking typically emerge during adolescence, highlighting the importance of investigating the BNST during this stage of development. Understanding the development of BNST during adolescence has been hampered by significant time required to manually trace the BNST. To address this barrier, we will develop automatic BNST segmentation algorithm to identify BNST and acquire BNST measures in the NCANDA dataset, facilitating investigation into BNST development in adolescents and the impact of BNST changes on the emergence of anxiety and alcohol consumption. Our central hypothesis is that developmental increases in BNST volume and function will be associated with increased alcohol use and heightened negative affect during adolescence. In Aim 1, we will develop the first automatic BNST segmentation model via deep learning. Our work will address two key challenges in BNST segmentation through deep learning: the scarcity of annotated samples and the inconsistency in segmented BNSTs from diverse sources. In Aim 1-A, we plan to generate synthetic brain-segmented BNST pairs using a generative adversarial network and transfer learning for data augmentation. This method aims to closely replicate the distribution of real data, facilitating the creation of a more comprehensive training dataset for subsequent deep learning-based segmentation. In Aim 1-B, we will construct an automatic BNST segmentation model with label fusion through deep learning. The label fusion net in this model will integrate individually segmented BNSTs obtained through deep learning with multiple BNST atlases, enhancing the overall accuracy of segmentation. In Aim 2, we will investigate whether the increase of BNST volume and function can predict increases in alcohol drinking or negative affect during adolescence. Aim 2-A will examine whether the increase BNST volume and function at initial visit can predict increases in alcohol use or negative affect. Aim 2-B will measure BNST volume and function developmental trajectories and determine whether they are positively correlated with increases in alcohol use or negative affect. The study's impact lies in filling critical knowledge gaps regarding BNST development in adolescents and the impacts BNST development on alcohol use and negative affect. Insights gained could inform targeted interventions to mitigate alcohol-related risks during adolescence.

Indian Health Service

To support urban Indians in four program areas - immunization, health promotion & disease prevention, mental health, alcohol and substance abuse.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Chronic exposure to stress and its hormone cortisol is associated with psychiatric disorders such as depression, anxiety, and bipolar disorder. Studies have suggested that these disorders develop, in part, due to the ability of stress and cortisol to cause epigenetic changes that in turn lead to persistent changes in the function of genes that are critical for brain function and neurodevelopment. These stress-associated epigenetic changes are important because they represent environmental risk factors that work in conjunction with genetics to precipitate psychiatric symptoms. Unfortunately, there are very few effective medications that can reverse or attenuate the epigenetic changes caused by environmental stressors. Recently, we have developed a novel tool that can potentially alleviate the effects of stress on gene dysregulation. We found that a simple fragment of modified, single-stranded (ss) DNA probe designed against specific locations in the genome can cause epigenetic changes to occur. We tested this tool on a candidate stress response gene that we have previously shown to undergo cortisol- and stress-induced epigenetic changes. Application of our ssDNA probe against a crucial regulatory region of this gene in neuronal cells caused the reversal of much of the epigenetic change brought about by cortisol exposure. In addition, we also engineered lipid-based extracellular vesicles (EVs) capable of packaging and delivering the ssDNA probe to the brain. We found that expressing brain-derived proteins on the surface of these EVs can increase their targeting efficiency to the brain. Combined, these approaches constitute a potentially powerful translational tool for treating psychiatric disorders. To apply this technology in an animal model, we propose the following two aims. In Aim 1, we will test whether epigenetic changes in the brain of stressed mice can be reversed by injecting EVs carrying the ssDNA probe. We will use EVs that we have previously demonstrated to show increased uptake efficiency in the brain. EV-injected animals will be assessed for reversal of epigenetic changes as well as other molecular changes in gene expression, protein levels, and protein function. In Aim 2, we will further engineer EVs by performing a survey of cell surface proteins of different brain regions. Brain regions such as the hippocampus, amygdala, hypothalamus, and cortex are all impacted by stress and highly relevant to psychiatric disorders. By expressing surface proteins that are specific to each brain region, we anticipate steering the uptake of EVs to any brain region of interest. Stressed animals will be tested as in Aim 1 but this time incorporating the engineered EVs. Since the ssDNA probes and EVs are easy to manufacture, a successful completion of the aims can lead to the development of a powerful therapeutic tool that can be customized to any gene and brain region of interest to reverse stress-induced epigenetic changes in the brain.

NIH

Background: How can we apply the community health worker (CHW) model to help both care partners and Veterans with serious illness in rural areas? Little is known about this approach. We will test a VA-supported intervention successfully piloted in the Durham VA and surrounding rural communities in 2021. VA’s Office of Rural Health, Caregiver Support Program and National Social Work Office are aware and support this work. Significance: Clinically, this work will help improve care for rural Veterans with serious illness by supporting care partners in their caregiving role in the community thus bolstering the care of Veterans receiving primary support from care partners in rural areas. A strength of our intervention is that it adapts and extends a successful model of individualized support commonly used outside of the VA. This approach maximizes the potential for sustainability, broad dissemination, and care delivery impact across the VA. This work will be generalizable. Strategically, this SDR proposal responds to the National Academies report recommending all health systems, including VA, develop processes to routinely identify, assess, and support needs of care partners. Our project meets rural health access, long-term care/aging, engagement science, and caregiving HSR priorities for investigator-initiated research focused on rural populations. Additionally, our proposed efforts fit squarely with the VA’s Rural Health State of the Art conclusion that we must expand VA partnerships in the community and help Veterans and their families understand their options for care and support in the community and at the VA. Innovation & Impact: This project is innovative because of its focus on social and practical needs of care partners, advances the science of community engagement in VA care and support, and situates a care partner- focused community health worker model squarely in the VA system for the first time. The entire project is guided by a Community Advisory Board (CAB) composed of social service, serious illness care, and rural care experts plus Veterans and care partners with lived experience. Specific Aims: Aim 1. Determine CHW effectiveness in reducing care partner burden, increasing Veterans' well-being, and increasing care partner-Veteran satisfaction with VA care in the intervention group compared with the usual care (CSP) group: We will apply our feasible CHW intervention to a larger sample, randomized control trial. (Hl) Care partners randomized to the intervention group will have lower mean Zarit-12 scores at 6 months compared to the control group. (H2) Care partners and Veterans randomized to the intervention group will have higher mean 1-item CAHPS Global Satisfaction scores at 6 months compared to the control group. (H3) Veterans randomized to the intervention group will have higher mean Warwick Edinburgh Mental Well- Being scores at 6 months compared to the control group. Aim 2: Following intervention, explore Veterans' and care partners' experience of care and support using subgroup semi-structured interviews in the intervention group. We then facilitate CAB Delphi Method sessions (including study Veterans, CHWs, and care partners) exploring Aims 1/2 data using equity-focused intervention mapping for wider implementation. Aim 3: Conduct budget impact analysis from the VA perspective to evaluate cost-drivers and assess feasibility to inform adaptation and implementation of the intervention within Durham VA Health Care System. Methodology: Two-arm randomized control trial using validated measures. We follow this using qualitative exploration with participants plus a Delphi method exploring implementation with the community advisory board and participants. We end with a unique business impact analysis of the intervention. Next Steps/Implementation: We are supported/advised by VA’s Office of Rural Health and Caregiver Support Program in Durham, NC with additional advisement from National Social Work Office, Chaplaincy, Palliative Care, county Veteran Services and Area Agencies on Aging (see LOS). If successful, this intervention can be added to the options available from CSP to support rural care partners and their seriously ill Veterans.