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NIH

Significance to VA: Adverse drug reactions (ADRs), the harmful unintended reactions resulting from the use of medications, can result in hospital visits, or even death. Polypharmacy is a known risk factor for ADRs. This is especially true for Gulf War Veterans (GWV); one fifth (21.2%) of GWV experience central nervous system (CNS)-active polypharmacy and 39.6% of these GWV experience an ADR. This is likely because ~30% of GWV meet criteria for Gulf War Illness (GWI). Two enzymes, CYP2D6 and CYP2C19, metabolize many of the drugs used to treat GWI, contribute to ADRs. Precision medicine, a medical approach that considers individual differences in genes, environment, and lifestyle, can improve treatment outcomes. This approach uses pharmacogenetic (PGx) testing, a method that examines how one's DNA affects the response to medications. To reduce risk of harm in GWV, prescribers could optimize pharmacologic treatment via precision medicine. This application is highly relevant to VA and Health Systems Research (HSR) priorities including: 1) The Commander John Scott Hannon Veterans Mental Health Care Improvement Act that requires the VA to implement precision mental health care; 2) suicide prevention; 3) quality and safety of health care; and 4) the Promise to Address Comprehensive Toxics (PACT) Act. This study will improve our understanding of the risk factors of ADRs among GWV, a result that will promote gene-informed prescribing which will in turn save lives, improve a patient's function and quality of life, and reduce hospitalizations. Innovation and Impact: Currently, there is growing evidence supporting the use of PGx testing for clinically relevant outcomes. This CDA-2 will provide observational evidence of the potential benefit of PGx testing to prevent ADRs in a high risk, high priority cohort within the VHA. It will also uncover barriers and facilitators of enhanced implementation of the VHA's PGx testing program; and help to clarify the pathway for the promotion of PGx testing in GWV by the creation [and pilot testing] of a clinical workflow that will identify [GWV with CNS-active polypharmacy] who may benefit from PGx testing, thus improving medication safety and selection. Specific Aims: Aim 1: Show that CNS-active polypharmacy (>3 medications) and other pharmacotherapy regimen characteristics are associated with ADRs among GWV who are connected to VHA clinical care from the Cooperative Studies Program (CSP) 2006/Million Veteran Program (MVP) 029 dataset, “Genomics of Gulf War Illness.” Aim 2: Demonstrate that genetic variants of CYP2D6/CYP2C19 moderate the relationship between CNS-active polypharmacy and ADRs, underscoring the potential to improve care with PGx testing. Aim 3: Partner with the National Pharmacogenomics Program (NPP) to design [and pilot test] a clinical workflow aimed at integrating PGx testing into clinical practice for [GWV with CNS-active polypharmacy.] Methodology: In Aim 1, we will conduct multivariable logistic regressions from GWV participants in CSP 2006/MVP 029 to examine the associations between CNS-active polypharmacy, other patient and pharmacotherapy regimen characteristics, and ADRs. In Aim 2, using the CSP 2006/MVP 029 dataset, we will perform moderation modeling to explore the impact that PGx tested pharmacogenes could have on ADRs among GWV with CNS-active polypharmacy who were newly exposed to a CNS-active medication. In Aim 3a, we will conduct semi-structured interviews of healthcare providers who evaluate and manage Veterans with documented [CNS-active] polypharmacy, including GWV, and who can order PGx tests to identify opportunities to improve the clinical impact of PGx testing. In Aim 3b, informed by combined results from prior Aims, we will use the NPP process of clinical workflow development to develop and refine a clinical workflow for [GWV with CNS-active polypharmacy; and in Aim 3c, we will pilot test the clinical workflow.] Path to Translation/Implementation: We will submit research proposals to further study the impact of PGx testing has in [both GWV and in all Veterans] and; support NPP's efforts to promote PGx testing in clinic.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Major depressive disorder (MDD) represents a critical but overlooked driver of type 2 diabetes (T2D) risk, with studies showing 60% increased T2D incidence among individuals with MDD. This risk is further amplified by antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), which carry largely unmonitored metabolic effects in routine psychiatric care. Despite this dual burden, three interconnected translational gaps prevent effective T2D prevention in this high-risk population. First, while polygenic and metabolomic risk scores effectively predict T2D in general populations, they remain unvalidated in psychiatric populations. Second, SSRIs lack systematic metabolic monitoring despite emerging evidence of risk. Third, no clinically deployable tools exist to integrate multi-omics insights with clinical data, leaving clinicians without evidence-based frameworks for T2D risk stratification at the critical point of MDD diagnosis. To address these gaps, Dr. Lee will leverage large-scale health system biobanks to develop a comprehensive framework for T2D risk assessment in psychiatric populations. Her approach recognizes that T2D risk in MDD patients originates from two distinct sources: (i) baseline biological susceptibility and (ii) medication-induced metabolic sensitivity. Aim 1 will validate multi-omics risk scores, including pathway-specific polygenic scores and metabolomic signatures, in SSRI-naïve MDD patients to establish baseline susceptibility for T2D. Aim 2 will characterize SSRI-induced metabolic sensitivity by tracking early biochemical changes within the first year of MDD diagnosis, identifying biomarkers particularly sensitive to SSRI exposure. Aim 3 will integrate these multimodal insights into transparent, clinically implementable risk stratification models, with external validation ensuring generalizability across distinct healthcare settings. This systematic approach will transform T2D prevention by providing evidence-based tools for metabolic risk assessment at MDD diagnosis, establishing the scientific foundation for monitoring guidelines and precision prevention strategies in psychiatric care. Dr. Lee's expertise in epidemiology, causal inference, and statistical genetics uniquely positions her to bridge psychiatric and metabolic medicine. Her comprehensive training plan integrates coursework across endocrinology, metabolic genetics, precision medicine, and biomedical informatics, supported by a multidisciplinary mentorship team spanning these critical domains. Primary mentor Dr. Jordan Smoller (precision medicine), co-mentor Dr. Miriam Udler (diabetes genetics), and collaborators Drs. Melina Claussnitzer (metabolic genomics), Arjun Manrai (biomedical informatics), and Lea Davis (psychiatric genetics) provide expertise across the full translational spectrum from genomic discovery to clinical implementation. This K01 will establish Dr. Lee as an independent investigator at the intersection of metabolic and mental health, advancing precision prevention strategies for T2D this high-risk population.

NIMH - National Institute of Mental Health

In recent decades, we have gained a deep understanding of brain function in health and disease with the advent of techniques relying on genetic manipulations such as opto- and chemogenetics. These methods allow the isolated investigation of well-delineated cell populations. Although the hippocampus is one of the most extensively studied brain regions, research progress has been severely hindered by the lack of genetic access to hippocampal subfields, thereby restricting the applicability of these trailblazing methodologies. Several adeno- associated virus (AAV) vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer- AAVs) were developed recently. We propose to develop hippocampal cell type-specific enhancer-AAV viruses for highly efficient and convenient targeting of hippocampal excitatory cell types by evaluating the potential of several candidate enhancers for neuron-type-specific targeting in the hippocampus using a publicly available hippocampal RNA sequencing (RNA-seq) dataset. First, we will develop enhancer-AAVs for selective targeting of dentate gyrus granule cells. Our preliminary results show highly specific granule cell labeling, which we will leverage to develop cell type-specific optogenetic and chemogenetic virus variants. Second, we will expand these efforts to other hippocampal excitatory cell types: CA3, CA2, and CA1 pyramidal cells and hilar mossy cells. The development of these selective methods will allow the research community to gain unprecedented insight into hippocampal function in healthy and pathophysiological conditions.

NIMH - National Institute of Mental Health

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.

NIMH - National Institute of Mental Health

This K99/R00 award will position the candidate to become an independent clinical researcher with expertise in individualized novel phenotyping and prediction of risk and resilience to psychosis and bipolar spectrum disorders (PBSD). Background. PBSD are among the most disabling conditions worldwide, evidenced by poor quality of life and premature mortality. These disorders demonstrate pluripotentiality and heterotypic continuity across clinical, cognitive, and neural phenotypes. The ability to predict transdiagnostic functional outcomes is critical for implementing precision-based interventions. Despite advances in identifying shared risk factors and pathophysiological mechanisms, translating research findings into clinical practice remains a challenge. Specific Aims. This project synthesizes data from NIMH-sponsored clinical high-risk (CHR) cohort, the North American Prodrome Longitudinal Study 2 and 3 (NAPLS-2, NAPLS-3) and Accelerating Medical Partnerships – Schizophrenia (AMP-SCZ), and translates empirical findings to electronic health records (EHR). Aim 1.1 will leverage the NAPLS cohorts to identify novel combinations of demographic, social determinants of health (SDOH), clinical, cognitive, and biological factors associated with risk, remission, and resilience using machine learning. Aim 1.2 will externally validate these models in AMP-SCZ and investigate the predictive power of digital phenotyping measures. Aim 2.1 will apply temporal deep learning and explainable artificial intelligence (XAI) to test these predictive models and align CHR variables with unique XAI-derived common data elements in the demographically-diverse Epic EHR using a longitudinal retrospective design. Aim 2.2 will design a clinician-facing nomogram for future deployment as an automated real-time predictor of PBSD as preparation for an R01 application. Training. The candidate will achieve these goals through a resource-rich institutional environment and cohesive training plan in: (1) PBSD etiology and course, including SDOH and immunological biomarkers; (2) advanced statistical modeling and machine learning techniques; and (3) optimization of EHR tools and registries. This training will support the development of an independent research program integrating novel digital and EHR phenotyping with clinical practice. Mentorship. The candidate will be supported by an expert interdisciplinary team: Robert Bilder, Ph.D. (primary mentor), Carrie Bearden, Ph.D. (co-mentor), David Miklowitz, Ph.D. (co-mentor), Steven Cole, Ph.D. (consultant), and Douglas Bell, Ph.D. (consultant). Impact. This project directly aligns with the NIMH’s Strategic Goals related to the pressing need to improve assessment platforms within healthcare to screen, detect, and treat mental illnesses; optimizing real-world data collection systems with computation modeling; evaluating the role of social determinants of health in the onset and course of mental illness; and developing decision-support tools for interventions and stepped care. The research outcome will develop innovative methods to prospectively identify individuals likely to demonstrate risk, remission, or resilience, enabling real-time individual- and population-level detection and interventions.

National Institutes of Health

This Funding Opportunity Announcement (FOA) issued by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Aging (NIA), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute on Drug Abuse (NIDA), National Institute of Environmental Health Sciences (NIEHS), National Institute of General Medical Sciences (NIGMS), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), and National Library of Medicine (NLM) solicits Research Project Grant (R01) applications from institutions/ organizations that propose to develop predictive multiscale models of the physiome in health and disease.

NIMH - National Institute of Mental Health

Modified Project Summary/Abstract Section More than 50% of people receiving HIV pre-exposure prophylaxis (PrEP) discontinue PrEP within 6 -12 months of initiation partly due to social and structural barriers, resulting in an unacceptable rate of new infections disproportionately affecting communities with less access to PrEP. While some may appropriately discontinue based on lifestyle changes, HIV seroconversion among those who discontinue is high, indicating premature discontinuation or lack of timely re-engagement in PrEP care. Despite identified barriers to PrEP persistence (encompassing retention and adherence), effective implementation strategies to support persistence are lacking compared to other steps of the HIV prevention continuum such as linkage and uptake. A greater understanding of patient preferences about PrEP persistence and re-engagement, with a focus on the factors most relevant to urban vs. rural clinics, is critical to creating innovative strategies to end the HIV epidemic. This research applies multidisciplinary methods to design and pilot-test preference-informed implementation strategies to improve PrEP persistence in urban and rural settings in Missouri, an Ending the HIV Epidemic priority state due to the burden of both urban and rural epidemics. This career development award will provide Dr. Aditi Ramakrishnan with the mentored training and research expertise to launch her career as an independent clinician-investigator leading the 1) design of preference-informed and community-engaged implementation strategies and 2) rigorous testing through implementation trials in urban and rural contexts. To achieve this goal, Dr. Ramakrishnan has assembled an expert mentoring team and proposed an impactful training plan to develop her skills in 1) stated preference methods for implementation science, 2) human-centered design and community-engaged research methods, and 3) implementation trial design. These training objectives complement a research study with the following Specific Aims: 1) Identify patient and provider preferences for HIV prevention strategies supporting persistence and re-engagement through a discrete choice experiment, 2) Design a multicomponent strategy, PREFER-PrEP, to improve persistence and re-engagement among individuals with ongoing indications for PrEP using human-centered design principles, and 3) Assess implementation outcomes (e.g., acceptability) and persistence (e.g., retention, adherence) of the PREFER-PrEP prototype. This study will leverage robust community-academic partnerships across urban and rural Missouri and provide preliminary data for an R01 application to test the PREFER-PrEP strategy through a Type 3 hybrid effectiveness-implementation cluster randomized controlled trial to optimize HIV prevention services. This career development award training, mentorship, and research, within the rich environment of Washington University in St. Louis School of Medicine, will position Dr. Ramakrishnan to independently lead the design and testing of preference-informed, community-engaged implementation strategies and interventions to improve HIV prevention in priority regions.

NIMH - National Institute of Mental Health

SUMMARY Profound behavioral, emotional, and cognitive changes begin in pregnancy to prepare for the transition to parenthood, underscored by plasticity in maternal brain structure and function. Translational research emphasizes evolutionarily conserved adaptation as occurring in this period, though little is known about plasticity of the human maternal brain during pregnancy. Advancing this knowledge is a public health imperative given the prevalence and severity of perinatal mood and anxiety disorders (PMADs), which frequently originate in the prenatal period. Consequences of PMADs are enduring and costly, and carry intergenerational consequences through their impact on infant development, yet very little is known about their neural bases. What is known: A small number of studies document anatomical change in the brain from pre-pregnancy to the postpartum. Associations between iron and mood are established, and maternal iron in pregnancy is a known predictor of offspring neurobehavioral development. Furthermore, brain iron is emerging as a key factor underlying neuroplastic processes across the life course. Iron deficiency affects up to 40% of women in the US, and in pregnancy iron demands are significantly heightened. PMADs also increase risk of developmental disorders and psychiatric problems in children, though mechanisms for risk transmission are poorly understood. What is unknown: Neuroimaging studies conducted during pregnancy are rare, so trajectories of brain changes during pregnancy, across multiple domains, have yet to be examined. Further, how brain plasticity relates to PMAD symptoms is also unknown, constraining potential for clinical translation in this emerging area. Brain iron changes in pregnancy and its relevance to PMADs have yet to be examined. The goal of the proposed research is to determine whether gestational neuroplasticity underlies individual differences in maternal mental health and influences offspring neural development. We will conduct multi-modal MRI in a sample of n=132 women at 2 prenatal and one postpartum time point, measuring PMAD symptoms until 6 months postpartum, and complete rigorous assessment of offspring neurodevelopment including infant fMRI. Novel eye tracking technology will be used to collect objective measures of emerging infant attentional processing. We will address 3 key aims: (1) Quantify maternal gestational neural change using an integrated multimodal imaging approach; (2) Isolate associations between gestational neuroplasticity and PMAD symptoms; and (3) Determine whether maternal neuroplasticity and brain iron, measured via novel quantitative MRI sequences, are associated with infant neurodevelopment. Expected outcomes are significant as they will advance the field beyond documentation of expected neuroplasticity and towards understanding of clinically meaningful implications of individual differences in change, significantly advancing understanding of PMAD etiology.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT PrEP Blueprint is a project designed to create a blueprint to assist clinics currently offering PrEP in scaling up these efforts and offering all types of PrEP options to persons who may benefit from PrEP. The study will take place in two phases. In the first phase (Aim 1, year 1), we will assemble and adapt the PrEP Blueprint with client, clinic staff, and community stakeholder input. We will do this through Human Centered Design (HCD) with client and clinic staff in San Francisco, California and Birmingham, Alabama to identify implementation barriers in scaling up PrEP and which strategies would be desired, feasible, and client-centered to best address the needs of potential or current PrEP users. We will conduct three half-day workshops with 10 clients, and 20 staff at each of two clinics, a community sexual health clinic in San Francisco, and a university infectious disease clinic in Birmingham. The goal of these HCD workshops is to brainstorm new ideas (Ideation Workshop) to improve PrEP implementation within the clinical context; develop potential strategies (Prototyping Workshop) to address the implementation challenges; and review the prototypes identify the solutions which are most acceptable, feasible, and efficient (Testing Workshop) prior to implementation. Through these HCD activities we will determine what is feasible for each of the clinics to implement, and what client-facing (e.g., PrEP decision support tool to help people select the type of PrEP that best suits their needs) and clinic-facing resources (e.g., work flow templates, provider educational materials, insurance flowsheets, visit-type protocols) would best serve the needs of the clinics. We will also establish and consult with a Stakeholder Advisory Board to discuss the HCD, brainstorm strategies to reach a broader number of persons in the priority populations, and to provide ongoing feedback on the study implementation. In Phase 2 (Aims 2 & 3, years 2-5), we will launch the PrEP Blueprint in these 2 clinics and assess their implementation and impact using the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance). We will measure these outcomes through surveys every 6 months with staff and clients; interviews with staff; and extracting data from the electronic medical records. At the end of this project, we will have an adaptable PrEP Blueprint that will contain multiple features that a variety of clinics in the US could use to increase the number of persons starting and staying on PrEP.

NIMH - National Institute of Mental Health

Emerging (18-24 years old) and young (25-29 years old) adult men in the U.S. are at high risk for HIV infection. Pre-exposure prophylaxis (PrEP) is a highly effective biomedical prevention strategy to reduce HIV transmission and a priority for ending the HIV epidemic in the U.S. However, the effectiveness of PrEP depends on achieving protective PrEP blood drug levels through optimal adherence behaviors. mHealth interventions hold promise for delivering timely and tailored PrEP adherence support for higher risk communities. Our team was funded (NIMH R34MH116878) to develop and pilot test the PrEP iT! mHealth intervention to improve PrEP adherence among a national sample (n=80) of 18-29 year old men in the U.S. (Mage=25 years; 54% racial/ethnic minority), and we demonstrated high feasibility (>90% retention) and strong acceptability of the intervention. Among participants in the PrEP iT! intervention, those with protective PrEP blood drug levels (from dried blood spots) at months 3 and 6 were significantly more engaged in the intervention than those with non-protective PrEP drug levels, suggesting benefit for some, but not all, participants. Based on lessons learned of this pilot study, we propose here an RCT to test a stepped-care intervention - called PrEPStep - to improve protective PrEP blood drug levels among 300 18-29 year old men. Participants on PrEP and experiencing adherence barriers will be randomized (2:1) to either the updated PrEP iT! mobile app or an information-only control condition. Those who do not show improvement in PrEP adherence at 3-months will be re-randomized (2:1) to also receive remote eCoaching based on motivational interviewing (MI) and cognitive behavioral therapy (CBT) principles or remain in the PrEP iT! app alone for an additional 6 months, for total follow-up of 9 months. Additionally, we will use this opportunity to include information and tools to encourage uptake and proper use of doxycycline post-exposure prophylaxis (DoxyPEP) to reduce sexually transmitted infections. The proposed study aims are: Aim 1: Achieve a higher proportion of protective PrEP drug blood levels at 6- (primary outcome) and 9-months (secondary outcome) among participants randomized to a novel stepped-care mHealth and eCoaching intervention, called PrEPStep, compared to an information-only control condition; Aim 2: Evaluate the components of the PrEPStep intervention package at months 6 and 9 to characterize: 2a. the effect of receiving the updated PrEP iT! mobile app alone compared to the control condition; 2b. the additive benefit of receiving eCoaching compared to only receiving the PrEP iT! mobile app; Aim 3: Assess acceptability, uptake, and protective coverage of DoxyPEP among participants randomized to PrEPStep compared to those in the information-only control condition using in-depth interviews and survey results. The proposal has high public health impact by providing a scalable mHealth and eCoaching approach to address gaps in effective PrEP adherence interventions to reduce HIV among 18-29 year-old men in the US, as well as the initiation and protective coverage of DoxyPEP. Results of this work will inform a future Hybrid Type III implementation trial of PrEPStep more broadly in the US.

NIMH - National Institute of Mental Health

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but only a subset experience chronic negative psychiatric outcomes such as post-traumatic stress disorder (PTSD) and depression. Several cohort studies over the past 10 years have identified brain-based risk mechanisms early after trauma, which predict risk for chronic symptoms such as hyper-arousal, intrusive memories of the trauma, and negative affect. One of the most widely-replicated and theoretically-grounded such mechanisms involves early high amygdala responses to threat cues. Given the strength of current evidence, we propose that this is an actionable target for intervention early post-trauma, to prevent chronic impairing and distressing symptoms. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can induce functional brain changes as potential intervention for neuropsychiatric disorders. Emerging findings along with our preliminary data suggest that the amygdala can be reached and dampened via stimulation of a functionally connected cortical prefrontal area. Here we propose that using TMS to dampen amygdala hyperreactivity will prevent a cascade of symptoms that could develop following trauma exposure. We propose to identify Emergency Department patients who have experienced a recent traumatic event (meets DSM-5 Criterion A), and who have high initial PTSD symptoms at 1 week post-trauma. In the R61 phase we will deliver a staged single-blind TMS intervention with a lead-in sham, followed by active treatments with increasing doses, measuring amygdala reactivity at each phase. R61 milestones involve: 1: Target engagement: Determination that active TMS versus sham decreases within-subject amygdala threat reactivity (decrease in reactivity to fearful faces). 2: Dose response: Determination that 4 vs 1 session of TMS decreases these same targets. 3: Safety and feasibility: Demonstrating feasibility of recruitment and retention (75% of participants are able to complete 75% of sessions), and no Serious Adverse Events (SAE) deemed related to the TMS intervention. If these are met, the R33 phase will involve a randomized double-blind sham-controlled trial, providing a double- blind replication of the immediate effects on the amygdala target and 1-month later, as well as longitudinal assessments of TMS effects on both PTSD and depression symptoms over 3 months post-trauma. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state-of-the-art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for chronic trauma-related symptoms through the Grady Trauma Project and Grady Healthcare System, and a strong community of experts in trauma and neuromodulation. If the hypotheses are confirmed, this study will lay the groundwork for future early intervention trials using non- invasive dampening of amygdala reactivity to prevent chronic trauma-related symptoms.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT The purpose of this Mentored Patient-Oriented Research Career Development Award is to prepare Evan Dalton, MD, MSHP for a career as an independent clinician-investigator with expertise in developing and implementing interventions that transform care delivery for hospitalized children with autism spectrum disorder (ASD) and improve their outcomes on pediatric medical units. Dr. Dalton’s proposal includes training, mentorship, and research activities that will enable him to conduct a full-scale clinical trial of a systems-level intervention for children with ASD and aggression at a pediatric medical hospital. Dr. Dalton has developed a comprehensive career development and research plan that builds on his foundation in health services and quality improvement research to: 1) obtain advanced training in participant-engaged mixed methods for intervention development and redesign, 2) enhance his knowledge of human-centered design and practice its application within the pediatric hospital work system, and 3) gain the expertise in clinical trial methodology necessary to carry out a full-scale controlled trial at a pediatric medical hospital. The prevalence of ASD has risen above 3% in the United States and children with ASD are frequently hospitalized for their co-occurring medical and psychiatric disorders. Many children with ASD have inherent sensory sensitivity, restricted interests, and repetitive behaviors that are difficult to accommodate in the medical hospital setting. In addition, few specialized psychiatric hospitals exist for children with ASD, so pediatric medical hospitals provide psychiatric care for many children with ASD. The objective of the proposed research studies is to redesign an ASD-specific care pathway, which has demonstrated effectiveness at a psychiatric hospital, for implementation with children with ASD and aggression, their caregivers, and their observers in a pediatric medical hospital. To accomplish this objective, Dr. Dalton will pursue the following specific aims: 1) identify usability challenges and adaptation needs of an ASD-specific care pathway within the pediatric hospital work system, 2) redesign and iteratively refine the ASD-specific care pathway with Advisory Board collaboration, 3) pilot test the redesigned ASD-specific care pathway in a non-randomized, single-arm trial on a pediatric medical unit. This pilot study will assess the pathway’s usability, acceptability, and feasibility, evaluate the hypothesized mechanisms (e.g., observer beliefs, comfort, and knowledge), and examine clinical outcomes including patient aggression, physical restraint use, and staff injuries. The data generated by this project will serve as the foundation for a future R01 which will test the ASD-specific care pathway in a full-scale controlled trial at a pediatric medical hospital. This proposal addresses the National Institute of Mental Health Strategic Goal 4.2.B of “building models to scale-up evidence-based practices” by adapting an evidence-based intervention with demonstrated effectiveness in a psychiatric hospital for use with patients with ASD in pediatric medical units.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT We are proposing a hybrid type I trial to assess the effectiveness and implementation determinants of an innovative peer-led court navigator program that facilitates linkage to substance use disorder treatment. The courthouse is a venue where people with behavioral health needs who are justice-involved and at various points along the sequential intercept model converge in time and space; however, despite considerable attempts to link these populations to evidence-based treatment, outside of specialty court models, courthouses themselves are underexplored as an intervention setting. We will test whether court navigator intervention, led by peer recovery specialists and implemented in county courthouses, can be an effective strategy to facilitate linkages to substance use treatment. Court navigators are civilians who provide adjunctive legal-related services to those passing through courthouses, and the investigative team published pilot data demonstrating the feasibility of treatment linkage. Peer recovery specialists (persons with lived experience of substance use recovery) have been associated with reduced substance use outcomes and are being integrated into multiple criminal-legal intercepts and settings; however, peer-led court navigation is an innovative and unexplored approach within research and an ideal fit for a Justice Community Opioid Innovation Network Phase II Innovation Hub project. The proposed hybrid type I trial of a manualized court navigation intervention delivered by certified peer recovery specialists and compare the effectiveness through a pragmatic randomized controlled trial with an information-only control in two Indiana courthouses. Guided by Social Cognitive Theory and the Consolidated Framework for Implementation Research, our aims are as follows: Aim 1: Assess the effectiveness of court navigation vs. an information-only control on linkage to substance use treatment in a randomized controlled trial; Aim 2: Assess the effectiveness of court navigation vs. an information-only control on overdose and public safety outcomes in a randomized controlled trial; Aim 3: Explore barriers and facilitators implementing peer-led court navigation in criminal-legal systems. For the clinical trial, we will randomly select times of day that the court navigator intervention will be available and enroll 600 subjects over 24 months with 12 months of follow-up data by linking statewide administrative records. We will also conduct interviews to identify barriers and facilitators for implementing the intervention (N=64). The proposed study will be led by Dr. Bradley Ray, an experienced research sociologist, and supported by an interdisciplinary investigative team of qualitative and quantitative experts with senior justice and behavioral health leaders from the Indiana Supreme Court and Indiana Division of Mental Health and Addiction. This study has the potential to identify a new setting (courthouses) and strategy (court navigation) for linking those in need to community-based behavioral health services, thereby improving public health and safety. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the overdose epidemic, including opioid and stimulant use disorders. The NIH HEAL Initiative bolsters research across NIH to address the national opioid public health crisis and improve treatment for opioid misuse and addiction.

Centers for Disease Control - NCIPC

The purpose of this NOFO is to provide multiyear funding to state, territorial, tribal, and local health departments to implement and evaluate comprehensive primary prevention strategies that prevent multiple forms of violence and promote healthy development among adolescents and young adults. Building on the prior PREVAYL cooperative agreement, this NOFO emphasizes: Improving data-driven decision-making, including surveillance, data linkage, and use of real-time data for prevention, evaluation and implementation science Building capacity and strengthening implementation and reach of evidence-based prevention strategies that address shared risk and protective factors Advancing whole-child and whole-community violence prevention approaches that integrate youth mental health and family support strategies Engaging in strategic collaboration through multisector partnerships to facilitate youth engagement, and build and support a skilled violence prevention workforce Prioritizing primary prevention of multiple forms of violence impacting youth including interpersonal violence, intimate partner/teen dating violence, bullying, community-based violence, online/technology-facilitated violence, and adverse childhood experiences (ACEs)

Centers for Disease Control - NCIPC

<p style="margin-left:0px;">The purpose of this NOFO is to provide multiyear funding to state, territorial, tribal, and local health departments to <strong>implement and evaluate comprehensive primary prevention strategies that prevent multiple forms of violence</strong> and promote healthy development among adolescents and young adults. Building on the prior PREVAYL cooperative agreement, this NOFO emphasizes:&nbsp;</p><p style="margin-left:0px;">&nbsp;</p><ul style="list-style-type:disc;margin-left:0px;"><li style="margin-left:0px;" data-list-item-id="e00d033b2d5eb49d093b2e876632bdb92"><p style="margin-left:0px;">Improving <strong>data-driven decision-making</strong>, including surveillance, data linkage, and use of real-time data for prevention, evaluation and implementation science&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e00889545999c8e496f431b111259d8a2"><p style="margin-left:0px;">Building capacity and strengthening implementation and reach of evidence-based prevention strategies that address <strong>shared risk and protective factors</strong>&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e1393be9338f280fbf28b45e09da7c50b"><p style="margin-left:0px;">Advancing whole-child and whole-community violence prevention approaches that integrate <strong>youth mental health</strong> and <strong>family support</strong> strategies&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e00d3f7091d32818e01777f5395f85bc9"><p style="margin-left:0px;">Engaging in strategic collaboration through <strong>multisector partnerships</strong> to facilitate youth engagement, and build and support a skilled violence prevention workforce&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e80ec7a8032069bd5040ac9fbbb078e1b"><p style="margin-left:0px;">Prioritizing primary prevention of <strong>multiple forms of violence impacting youth </strong>including interpersonal violence, intimate partner/teen dating violence, bullying, community-based violence, online/technology-facilitated violence, and adverse childhood experiences (ACEs)&nbsp;</p></li></ul>

NIMH - National Institute of Mental Health

Project Summary Fragile X syndrome (FXS) stands as a prominent contributor to intellectual disability and autism spectrum disorders, stemming from mutations within the FMR1 gene. These mutations lead to severe reduction or absence of the FMRP protein. Despite extensive research, effective medical interventions for FXS remain elusive, hindered by a limited understanding of its underlying mechanisms. Biochemical investigations have consistently highlighted FMRP's role in modulating mRNA translation, with its absence correlating with increased translation levels of select FMRP- interacting mRNA targets. However, emerging evidence suggests broader dysregulation, as FXS neurons exhibit heightened overall protein synthesis, hinting at elevated translation of non-FMRP interacting mRNAs. This intriguing phenomenon underscores the need for a deeper exploration into the cellular dysfunctions characterizing FXS. This research initiative aims to unravel a novel facet of FXS pathology—nucleolar hyper-function. We propose that this hyper-function contributes to aberrant ribosome biogenesis, thus augmenting the cellular capacity for translation and driving the observed global increase in protein synthesis in FXS. Aim 1 will assess neuronal and glial nucleolar function in wild-type (WT) and Fmr1 knockout (KO) mice. Aim 2 will conduct a comparative analysis of genome-wide proteomic data encompassing nucleolar proteins in WT and Fmr1 KO samples, discerning molecular alterations integral to ribosome biogenesis and assembly. Aim 3 will assess nucleolar function in the peripheral tissue in Fmr1 KO mice, establishing the hyper-functional pathological outcome as a potential clinical biomarker. The successful execution of this exploratory R21 project promises to unveil previously unexplored cellular mechanisms underlying FXS pathology. This study will also suggest nucleolus-associated abnormalities as novel molecular/cellular measures and potential biomarkers.

NIMH - National Institute of Mental Health

Globally, people with HIV (PWH) with comorbid common mental disorders (CMDs) experience worse HIV-related outcomes than those without, including decreased antiretroviral therapy (ART) adherence, reduced viral suppression, and increased mortality. These same mechanisms drive poor HIV outcomes in the United States, underscoring the need for scalable mental health interventions to improve domestic HIV care. Despite their high prevalence and impact, CMDs remain under-diagnosed and undertreated among PWH, particularly in low- and middle-income countries (LMICs), due to weak mental health infrastructure and severe workforce shortages. Similar access barriers persist in resource-constrined United States settings, including rural and safety-net clinics, making task-shifting directly relevant to US populations. Testing task-shifted interventions in LMICs provides a rigorous scientific advantage. Conducting this study in Vietnam—rather than the US—is a deliberate strategy to evaluate the intervention under conditions where its core mechanisms are most observable. Vietnam’s limited mental health workforce and high burden of untreated CMDs create a high-contrast environment that amplifies intervention effects and clarifies causal pathways linking mental health improvements to HIV outcomes. This constraint-based setting enables identification of the minimally effective components, efficient delivery strategies, and essential supervision structures required for scalability. In contrast, more resource-rich and heterogeneous US systems can obscure these mechanisms, limiting the ability to optimize implementation. Establishing effectiveness and efficiency under constraint strengthens internal validity and enhances generalizability to resource-constrained U.S. settings facing similar barriers. Problem-solving therapy (PST) is an evidence-based, non-specialist-delivered intervention shown to improve mental health outcomes in sub-Saharan Africa. Yet, its impact on HIV outcomes among PWH has not been established, particularly among those initiating or re-initiating ART, who may derive the greatest benefit. We recently culturally adapted PST for PWH with CMDs in Vietnam and demonstrated feasibility, acceptability, and high-fidelity delivery in a pilot randomized trial, with promising signals of effectiveness. We propose a randomized, controlled, hybrid type I effectiveness-implementation trial to evaluate adapted PST versus enhanced usual care among PWH initiating or re-initiating ART with CMDs in Vietnam. We will assess CMD and HIV outcomes, cost-effectiveness, and implementation factors to support translation. We hypothesize that PST will improve CMD outcomes at 3 months and viral suppression at 6 months. By rigorously testing PST in a resource-constrained setting, we will generate actionable evidence and an implementation blueprint to support scalable, cost-effective integration of mental health care into HIV services, accelerating translation to improve outcomes in resource-constrained US populations.

NIMH - National Institute of Mental Health

Globally, people with HIV (PWH) with comorbid common mental disorders (CMDs) experience worse HIV-related outcomes than those without, including decreased antiretroviral therapy (ART) adherence, reduced viral suppression, and increased mortality. These same mechanisms drive poor HIV outcomes in the United States, underscoring the need for scalable mental health interventions to improve domestic HIV care. Despite their high prevalence and impact, CMDs remain under-diagnosed and undertreated among PWH, particularly in low- and middle-income countries (LMICs), due to weak mental health infrastructure and severe workforce shortages. Similar access barriers persist in resource-constrined United States settings, including rural and safety-net clinics, making task-shifting directly relevant to US populations. Testing task-shifted interventions in LMICs provides a rigorous scientific advantage. Conducting this study in Vietnam—rather than the US—is a deliberate strategy to evaluate the intervention under conditions where its core mechanisms are most observable. Vietnam’s limited mental health workforce and high burden of untreated CMDs create a high-contrast environment that amplifies intervention effects and clarifies causal pathways linking mental health improvements to HIV outcomes. This constraint-based setting enables identification of the minimally effective components, efficient delivery strategies, and essential supervision structures required for scalability. In contrast, more resource-rich and heterogeneous US systems can obscure these mechanisms, limiting the ability to optimize implementation. Establishing effectiveness and efficiency under constraint strengthens internal validity and enhances generalizability to resource-constrained U.S. settings facing similar barriers. Problem-solving therapy (PST) is an evidence-based, non-specialist-delivered intervention shown to improve mental health outcomes in sub-Saharan Africa. Yet, its impact on HIV outcomes among PWH has not been established, particularly among those initiating or re-initiating ART, who may derive the greatest benefit. We recently culturally adapted PST for PWH with CMDs in Vietnam and demonstrated feasibility, acceptability, and high-fidelity delivery in a pilot randomized trial, with promising signals of effectiveness. We propose a randomized, controlled, hybrid type I effectiveness-implementation trial to evaluate adapted PST versus enhanced usual care among PWH initiating or re-initiating ART with CMDs in Vietnam. We will assess CMD and HIV outcomes, cost-effectiveness, and implementation factors to support translation. We hypothesize that PST will improve CMD outcomes at 3 months and viral suppression at 6 months. By rigorously testing PST in a resource-constrained setting, we will generate actionable evidence and an implementation blueprint to support scalable, cost-effective integration of mental health care into HIV services, accelerating translation to improve outcomes in resource-constrained US populations.

NIMH - National Institute of Mental Health

Project Summary As life expectancy increases in people living with HIV (PLWH), the probability of developing other chronic conditions such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease also increases. PLWH live longer, develop multiple chronic conditions (MCCs), and experience polypharmacy, reinforcing a need to evaluate composite medication adherence across all chronic medications. Suboptimal medication adherence to essential treatments may limit treatment effectiveness, shorten survival, decrease overall population health, and increase health-system costs. Positioned at the nexus of therapeutic intent and success, medication adherence is influenced by myriad system, provider, and person-related factors that cannot be evaluated using claims-based studies alone. Therefore, the overarching goal of this research is to identify a taxonomy of composite medication adherence trajectories (MATs) over a 36-month observation period in older (50-99 years of age) PLWH and MCCs. The taxonomies will inform future research involving development and testing of comprehensive medication adherence interventions and clinical decision support strategies with the highest probability to positively impact medication adherence-related clinical outcomes in older PLWH and MCCs. We propose a mixed-methods explanatory sequential design by combining group-based trajectory modeling (GBTM) of medication refill data followed by 75 semi-structured interviews to fully understand the clinical, social, behavioral, cultural, structural, and economic perspectives that may influence medication adherence decision-making in PLWH and MCCs (i.e., T2DM, hypertension, and/or hyperlipidemia). We propose the following aims: 1. Apply group-based trajectory modeling of medication refill data to identify dynamic profiles of medication adherence behavior over time for older PLWH and MCCs. 2. Use qualitative, semi-structured interviews of older PLWH and MCCs to obtain in-depth understanding of social, behavioral, cultural, structural, and economic perspectives that align with each MAT profile. In contrast to disease-specific (intra-disease), dichotomous summary measures focused on antiretroviral therapy alone, this study uniquely identifies longitudinal MATs across MCCs (inter-disease). Qualitative assessment of lived medication use experiences and array of social, behavioral, cultural, structural, and economic perspectives contributing to MAT profiles advances understanding of needs for PLWH and MCCs to inform optimal, tailored interventions for unique MATs unachievable with claims-only studies.

Health and Human Services Department

In compliance with the requirement of the Paperwork Reduction Act of 1995 to provide opportunity for public comment on proposed data collection projects, the National Institutes of Health (NIH) will publish periodic summaries of proposed projects to be submitted to the Office of Management and Budget (OMB) for review and approval.

Health and Human Services Department

The Centers for Disease Control and Prevention (CDC), as part of its continuing effort to reduce public burden and maximize the utility of government information, invites the general public and other federal agencies the opportunity to comment on a continuing information collection, as required by the Paperwork Reduction Act of 1995. This notice invites comment on a proposed information collection project titled Advancing Violence Epidemiology in Real-Time (AVERT). The AVERT program provides funding to jurisdictions to conduct routine monitoring of Emergency Department visits related to violence-related injuries and mental health conditions, and to analyze these data in a timely manner.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Postpartum depression (PPD) affects approximately one in eight women in the year following childbirth, with significant implications for maternal and child outcomes. While theoretical perspectives emphasize the importance of social support during this challenging transition, particularly from partners, current research relies heavily on self-reported measures of support that are susceptible to cognitive biases and may be confounded with depression symptoms. A critical factor that may influence maternal mental health outcomes is the actual time spent in proximity with one's partner, as these periods provide opportunities for both emotional and practical support. In the proposed project, we will examine patterns of partner proximity across pregnancy and the extended postpartum period using innovative wearable devices (TotTags) that dynamically and unobtrusively measure physical distance between partners in their daily ecological context. Our central hypothesis is that reduced partner proximity will prospectively predict increases in maternal depression symptoms (Aim 1). We will also investigate the bidirectional relationships between both partners' depression symptoms and their proximity patterns (Aim 2) and examine how infant caregiving contexts influence these dynamics (Aim 3). This project addresses a critical gap in the perinatal mental health literature by advancing our understanding of how objective measures of partner support relate to depression risk during the transition to parenthood. This study will set the foundation for future research that can inform interventions aimed at preventing postpartum depression in both mothers and fathers. Through this project, the candidate will develop specialized expertise in perinatal mental health research, ecological assessment methods, and advanced statistical approaches for analyzing dynamic social interactions, positioning them to establish an independent research program examining how partner support shapes mental health outcomes during major life transitions.

NIDA - National Institute on Drug Abuse

The rapid shift in public perception of psychedelics, coupled with the expansion of their use and policy reform across the United States, has created a unique opportunity to assess the real- world impacts of psychedelic use. Over 7,000 people in Oregon have received legal, supervised psilocybin experiences. Similar services are set to begin in Colorado in 2025, and nine other states are currently considering psychedelic services legislation. Although early phase trials suggest psilocybin may be safe and effective for treating some mental health and substance use disorders (e.g., tobacco use), it is not known whether these effects extend to community- based settings with less standardized screening and counseling support. There is an urgent need to assess the safety of these programs and their impact on substance use, before more voters and policymakers are asked to consider their merits and drawbacks. The Psilocybin Research and Implementation study for Substance use and Mental health (PRISM) study is designed to fill this gap by enrolling a cohort of individuals who use substances and receive Oregon’s state-regulated psilocybin services and comparing them to a group of people who would access these services, if they were available. Using 12 months of rigorous longitudinal surveys and qualitative interviews, PRISM will detect potential safety risks and benefits of regulated psilocybin services and identify specific substances and subpopulations that may be responsive to psilocybin’s effects. The study has three Aims: 1) Assess the impact of state- regulated psilocybin services on safety events in people who use substances, 2) Assess the impact of state-regulated psilocybin services on substance use, and 3) Elicit stakeholder views of the impact of state-regulated psilocybin services on long-term safety and changes in substance use. The PRISM study seeks to generate rigorous real-world evidence that can effectively guide state and federal decision-making. The timing of this work is critical, given the rapid expansion of psychedelic policy reform across the United States. The findings will help shape policies that maximize potential benefits of psilocybin services while minimizing risks, offering a scientifically grounded framework for public health strategies, harm reduction efforts, and future psychedelic regulations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Increasing numbers of people, including adults, have been diagnosed with autism spectrum disorder (ASD). For people utilizing medications for ASD, results are often unsatisfactory and involve off-target effects, necessitating the identification of better treatments. This project will help address this significant gap in knowledge by investigating the ability of psychedelic drugs to normalize cognitive flexibility deficits and changes to prefrontal cortex circuits caused by Cntnap2 knockout (KO), a mouse model that captures some of the behavioral abnormalities associated with ASD, including cognitive rigidity. Cognitive flexibility, a fundamental process that is required for adaptive behavior, is compromised in many people with ASD. As the PFC is important for cognitive flexibility and control of behavior, ASD-related cognitive inflexibility may be correlated with the known alterations to density of dendritic spines, a proxy for synaptic connectivity, in prefrontal cortex pyramidal neurons. Similarly, decreases in cognitive flexibility, reductions in dendritic spine density, and attenuations in excitatory synaptic input to PFC pyramidal neurons have been reported in mouse models that capture ASD-associated behavioral phenotypes. In contrast, psychedelic treatment has been shown to improve cognitive flexibility, elevate dendritic spine density, and boost excitatory synaptic input to PFC pyramidal cells. Therefore, psychedelic-mediated repair of PFC circuits and associated flexible behaviors may represent a novel ASD treatment paradigm. Although psychedelic treatment is a promising target for both increasing reversal learning ability and enhancing PFC synaptic connectivity in people with major depression, it is unknown if psychedelic treatment is able to normalize cognitive flexibility alterations and repair neural circuits disrupted in ASD, leaving a critical unaddressed question. Here, using long-time scale behavioral measures of flexibility and synaptic morphophysiological analyses, we will test the central hypothesis that psychedelic treatment will improve reversal learning ability (Aim 1) and repair PFC circuit structure and function (Aim 2) that is compromised in the Cntnap2 KO mice. Successful completion of these aims has the potential to significantly improve our understanding of the utility of psychedelic medicine for the treatment of ASD, as this treatment paradigm holds the promise of improving flexible learning by fundamentally changing the underlying synaptic landscape in PFC.