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National Institutes of Health

NIMH seeks applications for pilot effectiveness projects to evaluate the preliminary effectiveness of therapeutic and service delivery interventions for the post-acute management of mental health conditions that are matched to the stage of illness in terms of both their focus (e.g., consolidating and maintaining gains from initial treatment, managing residual symptoms/impairment, preventing relapse, promoting adherence and appropriate service use) and intensity/burden. In this pilot phase of effectiveness research, the trial should be designed to evaluate the feasibility, tolerability, acceptability, safety, and potential effectiveness of the approach; to address whether the intervention engages the target(s)/mechanisms(s) that is/are presumed to underlie the intervention effects; and to obtain preliminary data needed as a pre-requisite to a larger-scale effectiveness trial (e.g., comparative effectiveness study, practical trial) designed to definitely test the effectiveness of interventions to improve post-acute outcomes. This Notice of Funding Opportunity (NOFO) supports pilot effectiveness research to evaluate the feasibility, tolerability, acceptability, safety and preliminary indications of effectiveness of post-acute phase intervention approaches and inform the design of definitive effectiveness trials. Support for fully-powered, definitive effectiveness studies focused on post-acute phase interventions is provided via the R01 currently TEMP-24813.

National Institutes of Health

This Notice of Funding Opportunity (NOFO) encourages pilot and preliminary research in preparation for larger-scale services research effectiveness trials. Relevant trials may test a wide range of approaches, including interventions, practices, and policies designed to optimize access to, and the quality, effectiveness, affordability and utilization of drug, tobacco, or alcohol use disorder treatments and related services, as well as services for comorbid medical and mental disorder conditions. Relevant approaches may include both those that are novel, and those that are commonly used in practice but lack an evidence base. This NOFO provides resources for assessing the feasibility, acceptability, and utility of these approaches, in addition to usual trial preparation activities.

National Institutes of Health

This Notice of Funding Opportunity (NOFO) encourages pilot and preliminary research in preparation for larger-scale services research effectiveness trials. Relevant trials may test a wide range of approaches, including interventions, practices, and policies designed to optimize access to, and the quality, effectiveness, affordability and utilization of drug, tobacco, or alcohol use disorder treatments and related services, as well as services for comorbid medical and mental disorder conditions. Relevant approaches may include both those that are novel, and those that are commonly used in practice but lack an evidence base. This NOFO provides resources for assessing the feasibility, acceptability, and utility of these approaches, in addition to usual trial preparation activities.

National Institutes of Health

Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement encourages pilot effectiveness studies focused on 1) optimizing the effectiveness of preventive and therapeutic interventions with previously demonstrated efficacy, for use with broader target populations or for use in community practice settings, and 2) developing and preliminary testing innovative services interventions. Consistent with the NIMH experimental therapeutics approach, this NOFO is intended to support pilot studies of intervention effectiveness or service delivery approaches that explicitly address whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (i.e., the mechanism(s) that accounts for changes in clinical/functional outcomes, changes in provider behavior, improved access or continuity of services, etc.).

National Institutes of Health

Pilot Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 Clinical Trial Required)

National Institutes of Health

Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement encourages pilot effectiveness studies focused on 1) optimizing the effectiveness of preventive and therapeutic interventions with previously demonstrated efficacy, for use with broader target populations or for use in community practice settings, and 2) developing and preliminary testing innovative services interventions. Consistent with the NIMH experimental therapeutics approach, this NOFO is intended to support pilot studies of intervention effectiveness or service delivery approaches that explicitly address whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (i.e., the mechanism(s) that accounts for changes in clinical/functional outcomes, changes in provider behavior, improved access or continuity of services, etc.).

NIMH - National Institute of Mental Health

Project Summary/Abstract This proposal addresses the significant public health concern of destructive interparental conflict (IPC), which is strongly associated with a range of adverse outcomes for children, including mental health disorders, substance use, academic challenges, risky behaviors, and suicidality. These effects are particularly pronounced in the context of parental separation and divorce, which impacts over half of U.S. children by age 15. Family courts frequently interact with families experiencing high levels of IPC, making them critical settings for implementing interventions aimed at reducing these negative outcomes. However, most parenting programs mandated or referred by family courts are not evidence-based, leaving a critical gap in effective support for families experiencing high IPC. This pilot study aims to address this gap by evaluating the feasibility, acceptability, and preliminary impact of intervention components designed to mitigate the effects of IPC on children’s mental health. Using the Multiphase Optimization Strategy (MOST) framework, we will pilot a highly efficient experimental trial design (N = 96) to gather preliminary data on five candidate intervention components: high- versus low-intensity delivery of IPC reduction approaches, inclusion of constructive IPC skills, inclusion of IPC resolution skills, inclusion of skills for repairing parent-child relationships after IPC events, and high- versus low-intensity home practice support. These components were selected based on empirical support for their potential to reduce child mental health problems. The findings from this pilot study will inform the design of a future fully powered trial to identify the most effective and scalable combination of components that can be delivered within the practical constraints of family courts. In Aim 1, we will assess the feasibility of recruitment, randomization, and trial procedures, and the acceptability of intervention components among parents and family courts. Quantitative and qualitative feedback will guide refinements to the components and trial design. In Aim 2, we will explore the components’ preliminary impact on children’s mental health using validated measures and explore hypothesized mechanisms of action, including quality of parents’ home practice and children’s emotional security. These findings will help refine the intervention’s conceptual model. In Aim 3, we will identify potential implementation barriers and facilitators by conducting qualitative interviews with judges and court administrators from three family courts of varying resources and sizes. Using the Consolidated Framework for Implementation Research (CFIR) and the Expert Recommendations for Implementing Change (ERIC), we will develop an Implementation Research Logic Model (IRLM) to guide scale-up planning for the fully powered trial. This pilot study will lay the foundation for a scalable and effective intervention addressing IPC, leveraging family courts as a key implementation context. The future fully powered trial will advance the development of effective, evidence-based parenting programs that improve children’s mental health outcomes in the aftermath of parental separation/divorce.

Administration for Children and Families - ORR

The Office of Refugee Resettlement (ORR) within the Administration for Children and Families (ACF), invites eligible applicants to submit applications to administer the Placement and Coordination (PC) program. ORR will provide funding to diversify providers of PC services through awards to eligible organizations not currently implementing the Program of Initial Resettlement (PIR). New providers will strengthen the national resettlement framework by contributing unique innovations and perspectives.PC providers will be responsible for administering services including the Program of Initial Resettlement (PIR) and Intensive Case Management (ICM) through one or more local service providers. Through PIR, PC providers will review refugee case profiles assigned by ORR, conduct outreach to identified U.S. ties, and confirm case placement locations. PC providers will either serve cases directly or place them with local resettlement providers (LRPs) in their network. After the refugee arrives, the LRP will assume responsibility for providing PIR services for 30 to 90 days after arrival in the United States, based on self-sufficiency needs of the case. Examples of services include airport pickup upon initial arrival, securing and furnishing housing, benefits applications, referrals, provision of cultural orientation, and provision of direct assistance. Through ICM, providers will serve individuals with significant vulnerabilities that create barriers to assimilation and self-sufficiency for a service period of six to 12 months, or 12 to 24 months for individuals with long-term physical or mental health conditions or disabilities. Examples of services include regular case management discussions, psychosocial support, and connections to external sources of assistance.

Administration for Children and Families - ORR

<p>The Office of Refugee Resettlement (ORR) within the Administration for Children and Families (ACF), invites eligible applicants to submit applications to administer the Placement and Coordination (PC) program. &nbsp;</p><p>ORR will provide funding to diversify providers of PC services through awards to eligible organizations not currently implementing the Program of Initial Resettlement (PIR). New providers will strengthen the national resettlement framework by contributing unique innovations and perspectives.</p><p>PC providers will be responsible for administering services including the Program of Initial Resettlement (PIR) and Intensive Case Management (ICM) through one or more local service providers. Through PIR, PC providers will review refugee case profiles assigned by ORR, conduct outreach to identified U.S. ties, and confirm case placement locations. &nbsp;PC providers will either serve cases directly or place them with local resettlement providers (LRPs) in their network. After the refugee arrives, the LRP will assume responsibility for providing PIR services for 30 to 90 days after arrival in the United States, based on self-sufficiency needs of the case.&nbsp; Examples of services include airport pickup upon initial arrival, securing and furnishing housing, benefits applications, referrals, provision of cultural orientation, and provision of direct assistance. &nbsp;Through ICM, providers will serve individuals with significant vulnerabilities that create barriers to assimilation and self-sufficiency for a service period of six to 12 months, or 12 to 24 months for individuals with long-term physical or mental health conditions or disabilities. Examples of services include regular case management discussions, psychosocial support, and connections to external sources of assistance.&nbsp;</p><p>&nbsp;</p>

NIMH - National Institute of Mental Health

Long-acting injectable HIV antiretroviral medications (LAIs) are a breakthrough in HIV treatment and prevention, alleviate daily medication challenges, and are extremely efficacious. While LAIs have the potential to transform and improve health outcomes for people living with HIV or with vulnerability to HIV infection, clinical implementation of LAIs has been suboptimal, including for populations most impacted by HIV. Without evidence-based implementation models that address systems level determinants, the potential for LAIs to help end the HIV epidemic is unlikely to be realized. One approach to meaningfully address health system barriers is by leveraging existing, organically developed efforts designed by system insiders: pharmacists and providers in federally qualified health centers (FQHCs) in the Bronx, NY (a high-priority jurisdiction with >2% HIV prevalence). Currently, clinical pharmacists have organically developed ad hoc implementation efforts where they play an integral role in LAI delivery, including patient counseling, coordination, procurement, cost coverage, delivery, with similar workflows for HIV prevention and treatment using LAIs (i.e., a status-neutral (SN) model). These efforts show promise and warrant systematic study and protocolization to guide potential replication and scale-up. Using rigorous implementation science methods and leveraging expertise from committed multidisciplinary stakeholders (including pharmacists, patients, providers, nurses, administrators, and researchers), this R21 study will develop, formalize, and pilot an embedded SN-LAI implementation model: “Planning for implementation of Long-Acting iNjectables in Status-neutral HIV primary care FQHCs (the PLANS study)”. We will first identify context-specific determinants of SN-LAI implementation and systematically identify existing or perceived barriers and facilitators (Aim1a) using innovative systems journey mapping interviews with patients and key informants. We will use these data to systematically develop, protocolize, and refine a package of SN-LAI implementation strategies with stakeholders (Aim 1b). In a test of concept, we will then pilot strategies for acceptability, feasibility, appropriateness, fidelity, and explore indicators of strategy effectiveness (Aim 2) in a Bronx FQHC to understand the potential of this organically- driven, multidisciplinary approach to overcome system-level barriers and enhance status-neutral LAI implementation.

NIMH - National Institute of Mental Health

The Contractor, Guild Associates, Inc., aims to develop an electrochemical aptamer-based sensor device for simple, rapid, and low-cost detection and quantification of antiretroviral therapy (ART) drugs in urine and blood samples at the point-of-care (POC).

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Drug overdose is now a leading cause of death among U.S. adolescents and young adults, rising substantially in the past decade due to the proliferation of highly lethal fentanyl alongside other shifts in drug involvement. In parallel, nonfatal overdoses have risen in adolescents and young adults. Nonfatal overdoses greatly increase the risk of repeat overdose and subsequent death and have lasting consequences, especially life-threatening or near-fatal overdose events that may indicate greater need for behavioral health treatment and higher risk of future morbidity and mortality. Thus, nonfatal overdoses treated in acute care settings represent critical opportunities for intervention; however, limited data are available to inform discharge planning, with existing studies indicating an unmet need to improve connections to behavioral health treatment. Our overall goal is to generate evidence that can be used to tailor effective prevention and treatment strategies in the high-risk population of youth with a nonfatal drug overdose. To accomplish this goal, we will build on current work by the investigative team to study a critical developmental window from adolescence to young adulthood when the prevalence of illicit substance involvement in overdoes increases, risk factors may shift, and treatment options widen. We will capture a range of overdose types, including those that are nonfatal, near-fatal, and fatal; involvement of multiple illicit and commonly misused drugs as well as polydrug involvement; and events with suicidal intent in addition to unintentional overdose to improve understanding of the complex relationship of substance use and co-occurring mental illness. An extended study period from 2016-2025 will detect trends related to an evolving drug environment and changing levels of risk, and data linkages will integrate individual and clinically relevant predictors of overdose and death with health systems and other structural factors known to influence treatment delivery and health outcomes. We will focus on a sample of adolescents and young adults aged 12-29 years with initial drug overdoses treated in emergency department or inpatient settings. Specific aims are to: (1) assess trends in near-fatal and fatal overdose events from 2016-2025 by overdose type (drugs involved, intent) and age group (early/late adolescence, emerging/early adulthood); (2) identify behavioral health treatment trajectories in the six months after nonfatal overdose and differences by overdose type; and (3) quantify the one-year incidence of repeat overdose and all-cause mortality and develop a predictive model to ascertain modifiable risk factors contributing to these adverse outcomes. To achieve the aims, the study team will leverage national longitudinal Medicaid claims data (2016-2025) comprising an estimated 678,000 index overdose events in youth aged 12-29 years. Individual-level Medicaid data will further be linked with mortality, health system, and population data for a valid and timely approach to yield novel, generalizable, and up-to-date evidence on sentinel events and critical opportunities for intervention. Findings will fill a significant gap in research that is required to successfully target future overdose prevention and treatment strategies for adolescents and young adults.

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

The largest contributors to maternal postpartum mortality are mental health and cardiovascular conditions and women that give birth prematurely are at the highest risk. To prevent maternal deaths, the American Academy of Pediatrics and American College of Obstetricians and Gynecologists have clear recommendations focused on screening for depression and treatment if necessary, and monitoring and management of high blood pressure in the first weeks after birth. Of the ~100,000 mothers that give birth annually to preterm infants <34 weeks, more than 40,000 do not receive recommended postpartum care because they are engaged in the care of their sick newborns in the neonatal intensive care unit (NICU), typically far away from home and separate from their own obstetric clinicians’ offices for weeks to months. Evidence is mounting that engaging doulas, peers with lived experience that provide emotional and logistical support for mothers, is associated with improved perinatal health care the routine antepartum, intrapartum and postpartum domains, but there have been no investigations of doulas in the NICU. Our team conducted a 1:1 randomized control pilot randomized controlled trial (RCT) of doulas in Postpartum Care in the NICU (PeliCaN) in a single center and found significant improvement in postpartum care receipt by 12 weeks among intervention (doula care) compared to control. Building on our pilot work, we now propose a Type 1 hybrid effectiveness- implementation, stepped-wedge cluster RCT in 10 metro-Philadelphia NICUs to rigorously test the effectiveness of doulas in promoting receipt of evidenced-based postpartum care to improve mental health and postpartum blood pressure – outcomes strongly associated with postpartum morbidity and mortality. We will analyze individual-level effectiveness outcomes for 900 mother- infant dyads (450 intervention, 450 usual care). In Aim 1, we will examine primary effectiveness of PeliCaN during NICU stay, to improve maternal adherence to recommended postpartum health screenings for depression and high blood pressure (BP) (or adherence to BP management if directed by obstetric clinician for existing hypertension), as well as attendance at a postpartum visit with an obstetric clinician by 12 weeks. In Aim 2, we will examine secondary effectiveness of PeliCaN to improve health outcomes at 6 months by decreasing the proportion of mothers’ screening positive for depression symptoms and increasing the proportion of mothers with hypertensive disorders attending a primary care physician or cardiologist for blood pressure management. In Aim 3, we will examine implementation outcomes of feasibility, acceptability, and fidelity of this innovative doula-driven healthcare delivery model in the NICU.

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

Background: Early academic success and positive mental health are critical for all children, because they are linked to long-term outcomes such as high school graduation, lower criminal involvement, lower likelihood of teen pregnancy, and higher earnings. While community childcare centers play a vital role in supporting early childhood education and psychosocial development for young children, their teachers often lack access to evidence-based resources, including traditional Early Childhood Mental Health Consultation (ECMHC) models. To address this gap, we developed Jump Start on the Go (JS Go)—a hybrid ECMHC intervention that delivers an AI-enhanced mobile application with human consultation. Methods: JS Go is based on our successful R01- funded Jump Start ECMHC program. JS Go, developed in English and Spanish, was designed using a community-based participatory research approach to ensure the intervention is relevant and culturally appropriate for all populations it serves. In a pilot randomized controlled trial (N=114 across six centers, three Jump Start vs three JS Go), JS Go demonstrated high feasibility, usability, and acceptability. The trial showed similar improvements in teacher-child interactions, reduced problem behaviors, and increased child prosocial skills, for JS and JS Go. User feedback identified key areas for intervention adaptation that were iteratively incorporated. Building on this work, we propose a Type 1 hybrid effectiveness-implementation trial (N=480 children, across 24 childcare centers) to rigorously evaluate JS Go’s impact on children’s psychosocial functioning, while also enhancing teacher skills and childcare center capacity to sustain effective mental health support. Using a 3-arm cluster-randomized controlled design, guided by the RE-AIM framework, we will compare (1) JS Go (AI-enhanced digital ECMHC + human consultation), to (2) traditional JS (human consultation only), and (3) attention control (digital + human consultation obesity prevention curriculum). Our hypotheses are: (1) children in both JS Go and JS arms will show greater improvement in psychosocial outcomes than the control arm; and (2) there will be no significant difference between JS Go and JS arms. In Aim 1, we will examine JS Go’s impact on child psychosocial outcomes over 24 months. In Aim 2, we will evaluate how teacher skills mediate child outcomes, and how family characteristics moderate these mechanisms. In Aim 3, we will Identify center-level implementation factors that contribute to sustained improvements in child psychosocial functioning. Our mixed-methods design will explore implementation barriers and facilitators to promote scalability. Impact: This project fills a critical gap in preventive mental health tools for childcare centers by offering a scalable and accessible hybrid mobile health intervention. If effective, JS Go could reduce early childhood behavioral challenges and improve social-emotional outcomes for children during the most formative years of development. By strengthening the daily childcare center environment where children grow and learn, this approach has the potential to create lasting improvements in academic success and long-term mental health outcomes.

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.

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.