Search Grants — Free, No Account Required

NIMH - National Institute of Mental Health

Project Summary/Abstract The accumulation of toxic responses to stressors – allostatic load – is strongly associated with a wide array of psychopathological outcomes. Treating or preventing allostatic load stands to improve the well-being and functioning of individuals currently struggling or at risk for psychopathology. Despite this broad consensus, no allostatic load intervention exists. One major limiting factor has been the field’s emphasis on cross-sectional designs which tell who might be at risk but not how and when individuals are at risk. Answers to how and when lay the foundation for treatment development and can be studied using intensive longitudinal designs (ILD). Recently, researchers have leveraged ILD to investigate allostatic load through three dimensions of the stress response: quantity of daily stressors, physiological reactivity, and the subjective psychological response to stressors—perceived stress. Yet, no current research has unpacked the dynamic interactions between all dimensions of the stress response together. This project will fill this significant knowledge gap by leveraging ILD to 1) identify causal links between daily stressors, physiological reactivity, and perceived stress on a day- by-day basis, and 2) use these dynamic processes to improve prediction of short-term psychopathology beyond prior symptom levels. Emerging adulthood is a critical period of elevated stressors and psychological and physiological response to stressors and marks the incidence of multiple forms of psychopathology. Importantly, college students are representative of the emerging adult population and can be easily recruited for participation in research. In this project, 100 college students, and an additional 50 college students, enriched for psychopathological distress, will be recruited from a large public university to take part in a two- week intervention (14 days). On each day, participants will complete two measures of physiological reactivity in the evening (i.e. heart rate variability, pupil light reflex) and three measurements of daily stressors and perceived stress throughout the day (morning, afternoon and evening). Aim 1 will identify to what degree physiological reactivity mediates the effect of daily stressors on perceived stress. Aim 2 will investigate a) whether the combined effects of physiological reactivity and perceived stress predict short-term psychopathology symptoms better than either alone, and, b) whether these variables predict psychopathology symptoms beyond prior symptom levels. Across all aims, we will identify distinct within- and between- person mechanisms to answer the question: what matters and for whom? By elucidating these complex stress dynamics, we will contribute a novel conceptualization and understanding of toxic stress accumulation and set the foundation for future research on intervention and treatments.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive impairment persists even with highly effective antiretroviral therapy (ART) in people with HIV (PWH). Persistent neuroinflammation is one of many factors that contributes to ongoing cognitive impairment in virally suppressed (vs)PWH. However, there is a critical gap in understanding the underlying cause of neuroinflammation and, as a result, no available therapies to target it. Long-acting broadly neutralizing antibodies (bNAbs) are considered the next generation of therapy for PWH. Currently, there are 50+ trials that involve bNAbs. Despite this substantial effort, there are no funded NIH studies focusing on if bNAb therapy in combination with ART may reduce neuroinflammation and improve cognitive function. As the mechanism of action for bNAbs is the rapid neutralization of virus and clearance of infected cells via engagement of the immune system, a downstream effect of this therapy may be lower levels of inflammation, as is observed with other Ab therapies. We have evidence that HIV-specific antibodies (Ab) play a protective role in the CNS, and others have shown that bNAb therapy enhances host Ab immunity to HIV and simian immunodeficiency virus (SIV). Therefore, our central hypothesis is that bNAb therapy will reduce neuroinflammation in the CNS, by directly eliminating infected cells capable of trafficking to brain resulting in a smaller CNS reservoir, neutralizing virus within the CSF, and indirectly by reducing peripheral inflammation, resulting in improved cognition. To test our hypothesis, we will use the SIVmac251 rhesus macaque model of HIV and an SIV-specific bNAb (ITS103). The SIV-infected ART-suppressed NHP model will allow us to assess the effects of bNAbs on CNS inflammation, reservoir, and cognition. Additionally, this model will allow us to determine if bNAbs have a direct effect on the CNS or indirect effect through altering peripheral inflammation. AIM 1: Determine if bNAb therapy during ART initiation reduces neuroinflammation. To model ART-naïve PWH receiving bNAb therapy simultaneously with ART, we will treat SIV-infected macaques with ITS103 at the time of ART initiation. We will assess the effect of acute ITS103 therapy on 1) brain macrophage transcription, 2) CNS reservoir size, and 3) cognitive performance after 1 year of suppression compared to ART alone. AIM 2: Determine if bNAb therapy during chronic ART reduces neuroinflammation. To model vsPWH receiving bNAb therapy combined with ongoing ART, we will treat SIV-infected macaques with ITS103 after 36 weeks of ART suppression and assess the effect of chronic bNAb therapy on the same outcomes as in Aim 1. AIM 3: Determine if bNAbs have a direct or indirect effect on neuroinflammation. To determine if ITS103 plays a direct role in the CNS we will assess 1) ITS103 concentrations in the CSF, 2) viral decay rates in CSF, 3) central vs. peripheral inflammation and 4) plasma and CSF Ab neutralization capacity with and without bNAb therapy. Our in vivo study utilizing a native SIV and SIV-specific bNAb is highly innovative as it will be the first to study on the effects of bNAb therapy on neuroinflammation and evaluate if this is a viable treatment for PWH.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive flexibility refers to our capacity to adjust our behavior in response to changes in the environment or in our own internal states. Psychiatric disorders often disrupt these cognitive functions, but little is known about the patterns of activity in the brain that underlie these capacities, impeding the development of effective treatments to target them. The overarching goal of this project is to more clearly elucidate the specific neural activity patterns supporting three examples of cognitive flexibility: switching between sets of rules that guide our behavior in a given situation, making correct decisions in new situations by drawing on past experiences, and learning to rapidly adjust a previously learned rule. In this project, I have developed a behavioral task which can engage each of these behaviors. I will use high- channel count electrophysiological methods to record activity from a brain circuit spanning the hippocampus, prefrontal cortex, and motor output regions while non-human primates perform this task. I will test the hypothesis that specific features of the patterns of activity in these brain regions support each type of cognitive flexibility described above. The results of this project will contribute an important step towards developing more effective treatments for cognitive dysfunction by identifying the specific patterns of activity that support specific cognitive functions and behaviors. This project will provide the additional training I require to position myself to perform cutting-edge research on cognition as an independent investigator. Specifically, through this project I will learn to perform precisely anatomically-targeted, high-channel count electrophysiological recordings from multiple brain regions simultaneously in order to probe brain activity patterns relevant to behavior as they occur in real time, distributed across the brain. I will also develop the necessary expertise to analyze the activity of large populations of neurons in relation to complex behavior. This award is thus critical to attaining my long-term goal of running an independent research lab at an academic medical center, where I will operate a non-human primate electrophysiology lab studying the neural mechanisms of adaptive, flexible behaviors that are disrupted in psychiatric disorders.

NIMH - National Institute of Mental Health

Project Summary/Abstract The hippocampus was long described by seminal memory models to not be necessary for procedural (motor) learning. In contrast, neuroimaging studies from the last two decades consistently show hippocampal recruitment during motor sequence learning. These conflicting results show that the extent to which the hippocampus contributes to motor learning is unknown. We argue that this knowledge gap is attributed to a lack of causal neuroimaging evidence elucidating the role of the hippocampus in motor memory. Failing to address this critical gap will be a missed opportunity to update the field’s conceptualization of memory system organization and will prevent the development of interventions targeting hippocampal-mediated motor learning and memory processes. The overarching goal of this project is therefore to causally test for the role of the hippocampus in motor memory in young healthy adults using a novel non-invasive experimental intervention (i.e., temporal interference stimulation - TIS). TIS is a potentially groundbreaking intervention that was developed in rodents and recently translated to human research. It enables focused - yet safe and noninvasive - neural stimulation at depth and therefore holds immense promise for the modulation of activity in deep brain regions. In this project, we will evaluate the effect of TIS on human hippocampal responses related to motor learning using functional magnetic resonance imaging (MRI). We will causally test a framework of hippocampal involvement in motor learning that will potentially reconcile previous contradictory findings. This framework proposes that the hippocampus supports abstract representations of motor sequences encompassing their spatio-temporal coordinates that are reactivated offline and can be generalizable across learning episodes. To causally test this framework, we will administer HC or sham TIS during motor learning and examine the effect of stimulation on both the behavioral (Aim 1) and neural (Aim 2) correlates of online and offline learning. Our central hypothesis is HC-TIS will specifically enhance offline motor learning via the modulation of HC responses. This innovative research project will lead to a breakthrough, as it will provide direct causal evidence for a role of the hippocampus in motor learning. It will also significantly impact the biomedical, behavioral and clinical fields because it will validate the use of TIS as a novel and groundbreaking technique to modulate motor learning-related (re)activation patterns in deep brain regions of the human brain. Ultimately, such an approach can be translated to the clinical domain in order to mitigate motor learning-related deficits in specific populations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Children and adults in the US are increasingly seeking treatment in Emergency Departments (EDs) for suicide ideation (SI) and suicide attempt (SA), and suicide is a leading cause of death across age groups. The ED setting has become a critical point of intervention to prevent suicide in the US. In spite of this demonstrated need, most EDs lack resources to address suicide risk, and there is an urgent need to identify strategies to improve evidence-based care for the high-risk and vulnerable individuals who seek ED care due to suicidal ideation or suicide attempt. There is increasing interest in the use of technology to address provider shortages and related gaps in care. Tele-mental health, hereafter “telehealth,” relies on technologies including video- and audio-conferencing with remote clinicians and use of shared electronic health records to improve access to remote mental health specialists. To date, little is known about how EDs use telehealth, and specifically how telehealth services integrate suicide prevention practices for patients at high risk of suicide. The objectives of this project are to gain a comprehensive picture of whether telehealth increases access to treatment and improves treatment outcomes, to understand which patients benefit most from telehealth and which elements of telehealth are most beneficial, and to gather information relevant to understanding the mechanisms by which telehealth influences outcomes. The study team will link data from a previous NIMH-supported survey about EDs’ use of telehealth with health care claims from national samples of individuals insured by Medicaid and Optum private payers to examine relationships between patient receipt of care via telehealth and patient outcomes of post-ED visit connection to follow-up mental health care within 30 days and ED or hospital revisit within 90 days. The team will conduct semi-structured interviews with a subset of ED leaders, clinicians, and mental health consumer advocates around the country to understand facilitators and barriers to telehealth implementation within EDs and mechanisms by which telehealth influences patient outcomes.

NIDA - National Institute on Drug Abuse

Rates of overdose (OD), suicide, substance use (SU) and mental health (MH) problems are elevated among young adults involved in the criminal legal system (YACL). The majority of YACL are under community supervision (probation or parole) and live in communities where risk for OD post-release is substantial, and SU and MH treatment must be obtained from resource-limited behavioral health systems. Although many YACL would benefit from treatment, both structural and individual-level obstacles limit treatment uptake. Indeed, YACL frequently deny a need for treatment and prioritize employment over treatment/recovery. As such, 80- 90% of YACL needing treatment do not receive community-based services. Interventions that address treatment access and reduce YACL’s OD and suicide risk and SU/MH problems are urgently needed. Therefore, we propose to tailor e-Connect -- our efficacious system-level intervention designed to improve identification of suicide risk, SU and MH problems, increase referrals and increase treatment uptake for adolescents on probation -- for YACL by integrating OD risk screening and integrating peer support for YACL to create e-ConnectYA. We will capitalize on an established, nationwide, evidence-based employment training program designed specifically for criminal-legal system involved individuals, to deliver e-ConnectYA, accessing an otherwise hard-to-reach and disengaged population and harnessing the motivation associated with employment program participation to engage YACL with unmet treatment needs in services. Guided by the GPM and EPIS frameworks, this 5-year study will first tailor e-Connect to accommodate the needs of YACL to create e-ConnectYA (Aim 1). In Aims 2 and 3, we will use a type 1 hybrid effectiveness-implementation stepped-wedge trial design in n=6 CEO sites across 6 states to examine the effectiveness of e-ConnectYA. Sites will be randomized to one of 3 waves of active intervention. We will compare at the site-level e- ConnectYA with care-as-usual (baseline) CEO staff practice on (i) YACL SU/MH treatment initiation (any, MOUD, stimulant; primary outcome); (ii) employment; (iii) recidivism; and (iv) OD/SIB mortality risk (exploratory outcome). In Aim 3, we will examine e-ConnectYA implementation (uptake, feasibility, fidelity, acceptability, sustainability). We will document the process of implementation, comparing advancement through implementation stages across the 6 sites, and we will explore the role of site differences and other EPIS and GPM derived factors on implementation completion to inform scale-up of e-ConnectYA beyond CEO to other supportive employment programs/models.

NIDA - National Institute on Drug Abuse

PROJECT ABSTRACT Family members (FMs; biological, extended, or chosen family) impacted by SUD experience chronic stress that places them at high risk for mental and physical health consequences. These consequences are exacerbated by the stigma, guilt, shame and self-blame that often occur in families with an individual using substances. As a result, FMs impacted by SUD often experience social isolation and are unsure how to best support their loved one in recovery. While these FMs are motivated to support their loved one in the treatment navigation process, they seldom seek support for themselves. Programs like Community Reinforcement and Family Training (CRAFT) provide support to FMs and equip them with tools to improve their own lives while supporting their loved one. While CRAFT is well-established in community settings for increasing their loved one’s SUD treatment initiation, less is known about the applicability of CRAFT in clinical SUD settings. Thus, it remains unclear whether CRAFT can enhance patient treatment retention in these settings and whether FMs who might not otherwise seek care would participate. To advance the science of engaging and supporting families impacted by SUD, we will take a multiphase approach and: (1) conduct an iterative, online process with FMs and clinic staff to identify potential family engagement strategies that community health clinics (CHCs) can deliver that may be effective, feasible, acceptable, and appropriate (R61 Aim 1; N=100), (2) test those strategies using a fractional factorial trial (R61 Aim 2; N=100), (3) combine the most effective strategy with CRAFT and conduct an RCT to test this optimized intervention versus usual care for patient and FM dyads recruited from CHCs that provide SUD treatment (R33 Aim 3; N=200 dyads). Finally, we will conduct interviews with FMs, clinic staff, and financing experts to assess factors influencing future implementation and dissemination of FM interventions in clinical SUD settings (Aim 4; N=30-35). By prioritizing strategies to engage FMs, we aim to enhance both the effectiveness and adoption of family-focused interventions, while also advancing research on how to best optimize the involvement of this often-overlooked group.

NIMH - National Institute of Mental Health

Over half of adolescents obtain insufficient sleep duration (less than age-based guidance) on school nights, while 10-40% report difficulty falling/staying asleep and poor sleep quality, all of which are linked to mental health problems. While TDM use is highly prevalent in adolescence and a critical factor in sleep problems, few effective sleep interventions specifically address family TDM use rules and can be scaled in primary care, an accessible setting where families often raise sleep and TDM use concerns in pediatrician visits. Our prior randomized trial found that pediatricians can deliver brief TDM-related counseling with positive youth and family outcomes. These findings contributed to the American Academy of Pediatrics (AAP) Family Media Plan (FMP), a highly accessible online tool to support families’ TDM use rule creation. However, the FMP does not address sleep beyond age-appropriate duration guidance. Our long-term goal is to implement feasible, effective, and scalable interventions to address adolescent TDM use-related sleep problems and mental health. This R34’s goal is to optimize and evaluate a Sleep-enhanced Family Media Plan (sFMP) for early adolescents’ sleep problems, in partnership with the AAP’s large, heterogeneous practice-based Pediatric Research in Office Settings (PROS) network. Building on our AAP-funded qualitative work, Aim 1 is to further refine an sFMP prototype that addresses adolescent sleep and TDM use problems and includes clinician-delivered TDM use counseling. Aim 1a is to conduct usability interviews, guided by human-centered design principles and socio-technical theory, at up to 4 PROS sites with n=3-5 adolescent-caregiver dyads and n=3-5 pediatric clinicians (N=9-15). Aim 1b is to conduct an open pilot of the sFMP delivered by up to n=10 clinicians with n=5-10 adolescent-caregiver dyads (N=20-30) to examine feasibility, usability, acceptability, and fidelity. Aim 2 is to conduct a pilot stepped wedge cluster randomized trial in 4 new PROS sites with N=80 adolescent-caregiver dyads and N=12-16 clinicians to evaluate sFMP feasibility, acceptability, fidelity, and initial youth sleep and mental health outcomes. Aim 3 is to explore whether intervention-induced changes in sFMP targets are linked to changes in youth sleep and mental health. MPI Moreno’s established Youth Advisory Board and the PROS study advisor, Steering Committee (clinicians, caregivers), and Coordinators (clinicians) will provide feedback throughout this work to ensure our procedures, intervention content and delivery methods, and dissemination plans are feasible and acceptable to end-users (pediatricians) and recipients (youth, caregivers). Our MPI model includes expertise in pediatric sleep, TDM use, and adolescent health, while our Co-Is bring expertise in primary care-based clinical trials and human-centered design. Results will inform an R01 hybrid effectiveness-implementation trial scaling the sFMP across AAP PROS to effectively and sustainably improve youth sleep and mental health, consistent with RFA-MH-25-130 and NIMH’s broader goals.

NIMHD - National Institute on Minority Health and Health Disparities

PROJECT SUMMARY/ABSTRACT Asian Americans (henceforth noted as Asians) have experienced high rates of poor sleep and endorse more sleep-related symptoms and daytime sleepiness compared to Whites or Hispanics. Robust research has consistently demonstrated that poor sleep is associated with a higher risk of various health outcomes. Given the significant effects of poor sleep on health, promoting population sleep health through effective interventions is a public health priority. Despite existing efficacious interventions for poor sleep, such as Cognitive Behavioral Therapy for Insomnia (CBT-I), none have been adapted or tested for Asians. Furthermore, numerous barriers to traditional CBT-I prevent Asians from accessing and benefiting from CBT-I. These include a lack of non-health professional interventionists who are linguistically and culturally competent; a perceived stigma of mental health treatment, including CBT-I, among Asians; CBT-I being developed and tested among primarily Whites; and a lack of scalability among Asians. We will address these barriers to improving sleep among Asians by testing a 5-week community-engaged, linguistically- and culturally adapted videoconference sleep intervention (ASLEEP [Asian American SLEep Empowerment Program]) delivered by trained bilingual and bicultural interventionists recruited from Asian communities in a randomized controlled trial. Participants will be identified and recruited from Asian communities, and a community advisory board will be established to provide input in every step of the program. The goal of this community-engaged project is to quantify the impact of ASLEEP on sleep and sleep-related outcomes (e.g., insomnia, sleep disturbance, sleep-related impairment, sleep duration, and depressive and anxiety symptoms) among 150 community-dwelling Chinese-, Korean-, and Vietnamese Americans adults who have poor sleep. Outcome assessments will occur at post-intervention, 3-, 6-, and 12 months to assess both short- and long-term effects of ASLEEP. We will also evaluate study process measures to inform future research on effectiveness. ASLEEP has been adapted and refined based on core components of CBT-I, conceptual models, findings from extensive preliminary studies, and input from our community advisory board. This project includes several innovations, including the first sleep intervention study for Asians, community engagement, cultural adaptation, and high potential for enhanced scalability. ASLEEP will be one of the first linguistically and culturally adapted sleep interventions for Asians, an understudied population at higher risk for poorer sleep and limited English proficiency. This community-engaged program would generate data for a potentially scalable sleep program tailored for Asians that overcome barriers to improving sleep and inform a larger future effectiveness study to improve sleep among a high-risk group and potentially reduce sleep-related health disparities.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Sleep spindle deficits are a promising biomarker and therapeutic target for schizophrenia spectrum disor- der (SSD), as they reflect underlying dysfunction in thalamocortical circuits. However, current non-invasive neuromodulation techniques lack the depth and precision to directly target deep brain structures like the thala- mus, where sleep spindles are generated. Temporal interference transcranial electric stimulation (TI-TES) of- fers a novel approach to selectively stimulate deep brain regions, such as the thalamus, while minimizing elec- tric fields elsewhere. Additionally, TI-TES permits simultaneous stimulation and high-density EEG (hdEEG) ac- quisition during sleep, a combination pioneered by the research team. Supported by preliminary data, the over- all objective of this project is to demonstrate that TI-TES can effectively target thalamic circuits and enhance sleep spindle activity in healthy subjects during non-rapid eye movement (NREM) sleep. Specifically, this pro- ject aims to 1) identify the optimal TI-TES parameters (frequency, location) for enhancing spindle frequency activity (SFA), and 2) determine the differential effects of thalamic TI-TES on fast and slow spindle subtypes, slow waves, and SO-spindle coupling. The central hypothesis is that slow and fast spindle subtypes can be selectively enhanced by modulating the location and frequency of thalamic TI-TES. The rationale for this pro- ject is that focal thalamic stimulation could restore normal spindle activity in SSD patients in a personalized manner, potentially improving thalamocortical connectivity and addressing broader neurobiological deficits. To achieve these aims, personalized, multipolar TI-TES combined with hdEEG will be applied to healthy subjects during the N2 sleep stages of a 90 min afternoon nap. Each participant will undergo bilateral thalamic stimulation at three target locations (broad thalamic, anterior, posterior) across separate nap sessions in a ran- domized, counterbalanced crossover design. Within each session, randomized stimulation frequencies will range from 8-16 Hz, along with a SHAM condition. Under Aim 1, increases in 8-16 Hz spectral power will serve as the primary metric for identifying the most effective stimulation parameters. Under Aim 2, detailed analyses of the recorded hdEEG data will explore the number, density, amplitude, duration, and topography of slow and fast spindles, as well as slow waves, and SO-spindle coupling. Individual spindles and slow waves will be iden- tified using automated detection algorithms. This research is highly innovative as it represents the first use of TI-TES to enhance sleep spindle activity, and, based on available literature, the first attempt to directly elicit spindles through thalamic stimulation in humans. The proposed research is significant because it is expected to provide strong scientific justification for future clinical trials of non-invasive neuromodulation therapies aimed at restoring normal spindle activity and alleviating thalamocortical dysfunction in patients with SSD, where cur- rent treatments remain inadequate.

NIMH - National Institute of Mental Health

SUMMARY Suicide is the second leading cause of death among youth and young adults ages 10-24, with rates having risen over 60% in the past 15 years. Emergency Department (ED) visits for psychiatric concerns among this population have also doubled, often prompted by suicide-related concerns. However, ED clinicians often find it difficult to identify those at the highest suicide risk and to judge whom to transition to higher levels of care when such care is limited. A history of prior self-injury, including both nonsuicidal and suicidal self-injury, has consistently been the strongest predictor of future suicidal behavior. Ample theoretical and empirical evidence suggests that the more severe, or medically lethal, prior self-injurious behaviors are, the greater the risk for future self-injury. However, the field has almost entirely relied on self-report to assess the presence and severity of prior self-injury, despite the fact that self-injury frequently leaves physical markings. Our prior R21 was the first application of computer vision with the goal of augmenting suicide risk detection through the analysis of images of tissue damage. Building on our promising R21 results, this R01 proposal seeks to expand the application of computer vision techniques to the ED to predict prospective suicide attempt (SA) risk more accurately by analyzing images of tissue damage for self-injury presence and severity. This study aims to determine the predictive utility of signals derived from standardized skin images in predicting prospective SA risk among ED patients beyond (1a) participant-report of past self-injury severity indicators and (1b) extant Electronic Health Record (EHR)-based suicide risk algorithms trained at Mass General Brigham (MGB). The performance of these models will be evaluated in racial and ethnic minority groups to mitigate bias in future research. Finally, this study aims to characterize implementation determinants of employing image-taking procedures and computer vision-enabled algorithms to automate EHR documentation of self-injury tissue damage within EDs. Youth and young adults ages 12 to 25 presenting with psychiatric concerns will be recruited at MGB EDs. At baseline, study participants will have standardized images of their arms taken; to assess prospective SAs, participants will complete remote assessments at 1 and 6 months and medical records will be examined. Images will be analyzed using deep learning techniques to detect and classify tissue damage indicators of suicide risk. Successful completion of this study will establish the utility of computer vision at the point of care and provide crucial insights into potential barriers and facilitators of its implementation that can be addressed in future scale-up. This research paves the way for implementing a novel, objective approach to suicide prevention that enhances detection and monitoring of youth and young adult suicide risk. This research aligns with the National Institute of Mental Health and the National Action Alliance for Suicide Prevention’s prioritized research agenda, targeting the development of innovative and effective suicide risk assessment tools in clinical settings.

NIH

Recovery-oriented care is an imperative for the VA, particularly in mental health programming for Veterans with serious mental illness (SMI). Collaborative decision-making (CDM) is a recovery-oriented approach to treatment decision-making that supports meaningful involvement for patients across all aspects of decision- making, thereby empowering patients and facilitating better decision-making based on patient values, preferences, and cultural context. CDM is associated with several important outcomes including improved personal recovery, treatment engagement, treatment satisfaction, and social functioning. However, current levels of CDM among Veterans with SMI are low. Collaborative Decision Skills Training (CDST) is a promising 10-session group intervention that support Veterans to gain knowledge, skills, comfort, and confidence to collaborate with their clinicians and other members of their treatment teams. CDST has undergone initial testing in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) and demonstrated feasibility for use among Veterans participating in PRRC care. This initial tests demonstrated preliminary evidence that CDST is effective at increasing Veteran-clinician collaboration, personal recovery, empowerment, treatment engagement, and social functioning. Therefore, the proposed study will examine CDST’s effectiveness among 119 Veterans with SMI participating in three PRRCs in the Southwestern United States (San Diego, Los Angeles, and Albuquerque). Veterans will be randomized to either CDST or active control (AC). The primary outcome measure will be functioning within the rehabilitation context, meaning Veteran CDM behavior during usual care VA mental health appointments. Secondary outcomes are treatment attendance, engagement, and satisfaction, along with functioning outside of the rehabilitation context (i.e., rehabilitation goal attainment, sense of personal recovery, empowerment symptom severity, and social functioning). Given that CDM is fundamentally an interaction between Veterans and their clinicians, the team will also assess whether clinician factors (i.e., engagement in CDST training or delivery; therapeutic alliance; work satisfaction; burnout; perceptions of self-efficacy; organizational climate; attitudes about recovery and CDM) moderate Veteran outcomes. Veterans in both groups will attend 10 hour- long group sessions held over 10 weeks. All Veterans will complete an assessment battery at baseline, post-intervention, at three-month post- intervention follow-up, and at six-month follow-up. This will allow the team to assess durability of CDST’s hypothesized benefits. Veterans who leave PRRC care and then return while the study is still active will complete one final assessment to further assess whether benefits are durable to re-entry to care. Additionally, the team will assess equity of benefits by assessing subgroup differences in benefits by race/ethnicity, gender, and sexual orientation. A team of Veterans and clinicians will be recruited to co-create consensus equity guidelines to support effective and equitable delivery of CDST in PRRCs. The results of the proposed study will confirm CDST’s benefits for Veterans in PRRC care and inform the utility of providing CDST broadly to Veterans with SMI. The results of this study will expand current understanding of CDM among Veterans with SMI by providing a large, diverse sample to 1) assess CDST’s overall benefits; 2) durability and equity of those potential benefits; 3) whether and how clinician factors impact those potential benefits; and 4) identify how to deliver CDST and related interventions effectively and equitably.

NIH

The overall goal of the proposed CDA-2 is for Dr. Fischer to obtain advanced training in various methods of psychiatric genomics (e.g., statistical genetics, epigenetics, transcriptomics) that he can use to supplement and strengthen his existing program of research, which examines environmental risk and protective factors for various psychiatric disorders and clinical problems, including suicidal thoughts and behaviors (STBs). This training will enable Dr. Fischer to systematically and comprehensively examine the biopsychosocial etiology of STBs, which will ultimately help to inform the treatment and prevention of STBs in U.S. Veterans. To accomplish this goal, Dr. Fischer will investigate how environmental (i.e., psychosocial) risk and protective factors interact with polygenic liability for STBs, along with how epigenetic processes are associated with STB phenotypes (i.e., suicidal ideation and suicide attempts). This project is innovative in that it will be one of the first to examine whether psychosocial risk and protective factors potentiate or mitigate polygenic risk for suicide in U.S. Veterans. It will also be, by far, the largest study to date on the epigenomics of STBs and the first to derive methylation risk scores for STBs. The proposed study will leverage cutting-edge statistical methods and state-of-the-art bioinformatics to provide novel insights into the complex etiology of STBs that will ultimately help inform efforts to reduce Veteran death by suicide. This CDA-2 grant will build on Dr. Fischer’s strong scientific background in Veteran mental health, psychiatric epidemiology, and environmental risk and protective factors, along with his ongoing experiences as a clinical psychologist, to provide him with crucial new knowledge and skills, which will support the generation of novel, multidisciplinary research. Through the proposed CDA-2, Dr. Fischer will develop the ability to: 1) generate polygenic risk scores; 2) conduct gene enrichment analyses and transcriptome-wide association studies (TWAS); 3) perform drug repurposing analyses; 4) conduct epigenome-wide association studies (EWAS); 5) derive methylation risk scores; and 6) leverage advanced machine learning approaches to evaluate multi-level predictive models. Dr. Fischer’s multidisciplinary mentorship team is composed of world-leading experts working within the VA Connecticut Healthcare System and Yale University. The high-quality research and collaborative environment present at these institutions will facilitate Dr. Fischer’s transition into an independent VA researcher and equip him with the tools needed to produce impactful, innovative research that advances the U.S. Department of Veterans Affairs top research and clinical goals: suicide prevention.

NIMH - National Institute of Mental Health

Project Summary/Abstract Fear is important for survival, but excess fear can be problematic when it interferes with daily functioning. One disorder marked by such exaggerated fear responses is post-traumatic stress disorder (PTSD) in which exposure to a traumatic event predisposes an individual to show excessive subsequent fear responding. Notably, women are nearly twice as likely as men to develop PTSD, suggesting there may be sex-specific mechanisms that gate sensitivity to acute stress. Recent work from our lab has identified the repressive histone deacetylase 3 (HDAC3) as a key mechanism that modulates the persistent effects of stress. Specifically, we found that acute stress reduces HDAC3 in the amygdala and locally blocking HDAC3 during weak stress transforms this event into one that drives persistent fear sensitization in male mice. Surprisingly, in female mice, the same mild stress drove persistent and robust fear sensitization that was not further enhanced by HDAC3 inhibition, suggesting that the threshold for inactivating HDAC3 is much lower in females. This proposal aims to systematically investigate the role of HDAC3 and histone acetylation more broadly in regulating stress-enhanced fear learning in male and female mice. Specifically, we hypothesize that acute stress establishes an epigenetic molecular memory in the amygdala primarily via histone acetylation, opening the local chromatin at key fear memory genes to enable their excessive transcription in response to subsequent mild fear conditioning. We further hypothesize that females require less intense stress to establish these changes. To fully test this hypothesis, we propose three aims. In Aim 1, we will determine the role of HDAC3 in establishing stress-enhanced fear learning in males and females. We will bidirectionally manipulate HDAC3 in the amygdala during varying amounts of acute stress and test whether that alters subsequent fear learning in male and female mice. In Aim 2, we will determine the mechanisms through which acute stress persistently enhances subsequent fear memory in both sexes. Using RNA- and ChIP-seq, we will test whether intense acute stress establishes an epigenetic molecular memory that enables excessive or aberrant expression of key fear memory genes in response to subsequent fear conditioning. Then we will use HSV-CRISPRi to causally test whether top candidate genes are required for this sensitization. Finally, in Aim 3, we will determine how HDAC3 modulates susceptibility in a sex-specific manner. Using 2-shock stress that establishes persistent sensitization only in female mice, we will determine which genes might support sex-specific sensitization. We will also determine which of these genes might promote sensitization in male mice when HDAC3 is blocked. Finally, we will bidirectionally manipulate these genes with our established HSV-CRISPRi and HSV-CRISPRa systems and directly test whether HDAC3 functions through these genes to promote stress-enhanced fear learning. Together, our findings will identify sex-specific mechanisms through which acute stress persistently changes the brain’s response to subsequent fear.

National Institutes of Health

This Funding Opportunity will establish the NIH Blueprint for Neuroscience Research Network to Guide Foundational Research on Human Consciousness, leveraging a trans-NIH collaboration of 14 Institutes, Centers, and Offices dedicated to reducing the burden of nervous system disorders. Consciousness is central to numerous serious biomedical conditions, including coma, delirium, dementia, traumatic brain injury, stroke, sleep disorders, metabolic disorders, and seizures - conditions central to NIH's biomedical mission. Yet the neural mechanisms that support conscious states remain insufficiently understood, limiting clinicians ability to diagnose and treat patients effectively. Advancing foundational science on human consciousness will strengthen clinical decision-making and improve outcomes for patients with costly and hard-to-treat neurologic and systemic illnesses by:Detecting consciousness in minimally responsive patients to guide prognosis, treatment, and ethical decisions (e.g., organ harvesting).Improving understanding of consciousness in Alzheimer s disease, related dementias, and delirium.Investigating altered states in mental disorders to inform treatments.Identifying sentience and state transitions under anesthesia and during recovery.Advancing knowledge of sleep states and improving treatments for insomnia and other sleep disorders.Exploring non-sensory visual perception (e.g., hallucinations, aphantasia) to deepen insight into mental health.Evaluating therapeutic effects of consciousness-modulating interventions such as meditation, hypnosis, and neurostimulation.Applying New Approach Methodologies (NAMs) to study human consciousness.Despite its importance, biomedical research on consciousness lacks shared standards, resulting in fragmented efforts and limiting understanding of underlying neurocircuitry. To accelerate rigorous, reproducible, and ethically grounded research, this initiative will create a national interdisciplinary Research Network to strengthen and integrate consciousness-related neuroscience, rather than support discrete, hypothesis-driven projects. The Network will develop coordination frameworks, standards, and infrastructure, uniting expertise from neuroscience, neurology, psychiatry, psychology, anesthesiology, sleep and meditation research, computational science, AI, bioethics, and philosophy.The Network s goal is capacity building: developing and providing needed research resources to advance understanding of the neural mechanisms supporting conscious states. It will lead planning and consensus-building activities to:Harmonize operational definitions across consciousness research.Identify research settings, model systems, and experimental designs with the greatest potential.Evaluate indicators and measures of consciousness for diverse scientific approaches.Determine which measures best reflect preserved or perturbed neurobiological function.Address essential ethical considerations.To strengthen U.S. leadership and cultivate a highly trained workforce, the Network will provide interdisciplinary cross-training opportunities, such as workshops and visiting scholar programs, not feasible in siloed environments. This initiative will create resources that enable rigorous biomedical research on the neural mechanisms of conscious states, aligning with NIH's strategic priorities to improve population health and well-being.

National Institutes of Health

<p>This Funding Opportunity will establish the <strong>NIH Blueprint for Neuroscience Research Network to Guide Foundational Research on Human Consciousness</strong>, leveraging a trans-NIH collaboration of 14 Institutes, Centers, and Offices dedicated to reducing the burden of nervous system disorders. Consciousness is central to numerous serious biomedical conditions, including coma, delirium, dementia, traumatic brain injury, stroke, sleep disorders, metabolic disorders, and seizures - conditions central to NIH's biomedical mission. Yet the neural mechanisms that support conscious states remain insufficiently understood, limiting clinicians’ ability to diagnose and treat patients effectively. Advancing foundational science on human consciousness will strengthen clinical decision-making and improve outcomes for patients with costly and hard-to-treat neurologic and systemic illnesses by:</p><ul style="list-style-type:disc;"><li>Detecting consciousness in minimally responsive patients to guide prognosis, treatment, and ethical decisions (e.g., organ harvesting).</li><li>Improving understanding of consciousness in Alzheimer’s disease, related dementias, and delirium.</li><li>Investigating altered states in mental disorders to inform treatments.</li><li>Identifying sentience and state transitions under anesthesia and during recovery.</li><li>Advancing knowledge of sleep states and improving treatments for insomnia and other sleep disorders.</li><li>Exploring non-sensory visual perception (e.g., hallucinations, aphantasia) to deepen insight into mental health.</li><li>Evaluating therapeutic effects of consciousness-modulating interventions such as meditation, hypnosis, and neurostimulation.</li><li>Applying New Approach Methodologies (NAMs) to study human consciousness.</li></ul><p>Despite its importance, biomedical research on consciousness lacks shared standards, resulting in fragmented efforts and limiting understanding of underlying neurocircuitry. To accelerate rigorous, reproducible, and ethically grounded research, this initiative will create a national interdisciplinary Research Network to strengthen and integrate consciousness-related neuroscience, rather than support discrete, hypothesis-driven projects. The Network will develop coordination frameworks, standards, and infrastructure, uniting expertise from neuroscience, neurology, psychiatry, psychology, anesthesiology, sleep and meditation research, computational science, AI, bioethics, and philosophy.</p><p>The Network’s goal is capacity building: developing and providing needed research resources to advance understanding of the neural mechanisms supporting conscious states. It will lead planning and consensus-building activities to:</p><ul><li>Harmonize operational definitions across consciousness research.</li><li>Identify research settings, model systems, and experimental designs with the greatest potential.</li><li>Evaluate indicators and measures of consciousness for diverse scientific approaches.</li><li>Determine which measures best reflect preserved or perturbed neurobiological function.</li><li>Address essential ethical considerations.</li></ul><p>To strengthen U.S. leadership and cultivate a highly trained workforce, the Network will provide interdisciplinary cross-training opportunities, such as workshops and visiting scholar programs, not feasible in siloed environments. This initiative will create resources that enable rigorous biomedical research on the neural mechanisms of conscious states, aligning with NIH's strategic priorities to improve population health and well-being.</p>

NIMH - National Institute of Mental Health

PROJECT SUMMARY AND ABSTRACT Autism spectrum disorder (ASD), a lifelong, neurodevelopmental condition defined by core behavioral symptoms encompassing social functioning, communication, restricted interests and repetitive behaviors, affects an estimated 1/36 children in the United States at a cost of $37B annually. Wide variations in ASD presentation and comorbidities affecting more than 50% of autistic individuals substantially impact diagnosis, and the planning and delivery of clinical care. Autistic children with more complex presentations due to medical and neurodevelopmental comorbidities (e.g., attention deficit hyperactivity disorder; ADHD, and/or developmental language disorder; DLD) can experience greater diagnostic and treatment delays, increasing the risk for poor developmental outcomes and quality of life. We propose to establish specificity and scalability of a promising biomarker for autism spectrum disorder (ASD) by combining innovative wearable high-density diffuse optical tomography (HD-DOT) functional neuroimaging with a Computerized Assessment of Motor Imitation (CAMI) developed by our team. Many fundamental social and communicative skills are learned through imitation and impaired imitation likely contributes to core difficulties in ASD. While movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including ADHD and DLD, deficits in motor imitation may help distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Our team has pioneered an automated CAMI, using a brief, engaging task that can be readily scaled to clinic and home settings, with published studies showing CAMI has robust diagnostic discrimination for identifying ASD as compared with neurotypical children (NTC). However, the specificity of imitation deficits and corresponding brain mechanisms for ASD relative to other neurodevelopmental conditions has had limited study. Addressing these gaps, we propose to to establish specificity of impaired motor imitation to ASD through simultaneous assessment of motion imitation fidelity via CAMI and brain function/connectivity via HD-DOT in school-age children (6-10 years) with ASD, ADHD, DLD, and NTC. Crucially, as part of Aim 1, we will collect CAMI data using both 3D depth cameras and more readily available 2D cameras and use machine learning to build multimodal representations of movements and develop metric learning techniques to quantify motor imitation from 2D camera data alone. Additionally, we will identify brain-behavior relationships between cortical activity and connectivity with motor imitation fidelity and relate them to both diagnostic and transdiagnostic traits (Aim 2). Finally, we will extend the motor imitation brain-behavior assessments to preschool age children (3-5 years) with and without ASD (Aim 3). Across all Aims, we will assess specificity by examining associations of CAMI and HD-DOT measures with diagnoses as well as established dimensional measures of ASD, ADHD, and DLD. Our proposed study has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children.

NIMH - National Institute of Mental Health

ABSTRACT The long term goals of these studies are to identify motor imitation as a biomarker of autism spectrum disorder (ASD) to both deepen understanding of brain and behavioral mechanisms for comorbid conditions and improve diagnosis with a cost-effective, objective, and reliable assessment method we developed. Although ASD is defined by core deficits in social-communicative functioning and restricted interests and repetitive behaviors, an ASD diagnosis is often accompanied by clear impairments in motor control and learning that present early and persist through childhood and into adulthood. Prominent among these ASD-associated motor impairments is difficulty imitating others’ actions (i.e., motor imitation). Imitation is crucial to social-communicative development, and impaired imitation has long been recognized as a likely contributor to the core difficulties in ASD. Crucially, while movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID), current literature suggests that deficits in motor imitation may distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Efforts to establish imitation as a biomarker of ASD have been hampered by a lack of objective, reliable assessment, with studies thus far applying labor intensive methods that require subjective assessment by highly trained researchers/clinicians. Our team has pioneered the development of an automated Computerized Assessment of Motor Imitation (CAMI) to quantify ASD-associated imitation deficits with better diagnostic discrimination ability than traditional methods. A remaining challenge in developing motor imitation as a phenotypic biomarker is to establish the specific neural mechanisms contributing to imitation deficits. Previous fMRI studies on motor imitation in ASD have shown mixed results, possibly due to the significant limitations in assessing naturalistic motor imitation in the fMRI scanning environment, where there are substantial constraints on motion. To address this challenge, our team develops high-density diffuse optical tomography (HD-DOT) that enables fMRI-comparable image quality in an open setting. Herein, we propose to establish the specificity of motor imitation impairments (Aim 1) as well as the brain mechanisms underlying such impairments (Aim 2) of ASD relative to ADHD and ID. Our proposed study, by integrating state-of-the-art methods for quantitative, objective motor imitation assessment and concurrent identification of ASD-specific underlying neural correlates, has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children. ASD-specific neurobehavioral biomarkers identified through our proposed CAMI and HD-DOT methods may advance clinical subtyping of ASD and opportunities for individualized treatment, refine monitoring response to intervention, and inform underlying neurobiological mechanisms.

NIDA - National Institute on Drug Abuse

Over 10 million students in the US attend schools with police but no counselor, nurse, psychologist, or social worker. Yet, more than a third of the low proportion of adolescents who receive the substance use treatment they need (6%) access it only at school. Schools are thus crucial public health intervention targets for substance use and behavioral health treatment and prevention. But instead, many adolescents experience school as a school-to-prison pipeline; a set of policies and practices that criminalize adolescents and ensnare them in the legal system rather than provide support for underlying educational and developmental needs. School-based arrests increased 300-500% and exclusionary school discipline (suspensions and expulsions) doubled over the past 40 years. Some subgroups of students are more than three times as likely to be suspended or expelled as other students, and students removed from school are more than twice as likely to be arrested in the same month than those not removed. Our preliminary evidence suggests that the school-to-prison pipeline is a previously unidentified population driver of adolescent substance use and mental illness. Moreover, the pipeline coincides with rises in aggressive community policing in schools’ surrounding communities. However, there is no research on the public health implications of these intersecting trends. In the proposed R01, we will collaborate with the New York City Office of School Health (OSH) to quantify relationships between aggressive community policing, school discipline, and student substance use/mental illness in NYC. We will create a unique geocoded 2000-2022 dataset linking all police stops/arrests; school- and student-level exclusionary discipline; restricted school-level Youth Risk Behavior Survey (YRBS) data (e.g., tobacco, alcohol, cannabis, other drug use); and OSH’s database of student health services records (e.g., nurse, counselor visits, referrals to behavioral health/substance use treatment). We will (Aim 1) characterize direct and mediated relationships between community policing and school discipline on school-level and (Aim 2) student-level substance use and behavioral health outcomes; and test (Aim 3) whether the intensity of policing around schools modifies the relationship between school discipline and student substance use/mental health. This high-impact project responds to NIDA’s interest in improving SUD treatment for at-risk populations in schools and the juvenile legal system, as well as leveraging data science to improve SUD prevention. Our interdisciplinary team, led by an early-stage investigator PI, has expertise in substance use, psychiatric, and social epidemiology; school health; the sociology of group differences in population health, education, and policing; spatial epidemiology/health geography; and data science. Findings will be utilized by policymakers and project stakeholders (including city, state, and federal policymakers) working to end the school-to-prison pipeline and prevent adolescent substance use/mental illness.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The NIH and other sponsors are investing heavily in translational research on new neural, brain, and pain relief devices. Many translational studies involve first in human subjects and include the implantation of brain devices in study participants. Translational neurodevice research raises many important ethical issues. One area that has received comparatively little empirical investigation and attention involves the ethics of decision-making about participation in early translational first-in human (FIH) neuro device research. This gap is concerning given that patients who decide whether to participate in FIH neuro device research are vulnerable due to refractory medical conditions, last resort options, trust and power dynamics with their team, and documented decisional biases such as optimism bias and “translational misconception”. At the same time, we must avoid unjustified paternalism—the belief that patients cannot provide true informed consent to participate in such research or that they should not be allowed to do so. What is essential is patient-centered perspectives on the vulnerabilities and value of participating in FIH neuro device research, their decisional and informational needs, accompanied by tools and approaches to improve decision making. The objective of this proposal is to identify and to address pressing ethical issues related to decision making about enrollment and participation in first-in-human translational research. In Aim 1, we will examine clinician- researchers’ and patient-subjects’ views on the value, vulnerabilities, and decisional and informational needs associated with participation in translational first-in human neuro device research. We will collaborate with and draw upon NIH-funded early and FIH translational research that represent growing areas of translational research with broad application and significance to patient populations: closed loop deep brain stimulation for a.) refractory and chronic pain and b.) treatment resistant mood disorders. In each case study will interview 1) patients with experience participating in first in human translational neuro-device research and patients who are potential future research subjects, 2) their family members and caregivers, 3) clinician researchers (e.g., neurosurgeons) who design the research studies, care for these patients, and implant translational neuro- devices, 4) other care team members including nurses, and 5) study coordinators with experience enrolling patients. In Aim 2 of the project, we will translate our findings from Aim 1 into a communication-decision tool for clinician researchers to use with patients considering participation in translational neurodevice research. We will alpha test this tool and disseminate it to key stakeholders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Neurocognitive abilities relevant to adaptive decision making and self-regulation (e.g., inhibition, working memory) mature from childhood through adolescence and play a critical role in the emergence of psychopathology. However, one-to-one mappings between these abilities and risk for specific psychiatric diagnoses have been elusive. The field’s struggle to identify such mappings is nonetheless consistent with high rates of comorbidity among disorders and the presence of a general factor for psychopathology (“p-factor”) suggesting many etiological mechanisms have a broad influence across diagnostic boundaries. Common factors also account for a substantial proportion of developmental change and individual differences in specific neurocognitive abilities, suggesting many of the associations between neurocognition and psychopathology are mediated through general processes that drive adaptive functioning across many tasks, contexts, and diagnoses. Efficiency of evidence accumulation (EEA)—a biologically plausible cognitive mechanism that has been well-characterized in computational modeling and neurophysiological research—is a compelling candidate for a general factor that can explain neurocognitive contributions to transdiagnostic psychopathology risk. EEA is a reliable higher-order factor that accounts for performance across a wide variety of cognitive functions—from simple decisions to complex executive tasks—and is impaired in multiple disorders linked to self-regulatory difficulties and maladaptive decision making. We posit that EEA is a developmental catalyst that supports adaptive decision making across many contexts, that EEA’s development is strongly influenced by the interplay between environmental factors (e.g., family conflict, socioeconomic resources) and the maturation of largescale brain networks, and that aberrant development of EEA conveys transdiagnostic risk for psychopathology. EEA’s well-characterized computational definition and biological underpinnings promise to provide a novel bridge between computational neuroscience and developmental psychopathology research. Furthermore, recent indications that EEA’s development may be impeded by specific adverse environments suggest that knowledge about EEA could inform targeted prevention efforts. To spur a program of computationally rigorous research on EEA as a general, and potentially malleable, neurodevelopmental influence on psychopathology, we will leverage four large longitudinal neuroimaging data sets to accomplish the following aims: 1) map the canonical maturational trajectory and nomological network of EEA across development, 2) quantify the influence of genetic and diverse environmental influences on the development of EEA, and 3) examine EEA’s co- development with psychopathology, environmental adversity, and neuroimaging metrics. Knowledge gained through this project will allow the field of developmental psychopathology to leverage key benefits of well- established computational models to establish precise and biologically plausible accounts of neurocognitive risk factors for psychopathology, their environmental determinants, and potential translational applications.

NIH

Significance to VA: Hundreds of thousands of Veterans are affected by unemployment each year, and those with mental health and/or substance use conditions are at highest risk. Unemployment has consequences across all areas of life and functioning including economic insecurity, homelessness, worsening mental health and physical health, increased substance use, disability, and suicide. The Veterans Health Administration (VHA) has sought to address the critical problem of Veteran unemployment through vocational rehabilitation (VR) programming. Unfortunately, existing programming appears inadequate, with national data indicating that the most commonly utilized VHA VR program – transitional work (TW) – leads to an average employment rate of only 38.6%. TW aims to rapidly restore functioning by providing Veterans with a temporary, paid work-role. In its current form, TW does not target intrinsic motivation and other psychological factors/skills (e.g., attitudes, self-efficacy, self-regulation) known to impact quality employment. We assert that failing to address intrinsic psychological motivators/skills associated with quality employment outcomes has contributed to TW’s subpar performance, and is a critical gap to address. Our team empirically developed, refined, and piloted a vocational counseling intervention, Purposeful Pathways, to address this gap. Innovation and Impact: The Purposeful Pathways intervention is a career development intervention designed specifically for Veterans with psychiatric conditions that targets psychological processes and skills that contribute to occupational functioning outcomes. By combining the strengths of TW (access to functional role) with Purposeful Pathways (addressing psychological motivators and skills), there is an opportunity to improve Veterans’ employment outcomes and downstream effects on quality of life, mental health, and substance use through this innovative VR pairing. Specific Aims: Aim 1: Evaluate the efficacy of Purposeful Pathways for improving occupational functioning (primary outcome). Hypothesis: Purposeful Pathways + TW, compared to TW only, will improve occupational functioning. Aim 2: Evaluate the efficacy of Purposeful Pathways for improving quality of life, and reducing mental health symptoms and substance use (secondary outcomes). Hypothesis: Purposeful Pathways + TW, compared to TW only, will improve quality of life, and reduce mental health symptoms and substance use. Aim 3 (Exploratory): Explore whether occupational functioning (competitive employment attainment) in the Purposeful Pathways + TW group is mediated by vocational identity, work hope, self-regulation, and/or employment motivation, key factors central to the Purposeful Pathways intervention. Methodology: We will conduct a phase II, multi-site, RCT comparing Purposeful Pathways + TW (n=127) to TW alone (n=127) among Veterans participating in TW at VA Bedford, VA Hines, and VA North Texas. Occupational functioning is the primary outcome (as measured by): rates of competitive employment, hours worked, income earned, career adaptabilities (Career Adaptabilities Scale), and meaningful employment (Positive Meaning Scale of the Work as Meaning Inventory). Secondary outcomes include: quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form), mental health symptoms (Patient Health Questionnaire), and substance use (Tobacco, Alcohol, Prestation medications, and other Substance tool). Candidate mediators include: vocational identity (Vocational Identity Scaled), work hope (Work Beliefs Scale), self-regulation (Short Self-Regulation Questionnaire), and employment motivation (Importance of Obtaining Preferred Position scale). Path to Translation/Implementation: Our study will set the stage for clinical dissemination and future studies on the effectiveness and implementation of Purposeful Pathways nationally through a subsequent effectiveness-implementation hybrid type 1 trial.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Tobacco use disorder (TUD) remains highly prevalent in people with serious mental illnesses (SMI), driving a significant mortality disparity in this population. First-line pharmacotherapies for TUD combined with behavioral support significantly increase tobacco abstinence rates in adults with SMI, yet are underutilized. Community health workers (CHWs) are lay health workers trained to provide health information and services, with a strong evidence base for improving uptake of health services in underserved communities. We showed CHW support from TTS trained lay staff with provider education on TUD treatment doubled tobacco abstinence rates in those with SMI through tripling TUD treatment uptake and impacting social determinants of health. Here we seek to test the effectiveness of CHW support, delivered by existing, trained, Medicaid-funded community behavioral health staff, for smoking cessation in adults with a SMI served by a Medicaid accountable care organization (ACO). Medicaid is the single largest payor of mental health services in the US. CHW deployment within Medicaid funded care structures to date has been generally limited to special waiver programs. Widespread adoption of Medicaid ACOs provides an opportunity to test whether existing behavioral care team members, with brief training, can function as CHWs, and whether such an innovation improves TUD, cardiovascular, and mental health outcomes. To do so, 937 adults with SMI and TUD, receiving behavioral healthcare through Medicaid ACOs in a large human services agency, will be enrolled and randomly assigned to receive behavioral health team support from their Intensive Case Manager (ICM) who has received brief CHW and TTS training or continue to receive usual ICM support (Enhanced usual care, EUC). All care team clinicians will be offered education on first-line, evidence-based TUD treatment in SMI. Our aim is to determine whether CHW support integrated into behavioral health care improves tobacco abstinence and cardiovascular risk in those with SMI and TUD when delivered by ICM staff within existing Medicaid ACOs, with the hypothesis that those assigned to Integrated CHW support will have higher rates of biochemically verified 7-day point prevalence combusted tobacco abstinence at 2 years than those assigned to EUC, the primary outcome, greater reduction in cardiovascular risk estimates at 2 years, greater improvement in psychiatric symptom severity, stress, and loneliness over two years, greater engagement with care, healthcare satisfaction ratings, and reduction in emergency department visits and inpatient hospitalization days in year 2 of the intervention than those assigned to EUC. Implementation of the Integrated CHW support intervention into existing Medicaid ACO behavioral care teams will be evaluated using quantitative data and qualitative stakeholder interviews. If effective, this intervention has the potential to be widely disseminated in existing, Medicaid funded systems of care and to be transformative in overcoming adverse SDoH to improve delivery of first-line, evidence-based medical care, reducing the enormous mortality disparity faced by people with SMI.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Cigarette smoking is the leading preventable cause of poor pregnancy outcomes in the U.S., contributing to serious adverse events ranging from catastrophic pregnancy outcomes to later-in-life metabolic syndrome. Perinatal smoking has a disproportionate adverse impact on populations with constrained access to healthcare (e.g., rural residents). We developed a clinic-based financial-incentives (FI) intervention for perinatal smoking cessation that has been shown to be efficacious and cost-effective in randomized controlled trials (RCTs) and meta-analyses. Indeed, in 2024 the United Kingdom announced national implementation of clinic-based FI for perinatal smoking delivered by National Health Service tobacco interventionists. Unfortunately, scaling clinic- based versions in the U.S. is difficult as many prenatal-care clinics and hospitals fail to provide smoking- cessation services, especially in rural regions where many obstetrical services or entire hospitals are closing. Hence, we developed a digital FI intervention in collaboration with DynamiCare Health Inc. In a Phase 2 RCT that we conducted with 90 pregnant participants recruited across 33 U.S. states, adding this digital FI intervention to best practices (BP+FI) increased odds of cessation 4-fold above BP alone. Maximum FI earnings possible in that trial were $1,620 across the approximately 9-month intervention, with a mean [SD] incentive payout of $331 [446] per women treated. This smartphone-based digital FI intervention previously received Food and Drug Administration (FDA) Breakthrough Device Designation. We are submitting this UG3/UH3 application to conduct Phase 2 (UG3) and Phase 3 (UH3) RCTs in collaboration with FDA with the overarching aim of having this digital FI intervention authorized as an FDA Approved Digital Therapeutic. The UG3 Phase 2 RCT will address a January 2025 Substance Abuse and Mental Health Services Administration advisory that caps maximum potential earnings in FI for treating substance use disorders at $750 when using federal funds. Because federal funds will be essential to successful U.S. implementation of this digital FI intervention, we propose to conduct a UG3 Phase 2 RCT (N=137) examining the efficacy of BP+FI with $750 maximum earnings versus BP alone. Based on prior FI RCTs and meta-analyses, we hypothesize that BP+FI will remain efficacious with a $750 maximum although with a smaller effect size than at the $1,620 value which is why we are proposing a larger sample size in the UG3 than our prior Phase 2 RCT. Go/no-go criteria for the UG3 phase are: (1) complete an FDA Q-submission and (2) the UG3 trial results support the efficacy of BP+FI at $750 maximum earnings for increasing antepartum smoking abstinence significantly above BP alone. If these benchmarks are met , we propose to conduct a UH3 effectiveness trial (N to be informed by UG3 results and FDA recommendations) examining overall smoking abstinence, birth outcomes, treatment acceptability, and cost-effectiveness. Overall, this digital FI intervention has potential to bring sorely needed and effective perinatal smoking-cessation services to U.S. women including rural residents and others with constrained access to healthcare.