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NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Cannabis use among pregnant women has increased more than 60% over the past decade. Up to 15% of women use cannabis prior to pregnancy and 6% prenatally, with differences by demographics, mental health symptoms, polysubstance use, and area-level factors. While evidence is building on the detrimental effects of cannabis use on adverse birth outcomes, the consequences of prenatal use on women's health during pregnancy or postpartum or on child health outcomes remains under-studied. The cannabis policy context has been evolving rapidly with 24 states and DC having legalized recreational cannabis. Significant gaps remain in understanding the effects of legalization on prenatal cannabis use and spillover effects on other substances, birth outcomes, maternal and child health outcomes, and provider assessment of use as well as variations in policy effects across individual- and area-level factors. The state of Maine provides an important natural experiment to understand the contextual landscape and trajectory of cannabis use among pregnant women. Maine legalized recreational cannabis in January 2017 and introduced retail sales in October 2020; municipalities were required to opt-in, providing staggered retail sales across the 16 counties. We propose a novel data linkage between Maine Pregnancy Risk Assessment Monitoring System 2016-2023 state-representative cohorts with birth certificates, All-Payer Claims Data and hospital health insurance claims to collate 6 years of data on each pregnant woman (N=6,307) and resulting child(ren) from 2 years prior to conception to 3 years postpartum, covering 2014-2026. With individual-level data and county-level identifiers, we will rigorously evaluate the effects of state- and county-level recreational cannabis policies on women's cannabis, tobacco, and alcohol use (referred to as substance use) before, during, and after pregnancy and, subsequently, on birth outcomes and maternal and child health outcomes. This project has three Specific Aims. Aim 1 will quantify the effects of state recreational cannabis legalization and county retail sales on women's substance use and health outcomes. Aim 2 will quantify the downstream effects of state recreational cannabis legalization and county retail sales on birth outcomes and child health outcomes. Aim 3 will examine the differential effects of state recreational cannabis legalization and county retail sales across demographic (race/ethnicity, education, health insurance status, age) and higher-risk (depression, polysubstance use) strata and area-level (rural/urban, federal poverty level) factors across Aims 1 and 2. The cannabis policy landscape is evolving rapidly. Study findings will (a) fill critical gaps in understanding the unintended consequences of emerging cannabis policies on pregnant women, birth outcomes, and maternal and child health; and (b) inform dissemination strategies that translate findings to guide policy and public health responses and inform clinical practice to protect the health of vulnerable mothers and children.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT There is an urgent need to address the high rates of anxiety among adolescents. While traditional therapeutic interventions have demonstrated reasonably good efficacy, they are often difficult for teens to access due to financial, cultural, and geographic barriers. Given the high rates of smartphone ownership among U.S. teens, digital technology may improve youth access to treatment. Over the past decade, many efficacious digital interventions have been developed, but the positive results do not often generalize beyond laboratory studies due to low rates of engagement in real-world settings. Thus, in addition to developing effective interventions, it is also critical to identify feasible and acceptable implementation strategies. Human support is one option for increasing adherence to digital interventions, but therapist availability is limited. With the right training, paraprofessionals such as teachers or religious leaders, may be able to support the delivery of mental health interventions to youth without requiring specific mental health expertise. One especially promising group of paraprofessionals is formal mentors. The structure and established relationships inherent to formal mentoring programs may overcome commonly reported barriers to youth engagement with other guided DMHIs, such as lack of trust in unknown providers/coaches. The widespread presence of formal mentoring programs across the U.S. also makes this a uniquely scalable framework with the option of flexible, program-specific implementation. A significant strength of this approach is its use of existing resources and systems, rather than attempting to create new and potentially burdensome workflows. The primary aim of the proposed study is to test the efficacy of a mentor-guided digital cognitive bias modification for interpretations (CBM-I) app for anxious youth aged 13-17 when implemented through mentoring programs. To do this, the applicant will work alongside sponsors Teachman and Deutsch to conduct a hybrid type I implementation/effectiveness randomized controlled trial testing a mentor-guided version of a youth-adapted CBM-I app (“MindTrails Teen”) against a mentoring-as-usual active comparison condition. CBM-I is well studied as an anxiety intervention and has been adapted successfully to a digital format. The proposed intervention, MindTrails Teen, performed well in a small open pilot trial in which 9/10 youth experienced reductions in anxiety. Preliminary feasibility and acceptability of the mentorship delivery model were established during the open pilot trial, but challenges with enrollment suggested a need to co-design implementation pathways in close collaboration with mentorship partner programs. In addition to the co-design plans, the secondary aims of this research proposal are to: 1) verify the feasibility and acceptability of a mentorship program delivery model for digital mental health interventions (DMHIs), and 2) examine if participating in the program can improve mentor/mentee relationship quality.

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.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Flexibly adapting to changing circumstances is a hallmark of human intelligence. This adaptation is often formu- lated as resulting from the use of a “model” of the environment that is used to reason about how decisions should change. However, standard approaches make simplifying assumptions about how the environment and actions are represented, leaving them unable to account for how people adaptively represent tasks. Deficits in learning task structure have been observed in psychiatric disorders and can considerably impact the difficulty of model- based reasoning. It is challenging to study this because the representations underlying model-based reasoning are believed to occur on a faster timescale than is amenable to standard neuroimaging methods. In addition, different planning strategies can often result in the same choices, making it difficult to predict planning represen- tations from behavior alone. The proposed research aims to address this gap. We develop two experiments to see how factorized task representations are used to simulate and plan. First, we examine an experiment that requires generating actions based on a well-learned sequence of stimuli and a per-trial cue for a response rule. While several task representations are possible, we hypothesize that people represent tasks in a highly factorized way, to generalize rapidly to future tasks. Second, we examine an experiment that requires planning, extending beyond simulation to generate action plans. We use eye tracking to record participant acquisition of task infor- mation, offering rich insight beyond choice data alone. Our task design also admits several task representations, making it possible to study how task representations influence the planning process, and are transformed into motor plans. We hypothesize that people plan in abstract task spaces, despite this process of transformation, because of the overall potential to simplify planning. In both aims, we will test these representational hypotheses by examining neural signals acquired with MEG, a method that is well-suited to testing the rapid sequences of neural activity associated with sequential simulation and planning. Going beyond existing methods developed to investigate sequential recall, our approach will reveal how sequential simulation interacts with selected task rep- resentations to support flexible behavior. This research will contribute novel understanding of how people select and use task representations for simulation and planning. While this work has no direct clinical aims, it will lay the groundwork for future investigations into the relationship between task abstraction learning and dysfunctional day-to-day decision making in psychiatric populations related to poor structure learning and generalization.

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

SUMMARY Reading comprehension (RC) is one of the most complex skills that we utilize daily and is crucial for functioning in modern society, but despite its significance for academic achievement, employment prospects, and mental health, many children and adults do not exhibit proficient RC abilities. New theoretical models aiming to explain variability in RC suggest a dynamic interplay and co-development among ‘precursor’ foundational and cognitive- linguistic skills, interacting with environmental and socio-ecological factors across the developmental timeline of learning to read. Behavioral and neuroimaging studies in school-age children have demonstrated critical mechanistic support for these multifactorial RC models by identifying the developmental trajectories of precursor skills and further showing that brain areas, tracts, and networks typically underlying language and cognitive skills are also involved in RC. Nevertheless, the precursor skills that support RC start developing in infancy and the brain correlates underlying these precursors begin to develop in utero, which suggests that typical and atypical RC developmental trajectories could diverge long before school age. As such, examining RC development using a multifactorial, longitudinal approach that includes brain and behavior starting in infancy is critical for developing theoretical frameworks that can inform early preventative and intervention strategies. Here, we propose a comprehensive longitudinal study of RC development in which we examine direct and indirect effects on RC from brain, behavioral, familial risk, and environmental data from infancy to adolescence. To achieve this goal, we will combine two existing longitudinal cohorts, one ranging from infancy to late childhood (n = 174) and the other from preschool to early adolescence (n = 137). By applying state-of-the-art pediatric neuroimaging analyses, multiple indicator growth model structural equation models, and an innovative behavior- brain co-development measurement index to this unique, combined dataset, we will be able to identify brain and behavioral measures in infancy that directly and indirectly support subsequent RC development (Aim1). We will further characterize how longitudinal trajectories of behavioral measures as well as brain structure, function, and white matter organization contribute to RC development and how familial risk and environmental factors shape these trajectories (Aim 2). Finally, we will examine how the co-development of brain and behavior, as measured with an innovative co-development index, relates to subsequent RC (Aim 3). If successful, we will contribute the first multifactorial longitudinal model of RC development comprising direct and indirect effects from brain, behavior, brain-behavior co-development, familial risk, and environmental measures beginning in infancy. Understanding RC development using a multifactorial longitudinal lens will be crucial for building theoretical models and developing experimental designs focused on early preventative and intervention approaches long before the start of formal schooling.

NIMH - National Institute of Mental Health

Project Summary Schizophrenia is a severe form of mental illness, characterized by psychotic symptoms, large cognitive impairments, and often life-long functional disability. While advances in early detection enable us to identify youth at clinical high risk for psychosis (CHR-P), a critical problem remains. To date, there are no gold- standard treatments to prevent the onset of the full disorder. A major barrier to developing such interventions is the clinical heterogeneity of the CHR-P population. This stems from the underlying complexity of the illness state itself, an active system of interacting factors. While we know many factors are associated with risk, we lack a clear understanding of the mechanisms by which these factors interact and reinforce each other to create the pathways that drive the transition to psychosis. This knowledge gap prevents the development of targeted, precision interventions. This project addresses this challenge by adopting a powerful alternative to traditional research models. We will apply cutting-edge network theory to a large sample of over 2,000 CHR-P individuals, modeling the high-risk state as a system of interacting factors. This approach allows us to move beyond simply listing risk factors to identifying those that are most central and influential in driving the illness forward. Specifically, we will construct the first multi-domain network in this population, comprehensively mapping the interplay between clinical symptoms, neurocognitive deficits, social functioning, and environmental stressors to reveal how they interact to accelerate illness progression. To achieve this, our research plan is threefold. First, we will establish the comprehensive baseline network structure of the CHR-P state, providing a foundational map of its interacting components (Aim 1). Second, we will isolate the critical network differences between youth who later develop psychosis and those who do not, pinpointing the specific interactions most predictive of illness onset (Aim 2). Third, we will incorporate longitudinal data to model how these network connections change over time, mapping the precise temporal pathways that constitute the progression to disease (Aim 3). This research is expected to provide a data-driven roadmap to the most potent and direct targets for preventative intervention. By identifying the system’s key drivers, our work will transform our understanding of psychosis risk. Ultimately, this will accelerate the development of personalized, mechanism-based treatments designed to disrupt the pathways to psychosis and prevent its onset in vulnerable young people.

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

Background. Neurodevelopmental disorders (NDDs) present a major global health challenge, particularly in low-resource settings like South Africa, where traditional diagnostic frameworks and access to comprehensive evaluations are limited. This research shifts the focus from formal NDD diagnoses to neurodevelopmental difficulties—measurable impairments in cognitive, social, emotional, and behavioral functioning—offering a more adaptable, resource-efficient approach grounded in the WHO’s International Classification of Functioning, Disability and Health (ICF). Given the rising prevalence of neurodevelopmental difficulties in South Africa and the critical role of caregivers, data-driven approaches are urgently needed to identify and support affected children. This study, which will utilize data from the Asenze Cohort Study (ACS), is the first to use adapted, non- specialist-administered measures alongside data-driven methods for a comprehensive assessment of neurodevelopmental difficulties in an LMIC context. Aims. Aim 1 will cross-sectionally identify neurodevelopmental profiles of children in Asenze at ages 5, 7, and 16 using latent profile analysis to identify distinct strata of children based on patterns of neurodevelopmental difficulties at each timepoint. Aim 2 will longitudinally characterize neurodevelopmental trajectories based on latent profile changes and examine the association between trajectories and cognitive and functional impairments in adolescence. Aim 3 will evaluate caregiver mental health, alcohol and other drug use as predictors of adolescents’ cognitive and functional impairments at age 16. Approach. This study leverages data from Waves 1-3 of the ACS, a longitudinal study conducted in KwaZulu-Natal, South Africa, which followed 1,581 children and caregivers from ages 5 to 16 between 2008 and 2021. Employing Latent Profile Analysis (LPA), we will identify distinct neurodevelopmental profiles at each wave, capturing the dynamic nature and heterogeneity of child development. Subsequently, these profiles will be used to track neurodevelopmental trajectories into adolescence, enabling us to assess the associations between trajectories and cognitive and functional impairments in adolescents. Finally, we will use Marginal Structural Models to evaluate the effects of caregiver mental and behavioral health on impairments in adolescents. Training. In this F31, the PI will establish expertise in the epidemiology of child and adolescent mental, neurological, and substance use disorders in low-resource settings, while developing a deeper understanding of neurodevelopmental difficulties and their assessment within LMIC contexts. Additionally, the PI will enhance professional development through manuscript and grant preparation, conference presentations, and engagement within scientific communities. This research will inform the development of focused interventions, applicable to resource-limited US populations, aiming to improve neurodevelopmental outcomes in vulnerable children and adolescents. This F31 will equip the PI with the expertise to become an independent researcher, driving advancements in global child neurodevelopment.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Adolescence is a period of neuroplasticity and change across physiological and behavioral domains. In particular, adolescence is an important window for brain maturation, during which both sleep physiology and myelin development play critical roles in neurodevelopment and depression. The present fellowship hones in on the relationship between sleep, myelin, and depressive symptoms in young people. Research with adults supports the impact of specific sleep physiology (e.g., spindles and slow wave activity) on white matter integrity and myelin content, and vice versa. As such, the central hypothesis of the proposed work is that both sleep physiology and myelin will provide independent as well as joint effects on depressive symptoms in young people. Specifically, the research aims the understand the relationship between sleep EEG signatures (i.e., spindles and slow wave activity) and myelin content (Aim 1) and the role of sleep EEG signatures and myelin in predicting depressive symptoms in young people (Aim 2). To address Aim 1 and 2, I will leverage data from two ongoing R01s of the sponsor where in both studies, participants are between 9-26-year-old. In the first project, participants have their overnight sleep recorded for 2-3 consecutive nights using an at-home wearable sleep device (Dreem3 headband). In the second project, participants undergo a single 3T MRI scan session which includes the Inhomogeneous Magnetization Transfer (ihMT) sequence, which is a novel, myelin-specific sequence. Participants also complete a survey battery (which includes the Beck’s Depression Inventory) at baseline and at yearly follow-up visits. As participants are between 9-26 years of age in both studies, there is often overlap in enrollment and participants will need to have participated in both R01s to be a part of the proposed project. The aims of the proposal have public health significance in that they will help better understand the neurobiological mechanisms of depression risk in adolescents, a sensitive developmental period of the lifespan. The findings may inform future intervention studies, particularly in collaboration with clinicians. Collectively, the proposed development plan integrates training in developmental neuroscience, sleep, neuroimaging, statistical analysis, and grant writing. This structured training will culminate in multiple first-author manuscript submissions to per- reviewed journals and establish a strong research foundation for a competitive early career funding proposal. The fellowship offers protected time and cross-disciplinary mentorship to ensure the successful achievement of these goals.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Deficits in attention are a common cognitive symptom across a range of neuropsychiatric and neurodegenerative disorders, including attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia, and Alzheimer’s disease (AD). The most commonly used test to assess attention deficits in these patient populations is the continuous performance test, or CPT. In humans, a wealth of studies have shown that the insula is consistently activated during tasks that require attention, including the CPT. Numerous other studies have demonstrated that patients with ADHD, MDD, and schizophrenia all have abnormal insula structure and function. These results point to the insula as a critical area of investigation for researchers interested in the pathophysiology of aberrant attentional processing in these disorders. Although the relationship between insula activation and attention is well established, we do not yet have a mechanistic understanding of how the insula contributes to attention. The overall objective of the proposed research is to provide links between insula function at the molecular, cellular, and circuit levels of analysis and behavior during the CPT. We will reach this objective by using a combination of cutting-edge techniques to measure neuronal activity in two projection-specific insula subpopulations (those that send axons to the locus coeruleus, or LC, and those that send axons to the prelimbic cortex, or PrL) during a translational, touchscreen-based rodent analogue of the CPT (the rCPT). In particular, we will pursue the following specific aims: 1) Characterize the molecular identities of LC-projecting and PrL-projecting neurons in the insula, and determine the functional relevance of these two subpopulations to the rCPT; 2) Identify patterns of activity between the LC, PrL, and insula during the rCPT, and; 3) Relate population activity in LC- projecting and PrL-projecting insula neurons to behavior during the rCPT. These data will vertically advance our knowledge of how cellular function in the insula contributes to attention, and will provide critical information about how anatomically distinct insula sub-circuits relate to disparate attentional domains, such as vigilance, impulsivity, and error monitoring in a translationally and clinically-relevant task. Patients with different neuropsychiatric disorders often have domain-specific attentional impairments; knowing which circuits underlie these domains, and how to effectively target them therapeutically, is therefore pivotal for effective treatment of attention symptoms in these disorders. This research, therefore, directly aligns with mission of the NIMH to “transform the understanding and treatment of mental illnesses through basic and clinical research”.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Child maltreatment is a pervasive public health issue, with long-term consequences for children’s mental health and development. Maltreated children are at heightened risk for psychiatric disorders, yet many do not receive timely or appropriate care. Child Advocacy Centers (CACs) are uniquely positioned to identify and address mental health concerns early in the trajectory of trauma exposure. As frontline responders for child maltreatment cases, CACs utilize multidisciplinary teams (MDTs) to conduct forensic interviews, provide medical evaluations, and coordinate referrals for mental health services. Despite this critical role, significant gaps remain in the consistent implementation of evidence-based mental health screening and referral practices within CACs, leaving many children lost to care. This project leverages the Exploration, Preparation, Implementation, Sustainment (EPIS) framework to systematically examine and strengthen mental health screening and referral practices in CACs. The study has three aims: (1) Identify barriers and facilitators of mental health screening and referral practices in CACs and similar settings through a scoping review; (2) Generate a detailed understanding of workflows in two CACs and primary determinants influencing consistent implementation of screening and referral using rapid ethnographic assessments (i.e., workflow observations and semi-structured interviews); (3) Collaboratively create practical roadmaps with CAC partners for improving screening and referral practices guided by causal pathway diagram (CPD) workshops. The scoping review will provide a comprehensive understanding of the factors that impact mental health screening and referral, creating a foundation for ethnographic exploration. Rapid ethnographic assessments will document detailed workflows and decision-making processes within CACs, identifying points where mental health screening and referral protocols can be strengthened. CPD workshops will use this contextual ethnographic knowledge to detail specific implementation strategies aligned with the determinants most significant to each CAC. Overall, this project will provide practical recommendations to enhance mental health screening and referral practices in CACs and will advance implementation science by applying novel partner-driven methods to multidisciplinary settings. Ultimately, this work aims to expand access to evidence- based mental health care for maltreated youth by addressing gaps in the early stages of the care cascade.

Food and Drug Administration

In 2018, OPSA launched an effort to develop of a quantitative system-dynamic model of the opioid crisis to help FDA a) understanding the complexity of the interconnected mechanisms of the crisis, and b) assess potential impacts (intended and unintended) of possible policy actions to address the crisis. In Sept 2019, OPSA awarded a 1-year cooperative agreement (Harvard/Mass General; FDA's RFA-FD-19-026) to complete an initial version of the model ready for policy analysis, and in Aug 2020, OPSA awarded a 1-year cooperative agreement (Harvard/Mass General; FDA's RFA-FD-20-031) to account for societal outcomes beyond overdose as well as cost-effectiveness of potential policies. The current proposal will expand the FDA's model to more comprehensively incorporate fentanyl, stimulants and polysubstance use and their interactive effects on opioids use, misuse, addiction, use disorder treatment, and associated outcomes. The main focus of this project would be on modeling the growing number of opioid overdose deaths involving people who are primarily stimulant or polysubstance users, as an important emerging aspect of the opioids crisis. The research will also include quantification of the effects of harm reduction approaches (e.g., naloxone distribution to opioid users, increasing treatment availability for Opioid Use Disorder [OUD]) on overdoses involving fentanyl and other polysubstance use . Additionally the research will identify and incorporate aspects of mental health that are feasible for inclusion into the model.

NIH

Significance to VA: Tinnitus is a common, but frequently misunderstood, chronic condition that negatively impacts function and quality of life. As of fiscal-year 2023, 2.9 million Veterans were diagnosed with tinnitus, the most prevalent service-connected disability. Tinnitus affects 10-15% of the adult population. Of this population, approximately 80% do not seek tinnitus-specific clinical services. For the remaining 20%, tinnitus impacts their lives—most commonly impairing sleep, concentration, and/or emotional reactions. Tinnitus often co-occurs with other chronic conditions, including post-traumatic stress disorder [PTSD], traumatic brain injury [TBI], anxiety, depression, and suicidal ideation. Access to rehabilitative services for bothersome tinnitus is inconsistent across VA settings. Innovation and Impact: This proposal expands the foundational work of a SPiRE pilot study (1 I2I RX004098- 01) by finalizing a patient health narrative module on bothersome tinnitus and evaluating the utility of patient narratives for clinician education. Patient narratives—stories told by patients about their health conditions and care experiences—are increasingly recognized for their ability to enhance medical consultation skills, support patient education and decision-making, and inform quality improvement initiatives. The “Database of Individual Patient Experiences” (DIPEx) is the gold standard for rendering patients’ narratives. DIPEx uses a maximum variation sampling strategy to illustrate the range and diversity of patient health experiences by including 35-50 narratives on a specific health topic. Specific Aims: This proposed project will address a critical need to improve Veterans’ access to patient- centered tinnitus care by: Aim 1: Amplify Veterans’ voices on bothersome tinnitus by conducting interviews (n=30) to expand our existing DIPEx module to reach saturation on non-biomedical themes (e.g., activity limitations and participation restrictions) known to impact patients with bothersome tinnitus. We will leverage a maximum sampling strategy to elicit diverse health experiences of Veterans living with tinnitus and use those narratives to expand our prototype DIPEx module into a full, web-based resource for those living with bothersome tinnitus and create a catalyst film for Aim 2; Aim 2: Evaluate the potential impact of integrating patient narratives into clinical education. VA clinicians (audiologists and mental health) will review a “catalyst” film developed from the patient narratives and complete an evaluation (n=50) to assess barriers and facilitators associated with the use of the catalyst film for clinician training. Catalyst films include clinically actionable content from patients’ narratives; Aim 3: Assess barriers and facilitators of the use of patient narratives for clinician education among VA operational partners (facility-level, VACO, VISN). We will conduct interviews with operational partners in audiology and mental health (n=15). Methodology: A five-phase qualitative analysis strategy will be used to analyze Aim 1 interview data. Semi- structured interviews (or Qualtrics survey) will be used to evaluate the catalyst film for use as a clinician training tool in Aim 2. Semi-structured interviews will be used to assess the barriers and facilitators on the use of patient narratives for provider training (Aim 3). A thematic qualitative analysis, using a hybrid deductive/inductive approach, guided by principles of rapid qualitative inquiry will be employed to analyze Aim 2 and 3 data. Path to Translation: This proposal involves multi-level stakeholder engagement (Veteran advisory panel members, VA clinicians and VA operational partners) to evaluate the utility of the catalyst film as a training tool for providers. Findings from Aims 2 and 3 will be presented to the VA Center for Evaluation and Implementation (CEIR) which provides individualized guidance to researchers, operations partners, managers, and policy makers to enable the scale up and spread of clinical innovations in VA settings.

NIMH - National Institute of Mental Health

ABSTRACT The prevalence of Major Depressive Disorder (MDD) among people with HIV (PWH) is 20-50%, which is 3 times higher than the prevalence of MDD in the general population. Depression is a leading risk factor for continuity of care among PWH, including adherence to anti-retroviral therapy (ART). Complicating clinical decision making and patient care are the overlapping symptoms of depression with those of HIV and side effects of ART (e.g., psychomotor slowing, difficulties thinking, sleep disruption, fatigue, apathy, and other comorbidities (e.g., anxiety). In addition to depression being underdiagnosed, our preliminary machine learning analyses indicate bidirectional associations between HIV and depression: (1) depressive symptoms predict chronic immune dysregulation (e.g., CD4/CD8 inversion) among virally suppressed PWH; and (2) elevated levels of peripheral inflammatory markers despite sustained viral control predict depression incidence and persistence. These findings suggest an urgent need for novel approaches to accurately identify and manage depression in PWH. Aligned with the NIMH’s Research Domain Criteria (RDoC), we propose an innovative paradigm shift to elucidate the interplay between these overlapping constructs by moving away from conventional a priori measurement selection and small single-study, group-level analyses to integrative, multimodal analyses leveraging existing data acquired prospectively across multiple longitudinal studies from 3962 PWH. To maximize research efficiencies, we will harmonize the datasets to the repository of the NIH-sponsored National NeuroHIV Tissue Consortium (NNTC). We will then create a pioneering, multimodal, explainable AI (xAI) framework that uses knowledge graphs to holistically capture individual-level neurobiological, cognitive, sociodemographic, and environmental determinants of depression in PWH. We will prioritize interpretability, scientific rigor (including reproducibility), and clinical relevance. We will ensure ethical and stakeholder-driven development in order to support the vision of this team in translating results into actionable clinical strategies capable of improving treatment outcomes for PWH. Specifically, in Aim 1, we will develop and validate HIV- specific data-driven models that will use knowledge graphs to predict depression from self-report questionnaires (e.g., Beck Depression Inventory-II), neuropsychological testing, and MR images. In Aim 2, we will create xAI capable of forecasting future incidents and non-remitting cases of depression based on longitudinal data in virally suppressed individuals. By sharing our validated explainable AI tools publicly, this research promises immediate, tangible benefits to HIV clinical care, with the potential of enabling precise identification and management of depression risk. Doing so will help refine clinical care strategies to reduce the clinical burden of depression in people with HIV.

NIMH - National Institute of Mental Health

Project Summary This application responds to PAR-25-035 “Building in vivo Preclinical Assays of Circuit Engagement for Application in Therapeutic Development”. Altered explore-exploit balance is a transdiagnostic target in serious mental health challenges, including schizophrenia and mood disorders. Addressing the mechanisms that govern transitions between explore and exploit behaviors are therefore a high-priority target for preclinical models and for testing interventions to alleviate cognitive deficits that contribute to poor prognosis and quality of life. In three Aims, we will uncover the key task, pharmacological, and neural parameters leading to alterations in explore-exploit tradeoffs in mice. Across Aims we will use two well-established touchscreen cognitive tasks and computational modeling to measure explore versus exploit behavior in mice on a trial-by-trial basis. In Aim 1 we will test further modifications to each task with the goal of identifying parameters that further increase the similarity between mouse and human decision making performance. In Aim 2 we will examine how current approved pharmacological treatments for depression and schizophrenia impact decision making, testing the hypothesis that these treatments push explore-exploit balance in opposing directions. Functional neuroimaging in humans reveals that depression and schizophrenia are each linked with distinct disruptions in activity in defined cortical networks, and explore and exploit decisions are associated with opposing patterns of activity in these cortical networks. In Aim 3 we will use a powerful preclinical technique, mesoscale imaging, to measure calcium activity of dorsal cortical networks during touchscreen decision making. We will test the hypothesis that we will see evidence for distinct network activity in explore versus exploit decisions that are cognate to components of human cortical networks, and that pharmacological treatments for depression and schizophrenia must impact these cortical networks to alter behavior. Collectively, these experiments will establish computationally amenable cognitive measures of explore-exploit balance for rodents, and their link to cortical network states, as a powerful new preclinical tool.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

SUMMARY The proposed R03 award will further Dr. Colin Orr’s path toward a career as an independent physician- scientist with expertise in the prevention, management, and treatment of pediatric obesity. Dr. Orr is a general pediatrician, and health-services trained researcher whose overarching research goal is to address the pediatric obesity crisis. Dr. Orr’s current work is supported by a K23 Career Development Award from NIDDK that focuses on preventing pediatric obesity developing and piloting the novel Peer Parent Coach Community Collaboration (P2C3) intervention that targets drivers of unhealthy infant weight gain such as inconsistent access to food, maternal mental health, and parental knowledge of infant growth and nutrition. Dr. Orr’s K23 career development has provided him with the necessary mentorship, research experiences, and training to have expertise in the analysis of longitudinal data, designing and conducting randomized clinical trials, qualitative methods, theories of behavioral change, and prevention of pediatric obesity. The proposed R03 will advance Dr. Orr’s professional development by building upon the mentorship, training, and research experiences that are currently supported by Dr. Orr’s K23 award. The proposed R03 will further Dr. Orr’s career development by expanding his research network, allowing him to develop content expertise in the management and treatment of pediatric obesity, and gain mentored experience in implementation science. Specifically, the aims of the proposed research study are to 1) leverage the Science, Technology, and Research and PEDsnet clinical research networks to create a national dataset of children with obesity to understand the current landscape of guideline-concordant pediatric obesity care and 2) guided by the Consolidated Framework for Implementation Science Research, conduct a mixed-methods study of patients, parents, and providers to understand the facilitators and barriers to guideline concordant pediatric obesity care. The findings from the study will address a critical gap in the literature, provide additional training for Dr. Orr’s progression toward an independent career as a physician-scientist, and provide data that can inform a future randomized clinical trial to test implementation strategies to increase the reach and uptake of evidenced-based pediatric obesity guidelines. Dr. Orr will meet regularly with his mentors who will provide feedback on research activities, training on implementation science, and support manuscript and grant writing activities. The proposed research proposal is consistent with the NIDDK’s mission of addressing the pediatric obesity crisis through rigorous science. The project is consistent with Dr. Orr’s overarching research agenda of addressing the pediatric obesity crisis and will prepare Dr. Orr for a career as an independent physician-scientist.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Major Depressive Disorder affects millions of Americans, many of whom do not respond to traditional antidepressants. Psychedelics, like psilocybin, offer a promising new therapeutic avenue, producing rapid and sustained benefits after a single dose. Research on the psychedelic psilocybin has revealed altered neuronal activity across many brain regions post-psilocybin exposure, but these studies often rely on low-resolution imaging like fMRI and therefore unable to resolve the single-neuron dynamics that drive these changes. Consequently, psilocybin’s precise impact on neural spiking, network communication, their temporal evolution, and neural correlates of behavioral alterations remains largely unexplored. This project will address this gap by using cutting-edge Neuropixels probes for chronic, high-density electrophysiology during freely moving behavior in male and female mice. This approach will allow for an unprecedented view of single-neuron activity across multiple brain regions over weeks. The project’s specific aims are: (1) To identify psilocybin's longitudinal impact on brain-wide neural dynamics during cognitive and social behaviors. (2) To elucidate the neural changes underlying psilocybin-induced resilience to stress using a chronic variable stress model of depression. This F31 fellowship training plan is designed to provide the applicant with essential skills in advanced surgery, behavioral neuroscience, and data analysis. The training will be conducted at Johns Hopkins University, a premier environment for both neuroscience and psychedelics research, under the guidance of a world-class multi-disciplinary mentorship team. The proposed research will create a foundational, high-resolution dataset of psilocybin’s neural effects, and elucidate the location, timing, and nature of altered neural activity across the brain following a single dose. Activities under this fellowship will equip the applicant with the skillset necessary for a career as an independent investigator focused on neuropsychiatric disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Over 930 million people worldwide are estimated to be living in fragile and conflict-affected settings (FCAS) – characterized by recurrent violence, conflict, or war – and experiencing food insecurity and mental distress. The detrimental effects of violent political events on food insecurity, and separately, on mental health are well documented. However, the impact of non-violent political events on food insecurity in FCAS is lesser explored. Furthermore, little is known about the differential cumulative impact of repeated political events – ranging from violent events (e.g., military assaults) to less extreme non-violent events (e.g., agreements) – on the relationship between food insecurity and mental health in FCAS. Quantifying the cumulative impact and capturing the intensity and severity of violent and non-violent political events is especially important in the context of protracted FCAS, where individuals endure prolonged exposure to violent and non-violent events, and stressors, such as food deprivation and insecurity, are likely to accumulate through time and impact mental health outcomes. We will leverage a longitudinal, geo-location political events dataset and three waves of repeated cross- sectional, representative household and corresponding individual survey datasets from a protracted conflict- affected setting, the occupied Palestinian territories (oPt); together, these data are uniquely positioned to permit examination of the relationships between political events, food insecurity, and mental health, and their intervening pathways. We reason that each discrete political event may function as a stressor and contribute to feelings of insecurity (across varying needs and including food) and mental distress. We expect that repeated occurrences of even non-violent, low extremity political events (e.g., establishing a political headquarter) each year can add up and exert its cumulative impact on food diversity, food insecurity experience, and on mental distress in a FCAS. Understanding the cumulative impact of violent and non-violent political events on food insecurity, incorporating individual behavioral changes and coping mechanisms, and mental health, will inform evidence- based interventions in FCAS. The evidence can allow for rapid response and improve the efficacy of humanitarian interventions during time of crises. This information is especially important given the recent increase in conflict and political events worldwide.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT SUMMARY Alcohol misuse in young adulthood is a significant public health concern, contributing to numerous adverse consequences and societal costs. Self-regulatory deficits strongly contribute to alcohol misuse in young adults, reflecting a maturational imbalance between heightened reward responsivity and underdeveloped cognitive control. Real-time fMRI neurofeedback (rtfMRI-nf)—an imaging approach that trains individuals to gain volitional control over targeted brain activity—is a powerful tool for more directly measuring self-regulatory brain function than is possible with traditional fMRI. Our prior work has shown that young adults can learn how to increase and decrease reward-related activity in the nucleus accumbens (NAcc) using rtfMRI-nf. Critical gaps remain in understanding how to sustain gains in reward-related self-regulation beyond the lab in real- world settings. This information is essential to maximize the scalability and clinical potential of rtfMRI-nf. In preliminary work, we have demonstrated the feasibility and acceptability of supplementing rtfMRI-nf with a phone app-based ecological momentary intervention (EMI) to extend in-scanner training in real-world contexts. The proposed R01 randomized controlled trial builds upon and extends this work in 240 18- to 30-year-olds (50% female; currently use alcohol). Participants will be randomized to one of three groups in a 1:1:1 ratio: Neurofeedback EMI (NF+EMI): Neurofeedback + EMI (experimental group); Neurofeedback Control (NF Control): Neurofeedback only, no EMI; or EMI Control: EMI only, no neurofeedback. All groups will complete a baseline scan, a 2-week twice-daily ecological momentary assessment (EMA) to report drinking and emotional/physiological states, and a follow-up scan. In addition to the EMA, NF+EMI and EMI Control groups will complete an EMI regimen to practice cognitive strategies used during in-scanner reward-related self- regulation. At both scans, the NF+EMI and NF Control groups will be instructed to up- and down-regulate NAcc activity through rtfMRI-nf; the EMI Control group will receive the same NAcc modulation instructions but without neurofeedback. Post follow-up scan, self-reported self-regulation, alcohol and other substance use, and mental health symptoms will be assessed monthly for 3 months. Specific Aims are: Aim 1) Examine the impact of EMI on improvements in NAcc modulation; Aim 2) Investigate state and context effects of EMI practice on NAcc modulation; and Aim 3) Test associations between neurofeedback training and EMI practice on out-of-scanner self-regulation. This proposed secondary intervention study, which integrates multimodal real-time technology, is both novel and highly innovative. Integrating EMI with rtfMRI-nf offers a powerful approach to extend the impact of neuroimaging-based self-regulation training into daily life, making it more scalable and fostering real-world skill transfer. Strengthening reward-related self-regulation is an important, modifiable treatment target with important downstream implications to reduce risk behaviors, including alcohol misuse, in young adults.

NIH

Significance: Tobacco smoking and its health consequences disproportionally impact Veterans. Veterans with serious mental illness (SMI Veterans; schizophrenia spectrum, bipolar spectrum, and other psychotic disorders) have among the highest rates of smoking in VA and die 10-15 years earlier than those without SMI, largely due to smoking-related conditions. Seven FDA-approved tobacco medications are available in VA that are low-cost, safe, and effective for SMI Veterans when combined with brief behavioral counseling: nicotine replacement therapies (lozenge, gum, patch, nasal spray), bupropion, and varenicline. Nearly 70% of SMI Veterans who smoke want to quit, but they are 26% less likely to be prescribed tobacco medication (10.9% vs. 14.3% prescription rate). SMI providers face numerous barriers to treating smoking. External facilitation can address these barriers by coordinating evidence-supported implementation activities, such as educational outreach and auditing with feedback, and shows promise for improving tobacco medication prescriptions in VA mental health clinics. Despite the availability of tobacco treatment in VA, smoking-related conditions remain the leading cause of death for SMI Veterans and account for nearly 8% of VA health care expenditures: $2.7 billion annually. Integrating tobacco medication into routine mental health care can maximize the use of existing resources and expand the reach of tobacco medication to Veterans with the highest smoking, but lowest treatment rates. Innovation & Impact: Innovations of this project include evaluating evidence-supported implementation strategies in mental health clinics, addressing barriers to tobacco treatment across patient, provider, and system levels, evaluating changes in prescribing practices for all FDA-approved tobacco medications, including non- prescribers in implementation activities, using data to refine the implementation strategy, and capitalizing on existing VA resources that support quality improvement and tobacco treatment. This project will serve as preliminary data for a fully powered effectiveness-implementation trial with the potential to improve timely access to care, address a leading cause of death for SMI Veterans, and reduce smoking-related health care costs. Specific Aims: This pilot study will refine and evaluate the feasibility and acceptability of an externalfacilitation strategy that aims to increase prescriber adoption of tobacco medication. Specific aims are to: Aim 1: Trial an external facilitation strategy designed to improve tobacco medication prescribing in Perry Point SMI clinics. Aim 2: Evaluate the feasibility and acceptability of the external facilitation strategy, monitor provider adoption of tobacco medication, and refine the strategy accordingly. Aim 3: Implement the refined external facilitation strategy in Baltimore SMI clinics, re-evaluate feasibility, acceptability, and adoption, and explore reach and effectiveness of tobacco medication. Methodology: This pilot study will use mixed methods to evaluate changes in the feasibility and acceptability of an external facilitation strategy and provider adoption of tobacco medication through activity tracking, surveys, and semi-structured interviews with providers (Perry Point n ~ 11, Baltimore n ~ 24) at two VA Maryland Health Care System facilities. Secondary outcomes will be changes in monthly reach of tobacco medication to SMI Veterans (Perry Point n ~ 75, Baltimore n ~ 165) and changes in smoking rates using EHR data. Path to Implementation: With support from local leadership, VA’s Quality Enhancement Research Initiative, and operational partners, results from this proposal will a yield an implementation blueprint for how to tailor implementation activities designed to improve tobacco medication to local needs. Additionally, findings from this proposal will serve as preliminary data for a fully powered, multisite hybrid effectiveness-implementation trial as part of a Merit application that can establish the effectiveness of using external facilitation to expand the reach of underutilized, cost-effective tobacco medications for SMI Veterans.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY / ABSTRACT Methadone is a highly effective medication for opioid use disorder (OUD) treatment. When taken regularly, it is associated with a 50% mortality reduction. Unfortunately, less than 5% of the estimated 7.6 million individuals with OUD receive methadone treatment. Hospitalization is a touch point to initiate methadone for out-of- treatment adults with OUD. While there are no federal restrictions on in-hospital methadone use for OUD, until recently, federal rules required that patients present to an Opioid Treatment Program (OTP) to complete a methadone intake before receiving methadone treatment in the outpatient setting. Current usual care for hospital to OTP linkage includes a referral to an OTP at hospital discharge. At best, only 40% of patients referred to an OTP at hospital discharge link to an OTP. Patient-reported barriers to hospital-to-OTP linkage include opioid withdrawal, lack of transportation, uncontrolled medical and mental health conditions, and stigma. Recent federal regulations governing OTPs relaxed methadone intake rules now allow non-OTP affiliated clinicians to compete the medical evaluation required for a federally compliant OTP intake. In one study, 77% of patients who completed an in-hospital OTP intake linked to an OTP after hospital discharge. Federal regulatory changes and the expanding workforce of hospital-based addiction clinicians provide a unique opportunity to expand in-hospital OTP intakes. Using a novel staircase cluster randomized design with a hybrid type 2 approach, sites will be randomly assigned a time when the study team implements a series of core activities encompassed in “implementation facilitation” (IF). These core IF activities support uptake of clinical activities by hospital-based addiction clinicians and facilitate completion of a federally compliant in-hospital OTP intake. Guided by the Practical, Robust Implementation and Sustainability Model (PRISM), we will begin by identifying site-specific contextual factors important to the implementation of core IF activities including collection of quantitative and qualitative data to inform tailoring of IF activities to account for the local needs and resources at diverse study sites. Next, we will implement IF across study sites based on their randomly assigned start date to cross over from usual care to IF. We will test the effectiveness of IF on hospital-to-OTP linkage by comparing linkage rates during the usual care phase versus the post IF evaluation phase. Implementation outcomes are informed by PRISM's Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework, and include measuring implementation fidelity to use of the core IF activities, adoption of the clinical activities required to complete an in-hospital OTP intake, measuring IF implementation costs, and measuring the proportion and characteristics of patients who did and did not link to the OTP. This study aims to measure the effectiveness of IF on hospital-to-OTP treatment linkage while also obtaining important implementation data for scaling to other treatment sites with an ultimate goal of expanding lifesaving OUD treatment to a vulnerable population.

NIH

Background and Innovation: The psychedelic serotonin 5-HT2A agonist psilocybin has shown unprecedented efficacy in the treatment of depression and post-traumatic stress disorder (PTSD). Veterans are up to four times more likely to experience PTSD compared to non-Veterans. Vivid intrusive memories of traumatic events are a primary symptom of PTSD. An appreciation for the critical role of mitochondrial dynamics in learning and memory is emerging. Individuals with PTSD and depression exhibit signs of mitochondrial dysfunction, possibly contributing to the chronic nature of these psychiatric conditions. Intriguingly, agonism of the serotonin 5-HT2A receptor induces robust biogenesis of mitochondria. We hypothesize that increased mitochondrial biogenesis is a critical mediator of the therapeutic effects of psilocybin. In this VA Merit Award proposal, our studies model the intrusive memories of PTSD using Pavlovian fear conditioning in mice. The overarching hypothesis is that psilocybin rapidly induces mitochondrial biogenesis and enhances plasticity, making therapy (i.e., extinction of fear) more durable. Our goal is to determine whether compounds that modulate mitochondrial dynamics can improve the efficacy and efficiency of psilocybin. We will use novel transgenic mouse models to visualize mitochondrial dynamics in excitatory and inhibitory neurons in response to psilocybin alone and with nicotinamide mononucleotide (NMN). NMN is a safe precursor for nicotinamide adenine dinucleotide (NAD+), a coenzyme critical for many metabolic and signaling reactions. [Adequate NAD+ levels might prime the brain for psychedelic assisted therapy, enabling optimal brain energetics during extinction. We will determine whether enhanced mitochondrial dynamics are necessary for psilocbyin’s effects using genetic manipulations of NAD+dependent pathways in specific neuronal subtypes. Quantitative histology, behavioral outcomes, and ex vivo electrophysiology will determine whether administration of NMN can promote the effectiveness of psilocybin and enhance extinction of fear.] Significance and Impact to Veterans’ Health: PTSD is the most common mental health issue among Veterans served by the VA. Prolonged exposure therapy accounts for half of the treatment hours for Veterans in VA outpatient treatment clinics and dropout rates are high. Salient, traumatic memories permit neutral events, like a smell or place, to become associated with the trauma, thereby triggering traumatic memories. Individuals with PTSD fail to use contextual cues to modulate retrieval of fear memories regardless of whether the context is threatening or safe. These results suggest that the ability to control retrieval and suppress traumatic memories is disrupted. Dysregulated mitochondrial dynamics have been identified in individuals with PTSD. Mitochondrial dysfunction is an overlooked aspect of mood disorders that might pose an obstacle to therapeutic intervention, making reappraisal of traumatic memories inefficient. Using the translationally relevant fear-potentiated startle preparation, the proposed experiments will determine the effects of psilocybin with and without NMN and determine whether mitochondria-focused combination therapies enhance psychedelic assisted therapy. Pathway to Translation and Implementation: This proposal is focused on the development of safe adjuvants to facilitate psychedelic-assisted psychotherapies.[ Mitochondrial adaptation to experience is necessary for new learning to occur.] Supplements that modulate mitochondrial health and activity are currently used by millions of people to enhance longevity and metabolic efficiency. We will determine whether this class of supplements can prepare the brain to inhibit fear across contexts. We predict that these compounds can improve psilocybin assisted therapy, and potentially reduce the dose of psilocybin needed to facilitate exposure therapy. Current treatment protocols require a hallucinogenic dose that lasts 8 hours or more, making treatment less accessible, requiring long supervised therapy sessions. If successful, our results will make psychedelic assisted therapies more available to and successful for Veterans.

NIMH - National Institute of Mental Health

Project Summary / Abstract Suicide is a leading cause of death among adolescents, and early identification of risk for suicidal behavior among youth remains a challenge. Novel approaches to identify earlier developmental indicators of risk for later psychiatric problems, including risk for suicidal behavior, are needed. Children who exhibit gender nonconformity (GNC) have higher risk for experiencing childhood abuse and rejection from parents and peers. Early psychosocial stressors related to GNC could dysregulate stress responses, leading to biological dysregulation in the hypothalamic-pituitary-adrenal axis and inflammatory pathways. Biological dysregulation in these pathways is associated with psychiatric symptoms and risk for suicidal behavior. Furthermore, psychosocial stressors and biological dysregulation have the potential to augment neurocognitive correlates of suicidal behavior among youth exhibiting GNC, including increased impulsivity and reactive aggression. Thus, psychosocial stress and biological dysregulation during childhood could contribute to psychiatric symptoms prior to adolescence among youth exhibiting GNC. While GNC could have utility in identifying children who will have future elevated risk for engaging in suicidal behavior, the existing literature examining associations between GNC and risk for suicidal behavior among children is critically limited. The proposed longitudinal feasibility study is designed to examine how GNC is associated with early indicators of risk for suicidal behavior among children ages 7–10, including psychosocial stressors, biological dysregulation, psychiatric diagnoses and symptoms, neurocognitive correlates of risk for suicidal behavior, and suicidal ideation. The aims of the proposed study are to accrue feasibility data by enrolling a sample of children enriched for GNC, collecting data on all variables of interest (clinical interview and self-report data from children and parents as well as biological and neurocognitive behavioral task data from children), and retaining participants in the longitudinal study at follow-ups over 9 months. We will develop a testable conceptual model for a future R01 study by examining associations between GNC, psychosocial stressors, biological dysregulation, psychiatric symptoms, suicidal ideation, and neurocognitive correlates of suicidal behavior. Results from the proposed study will facilitate the design of a future R01 proposal to conduct a long-term prospective study to enroll a large sample of children enriched for GNC and follow them into adolescence to assess developmental trajectories of GNC, psychosocial stress, and risk for suicidal behavior. This line of work has the potential to provide critical information to facilitate early identification of youth at risk for suicidal behavior, providing the information and time necessary to intervene prior to the development of risk for suicidal behavior among adolescents.