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NIMH - National Institute of Mental Health

PROJECT SUMMARY Adolescents experiencing psychosis-spectrum (PS) symptoms are at high risk for lifelong mental illness and impairment, including conversion to schizophrenia. Mechanisms influencing the onset or persistence of PS symptoms in adolescence are unclear. Sleep is altered in youth at clinical high risk for psychosis (CHR) compared to controls, and sleep problems may predict the transition to full-threshold psychosis and persist in first episode psychosis (FEP). Studies of sleep and PS symptoms in youth suffer from three main gaps. First, extant studies are overly correlational, with few studies using dense sampling across days to understand temporal fluctuations between PS symptoms and sleep in youth. Second, nonspecific behavioral indices of sleep (from self-report and actigraphy) may reveal the clinical presentation of sleep deficits but not the root mechanistic cause of these difficulties. Finally, studies of sleep in this population have omitted measurement of important co-occurring processes such as stress, which may mediate or moderate the sleep-psychosis relationship in ways important for treatment development. This study seeks to address these three critical gaps by investigating daily fluctuations in PS symptoms, sleep at behavioral and neurobiological levels, and psychological stress in adolescents with PS conditions (n = 40, aged 14-17 years). Across a 3-week sampling period, this study will measure PS symptoms (hallucinations and paranoia), subjective ratings of stress, and objectively measured sleep characteristics, including behavioral (actigraphy-estimated sleep duration, fragmentation, efficiency, timing, rhythmicity, and regularity) and biological (simultaneous PSG/EEG-indexed sleep spindle density, amplitude, duration) markers. Participants will first complete a baseline interview to assess eligibility, PS symptoms, sleep, and stress. For the subsequent 21 days, adolescents will (1) wear a patch-based actigraphy monitor to assess sleep and 24h rest-activity rhythms; (2) complete twice-daily digital diaries probing sleep, stress, as well as PS symptom type (e.g., hallucinations and paranoid thoughts), severity, impairment, and timing; and (3) wear PSG and wearable EEG for 2 consecutive nights to index sleep spindles. This measurement supports 2 specific aims: 1) Examine how subjective ratings of PS symptoms and stress fluctuate with respect to sleep on a daily basis, and 2) Examine the feasibility of collecting at-home EEG data from adolescents with early phase psychosis and establish early links among spindles, PS symptoms, and stress. This study aligns with NIMH objectives to 1) define brain mechanisms underlying complex behavior by characterizing sleep spindles in early psychosis, and 2) examine mental illness trajectories across the lifespan by exploring these mechanisms in an understudied adolescent population. If successful, this will be the first study to employ deep phenotyping of sleep in adolescents with early phase psychosis.

NIMH - National Institute of Mental Health

ABSTRACT Autism Spectrum (AS) is a complex, heterogeneous condition associated with hundreds of genes. Modeling the genes that cause the changes in behavior is complex due to the need to study a large number of genes both in isolation and in combination. Syndromic conditions, like Pitt-Hopkins, Coffin-Siris, Rett, and Fragile X syndromes and others, are considered monogenic, with single causal genes linked to these syndromes. They also share features with AS, including social withdrawal, intellectual disability, sensory sensitivity, and anxiety. The involved genes act at a higher order of gene regulation, regulating several downstream processes, including additional genes and molecular pathways associated with AS. Defining which downstream molecular pathways cause changes in neural circuits and behavior could help prioritize which genes should be investigated in future research on autism-related genes. In this proposal, I propose to conduct behavioral assays, sequencing, and imaging of monoamine circuits and brain-wide changes in activity in zebrafish with mutations in genes associated with several syndromes in humans, namely the Pitt-Hopkins gene tcf4, the Coffin-Siris gene arid1b, bcl11ba, tcf7l2, ash1l, foxp1b, and hivep2a, all of which have namesake syndromes. All of these syndromes have symptoms seen in individuals with autism, including intellectual disability, seen in 1 in 3 individuals with autism. Several of these genes are also implicated in dopamine signaling, which is critical for social behaviors and processes like learning and memory. In the first aim, I will define changes in molecular pathways caused by these genes by performing bulk RNA sequencing, CUT&RUN, and Single-cell Combinatorial Indexing (sci) sequencing, and manipulating downstream direct targets of my focal genes. In aim 2, I will define effects on brain activity during a working memory task, define effects on pre- and post-synaptic structures, and define effects on circuit development. The work in this proposal will greatly enhance our understanding of common and distinct pathways altered by these syndrome-causing genes and potentially identify key pathways and circuits that should be emphasized in AS-related investigations. The findings will also set the stage for larger-scale studies, both in the broader field of modeling AS-related genes and that I can build my future lab around to investigate the molecular networks of transcription factors that underlie brain development.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Memory abnormalities are a core feature of psychiatric and neurological disorders, as well as in aging. Persistent negative memories are a hallmark of Post-Traumatic Stress Disorder (PTSD) and are prevalent in anxiety disorders, while memory retention can be impaired in aging and other conditions. Thus, effective approaches to strategically modulate memory strength would enhance mental health and cognition across broad populations. Memory consolidation mechanisms represent a key opportunity for targeted memory modulation. While traditionally studied during sleep, recent research highlights the importance of consolidation during wakefulness, providing a new window of opportunity for strategic memory modulation. However, most human studies on awake consolidation focus on narrow time periods immediately post-learning and a single state (rest), making it unclear when consolidation peaks during wakefulness and thus when interventions should be applied for maximum effectiveness. Yet, recent work suggests that consolidation may peak: 1) multiple hours, not minutes, after learning and 2) during internally-oriented rather than externally-oriented states of high vigilance. The central goal of this research is to determine when memory consolidation maximally occurs during wakefulness, identifying effective time windows and cognitive states for memory modulation. Based on the emerging literature, we test the overarching hypothesis that memory consolidation varies across wakefulness. In two Aims, we systematically decompose awake post-learning periods to determine when memory consolidation is maximal across two key factors: extended time window (Aim 1) and cognitive state (Aim 2). In each Aim, we use an innovative combination of advanced fMRI methods and causal manipulations to measure and test the differential contribution of distinct time windows (Aim 1) and cognitive states (Aim 2) to consolidation. To determine when consolidation is maximal over time, in Aim 1A, we will measure consolidation across multiple extended post-learning time windows using cutting-edge fMRI methods, thus isolating windows with the strongest and weakest consolidation evidence. We will then test whether causal disruption of the strongest vs. weakest time windows differentially impairs memory using a combined Transcranial Magnetic Stimulation (TMS)+fMRI approach (Aim 1B). In Aim 2A, to test whether consolidation is most prevalent during internally focused states, we will measure consolidation evidence via fMRI while attention is directed internally vs. externally using a validated task paradigm. We will then test whether causal induction of consolidation (via cued reactivation) and its impact on memory is more robust during internally vs. externally-oriented states (Aim 2B). The proposed work will collectively characterize how consolidation varies across wakefulness, resulting in the identification of time windows and cognitive states to target for strategic memory intervention. This will enable future work to probe the potential of impacting memory consolidation in clinical and non-clinical populations, moving towards the goal of strategic memory modulation in stress and trauma research.

NIMH - National Institute of Mental Health

ABSTRACT The Brain Image Library (BIL) serves as a central repository for advanced microscopy data, ensuring valuable neuroscience datasets are preserved and shared following FAIR principles. While BIL successfully handles traditional microscopy data, it currently lacks specialized tools for spatial transcriptomics datasets, which present unique computational challenges due to their high dimensionality and complex metadata structures. This project will develop essential computational infrastructure to make spatial transcriptomics data in BIL more accessible and analyzable for the broader neuroscience community. We will implement four key components: (1) standardization of data submission and storage using the community-supported Spatialdata format, enabling efficient handling of large-scale molecular data with coordinate system transformations and alignment capabilities, (2) development of an intuitive browser-based visualization system that allows researchers to explore gene expression patterns through interactive scatter plots and maps with density-based rendering, (3) creation of a natural language search interface leveraging Large Language Models for complex queries across molecular and anatomical parameters, and (4) integration of foundational models for automated cell type annotation and metadata generation. By standardizing data organization and providing intuitive exploration tools, this work will maximize the reuse potential of these valuable datasets and lay the groundwork for future cross-modality analyses that combine molecular and imaging data to generate new biological insights.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Rates of adolescent depression are increasing, and 20% of adolescents in the United States now experience a depressive episode each year. Effective treatments exist, but most adolescents with depression do not receive them because they prefer to self-manage their symptoms, cannot access treatment, or perceive treatment to be too time-consuming or inconvenient. Delivering interventions digitally (i.e., through the internet or a smartphone application) is scalable, accessible, efficacious, and appealing to adolescents. However, digital interventions have low real-world uptake and engagement, and many users drop out in the first few minutes. Single-session interventions (SSIs) address these critical limitations by delivering an entire intervention in a single encounter and have shown promise for engaging mechanisms of action and ameliorating adolescent depression. Therefore, this project will adapt a gold standard treatment for adolescent depression – interpersonal psychotherapy for adolescents (IPT-A) – into a brief, web-based SSI. To reach adolescents with depression, this study includes a partnership with Mental Health America (MHA), a nonprofit advocacy organization that hosts a widely used online depression screen on their website. A deployment-focused approach will be utilized, with a focus on implementation on MHA’s screening website. Aim 1 will design the SSI based on pilot data and in consultation with experts in SSI design and IPT-A, an advisory board of adolescents and providers, and MHA staff. Aim 2 will refine the SSI by iteratively soliciting and incorporating feedback from three cohorts of five adolescents with depression (total n=15) recruited after screening positive for depression on MHA’s website. Among adolescents (n=200) screening positive for depression on MHA’s website, Aim 3 will evaluate the SSI’s acceptability, feasibility, immediate effects on the mechanism of action (interpersonal skill knowledge), and effects on depressive symptoms in a randomized controlled trial with follow-up assessments at 1 week, 1 month, and 3 months. In addition to directly addressing an important public health problem, this project includes training and research activities that will enable Dr. Funkhouser to gain expertise in: (1) digital mental health intervention design methods, (2) implementation science principles and methodologies, (3) clinical trials evaluating digital mental health interventions, and (4) grant writing and networking. The research aims and training goals will be accomplished with mentorship from leading experts in SSIs, implementation science, biostatistics, and IPT-A. This training and mentorship will also prepare Dr. Funkhouser to submit a R01 application and achieve his long- term career goal of becoming an independent investigator focused on designing, evaluating, and disseminating digital depression interventions that increase young people’s access to and utilization of effective support.

NIMH - National Institute of Mental Health

Project Abstract On a moment-by-moment basis, each animal must consider its environment, experience, and goals to choose future actions. The striatum, including its dorsal and ventral portions, is an evolutionarily old structure that helps animals choose their actions and update action plans based on experience. Within this structure, dopamine places a crucial function in these processes. Dopamine signals in two ways – with slowly changing “tonic” levels and rapidly changing “phasic” signals. It has been proposed that tonic dopamine has fundamentally different functions and represents different features of experience than phasic dopamine. We have developed methods to measure tonic and phasic levels of dopamine in real-time as mice behave in a variety of contexts. We will use this new technology to examine the mechanisms and function of tonic dopamine levels to understand how perturbations of dopamine contribute to the cause and treatment of human neuropsychiatric disease.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Excess dopamine in the dorsal striatum is thought to be a key driver of schizophrenia. Accordingly, there is a strong corre- lation between the potency of antipsychotic drugs and their affinity for D2 dopamine receptors (D2Rs). However, tradi- tional D2R-binding drugs are not effective for psychosis in ~30% of patients, do not address cognitive and negative symp- toms, and have many adverse effects. Recently, several new therapies have emerged that do not interact with D2Rs. These include promising drugs like xanomeline, an agonist of M1 and M4 acetylcholine receptors. One promise of this new drug class is its potential to work for more patients and address more symptoms than traditional antipsychotics. Capitalizing on this novel therapeutic mechanism requires a deeper understanding of how the drug class works. Recently, our lab used in vivo imaging to determine how two of these drugs (xanomeline and the M4 receptor selective modulator VU0467154) compare to more traditional antipsychotics. Paradoxically, we found that clinical antipsychotic efficacy was more strongly associated with the normalization of activity in striatal neurons that express D1 rather than D2 dopamine receptors (Yun et al., 2023). This was true for both traditional antipsychotics and the newer cholinergic receptor agonists—suggesting the two drug classes may have partly overlapping end effects in the brain. In parallel to these imaging studies, we developed two approaches to selectively activate (either transiently or persistently) dopamine projections to the dorsal striatum. Both approaches affect behavioral processes related to the symptoms of schizophrenia and are compatible with in vivo record- ing. Here will combine these models with in vivo imaging or microdialysis to understand the mechanism-of-action of novel cholinergic antipsychotics and use behavioral testing to explore the range of symptoms for which they may be ef- fective. Specifically, we will use dual-color in vivo imaging to simultaneously record striatal acetylcholine transmission and calcium activity in D1 or D2 receptor-expressing spiny-projection neurons (SPNs). After determining how acetylcho- line relates to D1-/D2-SPN activity and how each relates to locomotor activity, we will activate nigrostriatal dopamine neurons and observe the effects on acetylcholine and D1-/D2-SPN activity. After determining these effects, we will ask how different cholinergic receptor agonists or modulators (xanomeline, M1 agonist, M4 agonist, or an M1 positive allo- steric modulator) affect the relationship between acetylcholine and D1-/D2-SPN activity under normal and hyperdopamin- ergic conditions. The drugs we will test will allow us to directly compare receptor-specific agonism and positive allosteric modulation in isolation or in combination. Next, we will use the same drugs with our animal model of persistent nigrostri- atal dopamine neuron activation. We will use in vivo microdialysis to determine how striatal neurochemistry is altered in these animals and how different cholinergic drugs affect these changes. Finally, we will use behavior (working memory, social exploration, and auditory perception) to determine whether different cholinergic drug types normalize different be- havioral processes in this animal model. Altogether we expect these experiments will advance this new therapeutic strat- egy for psychosis by elucidating the mechanistic basis for its effects on striatal activity, neurochemistry, and behavior. In doing so, we hope to catalyze the development of better and more comprehensive treatments for psychotic disorders.

NIMH - National Institute of Mental Health

Project Summary Neuromodulators like dopamine are crucial for learning, driving synaptic changes in neurons, and shaping behavior. Furthermore, dysfunction in dopamine signaling is a hallmark of almost all psychiatric disorders. Traditionally, dopamine was thought to broadcast diffuse signals across broad brain regions. However, emerging evidence points to a more targeted mechanism, where dopamine acts on specific neurons engaged in behaviorally relevant tasks. This proposal raises a critical question: How does a widely distributed neuromodulator like dopamine contribute to precise, neuron-specific learning? This project will explore how dopamine shapes learning in sparse cortical populations. We will use two-photon microscopy and genetically encoded sensors to simultaneously track dopamine release and neuronal activity in real-time as mice perform a neuroprosthetic control task. We will use this task because it allows us to directly identify the neurons that drive behavior, providing a unique opportunity to examine whether dopamine signals are more focused on task-relevant neurons. We will measure both dopamine release and the activity of specific neurons involved in behavior to determine whether dopamine shapes learning at a single neuron level or across broader networks, and what type of information can be conveyed by dopamine signals at different levels of spatial resolution. This study will help us better understand the brain mechanisms underlying learning by revealing fundamental mechanisms of how dopamine modulates neural circuits. Our results will help us understand how disruptions in these processes contribute to conditions like depression, schizophrenia, and addiction, which involve pathological learning. This research could lead to more targeted therapies focusing on dopamine-related brain circuits, ultimately offering better treatment options for people with cognitive dysfunction and maladaptive behavioral patterns.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Current estimates hold that only 50% of individuals who die by suicide disclose their suicidal thoughts to anybody before death, making detection of high-risk individuals challenging. However, past research has only assessed direct forms of disclosure (i.e., explicitly telling somebody about thoughts of suicide), and may not capture indirect disclosure, whereby disclosure occurs euphemistically or vaguely (e.g., “I’m worried I might do something stupid”). Evidence has shown that indirect disclosure may serve as a proximal risk factor for suicide, indicating its importance as a potential point of intervention. However, indirect disclosure has not been previously characterized in the literature, and its prevalence is unknown. Most critically, no standardized assessment tool exists to detect or characterize indirect suicide-related disclosure. The field’s limited understanding of suicide- related disclosure critically limits clinicians’ and loved ones’ ability to detect risk, meaning that vital “cries for help” may go unnoticed and opportunities for prevention missed. The proposed project will refine and pilot a multi- informant, self-report measure to dyadically characterize direct and indirect suicide-related disclosure in adolescents and their caregivers. Adolescents and their caregivers will be recruited from a psychiatric inpatient unit on the basis of a recent suicidal crisis. Parent-adolescent dyads will complete qualitative interviews assessing disclosure in the period preceding the suicidal crisis, providing information about the content, function, and consequences of disclosure as well as caregivers’ detection of disclosure and response to it. Participants will also provide feedback on a preliminary, multi-informant measure characterizing disclosure processes. The measure will be revised in response to participant feedback and piloted in a new sample of parent-adolescent dyads, who will also complete one month of ecological momentary assessment probing family support. Analyses will test whether disclosure predicts improvements in family support over time, and whether this effect is moderated by parents’ detection of an adolescent’s disclosure. Results may ultimately inform interventions to both promote more adaptive help-seeking in suicidal adolescents, and to train caregivers to respond appropriately. A training plan has been developed that consists of coursework and mentorship in qualitative research methods, research conduct with suicidal individuals, measure development, and statistics for intensive longitudinal methods to build the applicant’s expertise in carrying out research in suicidal populations.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY The goal of the proposed K99/R00 award is to support Dr. Courtney Choy’s development as an independent, community-engaged implementation scientist and epidemiologist focused on the prevention and treatment of noncommunicable, cardiometabolic diseases (CMD). Obesity and cardiometabolic risk are emerging earlier in life than ever before and require urgent preventative interventions. The R00 phase of this award will co-design and pilot test a multicomponent lifestyle intervention to address obesity and CMD risk among children in Samoa, a low-resource population with a large United States (US) diaspora and one of the highest rates of obesity in the world. The K99 phase informed intervention design by identifying several prevention opportunities and demonstrating how modifiable risk factors influence childhood obesity and related CMD risk. Specifically, our data highlight a need for prevention before children reach 9 years old and to encourage healthy dietary behaviors, sufficient sleep, self-efficacy, mental wellness, and positive family relationships. In other settings, routine-based interventions have been effective in addressing these risk behaviors. Therefore, in the R00 phase, we will co-design and test a multicomponent, routine-based intervention to address obesity and CMD risk. The intervention will 1) focus on pre-school aged children, 2) use evidence-based behavior change strategies such as goal setting and positive reinforcement to encourage daily structure and household routines related to healthy eating, physical activity, sleep, and family communication (to support child mental health and parenting self-efficacy), and 3) align with community priorities, needs, and preferences for child health programs. We will assess preliminary efficacy using a hybrid type 1 randomized waitlist-controlled trial among n=40 families. We will evaluate changes in CMD risk behavior and outcomes (glycemic control, weight status, lipids, blood pressure, mental wellness). We will also use an established implementation science framework to examine feasibility, acceptability, and potential for sustainability. We expect to develop a program with the potential for replication in US populations experiencing a high burden of CMDs and comparable low-resource settings. The findings and innovations from this work are applicable to strengthening CMD care in the US.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This K23 award will facilitate Dr. Grau’s transition into an independent investigator who develops and tests scalable interventions with attention to health disparities to meet the variation in needs among individuals with post-traumatic stress disorder (PTSD) and hazardous alcohol use (HAU). Targeted research and training activities will extend his knowledge and build his expertise in developing and testing scalable interventions that integrate therapist-delivered and digital components to effectively engage and treat patients with PTSD+HAU in under resourced community settings like Federally Qualified Health Centers (FQHCs). Training: Dr. Grau proposes a comprehensive training plan with the following training aims: (1) Develop expertise in mobile health interven-tions, (2) Gain skills in qualitative data collection and analysis and (3) Acquire key skills in and knowledge of optimization trial design and conduct. Context: PTSD is an extremely damaging psychiatric condition when left untreated, especially for individuals with low-income who are served in FQHCs. Brief, modified evidence-based PTSD treatments are effective and feasible in FQHCs; however, co-occurring problems, most notably HAU, negatively impact treatment engagement and effectiveness. As such, there is a critical need to develop scala-ble interventions that treat PTSD+HAU while maximizing engagement in under resourced community settings such as FQHCs. Responsive to the NIMH Strategic Plan, Goal 3 (Strive for Prevention and Cures), Objectives 3.2 (Develop strategies for tailoring existing interventions to optimize outcomes), and 3.3 (Test interventions for effectiveness in community practice settings), the overall research objective is to develop and test a multimodal intervention that integrates therapist-delivered and digital interventions to treat PTSD+HAU in FQHCs. Re-search Plan: Aim 1 will assess the feasibility and acceptability of three stepped care, therapist-delivered inter-vention components for PTSD+HAU in our partner FQHC. Aim 2 will refine the therapist-delivered components and develop digital components (e.g., personalized text messages) in preparation for a PTSD+HAU hybrid ex-perimental design (HED). Aim 3 will assess the feasibility, acceptability, and preliminary effectiveness of a PTSD+HAU HED in FQHCs combining therapistdelivered and digital interventions to maximize engagement in treatment. Aim 3 results will inform a fully powered HED (future R01 submission) to create a multimodal adap-tive intervention for PTSD+HAU with patients in community health settings. Key innovations include state-of-the-art training, PTSD+HAU scalable intervention development with real world patients in community settings, and use of the HED design. Optimization of adaptive interventions for community patients with PTSD+HAU is a critical next step and will have significant impact on PTSD treatment in FQHCs.

NIMH - National Institute of Mental Health

The proposed research study seeks to address the disproportionately high rates of HIV among young adult Black and Hispanic/Latino men who engage with men (YBLMM) in the United States by increasing pre-exposure prophylaxis (PrEP) uptake and adherence among this population. Despite the effectiveness of PrEP in preventing HIV, its uptake and adherence among this population remains suboptimal due to various barriers, including inequitable patient-provider power dynamics. Researchers have recommended the development of PrEP decision aids (PDAs) to facilitate shared decision-making between patients and their providers; however, none have been developed for YBLMM-provider dyads. Dr. Laughney's research aims to develop, implement, and evaluate a tailored PrEP decision aid (PDA) for YBLMM and their providers to increase the uptake of PrEP among this population. The study is designed with three primary aims: 1) Identify key factors that affect decisions about the uptake of PrEP modalities among YBLMM by conducting in-depth interviews with YBLMM (n=20) and their providers (n=10) to generate novel PrEP PDA content that will be used to develop an “alpha” prototype of the PrEP PDA; 2) Design an “alpha” prototype of a web-based PrEP PDA using the key factors identified in Aim 1 and develop the “beta” version of the PDA through iterative feedback from YBLMM (n=10) and providers (n=10) using in-depth interviews; 3) Evaluate the feasibility, acceptability, and appropriateness of the beta PrEP PDA among YBLMM (n=40) and providers (n=10) in a one-arm pilot trial using mixed methods to evaluate the PDA tool use in clinical settings across 6 months. YBLMM and provider dyads will be created, with one provider being paired with four YBLMM participants, resulting in 40 dyads. These preliminary data will inform the development of an R series grant that will evaluate the effectiveness of the PDA at increasing PrEP uptake and adherence among YBLMM. This proposal includes comprehensive training goals to support Dr. Laughney's development as an independent researcher specializing in HIV prevention among YBLMM. Training goals include: 1) Advance knowledge of and develop expertise in shared decision-making in minority men’s health; 2) Obtain and apply training in mixed methods for HIV prevention, specifically to inform the design of a PrEP PDA; 3) Learn how to design and develop a web-based PrEP patient decision aid tailored for YBLMM and their providers; and 4) Learn how to design, pilot, evaluate, and refine behavioral interventions that use HIV prevention decision-making tools. Dr. Laughney will collaborate with a multidisciplinary mentorship team to guide hands-on research, readings, professional development, and coursework to support the candidate’s research aims and training goals.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Rural communities bear a disproportionate burden of opioid and stimulant use, yet many individuals face challenges engaging in and sustaining treatment. Stigmas surrounding substance use disorder (SUD) and medication for opioid use disorder (MOUD) pose substantial obstacles to both engagement in care and achieving optimal treatment outcomes, such as retention and sustained recovery. Internalized stigma, in particular, has been linked to a higher likelihood of overdose. Patients in rural areas describe internalized SUD and MOUD stigmas as significant obstacles to recovery and other treatment outcomes (e.g., retention, continued use, mental health) in recent qualitative work, which are often compounded by stigma related to polysubstance use. Thus, there is a clear need to develop novel solutions for decreasing internalized SUD and MOUD stigmas within under-resourced, rural communities. Peer recovery specialists (PRSs), or individuals with lived experience in SUD and recovery, may be a unique solution to shifting stigma through sharing their lived experience and normalizing the experience of living with or in recovery from a SUD. While research supports PRS-delivery of brief evidence-based interventions, recent evidence also suggests that PRS-contact through non-stigma focused interventions may not be sufficient in sustaining long-term decreases in internalized stigma. Interventions to target internalized SUD and related stigmas, such as acceptance and commitment therapy (ACT), have shown promise in decreasing internalized stigma and its associated consequences (e.g., avoidance, shame), even when delivered in brief formats. However, these interventions are often limited to high-resource settings. Given the vast resource constraints in rural contexts, a brief PRS-delivered intervention for stigma reduction may be particularly feasible in increasing access to evidence-based care and reducing internalized SUD and MOUD stigmas. Thus, this study aims to: (1) evaluate patient-perceived appropriateness and potential obstacles and facilitators in the implementation of the proposed intervention in an under-resourced, rural context using a qualitative approach with MOUD patients and staff (N = 30); (2) iteratively adapt the proposed intervention and implementation strategies with three structured co-creation sessions (N = 12), guided by ADAPT-ITT and human- centered design principles; and (3) guided by ADAPT-ITT’s theater testing approach, evaluate the feasibility and acceptability of the adapted intervention components using mixed methods (N = 15).

NIDA - National Institute on Drug Abuse

ABSTRACT The overarching goal of this Mentored Career Development Award (K01), responsive to PAS-22-206, is to support me in my development as an independent investigator focused on improving behavioral healthcare for mothers, their children and families. The proposed study focuses on the hundreds of thousands of U.S. women with opioid use disorder (OUD) who are pregnant or parenting children up to age 5 (“mothers with OUD”), a critical period of development for children and elevated motivation for OUD recovery in mothers. OUD severely impairs a person’s ability to function as a healthy parent and thus continues generational trauma and challenges that could be mitigated with treatment. Yet, mothers with OUD face significant punishment (child custody loss, involuntary commitment) and therefore avoid healthcare engagement and OUD treatment. However, these consequences have been lessening as more professionals recognize the benefits of harm reduction and trauma-informed approaches; it is time to better engage mothers with OUD in appropriate care. Integrated care, a multidisciplinary team that provides substance use, mental, and medical healthcare; social work; peer recovery and doula services, has been shown to be the most effective approach for mothers with OUD, but it is difficult to implement due to historical inertia keeping these services separate and other barriers. Research supporting effective implementation is needed. This innovative proposal will build on my strong clinical background treating substance use in families and my research experience with implementation science and integrating behavioral health into medical settings. It will support me in achieving three training goals: 1) Establish expertise in applied implementation research in health systems including EHR data management and usage, 2) Establish expertise in comprehensive perinatal addiction services and 3) Develop competency in multisite clinical and implementation trials methodology. These skills will allow me to achieve the following study aims: 1) Develop a feasible multi-level implementation strategy bundle for integrated care for mothers with OUD by piloting and adapting implementation strategies at Hennepin Healthcare, 2) Develop a micro-theory of implementing integrated care for mothers with OUD by interviewing key informants at successful programs, and 3) Finalize the implementation protocol for a future multisite implementation trial with prospective sites. My expert mentoring team includes two addiction medicine physicians, one specialized in substance use in pregnancy (Jones) and the other an experienced clinical trialist and PI of a NIDA CTN node (Bart); a psychologist with expertise in clinical and implementation trials related to substance treatment within healthcare systems (Japuntich), and an implementation scientist with experience implementing substance use treatment across the VA healthcare system (Hagedorn). Additional advisors in perinatal psychiatry (Kim) and biostatistics (Langworthy), and institutional resources, mean I will have the full support and knowledge needed to successfully complete my training and study aims and achieve R01-level funding to conduct a multisite trial.

NIMH - National Institute of Mental Health

Abstract Despite antiretroviral therapy (ART), HIV-associated brain injury (HABI) persists in over half of people with HIV (PWH), manifesting as chronic cognitive impairment. While HIV-1 primarily infects microglia, driving central nervous system (CNS) neuroinflammation, current preclinical models do not recapitulate the chronic, suppressed infection characteristic of the ART era. Furthermore, they do not capture complex patient genetics and multicellular, glial and neuronal, interactions in a scalable and efficient manner. To address this need for more physiologically relevant models, we propose the development of an AI-guided triculture platform comprising major CNS cell types. This platform will use induced pluripotent stem cell (iPSC)-derived microglia, astrocytes, and neurons, using both morphological profiling and other omics-based profiling to model HABI under ART suppression. AI/machine learning (ML)-driven analysis of cellular morphology, combined with multi-omic data integration, will facilitate rapid classification and prediction of microglial functional states and their impact on neuronal health. Leveraging Modulo's established triculture system, previously successful in yielding therapeutic candidates for amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) currently in Investigational New Drug (IND)-enabling studies, we will construct a scalable HABI model under ART suppression. Our objectives are to (1) develop and validate an HIV-infected, ART-suppressed triculture platform, utilizing AI/ML-driven morphological profiling to classify HABI-specific microglial states; and (2) comprehensively characterize this model through neuroinflammatory profiling, behavioral correlates, and integration with publicly available HABI patient datasets. We hypothesize that our combined computational lab-based triculture system can effectively model HABI pathophysiology under ART conditions, enabling both rapid disease state classification and identification of therapeutic targets. Through the integration of experimental and computational approaches, this platform will provide insights into HABI mechanisms and accelerate therapeutic development. We will disseminate this model to the scientific community through publication and collaboration. Connecting in vitro modeling with patient outcomes offers a powerful tool for investigating neuroimmune dysfunction in HIV and related neurological disorders. Successful implementation will yield a platform for modeling neuroHIV under ART suppression, advancing our understanding of disease mechanisms and facilitating the discovery of novel therapeutic strategies for PWH with cognitive impairment.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT SUMMARY Background. Firefighters are repeatedly exposed to potentially traumatic events and many experience posttraumatic stress (PTS) symptoms as a result. Over 50% of firefighters report past-month heavy alcohol use and many use alcohol to “self-medicate” from symptoms of hyperarousal, intense negative affect, and insomnia that follow traumatic events. Transcutaneous auricular neurostimulation (tAN) of the vagus nerve has shown promise for alleviating symptoms of PTS and opioid withdrawal symptoms but its effects have yet to be tested in a sample of firefighters with alcohol use disorders (AUD) and co-occurring PTS symptoms. Aims. We will collaborate with a firefighter Community Advisory Board to develop a culturally informed, Phase II randomized clinical trial (RCT) protocol testing tAN as an intervention that may reduce PTS symptoms driving heavy alcohol use for firefighters with AUD (Aim 1; Year 1). We will then conduct a feasibility trial of the protocol (Aim 2; Year 2; N = 20) using the Sparrow device—a patient-administered, ear worn device that delivers electrical stimulation to branches of the vagus and trigeminal nerves—to evaluate the acceptability and feasibility of the protocol, and the appropriateness of the tAN intervention for firefighters with PTS/AUD. Using data from the feasibility study, we will complete an FDA pre-submission with the revised trial protocol to support a PTS/AUD indication for Sparrow Ascent, finalize the protocol with FDA feedback, and write an R01 application for a fully powered Phase II RCT (Aim 3; Year 3). Methods. The feasibility trial will recruit firefighters who engage in heavy drinking, have at least a mild AUD, and report above-average PTS symptoms. Participants will use the Sparrow device for at least 1 hour/day for 5 days/week throughout the 4-week treatment phase, but may use the device more often if they wish. Participants in the active tAN condition (n = 10) will receive therapeutic stimulation from Sparrow; active sham participants (n = 10) will feel stimulation at the trigeminal site only, but below a therapeutic level. They will complete daily measures of traumatic event exposure (number and type), PTS symptom severity, alcohol use (standard drinks) and motivations (trauma-related drinking), and audio journals capturing their experience with symptoms and the device (e.g., helpfulness). Additionally, wearable sensors will record heart rate, heart rate variability, and sleep data throughout the intervention phase. Assessments immediately following treatment (Week 4) and one month later (Week 8) will measure protocol feasibility and tAN’s clinical effects outcomes including insomnia, mental health symptoms, and quality of life. Outcomes. The primary feasibility outcome is the mean of protocol ratings on the Feasibility of Intervention Measure. Secondary feasibility outcomes include ratings of protocol acceptability (Acceptability of Intervention Measure) and Sparrow Ascent appropriateness (Intervention Appropriateness Measure). Exploratory clinical outcomes include reductions in PTS symptom severity scores and heavy drinking events.

NIMH - National Institute of Mental Health

Project summary: The earliest prevention intervention currently available for schizophrenia spectrum disorder (SSD) targets the clinical high-risk for psychosis stage, but conversion to full psychosis remains high even with intensive prevention efforts at this stage. The proposed study will test a novel approach to develop preventive intervention for SSD in at risk but clinically still normal children before typical age of clinical high-risk and SSD onset, by relying on brain imaging pattern-based biomarker(s) that can track SSD risk effects on the brain. The project will recruit children aged 9 to 18 with significant family history of SSD and other modifiable risk factors but no subclinical or clinical psychosis and randomize them into family-based risk reduction therapy versus active control therapy. Participants will complete MRI and clinical and neuropsychological assessments at baseline, after 16 weeks of family-based risk reduction therapy, and 16 weeks after intervention has ended. The proposal will integrate evidence-based interventions for risk factors that are known to contribute to SSD and evaluate the intervention effects on SSD-like brain patterns in children. The trial will test the hypotheses that SSD risk factors contribute to SSD-like brain patterns in children before clinical psychosis while risk reduction intervention will significantly normalize the proposed biomarker through mitigating SSD risks and their effects on brain development.

NIMH - National Institute of Mental Health

PROJECT SUMMARY ABSTRACT Effective interventions to reduce the functional impact of core features of autism spectrum disorder (ASD) in school-aged children are critically needed. This R61/R33 application proposes to test whether in-person computer training delivered individually by a coach engages an electroencephalographic (EEG) biomarker of cognitive control (N2 event-related potential [ERP] amplitude) and whether changes in the target neural response mediate the reduction of restricted and repetitive behaviors and interests. An extensive clinical and cognitive neuroscience literature documents reduced cognitive control among autistic children compared to neurotypical children and a relation between cognitive control and repetitive features of autism––providing a solid rationale for our training program. Based on this work, we predict that developing more effective cognitive control, metacognition, and working memory will enhance neural responses to conflicting information (i.e., a neural marker of effective cognitive control) and changes will correspond with decreases in restricted and repetitive behaviors and interests. The R61 study will randomly assign 95 autistic children (ages 8-11yrs) to a novel computer-based Cognitive Control Training combined with Metacognition Coaching or to a waitlist control group. Before and after intervention, EEG will be used to examine engagement of the target neural responses. We expect the group assigned to Cognitive Control Training + Metacognition Coaching to exhibit significantly larger changes in N2 ERP amplitude in incongruent relative to congruent trials than the waitlist group. If this hypothesis is supported, the R33 will be implemented and 140 autistic children (8-11yrs) will be randomly assigned to either: 1) Cognitive Control Training + Metacognition Coaching; or 2) MentalUP Educational Games, an active control condition that provides computer-based cognitive training. Both Cognitive Control Training + Metacognition Coaching and MentalUP will be delivered individually during 15 in-person sessions. Before and after intervention, we will collect neural responses and behavioral measures of cognitive control and working memory. We expect target engagement (greater differentiation of N2 amplitude) to be associated with reduced restricted and repetitive behaviors and interests. This study is innovative in several ways and has the potential for large clinical and scientific impact. It is the first study to examine a cost-effective computer-based cognitive control intervention for ASD that provides in-person metacognition coaching. This could increase functioning for autistic children at a time when intensive intervention delivery is waning. The study will use biomarkers and validated behavioral measures of cognitive control and metacognition in the context of an ASD clinical trial. Finally, the study will provide critical information about the relation between cognitive control and clinically relevant ASD outcomes, thereby providing insight into the mechanisms underlying behavioral challenges for autistic children. Promising results from this study would provide the basis for a larger clinical trial to investigate the efficacy of cognitive control training and mediators and moderators of its effects.

NIMH - National Institute of Mental Health

Project Summary The proposed project will explore barriers and facilitators of HIV care and prevention service engagement and new intervention approaches to increase long-acting antiretroviral treatment (LAI-ART) and pre exposure prophylaxis (LAI-PrEP) uptake and persistence among 18-45-year-old Black and Latinx sexual minority men (B/LSMM) in San Diego, San Bernardino, and Riverside Counties, California, three EHE jurisdictions. This research will focus on B/LSMM with suboptimal care engagement, PrEP/ART adherence, or unknown or detectable viral load. Black and Latinx SMM bear a disproportionate burden of HIV in the US, accounting for 38% and 32% of new diagnoses among SMM, respectively. PrEP uptake is lower among B/LSMM than white SMM in California, and B/LSMM living with HIV (B/LSMM+) have lower overall ART adherence, and viral suppression. Of the 61 health jurisdictions in California, San Bernardino and San Diego Counties rank 46th and 48th in viral suppression rates and, in 2020, most Black (54%) and Latinx (52%) people with HIV (PWH) in Riverside County had received an AIDS diagnosis. Long-acting injectable forms of PrEP (LAI-PrEP) and ART (LAI-ART) have the potential to overcome some known barriers to oral PrEP and ART adherence such as missing daily PrEP and ART doses due to substance use or depression or lacking a safe and private place to store pill bottles. To date, little is known about the barriers and facilitators of LAI uptake among B/LSMM. For the proposed study we will adopt the CDC’s status neutral approach to elucidate the impact of these socio-structural inequities on LAI-PrEP and LAI-ART uptake. New strategies are needed to increase uptake of LAIs among those who can most benefit, such as B/LSMM with less than adequate care engagement and oral ART and PrEP adherence. Guided by intersectionality, syndemics theory, and the Health Equity Implementation Framework, this project has two aims. Aim1: Qualitatively explore knowledge, attitudes, and perceived barriers and facilitators of LAI-PrEP and LAI-ART uptake and identify acceptable and appropriate approaches to increase uptake among B/LSMM who report less than optimal oral PrEP/ART adherence. We will conduct 30 in-depth qualitative interviews with B/LSMM, evenly stratified by race and HIV status, and three focus groups (one in each EHE priority county) with staff and clinicians from community-based organizations serving B/LSMM. Aim2: Quantitatively assess knowledge, barriers, and facilitators of LAI-PrEP and LAI-ART uptake among B/LSMM and assess interest and acceptability of potential intervention approaches.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY AND ABSTRACT Approximately 15 million adults in the United States have serious mental illness (SMI). These individuals are likely to die 10 to 20 years earlier than people in the general population, due in large part to tobacco-related illness. Despite interest in and effort to quit smoking, adults with SMI have difficulty quitting smoking and sustaining abstinence with existing treatments. Novel interventions are needed to address the complex needs of this population, such as high stress, increased dependence and withdrawal symptoms, psychiatric and physical symptoms, and social isolation. There is robust evidence that mind-body interventions are among the most efficacious treatments for addictive behaviors and there are clear benefits of mind-body interventions for adults with SMI to address key barriers to tobacco cessation. Accordingly, we propose to develop a virtual, group-based multicomponent mind-body intervention integrating mind-body skills and social support with gold-standard tobacco treatment (i.e., medication and counseling) to improve tobacco cessation for adults with SMI. Eligible participants include those: ≥ 21 years old with a current diagnosis of SMI (severe recurrent major depressive disorder, schizophrenia, schizoaffective disorder, or bipolar disorder), on a stable medication regimen and presenting with stable psychiatric illness for at least 8 weeks, currently receiving care from a mental health professional, smoking ≥ 5 cigarettes/day in the past week, and living in Massachusetts. The proposed study has three specific aims: Aim 1: To develop a 12-week virtual, group-based, multicomponent MBI for tobacco cessation that integrates existing evidence-based behavioral counseling and tobacco cessation medication with mind-body skills and social support, tailored for adults with SMI. To guide manual/protocol development, we will conduct individual interviews with mental health clinicians (N=10) and caregivers (N=10), and patient focus groups (N=24); Aim 2: To refine the MBI in a single-arm open pilot trial with N=16 adults with SMI who smoke cigarettes (N=2 groups of 8). We will use ecological momentary assessments (EMA) to gain insights into their use of treatment skills in their daily lives. We will modify the intervention and assessments based on participants’ engagement and based on their post-group individual exit interviews. Aim 3: To conduct a pilot RCT to assess the feasibility and acceptability of the proposed treatment (a novel 12-week virtual, group-based MBI for tobacco cessation (N=32; 4 groups of 8) compared to an active time-matched control intervention (N=32; 4 groups of 8)) and the feasibility and acceptability of the RCT design to informed the design of a full-scale effectiveness RCT. In sum, I propose to develop and test a multicomponent mind-body intervention for adults with serious mental illness who smoke, leveraging training in 1) behavioral and mind-body intervention development, 2) mixed methods research, and 3) clinical trial design and longitudinal assessment. An anticipated outcome of this proposal is the development of a novel mind-body tobacco cessation intervention for adults with SMI. A long- term goal is to promote evidence-based tobacco cessation treatments for adults with SMI.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This application responds to PAR-25-178 (Pilot Hybrid Effectiveness-Implementation Trials for Mental Health Interventions, R01). The goal of the project is to refine and evaluate preliminary effectiveness of a novel peer- supported suicide prevention in routine care for clinical high risk for psychosis (CHR). Although individuals with CHR are at particularly high risk for suicide, there does not appear to be a standard approach for suicide prevention for this population. The present study aims to evaluate a new suicide prevention intervention, Recovery Integrated Safety and Engagement (RISE), which adapts an existing evidence-informed peer-led intervention developed by our group to the CHR population. RISE targets personal recovery and suicide prevention strategy recall to decrease suicide ideation and improve care engagement. RISE is a therapist and peer co-facilitated group intervention with four recovery-oriented modules (reasons for living, hope, recovery goals, social connection) that are dovetailed with compensatory cognitive strategies to increase recall of intervention material and a caregiver session focused on means restriction. We propose a 3-year two site hybrid type 1 pilot study that follows the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. First, in Aim 1 we will refine the protocol and intervention through qualitative interviews and community advisory board input. We will then conduct an open trial to evaluate fidelity and needs for further adaptations based on participant feedback. In Aim 2, we will conduct a pilot effectiveness randomized controlled trial (RCT) to collect preliminary effectiveness compared to treatment as usual (TAU), evaluating impact on targets and suicide ideation. In Aim 3, we will administer qualitative interviews with RCT participants and administrators/clinicians focused on implementation determinants resulting in an implementation tool kit for future sustainment. We will evaluate whether RISE leads to significant increases in personal recovery and suicide prevention strategy recall at follow- up and whether participants experience sustained reduction in suicide ideation severity as compared to TAU. This project responds directly to NIMH Strategic Objective 2.2 by determining novel intervention targets (e.g., personal recovery) in risk and protective factors for suicide in CHR and Objective 3.3 by testing a deployment- focused suicide prevention intervention for effectiveness and implementation in two early psychosis programs with input from patients, caregivers, and administrators/clinicians. Pending success of this pilot hybrid trial, RISE could fill important gaps in suicide prevention in routine early psychosis care.

NIH

305,509 veterans received a new diagnosis of strabismus (misalignment of the two eyes) between 2010 and 2021, and many of them have double vision (diplopia). Diplopia decreases the quality of vision and leads to the inability to perform tasks of daily living (like working, reading, and driving) with significant disability. Strabismus is a visible physical deformity that impairs the ability to make eye contact and affects self-esteem, mental health, employability, and overall quality of life. Eye- movement abnormalities and strabismus are sometimes associated with systemic or neurologic diseases. Diagnosis and treatment of eye movement abnormalities and strabismus rely on accurately determining the pattern and degrees of misalignment in different gaze positions and analyzing the accuracy of monocular and binocular eye movements. A team of professionals, including adult strabismus surgeons, orthoptists, and neuro-ophthalmologists, is involved in the labor and time-intensive process of obtaining this information. Treatment recommendations are broad, including placement of prisms in glasses, patching, surgery, imaging, labs, medication, or a combination. Immediate rehabilitation of quality of vision can be obtained by placing prisms in patient's glasses. A significant barrier to the care of veterans affected by strabismus is the lack of trained personnel (in and outside the VA system) to determine the magnitude, direction, and patterns of eye misalignment and eye movement abnormalities, leading to long wait times for an appointment. Thus, care and visual rehabilitation is frequently delayed for months. Eye-tracking technology that can be used to record eye movement abnormalities is commercially available. Still, a critical need exists for algorithms that can analyze this information to assist in patients' diagnosis, treatment, and workup. In this project, we aim to optimize current eye-tracking protocols and software to determine ocular misalignment, patterns of strabismus, and the dynamics of eye movements from the recordings. We will also employ machine learning computational techniques to uncover diagnostic characteristics from the eye movement recordings. The innovation of this proposal is to automate the eye movement and misalignment evaluation as well as the clinical interpretation and thereby reduce or eliminate the involvement of strabismus experts and neuro-opthalmologists. To validate the algorithms, we will compare them with the current standard of care - evaluation of sensorimotor manual measurements by experts. The availability of fast, reliable, and affordable assessments of eye motility and strabismus in every ophthalmology clinic in the VA Health Care system will make evaluation readily available and overcome current limitations. Treatment and workup recommendations will be immediately available, allowing veterans to be treated using existing technology and current personnel. The proposed study is the first and largest to use eye-tracking recordings to develop algorithms and software to classify eye misalignment and motility patterns, which will then be used to generate accurate treatment plans. At the Iowa City VA ophthalmology clinic and Center for the Prevention and Treatment of Visual Loss, we are uniquely positioned for success in this project by having an expert team of an adult strabismus specialist/surgeon, an orthoptist, and a neuro-ophthalmologist to perform manual measurements, accurate diagnosis, and treatment for these conditions. If successful, this system will assist healthcare professionals in detecting, diagnosing, and planning personalized treatment for strabismus patients, ultimately leading to improved outcomes and quality of care. Further, it will result in increased access to health care and faster treatment for Veterans, higher productivity for eye care providers, and reduced fee-based costs to the VA Health Care system for non-surgical cases. The veterans' ability to function independently and overall quality of life, self-esteem, and employability will improve.

NIMH - National Institute of Mental Health

Project Summary Mapping nanoscale brain architecture and molecular features across the entire mammalian brain remains out of reach using current technologies. Correlative light and electron microscopy (CLEM) is the only method capable of bridging structural and molecular information at this scale, but it is prohibitively slow, expensive, and complex, making it unsuitable for scaling to an entire mouse brain. Panluminate Inc. is developing a whole-organ 20X expansion technology called whole-brain pan-Expansion Microscopy (WBExM) that addresses these limitations directly. By combining ~20-fold linear expansion of intact mouse brains with novel bulk (pan) staining of proteins and lipids, WBExM enables molecularly annotated imaging of ultrastructure at sub-20 nm resolution across sections post-tissue expansion, minimizing alignment errors and enabling accurate tracing of neuronal processes for dense connectomics. Neurites including dendrites and axons can be traced by segmenting the pan-staining channel, while simultaneous immunolabeling identifies molecular targets of interest. Unlike EM/CLEM, WBExM is fully optical, scalable, and cost-effective, making it ideal for tracing brain circuits and investigating neurodegenerative disease mechanisms. Our proposed Phase I project is to develop and validate a complete workflow for brain-wide pan-ExM sample preparation and imaging. In particular, we will: (1) develop and optimize WBExM, including perfusion, embedding, clearing, and isotropic expansion protocols that preserve protein targets and tissue structure across the entire mouse brain; and (2) validate reconstruction of neuronal processes across sections, demonstrating that WBExM enables faithful tracing of long-range neuronal projections, synapses, and local circuits, overcoming alignment errors inherent in slice-based approaches. This work will establish WBExM as a practical and scalable platform for nanoscale brain imaging and prepare it for commercialization in Phase II as a research tool for molecular dense connectomics. Our long-term goal is for WBExM to become a core technology for generating nanoscale molecular brain atlases and for studying circuit-level abnormalities in neurodegenerative disease models, supporting discovery and therapeutic innovation aligned with the NIMH mission.

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).