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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 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).

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 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/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.

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required)

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).

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/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 two years of support for evaluation of target engagement and establishment of intervention parameters, and 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).

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required)

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/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 two years of support for evaluation of target engagement and establishment of intervention parameters, and 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).

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) is to request research applications to examine the neurobiological impact of psychotherapeutic medications upon the immature brain, with particular emphasis upon mapping the precise developmental profile of physiological response to psychotropic agents used in the treatment of mental disorders in children. Responsive research includes -studies in model systems, including animals, and in human populations. -Mechanism of Support. This funding opportunity will use the NIH Research Project Grant (R01) award mechanism. Applications of related or identical scientific scope are solicited also under the Small Research Grant (R03) and the Exploratory/Developmental Grant (R21) award mechanisms, responding to FOAs PA-06-180 and PA-06-181, respectively. -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Many evidence-based preventative interventions have been developed to prevent substance use, physical and mental illness, and promote positive educational and social outcomes among adolescents. Among these, caregiver-mediated interventions boast strong effects that are mediated by effective parenting skills. However, the impact of these interventions is severely limited by low rates of home practice of intervention skills among caregivers. To address this research-to-practice gap, researchers have been investigating barriers and facilitators of caregiver engagement, focusing in large part on intervention attendance. Strategies for increasing caregivers' home practice of skills remain underexamined. Yet, caregiver home practice is a key component of theorized intervention effectiveness and has been found to impact parenting behaviors and subsequent child outcomes over and above that of attendance. Therefore, the next important step in supporting parenting behavior change is to develop implementation support strategies for evidence-based interventions that target caregiver home practice specifically. This K01 Mentored Research Scientist Development Award will develop and pilot a digital behavior change intervention for use as an adjunct to an evidence-based preventative intervention. The digital behavior change intervention aims to increase caregivers' home practice of intervention skills. Informed by the theory of planned behavior, habit formation principles, and relapse prevention theory, the intervention will leverage mobile health technologies (mHealth) to circumvent and problem solve common barriers to home practice including home practice intention, frequency of practice, home practice competence, and maintenance of intervention skills. The intervention will be developed as a smartphone application (i.e., “app”) with components informed by a qualitative assessment of barriers to caregiver home practice and refined through direct stakeholder input on design requirements to optimize acceptability and feasibility. The intervention will be piloted with 48 caregiver participants as an adjunct to Bridges, an evidence-based intervention for adolescent substance use prevention and mental health promotion. Findings from this project have the potential to improve caregiver home practice, intervention engagement broadly, and ultimately boost effectiveness and public health impact of numerous caregiver- mediated interventions. In response to NOSI NOT-OD-23-031, this administrative supplement seeks the support of personnel to support the continuation of proposed project activities (e.g., participant recruitment, qualitative and quantitative data collection, pilot trial of the digital behavior change intervention) within the original timeline. No changes have been made to the aims, goals, or scope of the work proposed in the funded K01 application.

Administration for Community Living

<p>Under this particular DRRP priority, the grantee must conduct research toward resilience and positive mental health outcomes among people with spinal cord injury. This grant will have a 36-month project period, with three 12-month budget periods.<br><br><br>&nbsp;</p>

Administration for Community Living

Disability and Rehabilitation Research Projects (DRRP) Program: Research on Resilience and Positive Mental Health Outcomes Among People with Spinal Cord Injury

Administration for Community Living

Under this particular DRRP priority, the grantee must conduct research toward resilience and positive mental health outcomes among people with spinal cord injury. This grant will have a 36-month project period, with three 12-month budget periods.