Search Grants — Free, No Account Required

Substance Abuse and Mental Health Services Adminis

The purpose of this program is to support American Indian and Alaska Native tribes in planning and developing a comprehensive, community-based system of care (SOC). A SOC is defined as a coordinated network of effective mental health and essential supportive services organized to address and meet the varied needs of children, youth, and young adults (birth through age 25), and their families. The SOC approach strives to ensure that mental health services are family-driven and youth-guided, and community-based.

Substance Abuse and Mental Health Services Adminis

<p>The purpose of this program is to support American Indian and Alaska Native tribes in planning and developing a comprehensive, community-based system of care (SOC). A SOC is defined as a coordinated network of effective mental health and essential supportive services organized to address and meet the varied needs of children, youth, and young adults (birth through age 25), and their families. The SOC approach strives to ensure that mental health services are family-driven and youth-guided, and community-based.</p>

NIMH - National Institute of Mental Health

Project Summary / Abstract Enduring social bonds are essential for human health and well-being, yet their underlying neural mechanisms remain elusive due to limitations in traditional model organisms. Prairie voles, which naturally form lifelong pair bonds, offer a powerful system for investigating how the brain encodes stable social states. The medial amygdala (MeA) is functionally connected to a broad network of brain regions that collectively governs social behavior. Specifically, the MeA relays pheromonal cues that are critical for guiding context- appropriate behavior selection, yet how this region contributes to the behavior transition from a naïve to a bonded state in prairie voles is unknown. This proposal investigates how molecularly defined circuits in the MeA contribute to the emergence and maintenance of attachment behavior. Using single-cell RNA sequencing, I identified a sex-biased neuronal population that downregulates the neuropeptide gene Tac1 following pair bond formation. Intriguingly, the mouse equivalent of this population drives both affiliative and aggressive behaviors, and Tac1 itself has been linked to aggression control. In prairie voles, a bonded animal exhibits selective affiliation toward its partner and aggression toward all other opposite-sex conspecifics – a behavioral dichotomy that may be orchestrated by this population. I propose to characterize how this population is integrated into broader brain circuits of prairie voles and to monitor its activity during the formation of a pair bond. These experiments will clarify whether and how this population might serve as a neural substrate for the internal state of bondedness. Ultimately, this research may shed light on fundamental principles of social attachment and offer insight into how disruptions in such processes contribute to psychiatric illness. In addition to the proposed research, this application outlines a comprehensive training plan to prepare Dr. Wang for an independent career as a neuroscientist and psychiatrist. She will be mentored by Dr. Dev Manoli (UCSF), an expert in the molecular genetics and social behavior of prairie voles, and co-mentored by Dr. Michael Brainard (UCSF), a leader in the neurophysiology of complex behavior, and Dr. Vikaas Sohal (UCSF), who specializes in quantitative neural data analysis and circuit-level manipulations. Dr. Wang will also receive guidance on advanced molecular tool development from Dr. Nadav Ahituv (UCSF) and Dr. Josh Huang (Duke). Her career development is strongly supported by the UCSF Department of Psychiatry and Behavioral Sciences, which is committed to transitioning her to a full-time faculty position.

NIMH - National Institute of Mental Health

Two-third of individuals worldwide experience chronic adversity during childhood such as abuse, neglect or similar highly-stressful events. Such early-life adversity (ELA) is one of the best-characterized risk factors for developing psychiatric disorders associated with reward deficits including depression, substance use disorders and schizophrenia later in life. ELA related reward deficits are even observed in healthy individuals suggesting a link between pre-existing reward deficits and ELA-induced vulnerability to psychopathology. Mice exposed to ELA also show reward deficits later in life, however how ELA produces sustained changes at the neural circuit level to induce persistent reward-deficits is unknown. Reward processing is complex involves several aspects, governed by overlapping but still distinct reward circuits. A major challenge in studying circuit mechanisms underlying ELA-induced reward deficits have been a lack of dissection of the affected reward constructs. Our preliminary data suggest that ELA produces enduring deficits in hedonia in mice. Ventral pallidum (VP) and nucleus accumbens (Nac) have been implicated in reward processes, the historical view is that VP receives the reward-related information from Nac and modulates behavior through interactions with downstream targets. However recent findings challenge this view and show that VP encodes reward value and learned cue value more accurately and faster than Nac. Moreover, our preliminary findings show that the optogenetic stimulation of VP-Nac projection rescues reward deficits in ELA mice while the inhibition of this projection mimics the effects of ELA on hedonia. This proposal will test whether VP-Nac afferent activity is prominent in governing hedonia and whether disruptions of this circuit mediate the ELA-induced persistent reward-deficits. By employing fiber- photometry, Aim 1 will examine if ELA produces deficits in reward-related activity of VP cell populations, while Aim 2 will determine whether particularly the reduction of VP-Nac core activity is associated with ELA-induced hedonic deficits. Finally, Aim 3 will use pathway-specific optogenetic manipulations to test the role of VP-Nac afferents in ELA-related hedonic deficits such that if the inhibition of VP neurons projecting to different subregions of Nac suffices to induce hedonic deficits or the stimulation of the same circuit activity rescues the ELA effects on reward. We will also test the role of this pathway in hedonic encoding during cue-reward associations or instrumental learning in ELA. By combining these approaches, we will establish a pathway specific understanding of how ELA impairs reward processes with the goal of developing novel treatments for reward deficits.

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

Women with high levels of adverse childhood experiences (ACEs) are at significantly greater risk for negative health outcomes in pregnancy and postpartum, including gestational diabetes, PTB, and depressed mood. However, we still lack biomarkers or a sufficient understanding of causal mechanisms. Extracellular vesicles (EVs) are one of the most dynamic and abundant biological signals secreted into maternal circulation, largely produced by the placenta – where levels increase 4-5-fold during pregnancy. Similarly, removal of the placenta at delivery produces a dramatic drop in maternal EV concentration. Across species, we and others have identified significant EV changes during pregnancy associated with homeostatic regulation, including glucose and glucocorticoid levels, supporting key roles for EVs in maternal health. However, longitudinal studies in human pregnancy and postpartum have not been conducted. We know little as to the mechanisms controlling EV secretion or the roles for EVs in maternal pregnancy and postpartum health. Our decade’s long work identified the X-linked gene, O-glycosyltransferase (OGT), in mouse and human placenta as a master gage of the maternal milieu, where OGT regulation of annexin A1 (AA1) is key to EV cargo loading and secretion from the placenta. We recently reported that placental OGT levels positively correlate with maternal EV concentration. How this association may contribute toward postpartum health, including regulating maternal stress physiology and mood in humans is not known. We hypothesize that increased ACEs, similar to stress in preclinical models, are negatively associated with a cell’s ability to secrete EVs important to maintain homeostasis in the face of the challenges of pregnancy and postpartum, producing an increasingly unhealthy state. Therefore, the goals of these proposed studies in both mice and humans are as follows: 1) To identify cellular mechanisms involved in EV secretion important to maternal health outcomes utilizing the placenta as a tool to genetically target OGT in mice and examine maternal homeostatic control related to EV concentration and composition during pregnancy; 2) To examine the functional ability for a dynamic elevation in maternal EV concentration to improve homeostatic regulation in pregnancy and postpartum using chemogenetic activation (DREADDs) of placenta trophoblast cells in pregnancy, and by EV transfer by tail vein injection postpartum; and 3) To examine in women changes in maternal EVs in a longitudinal pregnancy and postpartum study in association with maternal glucose and cortisol changes, we will examine markers of physical (glucose challenge test), HPA stress (hair cortisol & stress- stimulated salivary cortisol) and psychological (Hamilton Rating Scale for Depression, Perceived Stress Scale) health across pregnancy and the postpartum period in 150 healthy women with varying degrees of exposure to ACEs as measured using the ACE Questionnaire (ACE-Q).

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), is to invite grant applications for clinical research that will reduce the burden of mental illnesses on older adults. The NIMH has a long-standing commitment to studying mental illnesses in older individuals. The intent of this FOA is to intensify investigator-initiated research in this area, to attract new investigators to the field, and to enhance interdisciplinary approaches to research. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. Applications of identical scientific scope are solicited also under the NIH Small Research Grant (R03), the NIH Exploratory/Developmental Grant (R21), and the NIMH Clinical Exploratory Research Grant (R34) award mechanisms, responding to FOAs PA-06-180, PA-06-181, and PA-06-248, 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.

NIA - National Institute on Aging

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ ABSTRACT Binge-eating disorder is the most prevalent and costly formal eating disorder, but has the lowest rate (<4%) of receiving eating disorder treatment. Binge eating often begins in adolescence and is strongly associated with obesity, physical and mental health impairment, and psychological distress. Yet, there are virtually no established treatments, and no clear standard of care, for adolescents with binge eating. Evidence-based treatments exist for adults, including psychological treatments (e.g., CBT-BED) and lifestyle behavioral obesity intervention (LBOI), but efficacy for adolescents remains largely unknown. LBOI is an effective treatment for adolescent obesity, but has only been tested post-hoc for binge eating. There is an urgent need for research identify and establish the efficacy of developmentally-appropriate interventions for adolescents with binge eating to improve adolescents’ health and quality of life. To address this pressing public health knowledge gap, CARE2 will test Cognitive and behavioral Approaches to Reduce binge Eating and Excess weight in adolescents. We will conduct a randomized controlled trial (RCT) in which participants are randomized to Psychological Treatment (CBT-BED), LBOI, or Active Control. We developed, refined, and tested adolescent-specific CBT-BED. Our pilot work showed that adolescent-specific CBT-BED was feasible, was more acceptable than nutrition education, and reduced binge eating. However, there has not been a definitive study that used an active control to establish efficacy, and patient characteristics that may be predictors and moderators of outcomes are not known. Further, CBT-BED has not been compared to LBOI, which shows promise for binge eating as well as weight. In the proposed study, we will compare both CBT-BED and LBOI to each other and to an Active Control. Active Control is daily self-monitoring (emotions, eating, exercise) on an “app”, mimicking real-world self-help, followed by treatment choice. After the delay, adolescents choose CBT-BED or LBOI and receive their treatment from a clinician (non-researcher). As such, the Active Control is both a control during the acute efficacy trial and an exploratory hybrid efficacy-effectiveness arm, in line with the NIH Stage Model of Psychotherapy Intervention Research. The specific aims of the CARE2 study are to 1) test whether CBT-BED and LBOI reduce binge eating and prevent excess weight gain, 2) test whether CBT-BED and LBOI reduce global eating disorder severity and improve quality of life, 3) explore durability of outcomes and patient characteristics that may moderate outcomes, and 4) explore adolescent treatment choice and effects on adherence and outcomes. Adolescents will be assessed at baseline, at end of treatment (6 months), and 6- and 12-months post-treatment. All visits occur via telehealth, allowing for national recruitment and pragmatic participation for families. Successful completion of CARE2 has the potential to improve health and reduce suffering during adolescence and improve lifelong health for adolescents with binge eating and excess weight.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Cognitive disengagement syndrome (CDS; previously termed sluggish cognitive tempo) is a set of behavioral symptoms characterized by excessive daydreaming, slowed thinking, and mental confusion. Despite being overlooked in psychopathology research for decades, it is now established that CDS symptoms (1) are distinct from other psychopathology including ADHD and internalizing symptoms, (2) can be reliably measured, and (3) increase across development. CDS is also associated with several significant areas of functional impairment including internalizing symptoms, suicide risk, and interpersonal difficulties. As CDS research advances, there is a need for developmentally-informed research that can advance theoretical models of CDS within broader models of psychopathology. We propose that CDS may be an important yet understudied transdiagnostic vulnerability to psychopathology that can inform models of heterotypic comorbidity while also being an untested gateway to the development and rise of internalizing problems across adolescence. However, there is a dearth of research examining CDS during adolescence, particularly with a longitudinal design. To address this gap in the existing scientific evidence base, we recently recruited a large, diverse community sample (N=341; ages 10-12 years) enriched for CDS symptoms to ensure the full range of CDS was represented. Participants are assessed at three timepoints over a 2-year period (i.e., baseline, 1-year follow-up, 2-year follow-up). Retention rates currently exceed 93%. Given its size and scope, this study comprises the most rigorous CDS study to date. However, despite the ongoing study being the only CDS-specific longitudinal sample in adolescence, it is limited to 3 timepoints over a 2-year period when the maximum age of participants will be 14 years. We thus have a unique opportunity to leverage this large, highly unique sample by conducting 4 additional assessments which will result in a total of 7 annual visits in a sample spanning the ages of 10-18 years. In this study we will (1) examine CDS as a transdiagnostic predictor of psychopathology (i.e., internalizing symptoms, dissociation, borderline features, insomnia) and suicidal ideation across adolescence, (2) test interpersonal functioning as a mechanism of the prospective link between CDS and internalizing psychopathology, (3) explore individual and diversity dimension factors that may moderate the prospective relation between CDS and internalizing, including trauma exposure, biological sex, and socioeconomic status, and (4) establish CDS in relation to theoretically-linked behavioral units of analyses, including task-assessed mind-wandering, processing speed, and negative attribution bias. Findings from our proposed 7-wave longitudinal design supporting the hypothesis that CDS uniquely predicts increased internalizing problems across the second decade of life would make a major advance in developing theoretical models of CDS, positioning CDS within broader hierarchical taxonomies of psychopathology, and providing avenues for targeted clinical assessment and treatment.

NIMH - National Institute of Mental Health

ABSTRACT Late-life depression (LLD) is a heterogeneous neuropsychiatric disorder that can take a chronic and recurrent course. Executive dysfunction (i.e., difficulties with complex mental tasks and planning) is prominent in recurrent LLD, persists despite remission of depressive symptoms, and corresponds with increased risk of cognitive decline and transition to dementia. Past work demonstrates executive function deficits are related to changes in the underlying structure and function of the brain’s executive control network (ECN). Combining targeted cognitive-enhancing interventions aimed at promoting neuroplasticity may strengthen the underlying ECN, thereby improving executive function performance. Multi-modal approaches using cognitive training and non- invasive neuromodulation (i.e., transcranial direct current stimulation; tDCS) support cognitive benefits in older adults. However, previous research used more general executive function-based cognitive training, while the current study proposes a targeted cognitive training (TCT) intervention that was created to specifically address executive function deficits found in LLD. Combining this with tDCS applied to the frontal lobes may help to maximally engage and benefit executive function-based cognitive and neural functions. The proposed study aims to identify cognitive and neural changes elicited by a multi-modal cognitive- enhancing intervention using a randomized clinical trial pilot study design. Sixty non-demented older adults presenting with executive dysfunction and recurrent LLD will undergo a 4-week daily intervention contrasting the effects of three conditions (bifrontal active tDCS+TCT, sham tDCS+TCT, and sham tDCS+non-targeted control cognitive training (CT)) on measures of executive functioning and ECN brain connectivity pre- and post- intervention. Specific aims are to determine whether stepwise ECN engagement across randomized groups (active tDCS+TCT > sham tDCS+TCT > sham tDCS+control CT) results in progressively greater benefit to executive functions (Aim 1) and functional connectivity between ECN regions (Aim 2). We will also explore whether intervention-related changes in ECN relates with executive function performance (Exploratory Aim) and changes in depressive symptoms. Resultant data will enhance understanding of mechanisms underlying this multi-modal cognitive-enhancing intervention in recurrent LLD and inform a more definitive randomized, mechanistically-focused clinical trial via an R01. This K23 will support my career development goals of building expertise in 1) delivery and optimization of multi-modal non-pharmacological interventions to enhance cognition, 2) functional connectivity neuroimaging analysis in LLD, and 3) clinical trials development, implementation, and management. Study results will establish the necessary groundwork for my development as an independent investigator focused on multi-modal targeting of the ECN (via TCT, tDCS) to enhance brain and cognitive functions in LLD, with goals of understanding mechanism, personalizing treatments, and altering the trajectory of cognitive decline to reduce dementia risk.

Cohen Veterans Network

Grants for establishing and expanding mental health clinics serving post-9/11 veterans, active duty, and families.

NIA - National Institute on Aging

PROJECT SUMMARY: OVERALL The Columbia University (CU) – Weill Cornell Medicine (WCM) Center for AIDS Research (CFAR) is a partnership between two large New York City (NYC) academic institutions, each with an expanding investment in HIV research and connected by the NewYork-Presbyterian hospital system, which spans four NYC counties designated as priority high-burden jurisdictions by the US Ending the HIV Epidemic (EHE) initiative. The overall specific aims of the CU-WCM CFAR are to (1) catalyze innovative, interdisciplinary, inter-institutional HIV research that addresses key HIV research priorities for ending the epidemic in NYC and beyond; (2) engage and support career development of HIV researchers, including early-career investigators (ECIs) and investigators new to HIV; and (3) advance community-engaged participatory research that promotes health for all people. The CU-WCM CFAR will accomplish these goals by establishing, engaging, and working through six Cores: The Administrative Core will provide leadership and management; implement strategic planning; and stimulate communication, collaboration, and capacity building. The Developmental Core will provide grant funding awards; mentoring and career development for new investigators; and provide resources, training, and feedback for mentors to improve their skills. The Structural Immunology Core will provide state-of-the-art imaging and immunological technologies; molecular structure determination; and bioinformatics to understand antibody-virus co-evolution, and structural modeling. The Virology Core will provide specialized assays to measure virus replication, infectivity, and cell susceptibility to infection; comprehensive reservoir characterization; and training in these methodologies. The Clinical Research Core will provide consultative support across the course of a study ranging from study design and biostatistical planning to participant recruitment, and data analysis. The Behavioral, Implementation and Community Sciences Core will support investigators engaged in behavioral, implementation, health services, and community science research and catalyze bi-directional collaborations with communities. We also will establish a Scientific Working Group – Integrating Systems of Care to End the HIV Epidemic – that will bring together a group of dynamic multi-sector collaborators to develop a robust research agenda that addresses fragmentation of care for HIV, mental health, and substance use care co-morbidities. The CU-WCM CFAR will add value to our institutions’ existing strong research portfolios through scientific leadership and strategic planning that builds synergistic new collaborations, enhances community engagement on HIV research and health, and supports innovation and research productivity as well as the next generation of leading HIV researchers.

HHS / SAMHSA

Block grants to states for community-based mental health services for adults with serious mental illness and children with serious emotional disturbances.

National Institutes of Health

-Purpose. The ultimate goal of this Funding Opportunity Announcement (FOA) is to support research partnerships between community-based, clinical/services settings and research institutions to reduce the burden of mental illness, behavioral disorders, and HIV/AIDS through research on mind, brain, and behavior. -Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) award mechanism. Only previous R21 awardees from PAR-07-004, are eligible to apply for the R01 grant. The R01 application must build on and further develop the pilot research, resources, and collaborations developed in the initial R21. -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 quality, duration, and costs of the applications received.

National Institutes of Health

-Purpose. The ultimate goal of this Funding Opportunity Announcement (FOA) is to support research partnerships between community-based, clinical/services settings and research institutions to reduce the burden of mental illness, behavioral disorders and HIV/AIDS through research on mind, brain, and behavior. -Mechanism of Support. This FOA will use the NIH Exploratory/Developmental (R21) award mechanism and runs in parallel with an FOA of similar scientific scope that solicits applications under the Research Project Grant (R01) mechanism and will be issued at a later date. R01 applications may only be submitted by awardees of this R21 FOA. The R01 application must build on, and further develop the pilot research, resources, and collaborations developed in the R21. -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 quality, duration, and costs of the applications received.

NIH

Significance to VA Obesity is present among 41% of VA patients and incurs many physical and mental health problems, increases mortality, and accounts for a large share of health care spending. Despite significant VA investment in the MOVE! behavioral intervention program and availability of bariatric surgery, obesity rates in VA remain high. Anti-obesity medications (AOMs) can result in clinically meaningful weight loss and are recommended as part of a comprehensive obesity treatment plan. The newer AOMs offer unprecedented effectiveness and tolerability with few contraindications. AOM use in VA is thus rapidly increasing and the potential impact on Veteran health is considerable. But strategic use of AOMs for Veterans with obesity is hindered by gaps in real-world data about use, clinical outcomes, and patient and clinician perspectives. We will provide the evidence for more strategic AOM use to treat obesity in VA, aligned with VA priorities of Evidence Based Decisions and Data as a Strategic Asset; the VHA Long-Range Goals of “providing health care-related data that benefits Veterans and the general public”, and the HSR priority of “Connect Veterans to the…best care (optimize Veteran access…and experience)”. Innovation & Impact We will assess new AOMs at a time of accelerating Veteran demand, provide the first rigorous evidence of AOM use and outcomes in men, examine weight change and clinical outcomes in real-world practice to complement trial evidence, and provide an in-depth understanding of patient, clinician, and organizational leadership perspectives on AOM use and continuation. Specific Aims Aim 1: Evaluate Veteran, clinician, facility, and VISN characteristics associated with using anti-obesity medications (AOMs) in 2021-2024 and characterize duration and rates of discontinuation. H: AOM users will have different baseline weight, race/ethnicity, and comorbidities than non-users. Aim 2: Compare real-world outcomes of AOM users and non-users in 2021-2024. H: AOM initiators will have greater weight loss and cardiometabolic changes than Veterans who do not initiate AOMs. Weight loss, GI adverse effects, and cardiometabolic changes will differ across AOMs. Aim 3: Characterize factors influencing decisions to initiate and continue AOMs as part of comprehensive obesity treatment, via qualitative interviews with Veterans, clinicians and pharmacy leaders. Methodology This is a sequential explanatory mixed-methods study. Aims 1 and 2 use a retrospective comparative effectiveness study design to examine use and outcomes of AOMs. Aim 3 will use qualitative interviews with patients (N=24), clinicians (N=24), and pharmacy leaders (N=24) to explore decision-making and the reasons for observed patterns of use. The quantitative and qualitative phases will be connected by our use of Aim 1 findings to inform Aim 3 sampling for interviews, and in Aim 3 we will also explore how Aim 2 outcomes influence decisions about continued use. We will use the qualitative data to enhance and enrich understanding of the quantitative findings about AOMs through synthesis of findings across Aims. Path to Translation/Implementation Operational partners in VA Pharmacy Benefits Management and the VHA National Center for Health Promotion and Disease Prevention, which manages MOVE!, will use our findings to inform prescribing guidance and program materials. Our team's next step will be to build on this study to develop and test an intervention to support AOM use among those Veterans that are most likely to benefit in terms of clinical and quality of life outcomes, which will in turn optimize VA resources and maximize Veteran benefit.

Substance Abuse and Mental Health Services Adminis

Comprehensive Opioid Recovery Centers

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Cognition depends on context. The way we perceive stimuli, the predictions we make, and the actions we take all depend on the current situation. Considerable research has provided insight into how context affects neural processing, but relatively little is understood about how context itself is represented and learned. Here, we propose to combine computational models and electrophysiology in non-human primates to investigate the neural mechanisms that support context-dependent behavior. Our research builds on three recent theoretical models that use three different mechanisms for learning context representations and then using them to guide situationally-appropriate behaviors. These mechanisms include learning within prefrontal cortex, through the interactions between prefrontal cortex and basal ganglia, and through interactions between prefrontal cortex and hippocampus. To test the predictions of these models, we will simultaneously record neuronal activity from prefrontal cortex, hippocampus, and striatum of monkeys as they perform a context-dependent sequence prediction task. The proposed research has two primary aims: First, we aim to understand the structure of context representations in the brain. Monkeys will perform a sequential prediction task in which they must infer the context based on a cue and use it to predict subsequent stimuli. Each context will be associated with a unique sequence structure and designed in a way that allows us to understand the structure of the neural representation of context (as either compositional or conjunctive) and how this structure supports the generalization of knowledge between contexts. Recordings in prefrontal cortex, hippocampus, and striatum will test neural predictions from all three computational models about the nature of context representations in the brain. Second, we aim to understand how new contexts are learned. We will examine how different training regimes (e.g., blocked vs. interleaved contexts and transient vs. persistent cues) impact the formation and structure of context representations. Previous empirical and modeling work suggests that blocked training, while more difficult for standard neural networks, may benefit human learning by promoting compositional representations. Using neural recordings, we will test whether these findings extend to non-human primates and examine the role of prefrontal cortex, hippocampus, and striatum in learning under different training conditions. Overall, our research will provide insight into how the brain represents context and how these representations are shaped by learning experiences. This will refine our understanding of cognitive flexibility and lay the foundation for understanding, and addressing, disruptions in context-dependent processing associated with mental disorders including schizophrenia, obsessive-compulsive disorder, and anxiety.

NIDA - National Institute on Drug Abuse

SUMMARY: Dopamine, serotonin, and norepinephrine neurotransmitters are known to be critically involved in process underlying substance use disorder and psychiatric illness, as well as healthy motivated behavior, decision-making, and learning. However, little is known about how these signals coordinate and modulate subjective feeling and motivate behavior as mammals (including humans) navigate the world. Progress has been hindered by a lack of technology that permits fast, real-time, measurements that can discriminate and track dopamine, serotonin, and norepinephrine release simultaneously in areas of the brain where two or more of these neurotransmitters are co-released. A major challenge to current methods (e.g., fast scan cyclic voltammetry) is that the calibration models use to interpret in vivo data are trained in vitro and it is unclear how the background signal changes between these environments and how this affects the measured responses. This proposal capitalizes on (and seeks to radically improve) a technological innovation developed by the principal investigator, which resulted in the first successful colocalized measurements of dopamine and serotonin release with sub-second temporal resolution from the brains of consciously behaving humans. Here, we pursue two specific aims, which seek to develop a computational approach to extend these kinds of measurements to include simultaneous detection of norepinephrine and make these methods available for a larger area of preclinical animal model research and human clinical neuroscience research. In both aims we will be testing the overarching hypotheses that 1) the ‘background’ signal present in fast scan cyclic voltammetry measurements can be quantitatively characterized, mathematically modeled, and therefore subtracted using a model-based approach in in vivo research paradigms; and 2) that the “in vitro bias” in the mathematical models used in model-based electrochemistry can be corrected for if we can obtain a better characterization of the background signals in each of the in vivo, ex vivo, and in vitro conditions. The experiments and analyses proposed will begin to provide much needed clarity on the impact biological ‘interferents’ have on interpreting in vivo fast scan cyclic voltammetry data – currently the only approach amenable to sub-second multi-neurotransmitter detection in humans. We expect to develop mathematical models and calibration methods that can be used to predict and control for unwanted interfering signals while significantly improving detection methods for multi-neurotransmitter detection. Notably, these advances – to be shared via open-source online repositories – would accelerate ongoing efforts in the field aimed at understanding how dopaminergic, serotonergic, and noradrenergic systems coordinate to motivate behavior in humans and pre-clinical model organisms, and thereby provide insight into mechanisms underlying human mental health.

National Institutes of Health

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement supports confirmatory efficacy testing of non pharmacological therapeutic and preventive interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach. In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the mechanisms of action through which any intervention produces therapeutic change.

National Institutes of Health

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement supports confirmatory efficacy testing of non pharmacological therapeutic and preventive interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach. In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the mechanisms of action through which any intervention produces therapeutic change.

National Institutes of Health

Confirmatory Efficacy Clinical Trials of Non-Pharmacological and Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required)

NIMH - National Institute of Mental Health

PROJECT SUMMARY The human serotonin transporter (hSERT) plays a critical role in regulating serotonin (5-HT) signaling across nearly all major systems in the body. Dysregulation of hSERT is linked to numerous psychiatric and gastrointestinal disorders, making hSERT a primary target for clinical therapeutics including selective serotonin reuptake inhibitors (SSRIs). While the core ion-coupled transport cycle of hSERT is well characterized, the allosteric mechanisms that fine-tune its activity to meet diverse physiological demands remain poorly understood. This proposal aims to define the structural mechanisms by which 5-HT and the microbial metabolite butyrate allosterically shape hSERT’s conformational landscape to modulate its function. Aim 1 will leverage innovative cryo-EM approaches capable of resolving the full range of conformational states that define hSERT’s transport cycle, enabling the distinct structural effects of ligand binding at the central (S1) and allosteric (S2) substrate- binding sites to be isolated and characterized. These conformational changes will be directly linked to transport activity using complementary 5-HT uptake and electrophysiological assays. Aim 2 will expand our understanding of hSERT allosteric regulation by identifying the binding site of butyrate, characterizing its effects on hSERT’s conformational equilibrium, and determining its impact on transport activity. The training plan outlined in this fellowship is designed to strengthen technical and conceptual expertise in membrane protein biochemistry, single-particle cryo-EM, and electrophysiology. Mentorship and training from Dr. Eric Gouaux, an internationally recognized leader in membrane protein structural biology, and Dr. Michael Kavanaugh, an expert in transporter electrophysiology, will ensure the successful completion of the proposed aims. Together, these studies will advance the fundamental understanding of hSERT regulation and contribute to a broader framework for understanding allosteric modulation in neurotransmitter transporters, informing the development of innovative therapeutic strategies for disorders involving transporter dysfunction.

Substance Abuse and Mental Health Services Adminis

The purpose of this program is to establish and operate a national TAC dedicated to addressing priority mental health needs of regional and national significance. These activities can include:Developing, delivering, coordinating, and evaluating technical assistance to organizations that are dedicated to addressing mental health needs through courses, seminars, workshops, and cohort support to build skills and best practices to expand operational and program capacity.Strengthening the organizational readiness and sustainability of mental health PROs,Supporting peer workforce pathways and the innovative utilization of the peer workforce across service systems, including behavioral health care settings, physical health care settings, homelessness services, and community and justice-related settings,Integrating the peer workforce across all systems that serve individuals with SMI, including strengthening the readiness of non-behavioral health care providers to integrate peers. PROs play a critical role in supporting adults with lived experience of SMI, andEfforts to work with new types of partners that can reach new populations, including via faith-based and community-based organizations.