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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.

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.

Colorado Veterans Commission

State grants for veteran service programs in Colorado including housing, employment, education, and mental health support.

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

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 the CCBHC State Planning Grants is to support states in: developing and implementing certification systems for CCBHCs; establishing Prospective Payment Systems (PPS) for Medicaid reimbursable behavioral health services; and preparing an application to participate in a four-year Section 223 CCBHC Demonstration program.

Substance Abuse and Mental Health Services Adminis

Cooperative Agreements for Certified Community Behavioral Health Clinic (CCBHC) Planning Grants

Substance Abuse and Mental Health Services Adminis

The purpose of this program is to improve state and territory response to all 988 contacts (including calls, chats, and texts) originating in the state/territory and improve service for populations at high risk of suicide and overdose.

Centers for Disease Control and Prevention - ERA

The National Institute for Occupational Safety and Health (NIOSH) supports research projects that address: (1) physical and mental health conditions related to the September 11, 2001, terrorist attacks; (2) diagnosing conditions for which there has been diagnostic uncertainty; and (3) treating conditions for which there has been treatment uncertainty. Conditions may have emerged since the treatment program began or since the WTC Health Program was established. This announcement solicits meritorious and scientifically rigorous applications that will: 1) improve diagnosis and treatment activities of the WTC Health Program; 2) expand knowledge about health effects related to the September 11, 2001, terrorist attacks; 3) answer critical questions about WTC-related physical and mental health conditions; and 4) apply lessons learned to improve response to future disasters. Potential projects may include, but are not limited to: (a) Screening research to evaluate current methods or facilitate the development of new or improved methods to detect disorders or health conditions; (b) Diagnostic research to evaluate current methods or facilitate the development of new or improved methods to identify diseases, disorders, or conditions; (c) Treatment research to evaluate or identify improved treatment interventions or methods, or to promote development of new or novel approaches; (d) Prevention research to identify or evaluate methods and interventions that prevent or mitigate the development or recurrence of diseases or disorders; (e) Quality of life research to identify, develop, or evaluate methods or interventions that improve comfort and quality of life for individuals with chronic illness or multimorbidity; (f) Omics research to improve methods for predicting disorders by identifying and understanding relationships between genes and illness (e.g., phenotypes and biomarkers), including how genetic factors influence disease development or response to treatment; (g) Epidemiologic or clinical research to identify patterns, causes, and control of adverse health effects among the 9/11-exposed population; (h) Health services research to examine access to care, cost of care, and outcomes associated with care delivery; (i) Implementation research to evaluate how research findings are disseminated, adopted, implemented, sustained, and scaled in real-world settings; and (j) Epidemiologic research to investigate emerging conditions where preliminary data suggest, but do not confirm, a causal relationship between 9/11 exposure and the condition. Examples can be found at https://www.cdc.gov/wtc/received.html.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Bipolar spectrum disorders (BSDs) are associated with major personal and public health burdens. Despite this heavy burden, the etiology of BSD is not fully understood. Further research on risk factors for BSD during adolescence, when likelihood of first onset of a BSD is highest, is needed to understand how BSD onset and symptoms can be better predicted and interventions delivered earlier. Determining the degree of risk for BSD conferred by various predictors is a vital step toward creating intervention and prevention programs that can identify individuals most at risk in order to reduce the likelihood of BSD onset, delay onset, or lessen course severity. Extant research has established several person-level factors that confer risk and influence dysregulation throughout the course of BSDs. The social and circadian rhythm model of BSDs posits that social and circadian rhythm dysregulation can result in mood symptoms and episodes. In another separate line of research, evidence suggests that hypersensitivity to rewards confers risk for BSDs. Researchers have suggested that the reward and circadian models of BSD risk and course can be combined into a joint, bidirectional model, such that disturbance in one of these systems, through a feedback loop, may promote dysregulation in both systems, contributing to mood symptoms and episodes. Additional theoretically and empirically supported predictors can be combined statistically with reward and circadian factors to better predict risk of bipolar symptoms. These factors include family history of BSDs, hypomanic personality, higher trait impulsivity, exposure to childhood adversity, affective lability, and substance use. However, the means by which predictive factors may be combined to better inform risk for bipolar symptoms is poorly understood. Although myriad risk factors for BSDs have been identified, little work has been done to statistically integrate information obtained through a multimodal approach to determine which individuals are most at risk. Thus, the proposed project seeks to evaluate empirically derived risk groups based on multimodal assessment of multiple risk factors for BSD during adolescence, a critical developmental period in which onset of BSDs is most likely. I will use participants from my sponsor's R01 study, which aims to examine the interplay of reward and circadian factors longitudinally to predict first onset of BSDs, add measures of additional risk factors, and statistically integrate these multimodal risk indicators with latent class analysis to evaluate the predictive utility of empirically-derived risk groups. My sponsors and I have designed a training plan involving coursework, workshops, experiential learning, and mentorship that will allow me to develop greater expertise in the development of mood pathology, learn advanced statistical methods required for this project, and gain the skills necessary for my future career as an independent clinical scientist. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neuropsychiatric disorders, prevalent in nearly half of the U.S. population over a lifetime, are increasingly linked to immune dysregulation. Among these, allergic inflammation has emerged as a key contributor, highlighting an understudied connection between the immune system and mental health. Animal models reveal a causal relationship between allergic inflammation and heightened avoidance behaviors, a core symptom of mood and anxiety disorders. Unlike predominantly studied bacterial or viral immune challenges, allergic inflammation represents a distinct T helper cell type 2 (TH2)-mediated response triggered by nonpathogenic environmental stimuli, which activates emotion-related brain centers, including the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). These regions are critical for regulating social and anxiety-like behaviors. Converging evidence positions interleukin-4 (IL-4), a key TH2 cytokine elevated during allergic inflammation, as a potential modulator of mPFC circuits and their projections to the BLA, driving avoidance behaviors. This project seeks to determine how IL-4 impacts mPFC dynamics and contributes to heightened avoidance during allergic inflammation. In Aim 1, we will investigate the quantitative relationship between mPFC IL-4 and avoidance behavior during allergic inflammation, identify local IL-4-producing cell types, and determine the impact of heightened mPFC IL-4 on mPFC-BLA responses during avoidance. In Aim 2, we will examine how IL-4 modulates mPFC microcircuit activity and alters mPFC-BLA output and its contributions to allergic inflammation-induced neuroadaptations, defining its role as a non-classical neuromodulator. In Aim 3, we will test the necessity of mPFC IL-4Rα in allergic inflammation-associated mPFC-BLA responses and avoidance behaviors. By integrating advanced molecular, cellular, and circuit-level approaches, this research will uncover novel cytokine-driven mechanisms underlying behaviors associated with neuropsychiatric disorders and identify new immune-based therapeutic targets to address these complex disorders.

NIMH - National Institute of Mental Health

Project Summary Bipolar disorder (BD) is among the deadliest and most costly psychiatric disorders in young people due to its severe and recurrent mood episodes of depression and mania which disrupt functioning, substantially increase the risk for suicide and premature death, and frequently require emergency or inpatient care. As each subsequent mood episode worsens prognosis, prevention of severe mood events in young people with BD is central to mitigating its enormous personal and societal burden. However, prevention is hindered by the lack of widely deployable tools to identify which affected individuals are at risk of a severe mood crisis event within a specific interval and which can guide individualized care. Through this mentored K23 award, the candidate, a PhD-prepared psychiatric nurse practitioner, will build upon her background in early intervention for BD, data- driven analytic approaches, and qualitative methods. Her program of training and research are designed to leverage real-world data and advanced analytic machine learning methods to efficiently identify young individuals with BD at risk for severe mood events and develop a deployment-focused clinical decision support intervention in partnership with clinicians and patients that could be rapidly translated to clinical care (NIMH Strategic Objectives 4.1 and 4.2). Through planned training activities, the candidate will gain a strong skillset in advanced predictive analytics and machine learning using electronic health record (EHR) and administrative data, mixed methods for stakeholder engaged intervention development, embedded health systems research, and BD clinical epidemiology. She will leverage robust, longitudinal health system data from two learning healthcare systems in the Mental Health Research Network, HealthPartners and Kaiser Permanente Northern California, and engagement with clinicians and patients where care is delivered. In Aim 1, rigorous machine learning methods will be used to estimate risk of severe mood crisis events, as indicated by mood-related inpatient hospitalization or emergency visits, over six-month intervals based on rich longitudinal EHR and claims data in a large sample of over 13,200 young patients with BD aged 15-39 years. In Aim 2, to maximize the translational impact of the models, clinicians and patients will be engaged, using a modified Delphi approach and qualitative interviews, in development and evaluation of a clinical decision support tool to guide personalized prevention and early intervention for BD mood crises. This research is a critical step in the candidate's long-term goal of leveraging data-driven approaches to improve individualized, patient-centered delivery of mental health services for individuals in the early course of BD and other serious mental illnesses. Her clinical and research background, expert mentoring team, and embedded research environment ideally positions her to accomplish the research and training aims, building the foundation for a next-step R01 that will externally validate and rigorously evaluate the risk prediction models and decision support tool developed in this proposal.