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NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Proper cerebellar function is important for many aspects of mental health, as evidenced by the wide range of neurological and neuropsychiatric disorders that have been associated with impaired neural processing in the cerebellum, from ataxia and dystonia to schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). To understand how the cerebellum contributes to both motor control and cognitive functions it is necessary to define what kind of inputs it receives, particularly via the massive mossy fiber system, which carries the bulk of all sensory, motor and cognitive signals sent to the cerebellum from the rest of the brain. Furthermore, variations in brain state are likely to alter the information content of mossy fiber inputs and have a major impact on how well and reliably the cerebellum can perform its function. Unfortunately, conventional extracellular recording methods do not offer enough stability and often fail to distinguish signals of mossy fibers from other cell types in the cerebellar cortex. As a result, there is very limited knowledge about mossy fiber activity in cerebellar tasks, and no information at all about state-dependent modulation of mossy fiber responses or which mossy fiber states may be associated with enhanced cerebellar function. The experiments in this application take advantage of Neuropixels probes and a recent semi-supervised deep learning algorithm to overcome previous technical limitations and record for the first time from identified mossy fiber populations while mice perform a cerebellar-dependent eyeblink conditioning task. The analysis of mossy fiber activity, both before and during conditioning trials, is meant to achieve the following goals: (1) to provide new biological insight into the moment-to-moment variability of mossy fiber states, (2) to help define which mossy fiber states are associated with ‘faulty’ vs ‘reliable’ cerebellar function and, (3) to reveal how locomotion and non-invasive stimulation of the prefrontal cortex can be used to steer mossy fibers toward favorable states that are linked to improved performance of cerebellar-driven motor responses. Thus, the findings will have important implications for enhancing cerebellar function, both in health and disease, by developing new therapeutic interventions that can be used to promote beneficial mossy fiber states. Given the well-established role of the cerebellum in the control of movement, it is expected that the findings will impact patients with motor problems most directly. However, cerebellar dysfunction has also been associated with impairments in executive function, abstract reasoning, working memory, high-level language processing and attentional control. To the extent that the neural signature of ‘faulty’ and ‘reliable’ mossy fiber states is similar in regions of the cerebellum involved in these cognitive functions, the aims of this application and the implications for future treatments may apply to them as well.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Non-suicidal self-injury (NSSI) is a prevalent and potentially devastating behavior that associates with severe psychopathology and suicide. Unfortunately, there are critical gaps in our understanding of variability in NSSI urges and behaviors over time. These scientific gaps limit our ability to develop more responsive, innovative, and effective interventions based upon temporally specific knowledge of brain-behavior relations. The proposed study will help disentangle static and dynamic fluctuations associated with longitudinal variabilityin NSSI. Ultimately, this could yield novel insights into NSSI-related biobehavioral mechanisms, which could be targeted clinically. With this proposed training grant, each scientific aim is structured to support the candidate’s development as an independent investigator with expertise in ecological momentary assessment (EMA; behavioral) and neuroimaging (biological) correlates of NSSI behaviors across time. This includes the use of a longitudinal design, allowing the candidate to build skills to understand dynamic change in NSSI as they relate to stable and changing risks for NSSI behaviors and the neural systems foundational to these risks. Specifically, she will determine whether proximal NSSI frequency and urges measured through EMA will covary with resting-state functional connectivity between the amygdala and regions associated with motor planning over time (Aim 1) and whether brain activation during rumination induction, which involves repetitive negative thinking, remains independent of NSSI changes (Aim 2). This will build her skills to successfully execute longitudinal studies in the future [Training Aim 1 (TA1)]. She will also acquire experience in collecting and analyzing data using EMA (TA2), and integrating EMA with neuroimaging data (TA3). The increasing rates of self-injurious thoughts and behaviors, including NSSI, among youths makes this research critically important. The Nationwide Children’s Hospital in Columbus, OH is home to the Center for Suicide Prevention Research, which includes phenomenal resources and some of the world’s leading experts on youth self-injurious thoughts and behavior, making NCH an exceptional setting for this project. The proposed project will collect clinical, EMA, and MRI data from 50 adolescents ages 14-17 with NSSI. Participants will complete 5 epochs of EMA spaced two months apart (T1-T5), with three of these timepoints also including clinical and MRI data spaced four months apart (T1, T3, and T5). By collecting data at five timepoints, the candidate will be able to leverage naturalistic environmental changes that potentiate NSSI, as measured by EMA, and identify specific neurobiological features that are associated with propensity for NSSI. This project provides the candidate with the opportunity to acquire critical skills that will greatly benefit the field of NSSI while collecting an extraordinarily rich dataset that will support a highly competitive R01 for the candidate.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Identifying individuals likely to respond to a specific intervention is a critical challenge in medical research. In the age of big data, where vast amounts of information are accessible, the potential for personalized interventions based on individual characteristics has become increasingly feasible. However, advancement comes with significant challenges. The sheer volume of data often leads to datasets with numerous factors which might influence outcomes. Moreover, the data may exhibit clustering or repeated measurements, with potentially informative cluster sizes, adding complexity to the analysis. For instance, researchers are interested in understanding why some pregnancies are more vulnerable to maternal immune activation (MIA), which impacts brain and behavioral development in offspring and increases the risk of autism, schizophrenia and other neurodevelopmental disorders. However, this task is complex due to the multitude of biomarkers and clustered or repeatedly measured outcomes over time and brain regions. Current statistical tools available are inadequate for handling the complexities of such data, thus impeding the progress of precision medicine. To address this significant gap, this proposal underscores the urgent need for innovative statistical methodologies that can adeptly handle the complexity of clustered and longitudinal datasets with numerous covariates, thereby advancing the field of precision medicine. By developing novel methods building on our preliminary statistical framework, integrating machine learning techniques, rigorously evaluating these methods through simulation studies that mimic real data, and applying these methodologies to real-world longitudinal and clustered datasets, we aim to make significant contributions to this field. Our preliminary simulation results and real-world examples demonstrate both the scientific merit and computational feasibility of these methods. We will apply these newly developed statistical tools to existing datasets as a proof-of-concept to uncover factors that predict susceptibility and resilience to MIA regarding the brain and behavior development outcomes in offspring. The innovative statistical methods developed hold significant promise for identifying biomarkers that elucidate the link between environmental exposure during human pregnancy and brain mechanisms associated with neurodevelopmental disorders. This advancement will assist in identifying high- risk pregnancies and tailoring interventions for offspring at risk due to MIA exposure. Furthermore, these innovative statistical approaches can be adapted to various interventions and a wide range of medical conditions. We will provide free, user-friendly programs and software to enable research communities to apply these methods easily. Consequently, this project presents a unique opportunity to tackle a complex issue in precision medicine and leverage existing datasets for groundbreaking insights.

NIA - National Institute on Aging

Abstract Over half of people living with HIV in the U.S. are now 50 or older, and this number is projected to increase to 70% by 2030. Aging with HIV presents a unique array of physical and mental health challenges. High prevalence of cardiovascular risk factors (e.g., obesity, dyslipidemia, hypertriglyceridemia, vascular dysfunction) and worsened mental health increase vulnerability to cardiovascular disease (CVD), depression and anxiety. Therefore, innovative, evidence-based interventions are needed to address the realities of aging with HIV and offer timely, practical solutions for improving physical, mental, and HIV-related outcomes. In the proposed study, 180 older adults with HIV age 50+ with documented cardiovascular risk will be randomized to either: (a) the Happy Older People are Engaged (HOPE) health promotion intervention (n=90) or (b) psychoeducation control (n=90). Assessment of cardiovascular risk, mental health, and HIV-related outcomes will be obtained at baseline, post intervention, 6-, and 12-months post intervention. The study has three specific aims: (1) to compare the efficacy of HOPE and the psychoeducation control in reducing cardiovascular risk among older adults with HIV with documented risk of cardiovascular disease; (2) to compare the efficacy of HOPE and the psychoeducation control in improving mental health and HIV-related outcomes in older adults with HIV; and (3) to examine mediators whereby HOPE reduces cardiovascular risk and improves mental health and HIV-related outcomes. Aims 1 and 2 will be tested separately using a Generalized Linear Mixed Model for main effects of group, time, and time-by-treatment interaction as the primary analytic strategy. For Aim 3, SEM will be applied to test mediation. As an exploratory aim, our team will explore CHW and decisionmaker perspectives on potential operational barriers and facilitators to the future implementation and dissemination of HOPE. Such data will yield useful information regarding future implementation of HOPE and related health promotion interventions. The proposed study will increase our understanding of the impact of HIV on older adults and has the potential to improve approaches for managing HIV-related comorbidities.

National Institutes of Health

Purpose. The purpose of this program announcement is to encourage applications that evaluate the efficacy of stress management interventions on intermediate outcomes purported to be in the biological or behavioral mechanistic pathway through which mental stress (MS) is thought to influence major adverse cardiac events (MACE) in patients with confirmed coronary artery disease (CAD). These include subclinical measures of atherosclerosis, measures of cardiac or endothelial function, or measures such as cardiovascular reactivity or neurohumoral response to a provocative mental stress test. The ultimate goal is to determine whether stress management interventions can slow progression of CAD or reduce MACE and, if so, to translate effective stress management interventions to clinical practice.

NIDA - National Institute on Drug Abuse

Homelessness and housing instability represent critical public health challenges in the US with more than 650,000 people experiencing homelessness (PEH) nightly. PEH experience differential health effects across various conditions, including chronic disease, substance use, and HIV, compared to their housed counterparts. An astounding 65% of PEH report having used illicit drugs regularly in their lifetime with 37% reporting regular drug use in previous 6 months. Homelessness and illicit substance use, in isolation and in combination, continue to be significant drivers of poor HIV outcomes and are highlighted as key priority targets under the Ending the HIV Epidemic (EHE) Initiative. EHE has identified evidence-based interventions, including rapid HIV testing, antiretroviral therapy (ART), low barrier clinics, and PrEP that need to be implemented, scaled, and sustained within communities most affected by HIV. To maximize the effectiveness of these interventions among PEH who use drugs and to address the HIV, overdose and homelessness syndemic, comprehensive healthcare models need to be developed, tested, and deployed where they are in comfortable environments that simultaneously address a key driver of HIV, namely untreated substance use disorders (SUD). The HIV Medicine Association has called for the scale-up of street medicine (delivering health services directly to unsheltered individuals where they are), counseling and differentiated service delivery to end the HIV epidemic. We developed, refined, and pilot tested Status Neutral Tele-Health ConcieRge (SN-THR), a telehealth-based, multicomponent care model originally designed for people with who inject drugs (PWID) with HIV then adapted it to include PWID without HIV for prevention via PrEP and MOUD. We hypothesize that SN-THR will increase access to HIV care (testing, prevention, treatment), SUD services, and mental health services through telehealth to augment street-based primary care (i.e. street medicine). We propose to test the efficacy, cost-effectiveness, and implementation of an innovative integrated HIV, addiction, and primary care model—SN-THR—in a street-based setting using a hybrid type I effectiveness-implementation approach. The specific aims are 1) Evaluate the efficacy of SN-THR vs. standard of care (patient navigation to off-site clinic) on HIV treatment and prevention adherence; 2) Perform an economic evaluation of SN-THR and estimate the cost-effectiveness of SN-THR; and 3) Assess the drivers of SN-THR implementation and their impact on implementation outcomes. We hypothesize that more participants in the SN-THR intervention condition will be adherent to ART for treatment or prevention than those in the control condition across 12-month follow-up This application is directly responsive to the priorities of NIDA’s RFA-DA-25-072 by testing a novel telehealth-based, status-neutral care model for integrating HIV and SUD services into street-based primary care for PEH who use drugs.

NIMH - National Institute of Mental Health

ABSTRACT Serotonin Type 3 Receptors (5-HT3Rs) are a subfamily of cationic pentameric ligand-gated ion channels (pLGICs) that play a critical role in gut-brain signaling. 5-HT3R pathophysiology is associated with neuropsychiatric conditions, including major depressive disorder (MDD). Previous studies have shown that antagonism of the 5-HT3R family has been implicated in the role of current antidepressant therapies such as mirtazapine (MTZ). The 5-HT3R family has five types of subunits (A-E), which influence the molecular binding and activation properties of the receptor. 5-HT3ABR is the only receptor subtype demonstrating tissue-specific expression within the brain. Animal studies have shown that the inhibition of the 5-HT3ABR has beneficial effects on mood and anxiety disorders. Despite the role that 5-HT3Rs play in MDD, there is little structural information on 5-HT3ABR and how antidepressants modulate 5-HT3Rs. As a result, 5-HT3Rs present an appealing target for novel antidepressant drug development. The overall goal of this study is to characterize the mechanistic details through which antidepressants modulate 5-HT3R activation across different subtypes. The proposal has two aims designed to address this deficit. Aim 1 will focus on determining the molecular mechanism by which MTZ inhibits 5-HT3AR. Utilizing a full-length m5-HT3AR construct, high-resolution MTZ-bound cryogenic electron microscopy (cryo-EM) structures will be determined with and without 5-HT. Based on this structural insight, site-directed mutagenesis and two-electrode voltage clamp (TEVC) electrophysiology will be used to assess the interactions necessary for MTZ binding. Residues involved in 5-HT binding are not present within the 5-HT3B subunit; therefore, aim 2 seeks to determine the key interactions required for MTZ and 5-HT binding. Aim 2 will address this by determining high-resolution cryo-EM structures of apo-5-HT3ABR and MTZ-bound 5-HT3ABR in the presence of 5-HT. Electrophysiology will be used to probe the role of each key amino acid and will be assessed for its effect on 5-HT3ABR activation. The results of this work will elucidate key interactions required for MTZ binding and highlight how antidepressants modulate different 5-HT3R subtypes. Overall, these studies will provide a deeper understanding of the role of 5-HT3R in the treatment of MDD. Finally, this work will lay the foundation for future drug development targeting 5-HT3Rs.

NINR - National Institute of Nursing Research

Project Summary In the United States, women are twice as likely to report depression and anxiety than men, and face stressors related to interlocking systems of oppression such as racism, sexism, and xenophobia. Interlocking systems of oppression can exacerbate inequalities in mental health by manifesting an unequal distribution of women’s resources and result in symptoms of depression and anxiety like exhaustion, hopelessness, and loss of interest. Despite the growing recognition of the mental health impacts of systems of oppression, several studies have analyzed this relationship at the individual-level, and not the structural or policy-level. Political intersectionality focuses on how policies and laws enact unfair practices against intersectional groups and subdue their rights. Policies related to structural gendered racism may shape the inequitable allocation of women’s social, economic, and political resources across racial, ethnic, and nativity groups, which may put racially and ethnically minoritized women at risk for depression and anxiety. The objective of this R01 grant proposal is to use novel theoretical frameworks and methodologies to examine how structural gendered racism-related policies impact depression and anxiety through intersectional social-structural factors among US- and foreign-born Black, Latina, and white women. This proposal will also aim to identify the best strategies to enhance adoption of supportive policies, and de-implement harmful policies that perpetuate systemic inequities. Informed by Intersectionality, Constrained Choice theory, and a policy implementation science, we propose a sequential explanatory mixed methods study with US- and foreign-born Black, Latina, and white women, and policy stakeholders. Aim 1 examines the direct and indirect relationships between structural gendered racism-related policies, intersectional social-structural factors, depression and anxiety among US- and foreign-born Black, Latina, and white women. Population-based data of adult women’s depression and anxiety from the National Health Interview Survey will be linked to state structural gendered racism-related policies, and an existing structural sexism and racism index of state social, economic, and political data from publicly available administrative sources. Aim 2 includes conducting focus groups with US- and foreign-born Black, Latina, and white women to explicate quantitative findings and identifying unanticipated themes. Aim 3 includes integrating findings from Aims 1 and 2 to systematically develop policy implementation strategies using a three-round Delphi method approach with US- and foreign-born Black, Latina, and white women, and policy stakeholders. This proposal responds to RFA-NR-25-004 by analyzing “relevant policies that reinforce intersectional social-structural factors and identify social-structural interventions to improve mental health.”

NIMH - National Institute of Mental Health

The overarching goal of this collaborative program is to understand how circuits in the mammalian brain are reorganized to encode new memories. We address this problem through detailed reconstruction of neuronal connectomes, single synapses, and glia at nanometer resolution using 3D Electron Microscopy (3D-EM). We combine 3D-EM with chemogenetic techniques for labeling cellular ensembles recruited for specific cognitive tasks and Artificial Intelligence (AI)-based computational tools for image segmentation. Using this interdisciplinary approach, we began to identify the morphological hallmarks of long-term associative memory in the mouse hippocampus. Our recent studies of the canonical CA3-CA1 pathway revealed principles by which pyramidal glutamatergic neurons (PNs) engaged during fear learning modify their local wiring diagrams, synaptic weights, and membrane organelles essential for energy metabolism and intracellular calcium buffering. Despite their broad physiological implications, these structural correlates of information storage share three features: (1) Their induction requires presynaptic activity elicited by sensory stimuli with negative valence; (2) Their manifestation transcends co-activated neurons; and (3) They involve multi-synaptic boutons (MSBs), atypical connections capable of simultaneously relaying neurotransmitter signals from one axonal terminal to several independent dendritic spines. Contrary to common dogma, we found that the initial cellular substrates of memory traces expand their connectivity via MSBs, thereby recruiting new neurons into the network while preserving the stable arrangements of individual synaptic sites on axons and dendrites. Taken together, these observations support the hypothesis that MSBs are pivotal for memory storage and that the structural plasticity of neural ensembles representing engrams does not adhere to traditional Hebbian rules. Our studies provide the first mechanistic explanation for representational drifts, a non-Hebbian phenomenon suggesting that population coding of a particular experience is not fixed over time. We will test out central hypotheses in the following specific aims: Aim 1. Investigate the spatiotemporal dynamics of non-Hebbian network remodeling via MSBs. We will determine if the synaptic architectures of an associative memory engram are reconfigured through MSBs globally or in a circuit-specific manner and will investigate the temporal dynamics of this process. Aim 2. Explore the physiological mechanisms of MSB morphogenesis. We will determine how the organization of MSBs reflects memory strength and will test if MSB morphogenesis is regulated by de novo protein synthesis, transcription, and synaptic activity. Aim 3. Define the composition of MSBs and their local microenvironment. We will comprehensively dissect the fine-scale architecture of MSBs and their postsynaptic partners. These analyses will involve reconstructions of active zones, PSDs, vesicles, other intracellular membrane organelles, astrocytes, and microglia.

NIMH - National Institute of Mental Health

Abstract Suicide remains a leading public health crisis, claiming over 49,000 lives in 2022. Among college-aged individuals, suicide is the second leading cause of death, with studies indicating that 6.4% of students develop new-onset suicidal ideation, exceeding rates seen in the general population. To address this, researchers increasingly utilize technological tools for real-time suicide risk assessment. While these tools enhance risk detection, they also introduce ethical challenges, particularly in balancing participant safety with scientific validity. Existing protocols for managing suicide risk in research lack empirical validation, creating inconsistencies that delay studies and hinder progress. The proposed study, Structuring Appropriate and Feasible Evaluations of Risk (SAFER), aims to address this gap by developing evidence-based suicide risk management protocols. SAFER will incorporate perspectives from students with lived experience and suicidologists to create and evaluate risk assessment and intervention protocols. The project has three primary aims: (1) examining stakeholder views on the acceptability of suicide risk management protocols, (2) evaluating the effects of different protocols on participant safety, and (3) assessing their impact on data validity. Aim 1 will develop a stakeholder panel consisting of ~16 students with lived experience and ~16 suicidologists. Semi-structured interviews will be conducted until saturation is reached. Aim 2 will assess the perceived acceptability and effectiveness of various suicide risk management protocols among high-risk college students (n=30) and suicidologists (n=10). Participants will evaluate different risk response strategies, including variations in outreach, safety measures, and resource provision. Aim 3 will test the impact of different levels of research personnel outreach on reports of suicidal ideation and behaviors. A cohort of 50 students at risk for suicide will complete daily assessments. Responses will trigger stratified interventions, ranging from automated resource reminders to direct outreach by research staff. Participants will evaluate the acceptability of these interventions at the study’s conclusion. This project will generate empirical data to refine ethical guidelines for suicide risk management, ensuring they are both protective and conducive to research integrity. By balancing participant safety with scientific feasibility, SAFER will provide scalable, evidence-based risk management strategies applicable to diverse research settings. These findings will contribute to national efforts in bioethics, aligning with the Belmont Report principles while addressing critical gaps in suicide research methodologies.

NINR - National Institute of Nursing Research

PROJECT SUMMARY Heart failure affects million adults in the U.S., is associated with high mortality, and is a leading cause for hospitalizations. The long-term objective of this project is to understand the impact of an existing, trauma- informed, community-based, nurse-led heart failure disease management program that provides care to heart failure patients with adverse social determinants of health and unmet social needs (poverty, unstable housing, substance use, mental illness). The Community Heart Failure Program (CHFP) is operated out of a safety-net hospital in the Pacific Northwest and delivers an innovative model of care, where staff provide clinical care in the location of the patient’s choosing, often a shelter, tent, apartment, or other non-clinic-based location. Point- of-care labs and ultrasound support clinical decision-making. Using trauma-informed care principles, including safety, trustworthiness, collaboration, empowerment, and choice, the CHFP and this research project were designed to engage patients with adverse social determinants of health and unmet social needs. This project advances health equity by removing barriers to high quality clinical care and clinical research participation. The short-term objective of this project is to establish feasibility of research study protocols that were designed to evaluate the impact of this innovative existing program. The proposed study is a prospective, longitudinal design (N=40). The specific aims of this project are to: 1) evaluate feasibility of research protocols, 2) compare healthcare utilization 6 months pre- and post-CHFP enrollment, and 3) compare guideline-directed medical therapy (GDMT), biomarkers, and patient-reported outcomes (PROs) at baseline and 3- and 6-months post-enrollment, and 4) examine associations between CHFP conceptual model key components (trust/relationship building, shared-decision making, care coordination, harm reduction) and outcomes (healthcare utilization, GDMT, biomarkers, and PROs). Descriptive statistics will be used for Aim 1. For Aim 2 and 3, paired t-tests (or Wilcoxon signed-rank test) will be used to compare outcomes pre- and post- enrollment, and effect sizes will be calculated to inform future intervention studies in this patient population. For aim 4, correlations (continuous variables) and chi-squared (categorical variables) will be used to examine the direction and strength of associations between key components of the conceptual model and model outcomes, in addition to multivariate regression to determine the independent effect of key components on outcomes. The goals of this project align with the strategic mission of the National Institute of Nursing Research to prioritize research that advances health equity by removing barriers to research participation, optimizes health for individuals and communities, and addresses pressing health challenges.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Juvenile idiopathic arthritis (JIA) is a chronic illness involving complex treatment plans with varying benefits and risks. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry collects extensive clinical and patient-/parent-reported data on over 12,000 North American children with JIA. However, the Registry lacks data on healthcare utilization, medication dispensing, and patients who do not consent, limiting its utility. Claims databases are large population-based datasets that permit study of large populations, rare diseases, and wide range of outcomes. However, claims data lack potentially critical clinical measures such as disease activity and patient-/parent-reported outcomes. To address these gaps and facilitate future observational and interventional clinical studies, we will perform the Study to Probe & Appraise Registry-Claims Linkage for Juvenile Idiopathic Arthritis (SPARCLe-JIA). This study aims to assess CARRA Registry data linked with the Komodo national claims database (>50,000 children and youth diagnosed with JIA). This linked dataset will allow for a comprehensive evaluation of the Registry's data coverage, consistency, and utility for conducting rigorous and broadly applicable research on JIA. The specific aims are: 1) to compare the characteristics of linked versus unlinked patients with JIA within the Registry and claims data; 2) to compare rates of uveitis and hospitalizations across datasets and evaluate whether use of linked data results in greater validity for an applied question on tumor necrosis factor inhibitors and hospitalized infection; and 3) to investigate how delays in biologic drug dispensing affect subsequent disease activity—a proof-of-concept study that can only be done using linked Registry and claims data. SPARCLe-JIA employs advanced analytical approaches to address critical gaps in pediatric rheumatology research by testing a novel and powerful resource for JIA research. The validation of this linkage between Registry and claims data will set a new standard in the field, providing a model that can readily be applied to other pediatric rheumatic diseases captured by the CARRA Registry, including systemic lupus erythematosus and juvenile dermatomyositis. The linked dataset will enable a wide variety of future investigations, including studies on risk factors, outcomes, healthcare utilization, comparative effectiveness, drug safety, biomarkers, adherence, deprescribing, mental health, and the transition from pediatric to adult rheumatology care, thereby improving JIA management and informing clinical and policy decisions. Through these aims, SPARCLe-JIA will enhance the utility of the CARRA Registry for future observational and interventional studies that will ultimately improve the management, monitoring, and outcomes of people with JIA and other pediatric rheumatic diseases.

NIMH - National Institute of Mental Health

PROJECT TITLE Suicidal Thoughts and Behaviors Among Youth Victims of Human Trafficking PROJECT SUMMARY / ABSTRACT Youth suicide is a significant public health concern in the United States. One population found to have higher rates of suicidal behavior are youth victims of human trafficking, a crime involving the exploitation of a person under the age of 18 for labor, services, or commercial sex. Minimal consideration has been given to the risk for suicide in youth victims of human trafficking. The few identified studies show up to 75% of youth victims of human trafficking endorsed lifetime suicide ideation and between 40% to 50% reported past suicide attempts. Evidence further suggests youth victims of human trafficking experience high rates of unmet physical and mental health needs, and that most health care providers are ill equipped to recognize and respond to these youth. The development of suicide prevention strategies tailored for youth victims of human trafficking is hampered by the limited evidence regarding risk in these highly vulnerable youth. Even less is known about successful approaches to implement these strategies. Victims of human trafficking represent an important understudied youth population that merits attention in the suicide prevention research. This proposed retrospective cohort study will uniquely identify characteristics (individual, familial, community) and clinical factors (mental health history, physical health conditions, health service utilization) that contribute to the risk for suicide among youth victims of human trafficking presenting to a juvenile court. Several states have implemented “Safe Harbor” laws that aim to avoid arrest and prosecution of trafficking victims, however many of these victims still find themselves involved with the legal system. Utilizing a mixed methods approach, this proposal will reinforce the interpretation of quantitative findings with data from key stakeholder interviews to gain additional insight on suicide risk in this youth population and to better inform targeted interventions. Consideration will be given to potential facilitators and barriers to intervention with youth human trafficking victims, including when, how, and where to intervene. This innovative study is the first to examine the complex array of factors linked to suicide risk in youth trafficking victims and to consider a systematic approach for translating these findings into tailored suicide prevention strategies for this high- risk population. The rationale for this research is that an improved understanding of youth victims of human trafficking at elevated risk for suicide is crucial to advance preventative interventions and reduce youth suicide.

NIH

BACKGROUND: Suicide is a chief concern in Veterans, particularly following a mental health stay. The Department of Veterans Affairs (VA) has invested heavily in strategies to prevent suicide in Veterans who are at risk of suicide following a Veterans Health Administration (VHA) mental health stay. These interventions, however, do not reach another high-risk population, namely Veterans who access VA-purchased care in the community (i.e., Community Care). This is particularly concerning because an increasing number of Veterans are using VA-purchased care. While Veterans are at high risk of suicide following a Community Care mental health stay, there is little knowledge about effective strategies to mitigate suicide risk in this population. A promising suicide prevention strategy, called the VA Brief Intervention and Contact Program (BIC), has been developed. VA BIC is designed to meet the unique needs of Veterans. Pilot studies of VA BIC in VHA settings have suggested that VA BIC may address key factors related to suicide risk during care transitions including social connectedness and treatment engagement. Based on these promising results and given the critical gaps in suicide prevention care in Veterans who are psychiatrically hospitalized in Community Care settings, it is essential to determine whether VA BIC can reduce suicide risk in this high-risk population. OBJECTIVES: The long-term goal is to design, study, and improve interventions to prevent death by suicide in Veterans. The overall objective of this proposed clinical trial is to determine whether the VA BIC intervention is an effective strategy to reduce suicide risk in Veterans who are admitted to Community Care mental health units. The short-term goal is to test whether the VA BIC intervention can decrease suicidal ideation after a Community Care mental health stay and increase [engagement in mental health care and social connectedness.] The central hypothesis is that VA BIC will [decrease suicidal ideation after discharge] as compared to treatment as usual (TAU). It is hypothesized that VA BIC will [increase engagement in mental health care and social connectedness after discharge] as compared to TAU. The expected outcome of the trial is to ascertain the efficacy of VA BIC in decreasing suicidal ideation and [increasing engagement in mental health care and social connectedness] following a Community Care mental health stay. The trial will inform the design of a future Cooperative Studies Program (CSP) multi-site trial that is powered to test the effect of VA BIC on suicide attempts in Veterans with a psychiatric hospitalization in a Community Care facility. METHODS: A randomized controlled trial of VA BIC will be carried out in Veterans who are psychiatrically hospitalized at Community Care hospitals located in [Northern] New England. Eligible Veterans will be recruited over a three-year timeframe and will be randomized to VA BIC plus TAU, or TAU alone. Participants will be followed for a total of [nine] months. Outcomes will be gathered at baseline and at [3, 6, and 9] months [post baseline.] [A generalized linear mixed model (GLMM)] will be used to determine whether VA BIC results in a significant decrease] in suicidal ideation. A GLMM will [also] be used to learn whether VA BIC results in a significant [increase] in [engagement in mental health care and social connectedness]. An exploratory analysis will examine the effect of VA BIC on suicide attempts. IMPACT: Little is known about effective strategies to prevent suicide in Veterans who are treated in Community Care settings. This proposal will address this concerning knowledge gap by testing a highly promising suicide prevention strategy in Veterans who are psychiatrically hospitalized in Community Care hospitals. The results of the trial will not only determine the impact of VA BIC on suicide risk in this population but also lead to a future CSP trial that is powered to detect the effect of VA BIC on suicide attempts. In the end, the proposal trial will enable the VA to identify a highly effective intervention to prevent suicide in a vulnerable Veteran population that may have little or no interaction with VA providers during a chief period of risk.

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

ABSTRACT Unhealthy and problematic use of technology and digital media (TDM) in childhood and adolescence have increased in prevalence over the past 20 years, with negative consequences for sleep, physical activity, in- person socializing, emotional health, and family relationships. However, interventional research is a major gap in the literature; no evidence-based approaches exist to support healthy TDM use in children. This proposal is conceptually grounded in the Interactional Theory of Child Problematic Media use, which posits that drivers of unhealthy TDM use include: 1) psychosocial factors such as family stress, 2) parent-child factors such as mood dysregulation, parenting self-efficacy, and maladaptive coping, and 3) technology factors such as engagement-prolonging design. Therefore the proposed randomized controlled trial will test two interventional components: Problem-Solving Education (PSE), an evidence-based cognitive-behavioral strategy that teaches parents problem solving skills as a means of managing parental stress, increasing self-efficacy and adaptive coping, and following through on goals; and TDM Settings assistance to enable parental controls on screen time, content, contacts, and reducing engagement-prolonging designs. These approaches leverage the expertise of the MPIs: Dr. Radesky is co-Medical Director of the American Academy of Pediatrics (AAP) Center of Excellence on Social Media and Youth Mental Health, through which she has created resources and guidance for healthy TDM use in families, while Dr. Kistin is an expert in community-based interventions to support problem-solving, self-efficacy, and positive parenting in stressed families. The application proposes to conduct a type 1 hybrid 2 x 2 randomized controlled trial design in 300 school-aged children (ages 6-10 years) and their parents, a developmental window when many children receive their first gaming console and/or mobile device, but parents still have some degree of control over TDM use. Parent-child dyads (N=300) will be randomized to the following study arms: 1) PSE only; 2) TDM Settings only; 3) PSE+TDM Settings; or 4) Control (AAP resources). Families will be followed for 4 months to assess the following Specific Aims: SA1) Primary outcomes: Test the effects of PSE alone, TDM Settings alone, and combined PSE+TDM Settings versus control on child mood dysregulation (externalizing/internalizing behaviors) and problematic media use symptoms. SA2) Secondary outcomes: Test the effects of PSE alone, TDM Settings alone, and combined PSE+TDM Settings versus control on child daily TDM duration, use of age-inappropriate content, bedtime media use, parent-child communication about media, and parent stress. SA2a) Exploratory outcomes: Measure intervention effects on the frequency of children’s in-person socializing, outdoor play, alternative activities, and positive family routines. SA3) Dissemination and implementation: Using the RE-AIM framework, evaluate intervention reach, adoption, fidelity, and other factors that impact future dissemination and sustainability in pediatric settings.

NIDCD - National Institute on Deafness and Other Communication Disorders

PROJECT SUMMARY The purpose of this Mentored Patient-Oriented Research Career Development Award application is to prepare Brittany Manning, PhD, CCC-SLP, for a career as an independent clinician-scientist with expertise in implementation science. The proposal includes specialized activities, mentorship, and research to support training in (1) community-engaged, co-design methods, (2) clinical trials of early language intervention, and (3) embedded implementation science frameworks. With specialized training in implementation science, Dr. Manning will build on her expertise in the intersection of early language delays and mental health vulnerabilities to adapt and implement interventions to support the complex needs of real-life children with language delays/disorders. Children with language delays are twice as likely to display elevated levels of irritability as their non-language-delayed peers. Elevated child irritability (i.e. a low threshold for frustration and disruptive behaviors) makes it difficult for speech-language pathologists (SLPs) to engage children in language facilitating interactions in intervention sessions. Evidence-based emotion/behavior management techniques are effective in reducing child irritability. However, despite adaptations for other settings (home, school) and implementers (parents, teachers), evidence-based emotion/behavior management techniques and training materials have not been adapted with early language intervention in mind. Thus, the objective of this research proposal is to create SKILL: Supporting Kids with Irritability in Language Learning, an intervention package of adapted emotion/behavior management techniques for early language intervention and a brief, online training for SLPs. Equipping SLPs with evidence-based irritability management techniques is critical for supporting language learning during early language intervention sessions. The research project will pursue the following aims: (1) Using a community-engaged, co-design process, adapt evidence-based emotion/behavior management for early language intervention with iterative input from SLPs, mental health clinicians, and parents; (2) conduct a pilot hybrid effectiveness-implementation type 1 trial to examine the feasibility/acceptability/preliminary effectiveness of SKILL in improving early language intervention outcomes; (3) elucidate barriers/facilitators and implementation strategies to support SKILL’s uptake. Results from the pilot study will inform the optimization of SKILL and the design of subsequent, fully powered hybrid effectiveness-implementation type 1 trial submitted under an R01 mechanism. This work has the potential to improve care for a substantial portion of children with language delays/disorders, improve SLP confidence and satisfaction in working with children with complex needs, and advance implementation science in the field of Communication Disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT We propose to broadly disseminate and extend intuitive, powerful cloud-based resources for optical brain mapping that facilitate efficient, accurate, and standardized processing that will harmonize the emerging set of optical measurement strategies within the growing ecosystem of network level analyses used throughout the greater brain mapping community. The neuroimaging community faces numerous challenges in data collection, preprocessing, estimation of brain connectivity, and analyses of relationships between brain connectivity and behavior. An ever-expanding community of researchers are employing optical methods based on functional near infrared spectroscopy (fNIRS) in order to infer pathophysiological states of the brain for detection/ characterization of disease or cerebral hemodynamics for understanding human brain health, development, and aging. Recent developments of high-density diffuse optical tomography (HD-DOT), a silent, flexible, and scalable technology have demonstrated dramatically improved anatomical specificity and image quality over traditional fNIRS. Further, recent developments in wearable HD-DOT, even using frequency domain and time resolved strategies, open the door to unconstrained mapping of naturalistic human brain function with superior image quality than previously possible. Given the growing worldwide adoption of fNIRS and HD-DOT methods and further developments of next-generation optical brain mapping methods via the BRAIN Initiative, there is an urgent and present need for standardized, accessible and flexible tools that directly support workflows from optical tissue parameter recovery to functional brain mapping to relating variance in brain function to behavior and outcome. Our team is funded by U24NS136402 to address these needs in the optical brain mapping community by developing and validating computational tools including NIRFASTer, NeuroDOT, and Network Level Analyses (NLA), for tissue parameter recovery, optical brain mapping, and model-based connectome-wide association studies of brain function and behavior, respectively. We address the unmet needs for data resources with: (1) greater dissemination and training for our tools with detailed documentation, training materials, and international workshops, (2) cloud deployment of our software to increase scale and accessibility, while easing the computational burden for the user, and (3) expanded utility of these sustainable, flexible tools to meet the evolving needs of users at the forefront of optical imaging technology development. This R50 will support a Research Software Engineer (RSE) to be an established senior RSE through gaining deeper experience expanding development, maintenance, and dissemination of the U24-supported tools while enhancing her skills and knowledge of best software engineering practices, FAIR standards, and optical neuroimaging methods, as well as common and emerging neuroimaging algorithms. This proposal directly supports execution of BRAIN Initiative goal 7 that seeks to integrate new technological and conceptual approaches to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease.

NIMH - National Institute of Mental Health

Project Summary/Abstract Parvalbumin-expressing inhibitory interneurons (PVs) are linchpins of synchronized neural computation. They are specialized to provide rapid perisomatic inhibition onto excitatory neurons (ENs) and are the primary source of inhibitory control in hippocampal CA1 – a region critical to learning and memory. PV dysfunction, circuit hyperactivity, and cognitive impairment are hallmark features of schizophrenia and are also observed in animal models with targeted deletion of glutamate receptors in PVs, implicating disrupted glutamatergic input onto PVs as a potential contributor to the disorder. While the underlying mechanisms remain unclear, the onset of schizophrenia in late adolescence suggests circuit instability may result from a gradual deterioration of PV synapse stability. Decades of research support a continuum of mechanisms at different spatial scales, from individual synapses to the network-level, through which activity homeostasis is achieved in ENs. While numerous studies have shown that PVs are plastic in learning-related contexts, how their synaptic inputs remodel following chronic alterations in network activity is not well understood. Similarly, homeostatic plasticity, of individual synapses on INs has not been explored in vivo and the mechanisms that allow PVs to preserve stability under circuit challenge remain poorly understood. This proposal will utilize a combination of high-resolution confocal imaging, circuit mapping techniques and electrophysiology to test the hypothesis that PV homeostatic remodeling helps maintain stable circuit behavior in the face of network challenge. In Aim 1, I will examine how glutamatergic synapses onto PVs structurally and functionally respond to chronic changes in circuit activity. Aim 2 then investigates the PV-enriched NMDA receptor subunit GluN2D, a schizophrenia risk gene, as a potential mechanism enabling PVs to sense changes in local activity and initiate compensatory responses. Together successful completion of the proposed experiments may help identify entry points for addressing an unmet need in restoring excitation onto PVs in conditions characterized by PV hypofunction such as schizophrenia, epilepsy, and autism. Through this proposal, I will be thoroughly trained in molecular biology, circuit-mapping, electrophysiology and genetic perturbation strategies. In addition, mentorship from Dr. Bygrave and co-sponsor Dr. Dulla will provide an environment with exceptional guidance and rigorous training, access to all necessary equipment, and opportunities for networking, mentorship, and career development activities. Collectively, this proposal will provide me with the scientific training and growth necessary for establishing the foundations for a future successful career as an independent academic scientist.

NIMH - National Institute of Mental Health

Abstract 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion in humans, with an incidence of ~1/4000 live births. Symptoms associated with 22q11.2DS are broad and unpredictable, ranging from cardiac defects to cognitive deficits and increased risk of schizophrenia. 22q11.2DS patients commonly experience learning delays and deficits in working memory, which have lifelong quality of life impacts. Notably, using a recently developed full deletion mouse model of 22q11.2DS, our lab has discovered dramatic deficits in synaptic structural plasticity in the hippocampal CA1 region. Our central hypothesis is that the learning and memory deficits of 22q11.2DS 22q patients are due to profound alterations to glutamatergic synaptic plasticity and signaling in the hippocampus. To test this hypothesis, we will investigate the synaptic signaling mechanisms (Aim 1) and single-cell gene expression profiles (Aim 2) underlying disruptions in plasticity of hippocampal CA1 neurons in 22q11.2DS model mice. Genome-wide sequencing suggests 22q11.2DS presents a threshold lowering effect for schizophrenia, and that the 22q deletion creates a vulnerable substrate for the manifestation of other schizophrenia risk factors. Perturbations in pathways that support synaptic structural plasticity likely contribute to this increased vulnerability to schizophrenia in 22q11.2DS patients. The proposed experiments will fill a gap in knowledge concerning the molecular and cellular mechanisms responsible for deficits in place memory and working memory associated with 22q11.2DS. Knowledge of these signaling pathways move us closer to developing therapeutics to manage the cognitive effects of this unpredictable and impactful disease.

NIMH - National Institute of Mental Health

ABSTRACT Synapses form trillions of connections between billions of neurons in the brain to establish neural circuits that allow us to sense, think, act, learn, and remember. Our goal is to understand how synapse structure supports learning and memory with a focus on dendritic spines, the tiny protrusions that host most of the excitatory synapses in the brain. While most neuroscientists agree that synaptic structural changes are vital for learning and memory, the cellular and molecular mechanisms that protect recent synaptic changes from being overwritten by ongoing plasticity remain ill-defined. Our three-dimensional reconstructions from serial section electron microscopy (3DEM) reveal distinct subregions of the postsynaptic density (PSD) where active zones (AZs) are associated with presynaptic vesicles and nascent zones (NZs) have no presynaptic vesicles. At the onset of long-term potentiation (LTP), presynaptic vesicles are rapidly recruited to the NZs, converting them to AZs. Protein filaments shorten and draw docked presynaptic vesicles closer to the enlarged AZs, and recruit vesicles to dock at weak AZs. This evidence of presynaptic plasticity would increase the area of release and probability of postsynaptic receptor response. The recovery interval following saturation of LTP is 1-4 hours depending on the preparation. During this interval, new NZs form, primarily on spines containing smooth endoplasmic reticulum, a local resource for regulating calcium and trafficking of lipids, proteins, and organelles. Clusters of spines form in the vicinity of these enlarged spines. We hypothesize that synapse-specific expansion of NZs during LTP provides a basis for learning and the advantage of spaced over massed learning to establish long- lasting memories. Furthermore, we hypothesize that LTD is driven by the conversion of AZs to NZs and ultimately elimination of spines without AZs. To address these hypotheses, we propose multidisciplinary approaches to investigate the cellular and molecular mechanisms that drive the conversion of NZ to AZ and limit plasticity at synapses—including slice physiology, optogenetics, molecular genetics and pharmacology, glutamate uncaging, and tomographic 3DEM of synapses along activated axons labeled with APEX. Our Specific Aims are: Aim 1) Determine the specificity of NZ to AZ conversion during synapse enlargement, resource utilization, and spine clustering underlying the saturation, recovery, and enhancement of LTP. Aim 2) Test whether saturating LTP at an isolated dendritic spine is sufficient to fill NZs and determine the role of PSD-MAGUK proteins and their interacting partners in recovery of LTP from saturation. Aim 3) Determine how the saturation and recovery of long-term depression (LTD) alters the structure of AZs, NZs, and spines, and influences the subsequent capacity for LTP. Outcomes promise new insights about synaptic mechanisms of learning and memory and new targets for understanding and treating learning disabilities.

NIMH - National Institute of Mental Health

PROJECT SUMMARY: This R21 proposal seeks to uncover how sleep and circadian rhythms (CR) regulate protein synthesis at neuronal synapses, key cellular sites for learning and memory, by defining the “synaptic translatome”: newly synthesized proteins localized at synapses. Sleep is essential for brain health and survival. Sleep need accumulates during wake and is resolved only by sleep. Although sleep behavior is governed by specific brain circuits, sleep need is distributed throughout the nervous system. Synapses are central to this distributed sleep need, as they undergo plastic changes during wake and are subsequently remodeled during sleep to support synaptic homeostasis, memory consolidation, and brain development. Synapses have thus emerged as a conserved and distributed 1. locus of sleep need, 2. target of restorative sleep function, and 3. site of dysfunction with sleep loss. Neurons rely on localized protein translation at synapses, far from the cell body, to support these plastic changes. The timing of this process is influenced by the circadian clock, a cellular mechanism involving “clock genes” that operate in nearly all cells. Previous multi-omic studies of purified forebrain synapses revealed that both CR and sleep need regulate the trafficking of mRNAs to synapses and the timing of their translation. Defining the synaptic translatome in response to wake/sleep states and circadian time is essential to revealing the biochemical basis of sleep’s restorative functions and its interactions with the CR. This research also addresses the intersection between sleep, synaptic development, and neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Disruption of sleep and circadian rhythms is a common feature in NDDs, and many NDD-associated genes encode synaptic proteins, such as SHANK3. Prior work using SHANK3+/- mice, a model for genetic vulnerbaility for ASD and SCZ, demonstrated that early life sleep disruption (ELSD, postnatal days 14–21) leads to persistent, sex-specific behavioral changes, highlighting an interaction between sleep, genetic vulnerability, and sex. Synapse-specific proteomic analysis in these mice showed that ELSD disrupts synapse maturation, particularly affecting protein synthesis and mRNA biology. To build on these findings, the proposal uses biorthogonal non- canonical amino acid tagging (BONCAT) to label newly synthesized proteins, combined our established synapse fractionation and quantitative proteomics to define the synaptic translatome. Aim 1 will characterize how the synaptic translatome is shaped by CR and sleep deprivation across development in juvenile, adolescent, and adult mice, across brain regions including cortex, hippocampus, and striatum. Aim 2 will determine how ELSD alters the synaptic translatome in wild-type and SHANK3+/- mice, to better understand how sleep disruption impacts synapse maturation in genetically vulnerable brains. This R21 will establish BONCAT as a powerful discovery platform to study synaptic protein synthesis in vivo, enabling novel insights into the mechanisms of sleep function, and how its disruption contributes to the etiology of neurodevelopmental disorders.

NIMHD - National Institute on Minority Health and Health Disparities

Revised Abstract Section ABSTRACT Sickle cell disease (SCD) is a chronic condition characterized by painful vaso-occlusive crises, fatigue, and frequent hospitalizations, which significantly impact mental health and quality of life. Depression affects 25– 35% of SCD patients, yet current screening tools, such as the Patient Health Questionnaire-9 (PHQ-9), fail to account for the overlap between somatic symptoms of depression and SCD-related physical symptoms. This leads to misclassification, resulting in inaccurate diagnoses and suboptimal treatment. This study aims to develop and validate a novel depression screening instrument tailored for SCD patients by empaneling a patient workgroup to conceptualize the depression experience among people with SCD and identify key symptom difference between depression and SCD-related distress (AIM 1); Modify the PHQ-9 screening tool by incorporating patient and clinician input to ensure accurate differentiation between depressive symptoms and SCD manifestations (AIM 2); and establish construct validity through psychometric analysis, including classical test theory and item response theory, to confirm internal consistency, test-retest reliability, and divergence from anxiety and PTSD measures (AIM 3). By addressing a critical gap in mental health screening for SCD patients, this study will improve diagnostic accuracy, enhance clinical decision-making, and reduce health disparities. The validated tool will facilitate appropriate mental health interventions, ultimately improving patient outcomes and quality of life.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Globally, there were 1.3 million new HIV infections in 2023, despite expanded access to biomedical HIV prevention products with high efficacy. Implementation strategies are needed to expand the reach of HIV risk screening and to facilitate the use of biomedical prevention among persons with risk. These implementation strategies are often delivered at the group-level or induce changes at the group-level (e.g., health clinics or health systems). Cluster randomized trials (CRTs) are integral to evaluating and optimizing strategies deployed at the group-level. CRTs provide an exciting opportunity to evaluate strategies aiming to both improve reach into the target population and health outcomes among persons reached. However, these CRTs create a complex missing data problem: the strategy improves outcomes directly and indirectly; yet, outcomes are only measured among persons reached. While machine learning can facilitate adjustment for missing data in simpler CRT settings, new methods are needed to minimize bias arising from this common CRT setting. CRTs also provide an exciting opportunity for intervention optimization by evaluating for whom and in what context the strategy works best. However, existing methods to evaluate effect heterogeneity in CRTs are prone to false conclusions (i.e., Type-I and Type-II errors). While machine learning can facilitate data-driven evaluation of effect modification in individually randomized trials, CRTs present distinct challenges due to their small effective sample sizes. In this proposal, we will address these crucial gaps in the analysis of CRTs. To do so, we will develop, apply, and disseminate new Targeted Machine Learning Estimators (TMLEs) to minimize bias due to missing data and to facilitate data-driven evaluation of effect modification. TMLE combines formal causal modeling, statistical theory, and machine learning to improve the accuracy, precision, and relevance of our findings. This proposal has the following aims. We will develop new TMLEs to minimize bias due to missing data and robustly evaluate overall effectiveness in CRTs of strategies that aim to improve both reach and health outcomes (Aim 1A). We will combine these TMLEs with novel sample-splitting and multiple testing procedures to data-adaptively identify and evaluate effect heterogeneity at multiple levels (Aim 1B). In secondary data analyses of two CRTs, we apply the proposed methods to generate new insights about the effectiveness and implementation of an HIV prevention strategy when offered at scale and when adapted to a new context (Aim 2). We will disseminate the proposed methods through a user-friendly and interactive website – facilitating the rigorous and reproducible use of our new methods (Aim 3). This work is timely and significant given the role of CRTs in evaluating and optimizing strategies to prevent HIV and other chronic conditions, such as hypertension, diabetes, and cardiovascular disease.

NIMH - National Institute of Mental Health

Project Abstract In recent years, the prevalence of depression has risen, and with it, the prescribing of serotonergic antidepressants. Approximately 13.2% of adults aged 18 and over report using antidepressant in the past 30 days. Anhedonia (loss of interest or pleasure in previously rewarding activities) is a common symptom of depression. First-line antidepressants, selective serotonin reuptake inhibitors (SSRIs), can effectively lift low mood, but often come at the cost of further blunting emotion and reward-processing. In contrast, psilocybin (a 5HT-2A psychedelic) has shown promise in alleviating anhedonia and improving emotional range, even outperforming SSRIs in head-to-head trials. Emerging clinical research supports the safety and efficacy psilocybin in individuals currently taking an SSRI, offering a promising new adjunctive treatment option for those experiencing residual anhedonia. Despite this potential, the neural mechanisms underlying psilocybin's therapeutic effects on anhedonia remain poorly understood. Parallel fronto-limbic circuits—connections between the medial prefrontal cortex (mPFC) and limbic system—regulate motivation and emotional response. One crucial circuit, connecting the pregenual anterior cingulate cortex (pgACC) and the nucleus accumbens (NAcc), forms the core of the brain’s reward system and is implicated in anhedonia. In anhedonia, activity and connectivity in this pgACC-NAcc circuit is suppressed. SSRIs may further suppress this circuit, leading to residual deficits in motivation and pleasure. This study will use a clinical trial to assess the effects of a single dose of psilocybin (25 mg single dose) or control (psilocybin 1mg) in individuals experiencing SSRI-induced anhedonia. We will utilize Precision Functional Mapping (PFM), a novel fMRI technique enabling individual-specific brain mapping, to investigate how psilocybin modulates fronto-limbic circuitry in individuals with SSRI-induced anhedonia. In addition to PFM, we will use well-validated task-fMRI (emotional processing, monetary incentive delay) to probe key fronto-limbic circuits. Then we will test the ability of psilocybin to engage reward circuitry relevant to anhedonia. This work will advance our mechanistic understanding of anhedonia, identify biomarkers for targeted treatment, and potentially lead to more effective therapies.