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NIMH - National Institute of Mental Health

Though bariatric surgery is the most effective and durable treatment for severe obesity, patients have a 4-fold increased risk for suicide compared to the general population. This is one of the highest adverse event rates reported following bariatric surgery, yet there has been little research to understand the etiology. The number of those undergoing bariatric surgery is rising and so we need to understand the unique reasons for increased suicide risk among this growing, at-risk population; otherwise, patients who undergo bariatric surgery remain at risk for suicide attempts and death. The purpose of the proposed study is to determine whether the bariatric surgery operation confers the increased suicide risk, investigate the times at which post-surgical risk is highest, identify factors associated with increased suicide risk, and understand perceptions regarding methods for suicide risk identification within health care systems. Our team of researchers are embedded in six health systems across the United States and are members of the Mental Health Research Network where data will be collected using a convergent mixed methods design. Quantitative data will be extracted from participating sites’ Virtual Data Warehouses, which store data from patients’ electronic health records, insurance claims, and government-reported official death records beginning in 2009. We will have more than 70,000 patients that have undergone bariatric surgery and these patients will be compared with a rigorously matched non-surgical cohort with severe obesity. Using the social-ecological suicide prevention model, we will examine unique factors after bariatric surgery that could explain increased risk including individual biological factors, individual psychiatric factors, societal factors, community factors, and interpersonal factors. Given that there are pharmacokinetic alterations of psychiatric medications after bariatric surgery, we will also explore the role of antidepressants. Patient interviews will be conducted to gain a deeper understanding of factors associated with suicide attempts after bariatric surgery beyond the available structured quantitative data. Patient and provider interviews will be utilized to understand optimal ways to identify and engage high-risk patients within health care systems. Our long-term goal is to prevent suicide attempts and death within health care systems. This project contains multiple innovative components that advances prior work on suicide after bariatric surgery including: access to a large, diverse and representative patient population; inclusion of a rigorously matched cohort; utilization of a mixed methods approach; longitudinal design; and use of machine learning to analyze these complex data. The proposed line of research is relevant to NIH’s mission because we will improve suicide risk identification following bariatric surgery. Results from this study would be significant and inform pre- and post-surgical monitoring of patients pursuing bariatric surgery. Findings will also lead to optimal methods of identifying and engaging at-risk patients in suicide prevention strategies within health care systems, which may also translate to other health care settings outside of bariatric surgery.

NIH

SIGNIFICANCE TO VA: In the past decade, the number of women Veterans of childbearing age using VA has nearly doubled, and over forty percent of these women have a diagnosis of serious mental illness (SMI; major depressive disorder, posttraumatic stress disorder, bipolar disorder, schizophrenia, other psychotic disorders). Veterans experience worse pregnancy and birth outcomes than civilians, a disparity largely attributed to their high burden of mental illness and trauma. Pregnant and postpartum Veterans with SMI—who often have numerous mental health, medical, and social challenges—are at high risk for perinatal exacerbation of mental illness, with consequences including maternal morbidity and mortality, poor functioning, and impaired child development. Reach Out, Stay Strong Essentials (ROSE), a brief evidence-based psychoeducational intervention for prevention of postpartum depression in women without mental illness, is being implemented in over two dozen VA facilities; feedback from ROSE implementers supports its use, but with noted limitations for Veterans with SMI. Building on lessons learned from ROSE implementation, I propose to develop and pilot ROSE+, a psychosocial intervention blending ROSE with peer support (i.e., support provided by Veteran peer specialists with personal experience of mental illness). Peer support is a key component of VA mental health care; while evidence exists for peer support in non-SMI perinatal and non-perinatal SMI populations, existing interventions are limited in applicability to the complex social, medical, and mental health needs of perinatal Veterans with SMI. ROSE+ will comprise adapted and combined components of ROSE and evidence-based perinatal and SMI peer support models, tailored to the VA context and the unique needs of perinatal Veterans with SMI. Developed in partnership with VA Office of Women’s Health and Office of Mental Health, this proposal aligns with key VA operations and HSR priorities including women’s health, mental health, maternal health, peer support, and Veteran engagement, and will fill a key gap in care for perinatal Veterans with SMI. INNOVATION & IMPACT: This research will not only set the foundation for the first perinatal mental health intervention for Veterans with SMI, but will also identify additional opportunities to strengthen VA perinatal mental health services and care coordination via an IIR submission in Year 3. SPECIFIC AIMS: 1) Engage Veterans and key VA clinical staff in identifying potential components of ROSE+; 2) Develop and refine the ROSE+ intervention; 3) Assess the feasibility, acceptability, and exploratory outcomes of ROSE+ in a pilot study. METHODOLOGY: Intervention development will be guided by the Transcreation Framework, an implementation science framework for community-partnered development of behavioral interventions for vulnerable populations. Aim 1: To assess the experiences, needs, and care preferences of perinatal Veterans with SMI and inform potential intervention components, I will conduct semi-structured interviews with pregnant and postpartum Veterans with SMI and VA women’s mental health providers, followed by focus groups with VA Maternity Care Coordinators and women VA peer specialists. Aim 2: Using Delphi methodology, I will present potential intervention components—drawn from existing interventions and accompanied by data from the literature and Aim 1 findings—to an expert panel of VA multilevel constituents to identify final components as well as adaptations to optimize fit to the target population and VA women’s health settings. I will then develop and refine the intervention prototype and materials with iterative feedback from partners and mentors. Aim 3: I will conduct a randomized feasibility pilot of ROSE+ compared to usual care including standard ROSE, with approximately 24 perinatal Veteran participants with SMI. The pilot will assess implementation outcomes, including acceptability and feasibility; feasibility of study processes including recruitment and randomization; and exploratory clinical outcomes. PATH TO TRANSLATION/IMPLEMENTATION: Results will inform a subsequent multisite efficacy study, for which I will seek independent VA funding in Year 5.

NIMH - National Institute of Mental Health

Autism research is facing a watershed moment that requires serious scientific investigation, similar to the debate in the early 2000s regarding the vaccines-cause-autism controversy. For the past five decades, behavioral approaches to early intervention have been the primary treatment mechanism for autism. These approaches are based on the principles of Applied Behavior Analysis (ABA) and have substantial research support demonstrating their effectiveness for improving communication, adaptive behavior, and cognitive skills. With the proliferation of the neurodiversity (ND) movement, autistic advocates and allies have called into question the safety, validity, and ethics of autism intervention. There is substantial variation in the concerns raised. The majority of these interventions were developed with the goal of ameliorating autistic characteristics or loss of diagnosis which is counter to autistic priorities. While many autistics endorse supports and/or services for promoting optimal quality of life, whether or not standard autism early intervention (EI) practices fit within that framework remains to be studied. Complicating matters is substantial variation in the implementation of EI in the community. Many community-based organizations (CBOs) deliver older, more rigid versions of EI models than are currently being studied and implemented by autism intervention researchers. Naturalistic developmental behavioral interventions (NDBIs) were developed to address previous limitations in EI models, though these are not well-utilized in CBOs. While some autistics support the adaptation of NDBIs to fit within a neurodiversity-affirming intervention (NAI) framework, others call for the cessation of intervention altogether. Disparate opinions coupled with limited data regarding advocates’ concerns have created a confusing landscape for caregivers who are pressured to make decisions regarding enrolling their newly diagnosed autistic children in EI services within developmentally critical periods. Additionally, autistic individuals are likely to suffer from a lack of fit of services to improve their quality of lives. The proposed projects will address these pressing challenges using community-partnered participatory research approaches to (1) gather information from focus groups with autistics, caregivers, and EI providers regarding acceptable practices; (2) identify adaptation targets that align with an NAI framework; (3) collaboratively develop an implementation toolkit to support an NAI framework in EI services; (4) explore differences in child outcomes and ratings of quality of life across EI approaches; (5) assess provider implementation of the NAI adaptations; and (6) assess the validity of the NAI framework. This innovative work addresses critical gaps in the literature related to modernization of autism EI to address significant stakeholder concerns. It lays the groundwork for future studies directly testing the adaptations, supporting the applicant’s career goals of increasing the equity and acceptability of meaningful evidence-based practices and improving service access.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract. South Florida is an epicenter of the United States HIV epidemic, yet evidence-based prevention and treatment does not reach South Floridians most in need. Mental health and substance use problems fuel the HIV epidemic, yet mental health and substance use treatment reach is suboptimal in South Florida. Our team found that HIV (e.g., PrEP, PEP, ART), mental health, and substance use services in South Florida are complicated to access and not coordinated across organizations, which drives their suboptimal reach. Our partners (Care Resource, Florida Department of Health) asked our team to centralize information about local services to facilitate community reach. With these partners, we developed the “Joining Under-connected Networks To Optimize Salud” (JUNTOS) Referral Network. The JUNTOS (“together”) app and website provides information about >60 organizations to enable community members to find HIV-relevant clinical services. Our partners house HIV self-testing programs and are eager to improve client linkage to PrEP, PEP, ART, and mental health/substance use treatment, as well as new interventions such as doxyPEP. HIV self-testing provides a powerful context in which JUNTOS could function as an adjunctive intervention – one that promotes engagement in other HIV-relevant clinical interventions – to address the gap between the availability of these interventions and their community reach. We propose a three-year R01 with the following Aims: In Aim 1, we will develop a scalable implementation blueprint for integrating JUNTOS into HIV self-testing programs. The blueprint will include client-level reach strategies to promote engagement with JUNTOS and program-level adoption and implementation strategies to support our partners in integrating JUNTOS into their self-testing programs. We will use co-design workshops and service mapping to develop the blueprint. In Aim 2, we will conduct a randomized controlled trial to evaluate JUNTOS and its implementation blueprint in our partners’ HIV self-testing programs. Self-testing clients (N=210) will be randomized 1:1:1 to three different reach strategy packages from Aim 1: (a) standard (palm cards in test kits); (b) enhanced (e.g., standard strategy + consistent text/email reminders); and (c) tailored (enhanced strategy + JUNTOS usage feedback, e-coach). We will compare JUNTOS reach across the three strategies, as well as HIV-relevant clinical intervention reach (e.g., PrEP/PEP or ART, mental health or substance use treatment) and evaluate appropriateness and acceptability using mixed methods. In Aim 3, we will evaluate self-testing program staff implementation outcomes, including acceptability, appropriateness, and feasibility of JUNTOS and the blueprint, as well as adoption and implementation using mixed methods. The project responds directly to our partners’ priorities of increasing client linkage to HIV-relevant clinical interventions using an adjunctive intervention that they co-developed in service of immediate public health and organizational goals. Findings will inform refinements to JUNTOS and the blueprint in preparation for a fully powered implementation trial of JUNTOS and its implementation blueprint to achieve national EHE goals.

NIMH - National Institute of Mental Health

Project Summary Social information influences many of our daily decisions, yet studies of the neurobiology of decision-making typically overlook social components. Importantly, to make a choice from multiple modalities, social and non- social information must, in principle, converge into a ‘common currency’. However, how these inputs are combined in decision-making circuits is largely unknown. To study how and to what extent social and non-social information are combined in decision-making circuits, we propose to develop a novel social foraging task for mice. In this task, two mice will simultaneously traverse a simple maze, making a left or right choice for water rewards. In contrast to when foraging alone, mice in the social task have additional information (i.e., the choice and reward history of the conspecific, gained through observation) that can be used to influence their decisions. In Aim 1, we will use reinforcement learning framework to model the cognitive and algorithmic process of how mice use social information, and test different learning rules by evaluating how well they fit mouse behavior. We will then use this model to quantify how overarching social relationships, such as biological sex, social familiarity, and hierarchical rank, influence the magnitude of which social information influences choice. In Aim 2, to understand how social information is integrated with other internal variables in decision-making circuits, we will record neurons in the posterior parietal cortex (PPC) and medial prefrontal cortex (mPFC), two central cites for decision-making in the mammalian brain, as mice perform both the social and non-social T-maze task. We hypothesize that social information will be more strongly encoded in mPFC, which has been previously associated with a wide variety of social behaviors, and that PPC will, in contrast, encode more general-purpose information about the moment-to-moment decision. This proposal aims to elucidate the overarching structure and organization of how decision-making circuits incorporate social information, and whether they serve as general ‘common currency’ circuits or support socially specific computations.

NIMH - National Institute of Mental Health

The purpose of this mentored career development award is to provide the candidate with rigorous and comprehensive training in preparation for an independent academic research career in molecular neuroimaging. Specifically, the completion of individualized training activities and proposed research over the course of the five-year award term will allow the candidate to develop the requisite expertise for a research career utilizing positron emission tomography (PET) in individuals with severe compulsive and impulsive behaviors, such as hoarding disorder (HD). The three career goals outlined in this training program include intensive, focused training in 1) Neurobiology and pathology of compulsive behaviors (emphasizing HD and relationships to functional outcomes and risk); 2) Intensive training in PET methodology and data acquisition; and 3) Advanced training in biostatistics for integration of PET and behavioral data. Integral to these goals is essential training in responsible conduct of research. The training plan will be executed with oversight from experts in neurobiology, molecular imaging, and psychiatry and performed in a rich academic environment (Yale School of Medicine), offering optimal resources and facilities for the proposed training and research. The proposed research consists of an innovative PET study in individuals diagnosed with DSM-5 HD. HD is a devastating and understudied psychiatric condition characterized by severe and compulsive difficulties with discarding and excessive acquisition, resulting in debilitating levels of clutter. HD is associated with profound personal and public health issues, including medical and psychiatric comorbidity, vast functional impairment, and increased risk for suicide. Alarmingly, studies report that fewer than one-third of patients achieve clinically significant change in treatment due in part to factors such as attrition and low treatment motivation. Currently, no FDA-approved pharmacological therapies for HD are available. Research into novel treatments is necessary to provide symptom relief, reduce risk, and improve quality of life. Moreover, pharmacological interventions addressing acute distress and increasing treatment retention may be needed to impart long-term behavior change. Evidence implicates kappa opioid receptors (KOR) in motivation, emotion regulation, compulsive behaviors, and in pre-clinical models of hoarding. Our promising pilot data show significantly lower KOR availability in subjects with hoarding behaviors (n=5) relative to healthy controls (HC). Here, we aim to extend these exciting findings by examining 1) KOR availability in-vivo using [11C]EKAP PET in individuals with HD relative to demographically matched HC; 2) relationships between KOR availability and clinically meaningful endophenotypes of HD; and 3) associations between KOR and functional outcomes in individuals with HD. Results have potential to significantly impact HD treatment development. Completion of the proposed training plan and research study will optimally position the candidate for a successful career conducting impactful research in psychiatric populations with severe compulsive behaviors.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Stable HIV reservoirs remain a significant challenge for the eradication of HIV-1 (HIV). While several anti- HIV latency strategies have been proposed to control HIV reservoirs, few have proven effective in reducing the size of the HIV reservoir in clinical settings. This suggests that our current understanding of how HIV achieves its persistent infection is limited and underscores the need for the development of alternative innovative tools for HIV cure. Recently, we and others characterized a unique integrated stress response (ISR)/ATF4 signaling pathway that is essential for HIV transcription and early seeding of HIV. Conversely, when ATF4 is knocked down, HIV transcription is inhibited. We further defined ATF4 as a new transcription factor of HIV, exploited by HIV for its own transcription after the recruitment of ATF4 to the ATF/CREB consensus site at the 5’ HIV long-terminal repeat. ATF4 induction leads to HIV activation from latency, indicating that ISR/ATF4 signaling activation promotes HIV transcription while the suppression of ISR signaling is associated with the establishment of HIV latency. Of note, prolonged activation of ISR/ATF4 signaling also induces cell death, mediated by ATF4 binding to the promoter of the CHOP gene, an essential protein driving apoptosis during persistent ISR/ATF4 activation. In a primary CD4+ T cell model of latency, prolonged ISR/ATF4 signaling activation disrupts latent HIV and selectively induces apoptosis in HIV+ CD4+ T cells, without affecting bystander HIV-negative CD4+ T cells. Notably, using viral outgrowth assays, we discovered that prolonged ISR/ATF4 signaling activation reduces replication-competent HIV by up to 2,300-fold in resting CD4+ T cells isolated from people with HIV receiving suppressive antiretroviral therapy (ART). Therefore, we hypothesize that the suppression of ISR/ATF4 signaling is essential for HIV persistence. This will be tested through three specific aims: Aim 1: Investigate how activation of the ISR/ATF4 signaling pathway eliminates HIV-latently infected T cells and brain microglia. Aim 2: Elucidate the unique mechanisms by which ISR/ATF4 signaling controls the stable HIV reservoir for the establishment of HIV latency. Aim 3: Determine the effectiveness of activating ISR/ATF4 signaling in eliminating HIV reservoirs in the hu-BLT mouse model of HIV latency in vivo.

NIH

Significance to VA: Elevated symptoms of depression and generalized anxiety disorder (GAD) are present in 10% and 8% of Veterans respectively and are associated with functional impairment and suicidality. Cognitive behavioral therapy (CBT) is a first line intervention for these conditions, yet few Veterans receive this treatment, in part due to the limited availability of mental health providers trained in CBT. The stepped care model offers one approach to addressing access by offering effective yet less resource-intensive treatments upon entry into mental health care for individuals with mild to moderate symptoms, stepping up the intensity and level of care as needed. Guided self-help (GSH) is one low intensity treatment format that could increase accessibility of CBT for depression and GAD. In GSH, patients follow a self-help version of an evidence-based behavioral intervention with coaching from a provider. A meta-analysis found that GSH is as effective as traditional psychotherapy treatments for depression and anxiety disorders. VHA’s Primary Care Mental Health- Integration (PCMHI) Service may be the ideal setting in which to deploy GSH. However, GSH is not widely used within VHA, and existing CBT interventions for depression and GAD would require adaptation to the GSH format and PCMHI setting and would benefit from Veteran input. One critical question is whether GSH can be feasibly delivered by non-psychologists, such as social workers and/or health coaches, to help address mental health access. This research may increase Veteran access to care through the availability of efficient, evidence-based programs at a lower level of the stepped care model of mental health treatment. Building Veteran-centered programs by incorporating Veteran feedback throughout the process may increase engagement with care. Overall, the project aligns with the VA strategic priority of implementation science. Innovation and Impact: This project proposes to innovate current practices in a lower level of the stepped care model of mental health treatment in VHA by providing GSH programs for prevalent conditions. If these programs can be feasibility delivered by non-psychologists, this has the potential to increase access to mental health care for Veterans, reduce costs to VHA over time, and help connect Veterans to soonest and best care. Specific Aims: The specific aims of this project are to 1) Conduct a formative evaluation assessing barriers and facilitators to the use of GSH for symptoms of depression and GAD in PCMHI via a national survey and qualitative interviews with PCMHI providers and clinic administrators, 2) Refine and conduct a pilot randomized trial of Behavioral Activation-GSH (BA-GSH) for depression (15 Veterans assigned to BA-GSH; 15 assigned to treatment as usual) in PCMHI as delivered by a group of non-psychologists. This pilot will evaluate the acceptability and feasibility of BA-GSH and explore preliminary effectiveness, and 3) Through iterative intervention design and adaptation, integrate Veteran feedback to adapt an existing CBT for GAD intervention (GSH-GAD) for delivery in PCMHI and conduct an open trial pilot of GSH-GAD with 10 Veterans in PCMHI. Methodology: For Aim 1, sequential explanatory mixed-methods evaluation will be used to identify barriers and facilitators to implementing GSH programs in PCMHI and as well as which provider type may be best suited to deliver GSH. For Aim 2, a randomized pilot trial will evaluate the feasibility and acceptability of a GSH program (BA-GSH) for symptoms of depression through qualitative interviews and an exploratory pre-post comparison of symptoms. For Aim 3, iterative intervention design and adaptation will be used to adapt a GSH program for symptoms of GAD. The resulting program will be evaluated in 10 Veterans through an open pilot. Path to Translation/Implementation: The training, piloting of methods, preparation of GSH programs for future implementation, and information gathered through this research will prepare Dr. Plasencia for becoming an independent VA investigator. With an initial focus on GSH, her work will seek to increase access to care by developing effective and Veteran-centered programs for mental health in VHA.

NIMH - National Institute of Mental Health

Financial capacity (FC) refers to the ability to complete a variety of everyday financial tasks and avoid financial exploitation or deception. The risk for diminished FC increases with age, is detrimental to both physical and mental health, and is associated with staggering financial costs. The early identification of seniors vulnerable to diminished FC is imperative in order to address this public health crisis threatening older adults. Importantly, compelling evidence suggests that older adults with major depression, also known as late life depression (LLD), are at significantly increased risk of diminished FC. However, this increased risk, and factors contributing to increased risk, has been understudied. Further, assessment of FC has previously required clinician administered evaluations, most existing studies of FC in LLD have been limited to relatively small samples which are not nationally representative, and have not allowed for investigation into the characteristics of LLD that contribute to diminished FC. In addition, the study of FC impairment in LLD has been challenging due to the high rate of comorbidity with MCI in this patient population. We propose the first comprehensive study in LLD to test a conceptual framework for this increased risk for diminished FC. We propose a conceptual model – the Mood, Motivation and Social Cognition Model of Diminished FC in LLD – and evaluate the validity of this model in a large nationally representative sample sufficient to test our hypotheses. We hypothesize that specific behavioral features of LLD (e.g., sadness, anhedonia, loneliness) detrimentally impact both the knowledge and abilities necessary to complete financial tasks and the ability to avoid susceptibility to deception. To accomplish our objectives, we will employ two novel ecologically valid electronic measures of FC (measured with the electronic financial capacity instrument or eFCI-SF) and susceptibility to financial deception (measured with phishing simulation) through the Brain Health Registry (BHR), a national online research registry that administers health questionnaire data every 6-months to over 60,000 older adults. We will enroll a national sample of 1,000 LLD and 1,000 non-depressed seniors into this study to complete online measures including the eFCI-SF as well as measures of financial history, mood, cognition, medical history, and socioeconomic status. In this large sample we will evaluate: 1) differences in FC between LLD and non-depressed (ND) seniors, and 2) the association between change in depression and change in FC over two years with depression and FC measured at six-month intervals. A subsample (n=300; 150 LLD and 150 non-depressed seniors) will complete a remote administered clinical assessment of neuropsychological and psychiatric functioning to validate the diagnoses (LLD and MCI) used in the large sample. These individuals will also complete the novel phishing simulation task. Completion of this study will inform the early identification of seniors at high risk for diminished FC and financial victimization which is necessary for the development of improved prevention and intervention strategies for loss of FC in older adults.

Indigenous Services Canada

Funds health promotion, disease prevention, mental wellness, and substance use programs for Indigenous communities.

NIMH - National Institute of Mental Health

Suicide is the leading cause of non-accidental death in adolescents in the US, and rates of suicide continue to rise in adolescent populations. Yet, the biological mechanisms leading to adolescent suicide that could inform effective preventive treatments for suicide remain unclear. To understand adolescent suicide, scientists often study suicidal ideation (SI), given that SI is strongly associated with suicidal behavior (SB) and is methodologically more feasible to study in adolescents. This K23 proposal will test a novel and integrative neurobiological model in adolescents with the hypothesis that circulating and stimulated peripheral inflammatory markers (PIMs; e.g. IL-6, TNFα, CRP) contribute to dysfunction in reward-related corticostriatal (CS) circuitry, and that this dysfunction in CS circuitry (and related behavioral correlates) contributes to adolescent SI. Prior research has linked PIM activation to SI/SB, but the biological mechanisms by which PIMs might contribute to SI remain unclear. Existing literature suggests that PIMs might affect CS functional connectivity, and that dysfunction in CS functional connectivity predicts SI and SB, though this integrative model has not been previously tested. Based on conceptual models and early clinical studies, one specific feature of reward processing - effort expenditure for reward (i.e., the amount of effort an individual is willing to expend for a reward) - may specifically be linked to SI/SB. In addition, the described integrative model is particularly relevant in adolescents, who are at a vulnerable developmental epoch for both reward circuitry and immune system maturation. This K23 will test the proposed model in 90 adolescents with unipolar depressive disorders, enriched with adolescents with a history of SI or SB. Adolescents will be followed over four timepoints over twelve months, with measurements of PIMs, CS functional connectivity during a reward task, and SI. This proposal will address key gaps in the field of adolescent suicide research, including understanding (1) the association between PIMs and CS connectivity in predicting future SI, (2) the relationships between PIMs and CS circuitry, and (3) the role of CS circuitry in explaining relationships between PIMs and SI. Understanding these gaps in the literature could elucidate clinically meaningful mechanisms of adolescent suicide, identify biobehavioral markers that could predict future SI, and potentially guide future interventions for adolescent SI/SB. The candidate will receive advanced training from an expert mentorship team, including knowledgeable co-mentors (Drs. Price, Brent, Forbes, and Marsland) and consultants (Drs. Brundin, Treadway, Thoma, and Wallace). The research environment at the University of Pittsburgh provides excellent resources. Consistent with the candidate’s career goals of better understanding biobehavioral mechanisms involved in adolescent suicidality, research findings from this K23 would inform future R01 proposals that could examine mechanisms by which PIMs contribute to SB in large samples, and aid development of interventions targeting PIMs or CS circuitry to reduce SI/SB.

NIMH - National Institute of Mental Health

PROJECT SUMMARY During sickness, the immune system and central nervous system coordinate to generate physical and behavioral changes, such as lethargy, anorexia, anhedonia, and social withdrawal, that can vary significantly in severity between individuals. While these symptoms help aid in sickness recovery, severe responses can be harmful and possibly life-threatening. What drives this symptomatic variation in sickness manifestation is still unclear, however, external factors such as social support may be a contributing factor. Prolonged social isolation not only impacts the immune response but is also associated with adverse physical and mental health outcomes. Previous studies have identified bi-directional interactions between immune signals and the central nervous system, suggesting a direct link between immune-activated neural circuits and sickness outcomes. Moreover, social isolation can have a dramatic effect on neuronal activity in specific brain regions. My preliminary studies demonstrate that social isolation exacerbates symptoms of sickness, such as body temperature and appetite, and increases circulating levels of immune factors known to mediate sickness state. Using activity pattern analysis, I found that activity in the insular cortex (IC) is dependent on both sickness and social isolation, suggesting integration of both social and immune signals. Therefore, I hypothesized that social isolation increases the severity and recovery time of sickness through specific neuronal and circuit mechanisms that integrate social behavior and sickness. I will address my central hypothesis by inducing sickness in isolated or group-housed mice through peripheral administration of bacterial lipopolysaccharides (LPS). In Aim 1, I will employ cell-type-specific functional manipulation approaches, including chemogenetic activation and permanent neuronal silencing, to determine the function of the “sickness neurons” in the IC. In Aim 2, I will identify the upstream neuronal inputs that convey social context to sickness-activated IC neurons using retrograde tracing and determine how these social inputs modulate sickness symptoms and behaviors using projection-specific activation. Together, the completion of this project will determine how the social environment influences sickness manifestation and recovery, revealing critical insight into long-standing observations linking isolated social environments with poor health.

NIMH - National Institute of Mental Health

Project Summary Advancements in biomedical strategies have the potential to prevent all new HIV transmissions in the US. Despite having the tools needed to end the HIV epidemic (EHE), HIV continues to disproportionately affect certain EHE priority populations. These groups have a heavy burden of HIV, experience suboptimal HIV prevention and care outcomes, and have a heavy burden of sexually transmitted infections (STIs). They also face structural barriers to HIV transmission elimination, such as challenges related to income, housing and substance use. In response, this EHE implementation science project aims to work with community-based partners to co-create a scalable type 4 social network alteration intervention capable of surmounting these structural barriers by updating and adapting the evidence-based WiLLOW program. Adaptation is a critical concept in Implementation Science and enhances the relevance, acceptability, feasibility, and cultural sensitivity of interventions. We will collaborate with our community-partners and federally qualified health center (FQHC) providers to implement study activities. The first aim of the project is to identify key network-driven determinants and features amenable to type 4 social network alteration intervention by structure (i.e., centrality measures including constraint, betweenness, bridging) and function (e.g., type of support: informational, social/emotional, material). The second aim is to conduct a series of 6 workshops involving key stakeholders (e.g., community members, CBO staff, CCHE providers) using human-centered design (HCD) methods (e.g., network mapping, journey mapping, card sorting; situated within the Discover-Design-Build-Test framework) to inform how to update and adapt WiLLOW. Using HCD will allow us to operationalize adaptation as a process of thoughtful and deliberate alteration of the design and delivery of WiLLOW with the goal to improve fit of the intervention with the needs, circumstances, and culture of end users, as informed by the community, and with that, strengthen potential effectiveness. In follow-up to the work for this project, the MPI’s will develop and submit an R34 proposal to evaluate the effectiveness and implementation of an adapted type 4 social network alteration intervention in an effectiveness-implementation hybrid study. In summary, this R21 project will help to address three EHE pillars (Diagnose, Prevent, Treat), and help to abate long-standing health challenges among an EHE priority population.

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

PROJECT SUMMARY/ABSTRACT The goal of the F99/K00 award is to provide Talia Kieu, MSPH, with the training needed to become an independent investigator focused on using advanced methods to identify the risk and protective factors of mental health outcomes among populations with multiple marginalized identities across the life course, as well as provide resources to augment and support researcher diversity. In 2019, the economic burden of major depressive disorder in the United States was estimated at $333.7 billion. Those with multiple marginalized identities (e.g., a low-income Black woman) are more likely to experience severe and persistent depression than those with a single or no marginalized identities. Depressive symptoms may be reflective of experienced life events; therefore, examining social conditions from adolescence and their effect into adulthood is critical to understand. Current literature on depression outcomes primarily sums the effects of social identities (e.g., race, sex) without exploring their multiplicative effects (i.e., how being both Black and a woman may uniquely compound risks for depression compared to each identity alone), often relying on cross-sectional analyses, which may contribute to the mixed findings in the current depression disparities literature. These conflicting findings highlight the need for a more nuanced understanding of how depression manifests longitudinally in marginalized populations. It is equally important to identify protective factors, such as social integration—the degree in which an individual is connected to their social environment. Research in the F99 phase (Aim 1) addresses these gaps by investigating 1) how depression evolves over the life course in those with multiple marginalized identities; 2) how multiple marginalized identities can have compounding, multiplicative effects on depression outcomes; and 3) how social integration manifests as a protective factor. Findings from this study will have implications for practice by identifying vulnerable populations and exploring strengths-based, protective factors for mental health interventions. Mental health interventions should also be well timed. Some marginalized populations, such as sexual/gender minority (SGM) communities, experience off-time sensitive periods due to multiple forms of stigma, which may result in overlooking optimal timing for mental health interventions. There is a need to examine how early-life experiences and off-time sensitive periods shape the mental health of SGM populations. Research in the K00 phase (Aim 2) will address these gaps by collecting mixed-methods data to 1) retrospectively explore the impact of holding multiple marginalized identities on the sensitive periods and mental health trajectories of older, SGM individuals of color; 2) explore the long-term impacts of adolescent experiences; and 3) validate findings through intergenerational member-checking sessions with adolescent and older SGM individuals. Findings from this study will have practical implications for timing mental health interventions effectively, and tailoring interventions to facilitate the protective qualities of SGM communities.

National Institutes of Health

The purpose of this Notice of Funding Announcement (NOFO) is to encourage innovative research that will inform and support the delivery of high-quality, continuously improving mental health services to benefit the greatest number of individuals with, or at risk for developing, a mental illness. This announcement invites applications for non-clinical trial R01-level projects that address NIMH strategic priorities for mental health services research.

National Institutes of Health

The purpose of this Notice of Funding Announcement (NOFO) is to encourage innovative research that will inform and support the delivery of high-quality, continuously improving mental health services to benefit the greatest number of individuals with, or at risk for developing, a mental illness. This announcement invites applications for non-clinical trial R01-level projects that address NIMH strategic priorities for mental health services research.

National Institutes of Health

The purpose of this Notice of Funding Announcement (NOFO) is to encourage pilot research that is not an immediate precursor to testing a service intervention but is consistent with NIMH priorities for services research. While NIMH now requires use of an experimental therapeutics model for all intervention studies, there is recognition that some mission-relevant areas of services research do not involve clinical trials.

National Institutes of Health

The purpose of this Notice of Funding Announcement (NOFO) is to encourage pilot research that is not an immediate precursor to testing a service intervention but is consistent with NIMH priorities for services research. While NIMH now requires use of an experimental therapeutics model for all intervention studies, there is recognition that some mission-relevant areas of services research do not involve clinical trials.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY First-ever data from Zambia on people who inject drugs (PWID) demonstrates major gaps in the HIV epidemic response. A recent biobehavioral survey show sharp health disparities along the entire PWID HIV care continuum, with gaps in HIV testing, linkage to ART, and viral suppression, and limited knowledge of PrEP. Failing to detect early HIV infections and address unsuppressed viral load poses a risk of ongoing community transmission as well as increased risk for HIV comorbidities and mortality, threatening the overall HIV epidemic control response in Zambia. The Zambia Ministry of Health has adopted a harm reduction approach to address the health disparities experienced by PWID. Starting in November 2024, the Zambia Ministry of Health will provide Medications for Opioid Use Disorder (MOUD) at two health facilities which also provide HIV services. There is currently minimal evidence in sub-Saharan Africa on MOUD integration with HIV care. The arrival of MOUD in Zamvia presents an exceptional opportunity to collaborate with Ministry of Health and key partners to develop a person-centered integrated collaborative care model for PWID and pilot testing implementation, feasibility, and preliminary effectiveness within the Zambian health system. We propose the Integrated Services for PWID using Person-centered Interactions, Reach, and Engagement (INSPIRE) study to co-adapt and evaluate an HIV status-neutral system-level integrated approach using a Collaborative Care Management Model (CoCM) for HIV prevention, HIV care, mental health, and MOUD. This implementation science study includes the following Aims: Aim 1: Assess the multilevel determinants of early implementation of MOUD services using rapid qualitative analysis. Aim 2: Co-adapt an HIV status-neutral CoCM with key stakeholders. Aim 3: Implement and evaluate the co-adapted CoCM, guided by Practical, Robust Implementation and Sustainability Model (PRISM), and including the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) outcomes. The research team, led by Multiple Principal Investigators (MPI), has expertise in psychiatry, HIV clinical care, implementation science, behavioral and social sciences, HIV clinical care, epidemiology, and mixed methods, and has a deep knowledge of HIV response and service delivery models in Zambia for marginalized populations, and experience implementing opioid use treatment both in the US, and in Kenya. We will also leverage the University of Maryland Baltimore’s decade of experience implementing MOUD and HIV programs in Kenya. Addressing the unmet needs of PWID is urgently needed to achieve and maintain HIV epidemic control; our findings will inform the implementation of integrated care models for PWID. Lessons learned from INSPIRE will help develop best practices for system-level approaches to improve OUD treatment and HIV prevention and treatment programs in both sub-Saharan Africa and the US.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Substance use disorders (SUD) and post-traumatic stress disorder (PTSD) are debilitating mental health disorders that frequently co-occur and have onset during adolescence. Approximately 9% of adolescents aged 12-17 meet criteria for a current SUD, with more than 70% of those having experienced a traumatic event and 35% meeting criteria for PTSD. If left untreated, a cyclical relationship between substance use and PTSD serves to maintain or exacerbate the other, leading to a chronic course of illness. Adolescents with co-occurring SUD/PTSD are at increased risk of developing other serious mental health problems (e.g., depression, suicidal ideation), HIV-related risk behaviors, and academic and interpersonal problems. There is a critical need to intervene earlier in the developmental trajectory to prevent the long-term deleterious outcomes associated with SUD/PTSD in adulthood. However, there are no effective individual treatments for adolescents with SUD/PTSD. Clinicians agree that comorbid SUD/PTSD among adolescents is a significant problem, and that a feasible and effective intervention is clearly needed. Efficacious, evidence-based treatments for adults with SUD/PTSD have been developed over the past two decades and can be adapted to address the unique developmental needs of adolescents with SUD/PTSD and improve outcomes and functioning for this highly understudied population. Based on promising preliminary data, the proposed study will directly address this need by evaluating an integrated, trauma-focused intervention, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE), specifically adapted for adolescents (COPE-A). A Stage Ia study of COPE-A demonstrated safety, feasibility, and significant pre- to post-treatment reductions in SUD and PTSD symptoms, while a Stage Ib pilot RCT comparing COPE-A to Person Centered Therapy (PCT) showed safety, feasibility, and preliminary efficacy in significantly reducing substance use and PTSD severity. Stage I studies also resulted in a treatment manual, clinician training protocol, and fidelity monitoring procedures, all of which will be used in the proposed study. The primary objective of this Stage II RCT is to evaluate the efficacy of COPE-A, compared to PCT, in reducing (a) substance use frequency and amount, and (b) PTSD severity among a larger sample of adolescents (N = 120) with co-occurring SUD/PTSD. Secondary objectives are to examine the effects of COPE- A on associated areas of functioning including depression, HIV risk behaviors, interpersonal functioning, and quality of life. In line with our prior work, we will recruit nationally and deliver the intervention via telehealth. Ecological momentary assessment (EMA) will monitor daily substance use and PTSD symptoms to examine their temporal and reciprocal relationship and identify underlying mechanisms of change to inform future research.

NIDA - National Institute on Drug Abuse

Substance use disorder (SUD) is a leading public health challenge, with long-term consequences for physical and mental health. In-person peer support groups are well-established as beneficial for recovery. However, as digital platforms increasingly serve as spaces for peer support, little is known about how engagement in online peer support recovery groups is associated with recovery outcomes. Emerging research has yielded conflicting results, with some studies suggesting benefits while others indicating relapse risks. This underscores the need to examine the content of discussions beyond engagement frequency. The present application seeks support for Xiangyu Tao, Ph.D., a postdoctoral associate at the Rutgers Addiction Research Center, gain the necessary training and set up a line of research to examine the role of online peer support recovery communities in SUD recovery. Specifically, she will integrate state-of-the-art artificial intelligence (AI) techniques, including Large Language Models (LLMs), with co-production to identify communication patterns and to examine their associations with recovery outcomes. LLMs offer a promising avenue for analyzing large-scale online discussions, yet they require human oversight to address challenges such as contextual misinterpretation and ethical concerns. Co-production, i.e., involving individuals with SUD recovery experience in all research stages, mitigates LLM limitations and ensures that results reflect lived experience. The mentored K99 phase will identify and characterize communication patterns in online recovery groups. Peer support and co-rumination patterns will be classified using LLMs and co-production (Aim 1); latent class analysis (LCA) will identify distinct communication profiles among users engaging in these online groups (Aim 2). During this phase, Dr. Tao will receive mentorship in co-production and AI methodologies, longitudinal data analysis and management, and responsible AI research. The independent R00 phase will build upon this foundation by examining how communication profiles are associated with recovery trajectories using longitudinal survey data from online recovery group participants (Aim 3). This project is highly innovative in its integration of LLMs and co- production to analyze large-scale digital recovery discussions, ensuring that AI-driven insights are both computationally rigorous and socially informed. Findings will enhance understanding of digital peer support for SUD recovery and will inform future mechanistic studies and SUD interventions. By identifying communication patterns associated with recovery trajectories, this project will guide digital health platforms, peer support programs, and clinicians in optimizing online recovery environments to better support individuals with SUD. This project aligns with the NIDA Strategic Plan Cross-Cutting Priority to "Leverage Data Science and Analytics to Understand Real-World Complexity" by utilizing advanced computational methods to analyze digital recovery support interactions. The project is highly significant in bridging advanced AI computational tools with the lived experiences of individuals to produce impactful research to promote substance use recovery.

NIMH - National Institute of Mental Health

Modified Project Summary/Abstract Section Early identification and intervention for autistic children significantly improve developmental and family outcomes, yet systemic barriers limit access to early intervention (EI) services. Many families experience difficulties in service access due to stigma, mistrust in healthcare systems, financial constraints, and a lack of responsive services. Family Navigation (FN), a casemanagement and family-support approach, has demonstrated effectiveness in improving access to some services, such as autism diagnostics, but its integration into Part-C EI systems remains understudied. Given that EI systems serve as a critical entry point for young autistic children and their families, embedding FN into EI services has the potential to improve caregiver engagement, increase adherence to evidence-based autism interventions and information, and enhance overall service delivery. However, to ensure successful implementation, tailored strategies are needed to address the unique challenges and constraints of EI systems, providers, and families. To address this gap, this study systematically examines FN implementation within Part C EI systems to enhance caregiver engagement and improve child outcomes. Guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework, this R21 project employs implementation mapping to identify key determinants and develop tailored implementation strategies for FN integration in EI across three states (GA, TX, WA). Using a convergent mixedmethods design, we will assess FN barriers and facilitators through surveys and focus groups with caregivers, EI providers, and administrators (Aim 1). We will then apply human-centered design strategies, including rapid prototyping, to refine implementation strategies, ensuring feasibility, acceptability, and scalability (Aim 2). This study is innovative in integrating FN alongside autism-focused EI services in Part C systems, which serve over 400,000 children annually. By engaging stakeholders and aligning strategies with existing EI service models, the project enhances the sustainability of FN in various EI settings. Findings from this study will inform a subsequent R01 effectiveness-implementation hybrid trial to evaluate FN’s impact on service access, caregiver engagement, and child outcomes. By addressing long-standing issues in autism service access, this research has the potential to transform EI service delivery by providing structured, evidence-informed strategies for FN integration. Ultimately, this project aims to improve quality in autism EI services, ensuring that all families receive the support they need to engage in high-quality, evidence-based intervention during the critical early years of their child’s development.

NIDA - National Institute on Drug Abuse

Project Abstract/Summary This Type 1 R34 implementation research pilot will provide critical, highly sought data to determine whether the unique and innovative biomedical profile of lenacapavir (LEN) pre-exposure prophylaxis (PrEP) is feasible and acceptable to people who use drugs (PWUD) in two street medicine contexts. PWUD remain vulnerable to HIV outbreaks in communities like Everett (Snohomish County), Washington, which lack the extensive HIV prevention infrastructure found in major urban centers. While twice-yearly, long-acting injectable LEN offers a promising advance by reducing dosing burden relative to daily oral or bi-monthly injectable formulations, its actual public health impact will depend on rigorously addressing barriers to LEN engagement, follow-up, and acceptability in real-world settings. This study meets a critical implementation gap regarding how workforce composition, same-day access, and differentiated mobile engagement models may influence LEN uptake and continuation among the most vulnerable PWUD. The project leverages two established, low-barrier mobile outreach programs in Everett: the Emergency Mobile Opioid Team Everett (EMOTE), offering immediate linkage to substance use and mental health treatment to all-comers and led by peers with lived experience in drug use and exchange sex; and the Harm Reduction Center (HRC) street medicine van, offering street-based advanced wound care, buprenorphine, phlebotomy, infectious disease testing/treatment and other medical services, and led by medical practitioners. In Aim 1 we will conduct formative, iterative work guided by the Consolidated Framework 2.0 for Implementation Research (CFIR 2.0). We will convene a Community Advisory Board and focus groups to co-design two tailored PrEP engagement models, each maximizing unique traits of EMOTE or HRC (EMOTE-PrEP and HRC-PrEP) to address LEN messaging, initiation, and retention for PWUD. In Aim 2, we will pilot these models by screening approximately 300 clients and enrolling about 70 eligible participants, with an anticipated 20 LEN initiations across both settings, to assess feasibility, acceptability, and PrEP cascade outcomes. Initiation and 6-month retention will be treated as implementation signals rather than efficacy endpoints. In Aim 3, qualitative interviews with participants who initiate, decline, or discontinue LEN will examine mechanisms influencing engagement, including trust, messenger effects (peer versus practitioner), perceived burden, and decision-making. Without evidence to inform engagement and retention strategies that support both initial uptake and six-month follow-up, the unique advantages of long- acting LEN PrEP will fail to reach the populations most vulnerable to outbreaks. Findings will have a significant public health impact, setting the stage for a fully powered trial of scalable LEN PrEP engagement and retention strategies for PWUD.

NIA - National Institute on Aging

PROJECT SUMMARY Over 50% of the 12.8 million low-income individuals who are dually eligible for Medicare and Medicaid (“dual eligibles”) qualify for Medicare because of disability. This varied population experiences physical, intellectual, developmental, cognitive, or mental disabilities that substantially limit major life activities. People with disabilities die 10-20 years earlier than those without disability, and much of this premature mortality is preventable. Dual eligibles with disabilities have high prevalence of multiple chronic medical (e.g., diabetes) and behavioral health (e.g., depression) conditions and high need for long-term services and supports (LTSS) for daily activities. Medicare and Medicaid have been poorly integrated to serve dual eligibles, leading to conflicting financial incentives, fragmented care delivery, and complicated administrative processes. Together, these issues drive high healthcare spending and poor health outcomes, including 40-60% avoidable premature mortality, among dual eligibles with disabilities. Integrated SNPs) or for with dual eligible special needs lans (integrated D- are a type of Medicare Advantage (MA) plan that contracts with state Medicaid agencies to cover some all Medicaid services coordinate Medicare and Medicaid benefits and streamline administrative processes dual eligibles. These plans aim to better align financial incentives toward “whole person” care consistent clinical guidelines and to provide comprehensive care management for chronic conditions. p , , Integrated D- SNP enrollment among dual eligibles with disabilities grew 12-fold between 2018 and 2024. Despite rapid growth, there is little evidence on the impact and implementation of integrated D-SNPs overall and none for dual eligibles with disabilities. This study aims to fill this gap using novel linked data capturing the entirety of Medicare and Medicaid services for 100% of dual eligibles with disabilities from 2018-2027. We will use a concurrent-embedded mixed-methods design integrating a quantitative trial emulation approach with difference-in-differences (Aim 1) and survival (Aim 2) analyses with qualitative study of integrated D-SNP implementation (Aim 3). Aims 1-2 will assess how integrated D-SNP enrollment influences care utilization, quality indicators, and chronic diseases management (Aim 1) and mortality (Aim 2) among dual eligibles with disabilities. Aim 3 will characterize integrated D-SNP implementation for dual eligibles with disabilities with the goal of identifying promising practices and areas for improvement. This project is well aligned with the NIH Strategic Plan for Disability Health Research FY26-FY30 and NIA's priority of promoting adherence to medical and behavioral regimens for healthy and adaptive aging in later life.