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NIMH - National Institute of Mental Health

SUMMARY Profound behavioral, emotional, and cognitive changes begin in pregnancy to prepare for the transition to parenthood, underscored by plasticity in maternal brain structure and function. Translational research emphasizes evolutionarily conserved adaptation as occurring in this period, though little is known about plasticity of the human maternal brain during pregnancy. Advancing this knowledge is a public health imperative given the prevalence and severity of perinatal mood and anxiety disorders (PMADs), which frequently originate in the prenatal period. Consequences of PMADs are enduring and costly, and carry intergenerational consequences through their impact on infant development, yet very little is known about their neural bases. What is known: A small number of studies document anatomical change in the brain from pre-pregnancy to the postpartum. Associations between iron and mood are established, and maternal iron in pregnancy is a known predictor of offspring neurobehavioral development. Furthermore, brain iron is emerging as a key factor underlying neuroplastic processes across the life course. Iron deficiency affects up to 40% of women in the US, and in pregnancy iron demands are significantly heightened. PMADs also increase risk of developmental disorders and psychiatric problems in children, though mechanisms for risk transmission are poorly understood. What is unknown: Neuroimaging studies conducted during pregnancy are rare, so trajectories of brain changes during pregnancy, across multiple domains, have yet to be examined. Further, how brain plasticity relates to PMAD symptoms is also unknown, constraining potential for clinical translation in this emerging area. Brain iron changes in pregnancy and its relevance to PMADs have yet to be examined. The goal of the proposed research is to determine whether gestational neuroplasticity underlies individual differences in maternal mental health and influences offspring neural development. We will conduct multi-modal MRI in a sample of n=132 women at 2 prenatal and one postpartum time point, measuring PMAD symptoms until 6 months postpartum, and complete rigorous assessment of offspring neurodevelopment including infant fMRI. Novel eye tracking technology will be used to collect objective measures of emerging infant attentional processing. We will address 3 key aims: (1) Quantify maternal gestational neural change using an integrated multimodal imaging approach; (2) Isolate associations between gestational neuroplasticity and PMAD symptoms; and (3) Determine whether maternal neuroplasticity and brain iron, measured via novel quantitative MRI sequences, are associated with infant neurodevelopment. Expected outcomes are significant as they will advance the field beyond documentation of expected neuroplasticity and towards understanding of clinically meaningful implications of individual differences in change, significantly advancing understanding of PMAD etiology.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT PrEP Blueprint is a project designed to create a blueprint to assist clinics currently offering PrEP in scaling up these efforts and offering all types of PrEP options to persons who may benefit from PrEP. The study will take place in two phases. In the first phase (Aim 1, year 1), we will assemble and adapt the PrEP Blueprint with client, clinic staff, and community stakeholder input. We will do this through Human Centered Design (HCD) with client and clinic staff in San Francisco, California and Birmingham, Alabama to identify implementation barriers in scaling up PrEP and which strategies would be desired, feasible, and client-centered to best address the needs of potential or current PrEP users. We will conduct three half-day workshops with 10 clients, and 20 staff at each of two clinics, a community sexual health clinic in San Francisco, and a university infectious disease clinic in Birmingham. The goal of these HCD workshops is to brainstorm new ideas (Ideation Workshop) to improve PrEP implementation within the clinical context; develop potential strategies (Prototyping Workshop) to address the implementation challenges; and review the prototypes identify the solutions which are most acceptable, feasible, and efficient (Testing Workshop) prior to implementation. Through these HCD activities we will determine what is feasible for each of the clinics to implement, and what client-facing (e.g., PrEP decision support tool to help people select the type of PrEP that best suits their needs) and clinic-facing resources (e.g., work flow templates, provider educational materials, insurance flowsheets, visit-type protocols) would best serve the needs of the clinics. We will also establish and consult with a Stakeholder Advisory Board to discuss the HCD, brainstorm strategies to reach a broader number of persons in the priority populations, and to provide ongoing feedback on the study implementation. In Phase 2 (Aims 2 & 3, years 2-5), we will launch the PrEP Blueprint in these 2 clinics and assess their implementation and impact using the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance). We will measure these outcomes through surveys every 6 months with staff and clients; interviews with staff; and extracting data from the electronic medical records. At the end of this project, we will have an adaptable PrEP Blueprint that will contain multiple features that a variety of clinics in the US could use to increase the number of persons starting and staying on PrEP.

NIMH - National Institute of Mental Health

Emerging (18-24 years old) and young (25-29 years old) adult men in the U.S. are at high risk for HIV infection. Pre-exposure prophylaxis (PrEP) is a highly effective biomedical prevention strategy to reduce HIV transmission and a priority for ending the HIV epidemic in the U.S. However, the effectiveness of PrEP depends on achieving protective PrEP blood drug levels through optimal adherence behaviors. mHealth interventions hold promise for delivering timely and tailored PrEP adherence support for higher risk communities. Our team was funded (NIMH R34MH116878) to develop and pilot test the PrEP iT! mHealth intervention to improve PrEP adherence among a national sample (n=80) of 18-29 year old men in the U.S. (Mage=25 years; 54% racial/ethnic minority), and we demonstrated high feasibility (>90% retention) and strong acceptability of the intervention. Among participants in the PrEP iT! intervention, those with protective PrEP blood drug levels (from dried blood spots) at months 3 and 6 were significantly more engaged in the intervention than those with non-protective PrEP drug levels, suggesting benefit for some, but not all, participants. Based on lessons learned of this pilot study, we propose here an RCT to test a stepped-care intervention - called PrEPStep - to improve protective PrEP blood drug levels among 300 18-29 year old men. Participants on PrEP and experiencing adherence barriers will be randomized (2:1) to either the updated PrEP iT! mobile app or an information-only control condition. Those who do not show improvement in PrEP adherence at 3-months will be re-randomized (2:1) to also receive remote eCoaching based on motivational interviewing (MI) and cognitive behavioral therapy (CBT) principles or remain in the PrEP iT! app alone for an additional 6 months, for total follow-up of 9 months. Additionally, we will use this opportunity to include information and tools to encourage uptake and proper use of doxycycline post-exposure prophylaxis (DoxyPEP) to reduce sexually transmitted infections. The proposed study aims are: Aim 1: Achieve a higher proportion of protective PrEP drug blood levels at 6- (primary outcome) and 9-months (secondary outcome) among participants randomized to a novel stepped-care mHealth and eCoaching intervention, called PrEPStep, compared to an information-only control condition; Aim 2: Evaluate the components of the PrEPStep intervention package at months 6 and 9 to characterize: 2a. the effect of receiving the updated PrEP iT! mobile app alone compared to the control condition; 2b. the additive benefit of receiving eCoaching compared to only receiving the PrEP iT! mobile app; Aim 3: Assess acceptability, uptake, and protective coverage of DoxyPEP among participants randomized to PrEPStep compared to those in the information-only control condition using in-depth interviews and survey results. The proposal has high public health impact by providing a scalable mHealth and eCoaching approach to address gaps in effective PrEP adherence interventions to reduce HIV among 18-29 year-old men in the US, as well as the initiation and protective coverage of DoxyPEP. Results of this work will inform a future Hybrid Type III implementation trial of PrEPStep more broadly in the US.

NIMH - National Institute of Mental Health

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but only a subset experience chronic negative psychiatric outcomes such as post-traumatic stress disorder (PTSD) and depression. Several cohort studies over the past 10 years have identified brain-based risk mechanisms early after trauma, which predict risk for chronic symptoms such as hyper-arousal, intrusive memories of the trauma, and negative affect. One of the most widely-replicated and theoretically-grounded such mechanisms involves early high amygdala responses to threat cues. Given the strength of current evidence, we propose that this is an actionable target for intervention early post-trauma, to prevent chronic impairing and distressing symptoms. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can induce functional brain changes as potential intervention for neuropsychiatric disorders. Emerging findings along with our preliminary data suggest that the amygdala can be reached and dampened via stimulation of a functionally connected cortical prefrontal area. Here we propose that using TMS to dampen amygdala hyperreactivity will prevent a cascade of symptoms that could develop following trauma exposure. We propose to identify Emergency Department patients who have experienced a recent traumatic event (meets DSM-5 Criterion A), and who have high initial PTSD symptoms at 1 week post-trauma. In the R61 phase we will deliver a staged single-blind TMS intervention with a lead-in sham, followed by active treatments with increasing doses, measuring amygdala reactivity at each phase. R61 milestones involve: 1: Target engagement: Determination that active TMS versus sham decreases within-subject amygdala threat reactivity (decrease in reactivity to fearful faces). 2: Dose response: Determination that 4 vs 1 session of TMS decreases these same targets. 3: Safety and feasibility: Demonstrating feasibility of recruitment and retention (75% of participants are able to complete 75% of sessions), and no Serious Adverse Events (SAE) deemed related to the TMS intervention. If these are met, the R33 phase will involve a randomized double-blind sham-controlled trial, providing a double- blind replication of the immediate effects on the amygdala target and 1-month later, as well as longitudinal assessments of TMS effects on both PTSD and depression symptoms over 3 months post-trauma. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state-of-the-art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for chronic trauma-related symptoms through the Grady Trauma Project and Grady Healthcare System, and a strong community of experts in trauma and neuromodulation. If the hypotheses are confirmed, this study will lay the groundwork for future early intervention trials using non- invasive dampening of amygdala reactivity to prevent chronic trauma-related symptoms.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT The purpose of this Mentored Patient-Oriented Research Career Development Award is to prepare Evan Dalton, MD, MSHP for a career as an independent clinician-investigator with expertise in developing and implementing interventions that transform care delivery for hospitalized children with autism spectrum disorder (ASD) and improve their outcomes on pediatric medical units. Dr. Dalton’s proposal includes training, mentorship, and research activities that will enable him to conduct a full-scale clinical trial of a systems-level intervention for children with ASD and aggression at a pediatric medical hospital. Dr. Dalton has developed a comprehensive career development and research plan that builds on his foundation in health services and quality improvement research to: 1) obtain advanced training in participant-engaged mixed methods for intervention development and redesign, 2) enhance his knowledge of human-centered design and practice its application within the pediatric hospital work system, and 3) gain the expertise in clinical trial methodology necessary to carry out a full-scale controlled trial at a pediatric medical hospital. The prevalence of ASD has risen above 3% in the United States and children with ASD are frequently hospitalized for their co-occurring medical and psychiatric disorders. Many children with ASD have inherent sensory sensitivity, restricted interests, and repetitive behaviors that are difficult to accommodate in the medical hospital setting. In addition, few specialized psychiatric hospitals exist for children with ASD, so pediatric medical hospitals provide psychiatric care for many children with ASD. The objective of the proposed research studies is to redesign an ASD-specific care pathway, which has demonstrated effectiveness at a psychiatric hospital, for implementation with children with ASD and aggression, their caregivers, and their observers in a pediatric medical hospital. To accomplish this objective, Dr. Dalton will pursue the following specific aims: 1) identify usability challenges and adaptation needs of an ASD-specific care pathway within the pediatric hospital work system, 2) redesign and iteratively refine the ASD-specific care pathway with Advisory Board collaboration, 3) pilot test the redesigned ASD-specific care pathway in a non-randomized, single-arm trial on a pediatric medical unit. This pilot study will assess the pathway’s usability, acceptability, and feasibility, evaluate the hypothesized mechanisms (e.g., observer beliefs, comfort, and knowledge), and examine clinical outcomes including patient aggression, physical restraint use, and staff injuries. The data generated by this project will serve as the foundation for a future R01 which will test the ASD-specific care pathway in a full-scale controlled trial at a pediatric medical hospital. This proposal addresses the National Institute of Mental Health Strategic Goal 4.2.B of “building models to scale-up evidence-based practices” by adapting an evidence-based intervention with demonstrated effectiveness in a psychiatric hospital for use with patients with ASD in pediatric medical units.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT We are proposing a hybrid type I trial to assess the effectiveness and implementation determinants of an innovative peer-led court navigator program that facilitates linkage to substance use disorder treatment. The courthouse is a venue where people with behavioral health needs who are justice-involved and at various points along the sequential intercept model converge in time and space; however, despite considerable attempts to link these populations to evidence-based treatment, outside of specialty court models, courthouses themselves are underexplored as an intervention setting. We will test whether court navigator intervention, led by peer recovery specialists and implemented in county courthouses, can be an effective strategy to facilitate linkages to substance use treatment. Court navigators are civilians who provide adjunctive legal-related services to those passing through courthouses, and the investigative team published pilot data demonstrating the feasibility of treatment linkage. Peer recovery specialists (persons with lived experience of substance use recovery) have been associated with reduced substance use outcomes and are being integrated into multiple criminal-legal intercepts and settings; however, peer-led court navigation is an innovative and unexplored approach within research and an ideal fit for a Justice Community Opioid Innovation Network Phase II Innovation Hub project. The proposed hybrid type I trial of a manualized court navigation intervention delivered by certified peer recovery specialists and compare the effectiveness through a pragmatic randomized controlled trial with an information-only control in two Indiana courthouses. Guided by Social Cognitive Theory and the Consolidated Framework for Implementation Research, our aims are as follows: Aim 1: Assess the effectiveness of court navigation vs. an information-only control on linkage to substance use treatment in a randomized controlled trial; Aim 2: Assess the effectiveness of court navigation vs. an information-only control on overdose and public safety outcomes in a randomized controlled trial; Aim 3: Explore barriers and facilitators implementing peer-led court navigation in criminal-legal systems. For the clinical trial, we will randomly select times of day that the court navigator intervention will be available and enroll 600 subjects over 24 months with 12 months of follow-up data by linking statewide administrative records. We will also conduct interviews to identify barriers and facilitators for implementing the intervention (N=64). The proposed study will be led by Dr. Bradley Ray, an experienced research sociologist, and supported by an interdisciplinary investigative team of qualitative and quantitative experts with senior justice and behavioral health leaders from the Indiana Supreme Court and Indiana Division of Mental Health and Addiction. This study has the potential to identify a new setting (courthouses) and strategy (court navigation) for linking those in need to community-based behavioral health services, thereby improving public health and safety. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the overdose epidemic, including opioid and stimulant use disorders. The NIH HEAL Initiative bolsters research across NIH to address the national opioid public health crisis and improve treatment for opioid misuse and addiction.

Centers for Disease Control - NCIPC

The purpose of this NOFO is to provide multiyear funding to state, territorial, tribal, and local health departments to implement and evaluate comprehensive primary prevention strategies that prevent multiple forms of violence and promote healthy development among adolescents and young adults. Building on the prior PREVAYL cooperative agreement, this NOFO emphasizes: Improving data-driven decision-making, including surveillance, data linkage, and use of real-time data for prevention, evaluation and implementation science Building capacity and strengthening implementation and reach of evidence-based prevention strategies that address shared risk and protective factors Advancing whole-child and whole-community violence prevention approaches that integrate youth mental health and family support strategies Engaging in strategic collaboration through multisector partnerships to facilitate youth engagement, and build and support a skilled violence prevention workforce Prioritizing primary prevention of multiple forms of violence impacting youth including interpersonal violence, intimate partner/teen dating violence, bullying, community-based violence, online/technology-facilitated violence, and adverse childhood experiences (ACEs)

Centers for Disease Control - NCIPC

<p style="margin-left:0px;">The purpose of this NOFO is to provide multiyear funding to state, territorial, tribal, and local health departments to <strong>implement and evaluate comprehensive primary prevention strategies that prevent multiple forms of violence</strong> and promote healthy development among adolescents and young adults. Building on the prior PREVAYL cooperative agreement, this NOFO emphasizes:&nbsp;</p><p style="margin-left:0px;">&nbsp;</p><ul style="list-style-type:disc;margin-left:0px;"><li style="margin-left:0px;" data-list-item-id="e00d033b2d5eb49d093b2e876632bdb92"><p style="margin-left:0px;">Improving <strong>data-driven decision-making</strong>, including surveillance, data linkage, and use of real-time data for prevention, evaluation and implementation science&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e00889545999c8e496f431b111259d8a2"><p style="margin-left:0px;">Building capacity and strengthening implementation and reach of evidence-based prevention strategies that address <strong>shared risk and protective factors</strong>&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e1393be9338f280fbf28b45e09da7c50b"><p style="margin-left:0px;">Advancing whole-child and whole-community violence prevention approaches that integrate <strong>youth mental health</strong> and <strong>family support</strong> strategies&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e00d3f7091d32818e01777f5395f85bc9"><p style="margin-left:0px;">Engaging in strategic collaboration through <strong>multisector partnerships</strong> to facilitate youth engagement, and build and support a skilled violence prevention workforce&nbsp;</p></li><li style="margin-left:0px;" data-list-item-id="e80ec7a8032069bd5040ac9fbbb078e1b"><p style="margin-left:0px;">Prioritizing primary prevention of <strong>multiple forms of violence impacting youth </strong>including interpersonal violence, intimate partner/teen dating violence, bullying, community-based violence, online/technology-facilitated violence, and adverse childhood experiences (ACEs)&nbsp;</p></li></ul>

NIMH - National Institute of Mental Health

Project Summary Fragile X syndrome (FXS) stands as a prominent contributor to intellectual disability and autism spectrum disorders, stemming from mutations within the FMR1 gene. These mutations lead to severe reduction or absence of the FMRP protein. Despite extensive research, effective medical interventions for FXS remain elusive, hindered by a limited understanding of its underlying mechanisms. Biochemical investigations have consistently highlighted FMRP's role in modulating mRNA translation, with its absence correlating with increased translation levels of select FMRP- interacting mRNA targets. However, emerging evidence suggests broader dysregulation, as FXS neurons exhibit heightened overall protein synthesis, hinting at elevated translation of non-FMRP interacting mRNAs. This intriguing phenomenon underscores the need for a deeper exploration into the cellular dysfunctions characterizing FXS. This research initiative aims to unravel a novel facet of FXS pathology—nucleolar hyper-function. We propose that this hyper-function contributes to aberrant ribosome biogenesis, thus augmenting the cellular capacity for translation and driving the observed global increase in protein synthesis in FXS. Aim 1 will assess neuronal and glial nucleolar function in wild-type (WT) and Fmr1 knockout (KO) mice. Aim 2 will conduct a comparative analysis of genome-wide proteomic data encompassing nucleolar proteins in WT and Fmr1 KO samples, discerning molecular alterations integral to ribosome biogenesis and assembly. Aim 3 will assess nucleolar function in the peripheral tissue in Fmr1 KO mice, establishing the hyper-functional pathological outcome as a potential clinical biomarker. The successful execution of this exploratory R21 project promises to unveil previously unexplored cellular mechanisms underlying FXS pathology. This study will also suggest nucleolus-associated abnormalities as novel molecular/cellular measures and potential biomarkers.

NIMH - National Institute of Mental Health

Globally, people with HIV (PWH) with comorbid common mental disorders (CMDs) experience worse HIV-related outcomes than those without, including decreased antiretroviral therapy (ART) adherence, reduced viral suppression, and increased mortality. These same mechanisms drive poor HIV outcomes in the United States, underscoring the need for scalable mental health interventions to improve domestic HIV care. Despite their high prevalence and impact, CMDs remain under-diagnosed and undertreated among PWH, particularly in low- and middle-income countries (LMICs), due to weak mental health infrastructure and severe workforce shortages. Similar access barriers persist in resource-constrined United States settings, including rural and safety-net clinics, making task-shifting directly relevant to US populations. Testing task-shifted interventions in LMICs provides a rigorous scientific advantage. Conducting this study in Vietnam—rather than the US—is a deliberate strategy to evaluate the intervention under conditions where its core mechanisms are most observable. Vietnam’s limited mental health workforce and high burden of untreated CMDs create a high-contrast environment that amplifies intervention effects and clarifies causal pathways linking mental health improvements to HIV outcomes. This constraint-based setting enables identification of the minimally effective components, efficient delivery strategies, and essential supervision structures required for scalability. In contrast, more resource-rich and heterogeneous US systems can obscure these mechanisms, limiting the ability to optimize implementation. Establishing effectiveness and efficiency under constraint strengthens internal validity and enhances generalizability to resource-constrained U.S. settings facing similar barriers. Problem-solving therapy (PST) is an evidence-based, non-specialist-delivered intervention shown to improve mental health outcomes in sub-Saharan Africa. Yet, its impact on HIV outcomes among PWH has not been established, particularly among those initiating or re-initiating ART, who may derive the greatest benefit. We recently culturally adapted PST for PWH with CMDs in Vietnam and demonstrated feasibility, acceptability, and high-fidelity delivery in a pilot randomized trial, with promising signals of effectiveness. We propose a randomized, controlled, hybrid type I effectiveness-implementation trial to evaluate adapted PST versus enhanced usual care among PWH initiating or re-initiating ART with CMDs in Vietnam. We will assess CMD and HIV outcomes, cost-effectiveness, and implementation factors to support translation. We hypothesize that PST will improve CMD outcomes at 3 months and viral suppression at 6 months. By rigorously testing PST in a resource-constrained setting, we will generate actionable evidence and an implementation blueprint to support scalable, cost-effective integration of mental health care into HIV services, accelerating translation to improve outcomes in resource-constrained US populations.

NIMH - National Institute of Mental Health

Project Summary As life expectancy increases in people living with HIV (PLWH), the probability of developing other chronic conditions such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease also increases. PLWH live longer, develop multiple chronic conditions (MCCs), and experience polypharmacy, reinforcing a need to evaluate composite medication adherence across all chronic medications. Suboptimal medication adherence to essential treatments may limit treatment effectiveness, shorten survival, decrease overall population health, and increase health-system costs. Positioned at the nexus of therapeutic intent and success, medication adherence is influenced by myriad system, provider, and person-related factors that cannot be evaluated using claims-based studies alone. Therefore, the overarching goal of this research is to identify a taxonomy of composite medication adherence trajectories (MATs) over a 36-month observation period in older (50-99 years of age) PLWH and MCCs. The taxonomies will inform future research involving development and testing of comprehensive medication adherence interventions and clinical decision support strategies with the highest probability to positively impact medication adherence-related clinical outcomes in older PLWH and MCCs. We propose a mixed-methods explanatory sequential design by combining group-based trajectory modeling (GBTM) of medication refill data followed by 75 semi-structured interviews to fully understand the clinical, social, behavioral, cultural, structural, and economic perspectives that may influence medication adherence decision-making in PLWH and MCCs (i.e., T2DM, hypertension, and/or hyperlipidemia). We propose the following aims: 1. Apply group-based trajectory modeling of medication refill data to identify dynamic profiles of medication adherence behavior over time for older PLWH and MCCs. 2. Use qualitative, semi-structured interviews of older PLWH and MCCs to obtain in-depth understanding of social, behavioral, cultural, structural, and economic perspectives that align with each MAT profile. In contrast to disease-specific (intra-disease), dichotomous summary measures focused on antiretroviral therapy alone, this study uniquely identifies longitudinal MATs across MCCs (inter-disease). Qualitative assessment of lived medication use experiences and array of social, behavioral, cultural, structural, and economic perspectives contributing to MAT profiles advances understanding of needs for PLWH and MCCs to inform optimal, tailored interventions for unique MATs unachievable with claims-only studies.

Health and Human Services Department

In compliance with the requirement of the Paperwork Reduction Act of 1995 to provide opportunity for public comment on proposed data collection projects, the National Institutes of Health (NIH) will publish periodic summaries of proposed projects to be submitted to the Office of Management and Budget (OMB) for review and approval.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Postpartum depression (PPD) affects approximately one in eight women in the year following childbirth, with significant implications for maternal and child outcomes. While theoretical perspectives emphasize the importance of social support during this challenging transition, particularly from partners, current research relies heavily on self-reported measures of support that are susceptible to cognitive biases and may be confounded with depression symptoms. A critical factor that may influence maternal mental health outcomes is the actual time spent in proximity with one's partner, as these periods provide opportunities for both emotional and practical support. In the proposed project, we will examine patterns of partner proximity across pregnancy and the extended postpartum period using innovative wearable devices (TotTags) that dynamically and unobtrusively measure physical distance between partners in their daily ecological context. Our central hypothesis is that reduced partner proximity will prospectively predict increases in maternal depression symptoms (Aim 1). We will also investigate the bidirectional relationships between both partners' depression symptoms and their proximity patterns (Aim 2) and examine how infant caregiving contexts influence these dynamics (Aim 3). This project addresses a critical gap in the perinatal mental health literature by advancing our understanding of how objective measures of partner support relate to depression risk during the transition to parenthood. This study will set the foundation for future research that can inform interventions aimed at preventing postpartum depression in both mothers and fathers. Through this project, the candidate will develop specialized expertise in perinatal mental health research, ecological assessment methods, and advanced statistical approaches for analyzing dynamic social interactions, positioning them to establish an independent research program examining how partner support shapes mental health outcomes during major life transitions.

NIDA - National Institute on Drug Abuse

The rapid shift in public perception of psychedelics, coupled with the expansion of their use and policy reform across the United States, has created a unique opportunity to assess the real- world impacts of psychedelic use. Over 7,000 people in Oregon have received legal, supervised psilocybin experiences. Similar services are set to begin in Colorado in 2025, and nine other states are currently considering psychedelic services legislation. Although early phase trials suggest psilocybin may be safe and effective for treating some mental health and substance use disorders (e.g., tobacco use), it is not known whether these effects extend to community- based settings with less standardized screening and counseling support. There is an urgent need to assess the safety of these programs and their impact on substance use, before more voters and policymakers are asked to consider their merits and drawbacks. The Psilocybin Research and Implementation study for Substance use and Mental health (PRISM) study is designed to fill this gap by enrolling a cohort of individuals who use substances and receive Oregon’s state-regulated psilocybin services and comparing them to a group of people who would access these services, if they were available. Using 12 months of rigorous longitudinal surveys and qualitative interviews, PRISM will detect potential safety risks and benefits of regulated psilocybin services and identify specific substances and subpopulations that may be responsive to psilocybin’s effects. The study has three Aims: 1) Assess the impact of state- regulated psilocybin services on safety events in people who use substances, 2) Assess the impact of state-regulated psilocybin services on substance use, and 3) Elicit stakeholder views of the impact of state-regulated psilocybin services on long-term safety and changes in substance use. The PRISM study seeks to generate rigorous real-world evidence that can effectively guide state and federal decision-making. The timing of this work is critical, given the rapid expansion of psychedelic policy reform across the United States. The findings will help shape policies that maximize potential benefits of psilocybin services while minimizing risks, offering a scientifically grounded framework for public health strategies, harm reduction efforts, and future psychedelic regulations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Increasing numbers of people, including adults, have been diagnosed with autism spectrum disorder (ASD). For people utilizing medications for ASD, results are often unsatisfactory and involve off-target effects, necessitating the identification of better treatments. This project will help address this significant gap in knowledge by investigating the ability of psychedelic drugs to normalize cognitive flexibility deficits and changes to prefrontal cortex circuits caused by Cntnap2 knockout (KO), a mouse model that captures some of the behavioral abnormalities associated with ASD, including cognitive rigidity. Cognitive flexibility, a fundamental process that is required for adaptive behavior, is compromised in many people with ASD. As the PFC is important for cognitive flexibility and control of behavior, ASD-related cognitive inflexibility may be correlated with the known alterations to density of dendritic spines, a proxy for synaptic connectivity, in prefrontal cortex pyramidal neurons. Similarly, decreases in cognitive flexibility, reductions in dendritic spine density, and attenuations in excitatory synaptic input to PFC pyramidal neurons have been reported in mouse models that capture ASD-associated behavioral phenotypes. In contrast, psychedelic treatment has been shown to improve cognitive flexibility, elevate dendritic spine density, and boost excitatory synaptic input to PFC pyramidal cells. Therefore, psychedelic-mediated repair of PFC circuits and associated flexible behaviors may represent a novel ASD treatment paradigm. Although psychedelic treatment is a promising target for both increasing reversal learning ability and enhancing PFC synaptic connectivity in people with major depression, it is unknown if psychedelic treatment is able to normalize cognitive flexibility alterations and repair neural circuits disrupted in ASD, leaving a critical unaddressed question. Here, using long-time scale behavioral measures of flexibility and synaptic morphophysiological analyses, we will test the central hypothesis that psychedelic treatment will improve reversal learning ability (Aim 1) and repair PFC circuit structure and function (Aim 2) that is compromised in the Cntnap2 KO mice. Successful completion of these aims has the potential to significantly improve our understanding of the utility of psychedelic medicine for the treatment of ASD, as this treatment paradigm holds the promise of improving flexible learning by fundamentally changing the underlying synaptic landscape in PFC.

NIDA - National Institute on Drug Abuse

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

The Psychiatric Genomics Consortium (PGC) has been at the forefront of psychiatric genetics for nearly two decades, massively advancing our understanding of the genomic underpinnings of psychiatric disorders. Building on its success with over 1,700 investigators and 755 impactful publications, the PGC proposes a new phase to harness the forthcoming influx of genetic and functional genomic data from across the US and around the world. This effort aims to deepen understanding of the genetic architecture of psychiatric disorders, address critical gaps in biological mechanisms, catalyze clinical relevance, and accelerate training and outreach on how genetic factors contribute to mental and physical health. We propose three synergistic Specific Aims: (1) Identify genetic variants associated with serious psychiatric disorders that afflict many Americans by rigorous integration and analysis of all available datasets using state-of-the-art methods to analyze common, rare, and structural variants. (2) Dissect heterogeneity of psychiatric and chronic medical disorders by examining shared and distinct genetic influences on risk. (3) Advance mechanistic understanding of psychiatric risk and resilience by fine-mapping genetic loci, identifying relevant biological contexts, and integrating functional genomic annotations. These aims create a cohesive framework where foundational discovery (Aim 1) informs efforts to resolve heterogeneity (Aim 2), and then to elucidate biological mechanisms (Aim 3). We will achieve these aims by leveraging our established analytical infrastructure and efficient organizational structure. This phase of the PGC will drive collaboration, accelerate genetic discovery, and deliver biological and clinical insights into psychiatric disorders, with the ultimate goal of improving patient outcomes. Including foreign sites is scientifically essential: the sample sizes required to detect genetic variants of small effect, variants that can have major public health implications for Americans, can only be achieved through global collaboration and our discoveries will accelerate genetic insights that benefit US patients.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Adolescence is associated with worsening anxiety, but the biological mechanism for this phenomenon is not understood. Much work has focused on how changes to social and cognitive processing during adolescence might contribute to anxiety symptoms. Very little work has investigated how pubertal changes to the body itself may contribute to worsening anxiety symptoms. Specifically, puberty is known to impact representation of the body in cortex. This in turn may impact the ability to identify and interpret interoceptive signals in a bottom-up manner, thereby exacerbating anxiety symptoms in vulnerable adolescents. Identification of novel neural targets and mechanisms associated with anxiety during adolescence can lead to interventions that reduce illness burden in adolescence and adulthood. Primary somatosensory (S1) and insular cortices are two potential neural substrates that are associated with cortical representation of the body, as well as interoceptive function. Both S1 and insular cortices show structural and functional shifts during puberty and are associated with anxiety symptoms in adults. The function of these regions during puberty and their relationship to anxiety symptoms has not been characterized. This functional magnetic resonance imaging (fMRI) study seeks to understand the neurofunctional correlates of body representation and interoceptive function and their relationship to anxiety symptoms during puberty. In this cross-sectional study, youth ages 11-15 (n=75) will complete assessments and self-reports of anxiety symptoms and pubertal development, as well as a magnetic resonance imagining (MRI) scan session. The MRI session will include an emotional cardiac interoceptive functional MRI task and a resting state scan. Participants will also complete an electrocardiogram task designed to assess interoceptive function, as well as a behavioral task designed to assess body representation, both outside of the scanner. We aim to understand the neural correlates of body representation during puberty and the relationship between interoceptive function/its neural substrates and physical symptoms of anxiety in adolescents. We also will explore the stability of these constructs over time and the predictive utility of the function of somatosensory and insular cortices for understanding anxiety symptoms. This study has the potential to identify novel targets for early intervention that could prevent or mitigate anxiety disorders in adolescence and adulthood.

NIMH - National Institute of Mental Health

Project Summary Strong, longstanding evidence points to important roles for the cerebellum in autism spectrum disorders (ASDs), yet cerebellar mechanisms remain understudied in ASDs compared to neocortical circuits. Anatomical and functional studies have pointed, in particular, to changes in the synapses of Purkinje cells, the sole output neurons of the cerebellum. Purkinje cells were reduced both in number and size in ASD cases, particularly in the cerebellar vermis and other sub-regions involved in cognition and emotional control. Genes localized to Purkinje cell synapses were down-regulated. Purkinje cell-specific conditional knockout mice for several ASD risk genes suggest direct effects of these cerebellar neurons on ASD-related behaviors and synaptic structure and function. However, cell type-specific transcriptional and epigenomic changes in the cerebellum of individuals with ASDs remain poorly characterized, and it is unknown whether the synaptic features identified in mouse models translate to the human condition. Here, we propose comprehensive multi-omic and synaptic imaging studies to address these knowledge gaps, utilizing a unique post-mortem brain tissue resource from the University of Maryland Baltimore Brain and Tissue Bank. We will generate single-nuclei multi-omic profiles of gene expression and chromatin accessibility in ~1.5 million cells from 100 ASD cases and 100 controls. In the same brain tissue samples, we will perform super-resolution confocal imaging to quantify the density, size, and nanostructure of Purkinje cell synapses. ~50% of the donors in our cohort will have known causal mutations, including multiple cases with tuberous sclerosis complex (TSC), Rett syndrome, and Fragile X syndrome, enabling us to define shared vs. unique features of ASDs with mutations in different genes. Key findings will be validated in a mouse model of TSC, Tsc1 conditional knockout mice, enabling us to determine which transcriptomic and synaptic phenotypes arise from the direct effect of this mutation in Purkinje cells.

NIMH - National Institute of Mental Health

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation methodology FDA- approved for treatment of major depressive disorder (MDD). While rTMS achieves higher antidepressant efficacy than conventional treatments, reported response and remission rates are highly variable across cohorts. To reduce this variability and enhance overall remission rates, an understanding of the biological mechanisms behind rTMS’s antidepressant efficacy is needed. Recent studies have identified that rTMS works through a common biological mechanism even across multiple neurological disorders being treated: reduction of neuroinflammation, specifically, reduction in microglia activation. This is particularly relevant for MDD, as increased neuroinflammation is well-documented, on average, in groups of patients with MDD, and microglia are reported to be the cells responsible for this neuroinflammation. We and others have shown that people with MDD exhibit a range of neuroinflammation and that only those with high neuroinflammation have an antidepressant response to anti-inflammatory treatment. Taken together, this suggests that the mechanism of action of rTMS may be through the reduction of neuroinflammation (specifically, microglia density) and that the reported heterogeneity in response to rTMS may be due to the heterogeneity of neuroinflammation in MDD itself. We seek to probe this in the proposed high-risk, high-reward proof-of-concept study in n = 10 treatment- seeking participants with MDD, who will undergo rTMS as part of their standard of care – this is not a clinical trial: Aim 1. Explore the relationship between rTMS-associated reductions in depression severity and reductions in microglial density, as measured by microglia-specific [11C]PS13 positron emission tomography (PET) tracer. We expect microglia density to decrease following rTMS based on published animal literature reporting a ~23% reduction in microglia after TMS. Data from our current study examining participants with MDD receiving anti-inflammatory medication suggest that reductions in depression severity will be correlated with this reduction in neuroinflammation. Aim 2. Explore the relationship between pretreatment microglia density as measured by [11C]PS13 PET and antidepressant response to rTMS. Data from our current study suggest that greater pretreatment neuroinflammation will be associated with better response to rTMS. This high-risk, high-reward R21 will be the first study to assess rTMS’s effects on microglia in patients with MDD, advancing our understanding of its mechanism of action, providing proof of concept to support future larger studies, and stimulating the development of both novel neuroinflammation-specific therapeutics and future improvements in rTMS protocols.

NIMH - National Institute of Mental Health

Title: R-loop-induced CGG contraction as a therapeutic approach for Fragile X syndrome PROJECT SUMMARY Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder and one of the most common monogenic causes of inherited intellectual disability and autism spectrum disorders (ASD). FXS has a higher incidence among males (~1:3000) than females (~1:6000). Approximately 60% of FXS individuals demonstrate autistic features, 86% have an anxiety disorder, and almost all exhibit cognitive, motor, and developmental delays. Disease-modifying treatments have been of major pharmaceutical interest. Clinical trials have largely targeted pathways downstream of FMR1 or alternative pathways to modulate disease phenotype, such as arbaclofen and metabotropic glutamate receptor 5 (mGluR5) antagonists, with a phosphodiesterase-4D (PDE4D) allosteric inhibitor recently shown to improve cognitive function. However, because FMRP — the gene product of FMR1 — has many functions in the brain, the molecular, synaptic, and circuit dysfunctions seen in FXS may not be easily corrected by targeting a single downstream or parallel pathway. Despite intensive efforts to better understand the etiology, there remains a dearth of disease-specific treatments. It is now known that restoring FMR1 expression can at least partially rescue FXS phenotypes. Towards this goal, we recently identified a new approach that corrects the underlying genetic defect by reactivating the silenced FMR1. By investigating conditions favorable to FMR1 reactivation, we found that two compounds (“2i”) — a MEK and a BRAF inhibitor — could fully turn back on FMR1 in cellular models. We traced the mechanism to 2i-mediated DNA demethylation and formation of site-specific R-loops that then recruit endogenous DNA repair mechanisms to excise the CGG repeat. We went on to demonstrate that the CGG contraction and gene reactivation could be recapitulated by driving site-specific R-loop formation using dCas9 and an FMR1-specific gRNA. These discoveries lead to a model in which R-loops induce a positive feedback cycle comprising DNA demethylation, de novo FMR1 transcription, and reinforcement of R-loops at the CGG repeat — which in turn drive recruitment of endogenous DNA repair mechanisms to remove the aberrant RNA:DNA structure. Excision of the long CGG repeat then enables the reactivation of FMR1. We observed that repeat contraction is specific to FMR1 and fully restores production of FMRP protein. Our study thereby identifies a novel and potential method of treating FXS. In the proposed research, we aim to obtain proof-of-concept that R-loops form and induce contraction of the CGG repeat in post-mitotic neurons and that the contraction can lead to FMR1 reactivation in a human 3D disease model for FXS. If successful for FXS, the R-loop approach could be a potential therapeutic for other tandem repeat disorders as well.

NIDCR - National Institute of Dental and Craniofacial Research

PROJECT SUMMARY/ABSTRACT The US faces a mental health crisis; nearly 83 million Americans experience mental illness, but fewer than 50% of these individuals accessed past year mental health services. There is a critical need for highly disseminable, potent mental health interventions. Standalone digital interventions offer promise for improving clinical outcomes at scale; however, efficacy of these interventions to date is modest, likely due in part to insufficient personalization to patient heterogeneity and to momentary changes in mental health symptoms. The present study seeks to rapidly improve the efficacy of precision psychiatry digital health interventions by developing real-world, person-centered maintenance models for psychopathology using ecological (i.e., in patient’s daily lives) data and dynamic systems modeling. Dynamic systems modeling of repeated time series data yielded by ecological momentary assessment (EMA) and smartphone sensors will be used to evaluate the individual and interactive effects of empirical maintenance factors to understand each individual’s maintenance system for psychopathology in their daily life. Just-in-time adaptive interventions (JITAIs) are prompts delivered in-the-moment via smartphone at identified instances of risk for maladaptive behaviors. Although often evaluated in aggregate across months, JITAIs could be conceptualized as ecological quasi-experiments that induce use of specific therapeutic skills at observable times. Accordingly, this study will use micro-randomized (in which the content of the JITAI is randomly assigned in the moment) JITAIs delivered at times of elevated risk for maladaptive behavior based on the individual’s developed dynamic system to evaluate the effects and mechanisms of specific therapeutic skills on outcomes of interest, to provide granular insight into treatment mechanisms. Eating disorders are the ideal population in which to test proof-of-concept for these methods to improve efficacy of precision psychiatry digital interventions, as they are characterized by easily measurable maladaptive behaviors (i.e., dietary restriction, binge eating, compensatory behaviors), are maintained by a complex intersection of biological, psychology, and social factors, and their frontline treatment, enhanced cognitive behavioral therapy (CBT-E), is primarily comprised of behavioral skills. The aims are: 1) test the hypothesis that person-centered dynamic models will describe risk for dietary restriction, binge eating, add compensatory behaviors with ≥ 60% average goodness-of-fit, 2) test hypothesized effects and mechanisms of CBT-E skills on eating disorder behaviors and primary maintenance factors using JITAIs, and 3) characterize feasibility and acceptability of the standalone JITAIs. The study will enroll N = 170 adults with eating disorders who will complete four months of ecological data collection and receive JITAIs to use CBT-E skills at times of elevated risk for 10 weeks of the data collection period. The study will set the stage for future randomized controlled trail to evaluate the optimized, standalone JITAI system, which will have the potential to substantially improve access to evidence-based mental healthcare.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Fetal Alcohol Spectrum Disorder (FASD) is a lifelong and highly consequential condition affecting up to 1 in 20 children in the U.S. Despite the availability of evidence-based treatment options, only a very small minority of pregnant women meeting criteria for an alcohol use disorder receives treatment; and of those not receiving treatment, 95% do not feel that they need it. Screening and brief intervention approaches (SBIRT) are designed to reach this non-treatment seeking majority and are widely recommended for use in pregnancy. However, although SBIRT is predicated on small effects that have a meaningful public health impact when delivered at scale, decades of research have shown that (1) its effects are smaller than once hoped, and (2) it is challenging to implement in busy healthcare settings. In response, we have extensively studied digital SBIRT approaches (e-SBIRT), with promising results regarding efficacy—particularly when pairing e-SBIRT with digital “dose” enhancers such as text messages and booster sessions. Unfortunately, implementation challenges have persisted despite the greatly reduced effort needed to implement e-SBIRT in prenatal care settings. Continued innovation is urgently needed. We propose two enhancements designed to increase e- SBIRT scalability and impact. First, we will improve scalability by testing e-SBIRT delivery within a whole- health pregnancy checkup and feedback model addressing a range of protective and risk factors, such as sleep, prenatal care adherence, mental health, and nutrition, in addition to alcohol. This adaptation will reduce stigma and increase perceived relevance among patients as well as clinic staff. Although allocating disproportionate time to alcohol, this approach will also allow delivery of content addressing factors known to contribute to alcohol use, such as depression. Second, we will improve impact by augmenting individual-level e-SBIRT with an engaging intervention to help family members, friends, and/or partners—selected by the pregnant participant—to effectively support the pregnant participant’s health in all areas, including alcohol. In the R61 phase, Aim 1 will use mixed methods to develop e-SBIRT multi, a user-centered, multi-level, and multi-target screening and brief intervention for pregnant participants and their key support network. R61 phase Aim 2 will evaluate e-SBIRT multi feasibility and acceptability in a single-arm trial. If e-SBIRT multi meets a priori benchmarks/milestones, R33 phase Aim 3 will test it against enhanced treatment as usual in a confirmatory two-arm randomized clinical trial (N = 326 pregnant women plus support participants). R33 phase Aim 4 of this hybrid type 1 trial will evaluate implementation outcomes among healthcare professionals, clinic staff, pregnant participants, and support network participants. This project will develop and rigorously evaluate two enhancements with the potential to increase brief intervention acceptability and impact while retaining the high-reach advantages of e-SBIRT. It represents an important step toward re-imagining SBIRT to achieve the goal of a true public health impact on FASD.

NIMH - National Institute of Mental Health

Project Summary/Abstract Amid an unprecedented youth mental health crisis, adolescents and young adults (AYA) have the most barriers to receiving mental healthcare. While digital tools are a scalable and accessible way to provide timely mental health screening and referral options, these tools have failed to engage AYA in their daily lives. This failure is driven by multiple factors, including a lack of: 1) understanding of implementation determinants for digital tools in community spaces; and 2) partnership with AYA, their caregivers, and support staff who work in key community settings where AYA spend their time. Consistent with the NIMH Strategic Plan and National Advisory Mental Health Council report, the goal of this R34 proposal is to target AYA engagement in the design and implementation of a digital low-intensity treatment for AYA in Chicago Park District (CPkD) Teen Programming. The CPkD is the largest park district in the country, and more than 40,000 youth are served daily across all 77 Chicago neighborhoods. This project harnesses on a partnership with CPkD and is grounded in the Accelerated Creation-to-Sustainment (ACTS) Model to guide the development of a technology (the “CPkD D-LITe”), as well as its service and implementation plans for CPkD sites. Aim 1 follows the first phase of the ACTS Model, Create. Human-centered design and community-engaged research methodologies will be used to collaborate with the existing CPkD Youth Advisory Board and Teen Programming participants, caregivers of AYA served by CPkD, and CPkD staff. Design activities will focus on targeting mechanisms that are believed to influence engagement: 1) individual-level barriers to care; 2) leveraging spaces where youth spend their time, including assessing determinants in these spaces; and 3) elevating key player input throughout design. The products of Aim 1 will include: an initial version of the “CPkD D-LITe” that demonstrates usability and acceptability by key players, a service protocol for integration of the “CPkD D-LITe” and potential higher clinical needs reported by AYA as a result of using the tool, and an implementation blueprint for integration into CPkD programming. Additionally, extended usability testing will pilot all trial activities to be conducted in Aim 2. In Aim 2, the second phase of the ACTS Model, Trial, will be followed by conducting a pilot randomized controlled trial in CPkD sites using an Optimization, Effectiveness, and Implementation trial methodology. The “CPkD D-LITe” will be compared to a control condition (digital workbook) across a pragmatic, rollout implementation trial. Primary outcomes include acceptability and feasibility, along with reductions of individual levels to mental healthcare, DMH use, and, secondarily, clinical outcomes (anxiety, depression). Optimization activities will occur across the trial period. In sum, the naturalistic approach of this work addresses multiple barriers to real-world digital tool engagement failures for AYA. It will provide key insights into engagement strategies, adaptations, and both service and implementation practices that will support AYA in community settings, both broadly and in a future R01 proposal.