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NIMH - National Institute of Mental Health

PROJECT SUMMARY: Menopause is a pivotal life stage that brings about lasting changes in mental and cognitive functioning, potentially leading to profound negative effects on multiple life domains in females. During this period, many females may experience the worsening of depressive symptoms or onset of major depressive disorder (MDD), the most prevalent and disabling psychiatric disorder worldwide. Despite the fact that females comprise about half of the global population, evidence that neurochemical alterations observed during menopause may be associated with dementia onset, and higher rates of depression and dementia in females, there are currently no effective treatments targeting the mood and cognitive alterations experienced during menopause. Converging evidence from human clinical studies, postmortem analyses, and preclinical research suggests that both depression and menopause may alter the same brain mechanisms that are crucial for maintaining brain health, particularly through synaptic alterations as possible neurochemical mechanisms. Recent advancements in in vivo quantification of synaptic density in humans have made it possible to measure the density of synaptic vesicle glycoprotein 2A (SV2A), a widely expressed marker of synaptic density, using positron emission tomography (PET) imaging. Our prior studies have revealed that synaptic density is lower in individuals with MDD across young to middle adulthood. In the current study, we aim to conduct the first known in vivo human PET imaging study of how menopause affects synaptic density, whether MDD may exacerbate menopause-related alterations in synaptic density, and how these synaptic changes relate to objective and subjective measures of mood and cognition. Our preliminary data reveal significantly lower synaptic density in corticolimbic regions in post-menopausal females compared to their pre-menopausal counterparts. They further indicate substantially more pronounced deficits in synaptic density in post-menopausal females with MDD compared to pre-menopausal females with MDD, suggesting an acceleration of synaptic degradation. In the proposed study, we seek to confirm these findings in a large, well-characterized sample of females, incorporating a Research Domain Criteria (RDoC) approach to evaluate the role of menopause in moderating the relation between synaptic density and the full spectrum of mood and cognition. To assess the clinical significance of these changes, we will examine how menopause- and MDD-related changes in synaptic density are associated with functional neural (i.e., electroencephalography) and behavioral (i.e., clinical interview) measures of negative and positive valence and cognitive systems. Results of the proposed study will provide the first human in vivo data on the effects of menopause and MDD on brain synaptic density, and whether these changes may underlie the mood and cognitive alterations experienced in menopause. In doing so, they will help inform a modifiable, precision medicine-based target for treatments aimed at improving mood and cognitive alterations associated with this significant life change among females.

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

SUMMARY Reliable tools for early prediction and effective treatments of spontaneous preterm birth (sPTB) are missing. This is due to an incomplete understanding of the subclinical pathobiology preceding sPTB. The long-term goal of this project is to integrate pathological, physiological, and psychological domains preceding sPTB to define mind- body crosstalk mechanisms that enable robust sPTB prediction and reveal potential targets for therapeutic intervention. The overall objective in this application is to establish neuroimmunoendocrine pathways as critical modulatory links between maternal mental state, immune imbalance, and sPTB. The central hypotheses are that (i) catecholaminergic (i.e., dopaminergic) signaling in maternal central and peripheral systems mitigates inflammation-induced parturition, supporting pregnancy maintenance, and that (ii) disruptions in neuroendocrine signaling may underlie an immune shift in the maternal circulation as well as at the maternal-placental interface promoting sPTB. The central hypotheses will be tested by pursuing three specific aims: 1) Determine whether central dopaminergic activity mitigates inflammation-induced PTB in mice; 2) Define predictive neuroimmunoendocrine trajectories of sPTB and their placental inflammatory signatures; and 3) Determine the effect of dopamine on the human maternal-placental interface, comparing sPTB vs. TB. Under the first aim, an established murine model of PTB will be combined with targeted neuromodulation of central reward circuitry to evaluate the effect on birth timing and peripheral immune state. In the second aim, human pregnancies at risk for sPTB will be longitudinally evaluated for multiple psychological (psychometric surveys, allostatic load) and physiological (blood immune function, non-invasive urine markers, cerebrospinal fluid markers, placental pathology) domains to define mind-body crosstalk prior to and at manifestation of clinical parturition pathology. In aim three, human endometrial stromal cells will be used to identify and causally link the effect of catecholamines on inflammatory signaling, differentiation, and protein secretion at the maternal-placental interface. The research proposed in this application is innovative because it represents a substantive advancement from the status quo by defining the basic principles of the maternal brain–immune–reproductive system axis in healthy pregnancies and those complicated by sPTB. The proposed research is significant because it is expected to offer a strong scientific framework whereby new strategies for the clinical management of patients at risk for sPTB can be developed.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Schizophrenia (SZ) remains one of the most debilitating psychiatric disorders and mechanistic understanding of the disease is minimal. Glutamatergic neurotransmission may play a role in SZ, but this has been difficult to study directly as the developing brain is inaccessible and complicated psychiatric syndromes cannot be easily replicated in non-human animals. Work using neurons derived from patient stem cells (iNeurons) has demonstrated a way to circumvent these limitations, and data from Dr. Anderson’s lab suggest the variable penetrance SZ in a well-defined neurodevelopmental disorder (22q11.2 deletion syndrome; 22qDS) corresponds to impaired oxidative phosphorylation (OXPHOS) in mitochondria. This proposal addresses the fundamental question of how alterations in mitochondrial function lead to complex psychiatric symptoms of SZ. AIM1 will test the hypothesis that mitochondrial dysfunction in presynaptic compartments results in diminished glutamate release in iNeurons from 22qDS individuals with SZ (22q+SZ) relative to those without SZ [22q(-)SZ]. Optical imaging of glutamate (AIM1.1) and synaptic vesicle cycling (AIM1.2) will be used to assess glutamate release from individual nerve terminals by independent methods under both high and low frequency neuronal stimulation. AIM2 will use computational modeling to access how alterations in presynaptic mitochondrial function contribute to circuit connectivity and entropy (disorder) in (22q+SZ) and [22q(-)SZ] iNeurons. This proposal fits within NIMH’s Strategic Plan to define brain mechanisms underlying behavior and mental illness and is expected to generate insights into mitochondrial influence on presynaptic function and glutamatergic neurotransmission in the emergence of SZ symptoms in 22qDS while also establishing a robust model of human cellular, synaptic, and circuit neuropathology in patient derived cells. Dr. Rossano will receive training in induced pluripotent stem cell models, medium-to-high throughput synaptic imaging in patient-derived cells, computational modeling of circuit connectivity, and integration of mitochondrial biology with synaptic physiology. Drs. Anderson and Goldberg possess complementary expertise and are uniquely suited for this proposal. A thoughtfully selected advisory committee will provide further scientific and career mentorship. Together with the world-class resources available at the Children’s Hospital of Philadelphia and the University of Pennsylvania the proposed scientific and training objectives will allow Dr. Rossano to establish an independent research program focused on synaptic neuroscience and mitochondrial biology as therapeutically targetable mechanisms underlying symptoms in SZ, autism, and additional neurodevelopmental disorders.

NIMH - National Institute of Mental Health

Abstract The medial prefrontal cortex (mPFC) is critical for executive function, yet how its dorsal (dmPFC) and ventral (vmPFC) motor-projecting (MP) neurons coordinate behavioral initiation, inhibition, and cognitive flexibility remains poorly understood. This R21 leverages four translational behavioral paradigms (head-fixed Persistent Licking/Shock-Escape; freely moving FED3-based Reversal Learning/Stop-Signal), high-density neural recordings, circuit manipulations, and Brian2 spiking neural network modeling to test our central hypothesis: dmPFC MP neurons drive action initiation and adaptive switching, while vmPFC MP neurons suppress impulsivity and perseveration. In Aim 1a, we quantify behavior using kinematic analyses (jerk, velocity, z-scored) aligned with human executive dysfunction metrics (Action Latency [AL], Reversal Accuracy [RA], Perseveration Errors [PE], Stop-Signal Reaction Time [SSRT]), combined with optogenetic (stGtACR2/ChR2) and chemogenetic (PSAM/varenicline) perturbations. Aim 1b employs optotagging and population analyses (PCA, SVM, Total Spiking Probability Edges) to decode dmPFC/vmPFC MP dynamics across tasks, resolving specialized versus mixed functional roles. Aim 1c integrates these datasets into Brian2 spiking network models to predict neural-behavioral correlations, validated through cross-validation. Exploratory analyses will link murine kinematic signatures to human stop-signal/reversal learning metrics. By elucidating strain-specific (C57BL/6 vs. CD1) circuit mechanisms and delivering translatable biomarkers (AL, RA, PE, SSRT, kinematics), this work addresses a critical gap in understanding neuropsychiatric disorders like ADHD (impulsivity) and schizophrenia (perseveration). The study’s innovative combination of recurrent neural network theory, FED3-based assays, and New Approach Methodology (NAM)-compliant computational modeling pioneers high-risk, high-reward tools for circuit dissection, fully aligning with NIH’s 2025 priorities.

Health Resources and Services Administration

<p>The RCORP-Child and Adolescent Behavioral Health Program provides funding to rural communities to establish and expand behavioral health care services, including mental health and substance use disorder for rural children and adolescents.&nbsp;</p>

Health Resources and Services Administration

The RCORP-Child and Adolescent Behavioral Health Program provides funding to rural communities to establish and expand behavioral health care services, including mental health and substance use disorder for rural children and adolescents.

NIMH - National Institute of Mental Health

Project Summary Despite widespread prevention efforts, suicide is the second leading cause of death among teens and young adults, and increasingly, suicide has become a public health concern among children <12-years-old. The emergency department (ED) often serves as the primary contact point for youth to receive care for suicide risk. Yet, among adolescents receiving inpatient or ED care, 10% will attempt suicide and 30% will exhibit suicidal behaviors within 3 months of discharge. This study aims to map the landscape of early suicide risk among children seeking ED care to facilitate the development of actionable intervention targets/methods. We will recruit N=250 children (8-12 years old) via multiple pediatric EDs (NewYork-Presbyterian, Montefiore) with diverse catchment areas and patients with typically less access to care. Children and their guardian will complete clinical interviews to probe suicide and related risk factors. Electronic health records will be probed for structured data on risk factors as well as using natural language processing of clinician notes. Children will also complete brief MRI scanning at baseline to assess brain structure (using clinically relevant MRI protocols) and midbrain dopamine (novel neuromelanin MRI). We focus on brief, clinically relevant sequences that are readily harmonized across site/scanners and can be assessed from brain imaging ordered as part of clinical practice. During a 6-month follow-up period, guardians will complete low-burden, weekly check-in surveys (via their personal smartphone) as well as brief 3- and 6-month remote interviews to characterize fluctuations in their child’s suicide risk, difficulties with safety plans, changes in risk factors (e.g., sleep, familial disruptions, impulsive behaviors), and any subsequent of suicide behaviors. These multi-faceted data will be leveraged to examine clinical and neural risk factors that predict post- discharge suicide events (e.g., suicide attempts, return to ED, or psychiatric hospitalization) in high-risk children. Weekly parental reports will help to map post-discharge changes over 6 months related to suicide events post- discharge. We anticipate that greater psychiatric comorbidity, sleep problems, and family stress will be critical risk factors for post-discharge suicide outcomes. Further, smaller prefrontal, striatal, and cingulate volumes relative to population levels as well as reduced midbrain dopamine will predict greater risk for future suicide events. Difficulty implementing safety plans, maintaining regular routines (e.g., bedtimes, home environment), and excessive family conflict in the post-discharge period will relate to subsequent suicide events. This work will inform the development of new screening (to ensure that key risk factors are clearly ascertained and documented), improve discharge plans for clinicians, and help families detect risk post-discharge. Improving care for high-risk young children is an urgent priority. Findings from this work may be able to address suicide risk in other settings (e.g. primary care) and populations.

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

PROJECT SUMMARY/ABSTRACT Youth in high school typically do not get enough sleep, and this lack of sleep can exacerbate the academic challenges of starting high school, as well as the risk for poor mental health, which is already elevated in this period. Youth with attention-deficit/hyperactivity disorder (ADHD), who make up ~9% of high school students, are more likely to struggle academically, develop comorbid mental health problems, and experience poor sleep compared to their peers. This combined risk makes the transition to high school an especially vulnerable period for youth with ADHD. Delaying high school start times is one approach to alleviate sleep-related challenges that youth face when starting high school, and there is mounting evidence suggesting that delayed start times improve academic and health outcomes. Critically, the neurobiological and behavioral mechanisms conveying the benefits of delayed school start times are still unclear. Further, it is unknown if youth with ADHD will see enhanced benefits from delayed school start times. This proposal will address these gaps by capitalizing upon a Florida state law mandating a delay in high school start times to no earlier than 8:30am in the 2026-2027 school year. To leverage this upcoming change, we propose a two-cohort quasi-experimental design with an ‘early-start’ (7:30am) cohort of 9th grade students to be collected in the 2025-2026 school year and a ‘delayed-start’ (8:30am) cohort to be collected in the 2027-2028 school year. Each cohort will include 50% youth with ADHD, and we will conduct a follow-up assessment of 80% of each cohort in 10th grade. Using rich behavioral data and sophisticated modeling of functional MRI (fMRI) data, we will test the following hypotheses: First, the delayed-start cohort will have better subjective and objective sleep, more structured morning routines, fewer mental health problems, including ADHD symptoms, and better academic achievement (Aim 1). Second, during resting state and reading fMRI tasks the delayed-start cohort will have more segregation between opposing brain networks that facilitate externally- and internally-focused attention (dorsal attention and default mode, respectively), as well as more integration of these two networks with a third network (fronto-parietal) that flexibly orchestrates the balance between the two attention-related networks (Aim 2). Third, youth in the delayed-start cohort will see more developmentally-appropriate changes in brain networks, increased grades, and decreased mental health problems in the transition from 9th to 10th grade (Aim 3). Throughout our aims, we hypothesize to see greater benefits of delaying school start times in youth with ADHD. Together, the findings from the proposed project will clarify how delaying school start times protects youth with and without ADHD during a pivotal transition period and, critically, will provide evidence for how delayed start times confer benefits to short- and long-term outcomes via modulation of sleep quality, morning routines, and functional brain networks supporting attention. This proposal stands to provide a comprehensive characterization of large-scale policy changes impacting youth during a vulnerable period.

NIMH - National Institute of Mental Health

Reducing the age at autism diagnosis is a crucial public health priority, as early diagnosis is associated with better developmental and mental health outcomes. Though autism can be reliably diagnosed in children as young as fourteen months, the average age at diagnosis in the United States is around four to five years. Documented differences in diagnostic timeliness exist by sociodemographic features. However, more research is needed on the modifiable, or scalable, aspects of the service system that can facilitate earlier access to autism diagnosis. Autism screening in primary care holds promise to reduce the average age at diagnosis, as autism-specific screening and attendance at well-child visits are associated with earlier age at diagnosis. Yet, to date, no comparative studies have been conducted to understand the differences in diagnostic timeliness between those screened versus those not screened for autism in primary care. Optimizing early identification of autism in primary care is crucial, as primary care is often children’s entry point on their pathway to a diagnosis. Of parallel importance, more research is needed on children’s complete pathway through services to the receipt of a diagnosis so that optimal pathways that facilitate earlier diagnosis can be identified. Therefore, the present study aims to understand what services work and in what context to lower the age at autism diagnosis, with a particular focus on autism screening in primary care. Prior studies of age at diagnosis have been limited by an over-reliance on Medicaid claims data, retrospective caregiver-report, and analysis of discrete variables in relation to age at diagnosis (e.g., number of appointments). The present study leverages the MarketScan Commercial Claims Database—a national claims database comprised of over 10 billion records from 70 million privately insured individuals. The present study is the first to examine autism screening in primary care using claims data. Analyzing data from a sample of children diagnosed with autism in early childhood, we aim to: 1) evaluate the effect of autism screening in primary care on child age at autism diagnosis using propensity score matched samples, 2) compare the effect of autism screening in primary care on child age at diagnosis in resource-poor or resource-rich areas, and 3) discover service pathways to a formal autism diagnosis using discrete sequence clustering analysis. A highly experienced mentorship team of investigators will support the principal investigator’s research and training plan to further her independence as a behavioral health services researcher, with a focus on autism-related services. Through a combination of carefully curated training activities, the principal investigator will: 1) deepen her understanding of autism-specific service disparities in early childhood and identify targets for intervention, 2) develop expertise in behavioral health services research methodology, 3) build mastery in administrative claims data management, 4) gain knowledge in rigorous analytic approaches for use in observational data, and 5) strengthen skills in scientific writing and related skills to bolster her independence as a scientist.

NIMH - National Institute of Mental Health

Approximately 4.5 million children in the United States (US) display severe emotional and behavioral disturbance. While it is not unusual for preschoolers to have occasional temper tantrums, it is considered symptomatic when temper outbursts (characterized by sudden, violent expression of strong feeling, anger, and aggression) occur most days that are severe enough to impair their academic, social, and family functioning. Evidence-based therapies such as parent child interaction therapy (PCIT) reduce behavioral challenges in children by improving parent-child relationships through parenting practices taught over a multi-week period. Despite the widespread availability of behavioral interventions, there are significant challenges: (a) the effectiveness of interventions is contingent upon parents remembering parenting practices taught during weekly therapy sessions to engage with their children, (b) there is limited education for affected children and their parents to help preempt temper outbursts and regulate their emotion, and (c) families from rural areas and populations with limited specialized pediatric mental health providers are less likely to have access to and utilize evidence-based therapies when it is available. The overarching goal of this convergent research proposal is to investigate the development of generative methods with closed-loop feedback from parents to individualize real-time interventions for children when a temper outburst is predicted. The project will accomplish the goal through the following aims. Aim 1: This project will develop generative algorithms with closed-loop feedback using 5.4 million minutes of smartwatch data collected from 50 children (aged 3 – 7 years) and parent-provided timestamps (closed-loop feedback) of disruptive behavior (characterized by temper outbursts). Aim 2: The developed technology will then be evaluated in a cohort of 50 new children to assess if parenting practices combined with child-initiated mindfulness (i.e., new patient-education) upon a predicted temper outburst could improve behavioral outcomes. Aim 3: Elucidate the perspectives of stakeholders (e.g., parents, schoolteachers) on the use of continuous monitoring devices for adaptive generative intelligence algorithms.

Education Department

The Department of Education (Department) announces final priorities, requirements, and definitions under the School-Based Mental Health Services (SBMH) Program, Assistance Listing Number (ALN) 84.184H. We may use one or more of these priorities, requirements, and definitions for competitions in fiscal year (FY) 2025 and later years. These final priorities, requirements, and definitions are designed to target activities with the purpose of increasing the number of credentialed school-based mental health services providers, specifically school psychologists, in high-need local educational agencies (LEAs) available to provide mental health services to students. These priorities, requirements, and definitions replace the Notice of Final Priorities, Requirements, and Definitions published in the Federal Register on October 4, 2022 (87 FR 60092). However, those priorities, requirements, and definitions remain in effect for previous grant competitions in which the notices inviting applications (NIAs) were published before the Department finalized the proposed priorities, requirements, and definitions in this notice.

NIMH - National Institute of Mental Health

PROJECT SUMMARY PTEN (Phosphatase and Tensin Homolog) is one of the strongest genes associated with autism spectrum disorders (ASDs) and one of the most highly pleiotropic. PTEN encodes a negative regulator of mTOR signaling – a central metabolic pathway controlling protein synthesis, cell growth, and survival, yet the mechanisms contributing to the considerable pleiotropy of PTEN mutations are not well understood. Here, we propose a highly innovative approach that leverages the unique features of zebrafish to illuminate basic neurodevelopmental mechanisms downstream of PTEN loss of function and rapidly screen the functionality of human PTEN variants and pharmacological candidates targeting these mechanisms. Our central goals are: (1) to screen the functionality of human PTEN variants in the developing vertebrate brain in vivo; and (2) to identify novel pharmacological suppressors of PTEN-associated phenotypes. Our central hypotheses are: (1) the in vivo functional effects of PTEN mutations will reveal novel genotype-phenotype correlations, expanding on existing in silico and in vitro analyses; and (2) targeting specific components of the mTOR pathway will selectively reverse these phenotypes. To test our hypotheses, we will perform in vivo zebrafish screens to assess the functionality of human PTEN variants in a developing vertebrate brain informed by multiple in silico and in vitro predictions (Aim 1); and conduct high-throughput pharmacological screens of mTOR-targeting compound libraries in zebrafish (Aim 2). Our team is uniquely suited to perform these experiments, given our complementary expertise in high-throughput zebrafish ASD gene mutant analyses (MPI Hoffman) and computational modeling of ASD gene variants (MPI Turner). The broader impact of this research is to establish a proof-of-principle for in vivo human variant and pharmacological screens in zebrafish and to illuminate basic mechanisms contributing to pleiotropy across neurodevelopmental disorder genes.

NIMH - National Institute of Mental Health

SeeMe: A multimodal behavioral-electrophysiological tool for real-time detection of motor behavior in brain injury patients Abstract An obstacle in clinical and basic science consciousness research is the lack of quantitative techniques to assess the recovery of voluntary behavior. Standard techniques for consciousness detection depend on subjective assessment of voluntary behavior. These methods are slow, observer-dependent, and lack the temporal resolution to study brain circuits supporting consciousness. In Phase R61 of this proposal, SeeMe, a novel, objective, real-time tool, will be developed to detect voluntary behavior. This multi-modal tool is based on the measurement of face and hand movements to command in recovering traumatic brain injury (TBI) patients who may appear unresponsive. SeeMe detects early signs of low-amplitude voluntary behavior currently unseen by clinical examiners. These detected movements will be linked with neural recordings to interrogate underlying circuits supporting voluntary behavior. This tool will be made freely available to researchers interested in consciousness and more generally studying brain-behavior relationships. Phase R33 will use SeeMe to time- lock vagus nerve stimulation to voluntary behavior in recovering TBI patients, analogous to its FDA-approved use in stroke. This framework will be used to study the neural correlates of voluntary behavior in TBI patients. When complete, this project will deliver 1.) a novel objective tool for analyzing voluntary behavior, 2.) a computational framework for synchronizing behavior with brain activity, and 3.) a closed-loop stimulation system to develop future neuromodulatory therapeutic approaches to facilitate the return of motor behavior after injury.

NIMH - National Institute of Mental Health

While several studies have characterized myeloid cells as the primary central nervous system (CNS) HIV reservoirs on long-term suppressive antiretroviral therapy (ART), significant knowledge gaps remain in understanding the role of CD4+ T cells in CNS reservoir seeding, viral persistence, and neuropathogenesis. The characterization, and ultimate eradication, of HIV persistence and neuroinflammation remain key goals of HIV research and defining the roles of T cells and their interactions with CNS cell populations driving these processes are essential. In this application, we propose to leverage our validated nonhuman primate model of HIV neuropathogenesis and persistence, our experience defining early CNS seeding, and past studies of T cell sequestration, to determine the impact of blocking T cell circulation during acute SHIV infection on the establishment of durable brain reservoirs. Our model of CNS persistence uses TF SHIV.D.191859 (SHIV.D), a CCR5-tropic virus that efficiently replicates in both CD4+ T cells and macrophages, and consistently infects the CNS, causes neuroinflammation, and persists through ART via long-lived myeloid reservoirs. Genetically barcoded SHIV.D has been validated in persistence experiments, enabling tracking of clonotypes across tissues over time. Our recent studies of barcoded SHIV.D-infected, ART-treated NHP have shown early seeding of the brain that persists through durable ART. Our team has also demonstrated in ART-suppressed SIV-infected rhesus macaques (RMs) that a clinically approved immunomodulating therapy for multiple sclerosis, FTY720, results in rapid and near-complete redistribution of CD4+ T cells from blood into peripheral tissues, with minimal impact on blood monocytes. Thus, FTY720-induced inhibition of T cell, but not monocyte, migration will enable us to dissect the specific role of CD4+ T cells in trafficking of SHIV to the brain and establishing short- and long- term brain reservoirs. RMs will be infected with barcoded SHIV.D and then treated with FTY720 either 1 week prior to infection (Arm 1), or 7 days post-infection (Arm 2), or left untreated (Arm 3). ART will be administered 1- month post-infection, with half of the animals in each arm to undergo necropsy early at 1 month ART, or later at 6 months ART. Arm 4 animals will be infected and receive FTY720 only and be necropsied at study month 2 to compare the effects of FTY720 without ART. In these coordinated NHP studies, we will test our hypothesis that FTY720-mediated inhibition of T cell migration to the brain will prevent early seeding of SHIV brain reservoirs, will limit the size and diversity of the persistent CNS reservoir, and will reduce neuroinflammation on suppressive ART. Using an array of molecular, immunohistochemical, and single cell analyses, we will assess the impact of peripheral CD4+ T cell sequestration on early and late SHIV brain reservoir seeding, then characterize the impacts on neuroinflammation and neurodegeneration. These studies will provide valuable insight into the role of CD4+ T cells in CNS reservoir seeding, including their contribution compared to monocytes, the timing of the reservoir establishment, and their contribution to neuroinflammation.

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

PROJECT SUMMARY According to a recent report by the Centers for Disease Control and Prevention, 60% of U.S. adults have reportedly had at least one early adverse experience (e.g., physical, emotional, or sexual abuse) with nearly 40% having two or more early adverse experiences. Extensive work has been done to uncover the mechanisms that link early adversity to mental health problems with self-regulation consistently emerging as a key contender. Self-regulation is consistently and highly heritable with its development facilitated by both biological and environmental processes. Importantly, the transition from middle childhood to early adolescence marks a critical period of growth in self-regulation. Attachment theory suggests that parents play an integral role in its development through shaping both the genetics and the environment of the child. Studies on the role of parenting in the development of self-regulation to date examine a single level and time scale at a time failing to capture the complex, multilevel nature of children's experiences of parenting that span from moment-to- moment interactions to consistent parenting styles and interplay between them. Dynamic Systems Theory (DST) further highlights this limitation by emphasizing the importance of examining multiple levels of a system across different timescales to fully conceptualize the complex developmental processes at play. Thus, the overarching purpose of the proposed project is to better understand the development of self-regulation across phenotypic and genetic levels and different timescales using the Arizona Twin Project, a large longitudinal study of racially/ethnically and socioeconomically diverse twins, across middle childhood and the transition to adolescence. To accomplish this, the current project has proposed three aims. First, we will examine the effects of moment-to-moment parenting behaviors on self-regulation in middle childhood. Second, we will investigate the effect of parenting behaviors on self-regulation longitudinally across middle childhood and the transition to adolescence. Third, we will elucidate the shared genetic and environmental etiology of parenting behaviors and trait-level self-regulation across middle childhood and the transition to early adolescence. By the end of my doctoral education, I want to develop an extensive expertise on parenting and self-regulation, quantitative methodology, and science communication to ensure that I am prepared for a multifaceted tenure-track career at a rigorous, research focused academic institution. My training objectives include: 1) gain an in-depth understanding of the role of parenting in the development of self-regulation; 2) obtain advanced training in quantitative methodology with a focus on intensive and long-term longitudinal data; 3) extend academic writing and communication skills to translating scientific information for the public. By accomplishing these training objectives in tandem with the proposed project, I will lay the foundation for my future work focused on improving individual, familial, and societal well-being.

NINR - National Institute of Nursing Research

ABSTRACT Intimate partner violence (IPV) poses significant social and health challenges, particularly affecting immigrant women who confront increased risk and adverse consequences. Chinese immigrants, the largest Asian ethnic group in the U.S., with over 4 million individuals, have received limited focus in existing IPV research and intervention efforts, despite a high prevalence of IPV reaching nearly 21% within the past year. They face substantial barriers to accessing IPV and mental health services, due to sociocultural factors such as stigma or shame, limited English proficiency, isolation from mainstream American society, unfamiliarity with available resources, and limited availability of linguistically and culturally appropriate services. Moreover, IPV’s substantial and well-documented effects on mental health further exacerbate the challenges faced by this population of women. However, there is a lack of culturally appropriate interventions that address these barriers while improving their acceptability and accessibility to address the mental health needs of abused Chinese immigrant women. To fill this gap, our proposed community-partnered intervention, Self-Compassion, Health, and Empowerment (SHE), adapts a structured safety and empowerment intervention while uniquely incorporating mental health elements, including relaxation and self-compassion meditation, to address abused Chinese immigrant women’s mental health needs. Leveraging mobile health technology, our intervention seeks to overcome barriers such as geographic dispersal, stigma, and privacy concerns that often hinder access to support. Our pilot randomized controlled trial (RCT) with 50 abused Chinese immigrant women has shown the feasibility and acceptability of the mobile-based SHE intervention, which forms the basis for this proposal of a fully powered two-arm RCT. The primary aim of the study is to test the efficacy of the mobile-based SHE intervention in improving mental health among Chinese immigrant women experiencing IPV and co-occurring symptoms of depression, anxiety, or posttraumatic stress disorder (PTSD). We will recruit 364 Chinese immigrant women and randomize them 1:1 to the intervention or attention control group. The 6-week SHE intervention consists of one phone session on IPV safety and empowerment and five weekly relaxation/self-compassion sessions via text. The attention control group will receive 6 weekly nutrition and health sessions, matched in delivery mode, timing, and contact frequency. We will compare the two groups for primary outcomes of depression, anxiety, and PTSD symptoms and the secondary outcome of IPV from baseline to 6-week, 3-month, 6-month, and 12-month follow-ups. Our findings will provide evidence for the application of the mobile-based SHE intervention to support the mental health needs of abused Chinese immigrant women. Our approach is innovative, and there is a high potential for scaling up the intervention to improve access to IPV and mental health support among Chinese immigrant women experiencing IPV.

NIMH - National Institute of Mental Health

Project Summary Mood disorders in adolescence are prevalent, disabling, and associated with future chronicity and severity of mood problems in adulthood, making this a developmental period in which effective early intervention is especially important. A critical common ingredient of many interventions for adolescent mood disorders is inter- session monitoring of behaviors and mood; such monitoring is used by patients and practitioners to support case conceptualization, identify patient-specific maladaptive behaviors, and evaluate treatment outcomes. However, adherence to inter-session monitoring is low among adolescents, undermining intervention effectiveness. To optimize and support delivery of effective interventions for adolescent mood disorders, we are in need of novel, low-burden strategies for monitoring behavior and mood. The proposed study aims to address this urgent need by validating and translating a novel smartphone-based intervention monitoring approach (Sensor-Based Intervention Monitoring, SBIM). Aims will be tested in an adolescent sample (n=33, ages 13-19 years) engaged in interventions for mood disorders through the Helen and Arthur E. Johnson Depression Center or the Child and Family Clinic at the University of Colorado Anschutz Medical Campus. Study participants will complete a baseline evaluation followed by an eight-week period of SBIM using smartphones to collect native digital sensors (e.g., GPS, accelerometer, log data of screen use, app use, call/text activity, and ambient light/sound) and ecological momentary assessment (EMA) of mood symptoms. Daily behaviors are measured by extracting behavioral features from digital sensors, and include sensor-based measures of behavioral activation, impulsivity, physical activity, social withdrawal, sleep/circadian disturbances, and goal-directedness. SBIM Reports, providing inter- session monitoring information about patient-specific behaviors, mood, and behavioral predictors of mood, are delivered to clinicians and patients biweekly. Clinicians and patients report on acceptability, appropriateness, and feasibility of SBIM, and treatment outcomes, biweekly. Aim 1 centers on rigorously validating SBIM, testing the predictive accuracy of personalized models and comparing personalized to general models. Aim 2 evaluates feasibility, appropriateness, and acceptability of SBIM for both patients and clinical providers, and Aim 3 tests convergent validity of SBIM with standard treatment outcomes. Exploratory Aim 4 explores subgroups to compare differences in SBIM outcomes between interventions (behavioral, medication management), diagnoses (unipolar, bipolar) and as a function of sex, age, or pubertal stage. Ultimately, we aim that this work will develop and validate a novel monitoring tool and explore translation to the clinic, providing a foundation for research that scales and investigates SBIM outcomes.

NIH

This is a Veteran’s Administration Career Development Award 2 proposal for Jessica M. Ross, Ph.D. entitled “Sensory Entrained Transcranial Magnetic Brain Stimulation (seTMS) for Major Depression.” The goal of this project is to study phase-aligned TMS (i.e. brain wave synchronized TMS) in Veterans, to enhance personalized neuromodulation and clinical outcome for the 60-80% currently not achieving remission while not increasing cost and burden. To bring phase-aligned TMS to Veterans, the PI developed Sensory Entrained TMS (seTMS), a clinic-ready augmentation therapy. The seTMS protocol uses music to synchronize brain waves during TMS, to deliver precisely-timed TMS when the brain is maximally excitable. seTMS operates within the guidelines of currently FDA-cleared protocols, does not require EEG or phase estimation algorithms, and is affordable and accessible because it only requires headphones and plug-and-play software that is compatible with existing equipment. This work will be a thorough investigation of seTMS for effective VA clinical use. The current study aims to 1) apply pulses of seTMS to the dlPFC in Veterans and compare brain changes (target engagement in electroencephalography, EEG) to those from standard pulses of TMS; 2) apply seTMS to the dlPFC in Veterans with depression and compare target engagement to those from standard pulses of TMS; 3) treat MDD with an accelerated form of seTMS (se-aTBS) or standard a-TBS to compare symptom reduction and long-term target engagement (lasting brain changes). Symptoms will be measured using standard clinical scales, administered during the first visit (Day 0), during the last visit following TMS, and at 1-month post-treatment. These scales are the Montgomery-Åsberg Depression Rating Scale (primary) and Columbia Suicide Severity Rating Scale (secondary), and the standard scales collected routinely in the Palo Alto MIRECC Precision Neuromodulation Clinic: Patient Health Questionnaire (PHQ-9), the Brief Symptom Inventory 18 (BSI-18), PTSD Checklist for DSM-5 (PCL-5), Beck Scale for Suicidal Ideation (BSSI), Generalized Anxiety Disorder 7-item (GAD-7), and the 36-Item Short Form Survey (SF-36) Health Survey. The PHQ-9 and GAD-7 will also be given to the Veterans on each day of treatment (Days 1-4) after the last protocol of the day. Perceptual ratings of scalp feeling and pain will also be recorded to assess tolerability and feasibility in Veterans. The overarching research hypothesis is that seTMS will enhance prefrontal circuit changes in non-depressed and depressed Veterans and improve clinical outcomes when used for treating Major Depression (MDD) while being feasible for clinical use. The specific hypotheses are that 1) seTMS will enhance TMS-induced brain changes in Veterans and 2) Veterans with MDD and 3) the se-aTBS treatment protocol will lead to greater reduction of clinical symptoms than standard aTBS, and be feasible and tolerable, in Veterans with MDD. This CDA-2 award would allow Dr. Ross to gain proficiency in 1) theory and models of brain plasticity in Veteran clinical populations, 2) traditional and innovative clinical design, 3) adaptive and personalized TMS methodologies, and 4) professional development for a career at the VA. Training and research for the project will be conducted at both the VA Palo Alto Health Care System (VAPAHCS) as part of the Mental Illness Research, Education and Clinical Center (MIRECC) and Stanford University School of Medicine, in the Department of Psychiatry and Behavioral Sciences. Both sites offer excellent intellectual and physical resources to complete the proposed work. SeTMS is a novel intervention that harnesses principles of sensorimotor neuroscience and has the potential to increase the efficacy of FDA-cleared TMS protocols without increasing cost for Veterans with Depression.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Challenges in executive functioning (EF) are highly prevalent in autism; however, profiles of EF vary greatly. Challenges in both “cool,” logical skills, such as working memory and planning, and “hot,” state-dependent skills, such as inhibition and emotional regulation, have been implicated. For both non-autistic and autistic individuals, EF predicts a myriad of key functional outcomes including adaptive behavior, academic success, and mental health. There is burgeoning evidence that EF serves as an underlying mechanism for the development and maintenance of mental health outcomes as well as the heterogeneity inherent to autism. Mental health and EF represent (1) two key drivers of quality of life in autism, (2) are endorsed by autistic people as a high priority for research and intervention, and (3) are tangible and frequent targets of personalized intervention approaches. As such, understanding distinct profiles of EF, the developmental course of EF, and how EF challenges vary as a function of key variables such as sex and age is a promising step towards individualized, actionable intervention across the lifespan. Data driven approaches have been promoted in autism to understand heterogeneity across constellations of traits, yet extant work has not been sufficiently powered to examine the unique and intersecting impact of sex, age of diagnosis, and chronological age on EF. The proposed project will adopt a data driven approach (Latent Profile Analysis–LPA) to parse the heterogeneity of EF across development (4 to 25 years), spanning critical developmental periods where EF development is rapid. In Aim 1, we will use multi-group LPA to identify profiles of EF in a large sample (N = 724) of autistic and non-autistic individuals, equally split on sex and diagnosis. Profile modeling will be based on 5 subscales from a caregiver-reported EF measure (Behavior Rating Inventory of Executive Functioning). In Aim 2, we will determine how profiles of EF vary as a function of age, sex, and age of diagnosis in our autistic cohort. In Aim 3, we will conduct exploratory analysis to examine how EF profiles predict internalizing behaviors in both cohorts. We hypothesize 3 profiles will emerge in each cohort, with the following profiles in the autistic cohort: (A) challenges across all EF domains, (B) challenges in shifting, working memory, and planning, and (C) challenges in emotional regulation and inhibition. We anticipate our variables of interest, including age, sex, and age of diagnosis, will differentially predict profile membership in line with existing literature. Identifying these profiles can (1) inform educational and therapeutic approaches, (2) promote autonomy and well-being for autistic individuals, and (3) elucidate the mechanisms by which EF challenges contribute to mental health across key developmental windows. Training aims include advancing Ms. Russell’s understanding of EF and its relationship to clinical outcomes, enhancing her statistical skills by training in data-driven approaches, and expanding her experience working with data from autistic adults. These aims will support Ms. Russell establishing herself as an expert within the field of autism phenotyping.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The overarching scientific goal of this mentored career development award is to elucidate sex differences in striatal cholinergic (CINs) and parvalbumin-expressing fast spiking interneurons (FSIs). Interneuron disruption is implicated in many neuropsychiatric disorders, including several, such as Tourette Syndrome (TS) and autism, that show marked male-female differences in prevalence. Postmortem studies reveal deficits in both CINs and FSIs in TS. Recapitulating this abnormality in mice produces abnormal stereotyped grooming and social deficits, but only in males. A better understanding of how interneurons differ between sexes may provide insight into the causes of these disparities in prevalence and presentation. We have recently published a careful anatomical analysis documenting differences in interneuron number and distribution between male and female mice. Here, Dr. Meghan Van Zandt will characterize structural, functional, and molecular differences in striatal interneurons in males and female mice. Aim 1 will determine whether gonadal or genetic mechanisms underlie sexual dimorphism in striatal CIN and PV density and distribution that we have recently documented, using the four-core genotype mice; we hypothesize that hormonal/anatomical sex will determine interneuron properties. Aim 2 will examine anatomical and molecular properties of interneurons in males and females, using 3D reconstruction to compare morphology (2A), anterograde and retrograde synaptic tracing techniques to analyze interneuron networks (2B), and single-nucleus RNA seq to examine gene expression specific to both CINs and FSIs (2C); we hypothesize that interneurons in the dorsal striatum will exhibit stronger synaptic connectivity in females, compensating for their lower number. Aim 3 will analyze the population activity of striatal interneurons during spontaneous behaviors using fiber photometry in males and females, including analysis of females in different estrus phases. Dr. Van Zandt intends to pursue a career investigating sexual dimorphism in the pathophysiology of neuropsychiatric disease. This career development award will provide her with advanced training critical to her career goals, with mentorship and didactics in anatomical techniques, transcriptomic analysis, and fiber photometry. In addition, her senior mentorship team will support her development as an independent scientist, through ongoing training in writing, presentation, teaching, ethics, professionalism, and networking – and, in the later years of the award, through active support of her search for an independent research and teaching position. Together, this experimental and training plan will provide a strong foundation to prepare her for a career as an independent researcher and a mentor to young scientists in her own right.

NIMH - National Institute of Mental Health

Project Summary/Abstract This proposal focuses on the fundamental sex differences in the vulnerability to acute traumatic stress (ATS) and the role of the sex hormone estrogen, and signaling via sex-specific hippocampal receptors, in the enduring memory problems that follow ATS. It is now recognized that acute traumatic events (e.g., mass shooting, earthquakes) may provoke enduring disturbances of hippocampus-dependent memory, and that these problems are more common in women. We leverage robust preliminary data to probe why males, and females at different phases of the estrous cycle, differ in their vulnerabilities to ATS, what these differences are and the mechanisms that drive them. This information will provide important targets for promoting resilience to ATS. We find ATS causes memory disturbances in male (♂) and proestrous female (♀) but not estrous ♀ mice, and the deficits are long-lasting only in proestrous ♀. ♂ and ♀ differ in numerous measures, including in levels of hippocampal estrogens: ♂ and proestrous ♀, both vulnerable to ATS, have high levels of hippocampal estrogen compared with estrous ♀. Estrogen acts via several receptors (ERs) and its enduring effects are thought to result from interactions of ERα or Erβ with the chromatin. Leveraging robust preliminary data we will (1) Test whether ATS-induced memory disturbances require ERα in ♂ and, in contrast, Erβ in ♀ (Aim 1). (2) establish if sex- and Estrogen-level dependent vulnerability to ATS in ♂ and proestrous ♀ mice is a result of sex and hormone-dependent hippocampal chromatin states, which elicit distinct transcriptional programs upon exposure to ATS (Aim 2). (3) use focal conditional ER deletions to test whether the unique vulnerability of proestrous ♀ to persistent ATS-induced memory disturbances results from activation of distinct transcriptional targets of ERβ in ♀ hippocampus. Together, the expected discoveries will illuminate the mechanisms for the fundamental sex differences in vulnerability to enduring trauma-induced memory disturbances and will offer targets for mitigation.

NIMH - National Institute of Mental Health

Project Summary/Abstract The purpose of this project is to provide a train-the-trainer program in machine learning and emerging artificial intelligence (AI) technologies – such as generative AI and large language models – for early, mid-career, and senior scholars in the social and behavioral sciences. The rapid growth of available data, computing capacity, and powerful AI models has the potential to reshape how research is conducted in social science domains relevant to health, including population health, population dynamics, child and adolescent development, and health economics. Although machine learning and related methods have been used increasingly, their adoption in the social sciences is being outpaced by the development of emerging AI technologies, such as generative AI. Within the social sciences, pedagogy for emerging AI methods remains largely undeveloped, leaving a gap in formal training infrastructure. There is a pressing need for cutting-edge, scalable training programs that not only equip researchers to use these technologies but also establish replicable models for instruction across institutions grounded in novel pedagogical strategies. The proposed program consists of a series of 8-week, remote summer workshops designed to equip trainees to use machine learning and emerging AI technologies in their own research. The curriculum will be structured to prepare trainees to offer their own versions of the course, magnifying the program’s impact beyond its immediate participants. Trainees will not be expected to have prior programming experience. The course will build on our wealth of experience in developing remote data science training programs across the social and behavioral sciences. The course will begin with an introduction to the Python programming language, emphasizing a data science perspective. Participants will then explore advanced topics such as machine learning, large language models, and generative AI, with an emphasis on integrating these technologies into research workflows and building practical fluency in computational tools. Practical skills, such as use of the command line, version control, and cloud computing will also be covered. The workshops will take an active learning pedagogical approach, utilizing a flipped classroom that combines pre-recorded content with live sessions focused on coding exercises, applied examples, discussion, feedback, and formative assessment. Trainees will develop their own projects, with mentorship and consulting support from program staff, which will continue beyond the formal course period. Each course will also feature a slate of guest speakers discussing innovative health research that leverages machine learning to generate new knowledge. The program will culminate in an in-person conference where participants will meet, present their work, and build future collaborations. To facilitate trainees’ future use of these methods in both research and teaching, the project will openly disseminate all curricular and pedagogical materials, including syllabi, computational notebooks, videos, and lesson plans. Overall, this program will build a sustainable and resilient foundation for integrating emerging AI into social science research and teaching.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Suicide is a leading cause of death among adolescents, and the developmental period of adolescence often marks the first onset of suicidal thoughts and behavior. Suicidal thoughts fluctuate dynamically over brief periods of time (e.g., hour-to-hour, day-to-day), creating critical proximal windows to better understand suicide risk. Prominent theoretical models and empirical research on suicide have largely focused on adult samples and predicting suicide risk over the course of months, years, or lifetimes. However, limited research has examined dynamic, developmentally salient processes that underlie the occurrence of suicidal thoughts during adolescence. One such developmentally salient process is identity development, in particular, identity exploration. Identity exploration has been demonstrated to fluctuate daily and predict increases in negative mood. Identity exploration has traditionally been conceptualized as an offline process; however, social media use is nearly ubiquitous among adolescents, perhaps changing the medium through which identity exploration occurs. The unique features of social media, including the publicness of content and quantifiability of social feedback, may amplify the effects of social media identity exploration experiences on psychopathology in comparison to offline identity exploration. Although previous research has identified that negative social media identity exploration experiences (e.g., engaging with self-injury related content for the purpose of identity exploration) are associated with suicidal ideation cross-sectionally, there is a dearth of research examining proximal relationships between positive and negative social media identity exploration experiences and suicidal thoughts. Identity functioning is a transdiagnostic construct longitudinally linked to suicide risk and proximally associated with other forms of self-injury. Self-concept clarity is a dimension of identity functioning that develops during adolescence and may be particularly implicated in suicidal thoughts. Understanding the short-term associations between self-concept clarity and suicidal thoughts can provide another developmentally salient target for suicide prevention. Furthermore, examining the short-term, bidirectional feedback between self- concept clarity and social media identity exploration experiences and this feedback loop’s effect on suicidal thoughts can provide critical insight into how social media effects adolescent development and suicide risk in real time. The current study will use intensive longitudinal monitoring to understand the relationship between social media identity exploration experiences, self-concept clarity, and suicidal thoughts in a community sample of 70 adolescents ages 14-16 recruited from social media platforms and the community. Participants will respond to questions 4x/day for 28 days. The goal of this research is to understand the relationship between these developmentally salient processes and suicidal ideation as they unfold in real-time and provide critical targets for intervention to support adaptive adolescent development and prevent suicide.

SHRM Foundation

Supports workforce development, workplace inclusion, mental health at work, and programs advancing HR management excellence.