Search Grants — Free, No Account Required

NIMH - National Institute of Mental Health

ABSTRACT Autism is a highly heritable neurodevelopmental condition, and males are over-represented in autism diagnoses. The X chromosome is enriched for genes associated with autism, suggesting it may contribute to the observed male bias. Loss-of-function coding mutations within these genes are often lethal in males, but females experience monogenic forms of autism. It is then possible that mild mutations within these genes are sufficient to cause autism in males but spare mosaic females. Males with idiopathic autism are enriched for maternally inherited noncoding mutations in cis-regulatory elements (CRE) proximal to these genes. The broad objective of this proposal is to characterize these X-linked CREs and autism-associated mutations found within them. MECP2 is a dosage-sensitive gene where loss- or gain-of-function mutations cause neurological disorders. Although MeCP2 levels are tightly controlled in typical individuals, the mechanisms by which its CREs, such as the promoter, control gene expression remain unclear. There are at least four mutations within the MECP2 promoter that are maternally inherited and segregate with autism in males. Using CRISPR-Cas9 technology, these mutations will be independently edited into the endogenous MECP2 promoter in human iPSCs (AIM 1). After differentiating these iPSCs into neurons, these mutations will be evaluated for their impact on MeCP2 levels and two representative target genes. For mutations that significantly alter MeCP2 levels, deep RNA sequencing will determine the effects of these mutations on the molecular phenotype of neurons. This dosage sensitivity could extend past MECP2. There are thousands of mutations in male autism probands that are inherited from the mother and localize to 197 different X-linked CREs in open chromatin in excitatory neurons. A majority of these CREs are proximal to 57 different X-linked genes known to cause neurological disease. Using a massively parallel reporter assay, these mutations will be functionally assessed in an unbiased, high-throughput screen (AIM 2). Downstream analyses will determine which genes and which specific regions are most impacted by autism-associated noncoding mutations. The top-ten autism-associated mutations that disrupt CRE activity will then be validated using a luciferase reporter assay. The overall impact of this proposal is to broaden the spectrum of known mutations that cause autism, addressing some of the missing heritability of autism. Additionally, by studying 197 X-linked CREs, this proposal will provide insight into the regulation of 57 separate X-linked genes known to cause neurological disorders, and it will provide a framework for investigating noncoding mutations. These results will enhance the current understanding of noncoding mutations and how they contribute to neurological disease.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Recurrent genomic deletion at chromosome 3q29 (3q29Del) is associated with developmental delay (DD), ADHD, autism spectrum disorders (ASD), and is the strongest known genetic risk factor for schizophrenia (SCZ). However, the phenotypic spectrum associated with 3q29Del is variable and broad. Most individuals have been found to have clinically significant neuropsychiatric impairment, but it is not yet clear why some individuals are much more severely affected than others. The variable expressivity of this important variant suggests environmental factors may influence outcomes. In this R21 project, we propose to assess iron deficiency (FeD) as an environmental factor that may strongly impact 3q29Del clinical outcomes. The 3q29Del results in heterozygosity of 21 protein-coding genes including TFRC, which encodes the transferrin receptor (TFRC). TFRC is the primary cell surface receptor for iron-bound transferrin and is critical for cellular iron import. Iron deficiency is the most common nutrient deficiency worldwide, and recent reports indicate it continues to be highly prevalent in the United States, particularly in children, adolescents, and during pregnancy. While it is well established that childhood FeD can negatively impact neurodevelopment and increase risk for ADHD, ASD, DD, and SCZ, the mechanisms of these processes in human neural cells are not well understood. Innovative in vitro modeling techniques such as 3D brain organoids open new possibilities to causally test the impact of nutrient deficiencies such as FeD on certain aspects of human neurodevelopment. Our preliminary studies indicate that individuals with 3q29Del have more than 10-fold increased risk for anemia. Additionally, 3q29Del cells were found to contain less iron than control cells and had severely reduced viability and mitochondrial function in FeD-like conditions. Together these data indicate that 3q29Del individuals are at extraordinarily high risk for iron deficiency, which may disrupt key neurodevelopmental processes. The aims of this proposal are to (1) determine the risk for FeD and connection to neuropsychiatric phenotypes in individuals with 3q29Del and (2) to model the effects of iron deficiency on the developing human cortex in vitro. We will expand an active R01 project to collect new data related to history of iron deficiency and/or anemia in 3q29Del study participants using gold standard instruments to measure multiple domains of cognitive function, prodromal and psychosis signs. We will measure mitochondrial function in human forebrain-like cortical neurons exposed to FeD-like conditions from both neurotypical control and 3q29Del backgrounds. Lastly, we will determine the effects of FeD-like conditions on human cortical organoid development. These studies will illuminate effects of iron deficiency on the developing human cortex and test environmental interactions with an important neuropsychiatric risk variant.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Anorexia nervosa (AN) is a devastating eating disorder that has severe effects on mental and physical health, and one of the highest mortality rates of any psychiatric disorder. AN is characterized by persistent restriction of food intake below the body’s needs, and particular restriction of dietary fat, leading to relapse following treatment to restore weight. Maladaptive choices about what to eat are remarkably resistant to treatment in AN, even among patients expressing desires for long-term recovery. Decision making is guided by a valuation process in which the ventromedial prefrontal cortex (vmPFC) encodes a value signal that represents individual preference for a given choice option. The ability to assign value to choices that are aligned with longer-term goals, but which do not confer immediate benefit, is supported by the vivid imagination of future scenarios, or episodic future thinking (EFT), and the effects of EFT on valuation are related to connectivity between the hippocampus and vmPFC. Recovery is a future outcome of eating energy-dense foods in AN, which in the short-term may be unpleasant. In this study we will begin to address the question of whether underuse of EFT during food choice contributes to the misalignment between goals of recovery and restrictive eating behavior among treatment-seeking patients with AN. Patients with AN and normal-weight healthy controls will complete a food decision making task in which they rate their preference to eat a range of items as a snack, while undergoing functional MRI scanning. The task is completed under two conditions (order randomized and counterbalanced): EFT, in which participants are oriented toward a personalized future event; and standardized episodic thinking (SET), in which participants are oriented toward a recent past event (playing video games). We will compare the effect of EFT versus SET manipulations, relative to no manipulation, among individuals with AN and HC across behavioral (preference for high-fat foods) and brain (functional connectivity between the hippocampus and vmPFC) levels. Findings from this study will identify 1) whether EFT ameliorates restrictive eating in AN; 2) whether patients with AN are able to recruit the neural circuits supporting EFT during valuation; 3) whether recruitment of these neural circuits is associated with the behavioral effects of EFT. A monetary decision task will be administered to compare the effects and mechanisms of EFT between AN and HC groups (normal-weight HC are not expected to change food preferences due to an EFT manipulation). Exploratory analyses will compare EFT ability and general future orientation between AN and HC groups, and examine the relationship between EFT ability, effects of the EFT manipulation, and clinical characteristics, in the AN group. This developmental study will provide preliminary data for large-scale investigation into the role of disturbances in EFT in AN pathology and interventional research targeting future thinking to improve eating behavior among patients with AN.

NIMH - National Institute of Mental Health

Project Summary Dysfunction of the Wnt signaling pathway has been associated with mental ilness, but the underlying molecular and cellular mechanisms remain elusive. Our laboratory has discovered an evolutionarily conserved role for the Wnt transcriptional effector Lef1 in generating hypothalamic neurons and innate behaviors linked to stress. LEF1 variants could thus contribute to human stress-related mood disorders, and we propose that the distinct expression and function of two highly conserved protein isoforms could provide a way to separate this role from the other essential roles of Lef1 in development. We will use zebrafish to test the hypothesis that isoform- specific control of Lef1-dependent transcription regulates hypothalamic neurogenesis and stress- related behavior. In Aim 1 we will determine how the Lef1 N-tail and B-tail isoforms affect protein function, and in Aim 2 we will determine whether each isoform is specifically required for neurogenesis and behavior. Our goal is to establish an evolutionarily conserved model that we can eventually translate to human mental health.

The Jed Foundation

Supports youth and young adult mental health programs on college campuses and in communities.

Kaiser Permanente

One of the largest nonprofit health systems, investing $300M+ annually in community health programs addressing health equity, healthy eating, active living, and mental health.

National Institutes of Health

NIMH seeks applications for innovative research projects to test strategies to increase the reach, efficiency, effectiveness, and quality of digital mental health interventions. This NOFO is intended to support the development of digital health test beds that leverage well-established digital mental health platforms,to rapidly refine and optimize existing evidence-based digital health interventions and conduct clinical trials testing digital mental health interventions that are statistically powered to provide a definitive answer regarding the intervention's effectiveness.

National Institutes of Health

NIMH seeks applications for innovative research projects to test strategies to increase the reach, efficiency, effectiveness, and quality of digital mental health interventions. This NOFO is intended to support the development of digital health test beds that leverage well-established digital mental health platforms,to rapidly refine and optimize existing evidence-based digital health interventions and conduct clinical trials testing digital mental health interventions that are statistically powered to provide a definitive answer regarding the intervention's effectiveness.

NIMH - National Institute of Mental Health

ABSTRACT Less than half of people with HIV (PWH) in the US are retained in outpatient HIV care, impeding access to life- saving antiretroviral therapy and increasing transmission risk. Hospitalizations are common among PWH, particularly PWH not engaged in care. An inpatient admission is an opportunity to link hospitalized PWH, either newly diagnosed or previously diagnosed but not in care, to outpatient HIV care following discharge. However, interventions to improve linkage to outpatient HIV care have been largely unsuccessful. Prior studies have been limited by fragmented data sources, often restricted to a single health system, cross-sectional data, or with insufficient variables to comprehensively examine complex risk factors influencing post-discharge care engagement. We propose to integrate complementary data sources that capture the full HIV care continuum among hospitalized PWH and collect qualitative data from key informants to investigate individual-, hospital-, community-, and policy-level determinants of post-discharge HIV care engagement. We will conduct this study in North Carolina (NC), where academic-public health partnerships have a proven track-record of using HIV surveillance data to inform public health interventions, improving care outcomes and interrupting transmissions. We will combine electronic health records (EHRs) from three of the largest health systems in NC with HIV surveillance data, including statewide viral loads, for the years 2018-2024. PWH will be matched across the data sources using highly accurate novel techniques that do not require sharing sensitive identifying data. Our study will include 34 hospitals that care for 80% of hospitalized PWH in NC. Care continuum outcomes and differences across hospitals will inform sampling for our qualitative work, engaging PWH, healthcare providers and administrators, and staff from community-based organizations involved in supporting engagement in HIV care for PWH. Our specific aims for this three-year grant are: 1) Characterize HIV care engagement pre- and post-discharge among hospitalized PWH; 2) Identify patient- and hospital-level predictors of post-discharge linkage to care; and 3) Explore key informants’ perceptions of factors that influence post-discharge linkage to care. In Aims 1-2, integrated EHRs capturing >600 in- and outpatient sites in all 100 NC counties and statewide HIV surveillance viral load data enables us to examine the full HIV care continuum among hospitalized PWH – diagnosis, linkage, retention, and viral suppression. Our collaboration capitalizes on clinical, epidemiological, and public health expertise at three academic institutions and the NC Division of Public Health, and leverages established partnerships with community-based organizations, local health jurisdictions, and community advisory boards. Combining HIV care continuum outcomes, predictors of care engagement following hospitalization, and a comprehensive examination of contextual determinants at individual, community, organization, and policy levels, we will identify modifiable targets from which we can develop tailored, multi-level interventions for subsequent testing.

NIMH - National Institute of Mental Health

Project Summary Retrieving memories of emotional events can result in (re)experiencing subjective feelings. Importantly, the feelings elicited by memories can influence current emotional states. For example, recalling positive events can both reduce current negative affect and diminish acute physiological stress responses. Similarly, recalling negative events can lead to current negative feelings and moods. The feelings of memories have also been linked to subjective clinical symptoms. The frequency of reported negative intrusive memories is related to both the severity of clinical symptoms in a treatment-seeking population and the likelihood of reporting clinical symptoms in a typical undergraduate population. Because of the impact of the feelings elicited by memories on current emotional health and well-being, understanding how the feelings of memories might change over time has to potential to suggest novel treatment innovations. The proposed research investigates techniques intended to alter the feelings associated with memories. Specifically, we take advantage of reactivation induced memory change (RIMC) to determine factors that may reduce or enhance the negative feelings elicited by memories. To explore how RIMC can modify the feelings of memories, the proposed studies examine three kinds of memories and two techniques to alter subjective feelings. There are three specific aims: Aim 1 examines whether RIMC interventions can be used to diminish the negative feelings elicited by memories for negative events. Aim 2 examines how RIMC mechanisms may enhance the negative feelings elicited by memories for negative events. Aim 3 examines if RIMC techniques can infuse negative feelings into previously neutral memories. In addition to examining the feelings elicited by memories, we will also examine the impact of these interventions on changes in physiological stress reactions and the pattern of blood oxygen level dependent (BOLD) signals when retrieving these memories. It is hypothesized interventions following the reactivation of a previous acquired memory will change the later expression of subjective feelings elicited by that memory more than interventions without reactivation. It is further hypothesized that the reactivation of a previously acquired negative memory without any intervention will result in strengthening the memory and enhancing negative feelings. We expect these changes will also be reflected in physiological stress reactions and BOLD response patterns during retrieval.

NIMH - National Institute of Mental Health

Abstract: Functional variants in GRIN2A, which encodes the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), have been found in patients with Schizophrenia (Scz) and have been linked to impaired working memory (WM). The consequences of GluN2A dysfunction on neural activity and behavior are poorly understood and there are no methods to restore impaired GluN2A function in Scz. Sarcoma Tyrosine Kinase (Src) regulates NMDAR current via GluN2A phosphorylation. Src serves as a hub upon which several proteins dysregulated in Scz interact to influence NMDAR function, including dysbindin-1 (dys-1), suggesting that a Src pathway influences glutamate function via GluN2A. Src activity is reduced in prefrontal cortex (PFC), a region critical for WM, in Scz patients. Indeed, reduction of Src activity in mice impairs trace fear conditioning (TFC), which relies on retention of a cue for 20 seconds, indicative of WM. Thus, the Src pathway is a promising mechanism to explain WM deficits across multiple etiologies, and a provides a means to restore GluN2A function across a range of molecular and genetic conditions. The current proposal will assess the role of the dys-1à Srcà GluN2A pathway on molecular (synaptosomal NMDAR co-immunoprecipitation), single cell (patch clamp), in vivo network function (multi-electrode arrays) and WM (TFC), using a cell-circuit-behavior approach to determine how dysfunctions at each level interact to impair outcomes. The synapse specific activator of Src (TAT-SAPIP), which increases Src availability, will be used to assess the extent to which increasing Src activity restores GluN2A function. Aim 1 will assess the effects of dys-1 removal on cellular, circuit, and behavioral measures related to WM. Dys-1 knockout (KO) increases NMDAR channel decay constant, gamma excitatory/inhibitory (E/I) balance, and TFC. Further, dys-1 KO reduces NMDAR EPSCs, which is restored by increasing Src activity. We propose that decreased dys-1 in KO mice impairs NMDAR activity by reducing GluN2A phosphorylation via Src, and that administration of TAT-SAPIP will restore GluN2A function, thereby restoring cellular, circuit, and behavioral outcomes. Aim 2 will assess the effects of reduced Src on cellular, circuit, and behavioral measures related to WM. Reduction of Src impairs TFC and reduces TFC-dependent GluN2A phosphorylation, reduces NMDAR EPSCs and disrupts E/I balance. Preliminary data indicate that TAT- SAPIP selectively enhances Src in the synapse, facilitates NMDAR EPSCs in wild type (WT) but not Src KO mice, and that chronic TAT-SAPIP restores TFC in Src het mice. We hypothesize that enhancing Src activity will restore normal GluN2A phosphorylation and function, thereby restoring each outcome. Aim 3 will assess the effects of reduced GluN2A availability on cellular, circuit, and behavioral measures related to WM. Reduction of GluN2A function (Grin2A het mice) slows receptor kinetics, will disrupt network gamma E/I balance, and TFC. TAT-SAPIP is expected to restore GluN2A function. This proposal advances a novel mechanistic approach to treating Scz that builds upon previous genetic, post-mortem and preclinical studies.

NIA - National Institute on Aging

ABSTRACT Career Goal: My career goal is to become a leading independent investigator contributing rigorous social science research to understand cognitive health differences among the growing population of older immigrants in the US. With the immigrant population 65 and older expected to double to 20 million by 2050, investigating the ways modifiable risk factors for Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) operate for immigrant populations is an imperative area of research. Training towards content area and methodological expertise will enable me to contribute to scholarship aimed at reducing the public burden of AD/ADRD in a growing US population. Career Development: I will undertake four training aims to enhance my knowledge and skills in (1) the biological and social pathways shaping AD/ADRD, (2) geriatric mental health and social relationships, (3) epidemiological causal inference, and (4) professional development for becoming an independent investigator. Research Project: Mexican immigrants, the largest group of immigrants in the US, are rapidly aging, but current research often aggregates US Latinos, overlooking origin- and nativity-specific social, structural, and migration-related factors that influence AD/ADRD risk. Attention to specific immigrant populations is necessary to address heterogeneity in cognitive risk factors. To address this gap, the proposed research focuses on loneliness, a risk factor for AD/ADRD that may be heightened in the older Mexican immigrant population. Using data from a nationally representative panel survey, complemented by data from a Rutgers-based cohort that collects advanced biomarkers, the proposed project uses causal inference to analyze the inter-relationship between loneliness, social relationships, inflammation, and cognition for Mexican immigrants in the US compared to non-migrants, advancing understandings of modifiable risk factors for AD/ADRD. Specific Aims: (1/K99) Determine loneliness trajectories, social relationship risk factors for loneliness, and the contribution of loneliness to cognitive functioning in the Mexican immigrant population compared to non-migrants. (2/R00) Quantify inflammation as a mediator in the loneliness-cognition pathway in the Mexican immigrant population compared to non-migrants. (3/R00) Characterize the loneliness- inflammation and loneliness-AD/ADRD relationships in the Mexican immigrant population compared to non- migrants using advanced biomarker data. Mentorship: A complementary set of accomplished experts in AD/ADRD, geriatric mental health, social networks, immigrant health, biomarker analysis, and causal inference will provide training and professional mentorship to ensure my successful transition to independent investigator. Future Directions: With the proposed training and research experience, I will have a unique combination of substantive expertise and methodological skills to become an independent scientist and submit successful R01 proposals to examine AD/ADRD social determinants among high-risk subpopulations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Chronic loneliness is a pervasive issue in persons with schizophrenia and can lead to downstream consequences of worsening symptoms (e.g., paranoia, cognitive and functional impairments), social withdrawal, and diminished quality of life. Central to these challenges are deficits in social motivation, encompassing both positive motivation (i.e., desire for connection) and negative motivation (i.e., avoidance due to anxiety). High rates of anxiety and depressive symptoms further exacerbate these motivation deficits, hindering social engagement and intensifying chronic loneliness. Despite the critical role of social motivation in shaping social interactions and mental health outcomes, existing research has primarily relied on static, retrospective assessments, which fail to capture the real-time fluctuations and bidirectional relationships between social motivation, mood, social interactions, and loneliness. The proposed F31 project will use ecological momentary assessment (EMA) to examine these dynamic processes as they unfold in daily life. By leveraging data from an NIMH-funded R01 study on loneliness and aging in schizophrenia, this study will evaluate moment-to-moment fluctuations in positive and negative social motivation, and their associations with mood, loneliness, and social interactions. Advanced statistical techniques, including linear mixed effects models and mediation analyses, will identify mechanisms linking social motivation to loneliness and mood over time. These insights aim to advance understanding of how momentary changes in social motivation shape real-world experiences in schizophrenia, with the goal of identifying modifiable targets for intervention. Through the training opportunities afforded by the F31 fellowship, the candidate will gain expertise in EMA methodologies, advanced statistical modeling, and translational research approaches. These skills will support the candidate’s long-term goals of becoming an independent investigator specializing in the social and psychological mechanisms of serious mental illness (SMI) and the development of technology-based interventions. The proposal aligns with the NIMH Strategic Plans by advancing the understanding of dynamic, modifiable processes underlying social motivation deficits in schizophrenia, and informing innovative, targeted intervention strategies.

NINR - National Institute of Nursing Research

PROJECT SUMMARY The period of emerging adulthood (ages 18-24) is a particularly critical developmental period in which significant decisions are made that set a life course towards adulthood, including training/education, employment/career, residential independence, relationships, and parenthood. The substantial physical, emotional, and developmental changes that occur during this developmental period put young people at risk for increased mood disorders, increased risk-taking behaviors, and decreased health seeking behaviors. Further, emerging adults experience the highest poverty rates of any group, contributing to their disproportionately adverse mental and physical health outcomes. Economic interventions have demonstrated improvements in economic stability and health for low-income communities. For young people transitioning to adulthood, an economic intervention could provide the support needed to develop healthy educational and employment trajectories before financial strain instills deepening disparities. The BEEM study (U01OD033266/ U01MD019398) is an NIH-supported randomized wait-list-controlled trial to determine the impact of an economic intervention including cash payments and opt- in financial mentoring on the physical, emotional, and financial well-being of low-income emerging adults. Since 2022, we have recruited and delivered the economic intervention to 300 emerging adults residing in low-income neighborhoods. We later began recruitment of a comparison cohort with 150 young adults from the same communities who were offered only tailored financial mentoring, without the cash payments, to work towards their financial goals. The current BEEM study is providing critical data on the short-term impact of cash on mental health and economic well-being. We have found that anxiety and depression were significantly lower after one year for participants receiving the cash compared to those who did not. However, the long-term sustainability of the health and wellbeing outcomes in BEEM needs to be established. Further, identifying the pathways and malleable targets for adjunctive interventions for those participants with suboptimal response can maximize the impact of economic interventions. We propose to follow these 450 low-income emerging adults, 300 who received cash and 150 who have not for an additional 3 years, collecting extensive information on psychosocial, economic, household, and neighborhood characteristics to : 1) assess longer term impacts of the economic intervention on mental health, 2) explore three mediating pathways (economic, psychosocial, and physical/behavioral) through which the economic intervention impacts mental health outcomes, and 3) identify malleable moderators operating at multiple levels (individual, household, neighborhood) that could be intervened on to maximize the impact of the economic intervention. This study will provide a roadmap to develop future economic interventions that are optimized to effectively address mental health in emerging adults.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT. Rates of anxiety disorders in childhood are increasing and anxiety in childhood often predates other diagnoses. Early identification of trait-based markers associated with anxiety disorder risk, and their neural correlates, is needed to develop childhood interventions that reduce later illness burden in adolescence and adulthood. High trait anxiety is one such behavioral marker that is present in children and is stable over the lifetime. High trait anxiety is characterized by misattribution of threat, such that nonthreatening stimuli are perceived as threatening. Given the developmental importance of social stimuli, faces are a particularly salient source of potential threat in those with high trait anxiety. Indeed, anxious adults tend to perceive threatening emotional expressions at a lower intensity, misattribute threat to neutral expressions, and perceive novel faces as threatening. While threat misattribution in anxiety disorders is often thought to involve reduced prefrontal regulation of limbic regions such as the amygdala, this model alone cannot account for differences in visual discrimination in anxiety, which are present at an early latency following stimulus onset and associated with differences in visual cortical networks. For example, in anxious adults, threat misattribution is associated with altered function of the ventral visual stream and limbic regions, particularly the fusiform gyrus and the amygdala. However, the function of this network and its relationship to anxiety has not been studied developmentally. Given the earlier development of visual cortices relative to prefrontal cortices, visual- limbic networks also likely play a role in high trait anxiety and anxiety disorder risk. Therefore, understanding the development of ventral visual stream regions associated with threat misattribution offers a potential novel target for early intervention. This longitudinal functional magnetic resonance imaging (fMRI) study seeks to characterize the development of the neurofunctional correlates of social threat perception in children ranging in trait anxiety. Children ages 8-12 (n=120) will be scanned, with a subset (n=60, ages 8 to 10 at baseline) scanned a second time two years later. We will collect measures of mood and anxiety symptoms at 3-month intervals following the baseline visit for all participants. The aims of this study are to assess the function of social threat perceptual networks in high trait anxiety. Specifically, we aim to understand the neural correlates of face identity discrimination (novel vs. familiar) and visual discrimination of subtle emotional expressions in children with high trait anxiety using a series of fMRI tasks. We also will explore the development of these circuits over time, and the predictive utility of the function of these regions for understanding the later development of anxiety symptoms and prefrontal regulation of the amygdala in anxiety.

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

Project Abstract Adverse mental health conditions are the most common complication of pregnancy and childbirth, affecting 1 in 5 birthing people in the US each year. Sexual and gender minority (SGM) individuals, including lesbian, bisexual, and queer women as well as transgender and gender nonconforming individuals, face increasing social stigma, animosity, and conflicts. Preliminary data suggests that these negative societal factors contribute to significant disparities in mental health outcomes among SGM birthing people. Two modifiable protective factors—access to quality healthcare and social support—are crucial for reducing the risk of pregnancy-related complications and mitigating adverse mental health effects. Unfortunately, SGM individuals often encounter unaffirming and inappropriate care, leading to elevated stress levels, non-compliance, and delays in seeking essential healthcare services. Additionally, the nature of support needed by SGM individuals often differs from that required by heterosexual cisgender women. Therefore, there is a pressing need for a deeper examination of SGM birthing people's experiences with medical care and social support to inform culturally sensitive interventions tailored specifically for SGM people, alongside comprehensive training for healthcare providers to deliver appropriate care. The main objective of Mx. Ezra's project is to elucidate how social support and medical care contribute to the mental health trajectories of SGM birthing people throughout the perinatal period. They will accomplish this objective by conducting a longitudinal mixed methods study to address three aims: (Aim 1) visualize and describe the trajectories of psychological distress and social support across the perinatal period among SGM birthing people; (Aim 2) explore mental health, support, and healthcare experiences of SGM birthing people during the perinatal period using qualitative longitudinal trajectory analyses; and (Aim 3) integrate the findings from Aims 1 and 2 to illuminate how psychological distress, social support, and healthcare experiences coalesce across the perinatal period for SGM birthing people. To accomplish the objective and aims of their proposed research plan, Mx. Ezra will seek out additional training to increase their conceptual, methodological, and dissemination skillsets which will augment their core training in Family Science. Their training plan combines formal coursework in family and maternal and child health, statistics, one-on-one mentoring, conference presentations, and publishing research to prepare them for a career as an independent researcher.

NIMH - National Institute of Mental Health

Aside from the recently approved muscarinic agonist xanomeline, all treatments for schizophrenia (SCZ) have been assumed to function by blocking dopamine-2 receptors (D2Rs) based on their in vitro binding profiles. Interest in the dopamine-3 receptor (D3R) was encouraged by findings, in preclinical models, that D3R antagonists reverse cognitive impairment and enhance locomotor activity of habituated rats, suggesting potential for improving negative symptoms. However, while numerous preclinical studies have demonstrated that the D3R is relevant to both the neurobiology and treatment of SCZ, in vivo studies initially and surprisingly reported that, after several weeks of administration, antipsychotic medications may not bind to the D3R but may paradoxically increase levels of the D3R. These findings were discrepant with our own findings in non- human primates and individuals with SCZ demonstrating that acute doses of antipsychotic medications bind to the D3R and D2R in ratios predicted by their in vitro binding profiles. In a later study conducted by our group, 10 days of chronic dosing of brexpiprazole (BREX) also led to increased levels of the D3R at 1mg and negligible binding at 4mg. Finally, in a study of the D3R-preferring antipsychotic medication cariprazine (CAR), there was robust binding to the D3R and D2R after both acute and subchronic dosing. These seemingly discrepant findings may be related to methodological differences, difference in the binding profiles of D2R- vs. D3R-preferring antipsychotic medications, or to homeostatic responses to chronic antipsychotic treatment (i.e., upregulation). The goals of this proposal are to elucidate the contribution of D3R binding to antipsychotic action, both acutely (SA1) and subchronically (SA2), in the same patients. We will also investigate the relationship between occupancy, upregulation, and therapeutic response (SA3, EA). To accomplish these goals, we will recruit 40 antipsychotic-free patients with SCZ. After screening and baseline procedures (e.g., MRI, PANSS, MATRICS, CAINS), subjects will be randomized to multiple doses of CAR or BREX and receive a total of three PET scans with [11C]-(+)-PHNO: one at baseline (baseline scan) followed by a second scan after one dose of their antipsychotic medication to measure acute occupancy (acute scan), and a third scan after 2 weeks of stable treatment. Our aims are to: 1) measure the acute binding of CAR/BREX to the D3R; 2) measure D3R availability for evidence of upregulation following subchronic administration of CAR/BREX in the same set of patients; and 3) explore relationships between acute and subchronic binding of CAR/BREX to, and upregulation of, the D3R vs. D2R and changes in positive and negative symptoms, cognitive deficits, and extrapyramidal side effects. By elucidating the contribution of D3R binding and upregulation to antipsychotic action the field may be able to develop more selective antipsychotic agents that improve upon current medications by demonstrating less side effects or greater efficacy against a range of symptoms.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Suicide is the third leading cause of death for youth aged 10 to 28, with Latine adolescents and young adults experiencing disproportionately high rates of suicidal thoughts and behaviors (STBs). Despite this, Latine youth are significantly underrepresented in suicide research. This R21 project aims to identify key risk and protective factors influencing the developmental trajectories of STBs in an existing sample of 674 Mexican-origin youth, followed longitudinally from age 10 to 28. The proposed research leverages data from the California Families Project (CFP), a 19-year longitudinal study that provides a robust, multi-informant, and multi-method dataset. This study is innovative in its focus on the interaction between clinical symptoms and sociocultural factors, and their combined influence on the trajectories of STBs across critical developmental stages. It is one of the first studies to comprehensively explore STB trajectories in Mexican-origin youth, a high-risk yet understudied group. Guided by the Family Stress Model (FSM), a culturally informed framework, this study will address significant gaps in the literature by examining STB trajectories, clinical predictors, and culturally relevant protective factors. Aim 1 will chart the longitudinal trajectories of STBs from preadolescence through young adulthood. Aim 2 will investigate how key clinical symptoms (depression, anxiety, substance use) predict the initial levels and rate of change in STBs. Aim 3 will identify sociocultural factors (ethnic pride, familismo) that compensate for or moderate the impact of clinical symptoms on STB trajectories. This research is significant because it has the potential to inform the development of culturally responsive and developmentally informed suicide interventions for Latine youth. By understanding the sociocultural context and specific risk pathways in Latine families, the findings could advance scientific knowledge and lead to targeted, effective strategies to reduce suicide rates among high-risk youth populations. The study’s innovative approach and the use of a rich longitudinal dataset underscore its feasibility and relevance to the NIMH mission of improving mental health outcomes and reducing suicide disparities for Latine youth.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Schizophrenia is a neuropsychiatric disorder which lacks clinically actionable biomarkers to guide diagnosis, treatment, and prognostication. There are, however, well-replicated neurobiological findings in schizophrenia – namely, decreased hippocampal volume, widespread cortical thinning, and ventricular enlargement. Decades of work from our lab and others have established the hippocampus as central to the pathophysiology of schizo- phrenia, with structural and functional deficits associated with illness severity and cognitive dysfunction. Despite this, the clinical utility of hippocampal imaging remains limited, largely due to unresolved questions about the origin, trajectory, and heterogeneity of hippocampal pathology. Recent advances in machine learning have enabled innovative approaches to address these core questions and disentangle the known individual- level heterogeneity in schizophrenia, revealing potential disease subtypes with distinct progression patterns. This work both identifies several possible epicenters of disease (including the hippocampus) and suggests a network-based progression model via which pathology spreads along the brain’s white matter tracts (i.e., the connectome). Notably, our work suggests an important structural and functional differentiation between the anterior and posterior hippocampus, implicating the former as crucial during the early stages of psychosis. Given this context, I hypothesize that schizophrenia is not a unitary disease, but comprises multiple subtypes with distinct spatiotemporal patterns of gray matter degeneration, including a subtype in which pathology originates in the anterior hippocampus and propagates through its structural connectome. To test this hypo- thesis, we will integrate advanced machine learning with longitudinal modeling using MR imaging, uniquely leveraging our lab’s rich data and technical expertise. In Aim 1, I will characterize group-level patterns of gray matter volume (GMV) change over the first decade of psychotic illness, stratified by clinical trajectory, using longitudinal structural modeling. In Aim 2, I will apply a cutting-edge machine learning algorithm – Subtype and Stage Inference (SuStaIn) – to a large, cross-sectional discovery sample to identify latent disease subtypes based on inferred patterns of GMV progression. In Aim 3, I will evaluate the external validity of these subtypes using our in-house longitudinal cohort of psychosis patients (see Aim 1). This will be the first study to utilize SuStaIn to specifically probe the differential roles of the anterior and posterior hippocampus in the patho- physiology of psychosis and will directly test the hypothesis that disease emerges and propagates along structural brain networks. By integrating machine learning with longitudinal neuroimaging, these experiments will identify and validate biologically grounded subtypes of schizophrenia, probing key features of hippocampal pathology and offering insight into hippocampal dynamics across illness stages. This innovative approach addresses a longstanding barrier in schizophrenia research – its vast clinical and neurobiological heterogeneity – and has potential to transform diagnosis, monitoring, and treatment following a first episode of psychosis.

NIMH - National Institute of Mental Health

Project Summary Anorexia nervosa (AN) is a serious disorder with a mortality rate among the highest of any psychiatric illness, and relapse rates range from 40-80% after acute treatment. Restriction of food intake is a central behavioral disturbance, and this persistent behavior is promoted by entrenched thoughts, feelings, and routines. Even with full weight restoration treatment, restrictive eating persists and has been linked to relapse. While many treatment approaches have been tried, there is little information about what elements of care contribute to maintaining remission. Relapse Prevention and Changing Habits (REACH+) targets the habitual control of maladaptive behavior to support patients with AN in the 6 months after acute treatment, a time of high vulnerability to relapse. Using the Multiphase Optimization STrategy (MOST) framework, we seek to identify an optimized, finalized, treatment package for relapse prevention in AN. The MOST framework is an ideal means for improving treatment efficacy by simultaneously and efficiently evaluating multiple possible intervention components to determine which contribute to positive treatment outcomes and thereby merit inclusion in a robust treatment package for relapse prevention. We have completed the Preparation Phase of the MOST framework and have shown feasibility and acceptability of REACH+, as well as preliminary support for treatment efficacy and target engagement. In this proposal, we conduct the next step: an Optimization Experiment to evaluate the components of REACH+ that will interrupt the habitual control of maladaptive behavior and, thereby, decrease relapse and improve outcomes. We will test competing versions of four components that together target habits: 1) Behavioral, 2) Cognitive, 3) Motivation, and 4) Food Monitoring. We will provide 6 months of REACH+ for 120 individuals with AN or atypical AN who have completed an acute weight-restoration treatment. REACH+ sessions are conducted via telehealth, to increase access and generalizability, and are augmented with psychoeducation and skill building through an online platform. Participants will be randomly assigned to different versions of each treatment component. Optimization criteria focus on the contribution of the component to weight maintenance (main effect), and will additionally consider effect sizes, treatment adherence, and end-of-treatment status. To ensure that the final treatment package will reach the patients we seek to help, we will obtain input from key end-users to plan for future effectiveness research.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT The perinatal period is marked by heightened vulnerability to mental health challenges, with perinatal substance use (PSU) and perinatal depression (PD) presenting significant concerns for maternal well-being and child development. PSU and PD often co-occur and pose bidirectional risks that exacerbate caregiving challenges. Despite evidence of their influence and overlap, research has yet to investigate how the interplay between PSU and PD impacts infant hippocampal development. Prior work in this area has been limited by assuming uniform impacts across the perinatal period and neglecting to evaluate these dynamic and bidirectional risk factors within the same model. Moreover, insights into how characteristics of PSU and PD (e.g., intensity, comorbidity, chronicity) may modify risk for development remains highly debated. To address these gaps, this study will be the first to model the longitudinal interplay between PSU, PD, and their combined impact on infant brain development. We hypothesize that utilizing person-centered, longitudinal, data-driven trajectories, rather than relying on static global reference values or clinical cutoffs, will provide more clinically valuable metrics for intervention, fostering intergenerational benefits. This study aims to (1) Characterize the interplay between PSU and PD and their reciprocal unfolding over the perinatal period. Specifically, testing whether within- or between-subjects models better capture the bidirectional interplay and change between PSU and PD across time to identify key windows and metrics of risk. (2a) Examine the impact of PSU/PD comorbidity on infant hippocampal volume and growth and test whether within- or between-subjects models better capture risk for offspring neurodevelopment. (2b) Compare models informed by developmental theory (Mismatch vs. Cumulative Stress vs. Mood Entropy) to evaluate which best characterizes the impact of PSU/PD on neurodevelopment in the first year of life. This research is responsive to the goals of NIDA’s 2022-2026 strategic plan to leverage data science to understand real-world complexity—including how comorbid mental health conditions and risk and protective factors interact to influence drug-related outcomes. Findings have the potential to refine screening practices, optimizing their timing and content to identify at-risk individuals more effectively. This work could ultimately enhance the capacity of healthcare systems to deliver timely and targeted interventions, improving health outcomes for families impacted by PSU and PD and reducing intergenerational consequences.

NIMH - National Institute of Mental Health

Psychiatric disorders are increasingly conceptualized as disorders of brain development. White matter (WM) structure develops rapidly in adolescence and has been linked to many psychiatric illnesses. However, the neurobiological mechanisms linking WM development, transdiagnostic psychiatric symptoms, and genetic risk for psychopathology remain poorly understood. This proposal tests the central hypothesis that transdiagnostic psychiatric symptoms and genetic risk will be associated with WM that undergoes the most protracted development: superficial regions of WM tracts connected to higher-order association cortices. We will leverage the large, longitudinal Adolescent Brain Cognitive Development (ABCD) study (n=11,875; ages 9-16), which includes multi-shell diffusion MRI, clinical, and genotype data. In Aim 1, we will characterize within-individual, along-tract WM development and we will evaluate whether associations with transdiagnostic symptoms are strongest in superficial WM regions adjacent to higher-order association cortices. In Aim 2, we will assess how polygenic risk scores (PRS) for transdiagnostic psychiatric illness relate to spatially precise WM microstructure metrics. We will assess whether PRS effects are strongest in superficial WM regions adjacent to higher-order association cortices. Together, this work will identify brain regions where protracted WM maturation is linked to transdiagnostic symptoms and genetic risk, advancing our understanding of how WM development is related to symptomatology and genetic liability for trans-diagnostic psychiatric illness.

Mass General Brigham

Invests in community health through grants addressing health equity, chronic disease, mental health, and social determinants in Massachusetts communities.

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

The R00 Pathway to Independence Award will establish the applicant's independent research program as a tenure track faculty member in the Departments of Psychiatry and Obstetrics, Gynecology and Reproductive Science (OBGYN) at the Icahn School of Medicine at Mount Sinai (ISMMS). The Developmental Origins of Health and Disease (DOHaD) framework is supported by a robust literature that provides evidence for the role of environmental exposures in shaping brain and behavior development through prenatal programming. Maternal childhood maltreatment has been associated with both maternal prenatal mental health and infant emotion regulation outcomes; however, most known transmission pathways are behavioral, with limited evidence for biological transmission. Well-established behavioral pathways are through maternal mental health and parenting sensitivity influencing infant emotion regulation and mother-infant interactions. Emerging evidence supports maternal childhood maltreatment effects on infant outcomes through biological pathways such as in utero programming of brain development. Despite the