NIMH - National Institute of Mental Health Grants

NIMH - National Institute of Mental Health

The Contractor, Guild Associates, Inc., aims to develop an electrochemical aptamer-based sensor device for simple, rapid, and low-cost detection and quantification of antiretroviral therapy (ART) drugs in urine and blood samples at the point-of-care (POC).

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Specific Aims: This proposal aims to identify opportunities to improve the prevention and mitigation of risks associated with cognitive impairment among people aging with HIV. Aim 1 will estimate the proportion of cognitive impairment cases potentially attributable to psychosocial and behavioral risk factors to prioritize those, which if intervened upon, could hypothetically result in the greatest prevention of cognitive impairment. Aim 2 will determine whether cognitive impairment increases the risk of losing one’s durable (sustained) viral suppression so we may mitigate this adverse outcome. Significance: As people with HIV (PWH) live longer due to treatment advances, they face a growing burden of age-related conditions, including cognitive impairment. PWH experience higher rates of cognitive impairment than people without HIV despite widespread viral suppression, which implicates non-HIV-related factors in their cognitive risk. Focusing on psychosocial and behavioral risk factors, which are prevalent in PWH and causally linked to cognitive impairment, can help to prioritize fruitful prevention strategies. In addition, cognitive impairment may threaten the durability of viral suppression, which could hinder cognitive maintenance and prevention of HIV transmission. Considering these issues in tandem can inform preparations for the long-term healthcare needs of people aging with HIV. Approach: These aims will leverage the Multicenter AIDS Cohort Study (MACS) (Aim 1), which includes 10 years of longitudinal cognitive screening data, and the Johns Hopkins HIV Clinical Cohort (JHHCC) (Aim 2), an urban cohort of PWH with rich clinical data. In Aim 1, we will estimate population attributable fractions for incident cognitive impairment, using longitudinal data and methods to account for time-varying risk factors, censoring, and competing risks. In Aim 2, we will employ a longitudinal closed cohort design to estimate the risk ratio for loss of durable viral suppression in PWH by cognitive impairment status. Training Information: The proposed research encompasses the dissertation of Madeline Brooks, a PhD student in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. The training plan consists of coursework, mentorship, and professional development to support the successful completion of these aims and prepare Ms. Brooks to become an independent research epidemiologist. These aims address priorities of the NIH Office of AIDS Research to address the role of non-infectious comorbidities in central nervous system complications and subsequent implications for HIV transmission.

NIMH - National Institute of Mental Health

Project Summary Social dysfunction following trauma is a pervasive reality for trauma victims in the United States, with one study finding that nearly half (45.2%) of trauma patients experience social deficits after the traumatic event. Traumatic events are often experienced in social contexts, yet most preclinical studies model trauma-related disorders with stressors experienced in isolation. Therefore, there is a gap in knowledge about how the social context in which trauma is experienced affects future social behavior. The experiments outlined in this proposal will fill this gap, and address Goal 1 of the NIMH Strategic Plan for Research to “Define the Brain Mechanisms Underlying Complex Behaviors.” Human studies have reported that an interesting phenomenon following trauma is social affiliation– the tendency to come together after traumatic events. Social buffering, which describes the presence of a conspecific attenuating the biological response to a traumatic experience, is thought to be a mechanism underlying the protective effects of social support. Yet, our understanding of the neural mechanisms underlying social buffering is poor. Despite the work from the field of social buffering that has studied the impact of social support during shared trauma, no research to date has studied alterations in the neural regulation of social affiliation after shared trauma. The neurons of the anterior cingulate cortex (ACC) are poised to facilitate this phenomenon as they are known to be involved in empathy, stress regulation, and observational fear learning. Using cutting-edge techniques in behavioral pose-estimation (Aim 1), and microendoscope calcium imaging in ACC (Aim 2), this proposal will test the central hypothesis that shared trauma, as opposed to solitary trauma, alters the neurobiology of ACC to foster social affiliation. As sex is among the most significant risk factors for the development of PTSD, with females having a two to three times higher risk of developing PTSD, both aims will be conducted in male and female mice. A successful outcome of this project would provide a mechanistic understanding of how shared trauma affects social behavior, revealing a circuit-level target to develop interventions for social dysfunction in trauma-related disorders. The proposed research will take place in the laboratory of Kay Tye at the Salk institute in affiliation with the University of California, San Diego. Through graduate coursework, mentorship, and hands-on learning, Jianna will gain experience in rodent behavior and calcium imaging techniques and analysis. These skills will be valuable for the completion of the proposed research, and for Jianna’s future career as a physician-scientist.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Bipolar spectrum disorders (BSDs) are associated with major personal and public health burdens. Despite this heavy burden, the etiology of BSD is not fully understood. Further research on risk factors for BSD during adolescence, when likelihood of first onset of a BSD is highest, is needed to understand how BSD onset and symptoms can be better predicted and interventions delivered earlier. Determining the degree of risk for BSD conferred by various predictors is a vital step toward creating intervention and prevention programs that can identify individuals most at risk in order to reduce the likelihood of BSD onset, delay onset, or lessen course severity. Extant research has established several person-level factors that confer risk and influence dysregulation throughout the course of BSDs. The social and circadian rhythm model of BSDs posits that social and circadian rhythm dysregulation can result in mood symptoms and episodes. In another separate line of research, evidence suggests that hypersensitivity to rewards confers risk for BSDs. Researchers have suggested that the reward and circadian models of BSD risk and course can be combined into a joint, bidirectional model, such that disturbance in one of these systems, through a feedback loop, may promote dysregulation in both systems, contributing to mood symptoms and episodes. Additional theoretically and empirically supported predictors can be combined statistically with reward and circadian factors to better predict risk of bipolar symptoms. These factors include family history of BSDs, hypomanic personality, higher trait impulsivity, exposure to childhood adversity, affective lability, and substance use. However, the means by which predictive factors may be combined to better inform risk for bipolar symptoms is poorly understood. Although myriad risk factors for BSDs have been identified, little work has been done to statistically integrate information obtained through a multimodal approach to determine which individuals are most at risk. Thus, the proposed project seeks to evaluate empirically derived risk groups based on multimodal assessment of multiple risk factors for BSD during adolescence, a critical developmental period in which onset of BSDs is most likely. I will use participants from my sponsor's R01 study, which aims to examine the interplay of reward and circadian factors longitudinally to predict first onset of BSDs, add measures of additional risk factors, and statistically integrate these multimodal risk indicators with latent class analysis to evaluate the predictive utility of empirically-derived risk groups. My sponsors and I have designed a training plan involving coursework, workshops, experiential learning, and mentorship that will allow me to develop greater expertise in the development of mood pathology, learn advanced statistical methods required for this project, and gain the skills necessary for my future career as an independent clinical scientist. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists.

NIMH - National Institute of Mental Health

Project Summary/Abstract The contribution of individual disease-relevant genes to brain development still remains unknown. The long-term goal of our laboratory is to elucidate the intersection of molecular signaling pathways that are disrupted in neurodevelopmental disorders with those pathways that are important for specific aspects of brain development. Two members of the FOXP family of transcription factors, FOXP1 and FOXP2, have been linked to monogenetic forms of intellectual disability, autism spectrum disorders, and specific speech and language deficits. Variants in FOXP1 or FOXP2 are among the most significant genes associated with autism spectrum disorders. We previously showed that Foxp1 and Foxp2 both have significant contributions to cortical and striatal development. We linked these developmental changes via studies of gene expression, electrophysiology, and behaviors. We further identified non-cell-autonomous changes in gene expression using newly available single-cell RNA- sequencing technology. Based on these data, the central hypothesis driving this proposal is that Foxp1 and Foxp2 are key orchestrators of transcriptional signaling cascades in a cell type-specific manner that are important for neuronal function and are at risk in neurodevelopmental disorders such as autism. We propose to identify these cell type-specific contributions in the developing cortex by using rodent models through three specific aims: 1) Determine the cell type-specific gene expression programs regulated by Foxp1 in the developing cortex; 2) Determine the cell type-specific gene expression programs regulated by Foxp2 in the developing cortex; and 3) Assess the role of Foxp1 and Foxp2 in cell type-specific activity-dependent neuronal function. Together, these aims will delineate the cell type contribution of both Foxp1 and Foxp2 to cortical development. The rodent models and cell-type specific genomic datasets will aprovide insight into the basic molecular mechanisms governing normal mammalian brain development.

NIMH - National Institute of Mental Health

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.

NIMH - National Institute of Mental Health

Project Summary/Abstract The goal of the proposed project is to develop to develop an innovative digital health platform to support families who have a teenager diagnosed with attention deficit hyperactivity disorder (ADHD) who is driving (during permit period or post licensure). Parents of teens with ADHD routinely cite that one of the greatest sources of stress and frustration centers on the issue of driving. Teens with ADHD are at significantly increased risk of crash, more likely to have multiple crashes, and more likely to have their driving license suspended. In addition, teens with ADHD are more likely to have challenges in securing a license during the permitting process. We propose the development of an app that will enable joint parent and teen goal setting, monitoring and personalized feedback. Telematics data enables that development of the proposed app. Development will also be guided by evidence-based strategies for engaging with parents and teens with ADHD and iterative feedback that will be collected from the intended user population. The needs of the intended population will be considered throughout the development process and in phase I, a prototype of the platform will be tested with the intended population for usability and acceptability. We have assembled a team with complimentary expertise to develop the methods of engagement, content, user interface and app, and to conduct the needed testing.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Somatic mosaicism, the genomic differences among the billions of cells in the human brain, may explain the incomplete penetrance and variable expressivity in highly heritable neurodevelopmental disorders. Thousands of clonal somatic mosaic variants (SMVs) in subpopulations of neurons have been discovered in brains of schizophrenia and autism patients, necessitating an urgent, unmet demand to determine if these diverse somatic mutations have a causal role in disease. Major challenges include (1) the inability of using conventional statistical methods for common variants to associate disease status with risk variant, (2) the vast space of non-coding candidates with unknown function, and (3) the unresolved relevant cell types and developmental stages linking mutations to phenotypes. Just as integrating high-throughput genomic-, CRISPR, and stem cell-based technologies resulted in significant progress in understanding germline risk variants, they represent a novel approach to uniquely address the major challenges in the field of somatic mosaicism. As a co-mentored computational and experimental biologist, I will leverage state-of-the-art functional genomic technologies and bioinformatic pipelines to systematically characterize all brain non-coding SMVs discovered to date, resolving their causal roles in neurodevelopmental disorders. From all SMVs identified in case and control brains, I will first create a functional catalog of expression-modulated SMVs in a developmental- and cell-type-specific manner by applying massively parallel reporter assays in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and post-mitotic neurons. By doing so, I will be able to interrogate whether differences in patterns of expression-modulated SMVs exist between cases and controls. Second, I will compare the somatic and germline genetic architectures across neurodevelopmental disorders, determining whether somatic mutations act via the same pathways as germline mutations, or affect genes relevant to diseases, indicating a causal role. By simultaneously uncovering the downstream transcriptomic profiles of hundreds of regulatory elements harboring SMVs with CRISPR screen, I will be able to pinpoint putative disease-causal SMVs. Finally, I will validate the phenotypic impact of putative causal SMVs in physiologically complex and relevant models including 3D brain organoids and “mosaicism-in-a-dish”, testing both cell-autonomous and non-autonomous mechanisms of SMVs. Overall, this work, representing a novel application of scalable functional genomic technologies to SMVs, provides a framework to identify SMVs with putative causal effects in neurodevelopmental diseases, advancing our understanding of a poorly understood disease mechanism. This fellowship will provide me with training encompassing computational genomics, stem cell models and broadly applicable phenotyping techniques, setting a foundation for me to launch an independent research program distinct from my mentors', querying somatic mosaicism's impact into novel cell types, contexts and diseases towards discovering novel therapeutic targets.

NIMH - National Institute of Mental Health

Project Summary Mapping nanoscale brain architecture and molecular features across the entire mammalian brain remains out of reach using current technologies. Correlative light and electron microscopy (CLEM) is the only method capable of bridging structural and molecular information at this scale, but it is prohibitively slow, expensive, and complex, making it unsuitable for scaling to an entire mouse brain. Panluminate Inc. is developing a whole-organ 20X expansion technology called whole-brain pan-Expansion Microscopy (WBExM) that addresses these limitations directly. By combining ~20-fold linear expansion of intact mouse brains with novel bulk (pan) staining of proteins and lipids, WBExM enables molecularly annotated imaging of ultrastructure at sub-20 nm resolution across sections post-tissue expansion, minimizing alignment errors and enabling accurate tracing of neuronal processes for dense connectomics. Neurites including dendrites and axons can be traced by segmenting the pan-staining channel, while simultaneous immunolabeling identifies molecular targets of interest. Unlike EM/CLEM, WBExM is fully optical, scalable, and cost-effective, making it ideal for tracing brain circuits and investigating neurodegenerative disease mechanisms. Our proposed Phase I project is to develop and validate a complete workflow for brain-wide pan-ExM sample preparation and imaging. In particular, we will: (1) develop and optimize WBExM, including perfusion, embedding, clearing, and isotropic expansion protocols that preserve protein targets and tissue structure across the entire mouse brain; and (2) validate reconstruction of neuronal processes across sections, demonstrating that WBExM enables faithful tracing of long-range neuronal projections, synapses, and local circuits, overcoming alignment errors inherent in slice-based approaches. This work will establish WBExM as a practical and scalable platform for nanoscale brain imaging and prepare it for commercialization in Phase II as a research tool for molecular dense connectomics. Our long-term goal is for WBExM to become a core technology for generating nanoscale molecular brain atlases and for studying circuit-level abnormalities in neurodegenerative disease models, supporting discovery and therapeutic innovation aligned with the NIMH mission.

NIMH - National Institute of Mental Health

Depression is a major public health issue affecting hundreds of millions globally, with significant implications for suicide risk and overall health. Reliable assessment of depression severity is crucial for the development and validation of new medications, yet the current FDA-approved scales, the Hamilton (HAM-D) and Montgomery and Åsberg (MADRS) Depression Rating Scales, are limited by their subjective nature and lack of standardization. These limitations introduce measurement error and contribute to the particularly high failure rate of Phase 3 clinical trials in depression. The Depression AICOA®, a novel multimodal AI-based tool, has been developed to address these challenges by providing a more reliable and standardized method for assessing depression severity. Utilizing a computational approach that objectively measures multimodal features of depression severity, AICOA® has shown high concurrent reliability with HAM-D scores. Recognizing its potential, the FDA has recently accepted AICOA® into its Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program, marking it as the first AI and Digital Health Technology, as well as the inaugural Neuroscience project in the program. This SBIR project aims to advance AICOA® to regulatory qualification and a commercially ready stage through extensive clinical validation. The project will support the technical development and clinical validation of AICOA® through a comprehensive study. The outcomes of this research will enable AICOA® to progress with FDA qualification as a Drug Development Tool, paving the way for more precise and reliable depression assessments in clinical trials, ultimately leading to the development of more effective treatments.

NIMH - National Institute of Mental Health

Project Summary The proposed project addresses the need for reliable, privacy-preserving real-world evidence (RWE) on the potential mental health effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Although preliminary evidence suggests neuropsychiatric benefits, current observational studies are hindered by confounding, exposure misclassification, and institutional data-sharing barriers. These challenges are especially relevant in mental health research, where treatment timing and adherence are often uncertain. Aim 1 will develop a one- shot, lossless federated target trial emulation (TTE) framework that produces pooled-equivalent causal estimates using summary data. The model will integrate sequential trial emulation to address immortal time bias, likelihood- based exposure correction, and calibration via negative control outcomes. Summary statistics will be computed locally and securely aggregated in a single communication round. Aim 2 will evaluate the framework using de- identified EHR data from Ividence and UTSW and deliver a prototype R package. The package will include tools for data preprocessing, federated estimation, and visualization, supporting scalable and reproducible use across sites. Feasibility will be assessed based on analytic performance, system usability, and concordance with benchmark evidence. This project will deliver a scalable, privacy-compliant solution for multi-site causal inference using EHR data. It will advance the generation of RWE for mental health drug repurposing and establish a foundation for future clinical research and commercialization.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Adolescence is a period of neuroplasticity and change across physiological and behavioral domains. In particular, adolescence is an important window for brain maturation, during which both sleep physiology and myelin development play critical roles in neurodevelopment and depression. The present fellowship hones in on the relationship between sleep, myelin, and depressive symptoms in young people. Research with adults supports the impact of specific sleep physiology (e.g., spindles and slow wave activity) on white matter integrity and myelin content, and vice versa. As such, the central hypothesis of the proposed work is that both sleep physiology and myelin will provide independent as well as joint effects on depressive symptoms in young people. Specifically, the research aims the understand the relationship between sleep EEG signatures (i.e., spindles and slow wave activity) and myelin content (Aim 1) and the role of sleep EEG signatures and myelin in predicting depressive symptoms in young people (Aim 2). To address Aim 1 and 2, I will leverage data from two ongoing R01s of the sponsor where in both studies, participants are between 9-26-year-old. In the first project, participants have their overnight sleep recorded for 2-3 consecutive nights using an at-home wearable sleep device (Dreem3 headband). In the second project, participants undergo a single 3T MRI scan session which includes the Inhomogeneous Magnetization Transfer (ihMT) sequence, which is a novel, myelin-specific sequence. Participants also complete a survey battery (which includes the Beck’s Depression Inventory) at baseline and at yearly follow-up visits. As participants are between 9-26 years of age in both studies, there is often overlap in enrollment and participants will need to have participated in both R01s to be a part of the proposed project. The aims of the proposal have public health significance in that they will help better understand the neurobiological mechanisms of depression risk in adolescents, a sensitive developmental period of the lifespan. The findings may inform future intervention studies, particularly in collaboration with clinicians. Collectively, the proposed development plan integrates training in developmental neuroscience, sleep, neuroimaging, statistical analysis, and grant writing. This structured training will culminate in multiple first-author manuscript submissions to per- reviewed journals and establish a strong research foundation for a competitive early career funding proposal. The fellowship offers protected time and cross-disciplinary mentorship to ensure the successful achievement of these goals.

NIMH - National Institute of Mental Health

Advances in defining the genetic contributions to neuropsychiatric disorders (NPDs), such as autism spectrum disorder (ASD) and schizophrenia (SCZ), have led to the identification of over 200 risk genes harboring rare, protein-disrupting heterozygous mutations. Understanding how mutations in these genes alter brain development or function is essential for elucidating disease mechanisms. Here, we address the substantial challenges posed by genetic heterogeneity and pleiotropy in these two NPDs by studying approximately 50 risk genes in a highly parallel manner. This approach allows us to efficiently identify areas of overlap and convergence among mutations within and across disorders. We leverage our scalable human iPSC engineering platform alongside high-throughput, high-content phenotyping to conduct multi-layered analyses of molecular and cellular alterations caused by heterozygous mutations in these risk genes. Mutant and control lines will be differentiated into 2D neuronal cultures, where high-content imaging will assess proliferation and morphological features. RNA sequencing and high-sensitivity proteomics will be performed to measure gene expression and identify perturbed pathways. These data will be augmented by automated calcium imaging to assess spontaneous and evoked neuronal activity and network synchrony. To model early cortical development in vitro, complementing the 2D system, we will also generate 3D human cortical organoids (hCOs), enabling investigation of cell type specification, maturation, and tissue architecture. We will apply advanced platforms including the Phenocycler for multiplexed spatial proteomics and mononucleotide Repeat Frameshift (MORF) technology coupled with CLARITY imaging to examine cell and dendritic morphology in detail in maturing 3D hCOs. Proteomic and transcriptomic data will be integrated using weighted gene co-expression network analysis (WGCNA) to identify shared and distinct biological pathways affected by the various mutations and to relate these changes to alterations in cellular morphology and physiology in parallel across genes. Our work will clarify whether there are convergent molecular pathways disrupted within and across disorders, and how such disruptions propagate from the molecular to the physiological level, illuminating underlying disease mechanisms. In addition, the resulting ≈200 highly characterized iPSC lines representing ASD and SCZ risk genes will serve as a valuable resource for the field, supporting in-depth follow-up studies, replication, and data integration across platforms.

NIMH - National Institute of Mental Health

Contact PD/PI: lewis, elinor PROJECT SUMMARY Second generation antipsychotics (SGAs) are widely used clinical tools for the treatment of severe mental illness. However, their utility is highly variable, and they take weeks to become effective. The mechanisms behind this time course are not understood. SGAs are thought of as antagonists at the D2 dopamine receptor. Yet our recent work suggests that some SGAs function as arrestin-biased agonists at the less-characterized D3 dopamine receptor (D3R). Activation of the arrestin-3 pathway leads to degradation of D3R, potentially altering response to these drugs over time. I have generated preliminary data that shows mice grow tolerant to preclinical measures of SGA activity after chronic treatment of an arrestin-biased SGA. I hypothesize that D3R neurons are the locus of tolerance to select SGAs, and this tolerance is driven by decreased D3R membrane expression caused by arrestin-3 recruitment to D3R. I will use in vivo optical methods to assess changes in D3-neuron activity after chronic SGA treatment. I will also measure behavioral tolerance to SGA treatment in transgenic mice with altered abilities to degrade D3Rs and compare D3R levels using saturation binding and PET scans. This project will reveal mechanisms of tolerance to select SGAs at gross anatomy, cell- type, and protein levels. Project Summary/Abstract Page 6

NIMH - National Institute of Mental Health

Project Summary/Abstract Depressive symptoms represent a serious challenge to youth mental health. There is therefore an urgent need for the identification of possible mechanisms underlying risk for youth depressive symptoms. This is especially crucial for certain high-risk populations, such as youth with a history of adversity exposure. Dysregulation of the oral microbiome, the community of microorganisms inhabiting the human oral cavity, may function as a mechanism underlying risk for depressive symptoms in youth. The oral microbiome is a compelling putative mechanism for youth depressive symptoms because it is manipulable via non-invasive interventions, such as probiotic supplementation, while, at the same time, remarkably resilient to insults once it has stabilized in early adulthood. Indeed, oral microbiome dysregulation has been linked to depressive symptoms, experimentally in animal models and observationally in human youth. However, in order for potential mechanisms underlying this link to be elucidated, there is a need for research that examines the oral microbiome and depressive symptoms longitudinally, that examines the microbiome at a functional level, and that incorporates neuroimaging to better understand depressive symptom etiology. The current project will address these gaps by leveraging a 3-year longitudinal study of youth, ages 6-16 at the first timepoint (N=152), with the first 2 timepoints completed and the 3rd underway. This project oversamples for adversity-exposed youth (N=66), a population at increased risk of both depressive symptoms and oral microbiome dysregulation. Oral microbiome composition and depressive symptoms will have been assessed at all three timepoints, and functional Magnetic Resonance Imaging (fMRI) conducted at the final timepoint. We will analyze the relationship between the oral microbiome and depressive symptoms, and the relationship between the oral microbiome and functional brain connectivity. We hypothesize that elevated pathogenic taxa, increased pro-inflammatory functions of the oral microbiome, and decreased aromatic amino acid precursor biosynthesis will be associated with increased depressive symptoms. We further hypothesize these same indicators of oral microbiome dysregulation will also be associated with altered functional brain connectivity, especially within the affective limbic network, reward network, default mode network, and cognitive control network. This project’s findings will yield critical understanding about potential peripheral mechanisms underlying depressive symptoms in both typically developing and high-risk youth.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Prior research has documented that social determinants of health such as neighborhood disadvantage and school context are associated with youth mental health3,7,10,11, with neighborhood effects on youth outcomes being mediated by parenting factors4. However, research on the role of these contextual factors in the trajectories of parenting and youth mental health and their relationships has been limited. Additionally, this prior work shows the importance of targeting parenting in family-focused preventive interventions in geographical areas with high contextual risk. While neighborhood economic disadvantage and subjective perceptions of neighborhood are associated with outcomes of preventive interventions32, 34, this prior work has used limited objective measures of social determinants of health, has had inconsistent longitudinal follow-up, focused on limited outcomes, and did not consider how social determinants of health influence intervention engagement. The proposed research will address these limitations with several aims: (1) Determine how neighborhood and educational risk and protective factors are related to youth mental health trajectories across childhood and adolescence and the role of parenting as a mediator between context and youth mental health trajectories, (2) Investigate whether neighborhood and educational risk and protective factors are associated with engagement in and response to the Family Check-Up, a family-focused preventive intervention, and (3) Determine whether findings from the first two aims differ based on urbanicity, race, or ethnicity. The results have implications for clinical practice and research in the development and dissemination of family-focused preventive interventions that promote positive family relationships and youth mental health for all families. The work addresses the NIMH Strategic Plan by aiming to examine trajectories of mental illness, strive for prevention, and advance services to strengthen public health. The proposed research and training plan, which will occur in a supportive, collegiate environment at Case Western Reserve University, will provide the researcher with critical training to support the transition to becoming an independent researcher in developmental psychopathology and prevention science. Specific training goals include (1) Develop a focused understanding of how neighborhood and educational social determinants of health influence parenting and youth mental health, focusing on how this perspective can inform development and dissemination of preventive interventions, (2) gain expertise in leveraging geocoded data to answer questions related to social determinants of health, family functioning, and intervention outcomes, and (3) master the use of complex quantitative methods to analyze longitudinal data. The applicant has assembled a mentorship team with an expertise in the areas which she plans to gain additional experience, and this team will provide superior guidance that will support her increasing independence as a researcher.

NIMH - National Institute of Mental Health

PROJECT SUMMARY This NIH F30 application describes a three-year plan for mentored research and career development for the PI, Jana Badrani. The scientific premise of this proposal is focused on the role of GR-1+ non-microglial myeloid cells (NMCs) on brain development and adulthood behaviors under normal conditions and following maternal immune activation (MIA). MIA encompasses any pro-inflammatory response within the mother during pregnancy and can be caused by infectious and non-infectious stimuli. MIA is a known risk factor for psychiatric and neurodevelopmental disorders, like schizophrenia and autism, in offspring. MIA is also implicated in hematopoietic changes and disruptions in immune cell development and differentiation. Here, we will elucidate the cellular and molecular mechanisms of meningeal and brain non-microglial immune cell interactions with neurons during normal brain development and following a representative MIA model of maternal systemic challenge with polyI:C (PIC). Our preliminary flow cytometric data identifies a prominent GR- 1+ NMC population that increases within the brains of male MIA offspring. scRNA-seq analysis identified GR-1+ neutrophil populations in the brain, with significant gene expression changes in PIC offspring compared to vehicle offspring. Male MIA offspring also demonstrated behavioral deficits in the elevated plus maze (EPM). Systemic depletion of GR-1+ cells improved the EPM behavioral deficits in PIC male offspring. Thus, our central hypothesis is that GR-1+ neutrophils in the brain impair neuronal function and behaviors via MMP in male PIC offspring. We will test this hypothesis through immunohistochemistry, flow cytometry, single-cell transcriptomics, and a variety of in vivo experiments, including the use of anti-GR1 depleting antibodies and MMP inhibitors. Understanding the involvement of GR-1+ non-microglial myeloid cells in brain development and following MIA will have a significant impact on our understanding of immune-brain interactions underlying brain homeostasis. The proposed training plan for the PI is sponsored by Dr. Shin-ichi Kano, MD, PhD, and Dr. Farah Lubin, PhD. Included in the training plan are experiences that will help Jana develop in three major areas: (1) rigorous neuroimmunological research in neuro-immune interactions, which includes developing familiarity with existing literature, critical evaluation of data, and training in responsible conduct of research; (2) rigorous training in advanced bioinformatics, high dimensional data analysis, and scRNA-sequencing analysis; and (3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research in immunology, neuroscience, and bioinformatics necessary for the PI’s future career as a clinician-scientist focused on neuropsychiatry and immunotherapy.

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

PROJECT SUMMARY/ABSTRACT Suicide is the second leading cause of death among young adults ages 15-241, with rates continuing to rise2. While research has identified some broad predictive factors3, our ability to predict who will experience suicidal thoughts and behaviors (STB) and when these crises will occur remains limited4. This challenge stems from the fact that suicide risk fluctuates dramatically in response to emotional and interpersonal distress5,6, with social threats often acting as precipitating events7,8. The tendency to respond impulsively to negative emotions (e.g., negative urgency9) may help explain why some individuals engage in STB as a maladaptive attempt to escape emotional pain following social threat or rejection. Evidence from neuroscience indicates that social- affective circuitry reflects subjective affective sensitivity to social threat10,11, and overlaps with putative neural correlates of negative urgency12,13, suggesting a potential neural profile that may drive associations between social threat and STB. To test this, I will utilize data from an ongoing R01 including 6 months of ecological momentary assessment (EMA), a personalized peer social feedback fMRI task, and self-report questionnaires from 150 young adults (ages 18-30) with chronic STB to examine how function in social-affective systems and real-world experiences of social threat interact to predict STB. The Specific Aims of this study are to: (1) test associations between negative urgency and STB using both baseline and prospective EMA assessments; (2) investigate associations between functional connectivity of social-affective systems during social threat and trait-level negative urgency; and (3) examine whether individual differences in neural response to social threat moderate same-day relationships between social rejection-generated negative affect and suicidal thoughts. This project, and the associated F31 fellowship at the University of Pittsburgh, will provide critical training for the applicant to become an independent researcher investigating how neural and behavioral responses to social contexts influence suicide risk during key developmental periods. To accomplish the proposed research, this application includes a comprehensive training and mentorship plan that builds on the applicant’s prior clinical psychology and developmental neuroscience training. These Training Goals will focus on expanding the applicant’s knowledge and/or skills in: (1) neurodevelopmental pathways to suicide; (2) negative urgency as a mechanism of suicidal thoughts; (3) task-based fMRI methods, with an emphasis on functional connectivity analyses; and (4) implementing mixed-effects modeling for intensive longitudinal data. These goals will be accomplished through mentorship meetings, workshops, conferences, and coursework with a committed interdisciplinary team. Complemented by support from a dedicated research environment at the University of Pittsburgh, this fellowship will accelerate the applicant’s trajectory toward becoming an independent researcher focused on using multimodal research to identify how individual neurobiology interacts with one’s social environment to create enduring risk for STB.

NIMH - National Institute of Mental Health

PROJECT SUMMARY A major advance for treating depression, the leading cause of disability worldwide, has been the non- pharmacological development of repetitive transcranial magnetic stimulation (rTMS). While rTMS is effective for some, only about half of patients demonstrate a sustained clinical response. This is partly due to stimulation parameters not being fully optimized. While recent research has focused on personalizing where to stimulate, a critical gap remains in optimizing how to stimulate for each patient. This study aims to improve rTMS treatment for depression by using prefrontal electrophysiological biomarkers to personalize stimulation. We seek to enhance target engagement and better understand how brain changes relate to clinical response. Our method centers on early local TMS-evoked potentials (EL-TEPs), which provide reliable measurements of prefrontal excitability at the individual level. Prefrontal EL-TEPs are altered in depression, correlate with treatment outcomes, and respond to neuroplastic interventions like intermittent theta-burst stimulation (iTBS). Our team has pioneered a novel method to optimize EL-TEP acquisition, significantly improving signal quality and reliability. We hypothesize that personalizing iTBS pulse count and intensity to maximize EL-TEP suppression will optimize neural effects and improve clinical outcomes. We propose a R61/R33 study to develop and validate a personalized iTBS protocol. The R61 phase will demonstrate target engagement based on prefrontal excitability changes in 80 patients with treatment-resistant depression (TRD). We will characterize how iTBS parameters affect EL-TEPs in an abbreviated protocol, focusing on acute neurophysiological effects. The R33 phase will confirm target engagement and relate brain changes to clinical response in 106 new patients with TRD, comparing EL-TEP-guided personalized iTBS treatment to non-personalized iTBS treatment. This phase will involve a randomized, triple-blind design with comprehensive neurophysiological, clinical, cognitive, and functional assessments at multiple timepoints. This research is innovative as it uses prefrontal electrophysiology to deliver personalized iTBS treatment. The significance lies in its potential to select treatment parameters based on brain changes. Impact: This project aims to improve iTBS treatment through neurophysiology-guided personalization. By demonstrating target engagement and relating brain changes to clinical outcomes of personalized iTBS treatment, we seek to advance our understanding of the neural mechanisms of depression. If successful, this research could lead to more effective and efficient personalized treatments for depression.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Social memory is a critical process for learning to navigate the world, and deficits in social processing are common in neuropsychiatric disorders like autism, and Fragile X syndrome (FX). Current treatments for these disorders often fail to effectively address these social deficits, highlighting the need for a deeper understanding of the underlying mechanisms. A shared characteristic among these disorders is dysfunction of the hippocampus, a brain region recently linked to social memory. Hippocampal area CA2 and signaling of the social neuropeptide oxytocin within CA2 play a known role in social memory. However, research on the specific role of the dentate gyrus, a hippocampal region that sends direct excitatory input to CA2, during social memory processing, including oxytocin signaling, is lacking. The goal of this project is to identify how oxytocin signaling within the dentate gyrus contributes to social memory processing. My preliminary data shows that oxytocin increases the excitability and enhances synaptic transmission of dentate granule cells in wild type mice, while granule cell excitability may be impaired in a mouse model of Fragile X syndrome (FX mice). This project will use in vitro electrophysiology to record from dentate granule cells in response to oxytocin in wildtype mice and FX mice. Specific Aim 1 will identify potassium channels modulated by oxytocin in dentate granule cells. This aim will test the hypothesis that oxytocin modulates KV1 voltage-gated and KIR potassium channels. Preliminary data suggest that oxytocin enhances synaptic transmission from the entorhinal cortex to dentate granule cells, however, the locus and mechanism of this effect is not known. Specific Aim 2 will investigate how oxytocin modulates synaptic transmission in the dentate gyrus. Preliminary recordings from FX dentate granule cells found reduced excitability compared to wild type. Specific Aim 3 will determine the cellular mechanisms underlying this lower excitability and investigate if granule cell responses to oxytocin are impaired in FX mice. The results from this project will provide insight into the mechanisms behind oxytocin’s modulation of the dentate gyrus and may inform future treatments for prevalent social deficits. The findings anticipated from these proposed experiments will be the initial evidence of oxytocin’s modulation of KV1 in dentate granule cells, and the first indication that oxytocin modulates synaptic transmission to the granule cell layer, which may play a crucial role in social cognition. This fellowship will allow me to learn a wide array of in vitro electrophysiological and microscopy techniques, practice disseminating my research at national conferences, and acquire skills in mentoring and teaching undergraduate students. Through this fellowship I aim to develop not only essential technical skills, but also conceptual and professional competencies necessary for establishing a career as an independent researcher at an R1 institution.

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.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) often result from mutations in genes essential for brain development and function. Recent advances in gene replacement therapy have shown promise for rescuing molecular and behavioral deficits in mouse models, even when gene restoration occurs postnatally. However, the context and feasibility of gene replacement for specific disorders remain unclear. This project focuses on Tatton Brown Rahman Syndrome (TBRS), a rare NDD caused by mutations in DNMT3A, a gene critical for DNA methylation and neuronal development. TBRS patients exhibit intellectual disability, overgrowth, joint hypermobility, and seizures. In mice, loss of DNMT3A leads to altered neuronal differentiation and synaptic function, emphasizing its importance in early brain development. Kim will explore the potential for restoring DNMT3A function using innovative mouse models and gene therapy approaches. In Aim 1, Kim will employ spatial transcriptomics and single-nucleus RNA sequencing to assess how DNMT3A loss impacts cell type distributions and gene expression in the cerebral cortex and whether these changes can be reversed by restoring DNMT3A expression. In Aim 2, she will evaluate the feasibility of gene replacement therapy for TBRS using adeno-associated viruses (AAVs). These studies will address timing, delivery methods, and baseline efficacy of DNMT3A reinstatement in both tamoxifen-inducible and disease-relevant mouse models. This work will determine whether postnatal DNMT3A restoration can rescue molecular, cellular, and behavioral deficits associated with TBRS and provide a foundation for gene therapy strategies targeting NDDs. The findings will contribute to understanding the therapeutic potential of gene replacement, with implications for improving outcomes and quality of life for patients and families affected by TBRS and related conditions. This project will be conducted at Washington University in St. Louis, a phenomenal research environment that integrates cutting-edge genomic technologies, advanced imaging platforms, and expertise in neurodevelopmental disorders. The lab is supported by collaborations with leading researchers in mouse behavior, epigenetics, and computational biology, ensuring access to unparalleled resources and mentorship. This environment fosters innovation, collaboration, and rigorous scientific inquiry, creating the ideal setting to achieve the goals set forth by this proposal.

NIMH - National Institute of Mental Health

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