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NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Non-suicidal self-injury (NSSI), the deliberate harming of one’s body without suicidal intent, is a transdiagnostic behavior affecting nearly one in five adolescents worldwide, with twice the rates for girls than boys. NSSI often occurs outside the context of formal clinical care, making early detection difficult. Traditional approaches to understanding risk rely on static characteristics, such as diagnostic labels, but emerging evidence suggests that NSSI risk unfolds dynamically, through moment-to-moment and day-to-day changes in mood and behavior. The proposed research utilizes passive mobile sensing, a cutting-edge and low-burden method that captures behavioral data from adolescents’ smartphones without requiring active input, to better understand these dynamic risk processes in real-time. NSSI is highly understudied using passive mobile sensing, despite its growing prevalence, transdiagnostic significance, and association with rapid changes in emotions. Using GPS technology, this approach provides an unprecedented opportunity to observe the associations between daily changes in movement and location with mood fluctuations that serve as potential signs of emotional distress and NSSI risk. This proposal leverages existing data from the Mobile Assessment for the Prediction of Suicide (MAPS; 1U01MH116923-01) study and the Transitions in Adolescent Girls (TAG) study (R01/R56 MH107418; R01 MH127408) to assess study hypotheses in a high risk clinical sample and a community sample. Both studies utilize the Effortless Assessment of Risk States (EARS) smartphone technology to collect continuous digital behavior data in adolescents, offering rich, ecologically valid, and temporally fine-grained indicators of risk. The MAPS study includes 221 high-risk adolescent boys and girls followed for 6 months, while TAG includes 94 adolescent girls from the community followed for one month. With the applicant’s background in adolescent development and longitudinal research, combined with advanced training from sponsors in developmental psychopathology and clinical science, digital phenotyping, statistical modeling of intensive longitudinal data, and grant writing and scientific communication, the research team is uniquely positioned to fulfill this applicant's highly innovative, translational F32 proposal. Findings will directly inform the design and implementation of scalable, real-time NSSI prevention approaches. In parallel, the training and mentorship provided through this fellowship will accelerate the applicant’s development as an independent translational scientist by strengthening her ability to secure funding and lead high-impact research on adolescent mental health that advances precision prevention efforts. In the long term, this work will contribute to a program of person-centered, dynamic research on adolescent mental health, moving the field beyond static predictors of risk and toward real-world, real-time strategies for promoting resilience and preventing self- harm.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Fearful temperament marks risk for developing mental health challenges, including anxiety, later in life. Emerging neuroscience data suggests that the subset of fearful children who exhibit perturbations in amygdala circuitry may be most likely to develop anxiety. However, limited data directly implicates amygdala circuitry in infancy, when fearfulness first emerges. At present, there are three major barriers to progress: (1) the reproducibility and specificity of existing infant brain-behavior associations remains unknown; (2) studies have not yet accounted for the dynamic functional changes in the infant brain; and (3) the extent to which these effects have prenatal origins in maternal stress or psychopathology remains unknown. This application responds to these critical gaps by leveraging data from a global infant MRI database (ENIGMA-ORIGINs; N=1,479 total; N=341 with longitudinal MRI data) and the ongoing HEALthy Brain and Child Development (HBCD) study (N=5,025 total). Both ENIGMA- ORIGINs and HBCD include infant MRI, parent-reports of infant temperament, and measures of maternal perceived stress. HBCD additionally includes observed assessments of fearfulness and rich maternal psychopathology data obtained during pregnancy. The primary objectives of this application are to (1) identify amygdala connectivity associated with fearful temperament across the first two years of life; (2) characterize longitudinal changes in amygdala connectivity associated with fearful temperament; and (3) characterize the impact of prenatal stress and infant amygdala connectivity on fearful temperament. Across all aims, we evaluate how maternal anxiety impacts these associations. Our approach evaluates brain-behavior associations across time (to isolate developmentally sensitive patterns), evaluates out-of-sample reproducibility, and utilizes sophisticated statistical techniques (mediation) to examine pathways to fearfulness. Sensitivity analyses will determine whether observed patterns generalize to other negative affect states or persist across different methods of measuring fearful temperament (i.e., observational assessments vs. parent-report). By pinpointing neurobiological profiles of infant fearfulness that converge across phenotyping methods, our approach builds on research showing that cross-informant information may possess enhanced predictive power for long-term psychopathology risk. This project will be the largest infant MRI study to evaluate associations between prenatal stress, resting state functional connectivity, and infant temperament. By leveraging ‘big data’ this work is uniquely suited to model sex-specific patterns and isolate the effects of demographics, which will enhance neurodevelopmental models of early-life risk. This rigorous work will advance our understanding of the neural mechanisms that underlie fearful temperament in infancy and prenatal risk transmission and will provide new insight into early brain development. The insights gained from pinpointing neurobiological profiles of infant fearfulness could aid in identification of developmentally sensitive neural markers of risk and inform how to pair at-risk infants with treatments.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY/ABSTRACT Pediatric Amplified Musculoskeletal Pain Syndrome (AMPS) is becoming increasingly common, affecting between 11 – 38% of youth. AMPS is associated with significant stress, psychological impairment, and functional disability, resulting in tremendous healthcare costs. Moreover, AMPS conditions often persist into adulthood, increasing lifetime risk for psychiatric and medical comorbidities and earlier mortality. There is a critical lack of understanding of the processes involved in the onset, maintenance, and exacerbation of chronic pain conditions in youth, hampering efforts to develop interventions, which are currently limited and ineffective for a significant subset of patients. Comprehensive understanding of the biopsychosocial factors underlying chronic pain disorders like AMPS are needed to inform the development of novel, effective prevention and treatment approaches. Data suggest that altered stress physiology (e.g., allostatic load) may play a role in chronic pain conditions, with possible intergenerational implications. Parallel lines of research indicate that adversity exposure (e.g., abuse, violence), neurobiological functioning, and psychological impairment across youth-parent dyads contribute to the onset and maintenance of pain. The overall goal of the proposed project is to test an intergenerational model of chronic amplified musculoskeletal pain syndrome (AMPS) in youth and their biological mother/birthing parent that incorporates these constructs to elucidate mechanisms responsible for AMPS, thereby identifying potential prevention and intervention targets. The project aims will be accomplished by following a cohort of pediatric AMPS patient-parent dyads (N = 170) and healthy control – parent dyads (N = 85) over a 2-year period, repeatedly assessing pain characteristics (e.g., intensity, frequency), stress exposures, neurobiological functioning (conceptualized as allostatic load), psychological impairment, and psychosocial- biobehavioral resilience. Analyses will (a) identify the combination of neurobiological stress measures in isolation and cumulatively (as allostatic load) most predictive of AMPS symptoms in youth; (b) define correspondence of these measures in parent-child dyads; (c) identify parental characteristics (e.g., adversity history, parent mental health, parent stress neurobiology, parent-child relationship quality) most predictive of AMPS symptoms in youth; (d) identify psychosocial and biobehavioral resilience characteristics (e.g., coping style, social support, physical activity) that buffer the effects of intergenerational adversity exposure on pain characteristics; and (e) compare neurobiological stress processes in chronic pain patients and sociodemographically-matched healthy controls. The findings may be translated into the development of mechanistically informed prevention and treatment methods that target the most influential modifiable biopsychosocial pathways involved in AMPS and stress physiology and that may be personalized based on individual and familial risk profiles for maximum benefit. Studying these phenomena in youth-parent dyads is critical given that the majority of research in this area has focused on adult populations or with individually focused (i.e., pediatric pain patients) cross-sectional designs.

Bureau of Justice Assistance

This is a notice of funding opportunity (NOFO) for the BJA FY2026 Public Safety and Mental Health Initiative (PSMHI). This opportunity supports comprehensive service networks addressing untreated mental illness and substance use to reduce the burden of on law enforcement and the justice system; restore order in communities affected by homelessness, mental illness, and substance use; decrease recidivism; reduce crime; and improve overall public safety and restore confidence in public spaces. This initiative supports coordinated, direct intervention efforts across public safety, justice, mental health, and substance use agencies to increase access to mental health and substance use treatment through civil commitment, institutional treatment, and step-down approaches from pre-arrest through reentry, using accountability measures that ensure compliance with treatment plans. This program moves beyond temporary interventions by supporting appropriate institutional care and civil commitment processes, when appropriate, for individuals unable to care for themselves.

Bureau of Justice Assistance

This is a notice of funding opportunity (NOFO) for the BJA FY2026 Public Safety and Mental Health Initiative (PSMHI). This opportunity supports comprehensive service networks addressing untreated mental illness and substance use to reduce the burden of on law enforcement and the justice system; restore order in communities affected by homelessness, mental illness, and substance use; decrease recidivism; reduce crime; and improve overall public safety and restore confidence in public spaces. This initiative supports coordinated, direct intervention efforts across public safety, justice, mental health, and substance use agencies to increase access to mental health and substance use treatment through civil commitment, institutional treatment, and step-down approaches from pre-arrest through reentry, using accountability measures that ensure compliance with treatment plans. This program moves beyond temporary interventions by supporting appropriate institutional care and civil commitment processes, when appropriate, for individuals unable to care for themselves.

NIMH - National Institute of Mental Health

Project Summary Schizophrenia is a severe chronic mental illness characterized by both dopamine dysregulation and neuroinflammation known to alter neural function. Neuroinflammation leads to a leaky blood-brain barrier (BBB), and damages dopamine neurons. By studying midbrain tissue using single-cell RNA sequencing, we can identify the damaging molecular communication pathways that resident immune cells and invading immune cells use to disrupt brain homeostasis. We will determine how endothelial cells are transcriptionally and morphologically changed during brain inflammation, which will open new avenues to support strengthening the BBB as a treatment in schizophrenia. We will focus on the inflammatory environment in the schizophrenia midbrain, where we have discovered elevated cytokine and complement expression along with gliosis and macrophage infiltration. Our study will examine multiple related inflammatory pathways that mediate neuronal damage and assess whether the transcriptional profile, number, or size of dopamine neurons differs with inflammation and schizophrenia diagnosis. We will determine and map the key molecular and cellular changes underpinning a "leaky" BBB in proximity to dopamine neurons in the midbrain of people with schizophrenia. Additionally, we will identify serum biomarkers that distinguish high and low inflammatory states and correlate with leaky BBB status in the midbrain by linking central (brain) and peripheral measures (blood) using machine learning. This will allow the field to prioritize blood biomarkers that can be used to identify those most likely to benefit from anti-inflammatory and BBB treatments and to track potential benefits of treatment over time. Ultimately, this research will deepen our understanding of schizophrenia neuropathology and contribute to the development of novel therapies aimed at inflammatory changes to the BBB.

NIH

Background: Employment is a major social determinant of health. In Veterans with substance use disorders (SUDs), employment is associated positive health and wellbeing. However, many Veterans with SUDs are unemployed and the majority do not have access to quality employment supports. In response, national VA policy by the Office of Mental Health and Suicide Prevention (OMHSP) mandated the implementation of empirically based supported employment (SE) services into SUD specialty treatment settings (SE-SUD) at 156 VA sites. SE was originally developed, tested, and used to help people with serious mental illness attain community work, hence, this SE-SUD initiate is a new application of this recovery service. To date, SE-SUD implementation has been slow, and the nature and effects of the rollout on Veteran outcomes are unknown. Significance: This project advances the President’s National Drug Control Strategy that emphasizes the employment needs of Americans with SUDs. The study will also further the goals of the 2016 Comprehensive Addiction and Recovery Act promoting the study and utilization of patient centered, behavioral approaches in opioid use disorders (OUD). SE-SUD represents a novel approach to enhance wellness in this population. In addition, this study tackles a chief social determinant of health, employment, in a marginalized population that has been historically underserved regarding their employment needs. Innovation & impact: Leveraging multiple sources of system-wide VA and non-VA community data and incorporating an array of stakeholder input and data, this project will used the expanded RE-AIM framework to study SE-SUD implementation outcomes, in addition to key contextual factors that impact these outcomes. Additionally, guided by the FRAME model, this is one of the first studies to examine the extent and nature of practice modifications as they are applied in the real world as related to patient outcomes involved in a complex integrative service in SE. Innovative methods, including configurational analyses, will identify causal relationships between modifications and employment outcomes. These findings will inform novel directions for other health services interventions that seek to address social determinants of health by optimizing practice through a balance of maintaining quality guidelines with empirically driven, planned adaptation s. Specific Aims: Aim 1 will assess the RE-AIM domains of SE-SUD adoption, factors driving adoption, and reach. The results will produce a range of high and low reach sites that will be the focus of intensive data collection in Aim 2, in which implementation process will be described and SE-SUD fidelity and modifications used by providers will be examined. Aim 3 will prospectively examine the effects of SE-SUD on Veteran outcomes. Lastly, the relationship between modifications, fidelity, and Veteran outcomes will be assessed. Methods: This study will use convergent parallel mixed methods design. Aim 1 will integrate national survey and administrative data to determine SE-SUD adoption, factors driving adoption, and reach. Using a case summary matrix approach, Aim 2 will combine data from site visits, chart reviews, and interviews at 24 sites to assess SE-SUD implementation process, fidelity, and modifications. Using an interrupted time series design, Aim 3 will examine effects of SE-SUD on Veteran outcomes across 9 months (primary endpoint) in a national sample of 180 unemployed Veterans receiving SE-SUD. Outcomes include employment, health, recovery, and suicidality. Configurational analysis will identify SE modifications associated with favorable Veteran outcomes. Next steps/Implementation: In close collaboration with OMHSP partners, BEST-SE findings will inform future policy changes regarding the integration of SE services into multi-tiered SUD treatment settings and practice guidelines that promote Veteran outcomes accompanied by empirically defined modifications that fit local context. The study will also provide information and tools to improve national uptake and maintenance of SE- SUD and will inform the ability of SE-SUD to improve employment in a vulnerable Veteran population.

European Commission - HORIZON

Boosting mental health of young cancer survivors through the European Cancer Patient Digital Centre (ECPDC). Call: Supporting the implementation of the Cancer Mission. Programme: HORIZON. Keywords: Man-machine-interfaces, Mental health, Patient care, Quality-of-life. Open call from the EU Funding & Tenders Portal.

NIMH - National Institute of Mental Health

Abstract Mass spectrometry imaging (MSI) enables spatially resolved identification of hundreds of molecules in a tissue sample, providing profound insights into biological and environmental processes across spatial dimensions. This multiplexing capability, combined with the label-free nature of the technique, has led to the widespread adoption of mass spectrometry as an emerging tool for molecular imaging. However, in terms of protein imaging of tissue samples by MSI, most of methods utilize “top-down” approach for protein analysis, which is challenging due to low sensitivity of MS instrument for intact protein ion detection (in comparison to peptide ion detection). As a result, the number of proteins identified in MSI experiments without digesting proteins into peptides is quite limited. To tackle this problem, in this project, we propose to develop a novel approach of “bottom-up” MSI for protein analysis directly from tissues using nano-DESI ionization in combination with online ultrafast microdroplet protein digestion technique. As our proposed “bottom-up” MSI technology focuses on peptide ion analysis instead of intact protein ion analysis, it would have higher sensitivity than “top-down” MSI approaches and enable identification of many more proteins based on their constituent peptide detection from one single MSI experiment. As proteins represent one of the most important functional molecules in tissue and cells, we expect that our proposed method would have very broad biomedical applications.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Pathophysiological studies in first episode psychosis (FEP) have been inconsistent due to the heterogeneity in age of onset, clinical presentation, and neurobiology in schizophrenia spectrum disorders (SSD). Neuroimaging studies, postmortem investigations, and blood-based biomarker experiments provide intriguing insights into potential abnormalities related to the barriers of the brain of individuals with SSD, but only 1% of existing studies have focused on mid- to late-life FEP. Clinical and biomarker studies in SSD have repeatedly shown three phenomena: First, is blood brain barrier (BBB) dysfunction in neuroimaging, postmortem, blood- and CSF-based studies in individuals with SSD. Second, is the involvement of the blood cerebral spinal fluid barrier (BCSFB) as evidenced by enlargement of the choroid plexus (ChP) in SSD, FEP and in individuals at high risk for psychosis. Third, there is a nascent but growing research area related to the disruption of the glymphatic system (GS) in SSD. Moreover, there is a growing body of evidence in aging, sleep, and neurodegenerative studies suggesting a link between disruptions in the BBB, BCSFB, and GS to clinical outcomes. These barrier systems, regulate trafficking between the blood and the brain through physical, enzymatic, transport, and immunological processes, and they have tightly regulated interrelationships between them to ensure a healthy brain environment. However, despite the complementary roles between the BBB, BCSFB, and GS, the interaction between these systems in mid- to late-life FEP has not been explored. Advances in neuromaging and blood-based techniques have improved upon existing tools to assess BBB, BCSFB, and GS function and they include gadolinium-enhanced MRI methods like dynamic contrast enhanced-MRI (DCE-MRI) and the isolation of circulating brain microvascular endothelial cells (cBMECs) in the blood. Therefore, the critical need and overall objectives for this study are to unite neuroimaging, cBMEC, and clinical phenotypes in the same individuals to mechanistically link barrier disruptions to clinical outcomes in mid- to late-life FEP. Our central hypothesis is that biomarkers of BBB, BSCFB, and GS dysfunction are associated with poorer clinical outcomes in mid- to late-life FEP. Here, we aim to test the hypothesis that: 1) barrier/GS disruptions are associated with mid- to late-life FEP, 2) cBMECs are a proxy of BBB deficits in mid- to late-life FEP, and 3) barrier/GS deficits are associated with worse symptoms, cognition, and functioning in mid- to late-life FEP. Lastly, we will determine the interrelationship between barrier and GS deficits in mid- to late-life FEP. The proposed research is innovative in combining in vivo imaging of the BBB, BCSFB, and GS with clinical measures in the same individuals to better understand the barrier/GS deficits associated with clinical outcomes in mid- to late-life FEP. The proposed research is significant because it will lay the groundwork for a robust non-invasive platform to screen for cBMECs to pathophysiologically stratify patients, a first for SSD, that may lead to the prioritization of novel therapeutic approaches to regulate barrier dysfunction in SSD.

Brain Canada Foundation

Brain Canada catalyzes brain research through the Canada Brain Research Fund, supporting projects on neurological and mental health conditions.

National Institutes of Health

<p>The National Institute of Mental Health (NIMH), with other NIH Institutes and Centers (ICs), intends to publish a notice of funding opportunity (NOFO) to solicit research applications for the BRAIN Initiative Cell Atlas Network (BICAN) Coordinating Unit for Biostatistics, Informatics, and Engagement (CUBIE). In accordance with NIH standard peer-review processes, the application(s) will be peer-reviewed, and only meritorious application(s) will be considered for funding. The overall goals of CUBIE are to (i) enable the exploration of large-scale brain cell atlas data and knowledge, and inspire research in brain function and disorders; and (ii) ensure research rigor and data reproducibility by making the data Findable, Accessible, Interoperable, and Reusable (FAIR), and the process transparent. This is a renewal that will continue the funding for a 2-year period. Applications are not being solicited at this time. Notice is being provided to allow eligible applicants sufficient time to develop meaningful collaborations and responsive projects. Applications are expected to collaborate with the broader research community to analyze and interpret all existing brain cell census/atlas data to enhance statistical power, ensure research rigor and data reproducibility, and foster the formation of a brain cell atlas ecosystem by leveraging recent Artificial Intelligence/Machine Learning (AI/ML) advancements.</p>

National Institutes of Health

The National Institute of Mental Health (NIMH), with other NIH Institutes and Centers (ICs), intends to publish a notice of funding opportunity (NOFO) to solicit research applications for the BRAIN Initiative Cell Atlas Network (BICAN) Coordinating Unit for Biostatistics, Informatics, and Engagement (CUBIE). In accordance with NIH standard peer-review processes, the application(s) will be peer-reviewed, and only meritorious application(s) will be considered for funding. The overall goals of CUBIE are to (i) enable the exploration of large-scale brain cell atlas data and knowledge, and inspire research in brain function and disorders; and (ii) ensure research rigor and data reproducibility by making the data Findable, Accessible, Interoperable, and Reusable (FAIR), and the process transparent. This is a renewal that will continue the funding for a 2-year period. Applications are not being solicited at this time. Notice is being provided to allow eligible applicants sufficient time to develop meaningful collaborations and responsive projects. Applications are expected to collaborate with the broader research community to analyze and interpret all existing brain cell census/atlas data to enhance statistical power, ensure research rigor and data reproducibility, and foster the formation of a brain cell atlas ecosystem by leveraging recent Artificial Intelligence/Machine Learning (AI/ML) advancements.

NIMH - National Institute of Mental Health

To take advantage of recent and ongoing advances in intensive and large-scale computational methods and to preserve the scientific data created by publicly funded research projects, archives for sharing data must be created, as well as standards for specifying, identifying, and annotating deposited data. The value of an interest in such archives among researchers can be greatly increased by adding to them an active computational capability and framework of analysis and search tools that support further analysis as well as larger-scale meta-analysis and large-scale data mining. OpenNeuro.org, founded as a repository for functional magnetic resonance imaging (fMRI) data, is such an archive. We have built a web portal, NEMAR, to OpenNeuro data for human electrophysiology data (EEG and MEG) and for intracranial (iEEG) data recorded from clinical patients during planning for brain surgery or other therapies – we here refer to these as neuroelectromagnetic (NEM) data. NEMAR, maintained at the San Diego Supercomputer Center, acts as a portal to NEM data shared publicly via the OpenNeuro data archive. Upon receipt by OpenNeuro, NEM data are copied to NEMAR and made available for processing without charge on the ACCESS high-performance computing resources of the San Diego Supercomputer Center (SDSC) via the Neuroscience Gateway (NSG) project. NEMAR offers a search engine for NEM data whose results can be inspected in detail from a web browser, including visualizations of data from each subject plus a number of data activity measures and quality estimates. A forum for each dataset records visitors’ comments and lists papers citing the data. Next, we will build large, multimodal foundational deep neural network models allowing users to explore relationships between NEM signal brain dynamics, experience, and behavior.

National Institutes of Health

<p>The National Institute of Mental Health (NIMH), with other NIH Institutes and Centers (ICs), intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications to develop web-accessible data archives to capture, store, and curate data related to the Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative activities. The data archives teams will work with the research community to incorporate software tools that enable users to analyze and visualize the data, and to use appropriate standards to describe the data. A goal of this program is to advance research by creating a data archive that meets appropriate standards and provides summary information which is broadly available and accessible to the scientific community furthering research. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the R24 activity code. Applications to this NOFO must propose the development of archives that support rigorous data sharing, analysis, and collaboration across sub-domains while enabling future linkage into a broader data ecosystem.</p>

National Institutes of Health

The National Institute of Mental Health (NIMH), with other NIH Institutes and Centers (ICs), intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications to develop web-accessible data archives to capture, store, and curate data related to the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative activities. The data archives teams will work with the research community to incorporate software tools that enable users to analyze and visualize the data, and to use appropriate standards to describe the data. A goal of this program is to advance research by creating a data archive that meets appropriate standards and provides summary information which is broadly available and accessible to the scientific community furthering research. Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO will utilize the R24 activity code. Applications to this NOFO must propose the development of archives that support rigorous data sharing, analysis, and collaboration across sub-domains while enabling future linkage into a broader data ecosystem.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Individuals with autism spectrum disorders (henceforth, autism/autistic) exhibit repetitive behaviors and deficits in social cognition and communication, often accompanied by co-occurring neurological, psychiatric, and/or health conditions. Autism affects one in 36 children in the United States, and optimal support for this large population depends on a clear causal model of core deficits. Autism has been linked to numerous genetic variants, and neuroimaging research points to altered connectivity as a consistent feature of the autistic brain. However, the neurobiological mechanisms that give rise to social cognition deficits in autism remain poorly understood. The proposed project will investigate brain metabolic dysfunction as a central mechanism underlying altered brain connectivity and social cognition deficits in autistic adolescents relative to non-autistic peers. We will investigate metabolic dysfunction by using non-invasive magnetic resonance spectroscopy (MRS) to measure metabolites, natural chemicals in the brain that serve as markers of metabolic dysfunction. We will study three metabolic systems involved in brain development and functioning: the glutamate/GABA-glutamine cycle, energy metabolism, and phospholipid metabolism (Aim 3). In addition, we will acquire magnetic resonance imaging (MRI) measures of functional and structural brain connectivity, and test whether dysfunction in each metabolic system is related to social cognition via altered brain connectivity. Specific Aim 1 will examine the association between glutamate/GABA-glutamine cycle dysfunction, functional connectivity, and social cognition in autism. Specific Aim 2 will identify alterations in brain energy metabolism in autism and examine associations between brain energy metabolism and functional connectivity and social cognition. Specific Aim 3 will investigate phospholipid metabolic dysfunction as a source of weakened structural connectivity and impaired social cognition in autism. Together, these aims will enable us to define mechanistic pathways underlying core autism symptoms from metabolism to brain connectivity to cognition. Identifying metabolic dysfunction of specific systems in autism will provide new insight to guide targeted interventions that mitigate core social deficits by modulating dysfunctional metabolic processes in the brain. Importantly, this career development award will provide the candidate, who has a strong background in developmental psychology and pediatric neuroimaging, with additional training needed to successfully transition to an independent research career. The training objectives of this award include specific training in (1) the cognitive profile of autism, (2) functional connectivity analysis, and (3) advanced MRS methods under the guidance of world-class mentors in each of these areas. This training is critical to the candidate’s success as an independent investigator who advances the understanding of neurobiological mechanisms of autism and other neurodevelopmental conditions.

NIMH - National Institute of Mental Health

The brain’s reward system comprises a set of interconnected regions that jointly direct goal-oriented behavior and underlie numerous pathologies. In order to understand how this system promotes behavioral outcomes, it is essential to characterize how neural information propagates among multiple brain structures and cell populations in the reward network, and how this leads ultimately to actions. Here we propose to use cutting-edge functional magnetic resonance imaging (fMRI) techniques to study integrated input/output relationships between brain re- gions involved in reward-related tasks. The centerpiece of our approach is a novel genetically encoded sensor for fMRI, called NOSTIC, that permits noninvasive functional imaging of discrete neural circuit components at a population level; the NOSTIC probe can be applied using a retrogradely transported virus to enable selective functional imaging of afferent input to any targeted region of the brain. We will use NOSTIC-based circuit-specific fMRI, in combination with complementary anatomical and physiological measurements, to dissect the propaga- tion of neural information during rewarding stimulation, reward-based classical conditioning, and closed-loop rewarding self-stimulation. Experimental data will be used to construct network-based models of reward system function and address fundamental hypotheses about information flow between brain regions, the origin of reward prediction signals, the basis of reward-induced plasticity, and the relationship between individual behavior and defined neural circuit components. Our agenda consists of three aims: In Aim 1 we will use the NOSTIC tech- nology to examine how functional inputs from across the brain converge on three key structures, the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC), during rewarding stimulation in rats. Results will define for the first time the broad topographies of information flow among multiple brain regions during rewarding stimulation, dissecting inputs from functionally and neurochemically distinct brain regions and testing the hypothesis that these inputs combine in approximately linear fashion to produce regional activity. In Aim 2, we will apply NOSTIC to examine circuit-level bases of brain-wide plasticity during paradigmatic classical conditioning paradigms, addressing key questions about the origins of reward prediction error signals in the brain at a comprehensive spatial scale. These studies will be performed in complementary awake rat and mouse preparations implemented in two laboratories, serving to disseminate NOSTIC technology as well as apply it. Then in Aim 3, we will introduce a cell type-specific application of NOSTIC that enables separate excitatory and inhibitory contributions to reward circuit dynamics to be measured and interpreted in the experimental paradigms of Aims 1 and 2. Collectively, these experiments will provide a first-of-their-kind spatially comprehensive dissec- tion of neural circuit mechanisms involved in diverse reward-related brain functions.

NIH

Ischemic stroke and traumatic brain injury (TBI) are major causes of mortality and long-term functional deficits in veterans and service personnel. Dr. Vemuganti’s current research is to identify new molecular targets to develop therapies for protecting the brain and promote the functional recovery following stroke and TBI. Although stroke is #1 cause of disability in adults, there is no efficacious therapy to prevent post- stroke brain damage and functional deficits. Several classes of noncoding RNAs such as microRNAs (miRNAs) and long noncoding RNAs are known to modulate the post-stroke brain damage. Dr. Vemuganti’s currently funded Merit Review Grant is evaluating if a miRNA known as miR-21 upregulated after stroke can potentially target the mRNAs that promote inflammation, oxidative stress and apoptosis. The project is specifically evaluating if treatment with a miR-21 mimic protects the brain and promotes better motor, neuropsychiatric and cognitive functional recovery after stroke induced by transient middle cerebral artery occlusion (MCAO) in mice of both sexes. The proposal is comprehensively testing the efficacy of miR-21 mimic in modulating long-term outcomes as a function of sex, age and comorbid conditions. Recent studies showed that gut microbiome influences neuroinflammation and other pathologic events after stroke. Hence, the project is also testing if miR- 21 mediated post-stroke neuroprotection is due to prevention of gut microbiome dysbiosis leading to better outcomes. The overall goal is to test the therapeutic potential of miR-21 to translate further to human studies. If successful, these studies lead to establishment of miR-21 as a new therapy to help service personnel and veterans who suffer a stroke. TBI promotes significant motor, cognitive and neuropsychiatric dysfunction. The effects of TBI in surviving veterans can often be seen for decades after the initial injury. Vitamin C (ascorbate) is highly concentrated in brain and known to promote neuroprotection after acute and chronic CNS insults. However, its efficacy in TBI was not yet tested comprehensively. In a VA funded Merit Review Grant, Dr. Vemuganti’s lab is testing the efficacy of ascorbate treatment in reducing the secondary brain damage and promoting better motor and cognitive functional outcome in adult mice subjected to controlled cortical impact-induced TBI. Epigenetic changes are known to significantly influence the gene expression and outcome after TBI. Of particular interest, hydroxymethylation of cytosine in DNA catalyzed by TET hydroxylases forms 5-hydroxymethylcytosine (5hmC), which is a transcriptional de- repression mark that increases cell survival under adverse conditions. As brain contains ~10-fold higher 5hmC levels than other organs of the body, we are testing if ascorbate treatment enhances cerebral TET activity and 5hmC levels after TBI and if this epigenetic modification is a major mechanism of ascorbate-induced neuroprotection after TBI. The long-term goal is to provide a therapy to help service personnel and veterans who suffer a TBI.

NIMH - National Institute of Mental Health

Abstract Schizophrenia is a devastating mental disorder with enormous personal disability and societal cost. Cognitive impairment, especially working memory (WM), is a core symptom driving disability, so cognitive rehabilitation treatments are desperately needed to improve functioning in individuals with schizophrenia. In the past decade, neuromodulation of gamma frequency brain rhythms has emerged as a promising new treatment target to improve cognition. Cognitive impairment, especially WM, has been associated with deficient frontal cortex gamma activity and a number of promising gamma neuromodulation treatments suggest enhancing gamma can enhance memory in schizophrenia. Thus, increasing frontal gamma may improve WM. Electroencephalographic neurofeedback (EEG-NFB) is a promising treatment that can guide an individual to enhance frontal gamma waves by providing positive feedback via visual and auditory cues typically in a game (e.g., racing a car). Our prior NIMH-funded research has shown that gamma-NFB can improve frontal gamma and WM memory in individuals with schizophrenia in our university lab setting. In this Phase I project, our company, BioSignal Solutions, will translate this promising approach out of the lab to a mobile platform (BrainGain® app with wireless EEG headband), so individuals with schizophrenia can enhance their memory circuits at home or in a community clinic setting. Using an iterative, user-centered co-design process (e.g., hands on usability workshops with patients, caregivers and healthcare staff), we will convert headsets currently used in our in-lab clinical trials into simplified versions for patients to use at home. We will validate the mobile BrainGain® platform through equivalency testing with our in-lab UC San Diego gamma-NFB protocol to demonstrate reliable and accurate signal acquisition and preprocessing and key gamma-NFB training metrics (gamma coherence and dynamic reinforcement thresholds). We will then conduct a preliminary randomized controlled trial (RCT) to test the feasibility and efficacy of BrainGain when self-administered by individuals with schizophrenia at home. Product development will also include working with expert consultants with commercial medical device and FDA-approval experience. After this Phase I device development project and estimating effect sizes in the preliminary RCT, we will finalize design and production of the product for FDA-compliant Phase II clinical testing in a larger confirmatory RCT. Ultimately, we aim to deliver safe, effective and accessible mobile gamma-NFB treatment to improve memory and functioning in millions of Americans living with schizophrenia. 1

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

PROJECT ABSTRACT Sub-Saharan Africa (SSA), a region dominated by low-resource communities and relatively poor families, is experiencing rising HIV prevalence among adolescents and youth (AY). Household economic hardships heighten the risk for AY’s engaging in health-compromising behaviors and their poor engagement with care. This increases their risk for contracting and transmitting HIV and non-adherence to ART treatment. Economic empowerment (EE) interventions have demonstrated substantial promise in reducing HIV-related risk-taking behaviors, and improving ART treatment adherence and mental health outcomes. Based on 10+ years of research utilizing savings-led EE interventions focused on HIV prevention, care and support for AY affected by HIV [AYaAIDS] (including AY living with HIV [AYLHIV]; and AY orphaned by AIDS [AYoAIDS] in SSA, our group has demonstrated the effectiveness of a multi-component EE intervention, Bridges, in four NIH-funded randomized control trials (RCT) in Uganda (R01 HD070727, R01HD074949, R34MH081763, R01MH113486), and one foundation-funded study in Kenya. Bridges involves: 1) financial literacy training (FLT) and mentorship; 2) family income-generating activities (IGA); and 3) incentivized savings via a matched Youth Development Account (YDA). Bridges has demonstrated robust effects on HIV-related risk-taking behaviors, ART adherence, mental health, psychosocial outcomes, educational achievement, family economics, and family cohesion. Yet, scaling EE interventions has been a challenge, signaling the need to identify and test scale-up strategies and examine determinants of implementation and sustainment. In Bridges2Scale, we will compare two multifaceted strategies (standard vs enhanced) for scaling Bridges in a two-arm Hybrid III effectiveness-implementation cluster RCT. The standard implementation strategy has been applied in our prior RCTs and involves educational meetings that prepare staff to deliver Bridges with minimal disruption to site workflow. This will be compared to an enhanced strategy that will be developed using Implementation Mapping. We will use the public school system to recruit 1440 AYaAIDS (ages 13-17 years) from 48 schools in the Greater Masaka region of Uganda, a region with 11.7% HIV prevalence. Schools will be the unit of randomization (n=24 schools per arm; n=720 students per arm). Four specific aims guide our study: Aim 1. Compare the implementation effectiveness of the standard implementation strategy vs. an enhanced implementation strategy; Aim 2. Determine the clinical effectiveness of Bridges implemented via a standard vs. enhanced implementation strategy; Aim 3. Explore implementation processes, mechanisms, and determinants; and Aim 4. Compare the cost and cost-effectiveness of the two implementation strategies. The study will address a critical challenge: how to best support the implementation, scale-up, and sustainment of EE interventions, which have been proven to be highly efficacious in improving youth-focused HIV prevention, care, and support outcomes, but are yet to be widely scaled up.

NIMH - National Institute of Mental Health

SUMMARY Bipolar disorder (BD) is a major public health problem, as it causes significant disability and suicide risk. There is a great clinical need to improve the treatment for the depressed phase of BD. The pathophysiology of BD is largely unknown, and understanding its pathophysiology could help to advance treatment. Previous neuroimaging and post mortem brain studies have provided indirect evidence that mitochondrial pathology may be occurring as part of BD’s pathophysiology. Recent animal model studies indicate that mitochondrial pathology can induce behavioral symptoms of BD. This study will use broadband Near Infrared Spectroscopy (bNIRS), a novel optical neuroimaging research tool, to directly measure cytochrome c oxidase (oxCOX) signal as an index of mitochondrial activity in the brain. Our preliminary data with the technique suggests that participants with BD may have lower oxCOX signal than healthy volunteers (HV’s), and that oxCOX signal had an inverse association with depression severity. Previous studies of BD have indicated differences in blood indices of mitochondrial pathology, including lower Mitochondrial Health Index (MHI). MHI is a composite measure of both mitochondrial enzymatic activities and mitochondrial DNA copy number within peripheral blood monocyte cells, and it was developed by a co-investigator on the project, Martin Picard. This project will test whether MHI is associated with brain oxCOX signal to assess whether a brain mitochondrial pathology may be caused by or part of a broader systemic mitochondrial abnormality. Other aspects of BD’s pathophysiology, including levels of life stress and past course of mood episodes may be related to mitochondrial pathology based on previous data, and will be measured here. bNIRS is low cost and non-invasive, and it does not require specialized facilities or operational training. It therefore has broad potential for clinical research and treatment use. A tool to track the clinical course of BD would allow for clinical decisions to be based on an objective measure, improving cost and delivery of care. This study aims to advance the bNIRS technique towards this purpose. 30 participants with BD in a major depressive episode and 20 HVs will be recruited. Participants will receive bNIRS using hypocapnia and hypercapnia challenges, the Bipolar Depression Rating Scale (BDRS), the STRAIN, venipuncture and a thorough clinical history. BD participants will then receive a structured clinical treatment with a medication that is FDA approved for depression in BD. bNIRS, MHI and BDRS will be repeated at weeks 3 and 6 of treatment. Aim 1 will be to determine whether brain mitochondrial function in the prefrontal cortex, measured by bNIRS, is lower in BD than HVs. Aim 2 will be to assess whether bNIRS can be used to track mood symptoms during an acute treatment course of depression in BD, and whether it is associated with depression severity. Aim 3 will be to determine if the MHI is associated with brain oxCOX signal in BD. The Exploratory Aim will assess whether bNIRS oxCOX activity is associated with either measures of life stressors on STRAIN, or duration and severity of past mood episodes.

NIMH - National Institute of Mental Health

Obsessive-compulsive disorder (OCD) is a disabling illness that significantly impairs quality of life and functioning. First-line treatments include cognitive behavioral therapy consisting of exposure and response prevention (EX/RP) and pharmacotherapy with serotonin reuptake inhibitors (SRIs). Randomized controlled trials (RCTs) have shown that EX/RP alone or combined with SRIs helps up to two-thirds of patients attain minimal symptoms. EX/RP (alone or combined with medication) is also the treatment patients typically prefer compared to medications alone. However, despite its proven efficacy and this patient preference, EX/RP is greatly underused in community settings. This R34 will begin to address this treatment gap by testing scalable implementation strategies to train community clinicians to deliver EX/RP. In response to PAR-21-131 (Pilot Effectiveness Trials for Treatment, Preventive, and Services Interventions) and NIMH NOT-MH-22-170 (Research Using Implementation Science to Support the Delivery of Evidence- Based Practices in Certified Community Behavioral Health Clinics (CCBHCs), this R34 will develop and evaluate the feasibility and preliminary effectiveness of a fully remote EX/RP learning collaborative, called SCALE-EX/RP, developed with and for CCBHC clinicians. First, we will use behavior change theory to guide a mixed-method evaluation consisting of surveys and interviews with clinicians, and interviews with supervisors and clinic leaders from six CCBHC clinics to identify barriers and facilitators to EX/RP use. We will use these data to refine our initial plan for SCALE-EX/RP that includes self-paced online EXRP training courses, remote 1:1 consultations with experiential training, and a virtual learning community comprised of CCBHC clinicians and an implementation specialist where clinicians will engage in case-based learning, self-audit and receive feedback while delivering EX/RP (Aim 1). Next, we will conduct a pilot cluster RCT in adults with OCD to test our hypotheses that SCALE-EX/RP will lead to superior clinician fidelity to EX/RP compared to online EX/RP training courses alone and to greater improvement in hypothesized mechanisms of action: clinician knowledge, attitudes, and confidence (Aim 2). Acceptability and feasibility will be evaluated with clinician surveys, time spent in training and training completion rates. Qualitative interviews with clinic members in SCALE-EX/RP will be used to identify barriers and facilitators to future implementation. We will also explore how clinician EX/RP fidelity influences patient EX/RP adherence, and improvement in OCD symptoms and quality of life (Exploratory Aim). Results will inform the design of a larger scale cluster RCT powered to test the hypothesis that training CCBHC clinicians with SCALE-EX/RP will lead to better patient outcomes. Our long-term goal is to increase access to EX/RP (our most effective, patient-preferred OCD treatment) while advancing knowledge of how learning collaboratives can be used to implement evidence-based treatments for severe mental illness (like EX/RP) in behavioral health.

National Institutes of Health

-Purpose. This Funding Opportunity Announcement (FOA) is intended to encourage the development of collaborative partnerships between scientists who study basic behavioral processes and those who study the etiology, diagnosis, treatment, and prevention of mental and behavioral disorders (including drug abuse and addiction) and the delivery of services to those suffering from those disorders. The National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), are issuing this FOA as part of a major, long-term commitment to (a) encourage the systematic translation of basic behavioral theory, methods, and findings into research designed to reduce the burden of mental illness and behavioral disorders (including drug abuse and addiction) and (b) encourage basic behavioral scientists to seek a further understanding of behavioral processes through an exploration of how those processes are altered by mental and behavioral disorders. This FOA was developed in response to a report written by the National Advisory Mental Health Council's Behavioral Science Workgroup, entitled "Translating Behavioral Science into Action," http://www.nimh.nih.gov/tbsia/tbsiatoc.cfm. -Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) award mechanism and runs in parallel with FOAs of identical scientific scope, PAR-06-355 and PAR-06-357, that solicit applications under the Exploratory/Developmental (R21) and the Resource-Related Research Projects (R24) grant mechanisms, respectively. Collaborative R01 grant applications are also solicited (See FOA PA-07-092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, AIDS, and Alcohol Use Disorders (R01) for additional information on the Collaborative R01 grant mechanism.