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National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to support investigators who have the interest and capability to join efforts for the discovery of in vivo chemical probes for novel brain targets. It is expected that applicants will have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds.Through this NOFO, NIH wishes to stimulate research in:Discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Eye Institute (NEI), and/or National Institute on Aging (NIA) andDiscovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms.Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes.

NIMH - National Institute of Mental Health

Abstract Despite the high prevalence of major depressive disorder (MDD) and its projected rise as the leading cause of global disease burden by 2030, treatment efficacy remains suboptimal. First-line antidepressants have modest efficacy (~50%), and high placebo response rates (~40%) contribute to the failure of antidepressant trials and hinder new drug development. While research underscores the role of antidepressant expectancies in modulating mood across various brain regions, there is a critical need to elucidate how expectancy-driven neural dynamics interact with downstream mood regulation processes to induce sustained mood improvement. Our recent work provides the first computational account of antidepressant placebo effects, where reinforcement learning (RL) model-predicted expectancies—encoded in the salience network (SN)—trigger mood changes perceived as reward signals, which reinforce antidepressant expectancies through an expectancy-mood loop. Furthermore, we and others have demonstrated that enhanced functional connectivity (FC) between the SN and default mode network (DMN) during expectancy processing and at rest predicts long-term antidepressant placebo effects. This evidence suggests that antidepressant expectancies, originating from contextual treatment cues, are represented in the SN and influence mood regulation through top-down connections with the DMN. To test this hypothesis, this study will investigate the causal roles of the SN, DMN, and SN-DMN FC in antidepressant placebo effects using Theta Burst Stimulation (TBS). In a 2x3 factorial design, 200 patients with MDD will be randomized to three counter-balanced TBS conditions (intermittent, continuous, and sham, within-subject) targeting either the SN or DMN (between-subject). These acute experimental manipulations will modulate trial-by-trial expectancy and mood ratings and the neural encoding of model-based expectancies and mood reward signals during the “antidepressant placebo fMRI task”, which manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and sham visual neurofeedback. Led by experts in placebo effects, reinforcement learning, depression, and neuromodulation, this study combines a robust theoretical framework, state-of-the-art neuroimaging, precision functional mapping for personalized TBS targeting, and accelerated TBS, ensuring scientific rigor. The insights gained from this study will deepen our understanding of the neural mechanisms behind placebo effects, enhancing clinical trial design, advancing neuroimaging predictors of treatment response, and accelerating the development of expectancy-based interventions for MDD.

NIMH - National Institute of Mental Health

Prenatal infections cause maternal immune activation (MIA), a major risk factor for several neurodevelopmental disorders, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). Consequently, elucidating the mechanisms by which MIA alters brain function is critical for understanding the pathophysiology of these disorders and developing effective treatments. While the effects of MIA on neurons and microglia have been extensively studied, the impact of MIA on astrocytes, key regulators of brain physiology and homeostasis, remain unknown that significantly impedes our understanding the mechanisms of MIA-induced neurobehavioral abnormalities. To address this major knowledge gap, we conducted pilot studies that suggest that MIA increases impulsivity-like behaviors and amphetamine-induced hyperactivity and enhances extracellular levels of glutamate (GLU) and dopamine (DA) in the dorsal striatum (DS). MIA also increased pro-inflammatory signatures of astrocytes, including up- regulation of the Nuclear Factor kappa B (NF-κB) pathway and increased GFAP immunoreactivity in DS astrocytes. Collectively, these novel findings support our overarching hypothesis that MIA increases astrocyte reactivity, leading to increased gliotransmission (e.g., GLU), which in turn enhances DS DA release and DA- dependent behaviors. To test this hypothesis, we will leverage the expertise of the research team in molecular, physiological and neurobehavioral approaches and conduct the following Specific Aims: In Aim 1, we will identify the MIA-induced cellular and physiological changes characteristic of astrocyte reactivity. In Aim 2, we will determine the circuit mechanisms by which MIA increases DA signaling. In Aim 3, we will identify the molecular mechanisms whereby reactive astrocytes contribute to MIA-induced cellular and behavioral abnormalities. These studies will enhance the current understanding of the effects of MIA on brain functions and generate new insight into potential treatment strategies for MIA-associated neurodevelopmental disorders.

NIMH - National Institute of Mental Health

7. Project Summary/Abstract We make hundreds of decisions a day. Value-based decision-making requires the orchestration of multiple processes that enable us to learn from prior experience and then use this information to guide our behavior. Deficits in decision-making are common in psychiatric disorders that result from disruptions in how value is estimated or assigned, how value estimates influence action selection, or the ability to make inferences about the environment to guide decisions. These disruptions are unresponsive to current treatments and contribute to the functional disability evident in mental illness. Hence, a deeper understanding of the mechanisms underlying adaptive and maladaptive reward learning is required to address this unmet therapeutic need. Here, we will use fiber photometry, optogenetics, and computational modeling in rats performing two translational behavioral tasks to identify the neurophysiological mechanisms underlying value-based decision-making. The orbitofrontal cortex (OFC) and the striatum are essential mediators of reward processing and decision-making, and both the ventromedial and lateral subregions of the OFC (vmOFC and lOFC, respectively) project glutamatergic neurons to the striatum in a topographic manner; the vmOFC mostly innervates the medial striatum (mS) whereas lOFC preferentially targets central striatal regions (cS). Identifying how these distinct orbito-striatal pathways contribute to specific aspects of value-based decision-making is essential. We aim to (1) identify how dynamic changes in vmOFC→mS and lOFC→cS circuit activity mediate flexible reward learning and (2) determine how alterations in circuit activity disrupt this process. Specific Aim 1 will use dual-color fiber photometry to measure the activity of the vmOFC→mS or lOFC→cS circuits with simultaneous measurement of local OFC parvalbumin-positive (PV+) GABA interneuron activity. Specific Aim 2 will use complementary gain- or loss-of-function optogenetic interventions to confirm the functional relevance of neural activity during behavior. These optogenetic manipulations – targeting orbito-striatal glutamate circuits or OFC PV+ interneurons – will be delivered to (1) enhance the dynamic changes in neural activity associated with optimal task performance or (2) perturb normal neural activity and induce behaviorally distinct disruptions value-based decision-making. Each Specific Aim will evaluate value-based decision-making in rats tested in a probabilistic reversal learning (PRL) or 2-step reinforcement learning task. Computational models of reinforcement learning will provide an in-depth analysis of behavioral performance, and regression analysis will determine how changes in neural activity contribute to task performance. With a multidisciplinary approach and high cell-type- and circuit-specificity, our findings will elucidate the neurobiological mechanisms underlying decision-making and provide critical insight for the development of new and effective therapeutic strategies for mental illness.

NIMH - National Institute of Mental Health

Project Summary: Although the resting memory CD4+ T cells are the best-recognized long-lived reservoirs of latent HIV provirus, it is now well accepted that the myeloid cells, especially of the central nervous system (CNS), including perivascular macrophages and microglial cells are the major target of HIV. The molecular mechanisms relevant to HIV latency are primarily defined by analyzing HIV latency in latently infected CD4+ lymphoid cells. However, very little is known about HIV latency/persistence in myeloid cells. Notably, the presence of HIV-harboring myeloid cells in the CNS is documented to be the key factor contributing to CNS inflammation and promoting HIV-associated neurocognitive disorder (HAND) in HIV patients. Microglial cells are the main HIV reservoir in the CNS, yet there is a gap in the knowledge regarding our understanding of the molecular mechanisms that maintain HIV reservoirs in those cells. Our long-term goal is to identify and characterize the underlying molecular mechanisms that regulate HIV latency in the CNS. We have shown the vital role of DNA-PK in supporting HIV transcription and latency-reactivation in both lymphoid and myeloid cells. Recently, we published one more article, bringing a total of 3 articles on this subject. The objective of this grant is to characterize the role of DNA-PK during HIV latency and define the molecular mechanisms by which DNA-PK supports HIV transcription in the main CNS reservoir, microglial cells. Based on our published and preliminary findings, we have hypothesized that DNA-PK modulates HIV transcription in microglial cells by reducing RNAPII pausing during HIV transcription. For testing our hypothesis, in Aim 1, we will establish the role of DNA-PK in relieving RNAPII pausing during HIV transcription and latency- reactivation in microglial cells, by Stimulating RNAPII processivity (elongation capability) and Relieving restrictions exerted by negative elongation factors to HIV transcription. In Aim 2, we will characterize the role of DNA-PK-induced chromatin modifications in regulating HIV gene expression and latent reservoir in microglial cells. Our rationale is that since HIV latency is primarily regulated at the transcriptional level, defining the precise and all mechanism(s) that regulate HIV transcription in microglial cells will offer novel therapeutic opportunities to target HIV reservoirs in the CNS. These studies will also provide a well-defined therapeutic target in the form of DNA-PK, and this new knowledge will be valuable for both basic and translational research. The proposed research is innovative because, besides iPSCs-derived human microglial cells (IDMs), it uses a novel ex vivo model system for HIV latency in microglia, that for the first time, allows the studies of the molecular correlates for HIV entry and exit into latency in microglial cells, which is otherwise an impossible task due to insufficient availability of brain autopsy specimens. This contribution is significant since the identified mechanisms, which regulate HIV transcription and latency in microglial cells, will facilitate the designing of optimized therapies targeting CNS reservoirs of HIV, and contributing towards cure approaches.

Health Resources and Services Administration

The purpose of the Early Childhood Comprehensive Systems SEED Project: Scaling Effective Early Childhood Systems Development (ECCS SEED) is to address the root causes of chronic disease in early childhood by improving families" access to health care, screening kids early for physical and mental health needs, and connecting parents to services that enable them to provide for their children. The ECCS SEED Project will partner with states and communities to support evidence-based strategies that improve access to quality care for prenatal-to-age-5 (P-5) families and promote healthy child development and family well-being.

National Institutes of Health

Purpose. This Funding Opportunity Announcement (FOA) issued by the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), invites investigator-initiated research grant applications for studies focused on the early identification and treatment of mental disorders in children and adolescents. Specific examples include studies focused on: the validation of early diagnosis of mental disorders in youth, especially in young children; the development of new interventions to treat mental disorders and prevent the exacerbation of associated functional impairment; the efficacy and safety of new and existing treatments; the identification and evaluation of predictors of treatment response and underlying mechanisms of action for new and existing treatments; the long-term effectiveness and impact of early intervention on later course; and the factors that promote or impede access to services and impact the effectiveness of services for these patients in community and practice settings. Assessment methods may include behavioral, neuropsychological, neuroimaging, and other physiological measures or markers. Intervention strategies to be studied may include pharmacological, psychosocial, and rehabilitative interventions, separately or in combination. Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) award mechanism. Applications of related or identical scientific scope are also solicited under the NIH Small Research Grant (R03), the NIH Exploratory/Developmental Grant (R21), and the NIMH Clinical Exploratory Research Grant (R34), responding to FOAs PA-06-180, PA-06-181, and PAR-06-248, respectively. Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received. Eligible Institutions/Organizations. Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Small Business; For-Profit Organization (Other than Small Business); State Government; U.S. Territory or Possession; Indian/Native American Tribal Government (Federally Recognized); Indian/Native American Tribal Government (Other than Federally Recognized); Indian/Native American Tribally Designated Organization; Non-domestic (non-U.S.) Entity (Foreign Organization); Hispanic-serving Institution; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); Alaska Native and Native Hawaiian Serving Institutions; Regional Organization; Other(s): Eligible agencies of the Federal government; Faith-based or community based organizations.

National Institutes of Health

NIMH requires an experimental therapeutics approach for the development and testing of therapeutic interventions, in which studies both evaluate the clinical effect of an intervention and generate information about the mechanisms underlying a disorder or an intervention response. As part of NIMHs Clinical Trial Pipeline, this NOFO encourages early stage testing of pharmacologic interventions with novel mechanisms of actions or device-based interventions. More specifically, this NOFO is intended to support early stage testing of pharmacologic or device-based interventions using a protocol design where the presumed mechanism of action of the intervention is adequately tested, to provide meaningful information where target modulation yields a dose-dependent neurophysiological/clinical/behavioral effect.

National Institutes of Health

Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R33- Clinical Trial Required)

National Institutes of Health

Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R61/R33 Clinical Trial Required)

National Institutes of Health

NIMH requires an experimental therapeutics approach for the development and testing of therapeutic interventions, in which studies both evaluate the clinical effect of an intervention and generate information about the mechanisms underlying a disorder or an intervention response. As part of NIMHs Clinical Trial Pipeline, this NOFO encourages early stage testing of pharmacologic interventions with novel mechanisms of actions or device-based interventions. More specifically, this NOFO is intended to support early stage testing of pharmacologic or device-based interventions using a protocol design where the presumed mechanism of action of the intervention is adequately tested, to provide meaningful information where target modulation yields a dose-dependent neurophysiological/clinical/behavioral effect.

National Institutes of Health

NIMH requires an experimental therapeutics approach for the development and testing of therapeutic interventions, in which studies both evaluate the clinical effect of an intervention and generate information about the mechanisms underlying a disorder or an intervention response. As part of NIMHs Clinical Trial Pipeline, this NOFO encourages early stage testing of pharmacologic interventions with novel mechanisms of actions or device-based interventions. More specifically, this NOFO is intended to support early stage testing of pharmacologic or device-based interventions using a protocol design where the presumed mechanism of action of the intervention is adequately tested, to provide meaningful information where target modulation yields a dose-dependent neurophysiological/clinical/behavioral effect.

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.

National Institutes of Health

NIMH seeks applications for research projects to evaluate the effectiveness of therapeutic and service delivery interventions for the post-acute management of mental health conditions affecting youth, adults, and older adults. This Notice of Funding Opportunity (NOFO) encourages clinical trials to establish the effectiveness and test hypotheses regarding moderators, mediators, and mechanisms of action of post-acute phase therapeutic and services interventions that are matched to the stage of illness in terms of both their focus (e.g., consolidating and maintaining gains from initial treatment, managing residual symptoms/impairment, preventing relapse, promoting adherence and appropriate service use) and intensity/burden for promoting optimal longer-term outcomes. This NOFO is intended to support effectiveness trials testing post-acute phase interventions that are statistically powered to provide a definitive answer regarding the study intervention's effectiveness. Support for pilot effectiveness trials to evaluate the initial feasibility, tolerability, acceptability, safety and preliminary indications of effectiveness of post-acute phase intervention approaches is provided via a companion R34 (Currently TEMP-24814)

National Institutes of Health

NIMH seeks applications for research projects to evaluate the effectiveness of therapeutic and service delivery interventions for the post-acute management of mental health conditions affecting youth, adults, and older adults. This Notice of Funding Opportunity (NOFO) encourages clinical trials to establish the effectiveness and test hypotheses regarding moderators, mediators, and mechanisms of action of post-acute phase therapeutic and services interventions that are matched to the stage of illness in terms of both their focus (e.g., consolidating and maintaining gains from initial treatment, managing residual symptoms/impairment, preventing relapse, promoting adherence and appropriate service use) and intensity/burden for promoting optimal longer-term outcomes. This NOFO is intended to support effectiveness trials testing post-acute phase interventions that are statistically powered to provide a definitive answer regarding the study intervention's effectiveness. Support for pilot effectiveness trials to evaluate the initial feasibility, tolerability, acceptability, safety and preliminary indications of effectiveness of post-acute phase intervention approaches is provided via a companion R34 (Currently TEMP-24814)

National Institutes of Health

This R61/R33 concept complements NIMHs suite of clinical trial NOFOs by supporting feasibility and infrastructure development (R61) followed by well-powered clinical trials (R33) to test the effectiveness of system interventions and strategies for improving the organization, delivery, coordination, and clinical and functional outcomes of mental health services. System interventions - which may span, for example, structural, policy, organizational, and interpersonal domains - attend to issues about the access, equity, engagement/utilization, value (cost/financing), management, or quality and safety of mental health services, with the goal of improved care processes and clinical and functional outcomes. Accordingly, the focus of system interventions may include a variety of care settings, such as health systems and organizations, mental health and community clinics, schools, and child welfare or juvenile justice systems

National Institutes of Health

This R61/R33 concept complements NIMHs suite of clinical trial NOFOs by supporting feasibility and infrastructure development (R61) followed by well-powered clinical trials (R33) to test the effectiveness of system interventions and strategies for improving the organization, delivery, coordination, and clinical and functional outcomes of mental health services. System interventions - which may span, for example, structural, policy, organizational, and interpersonal domains - attend to issues about the access, equity, engagement/utilization, value (cost/financing), management, or quality and safety of mental health services, with the goal of improved care processes and clinical and functional outcomes. Accordingly, the focus of system interventions may include a variety of care settings, such as health systems and organizations, mental health and community clinics, schools, and child welfare or juvenile justice systems

National Institutes of Health

Effectiveness Trials to Test Mental Health System Interventions (R61/R33 Clinical Trial Required)

National Institutes of Health

-Purpose. The National Institute of Mental Health (NIMH), National Institutes of Health (NIH), invites research grant applications on services delivered to children, adolescents, and their families through the Center for Mental Health Services (CMHS) Comprehensive Community Mental Health Services for Children and Their Families Program initiative (hereafter referred to as the Children s Services Program ). This Funding Opportunity Announcement (FOA) encourages studies of the effectiveness of interventions delivered at these sites, the nature and impact of routine prevention or clinical practice, and factors related to successful implementation of preventive or treatment interventions. -Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) grant mechanism. Applications of related or identical scientific scope are also solicited under the NIH Small Research Grant (R03), the NIH Exploratory/Developmental Grant (R21), and the NIMH Collaborative Program (R01) award mechanisms, responding to FOAs PA-06-180, PA-06-181, and PA-07-092, respectively. (For inquiries, see Section VII, Agency Contacts. ) -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the quality, duration, costs, as well as the number of applications received.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Episodic memory allows us to project ourselves back in time to mentally re-experience the past in vivid detail. This remarkable feat helps to define our personal identities and enables context-appropriate predictions that guide adaptive behavior. Unfortunately, episodic memory loss is a common cognitive consequence of neurological disease, psychiatric disorders, and normative aging, that reflects dysfunction in the hippocampus and the neocortical network to which it connects. This decline can present along a range of severity that spans an impoverished ability to recollect fine-grained event details, e.g., the color of the shirt your spouse was wearing at a birthday party, to forgetting course-grained event details, e.g., having attended a birthday party last weekend. Treating these kinds of memory loss remains challenging because interventions must target information that is definitionally idiosyncratic. However, recent methodological and theoretical advances in cognitive neuroscience reveal novel strategies that may solve this problem. Evidence from behavioral, neuroimaging, and computational modeling studies suggest that the degree to which episodic memories overlap in the hippocampus can be modified in a predictable, experience-dependent manner. Specifically, strong concurrent reactivation of multiple memories can enhance recall of coarse-grained episodic information by increasing hippocampal integration. Conversely, coupling strong and moderate reactivation of memories can enhance recall of fine-grained episodic information be increasing hippocampal differentiation. Consistent with this idea, recent evidence suggests that using a smartphone to record and subsequently replay real-world memory cues can indeed improve episodic memory by reducing representational overlap among memories in the hippocampus. Against this background, this proposal is organized around two primary aims. First, we seek to establish smartphone-guided memory reactivation protocols that selectively promote integration and differentiation of real-world episodic memories in the hippocampus. Experiments in this aim will specifically ask whether unstructured and structured (in terms of narrative, space, and time) reactivation can be used to achieve these outcomes. Second, we will ask whether the benefits of memory reactivation are associated with behavioral and representational costs. Experiments in this aim will probe for undesirable downsides that accompany, or potentially explain, reactivation-based improvements in episodic memory. Our approach combines smartphone technology, pattern-based analysis of functional neuroimaging data, and careful characterization of recall data with neurocognitive theory inspired by computational models of learning mechanisms. Achieving our aims will establish an empirical foundation on which future interventions can be built to systematically target real-world episodic memories at a level of abstraction, i.e., fine-grained vs. coarse-grained detail, that is appropriate for the severity of memory loss.

NIDA - National Institute on Drug Abuse

Project Summary Cannabis use among pregnant women has increased more than 60% over the past decade. Up to 15% of women use cannabis prior to pregnancy and 6% prenatally, with disparities by socio-demographics, mental health symptoms, and polysubstance use. The cannabis policy context has been evolving rapidly with 24 states and DC having legalized recreational cannabis. Significant gaps remain in understanding the effects of legalization on prenatal cannabis use and spillover effects on other substances, birth outcomes, and provider assessment of use as well as variations in policy effects by demographic and higher-risk strata. The overarching goals of the study are toexamine the effects of state recreational cannabis laws on disparities in women's use of cannabis, tobacco, and alcohol (referred to as substance use) during pregnancy as well as health care providers' assessment of prenatal substance use. We will evaluate the 2016-2023 Pregnancy Risk Assessment Monitoring System (PRAMS), the only state-representative data on prenatal cannabis use, which asks new mothers in 25 states and DC (15 have legalized cannabis) about their substance use and providers' assessment of use. Differences in state cannabis laws linked to monthly PRAMS data creates a natural experiment, which can be rigorously evaluated. This project has two Specific Aims. Aim 1 will evaluate the effects of state recreational cannabis laws on women's substance use preconception, prenatally, and postpartum as well as the downstream effects on birth outcomes. Aim 2 will evaluate the effects of state laws on women's self-reports of health care providers' assessment of prenatal substance use. Across Aims 1 and 2, the project will assess the overall effects of recreational cannabis legalization as well as differential effects of state laws by demographic (race/ethnicity, education, age) and higher-risk (mental health symptoms, polysubstance use) strata. The cannabis policy landscape is evolving rapidly. Study findings will (a) fill critical gaps in understanding the unintended consequences of emerging recreational cannabis laws on disparities in prenatal substance use, birth outcomes, and providers' assessment of prenatal use; and (b) inform public health responses in states with current cannabis laws or states contemplating legislation and clinical practice, including assessment of prenatal substance use, with the ultimate aim to improve the health of vulnerable mothers and infants.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Catatonia is a potentially fatal, often curable, and highly underdiagnosed neuropsychiatric disorder characterized by motor phenomena, changes in affect, and cognitive-behavioral disturbances. Once identified, catatonia can be rapidly and effectively treated, but in present clinical practice most cases of catatonia are not appropriately diagnosed. Thus, there is a critical unmet need to develop biomarkers to detect catatonia and to longitudinally monitor its treatment. This K23 Mentored Patient-Oriented Research Career Development Award will use detailed clinical phenotyping and machine learning analysis to transform clinical electroencephalography (EEG) recordings into valid, reliable, and accurate digital biomarkers for the detection and monitoring of catatonia. This will involve Aims of 1) developing a physiologic grading scale for catatonia using EEG recordings and contemporaneous clinical exam in the largest ever (N=1,400) prospective cohort of patients hospitalized with altered mental status; and 2) monitoring longitudinal EEG and clinical changes in patients with catatonia as they receive gold-standard treatment with benzodiazepines during the “lorazepam challenge test.” This research plan will be accompanied by a rigorous 5-year career development plan to advance the Principal Investigator, James Luccarelli, MD, DPhil, as a clinician-scientist with expertise in 1) prospective clinical research; 2) responsible conduct of research; 3); neurophysiology; 4) data science; and 5) scientific leadership and communication. This career development plan will build directly on Dr. Luccarelli’s clinical expertise in catatonia treatment for patients of all ages as a child, adolescent, and adult psychiatrist and his existing strengths in computational analysis and retrospective clinical research. On this foundation, training will be guided by a stellar team of mentors. Primary mentorship will be provided by Brandon Westover, MD, PhD, a neurologist and world leader in applying machine learning to human neurophysiology, along with co-mentor Timothy Wilens, MD, a child, adolescent, and adult psychiatrist and expert in prospective clinical research in psychiatric populations. Critical additional mentorship will be provided by cross-disciplinary team of scientific advisors: Paul Croarkin, DO (child psychiatry at the Mayo Clinic); Hang Lee, PhD (biostatistics); Sahar Zafar, MBBS (neurology); and Thomas McCoy, MD (bioethics). By leveraging the deep expertise of these world-class mentors and the unparalleled institutional environments of the Massachusetts General Hospital and Harvard Medical School, this K23 Award will support an innovative program of career development and patient-oriented research. This will provide Dr. Luccarelli with the skills necessary to become an independent investigator leveraging a clinically actionable biomarker for the enhanced clinical detection and monitoring of catatonia that will set the stage for future EEG-guided clinical trials of new treatments.

NIMH - National Institute of Mental Health

Suffolk County, an Ending the HIV Epidemic (EHE) priority area in Massachusetts, has seen a dramatic increase in bacterial sexually transmitted infections (STIs). Although diagnosis of bacterial STIs is an indication to consider HIV pre-exposure prophylaxis (PrEP), uptake of PrEP remains inconsistent across patient populations, often not reaching those at greatest risk for HIV acquisition. To address the rising rate of STIs, the Massachusetts Department of Public Health (MDPH) is implementing a provider-initiated electronic partner notification (ePN) platform for STIs, through which index patients can anonymously alert their sexual partners about STI exposure and link them to care resources. The goals of this platform, which, to our knowledge, is the first state-sponsored, statewide ePN intervention in the US, include not only an increase in the number of people tested and treated for STIs, but also the promotion of HIV testing and PrEP. ePN has the potential to overcome barriers to STI/HIV services by increasing awareness and linking notified individuals to accessible, low-cost care. How best to design and implement ePN to promote integrated STI/HIV services that serve populations at increased risk for STIs and HIV in community settings is unknown. In collaboration with MDPH and three high-volume sexual health clinics in Suffolk County, we propose to leverage this statewide "natural experiment" through the following three specific aims: 1) To evaluate the impact of ePN implementation on number of partners notified and engaged in care statewide when: 1a) used by field epidemiologists as an adjunct for assisted partner notification services for people diagnosed with syphilis; and 1b) initiated by clinicians at STI clinics for people diagnosed with gonorrhea and chlamydia; 2) To identify determinants of ePN implementation for STIs via qualitative interviews with index patients, partners, field epidemiologists, and clinicians and use the ADAPT implementation process to develop enhancements that incorporate HIV services; and 3) To implement and evaluate the impact of ePN platform enhancements on PrEP uptake and HIV care re-engagement at three selected high-volume MDPH-funded STI clinics deploying ePN and statewide, including an assessment of reach into different patient populations. We hypothesize that ePN will increase the number of partners notified and engaged in sexual health care and that enhancements to ePN will increase PrEP uptake and HIV care re-engagement among notified individuals, thereby helping to address both the STI and HIV epidemics. This proposal is directly responsive to the NIH HIV/AIDS research priorities to improve uptake of multi-level HIV prevention interventions, develop prevention strategies for HIV-relevant coinfections, and address high HIV incidence populations. It is also responsive to the NIH Director's strategic priority to use implementation science to advance EHE efforts in the US. This work will shift the paradigm of HIV and STI care by reimagining partner notification for the digital age and expanding its reach to enable more effective linkage to HIV services.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Obsessive-compulsive disorder (OCD) is a severe psychiatric illness affecting 1–3% of the population, causing debilitating distress and impairing everyday functioning. Up to 20% of individuals with OCD remain severely symptomatic despite standard treatments, making deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) a promising neurosurgical option. However, DBS therapy for OCD remains challenging due to the absence of objective, reliable neural biomarkers of symptom severity, leading to prolonged trial-and-error programming, unpredictable clinical outcomes, and limited access for eligible patients. Early intracranial electrophysiology studies have shown that neural activity in the VC/VS is closely linked to OCD pathophysiology, with low-frequency VC/VS oscillations reflecting processes such as symptom intrusions, error monitoring, and reward processing. These discoveries have advanced our understanding of OCD neurophysiology. Recent advances in sensing-enabled DBS technology now offer a unique opportunity to chronically record neural oscillations (local field potentials, LFPs) directly from DBS electrodes in freely moving patients, enabling longitudinal, real-world tracking of neural activity. Yet critical questions remain regarding the robustness, ecological validity, and clinical utility of VC/VS oscillations as biomarkers of OCD symptom states. This project aims to rigorously establish VC/VS alpha oscillations as an objective biomarker for OCD symptom states and translate this knowledge into clinical practice. First, I will determine whether chronic fluctuations in VC/VS alpha oscillations systematically track real-world transitions between symptomatic and non-symptomatic states by combining at-home DBS recordings with wearable sensor-based behavioral tracking and ecological momentary assessments. Next, I will leverage intraoperative neural recordings—uniquely available during DBS implantation surgeries—to map acute electrophysiological responses in the VC/VS and related frontal circuits during personalized symptom-provocation tasks, providing functional guidance for surgical lead placement. Finally, I will operationalize VC/VS alpha oscillations as a practical biomarker during outpatient DBS programming, using immersive virtual reality-based OCD symptom challenges combined with real-time neural and physiological measurements to identify optimal stimulation parameters. In addition, this award will allow me to complete a multifaceted career development plan. Since my background is primarily in engineering and my clinical exposure to OCD patients is limited, I will acquire fundamental clinical knowledge of OCD symptom dimensions and standard inpatient and outpatient treatments, facilitating the integration of clinical and research efforts. My training will be guided by leading experts at MGH, one of the world’s leading institutions in the clinical and research work with this patient population. I will further attend seminars and conferences, to develop not only a researcher, but also as an independent leader and science communicator. Together, this will provide me with the necessary set of skills for my transition to independence.