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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.

NIEHS - National Institute of Environmental Health Sciences

ABSTRACT Exposure to endocrine-disrupting chemicals (EDCs) such as phenols and Organophosphate Esters (OPEs) is inevitable given their pervasive usage in manufacturing, commercial and domestic products. Phenols and OPEs are detectable in over 80% of the U.S. population and the rise in these exposures, mirrors increasing fertility challenges (early pregnancy loss, delayed conception) in the U.S. Both conditions carry profound physical and mental health impacts. Alarmingly, a substantial proportion of these cases remain unexplained. Phenols and OPEs may significantly affect fertility by disrupting the hypothalamic-pituitary-gonadal (HPG) axis that regulates the endocrine processes in pregnancy. However, there is a lack of population-level evidence linking mixtures of phenols and mixtures of OPEs to impaired fertility, which is essential for informing environmental policies and health recommendations. Existing epidemiologic studies on EDCs often begin in the late first trimester, missing early pregnancy losses and key early windows of susceptibility, as well as the opportunity to assess fertility outcomes. Alternatively, the focus of many studies on populations undergoing fertility treatments has limited generalizability of their findings. Additionally, reliance on single-day urine samples to measure metabolites of phenols and OPEs, which exhibit high temporal variability, limits the accuracy of exposure assessments and their potential impact on reproductive health. This proposal addresses these gaps by leveraging an established preconception cohort that includes daily urine samples from critical windows of susceptibility, along with detailed data on early pregnancy losses and other markers of fertility. By applying novel hybrid pooled-unpooled design to measure EDCs in daily urine samples and utilizing a suitable regression calibration to account for the temporal variability of these often costly EDCs, this research will overcome measurement challenges seen in prior studies. Aim 1 will trace the causes of anovulation, reduced fecundability, and early pregnancy loss by linking preconception phenol mixture levels with outcomes. Aim 2a will provide insights into the effects of preconception OPE mixture exposure on anovulation, reduced fecundability, and early pregnancy loss; Aim 2b will extend these insights to multi-class EDC mixtures exposure. Aim 3 will expand on Aim 2a by assessing whether early pregnancy OPE exposure has stronger effects than preconception exposure on early pregnancy loss, helping to define key windows for intervention. The K99/R00 Pathway to Independence award will provide essential training to achieve these aims, including but not limited to environmental toxicology, reproductive endocrinology, and advanced mixture modeling. These training objectives will be met with the guidance of an exceptional mentorship and advisory team. In summary, this proposal lays the groundwork for a future independent research program dedicated to evaluating the relationships between environmental exposomes and reproductive outcomes using advanced methodologies with the ultimate goal of informing interventions to improve reproductive success.

NIMHD - National Institute on Minority Health and Health Disparities

Obesity disproportionately affects Black and Latino populations in California, placing them at higher risk of poor mental and physical health. Addressing obesity disparities requires approaches that engage and empower trusted community institutions such as churches, which have a long history of supporting the health and well-being of Black and Latino congregants. Faith-based interventions have been shown to improve health behaviors, but few have a) included both Black and Latino populations, b) targeted factors beyond the individual, c) examined causal mechanisms, or d) studied factors that influence effective implementation. Through an NIH-funded pilot, we developed and tested a faith community-level intervention called Eat, Pray, Move (EPM), which engaged both Black and Latino churches in South Los Angeles (LA) and resulted in improved obesity outcomes among adults (e.g., less weight gain and greater weight loss). The study’s pilot nature limited our ability to examine longer-term effects and sustainability and analyze mediators. Specific Aims: We propose to conduct a fully powered, cluster randomized controlled trial (RCT) of EPM to 1) Determine the efficacy of a faith community-level intervention on obesity-related outcomes among Black and Latino adult congregants (n=1120); 2) Examine mechanisms by which the intervention affects intermediate and obesity outcomes; and 3) Evaluate facilitators and barriers of intervention implementation and sustainment. Design and Methods: We will conduct a cluster RCT involving 28 churches (14 predominantly Black and 14 predominantly Latino) in South LA to test the impacts of EPM on body mass index and weight among adult participants at 6-, 12-, and 24-months follow-up. Churches will be pair-matched on race/ethnicity, church size, and denominational grouping and randomly assigned to intervention or control. The intervention will target the physical and social environments at the faith community-level as well as interpersonal- and individual-levels. In addition to examining effects on obesity outcomes, we will examine potential mediators such as faith community-level access to healthy eating and physical activity and social norms and support. The Consolidated Framework for Implementation Research will guide evaluation of implementation barriers and facilitators across multiple domains (e.g., inner/outer setting) from the perspective of faith community leaders and collect process evaluation data to explore community-level impacts and sustainability. Innovation and Impact: This is the first full-scale cluster RCT of a faith community-level intervention to engage both Black and Latino congregations. Findings from the proposed work will fill a critical gap in knowledge regarding the causal mechanisms by which faith-based interventions impact obesity outcomes and will enhance understanding of determinants that influence successful implementation and sustainability. The intervention has the potential to address obesity disparities in two high-risk population groups while empowering trusted institutions to deliver effective obesity prevention strategies, which may serve as a sustainable model to improve health outcomes in congregations and more broadly in their communities.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) and psychiatric disorders are highly prevalent globally and interconnected through biological and behavioral pathways. Psychiatric disorders are thought to exacerbate TB severity, mortality, drug resistance and risk for disease progression. Among people with TB, an estimated 50% and 30% experience depression and post-traumatic stress disorder (PTSD), respectively. While preliminary evidence suggests that psychiatric symptoms may increase risk of TB, evidence from high-quality longitudinal data sources remains scarce. Furthermore, pregnancy may be a critical period when mental health service integration can reduce TB incidence among mothers and children. The overall objective of the proposed project is to estimate the impact of depressive and PTSD symptoms on tuberculosis disease risk among mothers and children. Aim 1 will focus on estimating the effect of depressive and PTSD symptoms on TB risk among mothers. Aim 2 will focus on estimating the effect of maternal depressive and PTSD symptoms during pregnancy on child risk for TB disease and infection. Data will come from the Drakenstein Child Health Study (DCHS), a multi-morbidity birth cohort in Western Cape, South Africa, which follows mothers and children from 28-32 weeks’ gestation through age 10. Aim 1 will use a nested case-control design with conditional logistic regression and Aim 2 will use multivariable Cox proportional hazards regression. This will be the first study to examine how PTSD symptoms predispose people to developing TB and how maternal mental health during pregnancy influences TB risk in children. Understanding how psychiatric disorders impact susceptibility to TB disease and infection will lay the foundation for research on strategic mental health screening and interventions to achieve TB reduction and elimination. This research aligns with NIAID’s mission to advance understanding of infectious diseases to inform response to reemerging disease threats, including the 2026 council-approved focus on the role of comorbidities on TB disease progression. My mentoring team has outstanding expertise in TB epidemiology, psychiatric epidemiology, and biostatistical methods, and is fully committed to supporting me in my training and professional development. We have designed a training plan which includes coursework and workshops in psychiatric and TB epidemiology, career development, and mentored research. Through this fellowship, I will develop the skills to become an independent researcher at the intersection of mental health and infectious disease.

NIMH - National Institute of Mental Health

Tuberculosis (TB) is the leading infectious cause of death, with recent rising incidence in the U.S. Depression and unhealthy alcohol use (UAU) increase nonadherence to TB medications and poor TB treatment outcomes. Yet, mental and behavioral health services have not been integrated into routine TB care in the U.S. or elsewhere. No high-quality randomized controlled trials (RCTs) have evaluated the impact of treating depression and UAU on TB outcomes. Critical barriers preventing integration of these services into TB care include lack of trained personnel and limited benefits of therapies focused on a single condition, such as depression or UAU alone, when people with TB often also have comorbid problems, such as anxiety or trauma. A transdiagnostic intervention, in which multiple mental and behavioral health problems can be addressed by a single provider, may be more clinically effective and efficient to implement. We previously demonstrated the effectiveness of a transdiagnostic cognitive behavioral therapy-based intervention, the Common Elements Treatment Approach (CETA), which trains lay health workers to address an array of potentially co-occurring mental and behavioral health problems. Despite evidence that CETA improves mental and behavioral health, it has not been implemented as part of TB care. Our hypothesis is that CETA can improve mental and behavioral health outcomes while decreasing unfavorable TB outcomes. In this R01, we will rapidly optimize CETA for delivery by trained TB survivors within TB care. We will then conduct a type 1 hybrid effectiveness-implementation RCT, in which we will randomize 494 people with TB who have depression, UAU, or both to receive CETA or enhanced usual care. Mental and behavioral health outcomes will be evaluated at three- and five-months post-baseline. Participants will be followed during TB treatment and for 12 months after treatment completion to assess unfavorable TB outcomes, defined as the composite of death, treatment failure, treatment non-completion, and TB recurrence. We will conduct a chained multiple mediation analysis to assess CETA’s effectiveness for reducing depression and UAU (primary mental and behavioral health outcomes), while assessing their mediating effects for reducing medication nonadherence and unfavorable TB outcomes (primary TB outcome). To inform future CETA scale-up within TB care, including for use in low-resource communities in the U.S., we will quantitatively assess CETA provider fidelity and CETA completion by people with TB, while qualitatively examining implementation barriers and facilitators with people with TB, CETA counselors, and TB program stakeholders, informed by the Consolidated Framework for Implementation Research. To ensure the feasibility of answering this critical scientific question, the field research will be conducted in India, which has the world’s highest TB incidence, to be able to provide vital evidence on an intervention that could improve outcomes for the >10,000 people with TB disease annually in the U.S., many of whom concurrently experience mental health and substance use challenges.

NIMH - National Institute of Mental Health

Summary/Abstract Non-medication options are necessary for the treatment of adult ADHD due to medication’s inconsistent availability, poor tolerability or palatability for some patients, and limited effects on some meaningful patient outcomes (e.g., impairment, quality of life; Bellato et al., 2025; Coghill et al., 2017). Cognitive behavioral therapy (CBT) is the other evidence-based treatment for adult ADHD (Knouse et al., 2017; Ostinelli et al., 2025) but faces engagement and implementation challenges in real world settings (Gaddis et al., in press; Staley et al., 2024; William et al., 2024). Motivational Interviewing (MI) is a set of therapist techniques that help people explore and accomplish behavior change and has been validated in over 500 RCTs (Miller & Rollnick, 2023). MI has been successfully blended with CBT for adolescents with ADHD to improve engagement and effectiveness outcomes in routine care settings (Sibley et al., 2021a/b). In this study, we propose a randomized hybrid implementation effectiveness trial that serves as the first evaluation of CBT+MI for adult ADHD (versus CBT alone) delivered to 216 adults with ADHD by 72 real world independent psychotherapy providers (double randomization of clients and therapists). The setting of the trial will be the U.S.’s decentralized telepsychology system and providers will be licensed psychologists with a current PsyPact credential. In year 1 of this trial, we will conduct a small pilot open trial (N=6 therapists, N=6 clients) with weekly feedback and end-of-trial focus groups designed to refine remote implementation supports and digitized manual and materials prior to the start of the trial’s RCT phase in years 2-5. Effectiveness outcomes will be measured at baseline, post-treatment, and one-year follow-up and include self and informant reports of ADHD symptoms, impairment, comorbid depression and anxiety symptoms, and quality of life. Target mechanisms will also be measured at these timepoints and include: (1) executive functioning skills, (2) self-concept, and (3) emotion regulation, which will be tested as mediators of effectiveness outcomes. Implementation outcomes will follow Proctor et al., (2009)’s implementation research framework to include multimethod, multidimensional indices of both implementation and engagement outcomes, which will also be measured as mediators of effectiveness outcomes. We will examine client and therapist-level treatment moderators as well as mixed method barriers and facilitators of implementation and engagement (including safety). Cutting edge aspects of this application include a rigorous differential diagnosis process at intake, leveraging this research team’s previously developed therapy process coding system (Sibley et al., 2025), intervention co-designed by adults with ADHD, and enriching the sample with ethnically diverse adults who previously participated in ADHD research as teens and may be treatment ambivalent, rather than eager. Our application is well-aligned with NIMH’s strategic priority of leveraging remote implementation supports to improve the reach of mental health services and expediting the adoption of mental health services by working within existing telehealth infrastructures (NIMH Strategic Framework, 2025).

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

-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 Adolescence is a dynamic developmental period marked by brain circuit refinement. Social stress during adolescence can influence the development of maladaptive behaviors and increase the risk of later-life psychiatric disorder. Despite wide appreciation for this link, the mechanisms connecting adolescent stress to later psychiatric risk remain unclear. The nucleus accumbens (NAc) is a critical integrative hub within the brain that undergoes refinement during adolescence and is essential for processing social information. Within the NAc, astrocytes are uniquely positioned to sense a diversity of neurotransmitters and regulate incoming circuit projections. As astrocytes are susceptible to stress-induced dysfunction, it is likely that they contribute to the behavioral deficits seen after adolescent social isolation. In support of this, preliminary data reveal that socially isolating rats during adolescence induces a dramatic decrease in astrocyte structural complexity within the NAc core, compared to group-housed controls, in adulthood. Isolation also increased microglia phagocytosis, and phagolysosomes within microglia contained the astrocyte marker GLT-1, suggesting that microglia engulf astrocytic elements. This proposal will test the novel hypothesis that adolescent social isolation stress induces microglial pruning of astrocytes, resulting in astrocyte/synaptic decoupling in the NAc core across development. Aim 1 will examine how social isolation stress induces microglia phagocytosis of astrocytes and astrocyte/synapse decoupling throughout adolescent social isolation using confocal microscopy and three- dimensional cellular image analysis and will test the prediction that isolation-induced astrocyte and behavioral deficits can be rescued by pharmacological blockade of phagocytosis in vivo. Aim 2 will assess how isolation stress affects the ability of astrocytes to sense and/or regulate synaptic transmission in the NAc core using a combination of ex vivo slice calcium imaging and electrophysiology. Together, these findings will reshape appreciation of microglia/astrocyte interactions and provide novel insights into how glial dysfunction affects neural circuit activity in response to stress. The Mentored Research Scientist Development Award will additionally provide essential training in the conceptual and technical approaches needed for a long-term program of study to investigate how adolescent social stress shapes astrocyte-neuron interactions and neural circuit function. Building upon prior training in microglia physiology and developmental neuroscience, this proposal will specifically provide additional advanced training in 1) the methodological and experimental design for models of early life adversity, 2) ex vivo slice astrocyte calcium imaging, and 3) patch clamp electrophysiology, to establish a strong foundation for an independent research career. Results obtained from the proposed studies will also pave the way for future evidence-based studies regarding maladaptive effects of stress on glial function.

NIA - National Institute on Aging

PROJECT SUMMARY Family plays a central role in shaping the experiences of aging. Any health shock not only affects the patient but also reverberates throughout the family unit, taking a physical, emotional, and financial toll on family members. The effect on families is likely to be particularly pronounced for health shocks that lead to a pronounced decline in independence, as, for example, happens with the progression of Alzheimer’s Disease and Related Dementias (ADRD). The ways families manage sharp changes in health can have profound effects on both the patient’s well-being and that of their caregivers. Despite the intricate relationship between family dynamics and health outcomes at older ages, public policies and much of the existing research in the U.S. have predominantly focused on individual patients rather than the broader family context. The dearth of evidence relates not to the lack of interest, but to the absence of datasets that could allow studying the effects of health shocks on families. In this project, we propose to start closing this gap in knowledge by leveraging the new extensive U.S. Census Bureau infrastructure for linking administrative data. We will construct and analyze a novel individual-level database that links the health trajectories of older adults to the physical, mental, and economic well-being of their family members across multiple generations, covering twenty-five years from 1999 to 2024. Using this new database, we will comprehensively examine the interdependencies between the mental, physical, and economic well-being of older adults and their families in the United States. First, we will describe the variation in family circumstances of older adults at the time of different health shocks. We will consider variation across demographic groups, local geographies, and socio- economic circumstances. Second, we will use state of the art econometric techniques for causal inference to quantify how much deaths and major but non-fatal health shocks affect the health and economic well-being of family members, including spouses and adult children.

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. The strength and persistence of emotional memories is believed to depend on the amygdala. Animal models demonstrate a central role of the amygdala on enhancing long-term retention of different forms of learning and memory. However, except for small studies in clinical populations with rare lesions or intracranial recordings, human neuroscience research on emotional memory processes is correlative in nearly all cases. The long-standing premise that the human amygdala is central to the enhancement of emotional memory has received limited causal support. It is possible that the human amygdala plays a more dispensable or nuanced role in the enhancement of emotional memory than assumed from animal neuroscience. Importantly, the amygdala remains a major target for translational neuroscience research focused on mental health disorders characterized by abnormalities in emotional learning, memory, and behavior. There are increasing efforts to directly target the amygdala using neurostimulation protocols as a cutting-edge treatment modality for psychiatric conditions such as posttraumatic stress disorder, with early reports of implanted deep-brain stimulating electrodes in PTSD patients. Yet, basic research using causal neurostimulation to directly target the amygdala is extremely limited. This project investigates the causal role of the amygdala in explicit emotional memory processes using a cutting-edge direct neuromodulation technique in combination with a validated emotional memory paradigm during functional MRI in healthy adult volunteers. Specifically, we directly test whether directly modulating amygdala activity with low-intensity transcranial focused ultrasound (tFUS) affects explicit memory processes using a within-subjects sham-controlled double-blinded crossover design. To date, there are no studies testing whether modulating amygdala function using tFUS affects episodic memory. For this R21 proposal, tFUS sonication (or sham) is administered to MRI-targeted left amygdala immediately prior to memory encoding, and memory retrieval is tested 24-hours later. The hypotheses and design of this proposal is supported by two separate lines of preliminary evidence from our laboratories at the University of Texas at Austin. First, we have demonstrated that focused ultrasound parameters designed to down-modulate amygdala function acutely inhibits amygdala blood oxygenation-level dependent (BOLD) signal during fMRI, providing proof-of-concept for non-invasive amygdala neuromodulation capability. Second, provocative preliminary behavioral data indicates that tFUS delivered to the left amygdala using these parameters, designed for down-modulating amygdala function, counterintuitively enhances the encoding of long-term episodic memories. The goal of this R21 is to help illuminate this finding by administering tFUS concurrent with fMRI followed immediately by emotional memory encoding also during fMRI. These findings could be of broad significance toward translational research efforts translating animal neuroscience models of learning and memory to humans, and ultimately determine how the amygdala directly contributes to episodic memory processes in the human brain.

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.

NIMH - National Institute of Mental Health

Project Summary/Abstract The accumulation of toxic responses to stressors – allostatic load – is strongly associated with a wide array of psychopathological outcomes. Treating or preventing allostatic load stands to improve the well-being and functioning of individuals currently struggling or at risk for psychopathology. Despite this broad consensus, no allostatic load intervention exists. One major limiting factor has been the field’s emphasis on cross-sectional designs which tell who might be at risk but not how and when individuals are at risk. Answers to how and when lay the foundation for treatment development and can be studied using intensive longitudinal designs (ILD). Recently, researchers have leveraged ILD to investigate allostatic load through three dimensions of the stress response: quantity of daily stressors, physiological reactivity, and the subjective psychological response to stressors—perceived stress. Yet, no current research has unpacked the dynamic interactions between all dimensions of the stress response together. This project will fill this significant knowledge gap by leveraging ILD to 1) identify causal links between daily stressors, physiological reactivity, and perceived stress on a day- by-day basis, and 2) use these dynamic processes to improve prediction of short-term psychopathology beyond prior symptom levels. Emerging adulthood is a critical period of elevated stressors and psychological and physiological response to stressors and marks the incidence of multiple forms of psychopathology. Importantly, college students are representative of the emerging adult population and can be easily recruited for participation in research. In this project, 100 college students, and an additional 50 college students, enriched for psychopathological distress, will be recruited from a large public university to take part in a two- week intervention (14 days). On each day, participants will complete two measures of physiological reactivity in the evening (i.e. heart rate variability, pupil light reflex) and three measurements of daily stressors and perceived stress throughout the day (morning, afternoon and evening). Aim 1 will identify to what degree physiological reactivity mediates the effect of daily stressors on perceived stress. Aim 2 will investigate a) whether the combined effects of physiological reactivity and perceived stress predict short-term psychopathology symptoms better than either alone, and, b) whether these variables predict psychopathology symptoms beyond prior symptom levels. Across all aims, we will identify distinct within- and between- person mechanisms to answer the question: what matters and for whom? By elucidating these complex stress dynamics, we will contribute a novel conceptualization and understanding of toxic stress accumulation and set the foundation for future research on intervention and treatments.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive impairment persists even with highly effective antiretroviral therapy (ART) in people with HIV (PWH). Persistent neuroinflammation is one of many factors that contributes to ongoing cognitive impairment in virally suppressed (vs)PWH. However, there is a critical gap in understanding the underlying cause of neuroinflammation and, as a result, no available therapies to target it. Long-acting broadly neutralizing antibodies (bNAbs) are considered the next generation of therapy for PWH. Currently, there are 50+ trials that involve bNAbs. Despite this substantial effort, there are no funded NIH studies focusing on if bNAb therapy in combination with ART may reduce neuroinflammation and improve cognitive function. As the mechanism of action for bNAbs is the rapid neutralization of virus and clearance of infected cells via engagement of the immune system, a downstream effect of this therapy may be lower levels of inflammation, as is observed with other Ab therapies. We have evidence that HIV-specific antibodies (Ab) play a protective role in the CNS, and others have shown that bNAb therapy enhances host Ab immunity to HIV and simian immunodeficiency virus (SIV). Therefore, our central hypothesis is that bNAb therapy will reduce neuroinflammation in the CNS, by directly eliminating infected cells capable of trafficking to brain resulting in a smaller CNS reservoir, neutralizing virus within the CSF, and indirectly by reducing peripheral inflammation, resulting in improved cognition. To test our hypothesis, we will use the SIVmac251 rhesus macaque model of HIV and an SIV-specific bNAb (ITS103). The SIV-infected ART-suppressed NHP model will allow us to assess the effects of bNAbs on CNS inflammation, reservoir, and cognition. Additionally, this model will allow us to determine if bNAbs have a direct effect on the CNS or indirect effect through altering peripheral inflammation. AIM 1: Determine if bNAb therapy during ART initiation reduces neuroinflammation. To model ART-naïve PWH receiving bNAb therapy simultaneously with ART, we will treat SIV-infected macaques with ITS103 at the time of ART initiation. We will assess the effect of acute ITS103 therapy on 1) brain macrophage transcription, 2) CNS reservoir size, and 3) cognitive performance after 1 year of suppression compared to ART alone. AIM 2: Determine if bNAb therapy during chronic ART reduces neuroinflammation. To model vsPWH receiving bNAb therapy combined with ongoing ART, we will treat SIV-infected macaques with ITS103 after 36 weeks of ART suppression and assess the effect of chronic bNAb therapy on the same outcomes as in Aim 1. AIM 3: Determine if bNAbs have a direct or indirect effect on neuroinflammation. To determine if ITS103 plays a direct role in the CNS we will assess 1) ITS103 concentrations in the CSF, 2) viral decay rates in CSF, 3) central vs. peripheral inflammation and 4) plasma and CSF Ab neutralization capacity with and without bNAb therapy. Our in vivo study utilizing a native SIV and SIV-specific bNAb is highly innovative as it will be the first to study on the effects of bNAb therapy on neuroinflammation and evaluate if this is a viable treatment for PWH.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive flexibility refers to our capacity to adjust our behavior in response to changes in the environment or in our own internal states. Psychiatric disorders often disrupt these cognitive functions, but little is known about the patterns of activity in the brain that underlie these capacities, impeding the development of effective treatments to target them. The overarching goal of this project is to more clearly elucidate the specific neural activity patterns supporting three examples of cognitive flexibility: switching between sets of rules that guide our behavior in a given situation, making correct decisions in new situations by drawing on past experiences, and learning to rapidly adjust a previously learned rule. In this project, I have developed a behavioral task which can engage each of these behaviors. I will use high- channel count electrophysiological methods to record activity from a brain circuit spanning the hippocampus, prefrontal cortex, and motor output regions while non-human primates perform this task. I will test the hypothesis that specific features of the patterns of activity in these brain regions support each type of cognitive flexibility described above. The results of this project will contribute an important step towards developing more effective treatments for cognitive dysfunction by identifying the specific patterns of activity that support specific cognitive functions and behaviors. This project will provide the additional training I require to position myself to perform cutting-edge research on cognition as an independent investigator. Specifically, through this project I will learn to perform precisely anatomically-targeted, high-channel count electrophysiological recordings from multiple brain regions simultaneously in order to probe brain activity patterns relevant to behavior as they occur in real time, distributed across the brain. I will also develop the necessary expertise to analyze the activity of large populations of neurons in relation to complex behavior. This award is thus critical to attaining my long-term goal of running an independent research lab at an academic medical center, where I will operate a non-human primate electrophysiology lab studying the neural mechanisms of adaptive, flexible behaviors that are disrupted in psychiatric disorders.

NIMH - National Institute of Mental Health

Project Summary/Abstract The hippocampus was long described by seminal memory models to not be necessary for procedural (motor) learning. In contrast, neuroimaging studies from the last two decades consistently show hippocampal recruitment during motor sequence learning. These conflicting results show that the extent to which the hippocampus contributes to motor learning is unknown. We argue that this knowledge gap is attributed to a lack of causal neuroimaging evidence elucidating the role of the hippocampus in motor memory. Failing to address this critical gap will be a missed opportunity to update the field’s conceptualization of memory system organization and will prevent the development of interventions targeting hippocampal-mediated motor learning and memory processes. The overarching goal of this project is therefore to causally test for the role of the hippocampus in motor memory in young healthy adults using a novel non-invasive experimental intervention (i.e., temporal interference stimulation - TIS). TIS is a potentially groundbreaking intervention that was developed in rodents and recently translated to human research. It enables focused - yet safe and noninvasive - neural stimulation at depth and therefore holds immense promise for the modulation of activity in deep brain regions. In this project, we will evaluate the effect of TIS on human hippocampal responses related to motor learning using functional magnetic resonance imaging (MRI). We will causally test a framework of hippocampal involvement in motor learning that will potentially reconcile previous contradictory findings. This framework proposes that the hippocampus supports abstract representations of motor sequences encompassing their spatio-temporal coordinates that are reactivated offline and can be generalizable across learning episodes. To causally test this framework, we will administer HC or sham TIS during motor learning and examine the effect of stimulation on both the behavioral (Aim 1) and neural (Aim 2) correlates of online and offline learning. Our central hypothesis is HC-TIS will specifically enhance offline motor learning via the modulation of HC responses. This innovative research project will lead to a breakthrough, as it will provide direct causal evidence for a role of the hippocampus in motor learning. It will also significantly impact the biomedical, behavioral and clinical fields because it will validate the use of TIS as a novel and groundbreaking technique to modulate motor learning-related (re)activation patterns in deep brain regions of the human brain. Ultimately, such an approach can be translated to the clinical domain in order to mitigate motor learning-related deficits in specific populations.