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NIMH - National Institute of Mental Health

PROJECT SUMMARY In a dynamic environment, learning is an evolutionary advantage. When faced with a novel situation, animals that adapt their behavior appropriately may live to reproduce another day. Associative learning requires linking distinct events across time, such as a sensory event with a motor command that results in the desired outcome. How are flexible sensorimotor associations implemented in the brain? The brain regions supporting the encoding of these events are broadly distributed suggesting that learning- related plasticity would benefit from neural mechanisms that operate across multiple timescales and brain regions. Ascending neuromodulatory systems—with their broad projection architecture and multiple timescales of activity—fulfill these criteria and could serve as a potent mechanism to link the different sensory, motor and outcome components. More specifically, the cholinergic basal forebrain (CBF) is the ideal candidate to support rapid learning-related plasticity across multiple cortical regions. This builds on a robust literature showing a pleiotropic role of the CBF to establish both sensory and motor cortical plasticity. Additionally, CBF neurons respond precisely to reinforcement, movement, and sensory events. The overall hypothesis is that the CBF phasic activity serves as a ‘teaching’ signal, locally integrating distinct events, and then projecting conjoint signals (i.e., sensory-motor contingencies) to recipient regions on the timescale of contingency acquisition. The mentored phase will exploit a novel behavioral approach that isolates the timing of acquisition of novel sensorimotor contingencies combined with state-of-the-art optical and physiological tools to test this specific hypothesis. Aim 1 will determine the spatiotemporal dynamics of cholinergic signaling to the Auditory Cortex (AC) and Motor Cortex (MC) during early task acquisition. Aim 2 will identify the causal role of CBF in associative audiomotor acquisition. In the R00 phase this framework will be expanded to implicit learning, when previously acquired sensorimotor contingencies are subject to rapid changes. Aim 3 will determine the role of CBF in implicit learning of auditory regularities. Using a combination of state-of the art optical tools, cell-type specific and temporally precise optogenetics and custom computational analysis and tools, this project unveils the role of cholinergic inputs to distinct cortical targets in learning. There is growing evidence that hearing loss and dementia are tightly linked. Cholinergic circuits play a prominent role in essential cognitive functions which are impacted during cognitive decline. Interestingly, it is one of the earliest regions to exhibit neurodegeneration in Alzheimer’s disease. Understanding how cortical networks are modulated by cholinergic inputs to produce the appropriate behavior will advance our understanding of basic cognitive functions and help develop targeted approaches to fend-off cognitive decline.

NIMH - National Institute of Mental Health

Abstract Adolescents with depression may be particularly vulnerable to developing problematic patterns of social media use. There is a need for effective, and sustainable tools to help teens with depression to regulate their social media use. In our prior qualitative studies of 50+ young social media users and their experiences with the technological ecosystem, we observed something we call the “runaway train” effect, in which the combination of problematic content, excessive use and a perceived lack of control results in negative impacts on wellbeing. Our results demonstrated that the runaway train effect is heavily driven by both the algorithmic organization of content and the content itself. Participants described how algorithms drive unhealthy patterns of over- engagement and poor self-regulation, (i.e., getting “stuck” looking at content and continuously scrolling despite awareness of the damaging impact on their wellbeing.) In our theoretical framework, excessive exposure to negative content leads to self-dysregulation and loss of wellness-promoting activities; these changes in turn amplify and maintain persistent low moods of depression. To address this, we draw on the feedback from our young adult participants, who said that when caught in the runaway train, they wanted to be given a set of options to break out of it. We now propose to develop and test a novel, personalized intervention designed to disrupt the “runaway train” effect of social media use in adolescents with depression in a way that is acceptable and sustainable. Centering the preferences of the young participants in our prior qualitative studies, the Choose Your Own Adventure (CYOA) application (app) is a personalized approach, designed to promote agency rather than “forcing” discontinued use. Adolescents will collaborate with the research team to identify situations or patterns in their social media use that may be harming their well-being. The app will then sense and characterize content and engagement patterns; when it detects a “runaway train” according to the pre- defined threshold, it will offer options according to the personalized plan. Adolescents will then select from a set of pre-specified options for what to do when needed (e.g., pause for 30 minutes, reboot settings, remove problematic content from the feed). Following technical development during the first year of the grant period, we will conduct a mixed-methods pilot study in 45 adolescents with depression to test the feasibility, acceptability, preliminary impact and mechanism of CYOA versus a standard timer and no intervention. In addition to self report data, we will collect objective data on social media algorithmic behavior and user behavior. We will also conduct interviews with adolescents to establish a co-creation process to inform the next steps of the research. This project will shed light on the links between social media use and depression in teens, and will pave the way toward an innovative, person-centered and personally-tailored intervention to help teens regulate their social media use.

African American Reach and Teach Health

The African American Reach and Teach, (AARTH), is planning educational activities and forums that focus on chronic diseases and mental health outreach. The forums will take place at 5237 Rainer Avenue South. AARTH will develop and host a series of information awareness activities on chronic diseases including diabetes, chronic kidney disease, and mental illness. Peer leader trainings will also be held. The main goal is to increase awareness and knowledge on how to better address chronic health conditions, reduce the stigma of mental illness and create a network of peer supporters for a healthier, more conscious society. The outreach will take place between January and December 2020.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Nursing Research (NINR), the National Institute of Child Health and Human Development (NICHD), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Cancer Institute (NCI), and the Office of Dietary Supplements (ODS) is to solicit research to improve self-management and quality of life in children and adolescents with chronic illnesses. Biobehavioral studies of children in the context of family and family-community dynamics are encouraged. Children diagnosed with a chronic illness and their families have a long-term responsibility for self-management. The child with the chronic illness will have a life-long responsibility to maintain and promote health and prevent complications. Research related to biological/ technological factors, as well as, sociocultural, environmental, and behavioral mechanisms that contribute to successful and ongoing self-management of chronic illnesses in children is also encouraged. This FOA is restricted to studies of chronic illnesses in children and adolescents ages 8 to 21 grouped by developmental stages according to the discretion of the investigator. Studies of chronic mental illness or serious cognitive disability are beyond the scope of this FOA. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism and runs in parallel with FOAs of identical scientific scope, PA-07-099, that solicit applications under the R21 mechanism, and PA-07-098, that solicit applications under the R03 mechanism. -Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Nursing Research (NINR), the National Institute of Child Health and Human Development (NICHD), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Cancer Institute (NCI), and the Office of Dietary Supplements (ODS) is to solicit research to improve self-management and quality of life in children and adolescents with chronic illnesses. Biobehavioral studies of children in the context of family and family-community dynamics are encouraged. Children diagnosed with a chronic illness and their families have a long-term responsibility for self-management. The child with the chronic illness will have a life-long responsibility to maintain and promote health and prevent complications. Research related to biological/ technological factors, as well as, sociocultural, environmental, and behavioral mechanisms that contribute to successful and ongoing self-management of chronic illnesses in children is also encouraged. This FOA is restricted to studies of chronic illnesses in children and adolescents ages 8 to 21 grouped by developmental stages according to the discretion of the investigator. Studies of chronic mental illness or serious cognitive disability are beyond the scope of this FOA.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Nursing Research (NINR), the National Institute of Child Health and Human Development (NICHD), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Cancer Institute (NCI), and the Office of Dietary Supplements (ODS) is to solicit research to improve self-management and quality of life in children and adolescents with chronic illnesses. Biobehavioral studies of children in the context of family and family-community dynamics are encouraged. Children diagnosed with a chronic illness and their families have a long-term responsibility for self-management. The child with the chronic illness will have a life-long responsibility to maintain and promote health and prevent complications. Research related to biological/ technological factors, as well as, sociocultural, environmental, and behavioral mechanisms that contribute to successful and ongoing self-management of chronic illnesses in children is also encouraged. This FOA is restricted to studies of chronic illnesses in children and adolescents ages 8 to 21 grouped by developmental stages according to the discretion of the investigator. Studies of chronic mental illness or serious cognitive disability are beyond the scope of this FOA. -Mechanism of Support. This FOA will use the NIH Exploratory/Developmental (R21) grant mechanism and runs in parallel with FOAs of identical scientific scope, PA-07-097, that solicits applications under the R01 mechanism, and PA-07-098, that solicits applications under the R03 mechanism. -Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

CID Cares Committee

CID Cares: Care for Community, Care for Self will be held in International District/Chinatown Community Center located at 719 8th Ave S Seattle, WA, on October 26th, 2024 from 11am-3pm. This event will be free and open to the public. We will offer voting assistance for our elderly, with appointments for much needed medical check-ups and immunizations, bystander safety training for elderly and neighborhood watch groups, as well as mental health awareness and counseling in language.

NIMH - National Institute of Mental Health

Project Summary / Abstract Enduring social bonds are essential for human health and well-being, yet their underlying neural mechanisms remain elusive due to limitations in traditional model organisms. Prairie voles, which naturally form lifelong pair bonds, offer a powerful system for investigating how the brain encodes stable social states. The medial amygdala (MeA) is functionally connected to a broad network of brain regions that collectively governs social behavior. Specifically, the MeA relays pheromonal cues that are critical for guiding context- appropriate behavior selection, yet how this region contributes to the behavior transition from a naïve to a bonded state in prairie voles is unknown. This proposal investigates how molecularly defined circuits in the MeA contribute to the emergence and maintenance of attachment behavior. Using single-cell RNA sequencing, I identified a sex-biased neuronal population that downregulates the neuropeptide gene Tac1 following pair bond formation. Intriguingly, the mouse equivalent of this population drives both affiliative and aggressive behaviors, and Tac1 itself has been linked to aggression control. In prairie voles, a bonded animal exhibits selective affiliation toward its partner and aggression toward all other opposite-sex conspecifics – a behavioral dichotomy that may be orchestrated by this population. I propose to characterize how this population is integrated into broader brain circuits of prairie voles and to monitor its activity during the formation of a pair bond. These experiments will clarify whether and how this population might serve as a neural substrate for the internal state of bondedness. Ultimately, this research may shed light on fundamental principles of social attachment and offer insight into how disruptions in such processes contribute to psychiatric illness. In addition to the proposed research, this application outlines a comprehensive training plan to prepare Dr. Wang for an independent career as a neuroscientist and psychiatrist. She will be mentored by Dr. Dev Manoli (UCSF), an expert in the molecular genetics and social behavior of prairie voles, and co-mentored by Dr. Michael Brainard (UCSF), a leader in the neurophysiology of complex behavior, and Dr. Vikaas Sohal (UCSF), who specializes in quantitative neural data analysis and circuit-level manipulations. Dr. Wang will also receive guidance on advanced molecular tool development from Dr. Nadav Ahituv (UCSF) and Dr. Josh Huang (Duke). Her career development is strongly supported by the UCSF Department of Psychiatry and Behavioral Sciences, which is committed to transitioning her to a full-time faculty position.

NIMH - National Institute of Mental Health

Two-third of individuals worldwide experience chronic adversity during childhood such as abuse, neglect or similar highly-stressful events. Such early-life adversity (ELA) is one of the best-characterized risk factors for developing psychiatric disorders associated with reward deficits including depression, substance use disorders and schizophrenia later in life. ELA related reward deficits are even observed in healthy individuals suggesting a link between pre-existing reward deficits and ELA-induced vulnerability to psychopathology. Mice exposed to ELA also show reward deficits later in life, however how ELA produces sustained changes at the neural circuit level to induce persistent reward-deficits is unknown. Reward processing is complex involves several aspects, governed by overlapping but still distinct reward circuits. A major challenge in studying circuit mechanisms underlying ELA-induced reward deficits have been a lack of dissection of the affected reward constructs. Our preliminary data suggest that ELA produces enduring deficits in hedonia in mice. Ventral pallidum (VP) and nucleus accumbens (Nac) have been implicated in reward processes, the historical view is that VP receives the reward-related information from Nac and modulates behavior through interactions with downstream targets. However recent findings challenge this view and show that VP encodes reward value and learned cue value more accurately and faster than Nac. Moreover, our preliminary findings show that the optogenetic stimulation of VP-Nac projection rescues reward deficits in ELA mice while the inhibition of this projection mimics the effects of ELA on hedonia. This proposal will test whether VP-Nac afferent activity is prominent in governing hedonia and whether disruptions of this circuit mediate the ELA-induced persistent reward-deficits. By employing fiber- photometry, Aim 1 will examine if ELA produces deficits in reward-related activity of VP cell populations, while Aim 2 will determine whether particularly the reduction of VP-Nac core activity is associated with ELA-induced hedonic deficits. Finally, Aim 3 will use pathway-specific optogenetic manipulations to test the role of VP-Nac afferents in ELA-related hedonic deficits such that if the inhibition of VP neurons projecting to different subregions of Nac suffices to induce hedonic deficits or the stimulation of the same circuit activity rescues the ELA effects on reward. We will also test the role of this pathway in hedonic encoding during cue-reward associations or instrumental learning in ELA. By combining these approaches, we will establish a pathway specific understanding of how ELA impairs reward processes with the goal of developing novel treatments for reward deficits.

NIMH - National Institute of Mental Health

Project Summary Animals select actions based on behavioral context. The ability to appropriately select actions from a set of relevant options is dependent on the basal ganglia, which receive inputs at the striatum and produce outputs via the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr). Foraging mice exploring novel environments are a robust model for action selection for the following reasons: 1) Water-deprived mice learn to suppress escape if doing so maximizes the chance for a water reward, an effect known as learned suppression of escape (LSE). 2) Threat and reward encoding dopamine neurons from the midbrain project to separate subregions of the striatum, the Tail of the Striatum (TS) and caudal Ventrolateral Striatum (cVLS) respectively. 3) Somatostatin(Sst)+ EP neurons signal the outcome of reward-seeking and threat-avoidant actions and receive partially overlapping but largely distinct input from TS and cVLS. 4) Sst+ EP neurons in turn project exclusively to the lateral habenula (LHb), a structure which encodes a negative reward prediction error and is implicated in learning of aversive action outcomes (Sst+ LHb-projecting EP neurons will throughout this proposal be referred to simply as EPLHb neurons). The striatum and EPLHb neurons are likely implicated in the shaping of future action selections through experience with threat and reward during behavior, but how these structures cooperate in this function has not been explored. Central Hypothesis: EPLHb neurons are topographically organized by monosynaptic TS or cVLS input into subcircuits which signal threat or reward signals and which are necessary for different aspects of LSE. Aim1: Map the strength and topographical organization of direct synaptic connections between striatum and EPLHb neurons. Unique subpopulations of EPLHb neurons receive projections from either threat-related TS or reward-related cVLS. It has not been confirmed whether EPLHb subpopulations receive monosynaptic GABAergic input from TS and cVLS as canonical basal ganglia models would suggest. In Aim1 I will use optical excitation of TS/cVLS axons coupled with ex-vivo patch clamp electrophysiology of EPLHb neurons throughout the EPLHb population to test for the presence, strength, density, and spatial locations of monosynaptic GABAergic inputs to EPLHb from the TS/cVLS. Aim2: Determine the activity patterns and necessity of striatal input-defined EPLHb neurons in guiding threat/reward conflict behavior. Silencing EPLHb neurons with tetanus toxin accelerates LSE, confirming expectations that these neurons shape action selection under threat/reward conflict conditions. EPLHb neurons have traditionally been studied in vivo using methods which do not distinguish between neuron subpopulations identified by input source. In Aim2a I will leverage fiber photometry of TSEP or cVLSEP neurons in vivo to distinguish their signaling of threat and reward as mice undergo LSE. In Aim2b I will silence synaptic release from TSEP or cVLSEP neurons to determine whether these are uniquely necessary for typical LSE.

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

Women with high levels of adverse childhood experiences (ACEs) are at significantly greater risk for negative health outcomes in pregnancy and postpartum, including gestational diabetes, PTB, and depressed mood. However, we still lack biomarkers or a sufficient understanding of causal mechanisms. Extracellular vesicles (EVs) are one of the most dynamic and abundant biological signals secreted into maternal circulation, largely produced by the placenta – where levels increase 4-5-fold during pregnancy. Similarly, removal of the placenta at delivery produces a dramatic drop in maternal EV concentration. Across species, we and others have identified significant EV changes during pregnancy associated with homeostatic regulation, including glucose and glucocorticoid levels, supporting key roles for EVs in maternal health. However, longitudinal studies in human pregnancy and postpartum have not been conducted. We know little as to the mechanisms controlling EV secretion or the roles for EVs in maternal pregnancy and postpartum health. Our decade’s long work identified the X-linked gene, O-glycosyltransferase (OGT), in mouse and human placenta as a master gage of the maternal milieu, where OGT regulation of annexin A1 (AA1) is key to EV cargo loading and secretion from the placenta. We recently reported that placental OGT levels positively correlate with maternal EV concentration. How this association may contribute toward postpartum health, including regulating maternal stress physiology and mood in humans is not known. We hypothesize that increased ACEs, similar to stress in preclinical models, are negatively associated with a cell’s ability to secrete EVs important to maintain homeostasis in the face of the challenges of pregnancy and postpartum, producing an increasingly unhealthy state. Therefore, the goals of these proposed studies in both mice and humans are as follows: 1) To identify cellular mechanisms involved in EV secretion important to maternal health outcomes utilizing the placenta as a tool to genetically target OGT in mice and examine maternal homeostatic control related to EV concentration and composition during pregnancy; 2) To examine the functional ability for a dynamic elevation in maternal EV concentration to improve homeostatic regulation in pregnancy and postpartum using chemogenetic activation (DREADDs) of placenta trophoblast cells in pregnancy, and by EV transfer by tail vein injection postpartum; and 3) To examine in women changes in maternal EVs in a longitudinal pregnancy and postpartum study in association with maternal glucose and cortisol changes, we will examine markers of physical (glucose challenge test), HPA stress (hair cortisol & stress- stimulated salivary cortisol) and psychological (Hamilton Rating Scale for Depression, Perceived Stress Scale) health across pregnancy and the postpartum period in 150 healthy women with varying degrees of exposure to ACEs as measured using the ACE Questionnaire (ACE-Q).

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), is to invite grant applications for clinical research that will reduce the burden of mental illnesses on older adults. The NIMH has a long-standing commitment to studying mental illnesses in older individuals. The intent of this FOA is to intensify investigator-initiated research in this area, to attract new investigators to the field, and to enhance interdisciplinary approaches to research. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. Applications of identical scientific scope are solicited also under the NIH Small Research Grant (R03), the NIH Exploratory/Developmental Grant (R21), and the NIMH Clinical Exploratory Research Grant (R34) award mechanisms, responding to FOAs PA-06-180, PA-06-181, and PA-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.

NIA - National Institute on Aging

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT New experiences are cemented as long-term memories through processes that unfold after initial encoding. Evidence from animal models and human neuroimaging suggests that a key process that may be involved in generating a stable and enduring memory is the spontaneous reactivation of the neural ensembles that encoded the original event. While there have been robust demonstrations of spontaneous neural reactivation of past experiences during sleep and periods of quiet rest, it is unclear whether these effects are epiphenomenal or if they are causally important for memory consolidation. Critically, technology for testing the causality of reactivation is limited, in part because reactivation events are comprised of spatially distributed, intermingled patterns of neural activity that are difficult to manipulate with precision. Developing tools that can causally test the role of reactivation in memory stabilization is crucial for understanding the foundational principles of long-term memory formation and retention. In this project, we will establish proof-of-principle of a novel real-time neuroimaging (fMRI) approach—closed-loop neural reinforcement—to test the impact of reactivation on memory retention. This approach is uniquely capable of directly modulating distributed neural activity patterns like reactivation events. In a unique, four-session experiment, we will further determine the reliability of broader neural correlates of reactivation in the hippocampus and default mode network. In Aim 1, we causally test whether cortical reactivation promotes long-term memory retention. We will use a closed-loop neuroimaging protocol in which participants up-regulate memory-specific reactivation after encoding new information. This protocol includes a category manipulation to serve as a within-participant control: participants will encode visual events comprising scenes and faces, but only a scene- or face-sensitive cortical region (i.e. paraphippocampal place area or fusiform face area) will be reinforced. We predict that participants who successfully induce reactivation will exhibit increased memory after a delay of 24 hours, but only for the category of memoranda related to the reinforced cortical region. In Aim 2, we determine the stability of interactions between reactivation on network-level consolidation processes, as cortical reactivation is thought to be one component of a broad collection of neural dynamics that unfold after learning in service of memory stabilization. We plan to leverage our protocol’s within-subjects design to characterize the reliability of relationships between cortical reactivation and other putative consolidation processes, including hippocampal reactivation, hippocampal-cortical dynamics, and default mode network activity. By experimentally manipulating cortical reactivation to determine causal involvement in memory performance, our project will both advance theory and offer clinically-relevant information about whether reactivation could serve as a promising new target for enhancing consolidation processes in rehabilitation of memory impairment.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ ABSTRACT Binge-eating disorder is the most prevalent and costly formal eating disorder, but has the lowest rate (<4%) of receiving eating disorder treatment. Binge eating often begins in adolescence and is strongly associated with obesity, physical and mental health impairment, and psychological distress. Yet, there are virtually no established treatments, and no clear standard of care, for adolescents with binge eating. Evidence-based treatments exist for adults, including psychological treatments (e.g., CBT-BED) and lifestyle behavioral obesity intervention (LBOI), but efficacy for adolescents remains largely unknown. LBOI is an effective treatment for adolescent obesity, but has only been tested post-hoc for binge eating. There is an urgent need for research identify and establish the efficacy of developmentally-appropriate interventions for adolescents with binge eating to improve adolescents’ health and quality of life. To address this pressing public health knowledge gap, CARE2 will test Cognitive and behavioral Approaches to Reduce binge Eating and Excess weight in adolescents. We will conduct a randomized controlled trial (RCT) in which participants are randomized to Psychological Treatment (CBT-BED), LBOI, or Active Control. We developed, refined, and tested adolescent-specific CBT-BED. Our pilot work showed that adolescent-specific CBT-BED was feasible, was more acceptable than nutrition education, and reduced binge eating. However, there has not been a definitive study that used an active control to establish efficacy, and patient characteristics that may be predictors and moderators of outcomes are not known. Further, CBT-BED has not been compared to LBOI, which shows promise for binge eating as well as weight. In the proposed study, we will compare both CBT-BED and LBOI to each other and to an Active Control. Active Control is daily self-monitoring (emotions, eating, exercise) on an “app”, mimicking real-world self-help, followed by treatment choice. After the delay, adolescents choose CBT-BED or LBOI and receive their treatment from a clinician (non-researcher). As such, the Active Control is both a control during the acute efficacy trial and an exploratory hybrid efficacy-effectiveness arm, in line with the NIH Stage Model of Psychotherapy Intervention Research. The specific aims of the CARE2 study are to 1) test whether CBT-BED and LBOI reduce binge eating and prevent excess weight gain, 2) test whether CBT-BED and LBOI reduce global eating disorder severity and improve quality of life, 3) explore durability of outcomes and patient characteristics that may moderate outcomes, and 4) explore adolescent treatment choice and effects on adherence and outcomes. Adolescents will be assessed at baseline, at end of treatment (6 months), and 6- and 12-months post-treatment. All visits occur via telehealth, allowing for national recruitment and pragmatic participation for families. Successful completion of CARE2 has the potential to improve health and reduce suffering during adolescence and improve lifelong health for adolescents with binge eating and excess weight.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Cognitive disengagement syndrome (CDS; previously termed sluggish cognitive tempo) is a set of behavioral symptoms characterized by excessive daydreaming, slowed thinking, and mental confusion. Despite being overlooked in psychopathology research for decades, it is now established that CDS symptoms (1) are distinct from other psychopathology including ADHD and internalizing symptoms, (2) can be reliably measured, and (3) increase across development. CDS is also associated with several significant areas of functional impairment including internalizing symptoms, suicide risk, and interpersonal difficulties. As CDS research advances, there is a need for developmentally-informed research that can advance theoretical models of CDS within broader models of psychopathology. We propose that CDS may be an important yet understudied transdiagnostic vulnerability to psychopathology that can inform models of heterotypic comorbidity while also being an untested gateway to the development and rise of internalizing problems across adolescence. However, there is a dearth of research examining CDS during adolescence, particularly with a longitudinal design. To address this gap in the existing scientific evidence base, we recently recruited a large, diverse community sample (N=341; ages 10-12 years) enriched for CDS symptoms to ensure the full range of CDS was represented. Participants are assessed at three timepoints over a 2-year period (i.e., baseline, 1-year follow-up, 2-year follow-up). Retention rates currently exceed 93%. Given its size and scope, this study comprises the most rigorous CDS study to date. However, despite the ongoing study being the only CDS-specific longitudinal sample in adolescence, it is limited to 3 timepoints over a 2-year period when the maximum age of participants will be 14 years. We thus have a unique opportunity to leverage this large, highly unique sample by conducting 4 additional assessments which will result in a total of 7 annual visits in a sample spanning the ages of 10-18 years. In this study we will (1) examine CDS as a transdiagnostic predictor of psychopathology (i.e., internalizing symptoms, dissociation, borderline features, insomnia) and suicidal ideation across adolescence, (2) test interpersonal functioning as a mechanism of the prospective link between CDS and internalizing psychopathology, (3) explore individual and diversity dimension factors that may moderate the prospective relation between CDS and internalizing, including trauma exposure, biological sex, and socioeconomic status, and (4) establish CDS in relation to theoretically-linked behavioral units of analyses, including task-assessed mind-wandering, processing speed, and negative attribution bias. Findings from our proposed 7-wave longitudinal design supporting the hypothesis that CDS uniquely predicts increased internalizing problems across the second decade of life would make a major advance in developing theoretical models of CDS, positioning CDS within broader hierarchical taxonomies of psychopathology, and providing avenues for targeted clinical assessment and treatment.

NIMH - National Institute of Mental Health

ABSTRACT Late-life depression (LLD) is a heterogeneous neuropsychiatric disorder that can take a chronic and recurrent course. Executive dysfunction (i.e., difficulties with complex mental tasks and planning) is prominent in recurrent LLD, persists despite remission of depressive symptoms, and corresponds with increased risk of cognitive decline and transition to dementia. Past work demonstrates executive function deficits are related to changes in the underlying structure and function of the brain’s executive control network (ECN). Combining targeted cognitive-enhancing interventions aimed at promoting neuroplasticity may strengthen the underlying ECN, thereby improving executive function performance. Multi-modal approaches using cognitive training and non- invasive neuromodulation (i.e., transcranial direct current stimulation; tDCS) support cognitive benefits in older adults. However, previous research used more general executive function-based cognitive training, while the current study proposes a targeted cognitive training (TCT) intervention that was created to specifically address executive function deficits found in LLD. Combining this with tDCS applied to the frontal lobes may help to maximally engage and benefit executive function-based cognitive and neural functions. The proposed study aims to identify cognitive and neural changes elicited by a multi-modal cognitive- enhancing intervention using a randomized clinical trial pilot study design. Sixty non-demented older adults presenting with executive dysfunction and recurrent LLD will undergo a 4-week daily intervention contrasting the effects of three conditions (bifrontal active tDCS+TCT, sham tDCS+TCT, and sham tDCS+non-targeted control cognitive training (CT)) on measures of executive functioning and ECN brain connectivity pre- and post- intervention. Specific aims are to determine whether stepwise ECN engagement across randomized groups (active tDCS+TCT > sham tDCS+TCT > sham tDCS+control CT) results in progressively greater benefit to executive functions (Aim 1) and functional connectivity between ECN regions (Aim 2). We will also explore whether intervention-related changes in ECN relates with executive function performance (Exploratory Aim) and changes in depressive symptoms. Resultant data will enhance understanding of mechanisms underlying this multi-modal cognitive-enhancing intervention in recurrent LLD and inform a more definitive randomized, mechanistically-focused clinical trial via an R01. This K23 will support my career development goals of building expertise in 1) delivery and optimization of multi-modal non-pharmacological interventions to enhance cognition, 2) functional connectivity neuroimaging analysis in LLD, and 3) clinical trials development, implementation, and management. Study results will establish the necessary groundwork for my development as an independent investigator focused on multi-modal targeting of the ECN (via TCT, tDCS) to enhance brain and cognitive functions in LLD, with goals of understanding mechanism, personalizing treatments, and altering the trajectory of cognitive decline to reduce dementia risk.

Cohen Veterans Network

Grants for establishing and expanding mental health clinics serving post-9/11 veterans, active duty, and families.

NIA - National Institute on Aging

PROJECT SUMMARY: OVERALL The Columbia University (CU) – Weill Cornell Medicine (WCM) Center for AIDS Research (CFAR) is a partnership between two large New York City (NYC) academic institutions, each with an expanding investment in HIV research and connected by the NewYork-Presbyterian hospital system, which spans four NYC counties designated as priority high-burden jurisdictions by the US Ending the HIV Epidemic (EHE) initiative. The overall specific aims of the CU-WCM CFAR are to (1) catalyze innovative, interdisciplinary, inter-institutional HIV research that addresses key HIV research priorities for ending the epidemic in NYC and beyond; (2) engage and support career development of HIV researchers, including early-career investigators (ECIs) and investigators new to HIV; and (3) advance community-engaged participatory research that promotes health for all people. The CU-WCM CFAR will accomplish these goals by establishing, engaging, and working through six Cores: The Administrative Core will provide leadership and management; implement strategic planning; and stimulate communication, collaboration, and capacity building. The Developmental Core will provide grant funding awards; mentoring and career development for new investigators; and provide resources, training, and feedback for mentors to improve their skills. The Structural Immunology Core will provide state-of-the-art imaging and immunological technologies; molecular structure determination; and bioinformatics to understand antibody-virus co-evolution, and structural modeling. The Virology Core will provide specialized assays to measure virus replication, infectivity, and cell susceptibility to infection; comprehensive reservoir characterization; and training in these methodologies. The Clinical Research Core will provide consultative support across the course of a study ranging from study design and biostatistical planning to participant recruitment, and data analysis. The Behavioral, Implementation and Community Sciences Core will support investigators engaged in behavioral, implementation, health services, and community science research and catalyze bi-directional collaborations with communities. We also will establish a Scientific Working Group – Integrating Systems of Care to End the HIV Epidemic – that will bring together a group of dynamic multi-sector collaborators to develop a robust research agenda that addresses fragmentation of care for HIV, mental health, and substance use care co-morbidities. The CU-WCM CFAR will add value to our institutions’ existing strong research portfolios through scientific leadership and strategic planning that builds synergistic new collaborations, enhances community engagement on HIV research and health, and supports innovation and research productivity as well as the next generation of leading HIV researchers.

NCI - National Cancer Institute

PROJECT SUMMARY In 2025, at least 63 million people in the U.S. served as family caregivers, the partners, relatives, and friends who care for patients with often life-threatening, incurable illnesses. Caregivers are increasingly tasked with responsibilities once performed by medical professionals, and the availability and health of caregivers is more critical than ever. The growing number of caregivers who provide care to patients with advanced, life-limiting cancers play a significant role in healthcare communication and advanced care planning (ACP). In fact, effective ACP often depends on caregivers who broker information between patients and healthcare professionals (HCPs). In the absence of ACP discussions, caregivers are generally unsuccessful in estimating treatment preferences, and poor communication magnifies these discrepancies, whereas open communication is associated with prognostic awareness and documented goals of care. Hence, equipping caregivers with the skills necessary to engage in vulnerable and productive ACP discussions and eventually, to advocate for their care partners' wishes, is critical to ensuring patients' interests are represented at the end of life. To date, however, there are no support programs or interventions for caregivers that explicitly target the communication skills necessary to engage in ACP discussions. We developed a Communication Skills Training Program for Caregivers (CT-C) to address caregivers' unmet communication skills needs. The brief two-hour training includes an overview of ACP, instruction in six communication skills, and role-play exercises using actors coached to portray patients and healthcare professionals. Results of our pilot randomized controlled trial demonstrated the CT-C's feasibility, acceptability, and superiority in improving distress, anxiety, and preparedness for death. In the proposed trial, we will more rigorously evaluate the efficacy of the CT-C through a randomized controlled trial of 200 caregivers of patients with advanced (Stage III/IV solid tumor) cancer who will receive either the CT-C or Enhanced Usual Care (EUC; distress screening and the provision of targeted referrals). Participants will undergo assessments of anxiety and the occurrence of ACP discussions with patients (primary outcomes), and ACP readiness, confidence in communication, distress, depression, dyadic coping and ACP discussions with HCPs (secondary outcomes) at baseline, 1-month, 6-months, and 12-months post-training. Bereavement outcomes including pre- and post-loss grief, preparedness for loss, and risk for bereavement mental health challenges will also be evaluated at each time point. While not a requirement for caregiver enrollment, the patients for whom caregivers provide care will be invited to complete assessments of advance directives completion, dyadic communication, and relationship quality with HCPs on the same timeline. We predict the CT-C will result in greater improvements in primary and secondary outcomes, and bereavement and patient outcomes. Our results will enhance our capacity to support caregivers in their roles as healthcare proxies, and by extension, improve their capacity to provide critical care to patients at end-of-life.

National Institutes of Health

-Purpose. The ultimate goal of this Funding Opportunity Announcement (FOA) is to support research partnerships between community-based, clinical/services settings and research institutions to reduce the burden of mental illness, behavioral disorders, and HIV/AIDS through research on mind, brain, and behavior. -Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) award mechanism. Only previous R21 awardees from PAR-07-004, are eligible to apply for the R01 grant. The R01 application must build on and further develop the pilot research, resources, and collaborations developed in the initial R21. -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, and costs of the applications received.

National Institutes of Health

-Purpose. The ultimate goal of this Funding Opportunity Announcement (FOA) is to support research partnerships between community-based, clinical/services settings and research institutions to reduce the burden of mental illness, behavioral disorders and HIV/AIDS through research on mind, brain, and behavior. -Mechanism of Support. This FOA will use the NIH Exploratory/Developmental (R21) award mechanism and runs in parallel with an FOA of similar scientific scope that solicits applications under the Research Project Grant (R01) mechanism and will be issued at a later date. R01 applications may only be submitted by awardees of this R21 FOA. The R01 application must build on, and further develop the pilot research, resources, and collaborations developed in the R21. -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, and costs of the applications received.

NIH

Significance to VA Obesity is present among 41% of VA patients and incurs many physical and mental health problems, increases mortality, and accounts for a large share of health care spending. Despite significant VA investment in the MOVE! behavioral intervention program and availability of bariatric surgery, obesity rates in VA remain high. Anti-obesity medications (AOMs) can result in clinically meaningful weight loss and are recommended as part of a comprehensive obesity treatment plan. The newer AOMs offer unprecedented effectiveness and tolerability with few contraindications. AOM use in VA is thus rapidly increasing and the potential impact on Veteran health is considerable. But strategic use of AOMs for Veterans with obesity is hindered by gaps in real-world data about use, clinical outcomes, and patient and clinician perspectives. We will provide the evidence for more strategic AOM use to treat obesity in VA, aligned with VA priorities of Evidence Based Decisions and Data as a Strategic Asset; the VHA Long-Range Goals of “providing health care-related data that benefits Veterans and the general public”, and the HSR priority of “Connect Veterans to the…best care (optimize Veteran access…and experience)”. Innovation & Impact We will assess new AOMs at a time of accelerating Veteran demand, provide the first rigorous evidence of AOM use and outcomes in men, examine weight change and clinical outcomes in real-world practice to complement trial evidence, and provide an in-depth understanding of patient, clinician, and organizational leadership perspectives on AOM use and continuation. Specific Aims Aim 1: Evaluate Veteran, clinician, facility, and VISN characteristics associated with using anti-obesity medications (AOMs) in 2021-2024 and characterize duration and rates of discontinuation. H: AOM users will have different baseline weight, race/ethnicity, and comorbidities than non-users. Aim 2: Compare real-world outcomes of AOM users and non-users in 2021-2024. H: AOM initiators will have greater weight loss and cardiometabolic changes than Veterans who do not initiate AOMs. Weight loss, GI adverse effects, and cardiometabolic changes will differ across AOMs. Aim 3: Characterize factors influencing decisions to initiate and continue AOMs as part of comprehensive obesity treatment, via qualitative interviews with Veterans, clinicians and pharmacy leaders. Methodology This is a sequential explanatory mixed-methods study. Aims 1 and 2 use a retrospective comparative effectiveness study design to examine use and outcomes of AOMs. Aim 3 will use qualitative interviews with patients (N=24), clinicians (N=24), and pharmacy leaders (N=24) to explore decision-making and the reasons for observed patterns of use. The quantitative and qualitative phases will be connected by our use of Aim 1 findings to inform Aim 3 sampling for interviews, and in Aim 3 we will also explore how Aim 2 outcomes influence decisions about continued use. We will use the qualitative data to enhance and enrich understanding of the quantitative findings about AOMs through synthesis of findings across Aims. Path to Translation/Implementation Operational partners in VA Pharmacy Benefits Management and the VHA National Center for Health Promotion and Disease Prevention, which manages MOVE!, will use our findings to inform prescribing guidance and program materials. Our team's next step will be to build on this study to develop and test an intervention to support AOM use among those Veterans that are most likely to benefit in terms of clinical and quality of life outcomes, which will in turn optimize VA resources and maximize Veteran benefit.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Despite gains in men’s engagement in HIV testing, prevention, and treatment in sub-Saharan Africa (SSA), men are still less likely than women to test for HIV, less likely to start antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP), and more likely to default from care and have virological failure. Highly mobile Lake Victoria fishermen in Kenya are at high risk of HIV acquisition due to their mobility and a transactional sex economy embedded within the fish trade. Fishermen have difficulty accessing services during typical clinic hours, and HIV-related stigma and gender norms that run counter to men’s healthcare- seeking also limit their uptake of HIV testing, prevention and treatment. Our recently completed social network-based, HIV status-neutral intervention (“Owete”) significantly increased HIV testing and linkage for ART or PrEP among Kenyan fishermen. HIV self-testing was higher in intervention network clusters (60% vs. 10%, p<0.001), as was linkage to health facilities among those who tested (67% vs. 16%, p<0.001). In Owete we identified close social networks of men and trained socially connected men in networks to act as “Promoters” of HIV testing, prevention and treatment. Promoters distributed HIV self-test kits and a small (KSh500, $4) transport voucher redeemable at linkage to health facilities to men in their networks. Promoters were trained to encourage peers to test and link to either PrEP or ART. We have engaged the Kenya Ministry of Health to now address how the Owete intervention can best be deployed at scale to proceed with wide-scale implementation of the intervention. Challenges to wider-scale implementation of Owete in Kenya are: costs and complexity of full social network surveys and promoter selection, and a limited evidence base for the amount and use of vouchers as an incentive to link to care. We will use the Multiphase Optimization Strategy (MOST) to identify an effective, scalable, and cost- effective version of Owete. In the MOST Preparation Phase, we will Identify scalable options for selection of network central Promoters and incentive levels (Aim 1). We will: use existing data from Owete and modeling to identify candidate components, set optimization criterion, and pilot-test candidate components in one beach. In the MOST Optimization Phase, we will comparatively test Promoter selection strategies, voucher effects, examine mechanisms of intervention action (Aim 2). In a 2x3 factorial trial, we will assess HIV self-testing and linkage outcomes at 3 and 6 months in 6 beaches, and use mixed methods to identify pathways of intervention action. We will estimate the incremental cost-effectiveness of candidate intervention combinations (Aim 3), employing time-driven activity-based costing and Markov modeling to assess cost-effectiveness; and use optimization criteria to identify the most effective, feasible, and cost- effective combination of Promoter selection strategy and incentive level for scale-up. Impact: This research will result in a scalable approach to engaging mobile men in HIV testing and care to reduce HIV in Africa.