Rachel Marsh - US grants

DESCRIPTION (provided by applicant): Advancing our understanding of abnormalities in these systems may shed light on the pathophysiology and pathogenesis of disorders in which children and adolescents are plagued by the presence of impulsive and habitual behaviors. This award supports the career development of Dr. Rachel Marsh and her research plan to study self-regulatory control processes and habit learning in adolescents with Bulimia Nervosa (BN). The career development activities build on Dr. Marsh's background in developmental and experimental psychology and capitalize on the resources at Columbia University to allow her to achieve her long-term goal of becoming an independent investigator of childhood psychopathologies. Dr. Marsh proposes to use fMRI to identify functional impairments of frontostriatal circuitry, the primary mediator of self-regulatory control, in adolescents with BN that may predict the presence or perpetuation of the disorder. The proposed research will also help to define the functional characteristics of habit-learning systems within the basal ganglia that may be abnormal in adolescents with BN and contribute to their habitual binging and purging behaviors. Disturbances in frontstriatal systems may release the underlying vulnerabilities to develop BN from regulatory control, contributing to the expression of these habitual behaviors. Findings from this study will have wide-ranging importance for the understanding of the development and treatment of BN and help to define the role of self-regulatory control and habit-learning systems in other pathological conditions that originate in childhood.

DESCRIPTION (provided by applicant): Bulimia Nervosa (BN) is defined by the frequent occurrence of binge-eating episodes that are associated with a severe sense of loss of control, followed by compensatory behaviors to avoid weight gain. Our preliminary data suggest that anatomical and functional abnormalities in frontostriatal neural systems are associated with binge- eating and other impulsive behaviors in adults and adolescents with BN. However, the peak onset of BN in adolescence suggests that understanding the development and progression of frontostriatal abnormalities during this period is necessary to understand the biology of BN and design novel treatments and prevention strategies. This multimodal imaging study will use functional MRI, anatomical MRI, and diffusion tensor imaging measures to assess longitudinal changes (over 3 years) in the function, anatomical characteristics, and organization of frontostriatal systems in 50 adolescents who meet the proposed DSM-5 criteria for BN compared with 50 matched controls, 13-18 years of age. We will determine how the trajectories of frontostriatal disturbances diverge from normal in the adolescents with BN whose symptoms worsen compared to those whose symptoms remit, and whether our brain imaging measures at baseline can predict the severity of symptoms at follow-up. This will be the first longitudinal imaging study of adolescents with BN, the first multimodal imaging study of any individuals with eating disorders, and the first longitudinal, multimodal imaging study of frontostriatal systems in the same sample of healthy adolescents. Thus, findings from this study may point to a useful biomarker (frontostriatal disturbances) for the early intervention of BN, and further our understanding of the normal maturation of these systems. PUBLIC HEALTH RELEVANCE: We propose a longitudinal multimodal imaging study of the structure and function of frontostriatal neural systems in adolescents with Bulimia Nervosa (BN). Identification of abnormalities in these systems will foster a better understanding of the pathophysiology of BN and point to a biomarker that will aid in the development of early interventions and individualized treatments for this disabling illness.

DESCRIPTION (provided by applicant): Obsessive-Compulsive Disorder (OCD) is a disabling illness that typically begins in adolescence and persists into adulthood. We hypothesize that OCD is due to dysfunction in frontostriatal brain circuits that subserve self-regulatory control processes, and that these disturbances affect stimulus-response 'habit'learning systems within the dorsal striatum and declarative memory systems within medial temporal lobe regions that are components of a mesocorticolimbic reward processing system. In this R21, we will use fMRI to assess the functioning of these three neural systems in 30 unmedicated adults with OCD (ages 18-45) compared to 30 age-matched healthy controls (Primary Aim). The functioning of frontostriatal control systems will be assessed using the well-validated Simon task. The functioning of habit learning and reward processing systems will be assessed using a novel fMRI paradigm directly analogous to tasks used to define the neural bases of learning and memory systems in animal research, tailored to a virtual reality environment within the MRI scanner. This paradigm provides a translational neuroscience approach to the study of brain function in OCD. After scanning, OCD patients will be offered 12 weeks of open treatment with a serotonin reuptake inhibitor (SRI), and we will explore whether our baseline fMRI measures predict SRI response (Secondary Aim). Identification of functional abnormalities (a biosignature) in any of these neural systems in OCD will support future studies to investigate the onset and progression of these brain abnormalities and the effects of treatment. If these abnormalities are associated with treatment response, these fMRI paradigms could become valid biomarkers for OCD. Our long-term goal is to identify a distinct pattern of brain abnormalities that underlies OCD and/or predicts treatment response, and to develop novel treatments that target these abnormalities directly. By validating the use of specific fMRI paradigms to examine potential brain mechanisms underlying OCD, this R21 application is a first step in this direction and consistent with the NIMH strategic plan to promote brain discovery and to identify biomarkers of treatment response. PUBLIC HEALTH RELEVANCE: We propose to investigate functional abnormalities in three neural systems that we hypothesize underlie Obsessive-Compulsive Disorder (OCD) and to explore whether these abnormalities are associated with OCD severity and/or predict treatment response. Identification of abnormalities in these neural systems will not only foster a better understanding of what causes OCD, but also enable future studies to examine when and how people with OCD develop these brain abnormalities and to develop novel treatments that directly target them.

DESCRIPTION (provided by applicant): Cognitive control and reward processing are hypothesized to be impaired in disorders with repetitive thoughts/behaviors, including obsessive-compulsive disorder (OCD), Tourette's Syndrome, and eating disorders (anorexia nervosa and bulimia nervosa). This R01 proposes to use multimodal imaging to investigate how dysfunction in neural circuits underlying these two RDoC constructs contributes to these pathological behaviors, using OCD as a model system (see reasons below). It will also examine how these circuits change following successful treatment with exposure and ritual prevention (EX/RP). The short-term goal is to clarify how circuit-based abnormalities contribute to repetitive thoughts/behaviors; these data will inform future transdiagnostic studies. The long-term goal is to identify abnormalities in cognitive control and reward circuits that could be targets for new transdiagnostic treatments. Specifically, multimodal imaging (fMRI, resting state functional connectivity, and diffusion tensor imaging) will be used to determine how the function, connectivity, and organization of the overlapping frontostriatal circuits that support cognitive control and reward processing differ across 40 unmedicated adults with OCD (ages 18-45) compared to 40 healthy control subjects (Aims 1 & 2). Circuit-based changes in OCD patients following 8 weeks of EX/RP treatment will be compared to non-specific changes in the healthy control group (Aim 3). All participants will complete self- reports, clinical interviews, and additional behavioral tasks of cognitive control and reward processing, allowing examination of how brain abnormalities link to behavioral performance and clinical phenotype. OCD provides a unique model system to address these aims because: 1) deficits in cognitive control and reward processing are hypothesized to underlie the repetitive thoughts/behaviors at the core of this disorder; 2) functional abnormalities in both control and reward circuits have been reported; and 3) EX/RP is an effective therapy that leads to clinical remission in some. This allows investigation of whether normalization of behavior leads to normalization of these circuits. If so, these circuit abnormalities could become new targets for treatment development. This approach-- leveraging multimodal imaging to understand circuit function, employing multiple units of analysis, and using treatment as an experimental tool to test brain-behavior relationships --is consonant with NIMH's RDoC Project and Strategic Plan. Repetitive thoughts/behaviors are hallmarks of various disorders and lead to functional impairment and reduced quality of life; thus understanding the brain mechanisms that underlie these symptoms and identifying new targets for treatment development can advance public health.

DESCRIPTION (provided by applicant): Obsessive-Compulsive Disorder (OCD) is a disabling illness that typically begins in childhood and persists into adulthood. Neuroimaging studies suggest anatomical and functional disturbances of frontostriatal circuits in OCD but few studies have assessed the functioning of these circuits in pediatric (child-onset) OCD which is likely a distinct OCD subtype, coinciding with developmental changes in the function and structure of the prefrontal cortex. We hypothesize that dysfunction in overlapping frontostriatal circuits contributes to OCD by impairing control over intrusive thoughts (obsessions) and repetitive behaviors (compulsions) and diminishing the capacity to process rewards. An over-reliance on the earlier developing striatum then allows compulsions to become habits. In this R21, we will use fMRI to assess the functioning of these circuits in 30 unmedicated children with OCD (ages 6-12) compared to 30 age-matched healthy controls. The functioning of dorsal frontostriatal control systems will be assessed using the well-validated Simon task. Functioning of the dorsal striatum and ventral frontostriatal circuits that support habit learning and reward processing will be assessed using a novel fMRI paradigm directly analogous to tasks used to define the neural bases of reward-based learning systems in rodents, tailored to a virtual reality environment within the MRI scanner. This paradigm provides a translational neuroscience approach to the study of brain function in OCD. We will also assess functional connectivity in dorsal and ventral frontostriatal circuits in the same children, and determine whether disturbances in these overlapping circuits are associated with OCD symptom severity. Identification of dysfunction in either of these circuits in OCD will support future longitudinal study of their neurodevelopmental trajectories in OCD. Our long-term goal is to identify a distinct pattern of brain abnormalities tht underlies OCD and to develop novel treatments that target these abnormalities directly. By validating the use of specific fMRI paradigms to examine potential brain mechanisms underlying OCD, this R21 application is a first step in this direction and consistent with the NIMH strategic plan to promote brain discovery.

? DESCRIPTION: This is an application for renewal of the T32, Translational Research Training in Child Psychiatry that has been funded continuously since 1980. The mission of this program is to recruit and train the next generation of translational scientists who recognize that the development of effective prevention and/or therapeutic strategies for neurodevelopmental disorders requires studying the bidirectional pathways between the underlying biology and environment at both the individual and population level. The success of the training program is reflected in both the accomplishments of the trainees and in the diversity of the fellows. Over the past 10 years, we successfully graduated 31 out of 33 (94%) trainees, and 18 have received substantial independent funding including 6 career development awards (K08, K12, and K23), 1 R01, 2 R21s, 1 grant from the NIEHS, 5 NARSAD awards, 16 foundation grants, 4 pilot awards from the American Academy of Child and Adolescent Psychiatry (AACAP), 3 awards from the Sackler Institute of Developmental Psychobiology, 4 NIH loan repayment awards, 4 awards from the New York State Office of Mental Health, and 1 Paul Janssen Fellowship. We currently have 6 fellows, 2 of whom are under-represented minorities. Two fellows are graduating this month and 2 female MD fellows have accepted to begin in July. In the last submission of this T32, the committee concluded that the preceptors and training environment were deemed outstanding by the review committee. The reviewers also commented that the program has a strong record of producing exceptional independently funded trainees. That submission described a training plan that strengthened the opportunities in translational research by enhancement of the didactic teaching program and strategic addition of mentors. To further improve the training program and recruitment of a diverse applicant pool we have taken substantive steps by restructuring the program leadership, involving a wider range of accomplished faculty, and revising the didactics.

Abstract. Subclinical Obsessive-Compulsive symptoms (OCS) in early development increase risk for OC- related impairment in adulthood, but wax and wane in middle childhood, suggesting a critical period for overcoming symptoms. Clinically significant OCS (Obsessive compulsive Disorder, OCD) also emerge during school age and also follow a variable course --- some patients remit, while others continue to suffer OCS, even after gold standard, cognitive behavioral therapy (CBT). Such different OCS trajectories may derive from differential engagement of cognitive control circuits, specifically fronto-parietal (FP) and cingulo-opercular (CO) task control (TC) circuits, since the normal development of these circuits parallels the maturation of cognitive control processes that are altered in pediatric OCD. Modulation of TC circuits could help to reduce childhood OCS, but identification of the specific changes in TC circuits that coincide with OCS reductions is first required. Our preliminary data suggests that TC alterations (e.g., increased or decreased activation) and associations with OCS depend on the specific TC circuit (CO or FP) and component cognitive control process engaged (i.e., conflict resolution, error processing), as well as the age, medication status and clinical severity of the patients studied. Accordingly, we will administer two cognitive control tasks embedded within a multi-modal imaging protocol, using pulse sequences consistent with the Adolescent Brain and Cognitive Development study and Human Connectome Project. We will use these cutting-edge MRI sequences to elucidate how TC circuit changes associate with OCS reductions in unmedicated children, aged 7-12 years. Drawing from the RDoC framework, imaging, behavioral, and clinical/self-report measures of symptoms will be collected in a large sample of children with OCD, subclinical OCS or no OCS (n = 180 total), recruited across 2 sites. Leveraging the normal to abnormal range of OCS represented by the combined sample, we will test the relation of TC circuitry and cognitive control processes with OCS across the full spectrum of severity (Aim 1). In OCD- affected children, OCS will then be manipulated with a standard, 16-week course of CBT to determine how TC circuit changes associate with changes in OCS severity across the remission, partial response and no response outcomes known to occur after CBT (Aim 2). Circuit-based changes will be compared to non-specific changes in healthy children who remain OCS-free. By pinpointing which cognitive control processes and TC circuit changes associate with reductions in OCS, this work will inform the selection of processes and neural targets to direct cognitive trainings to treat and prevent childhood OCS, setting the stage for future clinical trials.

Self-regulatory deficits are common across a variety of childhood psychiatric disorders in which children have difficulty regulating their thoughts, emotions, and behaviors. By leveraging previously collected prenatal and neonatal data and acquiring new data from mother-infant dyads, this study will identify circuit-based markers of regulatory deficits that are passed inter- generationally and persist from infancy to childhood. We will enroll 15-45 year-old pregnant women/mothers, approximately 75% Latina, who are receiving health care from our urban medical center, a sample that is underrepresented in U.S. biomedical research and facing significant psychosocial adversity. Age-appropriate measures of regulatory control processes will be acquired from their offspring at 4- and 14-months and during preschool and school age, including resting-state fMRI data from neonates and both resting and task-based fMRI data from school-aged children who were previously scanned as neonates. Behavioral measures of regulatory capacity and resting and task-based fMRI will also be acquired from the mothers, allowing us to associate maternal-neonatal indices of self-regulatory control. Thus, this study will uncover trajectories of control processes and circuits from infancy to school age and the intergenerational transmission of regulatory deficits from mothers to offspring. Findings will set the stage for future research aimed at engaging these circuits as targets for strategies to prevent the risk for future maladaptive behaviors and at identifying prenatal mechanisms underlying the intergenerational transmission of regulatory deficits, such as epigenetic and stress-mediated biological alterations. This study supports the NIMH strategic objective to chart mental illness trajectories to determine when, where, and how to intervene by elucidating the development of regulatory control across the first decade of life. This study also supports both the NIH BRAIN and precision medicine initiatives by evaluating the functional organization of control circuits across family generations and longitudinally, as well as using a novel imaging method to predict behavioral outcomes.

ABSTRACT The devastating effects of the COVID-19 pandemic have reverberated through every aspect of our civilization. While SARS-CoV-2, the viral etiology of COVID-19, seems to spare infants in terms of actual infection, it is currently unknown whether maternal infection during pregnancy will have long-term effects on children born during the pandemic. A variety of prenatal insults, including infections and stress, are well-known to lead to increased risk of affective disorders in both mother and child. With its disproportionate reach into already disadvantaged minority communities, the impact of the COVID-19 pandemic on the dyad is currently unknown and potentially of unprecedented magnitude with enduring consequences for women's mental health and children's developmental origins of health and disease (DOHaD). The COVID-19 Mother Baby Outcome (COMBO) initiative, a large multidisciplinary collaborative, was established at Columbia University Irving Medical Center to follow SARS-CoV-2 exposed laboring mothers and their newborns and compare their long- term health outcomes to case-matched dyads without prenatal exposure. This proposal will follow a subset of the larger COMBO cohort to study socioemotional circuits (fronto-limbic) and behavior (caregiving and bonding) in 100 mother-child dyads from prepartum to 18 months postpartum. The team assembled to carry out this study consists of two provider scientists (Dumitriu, pediatrician and neuroscientist, & Monk, clinical psychologist embedded in Ob/Gyn) and neuroscientist/pediatric neuroimager (Marsh). Using an innovative dyadic approach, olfaction testing, multimodal MRI, wearable in-home physiological recordings, observational mother and child assessments (free play, routine care, Harvard Reactivity and Still Face paradigms), this proposal will test the overarching hypothesis that prenatal SARS-CoV-2 exposure affects (1) mother and (2) child brain and behavior, and (3) demonstrate that the socioemotional health of each member of the mother- child dyad is intrinsically related to that of the other. Detecting COVID-19-related early neurobehavioral effects on mothers and the next generation will provide insights into intervention strategies and contribute significantly to DOHaD and stress science.

ABSTRACT The COVID-19 pandemic has highlighted and exacerbated health disparities related to structural racism and discrimination (SRD), economic marginalization, and other social determinants of health (SDOH). Pregnant and postpartum women face unique social and health vulnerabilities related to the pandemic, including risk for stigma, housing, food, income and employment insecurity, psychological distress, and even mortality ? risks and consequences which are disproportionately significant and adverse for women of color and low socioeconomic status (SES). However, the collision of these multiple intersecting 21st century public health crises have not yet been empirically or rigorously studied for inequities in maternal mental health and severe morbidity. The COVID-19 Mother Baby Outcome (COMBO) initiative is a large multidisciplinary collaborative established at Columbia University Irving Medical Center to follow SARS-CoV-2 exposed laboring mothers and their newborns and compare their long-term health and wellbeing to case-matched dyads without prenatal exposure. The focus of the parent NIMH ?COMBO? R01 MH126531 is to understand the effects of SARS-CoV- 2 on mother-infant brain-behavior functioning in a subset of 100 COMBO-enrolled dyads with and without prenatal SARS-COV-2 infections. Responding to key priorities of NOSI NOT-OD-21-071 and leveraging COMBO?s robust infrastructure, this administrative supplement (PA-20-272) expands the parent R01 to study the independent and interactive effects of SRD/SDOH and SARS-CoV-2 on inequities in maternal mental health, taking advantage of COMBO?s unique setting (first pandemic epicenter) and understudied socially disadvantaged sample (>600 mother-infant dyads enrolled to-date, with 63% mothers identifying as racial/ethnic minority and/or low-SES women). By expanding parent R01 brain imaging, surveys, semi- structured interviews, and electronic health record (EHR) extraction, we will test the overarching hypothesis that SRD/SDOH and SARS-CoV-2 independently and additively increase risk of adverse maternal mental health outcomes, with the magnitude of the negative impact being greatest for women of social disadvantage and the health disparity gap ballooning during ? and persisting post ? the pandemic. Findings will inform patient-centered, multi-level interventions to ameliorate the intersecting epidemics of SRD/SDOH and SARS- CoV-2 and their mental health sequelae for women of social disadvantage in NYC and beyond.