Jonathan Posner - US grants

CBET-0747917
Posner

Colloidal crystal films (CCF) are being developed as photonic crystals for integrated optical circuits, as super hydrophobic surfaces, and as solid-state sieving matrices for biochemical separations. Colloidal crystal films are comprised of 20 or more layers of face center cubic packed nanospheres (20-500 nm). These films are typically deposited by a fluid self-assembly process of a non-dilute colloidal suspension of nanoscale spheres. Current CCFs are plagued with unwanted defects in the range of 20-1000 sphere diameters that limit device applications. Solvent evaporation and electrophoretic deposition methods are largely developed by trial and error and suffer from a lack of fundamental understanding of the governing physics. The ability to control colloidal crystal film structure and reduce film defects is limited by the complex role of the fluid transport on the deposition process. These flows include the coupling of free surfaces and electric fields with high volume fraction suspensions and locally varying viscosity, density, surface tension, conductivity, and permittivity. They are time-dependent, three-dimensional and exhibit a wide range of time and length scales that make them difficult to model and observe. This research investigates the transport physics of colloidal crystal film deposition where high volume fraction colloidal suspensions flow with free surfaces and electric fields. A high-speed, spinning disk confocal microscope will be developed to measure the three velocity components and crystal structure in real-time and real-space. This research will enable depositions of defect-free colloidal crystal films and structures for a host of emerging technologies. The high speed confocal system will impact a wide range of disciplines including microfluidics, rheology, colloidal science, and real-time cellular imaging. Fundamental understanding of colloidal crystallization can be applied to molecular crystallization such as protein crystallography. This program integrates research with mentoring, education and outreach impacting students from middle school through graduate school. The study includes the development of a middle school outreach program ?got flow?? for underrepresented middle school students in the Phoenix metropolitan area. The ?got flow?? program has three phases: outreach modules directly inspiring 1000 8th graders to study math, science, or engineering; RET to provide research experience and state mandated professional training for middle school teachers; and educational transfer modules (ETM) that convey the modules to individual middle schools. The PI will expand undergraduate research opportunities for Hispanic and Native Americans who have relatively high enrollment at ASU, but low representation in engineering nationwide.

0853379/0853375
Posner, J./Wang, J.

Synthetic nanoscale motors represent a major step towards the development of practical nanomachines. Despite impressive progress, manmade nanomachines lack the efficiency and versatility of their biological counterparts. Extending the scope of synthetic nanomotors to diverse and realistic conditions requires deep understanding of their fundamental physical mechanisms. This proposed collaborative research aims at gaining such understanding of the underlying physical mechanisms of catalytic nanowire motors. The intellectual merit of the proposed work is to extend the fundamental understanding of the nanomotors propulsion, through a parallel experimental and theoretical approach, to guide the rationale design of powerful and versatile manmade nanomachines that can perform demanding tasks. The three main aims of the proposed work are: (1) understand physical mechanisms that govern the motion and performance of nanomotors using novel experiments and theoretical models (2) Identify and optimize nanowire properties (catalysts composition and morphology, wire shape, and surface coatings) that yield order of magnitude faster and more powerful nanomotors. (3) Fabricate nanomotors capable of operating in a wide range of environments (pH, ionic strength) and fuels (e.g. glucose, ethanol), enabling ranging operation in a variety of applications and demanding tasks such as directed drug delivery, directed nanoscale self-assembly, chemotactic environmental remediation, or microchip bioassays.

This research is transformative in that the improved understanding of the fundamental catalytic nanomotor physics will lead to powerful motors that are stable over long periods for performing complex tasks in a wide variety of environments and applications. To ensure success of the interdisciplinary research program, the team is comprised of two co-PIs with complementary experience. The proposed effort requires expertise in catalysis and electrochemistry (Wang), nanowire fabrication (Wang), low Reynolds number hydrodynamics (Posner), microscale diagnostics (Posner), electrokinetics and electrostatics (Posner). The PIs' extensive preliminary data, broad and complementary experience and past collaboration lay the groundwork for the success of the proposed activity.

The proposed effort will have broader impacts by integrating research with training, education, mentoring, and social outcomes. Particular emphasis will be given to the involvement of Hispanic students at the undergraduate and graduate research levels. They leverage the uniqueness of their locations by expanding undergraduate research opportunities for Hispanic students which have relatively high enrollment at ASU and UCSD, but low representation in engineering nationwide. This grant will provide distinctive experiences for undergraduate and graduate students to appreciate and participate in how their research on nanotechnology may transform society and to examine science and technology policy. In particular, they will develop a nanomachines course for a emerging nanotechnology curriculum in a new UCSD department of Nanoengineering. In addition, at ASU they aim to increase engineering graduate students' awareness of the societal and ethical implications of nanoscience and technology. In collaboration with faculty in the NSF Center for Nanotechnology in Society they will (1) develop a cross-listed, co-taught graduate level course entitled Societal and Ethical Implications of Scientific Research focusing on nanotechnologies; and (2) ASU and UCSD students will participate in a two week workshop in Washington, DC entitled "Science Outside the Lab: A Policy Dis-Orientation" which examines scientific policy and culture.

0932885
Posner

Over the past five years, there has been a growing interest in the health-related issue of toxicity of engineered nanomaterials. Cells have various routes for uptake of molecules and particles through their cell membranes to control their internal environment including highly selective membrane proteins and peptides as well as protein mediated endocytosis and phagocytosis. Nano-particle (NP) based drug delivery and molecular imaging applications that deliver NP into cells typically use biochemical functionalization which promote specific signaling and uptake. The lipid bilayers that make up cellular membranes are believed to be impenetrable to ions and unfunctionalized macromolecules, however, epidemiological studies have shown that unfunctionalized NPs can, under some conditions, cross or disrupt the cell membrane through passive, unmediated routes causing acute cellular toxicity and cell death. The unmediated NP adsorption onto and the uptake into cells is poorly understood. Recent research focuses on either collection of empirical epidemiological data (e.g. uptake of NP by cells, toxicity to organisms such as rats or fish) or precise NP characterization (e.g. size, shape, degree of aggregation, charge, and surface chemistry). However, it is almost impossible to transition from these measurements to detailed understanding of the mechanisms responsible for unmediated NP uptake into cells and disruption of the bilayer. Quantitative measures of nanomaterial bioavailability and toxicity need to be assessed so that the impact of nanotechnology on human health and the environment can be addressed.

Intellectual Merit: The intellectual merit of the proposed work is to understand the mechanisms and conditions under which engineered nanomaterials can cause disruption of, and passive transport through, simplified model cell membranes, namely lipid bilayers. The,investigators hypothesize that under some conditions engineered NPs can passively translocate across, and cause nanoscale defects in, bilayers which plays a role in cellular toxicity. The interaction of nanoparticles and lipid bilayers are unique because the particle and membranes have nearly the same length scale.

Broader impact: Fundamental understanding of the interaction between NP and lipid bilayers is potentially transformative because it may: (1) improve our understanding of toxicity of engineered and environmental NP; (2) enable rational design of benign NP for delivery of drugs and biomedical/molecular imaging; (3) result in high-throughput toxicity testing protocols; and (4) evidence-based regulation and protocols of nanomaterials. An experimental platform and methods will be developed for quantifying the NP transport through lipid membranes in real time as a function of the NP and lipid properties and the physicochemical environment. A "bottom-up" approach will be employed to increase the complexity of the bilayer through incorporation of membrane proteins as well as glycolipids to form an artificial glycocalyx.

Engineered nanoparticles are largely unregulated because the transport, fate, and toxicity of NP have not been adequately assessed. The proposed research focuses on the interactions of engineered nanomaterials with lipid bilayers, arguably the most important interface between life and the environment. This proposal addresses NP toxicity and has strong implications on the regulation of NP production, distribution, and application in medicine, clothing, cosmetics, etc. As an integral part of the proposed work, the PI aims to increase engineering and physical science graduate students' awareness of the societal and ethical implications of nano science and technology through: (1) development of a cross-listed graduate level course on the societal and ethical implications of nanotechnology; and (2) organization of a two week student workshop in Washington, DC which examines scientific policy and culture. The PI will also build upon his strong commitment to undergraduate research by funding underrepresented undergraduate researchers.

DESCRIPTION (provided by applicant): Attention Deficit/Hyperactivity Disorder (ADHD) is characterized by symptoms of inattention, hyperactivity, and impulsivity. Deficits in inhibitory control and associated frontostriatal (FS) circuits have long been implicated in association with the disorder, but recent studies suggest that abnormal emotional processing within frontolimbic (FL) circuits may also be an important component of the hyperactivity evidenced in children with ADHD. Deficits in either domain may therefore be associated with ADHD and determine the clinical phenotype that a particular child exhibits. Using functional magnetic resonance imaging (fMRI), the current study aims to investigate simultaneously the functioning of FS and FL circuits in the same group of children as this is the best means to determine whether these two circuits have dissociable functions and neuropsychological correlates in children with ADHD. The study will examine in 60 children (ages 8 - 12) with (N=30) and without (N=30) ADHD the functioning of FS circuits during the performance of an inhibitory control fMRI task and the functioning of FL circuits during the performance of an emotion processing fMRI task. The hypotheses are that the functioning of these circuits will not only differ in children with and without ADHD but also that a double dissociation will be found in the behavioral correlates of FS and FL circuits. This application for a Mentored Patient-Oriented Research Career Development Award (K23) also requests funding for Jonathan Posner, MD to pursue training essential to becoming an independent investigator. This funding would support a comprehensive program including formal didactics and seminars from experts in the fields of pediatric neuroimaging, cognitive and affective neuroscience, and pediatric psychopathology. These training activities would enhance Dr. Posner's knowledge of a) fMRI techniques;b) the pathophysiology, phenomenology, and treatment of ADHD, c) affective and cognitive neuroscience;d) longitudinal neuroimaging study design;and e) the ethical conduct of scientific research. PUBLIC HEALTH RELEVANCE: ADHD is associated with a wide range of negative long-term outcomes, and causes significant hardship for children and families. Developing a better understanding of the neurobiology of ADHD may help advance research into the etiology, genetics, and treatment of the disorder.

PI: Santos, Veronica J. and Posner, Jonathan D.
Proposal Number: 1264444 & 1264046

Intellectual Merit: Whether a prosthetic hand is a simple body-powered hook or an advanced anthropomorphic device, it will only be useful and desirable to an amputee if it improves quality of life and is intuitive to control. A prosthesis will be rejected if it poses too great of a cognitive burden on the user. One way to simultaneously reduce the cognitive burden on the user and enhance the functionality of the user to focus on high-level commands as opposed to low-level details that may be frustrating to control or even impossible to control given the "language barrier" between human and machine because of different timescales and resolutions of control. Amputees could be empowered with prostheses having autonomous, local reflex algorithms akin to short latency grip reflexes observed in humans, and even suites of basic behavioral building blocks that are critical for activities of daily living. The only way for a semi-autonomous system to gain the trust of its operator is through reliable, context-dependent performance. Such context-aware performance will require information about forceful interactions between the prosthetic hand and everyday objects in unstructured environments that can only be obtained through touch. The great number and dynamic range of tactile mechanoreceptors in the human hand (17000 tactile sensors total, 2000 in each fingertip) highlight the importance of rich multimodal tactile feedback for grasp and dexterous manipulation. Unfortunately, many tactile sensor designs have focused on detection of normal forces alone, which are necessary but not sufficient for reliable artificial grasp. What is sorely needed is a multimodal tactile sensor that can detect additional important features of finger-object interactions such as shear force, vibration, and slip direction. This proposal aims to strengthen the ability of an artificial hand to perform automated behaviors reliably by detecting, processing, and utilizing rich, real-time information about finger-object interactions with an innovative multimodal tactile sensor skin. This sensor system is transformative because it will reduce the cognitive burden on an amputee and will provide a foundation for paradigm-shifting advancements for automating complex behaviors by artificial hands and providing a conscious perception of touch through sensory feedback to the user. The long-term research objective of this proposal is to reduce the cognitive burden on the user of an upper extremity prosthesis. The following contributions to artificial hand systems are proposed: Research Goal 1) Design, model, fabricate, and test a flexible, multimodal tactile sensor skin system for artificial fingertips using a multilayer microfluidic architecture; Research Goal 2) Establish functional relationships between finger-object interactions and tactile sensor skin data for use in autonomous grip control algorithms; and Research Goal 3) Integrate the tactile sensor skin data into grip control algorithms and evaluate effectiveness for reducing the cognitive burden on prosthesis users.

Broader Impacts: The proposed translational research could enhance the functional capabilities of artificial, robotic manipulators intended for unstructured, unsafe, or limited-access environments (prosthetic, rehabilitative, assistive, space, underwater, military, rescue, surgery). The proposed work could play a critical role in improving the quality of life for end-users of prosthetic and assistive devices. Specific benefits to end-users of prosthetic devices include: automation of complex prosthesis behaviors, rich artificial sensory feedback, and "smart socket liners" for monitoring user safety and comfort.

Contributions to elementary school, undergraduate, and graduate-level education are proposed: Education Goal 1) Develop hands-on instructional modules for teaching elementary school students about sensors using low-cost materials, and deploy them locally for the benefit of students underrepresented in science, technology, engineering, and mathematics fields; Education Goal 2) Enhance undergraduate-level course titled Sensors and Controls and graduate-level course titled "Robotics" with a sensors module; and Education Goal 3) Promote interdisciplinary undergraduate research opportunities via internships related to the development, testing, and application of sensors.

The main objective of this proposal is to acquire an I-line stepper tool for high-throughput lithography with 350 nm feature resolution bridging the gap between electron-beam lithography and contact lithography. Nano-imprint and photolithography are usually done in separate machines and this proposal is to acquire an integrated machine that can do both simultaneously resulting in superior alignment. Numerous exciting projects will benefit from the acquisition of this equipment. Contact guidance studies using nanotopography, creating nanorachets for microfluidics, nanoelectrodes for energy, plasmonics are all high quality projects that will benefit from this acquisition. Overall, the projects are interesting and potentially transformative. The projects are cohesive and will rely on the stepper tool, it is well written and well organized proposal in all aspects. The PIs have the required expertise for use of this instrument in current and future research projects. The proposed tool will have a broad impact in research and education. The combination of projects including junior faculty with senior faculty is unique and well thought of. The acquisition of this tool will benefit the academic researchers and overall users for the UW NNIN node. The outreach efforts are broad and well described including involvement of students from community colleges, high schools and underrepresented minorities. The cleanroom facilities are already funded by NNIN, hence having this tool in the facility not only will serve a larger group of researchers, but also will be maintained well. More than100 academic users and about 40 industrial users are expected to use the tool.

DESCRIPTION (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common disorders in pediatric psychiatry affecting 3-8% of school age children. Although ADHD is primarily characterized by inattention, hyperactivity and impulsivity, emotional lability is a common and impairing symptom in this population. Little is known, however, about the neurobiological substrates that underlie emotional lability in children with ADHD. Moreover, psychostimulants, the first-line treatment of ADHD, are known to reduce ADHD symptoms including emotional lability, yet the neurobiological mechanisms by which psychostimulants have their salutary effects upon emotional lability have scarcely been studied. To address this knowledge gap, we propose to conduct a longitudinal, multimodal MRI study to examine the effects of psychostimulants on the brain's affective network in children with ADHD. We will combine a multimodal MRI study with a randomized clinical trial of the psychostimulant lisdexamfetamine such that study participants will have an MRI scan prior to treatment and then a second MRI scan after 12 weeks of treatment with either lisdexamfetamine or placebo. The study will advance our knowledge of the neurobiology underlying emotional lability in children with ADHD, as well as the mechanism by which psychostimulants alleviate this symptom. Advancing this type of knowledge is critical for several reasons, but most importantly a clearer understanding of the neurobiological mechanisms by which psychostimulants are effective will promote the development of more effective and targeted treatments, as well as advance our understand of the pathophysiology of ADHD.

The Neuroimaging core will acquire and process multimodal imaging data to enhance significantly our understanding of the effects of serotonergic signaling in the brain. It will provide the extensive expertise of its faculty and staff for conducting brain imaging research in mice, newborn babies, children, and adolescents using structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), perfusion MRI, MR spectroscopy (MRS), and high density EEG. By applying validated and reliable imaging and statistical methods, the core will ensure uniformity, consistency, and economy of scale across all projects of the center. The Core will contribute significantly to accelerate our understanding of the disturbances in the brain caused by serotonin availability at various stages during early brain development. To quantify disturbances in various cortical and subcortical brain circuits, research projects will acquire and analyze multimodal MR data, and compute various brain measures, including EEG power and coherence, local volumes of brain regions, and between-region connectivity. These measures will be correlated with genotype data to discern the gene-brain-behavior correlates across species, and age ranges from infancy to adulthood. Furthermore, the core will ensure data integrity by (1) quantifying identical brain measures using the same imaging and statistical methods across all projects; (2) rigorously evaluating methods developed to address better the challenges in analyzing data from a wide age range of participants; and (3) exploiting economy of scale by applying common components of image and statistical analyses across all projects, thereby greatly enhancing the efficiency and productivity of the center.

Anorexia nervosa (AN) is a serious illness associated with substantial morbidity and a mortality rate among the highest of any psychiatric illness. Illness commonly develops in adolescence, and current treatments are disappointing, with up to 50% of patients requiring re-hospitalization within a year of discharge. Comorbidity rates are high, with up to 66% of individuals also suffering from obsessive compulsive disorder (OCD). We have previously proposed a neurobehavioral model of AN, building from known mechanisms of OCD, suggesting that corticostriatal abnormalities, including the mesocortical system (MCS), underlie the highly obsessional characteristic of AN which, in turn, mediates rigid, ritualized eating behaviors that promote the underweight state. The MCS includes the ventral striatum (VS), and the orbitofrontal cortex (OFC). In a preliminary experiment, we successfully used a novel resting state functional connectivity MRI (rs-fcMRI) approach to demonstrate an inverse relationship between functional connectivity in the MCS and obsessional symptoms in individuals with OCD. Our early data suggest this finding in AN, as well. In this proposal, we are investigating a multimodal strategy that has not previously been applied to AN. We will examine functional connectivity (via rs-fcMRI) and white matter integrity (via DTI) and explore perfusion (via ASL). By combining imaging approaches, we will integrate functional and structural connectivity. We propose to study neurocircuitry in the acute phase of AN as well as after weight restoration to begin to evaluate the prognostic significance and stability of these findings. Specifically, we will evaluate whether individuals with AN, as compared with healthy peers, have reduced functional connectivity between the ventral striatum (VS) and orbitofrontal cortex (OFC) as measured by rs-fcMRI, reduced white matter integrity, as indexed by reduced fractional anisotropy (FA), in the orbitofrontal white matter, and reduced perfusion to the VS and OFC. We will measure whether MCS connectivity is associated with degree of obsessional symptoms, using an eating disorder specific obsessive-compulsive measure. We will study connectivity longitudinally, evaluating individuals with AN before and after acute treatment. In addition, we will collect preliminary data to investigate the relationship between this potential biomarker and longer-term course. The proposed study takes an innovative approach to the study of AN by focusing on the MCS, and by implementing new neuroimaging techniques for the field. This approach has the significant advantage of evaluating the neural circuit as a whole, thereby improving inferences about neural functioning. This study will create a foundation for using these techniques in a large scale R01 that will be able to definitively identify neural biomarkers and integrate neuroimaging with clinical outcome. Thus the data from this study will provide a new foundation for a program of research in AN that investigates neural models as the basis for understanding and treating this devastating illness.

Disadvantage can ensnare families for generations. Existing studies have identified the effects of childhood adversity on neurodevelopment in decrements in cognitive and social outcomes. This timeframe, however, may be too constricted, assiduously focusing on intra-generational effects, while ignoring inter-generational determinants. Considering a child's own adverse exposures, without noting experiences of adversity in that child's parents, may obscure intergenerational effects. Within an established, well-characterized, inter- generational and disadvantaged cohort, we aim to determine key factors influencing the cycle of disadvantage in which so many families get caught for generations. Our outcome of focus is neurodevelopment as indexed by executive functions (EF) and MRI measures of related neural substrates. EF dysfunctions are key determinants of subsequent social and occupational challenges. We also examine protective factors that may contribute to breaking this cycle of disadvantage and yield favorable neurodevelopmental outcomes. We would bring to the ECHO consortium a multi-generation, population?based sample of 2,491 Puerto Ricans living in the South Bronx, NY and San Juan, PR. The first generation of the cohort (G1) was assessed prospectively at 3 times points in childhood/early adolescence (ages 5-13) and once in late adolescence/early adulthood (ongoing). When ECHO is launched, G1 will be in early adulthood, and just beginning to have their own children (Generation 2 or G2 Probands). Our cohort is thus optimally poised to examine the effects of adversity during early childhood using a prospective design. We will assess G2 Probands including all new births during the study period (Prenatal/Birth Cohort, n~650) and all G2 Proband children born prior to the start of ECHO (Child Cohort, ages 3-10, n~830). We will use neuroimaging and behavioral assessments to characterize the influence of many forms of adverse exposures (e.g., physical abuse, neglect, parental mental illness). We will examine how one generation's experience of adversities may affect the development of the next, and how different sources of exposure, those experienced by one's parents as well as those a child faces on his or her own, impact neurodevelopmental outcomes. Our multidisciplinary team brings expertise in the epidemiology of disadvantaged populations (MPIs Duarte & Canino), fetal origins of health and disease (MPI Monk), and developmental neuroscience (MPI Posner). In addition to our specific aims, our study will enrich the ECHO consortium by providing biospecimens including DNA, placenta, cord blood, and deciduous teeth. These specimens will allow the ECHO consortium to investigate the influence of genetic and epigenetic factors as well as chemical exposures during early development within a high-risk, but understudied, population. In sum, our investigative team, the uniqueness of our cohort, and the novelty of our focus on intergenerational influences offer distinct contributions to the ECHO project both in terms of the specific aims of our proposal and to the larger goals of the ECHO consortium.

Project Summary This is a 4-year renewal for a multi-generation, 30-year longitudinal study of families at high- and low-risk for Major Depressive Disorder (MDD). The project has yielded important findings on the familial transmission of mood disorders and has contributed to the field's understanding of the long-term temporal sequences of disorders from childhood to adulthood, as well as the neurobiological correlates of these processes. However, despite these advances, the mechanisms through which familial risk leads to offspring impairment remains underdeveloped. NIMH's Research Domain Criteria (RDoC) offers a compelling model for testing potential mechanisms, by proposing functional systems (?constructs?) that combine neurobiological and behavioral information. This renewal therefore aims to prospectively test whether RDoC constructs are mechanisms (i.e., mediators) through which family history leads to adult functional outcomes and symptom trajectories. Leveraging a rich, 30-year, 3-generation longitudinal dataset, we will integrate data from multiple units of analysis (multiple MRI modalities, electrophysiology, behavior, and self-report) to define latent variables corresponding to 3 latent RDoC constructs: Acute Threat, Approach Motivation, and Response Inhibition. First, we will quantify the test-retest reliability of our RDoC indicators (MRI, physiology, behavior, etc.) by re-assessing each of these indicators in a representative subsample of participants (Aim 1). This is an important first step as it will afford robust modeling of the latent RDoC constructs and bolster the premise that the RDoC constructs are trait-like (i.e., stable) mechanisms of familial transmission. Second, we will use structural equation modeling to create the 3 RDoC constructs from these indicators and their reliability estimates. We will then prospectively examine whether the 3 latent RDoC constructs instantiate mechanisms by which family history of MDD leads to negative outcomes in adulthood (Aim 2). Third, we will leverage our multigenerational dataset to examine the inter-generational transmission of the RDoC constructs. We will test the incremental validity of the RDoC constructs over DSM defined psychopathology by examining whether their familial transmission is independent of the familial transmission of MDD (Aim 3). In sum, this renewal application advances this multi-generation study toward a focus on mechanisms of risk ? a critical step to developing novel interventions to prevent negative adulthood outcomes associated with familial depression. In addition to our Specific Aims, this renewal will also afford the opportunity to furnish the data from this unique study (i.e., many thousands of clinical and neurobiological data points collected from families from 1982? present) onto the NIH RDoC repository, making this 30-year longitudinal dataset available to the entire scientific community.

Project Summary Anorexia nervosa (AN) is a serious mental illness that confers the highest mortality rate of any psychiatric disorder. Current treatments are inadequate and no pharmacologic agents have proven effective. A better understanding of the development and pathophysiology of AN is greatly needed. We propose a longitudinal, multimodal MRI study of reward and habit circuits in youth (ages 14-18) with AN, compared with age-matched healthy controls (HC), followed over two years. We focus on adolescence because this is a critical, yet understudied, period in AN. Pathological dieting typically emerges during adolescence, and the course of AN is often determined during this period with approximately half of teens showing full recovery, whereas the rest endure persistent illness. Understanding the neurobiological mechanisms by which some teens develop persistent AN, while others remit, is critical to developing the most effective interventions. Our study will examine neural mechanisms guiding food choice and neural connectivity in mesolimbic and habit-related circuits among youth with AN who continue with illness compared with those who remit, and compared with HC. We will examine these neural circuits at baseline and study their developmental trajectories. Our Food Choice Task captures restrictive intake, a core behavioral disturbance in AN, and therefore we can directly examine the link between brain activity and eating behavior. Using longitudinal, multimodal MRI at 3- time points, we will first test whether the function and connectivity of mesolimbic reward and dorsal habit circuits predict the longer-term course of AN. Second, we will examine longitudinal changes within these two neural circuits of interest. We predict that at baseline, restrictive food choice in youth with AN will be mediated by mesolimbic reward circuitry; however, at year-2 follow-up, in teens for whom the disorder persists, restrictive food choice will be mediated by dorsal striatal habit circuitry. The study will (i) chart the developmental trajectories of reward and habit circuits in youth with AN; (ii) advance our understanding of the mechanisms by which AN persists to chronicity, and (iii) help develop targets for novel therapeutic strategies.

PROJECT SUMMARY This new R01 aims to study the effects of selective serotonin reuptake inhibitor (SSRI) antidepressant medication use by women in pregnancy on their offspring?s brain and cognitive development in the first two years of life. Fetal exposure to antidepressants is a critical public health question because prescriptions of SSRIs to pregnant women have increased 4-8-fold over the last 30 years, yet their impact on fetal neurodevelopment remains unknown. Although considered safe and effective for the mother, SSRIs readily cross the placenta and into the fetal brain, potentially altering the important neurotropic role of 5-HT during the fetal period. Whether this fetal exposure translates to long-term effects on the offspring remain unclear. The choices facing physicians and pregnant women are similarly unclear, as discontinuing SSRI and leaving maternal depression untreated can have deleterious consequences for both mother and child. To address these questions more definitively, we have partnered with the University of Sherbrooke (Quebec, Canada) to develop a new birth cohort and test the effects of SSRI and maternal depression exposures on offspring neurodevelopment. We will enroll pregnant women with (n=250) and without (n=125) a depressive disorder in their first trimester, and assess the course of their depressive symptoms and medication usage over the remaining pregnancy. By conclusion of pregnancy, we will know whether the infant was exposed to SSRIs; the quantity (dose) and timing (trimester) of that exposure; and the length and severity of maternal depression during the concurrent period. We will perform an MRI scan and EEG assessment when the infant is 1 month old, and then longitudinally follow the offspring with repeated EEG, as well as behavioral measures of emotion regulation through the first two years of life to test whether any abnormalities in brain structure or connectivity identified at 1 month have developmental consequences. We will also examine the influence of the post-natal family environment, monitoring parental (maternal and paternal) depression symptoms monthly, and conducting two in-home assessments of family. These detailed longitudinal assessments will allow our study to more definitively separate effects of medication from depression exposure, and to characterize the influence of the family environment on gestational SSRI effects. If funded, we will form the largest cohort testing brain and behavioral outcomes of fetal antidepressant exposure to date. Findings will be clinically informative regardless of their direction. If we find significant brain or behavioral problems in offspring who were fetal exposed to antidepressants, women can be directed to other medication and non-medication treatments for depression that may be safer for mother and child. And if we find no adverse effects, then this will provide reassurance for the safe use of SSRIs, and potentially increase compliance as well.

PROJECT SUMMARY Adverse childhood experiences (ACEs) - which includes physical/sexual abuse, neglect or parental mental illness - confer risk for psychiatric dysfunction not only to those directly exposed, but also to the next generation. However, mechanisms underlying these ACE-related intergenerational effects are unclear, significantly limiting a unique prevention opportunity. Our study aims to examine mechanisms by which maternal ACEs influence offspring neurodevelopment, with special focus on prenatal inflammation. Toward this end, we will enroll, in the Brazilian Universal Health Care system (SUS), pregnant women with (n=290) and without (n=290) a history of substantial ACEs and follow their offspring over the first two years of life focused on the neurodevelopment of cognitive control, a cornerstone in the future development of impulsive behaviors. First, we will start by testing associations between maternal ACEs and offspring brain-behavior development using infant MRI and behavioral assessments of cognitive control. Second, we will examine mechanisms underlying these associations, focusing on the role of prenatal inflammation and the placenta using techniques to examine DNA epigenetics and RNA sequencing, while also taking into account genetic influences. As suggested by preclinical research, we hypothesize differential effects of prenatal inflammation in male vs. female pregnancies. In addition, we will explore modifiable post-natal factors and their influence on offspring neurodevelopment, monitoring parental depressive/mood symptoms and conducting two in-home assessments of the family. Revealing mechanisms of intergenerational transmission of adversity, our study will set the stage for high-impact preventive research. We will establish research infrastructure within a São Paulo primary care clinic network in a high-risk, low-resource community where preventive effects can have their most substantial impact. This R01 proposal is designed to be highly responsive to the NIH-FAPESP Funding Initiative (NOT-TW-16-001), which aims to support collaborative international research between investigators in the US and a stellar research group in the State of São Paulo, Brazil.

Disadvantage can ensnare families for generations. Existing studies have identified the effects of childhood adversity on neurodevelopment in decrements in cognitive and social outcomes. This timeframe, however, may be too constricted, assiduously focusing on intra-generational effects, while ignoring inter-generational determinants. Considering a child's own adverse exposures, without noting experiences of adversity in that child's parents, may obscure intergenerational effects. Within an established, well-characterized, inter- generational and disadvantaged cohort, we aim to determine key factors influencing the cycle of disadvantage in which so many families get caught for generations. Our outcome of focus is neurodevelopment as indexed by executive functions (EF) and MRI measures of related neural substrates. EF dysfunctions are key determinants of subsequent social and occupational challenges. We also examine protective factors that may contribute to breaking this cycle of disadvantage and yield favorable neurodevelopmental outcomes. We would bring to the ECHO consortium a multi-generation, population?based sample of 2,491 Puerto Ricans living in the South Bronx, NY and San Juan, PR. The first generation of the cohort (G1) was assessed prospectively at 3 times points in childhood/early adolescence (ages 5-13) and once in late adolescence/early adulthood (ongoing). When ECHO is launched, G1 will be in early adulthood, and just beginning to have their own children (Generation 2 or G2 Probands). Our cohort is thus optimally poised to examine the effects of adversity during early childhood using a prospective design. We will assess G2 Probands including all new births during the study period (Prenatal/Birth Cohort, n~440) and all G2 Proband children born prior to the start of ECHO (Child Cohort, ages 3-10, n~870). We will use neuroimaging and behavioral assessments to characterize the influence of many forms of adverse exposures (e.g., physical abuse, neglect, parental mental illness). We will examine how one generation's experience of adversities may affect the development of the next, and how different sources of exposure, those experienced by one's parents as well as those a child faces on his or her own, impact neurodevelopmental outcomes. Our multidisciplinary team brings expertise in the epidemiology of disadvantaged populations (MPIs Duarte & Canino), fetal origins of health and disease (MPI Monk), and developmental neuroscience (MPI Posner). In addition to our specific aims, our study will enrich the ECHO consortium by providing biospecimens including DNA, placenta, cord blood, and deciduous teeth. These specimens will allow the ECHO consortium to investigate the influence of genetic and epigenetic factors as well as chemical exposures during early development within a high-risk, but understudied, population. In sum, our investigative team, the uniqueness of our cohort, and the novelty of our focus on intergenerational influences offer distinct contributions to the ECHO project both in terms of the specific aims of our proposal and to the larger goals of the ECHO consortium.