Deanna M. Barch - US grants

DESCRIPTION: (adapted from the applicant's abstract): Diverse evidence suggests that deficits in working memory and long-term memory in patients with schizophrenia reflect deficits in at least two putatively distinct cognitive domains. Furthermore, deficits in working memory have typically been linked to an underlying disturbance in prefrontal cortex function, while deficits in long-term memory (i.e., encoding and/or retrieval) have typically been associated with medial temporal/hippocampal deficits. The investigator proposes to test an alternative hypothesis that deficits in both working memory and long-term memory in patients with schizophrenia reflect a single underlying disturbance in prefrontal cortex function. This hypothesis would be tested by a neuroactivation analysis of cognitive tasks using functional magnetic resonance imaging (fMRI) techniques and an event-related neuroimaging design. The investigator proposes to define the distributed patterns of cortical function and dysfunction associated with the performance of both working memory and long-term memory tasks during the same imaging session and the same patients with schizophrenia and in matched normal comparison subjects. This design is novel in that it represents the first functional neuroimaging study in schizophrenia attempting to simultaneously assess multiple cognitive domains and thus could impact strongly the current understanding of the precise nature and mechanisms underlying cognitive impairments associated with schizophrenia. A related specific aim of the proposal would compare the task-related lateralized brain activation for working memory and long-term memory tasks using verbal versus non-verbal (non-nameable faces) stimuli in patients with schizophrenia and healthy comparison subjects. Cognitive impairments are increasingly recognized as core features of schizophrenia. Demonstrating that deficits in both working memory and long-term memory in schizophrenia stem from a single underlying disturbance in prefrontal cortex function would both simplify and clarify the conceptualization of cognitive dysfunction in schizophrenia. These studies could also provide the groundwork for the development of powerful new behavioral, as well as neuroimaging, probes of cognitive and neurobiological function in schizophrenia.

DESCRIPTION: (adapted from the applicant's abstract): Diverse evidence suggests that deficits in working memory and long-term memory in patients with schizophrenia reflect deficits in at least two putatively distinct cognitive domains. Furthermore, deficits in working memory have typically been linked to an underlying disturbance in prefrontal cortex function, while deficits in long-term memory (i.e., encoding and/or retrieval) have typically been associated with medial temporal/hippocampal deficits. The investigator proposes to test an alternative hypothesis that deficits in both working memory and long-term memory in patients with schizophrenia reflect a single underlying disturbance in prefrontal cortex function. This hypothesis would be tested by a neuroactivation analysis of cognitive tasks using functional magnetic resonance imaging (fMRI) techniques and an event-related neuroimaging design. The investigator proposes to define the distributed patterns of cortical function and dysfunction associated with the performance of both working memory and long-term memory tasks during the same imaging session and the same patients with schizophrenia and in matched normal comparison subjects. This design is novel in that it represents the first functional neuroimaging study in schizophrenia attempting to simultaneously assess multiple cognitive domains and thus could impact strongly the current understanding of the precise nature and mechanisms underlying cognitive impairments associated with schizophrenia. A related specific aim of the proposal would compare the task-related lateralized brain activation for working memory and long-term memory tasks using verbal versus non-verbal (non-nameable faces) stimuli in patients with schizophrenia and healthy comparison subjects. Cognitive impairments are increasingly recognized as core features of schizophrenia. Demonstrating that deficits in both working memory and long-term memory in schizophrenia stem from a single underlying disturbance in prefrontal cortex function would both simplify and clarify the conceptualization of cognitive dysfunction in schizophrenia. These studies could also provide the groundwork for the development of powerful new behavioral, as well as neuroimaging, probes of cognitive and neurobiological function in schizophrenia.

This proposal is designed to examine the relationships between structural brain abnormalities and both functional activation and cognitive deficits in individuals with schizophrenia and those at risk for this illness (siblings who are not yet affected). Anatomical abnormalities in regions such as the temporal cortex/hippocampus, the anterior cingulate (ACC), the prefrontal cortex (PFC), and the thalamus are a critical biological characteristic of schizophrenia. Many investigators have hypothesized that these structural abnormalities form the anatomical substrates of cognitive deficits in schizophrenia. Further, a growing functional imaging literature demonstrates that patients with schizophrenia exhibit activation disturbances in many of these same cortical regions during tasks that tap a range of cognitive processes, including working memory and long term memory encoding and recall. However, relatively little empirical evidence exists regarding the functional significance of brain structural abnormalities in schizophrenia. Thus, the goal of this project is to more clearly identify the relationship between particular brain structural characteristics and central functional activation and cognitive deficits in individuals with schizophrenia and those at risk for schizophrenia. To accomplish this goal, we will combine our cognitive challenge functional magnetic resonance imaging methods with state of the art structural imaging and high-dimensional brain mapping algorithms. This will allow us to test the hypotheses that in schizophrenia: 1) deficits in both working memory and long term memory arise from a disturbance in a set of functionally and structurally interconnected brain regions that normally work together to support a range of cognitive processes; 2) structural disturbances in these regions are related to disturbances in the ability to functionally activate these areas during cognitive challenge; 2) deficits in these brain structures arise as a result of a neurodevelopmental process, and are thus present in individuals genetically at risk for schizophrenia. Success in this work would represent a significant advance in both our theoretical and empirical efforts, and could provide the groundwork for the development of powerful probes for detecting bio-behavioral and genetic risk markers for the development of schizophrenia.

DESCRIPTION (provided by applicant): Schizophrenia is an illness with major public health consequences that is characterized by disturbances in emotion and cognition that often severely impair life function. Despite the central role of emotional disturbances in the phenomenology of schizophrenia, relatively little empirical work has been devoted to the study of emotion or emotion-cognition interactions in this illness. The goal of this project is to begin to elucidate the psychological and neurobiological bases of disturbances in emotional processing and emotion cognition interactions in this debilitating disorder. Building upon our previous work on cognitive deficits in schizophrenia, this proposal will test the following hypotheses: 1) at least a subset of emotional disturbances in schizophrenia, as well as abnormal emotion-cognition interactions, reflect an inability to contextually modulate emotional processing; and 2) difficulties modulating emotional processing in schizophrenia reflect disturbances in the function of dorsolateral prefrontal cortex and hippocampus and their connectivity with other brain regions involved in emotional processing (i.e., amygdala, anterior cingulate, orbital-medial prefrontal cortex). To test these hypotheses we will use state-of-the-art functional neuroimaging, behavioral, and psychophysiological techniques to study a large cohort of individuals with schizophrenia and demographically matched controls. The Specific Aims of this proposal will test hypotheses regarding: 1) conditions in which individuals with schizophrenia should demonstrate intact emotional processing (as indexed by self-report, autonomic responses and brain activity); 2) conditions in which individuals with schizophrenia should demonstrate reduced emotional processing; 3) conditions in which individuals with schizophrenia should demonstrate enhanced emotional processing and disturbed emotion-cognition interactions; and 4) which specific symptoms will and will not be associated with disturbed emotional processing in schizophrenia. The results of these studies have the potential to vastly advance our understanding of emotional processing in schizophrenia and its influence on cognition. Such deficits are core aspects of schizophrenia that lead to functional disability, and thus a better understanding of their nature and causes is central to our attempts to better prevent and treat this illness.

[unreadable] DESCRIPTION (provided by applicant): Abnormalities of brain structure and function are one of the key neurobiologic characteristics of schizophrenia. In schizophrenia subjects, losses of tissue volume, changes in neuronal density, and deficits of functional activation are present within a circuit of neural structures. The central scientific goals of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) are to more precisely define the anatomical pattern of these abnormalities in brain structure and function, to investigate their possible causes (i.e., genetic and/or environmental) and pathogenesis, and to establish functional links between these structural abnormalities and abnormalities of cognitive function (e.g., working and episodic memory) that may underlie psychopathology and disability. Our overarching hypothesis is that genetic liability for schizophrenia may be expressed in part by variation in neuroanatomical structure and function within a network of specific brain regions and that these same structures may be impacted by environmental insult during early development, ultimately leading to the cognitive and clinical abnormalities that currently define the disease. The proposed CCNMD will 1) carry out an integrated investigation of brain structure and function in schizophrenia subjects, their non-psychotic siblings, healthy controls and their siblings.2) Study the developmental progression of changes in brain structure in a macaque model of fetal environmental insult. and 3) elucidate the specific cellular elements of the neural circuit underlying working memory again using macaques. Finally, we will use recombinant, inbred strains of mice to identify genes that influence these neuroanatomical and behavioral phenotypes. Several themes are carried across the individual Projects proposed for the Center. Taken together with shared technologies and resources, the overarching hypothesis and these themes represent a strong rationale for the funding of this research as a Center, rather than a series of R01 projects. [unreadable]

DESCRIPTION (provided by applicant): Over the past decade there has been a growing awareness of the disabling effects of impaired cognition in individuals with schizophrenia. Along with this new awareness has come an increasing emphasis on the importance of developing new treatments that may positively impact these cognitive deficits. During this same period, the cognitive neuroscience field has seen an explosion of technical advances and new knowledge regarding the neural basis of cognition. Sadly, the translation and application of this cutting edge knowledge and paradigm development to new drug development in schizophrenia has lagged significantly behind overall progress in cognitive neuroscience, in large part due to the lack of data on the measurement properties of tasks used in cognitive neuroscience. This concern spawned the Cognitive Neuroscience Research To Improve Cognition in Schizophrenia (CNTRICS) initiative, which conducted a series of conferences designed to develop consensus on the constructs and paradigms from cognitive neuroscience that are ripe for translation, and the validation and psychometric goals when translating such tasks for use in clinical trials contexts. The current application is a logical and needed extension of the CNTRICS initiative that will begin the translation process for paradigms designed to assess four of the constructs identified as being ripe for translation in the first CNTRICS meeting. We have brought together a collaborative "translation" team that represents significant expertise from the many fields necessary for the success of this endeavor, including both basic and clinical cognitive neuroscientists, psychometricians, and clinical trials specialists. We have chosen to focus on four constructs that span both early (gain control and visual integration in perception) and higher-level (goal maintenance, relational encoding and retrieval) components of human cognitive processing. By examining multiple mechanisms, we will be able to establish the generality of the translational approach we propose across different levels and types of cognitive mechanisms. Specific Aim 1 is to validate (in both individuals with schizophrenia and comparison participants) optimized versions of the paradigms that assess our four constructs of interest, as well as to examine the relationship of task performance to clinical and functional outcomes in schizophrenia. By optimization, we mean examining modifications on already validated paradigms that are designed to: 1) minimize task length;2) simplify task administration across multiple sites;3) maximize sensitivity and selectivity in assessing the specific cognitive mechanisms of interest;and 4) enhance reliability and minimize floor and ceiling effects. By validation, we mean ensuring that such optimizations designed to enhance the psychometric properties of the task do not alter its construct validity. Specific Aim 2 will be to assess and optimize test-retest reliability and practice effects for the task versions validated in Specific Aim 1. PROJECT NARRATIVE This project has high relevance for public health by significantly improving our ability to translate paradigms developed into the basic cognitive neuroscience literature for use in clinical trials aimed at improving cognition in schizophrenia. Cognitive deficits in schizophrenia are a major predictor of functional outcome in this debilitating illness. Thus, we need to improve our methods for detecting and enhancing cognitive function in schizophrenia in order to help individuals with this illness lead more productive and fulfilling lives.

? DESCRIPTION (provided by applicant): Despite advances in the understanding of alterations in brain and behavior in adult affective psychopathology, and the more recent conceptualization of these illnesses as neurodevelopmental in origin, there is a dearth of early developmental data to inform this trajectory. The current proposal aims to fill this gap using data from a unique 13 year prospective longitudinal study, which started in the preschool period and contains three waves of functional and structural scan data: the Preschool Depression Study [PDS]. The proposed extension of this PDS study will focus on three constructs/RDoC domains encompassing specific aspects of emotion reactivity and regulation thought to be central to the development of affective psychopathology: 1) Negative Emotion Reactivity (NER), 2) Reward Reactivity (RR), and 3) Cognitive Emotion Re-appraisal (CER). Data from this sample has already shown that children who were depressed as preschoolers show similar alterations in brain structure and function relevant to the three constructs of interest as established in depressed adults. Brain markers of later recurrence, over and above behavioral symptoms have also been identified. Importantly, both hormonal and psychosocial factors influenced behavior and brain structure/function in the data to date. Follow-up of this unique sample with two additional waves of imaging and comprehensive assessment of these constructs, including measures of hormones, as they pass through adolescence represents an unprecedented, but time limited, opportunity to investigate early developmental antecedents and predictors of adolescent affective psychopathology. The proposed study will directly target the constructs of interest using parent and child report, direct behavioral assessments, and reward and emotion reappraisal tasks during fMRI scanning, as well as structural imaging and resting state functional connectivity, using tools developed in the Human Connectome Project. Using latent growth curve modeling approaches, we will test the hypotheses that specific patterns of individual differences in trajectories of the neural circuitry supporting NER (e.g., insula, hippocampus, amygdala), CER (e.g., dorsolateral prefrontal cortex and dorsal anterior cingulate and RR (e.g., striatum, insula) measured during preschool, school age and/or early adolescence predict: (1a) measures of the same constructs in mid to late adolescence; and (1b) risk for reoccurrence or new onset of affective psychopathology in adolescence, over key phenomenological and psychosocial variables assessed from preschool to school age. We will also test the hypothesis that pubertal timing and hormonal factors interact with both adaptive and impaired forms of NER, RR and CER to contribute to the emergence of sex differences in affective psychopathology during the high-risk phase of adolescence. This work will allow an investigation of the role of early childhood emotion and brain function in the course and trajectory of adolescent affective psychopathology, identification of potential markers of risk and pathways for early intervention, as well as potential mechanisms driving sex differences that emerge at this period.

DESCRIPTION (provided by applicant): This is a competitive renewal of an R01 project titled Schizophrenia, Prefrontal Cortex, and Emotion Regulation. In our current funding cycle, we tested the hypothesis that at least a subset of emotional disturbances in schizophrenia reflect deficits in the ability to use goals and context information maintained in dorsolateral prefrontal cortex (DLPFC) to and modulate emotional processing. Consistent with this hypothesis, the work conducted under the current funding cycle demonstrated that individuals with schizophrenia show: 1) relatively intact self-reports of valence and arousal in response to a range of affect producing stimuli; 2) relatively intact activity in frontal and limbic regions in response to emotionally evocative stimuli when emotional regulation is not required; and 3) altered DLPFC and anterior cingulate activity when required to use goals and/or context information to modulate the influence of affective stimuli on cognitive processing. Importantly, our data also suggest that individuals with schizophrenia have deficits in the ability to use affective information to regulate or facilitate goal directed behavior. Specifically, individuals with schizophrenia seem to have difficulties using internal representations of emotional experiences, previous rewards, and motivational goals to drive current and future behavior that should allow them to obtain desired outcomes. Such deficits have major implications for understanding functional outcome in schizophrenia, as many individuals with this illness seem unable to engage in goal directed behavior (e.g., social, occupational, and educational pursuits) that would bring them into contact with potentially enjoyable experiences and positive outcomes, despite an apparently intact ability to enjoy those experiences once achieved. Clinically, such disturbances manifest as abnormalities in motivation, social engagement, and even anhedonia, or the self-reported inability to experience pleasure (or at least to anticipate experiencing pleasure). We hypothesize that individuals with schizophrenia have impairments in the ability to use reward information to guide behavior because they cannot translate such information into action plans, due to deficits in DLPFC function. However, we need to determine whether such a deficit in reward translation is primary, or simply secondary to deficits in other parts of the system that identify, maintain, and update information about rewards. For example, there is mixed evidence as to whether individuals with schizophrenia can learn cues that predict reward, or compute and update value/utility representations that drive action plans. The goal of the current study is to use state-of-the art functional neuroimaging and behavioral paradigms derived from the affective science literature to examine the integrity of the components of the neural systems linking rewards and actions. We feel it is critical to examine the function of the different components of the system in the same study in the same individuals so that we can address issues related to heterogeneity in symptom expression that may be leading to conflicting results across different studies in the literature. For each of the Specific Aims, we ask: 1) do individuals with schizophrenia differ from either community controls; and 2) do the non-psychotic siblings of individuals with schizophrenia also show deficits compared to controls (as a way to study processes associated with liability for schizophrenia unconfounded by medication status).

Functional magnetic resonance imaging (fMRI) has become the most common tool for cognitive neuroscience, because it provides a safe, non-invasive, and powerful means to image human brain function. Based on recent rates of publication, there are currently more than 2000 fMRI studies being performed every year worldwide. The aggregation of data across multiple studies can provide the ability to answer questions that cannot be answered based on a single study. For example, using datasets from multiple domains one can start to investigate to what degree a region is selectively engaged in relation to a particular mental process, as opposed to being generally engaged across a broad range of tasks and processes. In addition, it provides the ability to integrate across specific tasks to obtain stronger empirical generalizations about mind-brain relationships, and to better understand the nature of individual variability across different measures. Recent work in neuroimaging analysis has focused on the application of methods such as machine learning techniques to understand the coding of information at the macroscopic level, and network analysis techniques to understand the interactions inherent in large-scale neural systems. The availability of a large testbed of high-quality fMRI data from published studies would also provide an important resource for the development of these and other new analytic techniques for fMRI data. However, sharing of raw fMRI data is challenging due to the large size of the datasets and the complexity of the associated metadata, and there is currently no infrastructure for the open sharing of new fMRI datasets.

This project, OpenfMRI, will provide a new infrastructure for the broad dissemination of raw data within cognitive neuroscience, addressing a critical need by providing an open data sharing resource for neuroimaging. The initial project is already online at http://www.openfmri.org with a limited number of datasets. The full project will greatly expand this repository by providing access to a large number of fMRI datasets from several prominent neuroimaging labs, spanning across a broad range of cognitive domains. Utilizing the substantial computational resources of the Texas Advanced Computing Center, the project will also perform standard fMRI analyses on all data in the repository using a common analysis pipeline, thus providing directly comparable analysis results for all of the studies in the database. The OpenfMRI project will support the development of infrastructural elements to make sharing of data by additional investigators more straightforward.

The repository of data that will be created by the OpenfMRI project will also serve as an important resource for teaching by providing students with the ability to replicate the analyses from published studies using the same data. By providing any researcher in the world with the ability to acquire large fMRI datasets, it will also provide all researchers with the ability to work with the same state-of-the-art datasets, regardless of institution. By creating the infrastructure for open sharing of research data, the project will also enhance the impact of other NSF-funded neuroimaging research projects by providing an infrastructure that can be used to make their data available. The planned work has the potential to benefit society by improving education, health, and human productivity through an increased understanding of mental function and its relationship to brain function.

DESCRIPTION (provided by applicant): The goal of our training program is to develop basic behavioral scientists with rigorous broad- based training in two biomedical sciences - neuroscience and genetics. To do this we developed a training program that focuses on the interface of psychology, neuroscience, and genetics. Trainees have been pre-doctoral students - 6 per year - with a strong interest in understanding human behavior from a biomedical perspective. The training program includes fairly equal participation from faculty in Washington University's Psychology, Neuroscience, and Genetics programs. The training program provides students with systematic exposure to the behavioral perspectives from psychology, integrated with biomedical perspectives from systems and computational neuroscience along with behavioral, molecular, statistical genetics, and genomics. The goal is to train young scientists who are able to apply concepts and methods from basic biomedical sciences to the study of behavioral phenomenon, such as memory, attention, decision making, and other cognitive functions, behavioral disorders, schizophrenia, alcoholism, aging, and problems with emotion regulation, and basic social phenomenon such as personality, attitudes, and social cognition. This training program provides benefits to trainees who are interested in research crossing traditional academic boundaries between psychology and two of the most important and exciting biomedical sciences - neuroscience and genetics. Educational opportunities of this kind are rare, and the unique nature of this training program makes our graduates attractive candidates for top post-doctoral or faculty positions in bio-behavioral programs at other universities. There are also benefits to the fields of neuroscience and genetics research, in which new lines of behavioral investigation are being opened (e.g., the Human Connectome Project, a large part of which is based at Washington University). Finally, through the process of recruiting and training students in research at the interface of psychology, neuroscience, and genetics, the core faculty members of the training program also benefit because the program fosters collaborative research endeavors among the very diverse set of Washington University faculty participating in the training program. This competing renewal application requests support for another 5-year period of training, to continue pre-doctoral support at six trainees per year.

Developmental neuroscience and psychopathology is a rapidly growing domain with established success and great potential to inform the understanding of the causal pathways and mechanisms of mental illness. This T32, which is focused on this domain, is co-led by Drs. Luby and Barch (with complimentary expertise in developmental psychopathology and neuroscience), and has been very successful in the first cycle of funding, enjoying a highly competitive national applicant pool and successfully launching all of the young scientists who have completed the program thus far. We seek to renew and expand this training grant, adding new expertise in a wider range of neuroimaging measures, as well as new faculty mentors with expertise in the neural effects of the gut microbiome. From a public health perspective, an infusion of new research scientists in the area of developmental neuroscience and psychopathology is a high priority. The proposed multi-disciplinary training approach is guided by a conceptual model that examines emotional, cognitive, behavioral, neurobiological and genetic and environmental aspects of psychopathology from a developmental perspective. Further, this training program is guided by a perspective that recognizes that the risk, onset, and course of psychiatric disorders arises through a complex interplay of brain developmental processes influenced by psychosocial, genetic, and biological (including gut microbial) factors that interact beginning in utero and continue throughout development. Numerous investigators at Washington University in St. Louis (WUSTL) have a rich track record of experience in many aspects of child neuroimaging and related methods, including a focus on structural and functional magnetic resonance approaches in very early childhood, evoked response potentials (ERP) and high density diffuse optical tomography (HD-DOT). Further, WUSTL has an international reputation in psychiatric genetics and gut microbiome work, with many investigators who can bring both behavioral and molecular genetic approaches to bear on understanding the neurobiology of developmental psychopathology. The program mentors have a rich body of available databases derived from longitudinal studies, several of which began in early childhood and in utero. The program mentors provide a unique multidisciplinary training environment in which to pursue this exciting domain focused on childhood, given the established collaborations between child researchers in the WUSTL School of Medicine clinical and basic departments, and the state of the program in neuroscience and neuroimaging at WUSTL that has been at the forefront of developmental cognitive and affective neuroscience. Further, interactions between researchers in basic and clinical developmental neuroscience offer an ongoing opportunity to help train the next generation of young scientists who can pursue questions about the developmental etiology of psychopathology from the perspective of core psychological and neural mechanisms of human behavior that can inform and span traditional boundaries of psychopathology, an approach central to the NIMH Research Domain Criteria Initiative (RDOC).

DESCRIPTION (provided by applicant): Clinical neuroscience is on the verge of a revolution. Traditional conceptualizations of disorders based on phenomenology are increasingly recognized as limited, but we have lacked a clear path toward a more valid approach. The Research Domain Criteria (RDoC) initiative has identified one such pathway; the examination of components of behavior linked to known neural systems that form the basis of core dimensions of psychopathology. This competing renewal will provide new insights into the cognitive and emotional processes underlying core symptom dimensions in major mental illness and provide a new set of valid and reliable tools to facilitate the aims of RDoC and Objective 1.4 of the NIMH Strategic Plan: Develop new ways of classifying disorders based on dimensions of observable behaviors and brain functions. This application will utilize the CNTRaC's infrastructure and expertise to optimize measures of WM capacity, positive and negative reinforcement learning (both implicit and explicit) and reversal learning, and then apply them together with previously validated measures. Specific Aim 1 is to validate (in individuals with schizophrenia, schizoaffective disorder and bipolar disorder, as well as comparison participants) optimized versions of the paradigms that assess our six constructs of interest, as well as to examine the relationship of task performance to clinical and functional outcomes in psychosis. Specific Aim 2 will be to assess and optimize test-retest reliability and practice effects for the task versions validated in Specific Aim 1. Specific Aim 3 will be to use these optimized measures of working memory capacity and reinforcement learning, along with our previously optimized measures of WM goal maintenance, relational encoding and retrieval, and visual integration to examine the relationship between performance on these measures of core constructs and dimensions of psychopathology across diagnoses (including medicated and un-medicated individuals with schizophrenia and schizoaffective disorders, as well as individuals with bipolar disorder). We hypothesize that impairments in the dorsal frontal- parietal and frontal-temporal systems supporting WM (capacity and goal maintenance) and relational encoding/retrieval contribute to disorganization symptoms and functional impairment and that these impairments and relationships cut across affective and non-affective disorder boundaries, forming a core dimension that helps explain the overlap in function and neurobiology across disorders. We also hypothesize that impairments in orbital frontal-striatal systems supporting reinforcement and reversal learning contribute to the negative symptoms of anhedonia/amotivation, which also cut across diagnostic boundaries. However, we hypothesize that anhedonia/amotivation may involve different aspects of reward processing and circuitry in primary mood versus non-mood disorders with our selection of measures motivated to test this hypothesis. We hypothesize that impaired visual integration, which is thought to reflect reduced horizontal and recurrent feedback, will be related to disorganized symptoms across disorders, but will not relate to mood pathology.

? DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the Twin Hub of the ABCD-USA Consortium is in response to RFA-DA-15-015; the proposal includes the University of Minnesota (hub leader), Virginia Commonwealth University, Washington University, and the University of Colorado to prospectively determine neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 800 twin pairs, ages 9-10 years, from four sites whose researchers are leaders in twin research, SU and abuse, and neuroimaging of cognitive and emotional functioning will be tested, together with 700 singletons, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. Participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) effects of substance use patterns on the adolescent brain; 2) effects of substance use on behavioral and health outcomes; 3) bidirectional relationships between psychopathology and substance use patterns; 4) effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) gateway interactions between use of different substances. The Twin Hub proposes to use classic and co-twin control designs to study genetic vs. environmental contributions to adolescent brain/behavioral development and how these contributions predict SU propensity. Using sophisticated growth trajectory modeling techniques, we will also identify the genetic and environmentally- determined consequences of substance use on brain and behavioral development, including the assessment of gene-by-environment interactions. In addition, we will develop biospecimen resources for future studies of genomic, epigenomic, metabolomics and microbiome changes that may influence substance use and its broad health consequences. Specific to this Twin-Hub, we will obtain baseline and follow-up serum, saliva, and in some cases gut microbiota from biological samples. This work enriches the full ABCD-USA Consortium given that disentangling G and E contributions to individual risk for addiction and sensitivity to SU's neurocognitive effects has highly significant public policy and prevention-based implications.

DESCRIPTION (provided by applicant): A Randomized Controlled Trial of PCIT-ED for Preschool Depression Data from several independent research groups have demonstrated that the onset of DSM-IV depressive disorders may occur as early as the preschool period. A stable and specific symptom constellation, family history of related disorders, characteristic alterations in stress cortisol reactivity as well as homotypic continuity with depression at school age provide strong support for the principle that preschool depression represents an early onset form of the later childhood disorder. Epidemiological studies from both U.S. and European sites estimate the prevalence rate of preschool onset depression (PO-MDD) at 1-2%, the same rate found in school- aged children. New data from our lab suggest that depressed preschoolers display alterations in functional brain activity similar to that found in adult depression. These brain changes were detected both during an acute preschool episode and later at school age, even after the depressive episode remitted. These findings taken together underscore the need for treatment of MDD during the preschool period. However, because PO-MDD has only recently been recognized, investigations of treatments remain uncharted. The need for effective treatments for PO-MDD go beyond the important goal of helping affected preschoolers but may also have implications for earlier and potentially more effective interventions in this chronic and relapsing disorder. Based on the large effect sizes reported in early interventions in several preschool disorders, an early intervention for PO-MDD, Parent Child Interaction Therapy Emotion Development (PCIT-ED) was developed and pilot tested. PCIT-ED is an expansion of PCIT, a well-known, widely used and proven effective treatment for preschool disruptive disorders. To address early disturbances of mood and affect, a novel ED module was added based on empirical data in emotion development. The ED module targets parent emotion learning skills with the goal of training the parent to serve as a more effective emotion teacher and coach to the child. The goal of the ED module is to enhance the child's capacity for emotion recognition and regulation or emotional competence. A pilot randomized controlled trial of PCIT-ED was conducted demonstrating feasibility and promise of efficacy. Following these findings, this application proposes a large scale well powered RCT of PCIT-ED for PO-MDD compared to a wait list control after which subjects will receive the active treatment. The aim is to rigorously test the efficacy of PCIT-ED, to estimate accurate effect sizes and to investigate mediators and moderators of treatment response.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving crucial to our understanding of normative variation in adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain development to new levels. This knowledge will critically inform prevention and intervention efforts targeting well known public health concerns (e.g., neurological and psychiatric disorders, poverty). The majority of developmental connectivity studies to date have used fairly coarse resolution, have not been multi-modal in nature, and few studies have used comparable methods to assess individuals across a sufficiently wide age range to truly capture developmental processes (e.g., early childhood through adolescence). Here we propose a consortium of five sites (Harvard, Oxford, UCLA, University of Minnesota, Washington University), with extensive complimentary expertise in brain imaging and neural development, including many of the investigators from the adult and pilot lifespan HCP efforts. Our synergistic integration of advances from the HARVARD-MGH and WU-MINN-OXFORD HCPs with cutting edge expertise in child and adolescent brain development will enable major advances in our understanding of the normative development of human brain connectivity. The resultant unique resource will provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to gain new insights about brain development and connectivity. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols on the widely available Prisma platform to respect practical constraints in studying healthy children and adolescents over a wide age range and will also collect a matched set of data on the original Skyra and proposed Prisma HCP protocols to serve as a linchpin between the past and present efforts. Aim 2 will be to collect 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents in the age range of 5-21, using matched protocols across sites, enabling robust characterization of age-related changes in network properties including connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal subsamples, task, and phenotypic measures that constitute intensive sub-studies of inflection points of health-relevant behavioral changes within specific developmental phases. Aim 4 will capitalize on our success in sharing data in the HCP, and use established tools, platforms and procedures to make all data publically available through the Connectome Coordinating Facility (CCF).

This is a competitive renewal of an R01 supporting a program of research delineating the psychological and neural mechanisms of impairments in motivation and goal-oriented behavior in psychosis, which will extend our work transdiagnostically. Motivational impairments are a key feature of both psychotic and mood pathology, and are included in the Research Domain Criteria (RDoC) Positive Valence System. Decreases in motivation impair work and social function transdiagnostically, reduce quality of life, and increase public health demands. Current treatments are not sufficiently effective at reducing impairments in motivation in every day life, in part due to the need to better understand the mechanisms that give rise to these symptoms. Our prior research provides strong evidence that abnormal effort-cost decision-making (ECDM; Effort valuation/Willingness to work in the RDoC Positive Valence System) may be a key contributor to motivational deficits in both psychotic and mood pathology. ECDM refers to calculations that individuals perform to estimate the amount of physical or cognitive ?work? required to obtain a reward. Individuals with schizophrenia, schizoaffective, bipolar disorder and depression are less motivated than healthy individuals to exert effort to obtain rewards on experimental tasks, and these deficits are related to symptoms of amotivation and function in every day life. Here we bring together a team with complimentary expertise for an innovative transdiagnostic study that would determine the similarities and differences in the psychological and neural mechanisms that contribute to impaired ECDM across forms of psychopathology. We will integrate state-of-the art functional neuroimaging methods developed in the Human Connectome Project, novel behavioral and imaging paradigms derived from the affective science literature (Consultants Treadway & Westbrook), and innovative mobile technologies to assess motivated behavior in everyday life (Co-Is Ben-Zeev, Campbell, & Moran). This study will address NIMH Strategic Objective #1 (Define the Mechanisms of Complex Behaviors) and inform novel targets for future interventions. Aim 1 will test the hypothesis that impairments in cognitive and/or physical ECDM cut across the spectrum of psychotic and mood disorders, and relate to each other. Aim 2 will test the hypothesis that altered ECDM in psychosis may be more associated with impairments in the RDoC construct of cognitive control, while altered ECDM related to depression may be more related to the RDoC constructs of reward responsiveness and learning. Aim 3 will test the hypothesis that altered ECDM in psychosis may be more associated with impairments in dorsal anterior cingulate and dorsolateral prefrontal cortex activity and connectivity, while altered ECDM in depression may be more related to impairments striatal, anterior insula, and ventral-medical prefrontal activity and connectivity. Aim 4 will test the hypothesis that ECDM predicts amotivation and function in every day life across the spectrum of psychotic and mood disorders, using ecological momentary assessment, mobile sensing (geo-location and actigraphy) and informant report.

Advancements in computational psychiatry allow us to isolate multiple, specific cognitive mechanisms that determine human behavior. This formal modeling framework generates quantitative parameter estimates that can serve as bridges between pathophysiology and psychopathology. A major goal of computational psychiatry is to translate these laboratory tools so that they can be used in the clinic. Two critical hurdles need to be overcome. First, the enhanced validity and sensitivity of computational metrics needs to be established relative to standard behavioral performance metrics in key psychiatric and nonpsychiatric populations. We propose to do that by addressing a range of cognitive and motivational domains that have been strongly implicated in psychopathology, including working and episodic memory, visual perception, reinforcement learning, and effort based decision making. Second, we need to establish and optimize the psychometrics of these computational metrics so that they can be used as tools in treatment development, treatment evaluation, longitudinal, and genetic studies. These powerful metrics must have adequate test-retest reliability, and not be limited by ceiling and floor effects. We propose to develop these methods using an open, flexible, and scalable framework and demonstrate that they provide valid data both in the laboratory and in large-scale Internet-based data collection, facilitating ?big data? studies of cognitive processes. To this end, the current project will leverage the expertise of Cognitive Neuroscience Task Reliability and Clinical applications in Serious mental illness (CNTRACS) consortium, a multi-site research group with an established record of rapid cognitive tool development and dissemination. Aim 1 is to establish that model based parameters for the measurement of cognitive function are more sensitive than standard behavioral methods in assessing deficits across a range of common mental disorders, and have an enhanced capacity to predict clinical symptoms and real-world functioning, with a sample of 180 patients with psychotic and affective disorders (both medicated and unmedicated) and 100 healthy controls. Aim 2 is to measure and optimize the psychometric properties (test re-test reliability, internal validity, floor and absence of ceiling and practice effects) of computational parameters described in Aim 1, in a new sample of 180 psychiatric patients and 100 healthy controls. Aim 3 is to establish the feasibility and replicability of model-based analytic approaches outside the laboratory for assessing RDoC dimensions of interest, and to assess their relationships to variation in psychotic-like experience, depression and anhedonia, as well as real- world functioning in a community sample of 10,000 recruited over the Internet. Aim 4 is to validate key model based parameters against well-characterized neurophysiological measures acquired using EEG recordings during task performance. Successful completion of these Aims will significantly advance the field by providing easily administered and scalable web-based tools for estimating the integrity of key neural systems that underlie normal cognition and motivation and form the basis of common forms of cognitive and affective psychopathology.

Abstract: A marked increase in suicidal thoughts and behaviors (STB) among pre-pubertal children over the last decade has been reported by the CDC. Death by suicide in children ages 10-14 more than doubled between 2007 and 2014 with rates of non-lethal self-inflicted injuries doubling during the same period. Despite these dramatic rises in STB rates, there has been little investigation of the prevalence, timing of onset, or correlates and causes of STB or non-suicidal self-injury (NSSI) in pre-pubertal children. In a longitudinal study of preschool depression, we reported that preschool-onset STB shows stability across childhood. Outside of case reports, there are no other published data on STB or NSSI in early childhood. Our findings, taken together with the CDC data, support the critical need for studies of STB and NSSI that start in early childhood to identify the predictors of STB and NSSI in middle childhood and adolescence. In a sample of 3-7 year olds screened for a treatment study of depression we again found alarmingly high rates of NSSI (21.3%) and STB (19.4%) at baseline. Supplemental NIMH funding was awarded to investigate the characteristics and neural and behavioral correlates of STB and NSSI in this depressed sample, and to add age matched healthy controls. We found both common and unique risk factors for STB and NSSI in young children, consistent with the extant adolescent literature. Building on these findings, we propose to follow this well characterized sample into school age and early adolescence to test developmental models of these phenomena. We will investigate the longitudinal course, mediators and moderators, and neural correlates of early onset STB and NSSI. We will conduct behavioral and ERP assessments at two time points, 18-months apart in our sample of N=314 who have data from the preschool period. We will also sample the frequency, intensity, and proximal precipitants of STB/NSSI using weekly mini-assessments (WMA). Building on preliminary findings, we will use ERPs to test hypotheses about RDoC constructs that map to the risk factors that may contribute to STB and NSSI, including responses to negative and positive feedback to reward, errors, and peer rejection. We will test specific hypotheses about both shared risk factors for NSSI and STB (greater depression, peer rejection, adverse life events, and harsh parenting, as well as stronger ERP responses to loss and peer rejection, and blunted ERP responses to wins and social acceptance) as well as risk factors that may be more selective for NSSI (greater shame, irritability, self-criticism and higher pain tolerance) versus STB (reduced belongingness, greater hopelessness and a family history of suicide). Given the young age of the ascertained sample at baseline, we also have the opportunity to investigate differences in risk as a function of developmental stage. The proposed study provides an unprecedented opportunity to follow the largest ever sample of young children with STB and NSSI to investigate developmental trajectories into school age and early adolescence, potentially identifying early developmental targets for earlier intervention.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child's changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.