Cameron S. Carter - US grants

DESCRIPTION (Adapted from applicant's abstract): The focus of this Mentored Clinical Scientist Development Award is training in the use of the tools and constructs of Cognitive Neuroscience to investigate the pathophysiological processes underlying schizophrenia. The candidate is a psychiatrist who has had limited training in cognitive neuroscience and in positron emission tomography (PET). The educational goals of this application are to consolidate the candidates' expertise in cognitive science through formal graduate level course work, and to develop skills in functional neuroimaging through a mentored program of research. The research plan proposes a series of (15-O)-H2O PET studies of normals schizophrenia patients using tasks designed to produce focal activation in the dorsolateral prefrontal cortex (DLPFC), the medial frontal cortex and anterior cingulate gyrus (ACG), and the superior temporal gyrus (STG). These studies test the hypothesis that there is physiological dysfunction in each of these three cortical regions in schizophrenia. All patients will undergo careful clinical assessment in order to test a secondary hypothesis which addresses the clinical significance of this finding. Specifically, it is hypothesized that cortical dysfunction is related to many of the behavioral abnormalities seen in schizophrenia and that differences in the relative involvement of the above three cortical regions may account for a significant degree of the clinical variability which characterized this illness.

This study is designed to test specific hypotheses regarding the role of abnormalities in CNS catecholamines in cognitive deficits in schizophrenia. Using a double-blind placebo controlled design, we will challenge schizophrenia patients and normal controls with 0.25 mg/kg of d-amphetamine or placebo and measure the effects of the drugs on cognitive performance in both groups.

DESCRIPTION (provided by applicant): Advances in cognitive and affective neuroscience allow us to conceptualize and measure functional neural systems that are related to core dimensions of psychopathology. These distinct neural systems bridge behavior and neurobiology and shed new light on the pathophysiology of mental disorders in a manner that may both clarify and cut across traditional diagnostic boundaries. Much of the preceding research on the pathophysiology of psychotic disorders has followed the categorical distinction between schizophrenia (SZ) and Bipolar Disorder (BD). However, recent genetic, clinical and outcome data suggest significant overlap between the disorders that could reflect shared pathophysiological processes. Hence there is a fundamental need to examine more basic mechanisms driving symptoms that underlie psychopathology in both disorders, as well as to understand points of divergence between SZ and BD. This need is especially salient in the context of first episode (FE) psychosis, where differential diagnosis is highly challenging and the benefits of targeted early treatments are most pronounced. Toward this aim, this proposal focuses on cognitive control and approach motivation in FE psychosis, two core dimensions recommended by RDoC and linked respectively to fronto-parietal (FP) and orbitalfrontal-ventral striatal (OFC-VS) functional brain networks. Using fMRI and two behavioral paradigms that engage 1) the goal maintenance component of cognitive control 2) positive incentive effects on behavior and 3) the effects of repeated incentives on cognitive control, in a prospective longitudinal design we will test the following hypotheses regarding the cognitive and neural mechanisms underlying core behavioral disturbances in SZ and BD. 1) FP dysfunction is related across diagnoses to impaired cognitive control and disorganization, and that in SZ this is a trait feature of the illness while in BD it is largely episode dependant 2) OFC-VS activity in response to positive incentives is reduced in SZ and intact or increased in BD and this is a trait feature o both illnesses and 3) BD patient have a unique pattern of responding to repeated incentives with increased OFC-VS and decreased FP activity and impaired cognitive control, as a trait feature of the illness. Successful completion of this project will provide important links between discrete neural circuits and core symptoms in SZ and BD and highlight areas of overlap as well as divergence in the illness. The results will provide important circuitry level insights into the natral history and pathophysiology of FE psychosis, contribute to the development of imaging biomarkers and help guide the development of interventions that focus on key dimensions of symptoms in FE psychosis.

DESCRIPTION: (provided by applicant) This is an application for an Independent Scientist Award (K02) from an applicant who is currently supported by a Mentored Scientist Award for Clinicians (K08), which ends 4/01 During the period of the KO8 the applicant has made significant progress in pursuing his training goals, which were to increase his expertise in basic cognitive neuroscience and to develop expertise in conducting functional imaging studies of impaired cognition in schizophrenia. In addition to accomplishing a significant level of productivity in these two areas, the applicant has also made the transition from advanced trainee to independent scientist during the period of the K08. The goals of the present application are 1) to develop new expertise in the use of ERP, and in the integration of ERP and fMRI, into multimodal imaging studies of human executive functions, 2) to build upon the applicants current expertise in the analysis of event-related fMRI data related to impaired cognition In schizophrenia and 3) to develop further expertise in cognitive modeling to facilitate the design and interpretation of future multimodal functional brain imaging studies of impaired cognition in schizophrenia. These goals will be pursued through a combination of course work and intensive consultation with world experts in the fields of ERP, fMRl and cognitive modeling. They will also be pursued in a series of experiments using fMRI and ERP both alone and in combination, to test hypotheses related to the neural basis of normal executive functions, as well as the neural basis of impaired executive functions in schizophrenia. Successful funding of this award will ensure that the applicant is freed up from clinical, teaching and administrative responsibilities for the next five years so that he can spend at least 80 percent of his time on research and on the further development of his research expertise.

The central hypothesis of the Center focuses on the role that functional abnormalities in the intrinsic circuitry of the dorsolateral prefrontal cortex (DLPFC) and in its interconnections with other brain regions, including the anterior cingulate cortex (ACC), play in the regulation of cognition in schizophrenia. These functional disturbances are hypothesized to arise during late brain (adolescent) development as a result of alterations in the molecular signals and structural elements that determine synaptic efficacy in the affected circuits. Studies conducted by this Project suggest that a specific form of cognitive dysfunction, a deficit in context processing, is a trait feature of schizophrenia that is present at the first episode, is stable across the course of the illness and is present in the unaffected relatives of schizophrenia patients. Basic functional MRI and computational modeling studies have suggested that context processing depends upon both the DLPFC (for representing and maintaining context), and the ACC (for monitoring for conflicts and modulating DLPFC accordingly). Using a multimodal functional neuroimaging approach that integrates high-density ERP and functional MRI, and a novel task that dissociates DLPFC and ACC functions in time, we propose 1) to investigate the relative contribution of DLPFC and ACC based cognitive functions to impaired context processing in never medicated first episode (FE) schizophrenia patients, and to determine the specificity of these abnormalities to schizophrenia, versus psychosis in general; 2) to test the hypothesis that the same deficits in DLPFC and ACC function in patients will be observed in their unaffected first degree relatives, confirming a relationship between impairment in the function of this circuit and the context processing deficits that are associated with a genetic liability to schizophrenia; and 3) to examine the developmental course of DLPFC and ACC based contributions to context processing in adolescent offspring of parents with schizophrenia, compared to non-high risk adolescent control subjects. This will enable us to directly test the hypothesis that cognitive deficits that reflect a genetic liability for schizophrenia are manifested through a disturbance in late brain development. These studies have many conceptual links to other projects in the Center and depend heavily on support provide by the Clinical Services Core-C and the Statistics and Data Management Core-D.

DESCRIPTION (provided by applicant): Strong evidence suggests that liability to schizophrenia is highly heritable. At the same time only a portion of the individuals with a genetic liability develop schizophrenia, which increases the difficulty of isolating relevant genes. The studies proposed in this application apply the tools and constructs of cognitive neuroscience to test the hypothesis that a specific impairment in context processing, a cognitive function related to the control of attention and working memory and associated with the function of dorsolateral prefrontal cortex (DLPFC), may reflect a valid and reliable endophenotype for genetic liability to schizophrenia. First, we will develop a second generation of context processing measures that is both sensitive to the subtle impairments in the healthy relatives of schizophrenia patients, while at the same time interpretable as a specific deficit associated with context processing. Second, the study will test the specificity of context processing impairments to schizophrenia and schizoaffective disorder by comparing schizophrenia and schizoaffective (bipolar type) patients with bipolar patients and controls. Finally, we will study brain activity associated with context processing impairments in the relatives of schizophrenia patients using IMRI. Previous work has found that context processing impairments in schizophrenia patients have been associated with DLPFC dysfunction. We hypothesize that a DLPFC dysfunction associated with specific impairments in context processing will be evident in patients' unaffected relatives. The work proposed in this application has the potential to have important implications for developing behavioral genetic tools to isolate the genes that cause schizophrenia.

bioimaging /biomedical imaging; brain imaging /visualization /scanning; computer program /software; computer system design /evaluation

[unreadable] DESCRIPTION (provided by applicant): Over the past decade there has been a growing awareness of the treatment refractory cognitive deficits that are present in schizophrenia and strongly and consistently related to poor functional outcome and behavioral disorganization. This has been accompanied by an increasing emphasis on the importance of developing new treatments that may positively impact these deficits, culminating in the recent MATRICS meetings. Over this same period there has been an explosion of technical advances and new knowledge regarding the neural basis of cognition. Converging data from animal and human research has led to an unparalleled expansion of knowledge of the mechanisms of normal cognition and its underlying neuropharmacology, and cognition related brain activity in humans may now readily be obtained using measures such as functional MRI. The application of this cutting edge knowledge and technology to new drug development has lagged significantly behind the overall progress in the field. Generally, the methodology for measuring the effects of drugs on cognition in schizophrenia has relied on measures from clinical neuropsychology whose development pre-dates the cognitive neuroscience era. During the final, "new approaches" MATRICS meeting it was broadly agreed that the major barrier to bridging the gulf between the new neuroscience and drug development is a lack of data on the measurement properties of the behavioral tasks used in cognitive neuroscience. In this R13 application we propose to maintain the momentum created by the MATRICS New Approaches meeting and take a step closer to a brain based approach to measuring the effects of treatments on impaired cognition in schizophrenia. To accomplish this goal we organize three conferences over an 18 month period. The first conference will develop a consensus on the key component processes related to a subset of the higher cognitive functions that are affected in schizophrenia, related to poor outcome and measurable in animal models. The second conference will clarify the psychometric issues relevant to translating tasks from cognitive psychology and neuroscience into useful measures for drug development, and establish benchmarks against which the psychometric properties of candidate tasks can be compared. The third meeting will develop a set of candidate tasks which measure key component processes of the cognitive systems impaired in schizophrenia which 1) can be linked to animal models and 2) are amenable to incorporation into neuroimaging studies of the underlying brain circuitry. These meetings and their published products will take the field a step closer to having a new set of brain based tools that can be used at both early and later stages of the drug development process to enhance the translation of new knowledge regarding the neuroscience of cognition into effective treatments for cognitive impairments in schizophrenia. [unreadable] [unreadable] [unreadable]

NIH Roadmap Initiative tag

The central hypothesis of the Center focuses on the role that functional abnormalities in the intrinsic circuitry of the dorsolateral prefrontal cortex (DLPFC) and in its interconnections with other brain regions, including the anterior cingulate cortex (ACC), play in the regulation of cognition in schizophrenia. These functional disturbances are hypothesized to arise during late brain (adolescent) development as a result of alterations in the molecular signals and structural elements that determine synaptic efficacy in the affected circuits. Studies conducted by this Project suggest that a specific form of cognitive dysfunction, a deficit in context processing, is a trait feature of schizophrenia that is present at the first episode, is stable across the course of the illness and is present in the unaffected relatives of schizophrenia patients. Basic functional MRI and computational modeling studies have suggested that context processing depends upon both the DLPFC (for representing and maintaining context), and the ACC (for monitoring for conflicts and modulating DLPFC accordingly). Using a multimodal functional neuroimaging approach that integrates high-density ERP and functional MRI, and a novel task that dissociates DLPFC and ACC functions in time, we propose 1) to investigate the relative contribution of DLPFC and ACC based cognitive functions to impaired context processing in never medicated first episode (FE) schizophrenia patients, and to determine the specificity of these abnormalities to schizophrenia, versus psychosis in general; 2) to test the hypothesis that the same deficits in DLPFC and ACC function in patients will be observed in their unaffected first degree relatives, confirming a relationship between impairment in the function of this circuit and the context processing deficits that are associated with a genetic liability to schizophrenia; and 3) to examine the developmental course of DLPFC and ACC based contributions to context processing in adolescent offspring of parents with schizophrenia, compared to non-high risk adolescent control subjects. This will enable us to directly test the hypothesis that cognitive deficits that reflect a genetic liability for schizophrenia are manifested through a disturbance in late brain development. These studies have many conceptual links to other projects in the Center and depend heavily on support provide by the Clinical Services Core-C and the Statistics and Data Management Core-D.

[unreadable] DESCRIPTION (provided by applicant): Over the past decade there has been a growing awareness of the treatment refractory cognitive deficits that are present in schizophrenia and strongly and consistently related to poor functional outcome and behavioral disorganization. This has been accompanied by an increasing emphasis on the importance of developing new treatments that may positively impact these deficits, culminating in the recent MATRICS meetings. Over this same period there has been an explosion of technical advances and new knowledge regarding the neural basis of cognition. Converging data from animal and human research has led to an unparalleled expansion of knowledge of the mechanisms of normal cognition and its underlying neuropharmacology, and cognition related brain activity in humans may now readily be obtained using measures such as functional MRI. The application of this cutting edge knowledge and technology to new drug development has lagged significantly behind the overall progress in the field. Generally, the methodology for measuring the effects of drugs on cognition in schizophrenia has relied on measures from clinical neuropsychology whose development pre-dates the cognitive neuroscience era. During the final, "new approaches" MATRICS meeting it was broadly agreed that the major barrier to bridging the gulf between the new neuroscience and drug development is a lack of data on the measurement properties of the behavioral tasks used in cognitive neuroscience. In this R13 application we propose to maintain the momentum created by the MATRICS New Approaches meeting and take a step closer to a brain based approach to measuring the effects of treatments on impaired cognition in schizophrenia. To accomplish this goal we organize three conferences over an 18 month period. The first conference will develop a consensus on the key component processes related to a subset of the higher cognitive functions that are affected in schizophrenia, related to poor outcome and measurable in animal models. The second conference will clarify the psychometric issues relevant to translating tasks from cognitive psychology and neuroscience into useful measures for drug development, and establish benchmarks against which the psychometric properties of candidate tasks can be compared. The third meeting will develop a set of candidate tasks which measure key component processes of the cognitive systems impaired in schizophrenia which 1) can be linked to animal models and 2) are amenable to incorporation into neuroimaging studies of the underlying brain circuitry. These meetings and their published products will take the field a step closer to having a new set of brain based tools that can be used at both early and later stages of the drug development process to enhance the translation of new knowledge regarding the neuroscience of cognition into effective treatments for cognitive impairments in schizophrenia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Recent findings from cognitive neuroscience have substantially shaped our understanding of the functional architecture of human cognition and its neural underpinnings. Furthermore, a wide range of new non- invasive behavioral and imaging tools have become available to investigate the neural basis of cognition and its impairment in clinical populations. The most rapid possible progress toward understanding and treating impaired cognition in schizophrenia requires the application of the most current and tools and constructs to this effort. The purpose of this R24 Developmental Translational Center for Integrative Behavioral Science is to build collaborations between some of the world's experts on the neuroscience of attention, memory, language and emotional processing, processes that are impaired in schizophrenia, senior schizophrenia researchers who focus their careers on these problems, and junior investigators and trainees who will benefit greatly from the interdisciplinary training provided by the Center. Over the course of the Award we will develop a Translational Research Center in which both forward and backward translation will occur. The development of a cohesive Center structure to support the design and execution of a set of studies that will test the overarching hypothesis that specific deficits in cognitive control functions normally supported by specific elements of the prefrontal cortex (PFC) are associated with specific deficits in attention, memory, language and emotional processing in schizophrenia. Further, it is predicted that these specific cognitive deficits and associated alterations in prefrontal function are associated with disorganization and negative symptoms, but not positive symptoms. To test this hypothesis we will pursue four Specific Aims, using state of the art behavioral, functional magnetic resonance imaging (fMRI) and event-related potential (ERP) methodologies in a single group of early schizophrenia patients. These Aims will test four specific hypotheses linked to the overall Center hypothesis. 1) Schizophrenia patients will show a deficit in the cognitive control processes that activate appropriate stimulus-response mappings and suppress competing stimulus-response mappings. 2) Schizophrenia patients will exhibit a specific deficit in dorsolateral PFC dependant cognitive control processes supporting relational processing in working memory and relational encoding into long term memory. 3) Schizophrenia patients have a deficit in the cognitive control processes that suppress contextually inappropriate information during language comprehension. 4) Schizophrenia patients have a specific deficit in maintaining an emotional response following the offset of an emotional stimulus. Successful completion of this work will enable us to develop an interdisciplinary collaborative research group that will generate a series of translational RO1's to conduct innovative translational research focused on understanding cognitive and neural mechanisms underlying impaired cognition in schizophrenia.

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.

The highly-interactive, interdisciplinary core of the Consortium (Projects 1-4), focusedon the development of targeted therapeutics for the neurodegenerative disorder, FXTAS, will be greatly enhanced by a post-graduate (T90) training component,the Interdisciplinary Training Program in Neurotherapeutics (ITN). In this non-traditional setting, the principal objective of the T90 will be to further the research effort of the Consortium, by attracting trainees who are intrinsically interested in interdisciplinary research and who will naturally bridge disciplines within the Consortium through inter-project, dual-mentorship. In turn, the Consortium will provide the trainee with an outstanding environment for training in interdisciplinary neuroscience, for it is an environmentthat fully spans both basic and clinical domains. Trainees from diverse disciplines and backgrounds, including chemistry, molecular biology, mouse biology and behavior, cognitive neuroscience and human functional neuroimaging, and clinical neuroscience disciplines (neurology, psychiatry, pediatrics and clinical psychology), will train together in the ITN. The ITNwill emphasize both individualized research training across at least two Consortium laboratories (dual mentorship) and a set of core competencies that spans the entire range of the represented disciplines. The program will target trainees who can be positioned to bridge different laboratories in order to create a new kind of investigator, one who can go beyond traditional roles and lead future mechanistic studies and intervention efforts aimed towards understanding and treating neurogenetic developmental disorders from a truly interdisciplinary perspective. The T90 will provide interdisciplinary research through an Individualized Training Plan, which will consist of five key elements: (1) mentored researchtraining bridging across two distinct projects in the Consortium;(2) participation in a didactic program to develop Core Competencies;(3) observational training in clinical assessments in neurogenetic disorders;(4) participation in selected individualized coursework;and (5) career development activities. In addition to the novel training opportunities provided through the T90, the training will leverage existing training programs in the DCDavis School of Medicine in autism research, clinical and translational research, and the responsible conduct of research.

DESCRIPTION (provided by applicant): Over the past decade there has been a growing awareness of the disabling and treatment refractory effects of impaired cognition in schizophrenia, which results in performance deficits that are strongly and consistently related to poor functional outcome and behavioral disorganization. Along with this new awareness has come an increasing emphasis on the importance of developing new treatments that may positively impact these deficits. The MATRICS meetings built a consensus between industry, academia, and the FDA on how to move forward in the development of therapies for impaired cognition in schizophrenia. During this same period there has been an explosion of technical advances and new knowledge regarding the neural bases of cognition. Converging data from animal and human research has resulted in a dramatic increase in knowledge regarding the neurobiological mechanisms underlying normal cognition, and cognition related brain activity in humans can now readily be obtained using measures such as functional MRI, MEG and ERP. The MATRICS measures identified for use in large scale clinical trials in schizophrenia have their basis in clinical neuropsychology. These measures have the measurement properties and ease of administration needed for clinical trial settings. However, due to their complexity, they are not easily understood in terms of the brain-based models of cognition developed in cognitive neuroscience, nor are they appropriate for use in non-invasive imaging studies of the neural correlates of cognition. To begin to develop a brain based set of tools for measuring cognition in schizophrenia, we initiated the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) process, funded by the R13 mechanism. The first phase of CNTRICS focused on enhancing the identification of cognitive targets from a cognitive neuroscience perspective, and then addressing critical measurement challenges associated with the use of these approaches in the drug development setting. We then identified of a set of tasks from cognitive neuroscience that are considered valid measures of the cognitive deficits targeted for intervention in schizophrenia. The results of the first two CNTRICS meetings have been published (in Biological Psychiatry and Schizophrenia Bulletin respectively)[5, 6] and the results of the third are in the process of being published in Schizophrenia Bulletin. An RFA followed the first meeting and a number of RO1's will be funded to refine and optimize tasks based upon the outcome of the CNTRICS process. There is anticipation of a future program announcement for ongoing translational research developing and adapting additional tasks from basic cognitive neuroscience for use in treatment development for impaired cognition in schizophrenia. In this competing renewal we propose to build on the initial progress made during the first three CNTRICS meetings, focusing on two areas where innovation may significantly enhance translational research and the treatment development process. The first of these is the identification and development of in vivo neural systems measures from non-invasive neuroimaging to serve as biomarkers/surrogate markers of treatment effects. The second is the development of new animal models that target processes most relevant for impaired cognitive and emotional processing in schizophrenia. Progress in these two areas will lead to a more integrated process of treatment development in which preclinical studies are more seamlessly integrated with early phase human studies. To accomplish this goal we will pursue the following two Specific Aims by organizing four conferences over a three-year period. There has been a recent explosion of new knowledge from the new field of cognitive neuroscience about how the brain supports human cognition. However most research approaches for developing treatments for cognitive deficits in schizophrenia use older clinical neuropsychological tasks which pre-date cognitive neuroscience and do not measure cognitive processes linked to discrete neural processes. This project involves organizing four meetings designed to build on the progress made during the initial funding period by identifying a set of new, non invasive cognitive neuroimaging measures for use in human subjects together with a related set of valid animal models of cognition relevant for impaired cognition in schizophrenia. These new human imaging tools and animal models will lead to enhanced "vertically integrated" translational research targeting impaired cognition in schizophrenia.

DESCRIPTION (provided by applicant): This application seeks funding for a Siemens 3T TIM Trio whole-body MRI system to be sited at the Center for Neuroscience at the University of California at Davis. Located in Davis California UC Davis is one of the premier neuroscience communities on the West Coast of the United States and home to two interdisciplinary neuroscience Centers, the Center for Neuroscience and the nearby Center for Mind and Brain, as well as the Western Regional Primate Center. The Center for Neuroscience is home to the Keck Imaging Center where an outstanding array of cellular and molecular imaging methodologies are supported. UC Davis also has an outstanding biomedical engineering program with strong molecular imaging capabilities and a high field small animal MRI facility. However there is no human or large animal research MRI scanner in Davis, making UC Davis the only comprehensive campus of the UC system lacking imaging capabilities. UC Davis Campus based investigators must travel 15 miles to Sacramento to conduct neuroimaging studies on the 3T Siemens Trio in operation at the UC Davis Imaging Research Center which is located on the School of Medicine Campus in that city. This presents substantial logistical challenges including the transportation of human subjects and macaque monkeys, together with research and veterinary staff back and forth from Davis to Sacramento. It also renders some kinds of research (e.g., functional MRI studies of awake, behaving monkeys) unfeasible. The installation of a state of the art research scanner on the Davis Campus would address the above logistical challenges, relieve substantial scheduling challenges due to a high volume of clinical and translational research being conducted at the IRC in Sacramento, and facilitate a wide range of new scientific opportunities presently not feasible, such as functional MRI studies in macaques. This new facility will leverage significant campus resources, including a new full-time professorial faculty position for a high-field MRI Physicist in the Department of Biomedical Engineering and the Center for Mind and Brain, as well as the highly developed administrative and technical resources of the existing Imaging Research Center, to ensure that UC Davis remains at the forefront in the application of MRI based neuroimaging in basic and translational neuroscience. By co-locating the MRI facility with the Keck Center, we will bring together imaging studies that cut across multiple levels of analysis and enhance collaborative and interdisciplinary research that will accelerate the search for cures for a range of mental, developmental and neurological disorders. PUBLIC HEALTH RELEVANCE: Neuroscience investigators on the main Campus at the University of California, Davis, are internationally recognized leaders in research designed to understanding the cognitive and developmental processes that are altered in serious mental and neurological disorders. At present these investigators must transport their human and animal subjects together with their research and support staff from Davis to Sacramento and this presents a substantial impediment to ongoing research, as well as to the development of new projects. This grant application will support the purchase of a state of the art human and large animal 3T Siemens TIM Trio MRI scanner for installation at the Center for Neuroscience in Davis, greatly enhancing the ability of our outstanding group of investigators to advance their research in fundamental and translational neuroscience.

DESCRIPTION (provided by applicant): This is a revised application for a jointly sponsored Ruth L. Kirchstein Institutional Predoctoral Training Program grant from the University of California, Davis. The goal of the program is to provide a broad training in the fundamental principles of neuroscience for entering students that will lay solid foundations for their specialized research in advanced years. It will also provide them with the broad perspective essential for their establishing successful independent research programs in neuroscience in their future careers. The program will operate under the auspices of the interdisciplinary graduate program in neuroscience at UC Davis, which offers the scope and flexibility needed to meet our training objectives. The Training Program requests support for 4 predoctoral trainees to be selected annually by an Advisory Committee. Trainees will receive one year of support from the grant, typically in their first year. Internal support mechanisms and other extramural grants including individual fellowship awards will be used for support of the remaining years of graduate training. Trainees will participate in a teaching program especially designed to give exposure to as broad a range of modern neuroscience subdisciplines and technologies as possible including cellular and molecular neuroscience, neuroanatomy and neurophysiology, neurogenetics, systems neuroscience, cognitive neuroscience, computational neuroscience and, the neurobiology of psychiatric and neurological disease. Trainees will receive a rigorous basic training through formal course work, seminars and journal clubs and laboratory rotations and will participate in colloquia in which they will be expected regularly to make oral presentations. Students will thus be well prepared for their dissertation research and for future, independent careers in basic and disease-related neuroscience research.

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): Schizophrenia is a prevalent mental health disorder that creates enormous social, economic, and interpersonal hardships for patients and their families. Although hallucinations and delusions are the most salient symptoms of this disease, language abnormalities are among the most prominent cognitive deficits in schizophrenia. The proposed research will explore the processes and circuits that underlie impaired discourse comprehension in schizophrenia. Discourse comprehension deficits are likely to have important functional implications, but there has been relatively little investigation of real-time discourse processing in schizophrenia, particularly in relation to other impaired cognitive and psycho-social functioning. Previous research in schizophrenia has related cognitive deficits to impairments in the ability to control the maintenance of context representations. We will test the hypothesis that deficits in controlled integration and maintenance of discourse context in schizophrenia will lead to difficulties in discourse comprehension, but will relatively spare processing of meanings of words and sentence structures. To do so we will combine electrophysiological (EEG/ERP) measures of language comprehension with measures of cognitive, social and occupational functioning in schizophrenia. Our approach will allow us to examine whether discourse comprehension deficits in schizophrenia relate to impaired cognitive, social and occupational functioning, and the outcome of this research can be used in the development and assessment of new treatments for this disease.

DESCRIPTION (provided by applicant): Reducing Duration of Untreated Psychosis (DUP) is a primary goal for improving long-term outcomes in young people with a first episode of psychosis (FEP). The standard of FEP care within the US focuses on targeted provider education1 regarding signs and symptoms of early psychosis to motivate patient referrals to FEP services, followed by initiation of services within largely clinic-based settings 2. Experience at the Early Diagnosis and Preventive Treatment (EDAPT) FEP specialty program at U.C. Davis in Sacramento has identified two important bottlenecks to reducing DUP, consistent with reports in the literature from other FEP clinics. These are 1) delays in the identification of psychotic symptoms by referral sources, and 2) delays or disruptions of patient engagement in specialty FEP care. Building upon a comprehensive and established referral network of 20 sites across the Sacramento area (schools/universities, ER/inpatient hospitals, outpatient mental health, primary care), we will address delays in patient identification and engagement using a two- phase, cluster randomized design. We will consecutively test the impact of two interventions to reduce DUP, defined in this RFA as time from first onset of psychotic symptoms to engagement in FEP specialty care. To address identification delays, we will examine the use of standard targeted provider education plus novel technology-enhanced screening compared to standard targeted provider education alone, testing the hypothesis that the education plus technology-enhanced screening will identify more patients, earlier in their illness. To address engagement delays, we will compare the use of a mobile community-based, telepsychiatry- enhanced engagement team to standard clinic-based procedures for intake, engagement and initiation of treatment, to test the hypothesis that the mobile approach facilitates earlier and more stable engagement, thereby reducing DUP. The proposed work will provide new specific evidence-based practices for reducing DUP and improving outcomes through specialty care of individuals with a first episode of psychosis.

SUMMARY: PROJECT 4 Despite genetic and epidemiological data implicating maternal exposures and neuroimmune mechanisms as a risk factor for schizophrenia (SZ) and the development of maternal immune activation (MIA) animal models of altered neurodevelopment, little is known about the specific mechanisms by which MIA leads to altered brain development, connectivity and behavior. Project 4 will address this critical gap in our knowledge by pursuing two Specific Aims related to the role of neural inflammation in MIA and SZ. Informed by our preliminary studies that found evidence of cortical inflammation and increased striatal pre-synaptic dopamine (DA) in MIA nonhuman primates (NHPs), Aim 1 will use Positron Emission Tomography (PET) and magnetic resonance imaging (MRI) in a new cohort of MIA NHPs to investigate the developmental course of inflammation and increased striatal DA, and their relationship to abnormal social interactions and cognition in these animals. Further, this aim will test a neurodevelopmental model in which cortical inflammation measured using [18F]PBR 111 PET during childhood precedes the development of increased subcortical DA measured using [18F] fluoromethyltyrosine (FMT) PET and worsening atypical behaviors after puberty. Aim 2 will investigate the clinical significance of the MIA model by using MRI-based measures of neuroinflammation (diffusion-based measurement of free water, glutathione spectroscopy) that will be also obtained longitudinally in the NHP's as well as in patients with first-episode SZ. Successful completion of this study will provide new insights into the developmental neurobiology of brain inflammation in the MIA NHP and the relationship between inflammation, excessive subcortical DA, and changes in social behaviors and cognition in these animals. Direct comparison of the NHP model and humans with first-episode SZ on MRI markers of brain inflammation will provide an important test of the clinical significance of the MIA model.

? DESCRIPTION (provided by applicant): Growing evidence from epidemiology, genetics and clinical neuroscience implicates neuroimmune mechanisms in the pathophysiology of schizophrenia (SZ) and other developmental psychiatric disorders. A new class of animal models of maternal immune activation (MIA), expressing developmentally phenotypic features related to SZ, has been developed; however, little is known about the mechanisms by which MIA results in changes to brain development, connectivity and behavior. The UC Davis Conte Center seeks to bridge that gap. Supported by pilot funding for the past three years, this team has worked together to develop hypotheses, design experiments and collect preliminary data to develop the present application. The Center comprises an accomplished group of investigators from molecular and cell biology, systems and behavioral neuroscience, biomedical engineering, neuroimaging, and clinical neuroscience and a highly integrated set of studies conducted across species and scale to test the hypothesis that MIA contributes to SZ by altering immune molecules in the brains of offspring, which, in turn, alters cortical connectivity, function and behavior during development. Synaptic changes, gene expression, structural and functional connectivity, neural inflammation and behavior will be measured in mouse and non-human primate (NHP) models at multiple ages to determine the timing and hierarchy of the effects of MIA. When possible, parallel studies in humans will be conducted to establish the clinical relevance of the MIA animal models. The Center will pursue two Specific Aims to determine: 1) if MIA increases risk for neurodevelopmental psychiatric disorders in offspring by altering neural circuitry through dysregulated signaling of immune molecules and gene networks throughout development; 2) the timing of the appearance and progression of structural and functional changes in the brains of MIA offspring relative to the onset of dopamine dysregulation, neural inflammation, and SZ-related behavioral disturbances in the MIA NHP and compare these data to those seen in first-episode SZ. The projects will measure changes in synaptic connectivity, gene expression, structural and functional connectivity, neural inflammation, and behavior in parallel mouse and NHP MIA models at multiple ages to determine the relative timing and hierarchy of these changes and understand the underlying mechanisms. These studies in the mouse and NHP model will be complemented by novel analyses of synaptic connectivity and gene expression in post mortem human tissue from SZ.

SUMMARY: ADMINISTRATIVE CORE The overall objective of the Administrative Core is to oversee and coordinate the scientific and administrative operations of the center's activities and foster interactions and synergism among the Conte Center's four research projects and the Nonhuman Primate Core. The Administrative Core will accomplish this goal by continuously monitoring the progress of each project and core, providing biostatistical support to ensure optimal research design and analysis and to ensure effective and ethical involvement of animals and human participants, and facilitating data sharing and coordination across center components. Furthermore, the Administrative Core will implement a training and outreach program to provide graduate students, postdocs and junior investigators opportunities for interdisciplinary training and professional development, and to disseminate center results to the general public and the regional mental health community. Finally, the Administrative Core will provide programmatic evaluation of the Conte Center both through formative and summative evaluation methods employed by a program evaluator and through an annual review by the External Advisory Board.

? DESCRIPTION (provided by applicant): The California National Primate Research Center (CNPRC), located at the University of California, Davis, requests funds to renew the base operating grant #P51-OD011107 for the next five year period (May 1, 2015 through April 30, 2020). The CNPRC renewal reflects a strategic emphasis on multidisciplinary research teams that focus on the development and use of nonhuman primate models of human health and disease. Currently in the 53rd year of operation, the CNPRC serves a range of NIH-supported investigators nationwide. From inception through the current year, the CNPRC has been highly responsive to the research community by providing high quality animals, facilities, tools, and services driven by the intellectual infrastructure of the Core Scientists that guide and conduct basic and translational research with nonhuman primates. The goals for the next funding period are reflected in the following Specific Aims: (1) Conduct state-of-the-art research and scientifically contribute to the understanding and treatment of human disease with nonhuman primate models across the age spectrum, (2) Provide exceptional nonhuman primate expertise and services to investigators at the local, regional, and national levels to advance NIH-supported research excellence, (3) Mentor and train the next generation of translational investigators with nonhuman primate expertise, and (4) Ensure the highest standards of responsible conduct of research and animal care. Plans for the next funding period build upon expertise, productivity, and innovation; strong ties with the host institution and national programs; and maximizing resources for NIH-funded research. Support is requested for Administrative Services (Director's Office, Administration and Operations Services, Information Technology Services, Facilities Improvement), Primate Services (Colony Management and Research Services, National Institute on Aging Colony, Primate Medicine Services, Anatomic and Clinical Pathology Services, Behavior Management Services, Genetics Management Services), Service Cores (Behavior Research, Endocrine, Immunology and Pathogen Detection, Inhalation Exposure, Multimodal Imaging), Scientific Research Units (Brain, Mind, and Behavior, Infectious Diseases, Reproductive Sciences and Regenerative Medicine, Respiratory Diseases), and for Outreach, the Pilot Research Program, and NPRC Consortium activities. Through targeted opportunities and University of California initiatives, the CNPRC will actively promote the recruitment of faculty to the program, and continue to build infrastructure, expertise, and essential services to meet the growing needs of investigators and trainees.

DESCRIPTION (provided by applicant): Reducing Duration of Untreated Psychosis (DUP) is a primary goal for improving long-term outcomes in young people with a first episode of psychosis (FEP). The standard of FEP care within the US focuses on targeted provider education1 regarding signs and symptoms of early psychosis to motivate patient referrals to FEP services, followed by initiation of services within largely clinic-based settings 2. Experience at the Early Diagnosis and Preventive Treatment (EDAPT) FEP specialty program at U.C. Davis in Sacramento has identified two important bottlenecks to reducing DUP, consistent with reports in the literature from other FEP clinics. These are 1) delays in the identification of psychotic symptoms by referral sources, and 2) delays or disruptions of patient engagement in specialty FEP care. Building upon a comprehensive and established referral network of 20 sites across the Sacramento area (schools/universities, ER/inpatient hospitals, outpatient mental health, primary care), we will address delays in patient identification and engagement using a two- phase, cluster randomized design. We will consecutively test the impact of two interventions to reduce DUP, defined in this RFA as time from first onset of psychotic symptoms to engagement in FEP specialty care. To address identification delays, we will examine the use of standard targeted provider education plus novel technology-enhanced screening compared to standard targeted provider education alone, testing the hypothesis that the education plus technology-enhanced screening will identify more patients, earlier in their illness. To address engagement delays, we will compare the use of a mobile community-based, telepsychiatry- enhanced engagement team to standard clinic-based procedures for intake, engagement and initiation of treatment, to test the hypothesis that the mobile approach facilitates earlier and more stable engagement, thereby reducing DUP. The proposed work will provide new specific evidence-based practices for reducing DUP and improving outcomes through specialty care of individuals with a first episode of psychosis.

PROJECT SUMMARY/ABSTRACT Cognitive control deficits are associated with poor functioning in schizophrenia (SZ). These deficits include an impaired ability to maintain task-relevant goals and attention to a task over time, and are connected to impaired functioning of the dorsolateral prefrontal cortex (DLPFC), a key hub in the neural network supporting cognitive control. The proposed research uses a non-invasive brain stimulation technique, transcranial direct current stimulation (tDCS) to test a set of mechanistic hypotheses about the role of the DLPFC in cognitive control deficits in SZ, focusing on stimulation-induced changes in neural oscillations and DLPFC GABA levels. To do so, we will use DLPFC-targeted tDCS in combination with electrophysiology (EEG) and magnetic resonance spectroscopy (MRS) methods to examine stimulation-induced changes in neural activity related to cognitive control in SZ. Preliminary data from our lab suggests that DLPFC-targeted anodal tDCS can enhance neural oscillations that support goal maintenance in both healthy controls and individuals with SZ. This neurostimulation approach offers an exciting new avenue for understanding the neural mechanisms underlying impaired cognition in SZ, which we propose to utilize with three specific aims. Aim 1: Compare the effects of task-engaged versus resting tDCS in order to optimize the impact of tDCS on goal maintenance related neural oscillatory activity and task performance in SZ. Aim 2: Establish the regional specificity of the impact of DLPFC tDCS (compared to Occipital tDCS) effects on brain circuitry underlying goal maintenance in SZ. Aim 3: Test hypotheses about relationships between tDCS effects on DLPFC GABA levels, DLPFC-related oscillatory activity and cognitive performance in SZ. Successful completion of these Aims will address critical gaps in the literature on cognitive disability in SZ, which has, to date, relied on correlative approaches and will provide new insights into the role of disrupted DLPFC related brain circuity in SZ and its underlying pathophysiological mechanisms. It will also provide important new insights into the mechanisms of tDCS effects on brain and cognition in this illness.

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.

The introduction of Coordinated Specialty Care (CSC) has transformed the standard of care and elevated treatment outcome goals for young individuals experiencing the initial stages of a psychotic illness (EP). The response to treatment for EP individuals receiving CSC, however, remains highly variable. A substantial proportion show minimal symptom reduction despite receiving the full range of evidence-based practices comprising this treatment model. Currently, clinicians have no way to predict which EP individuals entering CSC will respond to treatment and published data show that expert clinicians perform no better than chance. Early identification of treatment non-responders has very high clinical significance and would inform and enhance clinical decision making during the first few months of care. Surprisingly, little research has been conducted on baseline predictors of treatment outcomes in EP individuals entering CSC. During the past two decades, considerable progress has been made using neuroimaging to investigate pathophysiological processes during the early phases of illness. Furthermore, limited data suggest that fMRI measures of brain activity and PET measures of increased dopamine synthesis are related to treatment outcomes in EP. We have recently demonstrated in a moderately large sample of EP patients entering CSC that the ability to activate the frontal parietal (FP) cognitive control network (measured using fMRI during the AX- CPT task) is a significant predictor of who will meet responder criterion after one year of CSC. We propose to replicate and extend this result by examining the predictive ability of this and two other promising MRI based measures linked to pathophysiological processes related to psychosis: 1) free water diffusion tensor imaging (FW) - a putative biomarker of neuroinflammation that is increased in EP individuals, and 2) midbrain neuromelanin (NM) scans, which index midbrain dopamine, shown to be decreased in Parkinson's disease and increased in schizophrenia. Each of these measures will be used individually to predict responder status for EP participants entering CSC. In addition to these analyses we will use novel deep learning methods to optimize the prediction of treatment response in EP individuals entering CSC and to obtain new insights into the mechanisms underlying these effects. Our goal is to leverage recent progress in the development of MRI based imaging biomarkers to develop a precision medicine tool that can identify early psychosis patients entering CSC who are at high risk for non-response and thereby inform treatment decision making for all patients in order to optimize the recovery of young individuals following the onset of psychotic illness.