Martin P. Paulus - US grants

Patterns of rat behavior will be quantified based on techniques derived from nonlinear dynamical systems' analysis to assess the influence of drugs of abuse on the organization of behavioral sequences. Specifically, new mathematical approaches based on large fluctuation statistics and order parameter models will enable detailed analyses of behavioral sequences. Many drugs of abuse, particularly psychostimulants, profoundly alter the organization of behavioral sequences in addition to changing the amount of behavior. The development and validation of the theoretically driven measures will be based on evaluations of an existing data base of studies of psychostimulant effects on the sequential behavior of rats exploring a novel environment. In addition, selected studies are proposed to further test the validity of the theoretical approach. The project has 3 major aims: (1) To further develop the theoretical basis and mathematical tools to quantify behavioral organization, sensitive mathematical tools will be developed to assess behavioral sequences. The order parameter approach will be used to assess qualitative differences in behavioral subsets identified by distinct fluctuation spectra of both local dynamic entropies, S(h), and local spatial scaling exponents, f(d). Multi-dimensional fluctuation spectra functions will be developed to determine relationships between different local descriptors of behavior and to evaluate temporal influences on behavioral subsets. Analogies to statistical mechanics will be used to adapt the notion of a phase transition to behavior and to classify phase transitions in behavior. (2) To determine the influences of selected organismic, experiental, and neurobiological factors on normal and drug-induced behavioral organization. Using the Behavioral Pattern Monitor and the dependent measures from Aim 1, experiments will identify gender differences of psychostimulant's effects on behavioral organization and examine changes in behavioral organization associated with long- and short-term stressors. Neurobiological studies using neurotoxin lesions will seek to validate the theoretical developments by testing hypotheses about the anatomical substrates of dopaminergic influences on the behavioral topographies. (3) To identify predictors of enduring changes in behavioral organization induced by chronic psychostimulants. Behavioral sensitization after repeated administration of dopaminergic agents will be used as an experimental tool to identify long-term changes in behavioral organization and to test the utility of the concept of behavioral organization to predict individual differences of behavioral changes as a model for the susceptibility to drug use.

DESCRIPTION (adapted from applicant's abstract): Schizophrenia is a complex disorder characterized by the fragmentation and disorganization of cognition and behavior. Patterns of cognition and behavior emerge from organized sequences of individual cognitive and behavioral elements. Methods derived from nonlinear dynamical and complex physical systems have revolutionized the analysis of experimental data and allow for the quantitative assessment of complex cognitive and behavioral patterns. A two-choice guessing task is a simple behavioral paradigm that can be used to experimentally obtain sequences of thought contingent behaviors. This proposal is based on the general hypothesis that the quantitative characteristics of sequences of behavior in schizophrenia patients will provide a crucial window into understanding cognition and behavior. To test this general hypothesis, methods derived from nonlinear dynamical and complex physical systems and this simple, computerized choice task will be used to assess the sequential organization of behavior in schizophrenia patients, mood disorder patients, and comparison subjects. The fluctuation of the predictability of the response sequences can be quantified and is used to measure the degree of behavioral disorganization. This proposal will allow the investigators to further develop this simple behavioral task in combination with complex mathematical approaches in order to understand the complex dysregulation that characterizes many facets of schizophrenia patient's cognition. 3 specific aims will be addressed in this proposal: (1) Does clinical state, disorder subtype, and treatment significantly affect the dysregulation of behavioral sequences in schizophrenia patients? (2) Is the dysregulation of behavioral sequences specific to schizophrenia? (3) To what extent is the dysregulation of behavioral sequences influenced by changing the feedback (i.e. reinforcement) provided to the subject? The goals of the proposed studies are to clarify the utility of the simple choice task in conjunction with measures derived from dynamical systems theory in order to gain insight into the fundamental characteristics of cognition and behavior in schizophrenia.

DESCRIPTION: (Adapted from applicant's abstract) A number of potentially important cognitive deficits have been reported to occur in stimulant dependent men and women. Among areas of cognitive deficits, dysregulations of decision-making have important potential clinical impact, i.e. improving decision-making strategies may help to avoid relapse, but have not been studied carefully. Subjects with stimulant dependence show dysfunctional decision-making not unlike subjects with ventromedial prefrontal cortex lesions. Two research strategies will be used. First, investigators have developed a computerized two-choice paradigm and applied mathematical tools from nonlinear dynamical systems theory to measure decision-making strategies in humans, i.e. 'coming up with rules for actions'. Second, the investigators have begun to use functional neuroimaging techniques to link dysregulations in decision-making in subjects with methamphetamine dependence to patterns of activation in different neural substrates. Both techniques will be used to address the following specific aim: (1) to better define and document the dysregulation of decision-making in the presence of uncertainty in methamphetamine dependent subjects and (2) to determine which neural substrates underlie the decision-making dysregulation in these subjects. Three main hypotheses are addressed: (1) methamphetamine dependent subjects relative to comparison subjects show a decision-making dysfunction that is characterized by an increase dependence on previous stimuli. (2) Methamphetamine-dependent subjects relative to comparison subjects show a decreased activation of the ventromedial prefrontal cortex during the two-choice task relative to the choice reaction task. (3) The behavioral differences on two-choice task and the neural substrate differences between methamphetamine-dependent subjects and comparison subjects do not change over time. The results from these studies will provide important information whether chronic use of methamphetamine is associated with neural substrate changes that impair decision-making. Moreover, this study will provide the basis for future investigations to determine whether the dysregulation in decision-making is a consequence of chronic use or a risk factor for the development of stimulant dependence.

DESCRIPTION (provided by applicant): Unconditioned locomotor behavior has been used widely as a behavioral probe to examine the functional integrity of neural systems that are critically involved in the initiation or maintenance of drug-taking behavior. Typically, the amount of locomotor behavior provides an index of general arousal and is used to examine whether drugs have stimulant properties. However, unconditioned locomotor behavior reflects a complex set of behavioral processes that include approach/avoidance, spatial mapping, novelty seeking, and exploratory behaviors. The goal of this proposal is to extend this approach to the study of mouse behavior in order to answer the following central question: Can unconditioned locomotor behavior in mice be used to extract multidimensional behavioral profiles that are reliable and have predictive validity for underlying behavioral constructs, molecular substrates, and pharmacological effects of drugs of abuse? The validity and utility of this approach will be examined by comparing the behavioral profiles of both male and female C57BI/6J and l29SvJ mice in a test-retest design and after administration of methamphetamine or MDMA. In rats, methamphetamine increases locomotor activity and exploratory behavior, has no effect on the geometric patterns of behavior but increases the unpredictability of movement sequences. In contrast, although MDMA also increases locomotor activity, it decreases exploratory behavior and induces a perseverative movement pattern in rats. It is hypothesized that independent of the predicted trait-related differences in the behavioral profiles of the two strains of mice similar drug-specific behavioral profiles will be evident in mice. The specific aims are: 1. To establish the reliability and predictive validity of measures characterizing the behavioral profile of unconditioned locomotor behavior in mice in analogy to previously established behavioral profiles in rats. 2. To determine whether methamphetamine and MDMA predictably and reliably affect the behavioral profiles of unconditioned locomotor behavior in mice in analogy to previously established behavioral profiles induced by these drugs in rats. 3. To determine whether paradigmatic and pharmacological manipulations that affect approach/avoidance predictably change the baseline behavioral profile and the changes in the behavioral profile induced by methamphetamine and MDMA. The results from these studies will provide a set of measures derived from a widely used behavioral paradigm to examine the molecular basis of the effects of drugs of abuse using genetically modified mice.

dopamine antagonists; substance abuse related disorder; cognition disorders; developmental neurobiology; mood disorders; self organization; neurotransmitter transport; reinforcer; decision making; behavioral /social science research tag; clinical research; human subject;

DESCRIPTION (provided by applicant): Stimulant dependence is an important problem in the U.S. Relapse is a frequent and complex phenomenon that occurs within one year in more than 50% of people with stimulant dependence that seeks treatment. Although the cognitive and neural mechanisms that underlie relapse are not well understood, it appears that they are closely related to basic decision-making processes. This proposal builds on work that has been accomplished in a previous R21 aimed to determine the neural substrates that underlie decision-making dysfunctions in treatment seeking methamphetamine dependent subjects. We have assembled a model to clarify the role of neural substrates in cognitive candidate mechanisms underlying decision-making as well as their dysfunction in substance dependent subjects. This proposal focuses on examining three candidate mechanism dysfunctions proposed in this model. Specifically, we will use three decision-making tasks during functional magnetic resonance imaging to probe trend detection, error processing, and risk-taking. We will focus on three 'cortical epicenters' underlying these candidate mechanisms: (1) inferior prefrontal cortex (ventromedial and ventrolateral prefrontal cortex), (2) anterior cingulate and inferior parietal Iobule, and (3) anterior insula and posterior parietal cortex. Our preliminary data indicate that neural activation patterns during decision-making tests may be a sensitive indicator for relapse susceptibility. Our specific aims are, first, to extend our finding from methamphetamine to other psychostimulants. We will compare decision-making characteristics and neural substrate activation patterns in methamphetamine dependent and cocaine dependent with those of normal comparison subjects. Second, we will prospectively follow methamphetamine dependent subjects using a comprehensive assessment of relapse factors to determine which altered candidate mechanism(s) and which neural substrate activation patterns best predict relapse susceptibility in these individuals. Accomplishing these aims would provide evidence that (1) specific cognitive mechanisms underlying decision-making are dysfunctional in subjects with stimulant use disorders; (2) these dysfunctions can be linked to specific neural substrates; (3) one can utilize computerized behavioral tests to obtain an estimate of relapse susceptibility. This project will link systems neuroscience with clinical research in substance use disorders thereby providing cognitive neuroscience and neuroimaging insights into dysfunctions associated with substance use disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To understand more about the dysregulation of brain processes that predispose people to develop substance dependence and to identify brain activation patterns that relate to stimulant use, and predict the transition from stimulant use to stimulant dependence in young adults (age 18-24).

3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Behavioral; CRISP; Cognition Disorders; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Decision Making; Dopamine; Funding; Genetic; Grant; Hydroxytyramine; Institution; Investigators; Moods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Transmitter Substances; Neurotransmitters; Patients; Psychological reinforcement; Reinforcement; Reinforcement (Psychology); Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Rewards; Schizophrenia; Schizophrenic Disorders; Source; Substance Use Disorder; Thinking; Thinking, function; United States National Institutes of Health; abused drugs; cognitive disease; cognitive disorder; dementia praecox; drug of abuse; drugs abused; drugs of abuse; schizophrenic

[unreadable] DESCRIPTION (provided by applicant): Drug use is an important problem in the US. However, the complex and multifaceted mechanisms that lead to and support drug abuse are only vaguely understood. Increased impulsivity is commonly observed in drug users and is thought to be an important trait of individuals who have problems with illicit drugs. Impulsivity can be quantified experimentally using temporal discounting paradigms. Temporal discounting refers to the phenomenon that a reward, which occurs in the present time is valued more than rewards that occur some time in future. A poorly studied aspect of temporal discounting (and therefore impulsivity) is how individuals process time. Therefore, our proposal aims to examine the relationship between temporal discounting and subjective and objective measures of time perception in young adults (age 18-21) who use stimulants and are of risk for transition to stimulant dependence. The proposed study is based on the hypothesis that these individuals, relative to age and education matched comparison subjects show enhanced temporal discounting due to an altered sense of time. The specific aims are: (1) we will evaluate the relationship between delayed discounting in a decision making task and in subjective and objective measures of time perception in young adults who use stimulants and in matched controls; (2) we will evaluate the relationship of functional magnetic resonance imaging activation between delayed discounting in a decision making task and a time estimation task in young adults without stimulants use. These studies are based on the assumption that impulsivity, measured with temporal discounting, is dependent on a subjective focus on the present time and an overestimation of the duration of time intervals. We will use functional magnetic resonance imaging during temporal discounting and time estimation tasks in healthy volunteers to elucidate whether similar neural substrates underlie both processes. It is proposed that examining how individuals process time to how they process current versus future rewards using functional neuroimaging enhances our understanding of the biological underpinnings of impulsivity. Moreover, a better understanding of the neural mechanisms underlying temporal discounting may provide us with a marker to study the biological basis of risk for addiction. The current study will inform treatment programs to create intervention strategies that manipulate the temporal delay of rewards to shape more adaptive behavior. [unreadable] [unreadable] [unreadable]

After Care; After-Treatment; Aftercare; Brain; CRISP; Cell Communication and Signaling; Cell Signaling; Clinical Trials; Clinical Trials, Unspecified; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Emotional; Emotions; Encephalon; Encephalons; Functional Magnetic Resonance Imaging; Funding; Grant; Institution; Intracellular Communication and Signaling; Investigators; MRI, Functional; Magnetic Resonance Imaging, Functional; Measures; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; PBO; Paroxetine; Patients; Pattern; Piperidine, 3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-, (3S-trans)-; Placebos; Receptor Protein; Research; Research Personnel; Research Resources; Researchers; Resources; SSRI; Selective Serotonin Reuptake Inhibitor; Selective serotonin re-uptake inhibitor; Series; Sham Treatment; Signal Transduction; Signal Transduction Systems; Signaling; Social Phobia; Source; Standards; Standards of Weights and Measures; United States National Institutes of Health; biological signal transduction; blood oxygen level dependent; clinical investigation; fMRI; novel; receptor; serotonin reuptake inhibitor; sham therapy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1. To determine the role of the subjective sense of time in decision making 2. To evaluate the association between impulsive decision making and time perception

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deterime the basic neural systems important for decision making in healthy volunteers. Develop a basic systems neuroscience endophenotype based on decision-maiking and related processes for anxiety, mood and addictive disorders.

Abstract After marijuana, amphetamines are the most widely used illicit drug class worldwide. A recent report estimates that methamphetamine causes about 895 deaths per year in the U.S. and is responsible for an annual economic burden of $23.5 billion. Negative reinforcement occurs when (a) an action is selected to avoid an aversive outcome or (b) an individual in an aversive state acts to end such a state and has been considered an important mechanism underlying compulsive drug-taking behavior. The aversive state or outcome is processed by the interoceptive system, which includes the insular cortex and signals how we feel. Risk- taking decision-making is among the key dysfunctional behaviors in drug addicted individuals. Yet, there have been no studies to examine the causal influence of altering interoception on risk-taking decision-making, i.e. how feeling bad affects the choices one makes. In response to the RFA, we bring together two experimental approaches to examine to how anticipating or experiencing an aversive state alters risk-taking behavior decision-making in methamphetamine dependent (MD) individuals. These approaches include (1) using aversive direct interoceptive stimulation and negatively valenced faces as non-interoceptive stimuli to modulate the state of the individual and (2) measuring the frequency of risky responses during a risk-taking task and the adjustment to errors during a two-choice prediction task. These approaches are combined with functional magnetic resonance imaging (fMRI) to examine how negative reinforcement mechanisms are implemented in the brain and to lay the groundwork for neural substrate specific treatment interventions. Specific Aim 1: To determine the behavioral effects of anticipating and experiencing an aversive and pleasant interoceptive stimulus and the impact of negatively and positively valenced faces on risky decision making in MD individuals, relative to comparison subjects. Specific Aim 2: To determine the brain activation differences associated with anticipating and experiencing an aversive and pleasant interoceptive stimulus and their impact on brain activation during risky decision making in MD individuals relative to comparison subjects. Specific Aim 3: To evaluate the plasticity of the behavioral and neuroimaging findings as a function of sustained abstinence in MD individuals. Based on a neural processing model, it is proposed that MD individuals exhibit two types of abnormalities: (1) an increased sensitivity to anticipating and experiencing aversive events and (2) a decreased flexibility to adjust their behavior when anticipating or experiencing an aversive event. Two experiments are proposed. First, the effect of breathing restriction and the effects of negatively valenced faces on the frequency of risky decision making will be examined in a behavioral and neuroimaging study of 30 recently abstinent (3-6 weeks) MD individuals and 30 healthy volunteers. Second, if - as we hypothesize - MD individuals fail to adjust their risk-taking behavior in response to negatively valenced faces, we will determine in another experiment the effect of anticipation of aversive interoceptive stimuli on risky choices. Alternatively, we will test the effect of aversive interoceptive stimuli on decision-making adjustments to errors during the two- choice prediction task. We have found recently that the activation pattern within the insular cortex change as a function of duration of drug use and/or abstinence. Thus, we will extend the cross-sectional study to include a 6 months follow-up to determine whether sustained abstinence is associated with an attenuation of the hypothesized behavioral and neural abnormalities. The results from these experiments will determine whether the interoceptive system itself is sensitized or whether information from the interoceptive system, e.g. insular cortex, is not appropriately processed by other brain areas that are important for adjusting risk-taking and decision making, e.g. anterior cingulate and orbitofrontal cortex.

Project 2: After marijuana, amphetamines are the most widely used illicit drug class woridwide and recent evidence shows that methamphetamine causes about 895 deaths per year in the U.S. and is responsible for an annual economic burden of $23.5 billion. Interoception comprises the sensing of the physiological condition of the body, consciously representing this internal state within the context of ongoing activities, and inifiating mofivated action to homeostatically regulate this state. Previous investigations have shown that individuals with insular lesions reported they had "lost the urge to smoke," and our results indicate that attenuated activation in insula was related to an increase propensity to relapse. Although this links interoception to insular functioning abnormalities to drug addiction, the precise role of interoception in drug addiction is unclear. To test the hypothesis that dysregulated insular cortex function in amphetamine dependent (AD) individual results in an insufficient, instable, or non-adaptive adjustment to perturbations of the internal state, we will examine using event-related fMRI the neural processing of: (1) direct interoceptive stimulation during positively valenced and negatively valenced interoceptive stimuli, and (2) internally generated interoceptive stimulation using cue reactivity paradigms. The behavioral and brain response characteristics will be examined during: (a) anticipation, (b) stimulation, and (c) post-stimulus processing. The specific aims are: (1) To determine the status of the interocepfive system in response to positively and negatively valenced interoceptive sfimuli in adults with AD, adults in full sustained remission, and healthy comparison subjects;(2) To determine the sensifivity of the interoceptive system in response to internally generated interoceptive sfimulafion using cue reactivity in AD individuals, those in full sustained remission, and healthy comparison subjects;(3) To modify the neuroimaging paradigms in response to the animal studies (Project 3) and results from Wave 1 human studies to determine whether negafive or positively valenced interocepfive stimulation modulates cue reactivity in AD individuals at various stages of drug use. The clarification of the role of interocepfion and insular cortex functioning in various stages of amphetamine dependence would help to identify a "vulnerability window" when individuals are at high risk for relapse. Determining whether there is an altered valence-specific sensitivity of the interoceptive system in AD would help to select specific sfimulus materials for cognitive and emotional intervention approaches. Elucidafing the relationship betiA/een interoceptive dysfunctions and other psychological constructs, e.g. craving and selfefficacy, will help to relate interoception to existing theories of drug addiction.

DESCRIPTION (provided by applicant): This proposal requests continued NIMH funding for the University of California, San Diego "Fellowship in Biological Psychiatry and Neuroscience", T32-MH18399. This program represents a long tradition in mental health research training at UCSD. The success of the program is demonstrated by the remarkable productivity of its trainees in terms of publications, major awards, and subsequent funding. In the most recent project period alone, trainees have received five NARSAD Young Investigator awards, three NIH K-series training grants, and several other national prizes. Furthermore, all recent program graduates have published first-authored peer-reviewed research papers reporting their Fellowship work, and nearly all continue to work in full-time academic research positions. The need for training programs of this kind is profound. Both the scientific community and the informed public hope and expect that major recent advances in basic neuroscience and genetics, such as functional imaging of the living human brain and the genome project, will lead to breakthroughs in the understanding and treatment of mental disorders. However, complex research technologies take years of training to master, and a lack of researchers who can use these methods to understand the etiology of psychiatric disorders, and transform basic findings into new therapies, could prevent their potential from being realized. Especially problematic is a lack of clinician-scientists who have the training necessary to work at the forefront of biological psychiatry and also translate scientific achievements into new treatments. In the coming project period, the specific goals of the program are: 1) Maintain and improve both the ethnic and the academic diversity of the program trainees using specific recruitment strategies. 2) Foster innovation by promoting exchange between a dynamic mix of psychiatric physicians, clinical psychologists and basic neuroscientists. 3) Provide systematic oversight of mentor assignments, research projects, and trainee progress beginning prior to program entry and continuing throughout training. 4) Provide a strong core of research didactics, yet tailor requirements to meet the specific needs of each trainee. 5) Provide continual education and mentorship in career development "survival skills" which will foster the trainees'transitions to independent research careers.

DESCRIPTION (provided by applicant): This application requests initial support for an Exploratory Center for Translational Research on the Clinical Neurobiology of Drug Addiction (P20). The proposed UCSD Center on Interoceptive Dysregulation in Addiction (CIDIA) addresses the global question: How does the brain regulate the urge to use?, with a focus initially on What is the role of interoceptive systems in general, and insular cortex in particular, in amphetamine addiction? Interoception comprises sensing the physiological condition of the body, the conscious representation of this internal state within the context of ongoing activities, and the initiation of motivated action to regulate this state. Recent human and animal findings provide compelling evidence that interoceptive processing in the insula may mediate drug-related urges and preferences. Despite this evidence, it remains unclear how exactly the insula modulates these behaviors and what role interoceptive processing plays in different stages of addiction. To address these questions, we propose the following Specific Aims: (1) To determine the response characteristics of the interoceptive system using functional magnetic resonance imaging (fMRI) in adolescents and adults across stages of amphetamine use/addiction; (2) To delineate the causal role of interoceptive processing in mediating direct and conditioned rewarding or aversive effects in a rodent model using insula silencing via reversible inactivation of neural activity with muscimol; and (3) To integrate results of animal and human studies and provide translational predictions by (a) developing animal models of interoceptive dysfunction, (b) using predictions from animal finding to modify human neuroimaging paradigms, and (c) modifying target structures of animal silencing experiments based on human imaging studies. The goal for the Center is to impact the field of drug addiction in the following ways: (1) To develop and refine our understanding of the role of interoception for amphetamine dependence and, possibly, for addiction at large; (2) To develop translational paradigms to probe the sensitivity of the interoceptive system in animal models of drug addiction and humans in different stages of drug addiction; (3) To lay the groundwork for modulating the interoceptive system as a target for treatment; and (4) To discover risk factors or phenotypes for drug addiction involving interoceptive processing.

DESCRIPTION (provided by applicant): Neuroscience is among the fastest growing area of science and has produced remarkable developments that will have profound implications for the understanding and treatment of mental disorders. Innovations in brain imaging methods and enormous progress in molecular biology and molecular genetics have resulted in unprecedented advances that have extended visions of understanding and treating psychiatric disorders to the hope of preventing and even curing them. However, there is still a gap in applying knowledge and tools to psychiatric disorders that is due, in part, to a shortage of clinical researchers. Consequently, it is imperative train researchers to translate important basic science findings into clinically relevant treatments. This competitive renewal application requests continued NIMH funding for the long-standing, successful University of California, San Diego (UCSD) Fellowship in Biological Psychiatry and Neuroscience. The Fellowship is designed for provide education, research training, and career opportunities for 5 post-doctoral fellows with a particular emphasis on candidates that are focused on using biological tools to understand brain processes of psychiatric illness and develop potential treatments for these disorders. The overall goal is to train Fellows from diverse backgrounds to acquire the skills necessary for the conceptualization, planning, conduct and publication of research in biological psychiatry and neuroscience with the ultimate goal to become independent and funded researchers. Specific goals of the Fellowship are: (1) To provide a high level of training necessary for successful transition into an independent research career, which is focused on: a) Ethical conduct of research and research ethics;b) General methodologies applicable to research in biological psychiatry and neuroscience;and c) Specific approaches relevant for the fellow's research project. (2) To enable the Fellow to conduct and complete a specific research project that can be viewed as a seed for an independent research career trajectory and includes: a) Proposal of a research project based on NIH forms and guidelines;b) Implementation of this project with a UCSD-affiliated mentor, and c) Regular monitoring and evaluation. (3) To provide practical advice and support for career development, which includes: a) Opportunities for fellows to present their projects;b) Explicate milestones and career guidelines;c) Network with senior researchers, other organizations, and online resources. PUBLIC HEALTH RELEVANCE: This competitive renewal application requests continued NIMH funding for the long-standing, successful University of California, San Diego (UCSD) Fellowship in Biological Psychiatry and Neuroscience. The Fellowship is designed for provide education, research training, and career opportunities for 5 post-doctoral fellows with a particular emphasis on candidates that are focused on using biological tools to understand brain processes of psychiatric illness and develop potential treatments for these disorders. The overall goal is to train Fellows from diverse backgrounds to acquire and extend skills necessary for the conceptualization, planning, and conduct and publication of research in biological psychiatry and neuroscience with the ultimate goal to become independent and funded researchers, thereby addressing the shortage of clinical researchers who can translate advances in science to treatments for psychiatric disorders.

DESCRIPTION (provided by applicant): The NIMH Research Domain Criteria (RDoC) framework is a heuristic approach to integrate neuroscience with psychopathology. Thus, RDoC is the attempt to develop constructs that (a) connect across units of analysis, (b) are applicable across established diagnostic criteria, and (c) are a point of departure to provide measurable constructs that will be useful to gain a deeper understanding of psychiatric conditions. However, the lack of reliable, robust latent constructs derived from experimental measures is a critical barrier to organizing mental disorders along dimensions that can be mapped onto multiple units of analysis. We focus on the positive and negative valence system domains proposed by the RDoC using self-report, behavior, physiology, and neural circuit unit of analysis measures, apply them to a clinical population of individuals with anxiety or depression recruited from primary care clinics across two sites, and apply latent variable analysis to derive latent constructs of positiv and negative valence systems functioning that cut across units of analyses. The specific aims of the proposal are: (1) To recruit, assess, and analyze self-report, behavioral, physiological, and neural circuit unit of analysis data in an exploratory sample from a cohort of n=100 treatment seeking individuals presenting to primary care clinics at UCSD and UCLA. (2) To obtain a confirmatory sample of n=100 subjects at both sites using the same measurement approaches to determine the reproducibility and robustness of the latent constructs obtained from the exploratory sample. (3) To obtain a reliability sample of n=50 individuals at UCSD and UCLA that will be re-tested within a month to determine the reliability of the latent constructs. This wll be the first time neural indices of positive valence and negative valence are investigated within the same broadly defined sample of anxious or depressed patients. Extant studies of neural processes in emotional disorders are limited to relatively small sample sizes. By combining resources across two sites, we will recruit a large enough sample to conduct more comprehensive analyses than ever before achieved. Once the proposed aims are completed, we will have a robust and reliable dimensional set of variables that quantify the positive and negative valence domains based on a latent variable approach. These variables capture clinical variance and will have been obtained from two different clinical sites to provide empirical evidence of the generality of the negative and positive valence domains. These variables will subsequently be used to determine whether (a) they can be used as predictors for how well an individual will respond to pharmacological or behavioral treatment; (b) they can be differentially responsive to therapies that are specifically aimed at modifying the positive or negative valence systems, and (c) they can be used in subsequent computational and/or neural process models of anxiety and depression to gain a more fundamental understanding of the pathology that occurs in these individuals.

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 child and 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 University of California, San Diego and Laureate Institute for Brain Research is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (5/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1086 9-10 year olds enriched for high- risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD- USA Consortium. All 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) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This hub's Research Project focuses on mechanisms of substance use disorder, special populations with high use prevalence, and the use of drugs other than marijuana. (1) We will determine whether individual differences in neural processing of antireward (i.e., negative reinforcement mechanisms) in amygdala, insula, and anterior cingulate are associated with increased negative emotionality and pain, predict initiation of use and problem use, and are in turn further dysregulated by substance use. (2) We will determine whether protective environment factors and ethnic identification in minority youth are linked to healthier antireward processing and better substance use outcomes. (3) We will determine whether antireward neural processing predicts increased use of illicit drugs other than MJ including misuse of prescription drugs, if such use predicts subsequent exaggerated antireward processing, and if gateway interactions exist between substances. Finally, we will use machine learning approaches to develop a youth-specific risk calculator that will enable us to identify individually- based modifiable risk factor, providing brain-based targets of future novel prevention and intervention approaches.

Project Summary Mood and anxiety disorders will account for approximately $16 x 109 lost productivity or 25% of global GDP over the next 20 years. Eating disorders are among the deadliest psychiatric diseases and Anorexia Nervosa is two to three times more deadly than schizophrenia, bipolar and major depressive disorder. The Center for Neuroscience-based Mental Health Assessment and Prediction (NeuroMAP) aims to provide a (a) scientific, (b) operational, and (c) educational infrastructure for innovative neuroscience-based research to use individual differences on several biological levels together with sophisticated statistical approaches to generate clinically meaningful predictions of risk and outcomes for mood, anxiety, and eating disorders. The Laureate Institute for Brain Research (LIBR) in Tulsa, OK, is ideally placed to provide this infrastructure because: (a) LIBR has recruited young investigators with an impressive track record of scientific productivity, (b) LIBR is situated adjacent to the Laureate Psychiatric Clinic and Hospital (LPCH), one of the Midwest's largest psychiatric facilities that provides LIBR with a pipeline for patient recruitment, and (c) LIBR closely collaborates with the University of Tulsa (TU) on computational statistics and University of Oklahoma, Tulsa (OU) on bioassay research. The Specific Aims of NeuroMAP are: (1) To provide a state of the art neuroimaging and laboratory infrastructure to conduct biological experiments with multi-level assessments using core facilities; (2) To provide a mentoring infrastructure to a group of young investigators to conduct studies that identify predictive biological markers and processes for patients with mood or anxiety disorders; (3) To create a career development infrastructure to accelerate the investigator's transition from young investigator to established investigator; (4) To build an operational infrastructure that provides the tools necessary to conduct the research projects, standardize assessments and provide a data repository for future pilot projects. NeuroMAP will consists of: (a) an Administrative Core (Paulus): to establish the infrastructure necessary to expand the research efforts of the young investigators; (b) Research Core (Bodurka, Teague, McKinney): to provide the technical expertise to utilize multi-level approaches (from cell markers to symptoms) to quantify individual differences and generate outcome predictions. The Center proposes 5 different projects: (1) Cerebellar Role In Fear Conditioning And Extinction. (Cha) Mentor: Amit Etkin, Stanford; (2) Predicting Response To Exposure Therapy In Anxiety Disorders Using Neural And Behavioral Markers Of Interoceptive Habituation (Feinstein) Mentor: Murray Stein, UCSD; (3) Interoceptive dysfunction and Appetite Dysregulation in Depression (Simmons) Mentor: Luan Phan, University of Illinois Chicago; (4) Response To Inflammatory Challenge In Major Depressive Disorder (Savitz) Mentor: Mike Irwin, UCLA; (5) Dysfunctional Interoceptive Accuracy In Anorexia Nervosa, (Khalsa) Mentor: Walt Kaye, UCSD.

Project Summary The Administrative Core for Neuroscience-based Mental Health Assessment and Prediction (NeuroMAP) will set up and provide the basic infrastructure to (a) coordinate and integrate center activities, (b) provide day-to- day administrative support for the projects, (c) to oversee, monitor, and evaluate the development and progression of the young promising project PIs into R01-level funded independent investigators and (d) work closely with the internal and external advisory committee to keep NeuroMAP on track to create a pipeline for the development of future investigators. The central theme of the Laureate Institute for Brain Research is ?Improving Mental Health Through Neuroscience? and clearly emphasizes the applied nature of the research. The Administrative Core is responsible for establishing the Center as a regional, national, and international resource in developing neuroscience-based predictors of risk and outcomes in mood, anxiety and eating disorders. The goal is to allow for a continuous flow of young investigators who may be able to establish a self-sustaining infrastructure of highly competitive research. Mentorship by experienced investigators who may not be in the immediate vicinity of the center is a unique aspect of the CoBRE support mechanism. An organizational structure that initiates, oversees, and supports these types of mentoring relationship is critical for mentoring to be effective, i.e. to develop young investigators. Moreover, a second function of this core is to bind the projects together, to be the hub of activity that are supported by NeuroMAP, and to assure that a intellectual infrastructure is being created that assures mentoring and training of young researchers. The specific aims are: (1) To administratively coordinate and integrate center activities that bind together center- supported projects. (2) To provide fiscal and administrative support across projects. (3) To establish and oversee Research Training and Mentoring. Accomplishing these aims will (1) enable efficient administrative support to NeuroMAP investigators through the provision of coordinated grants management, human subjects protections procedures, human resources assistance, and other administrative support; (2) disseminate information about NeuroMAP research activities and programs to investigators at TU and OU as well as outside collaborators to encourage new collaborations and mentorship of new investigators who will do research focused on individual differences on multiple levels of assessment together with sophisticated statistical approaches to generate clinically meaningful predictions; (3) provide important training and mentoring to develop young investigators into independent investigators with R01 level funding. This core will set up a series of activities, lectures, and tasks that are aimed at improving research training for young investigators. Moreover, this core will provide the framework for effective mentoring between the junior project investigators and the outside mentors.

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.