Erika E. Forbes, Ph.D. - US grants

DESCRIPTION (provided by candidate): The educational aim of the proposed Mentored Research Scientist Development Award (MRSDA) is to train the candidate in adolescent developmental psychopathology and affective neuroscience relevant to understanding key aspects of adolescent depression. Decreased positive affect appears to be an important but little-studied component of adolescent depression. From an affective neuroscience perspective, it is valuable to examine positive affect through measures of reward processing. To accomplish the educational aim of the proposed MRSDA, the candidate will (1) learn from expert mentors and consultants on adolescent development, functional magnetic resonance imaging (fMRI), neuroimaging data analysis, and longitudinal data analysis;(2) complete coursework in adolescent development, affective neuroscience, statistics, and research ethics;(3) attend methodology workshops on fMRI, neuroimaging data analysis, and longitudinal data analysis;and (4) conduct a study of neural and subjective components of positive affect in adolescent depression. The proposed study has three specific aims. Aim 1 focuses on the hypothesis that adolescent depression is associated with low activation (as revealed by blood oxygen level-dependent signal intensities) in reward-related brain areas (including the ventral striatum, dorsal striatum, orbitofrontal cortex, and amygdala) in response to rewarding events. Aim 2 focuses on the hypothesis that adolescent depression is associated with low subjective experience of positive affect in natural settings, as measured by ecological momentary assessment. Aim 3 focuses on the hypothesis that brain reward activation in depressed adolescents in the fMRI study is related to the seeking and experience of positive affect in natural settings. Consistent with the priorities of the National Institute of Mental Health, the proposed MRSDA will foster a new course of study on the affective neuroscience of early-onset affective disorders by focusing on development and applying a translational approach with basic neuroscience techniques to clinical questions. Adolescent depression is a common, chronic disorder that leads to death (suicide), disability, and suffering. Advancing knowledge of the underlying emotional processes and real-life experiences in adolescent depression represents a crucial step in developing early intervention and prevention strategies. The ultimate goal is to decrease rates of a disorder that devastates the lives of so many adolescents and their families.

DESCRIPTION (provided by applicant): The goal of this project is to examine biological and early developmental factors in patterns of substance use in young men from early adolescence to the transition to adulthood. The project builds on an ongoing prospective, longitudinal study of 310 high-risk young men who have been followed since infancy using multiple methods (e.g., observation, interview) and informants (e.g., parents, teachers, peers) and spanning child, family, and extra-familial risk factors. As participants undergo the transition to adulthood and face challenges in interpersonal and instrumental domains, the project will incorporate data on genetics and brain function to understand how these individual differences in underlying, emerging biology factors, separately and in combination, influence patterns of use for drugs, alcohol, and nicotine. Assessments of brain function will examine the contribution of function in mesolimbic and corticolimbic neural circuits at two time points by conducting functional MRI of participants' striatal reactivity to reward stimuli, amygdala reactivity to threat stimuli, resting cerebral blood flow, and resting functional connectivity. The inclusion of fMRI at this point in the longitudinal study will provide detailed information on the association between brain function and genetic factors, early development, social context, and substance use. The guiding hypothesis of the project is that stable characteristics such as a history of antisocial behavior and impulsivity; family and extra- familial contextual risk; brain function; and genetic variants associated with substance use- related brain function will contribute to longitudinal patterns of substance use. In addition, it is expected that the success participants have in establishing stable romantic relationships and employment/educational training during the transition to adulthood will attenuate associations between risk factors and patterns of substance use in early adulthood. The project provides an unprecedented opportunity to examine factors spanning from early childhood through early adulthood that are related to substance use and to link such data with data on genes and brain function during the transition from adolescence to adulthood using a low-income sample of ethnically diverse males at high risk for maladaptive adult functioning. Thus, the study offers the potential to advance our understanding of pathways to substance use problems and guide developmentally informed prevention and intervention efforts.

DESCRIPTION (provided by applicant): The developmental timing of the increase in the rate and the emergence of sex differences in depression points to adolescence as a critical period for understanding the causal mechanisms underlying the development of depressive disorders in females. Adolescent neural development is likely to play a key role in the etiology of depression, but little is known about the interface between the development of neural circuitry and depression across adolescence. In response to PA-09-108 Women's Mental Health and Sex/Gender Differences Research, we will determine if developmental changes in the neural circuitry engaged by emotionally evocative stimuli are related to adolescent depression in girls. Mapping developmental trajectories of depression symptoms onto relevant neural systems will further our understanding of the maturational changes in brain function that contribute to age-related vulnerability. Investigators: Drs. Keenan, Guyer and Forbes are the PIs;they began collaborating on the neuroscience of depression two years ago. Dr. Kevin Grimm, a statistician specializing in longitudinal modeling, and Dr. Alison Hipwell an expert in female mental health, are Co- Investigators. Consultants are Drs. Gang Chen, Ronald Dahl, Constance Hammen, and Daniel Pine. Innovation: Brain-behavior perturbations in information processing are a major focus of clinical neuroscience research. Developmental shifts in neural circuits during adolescence are critical to understanding the emergence of psychopathology during this period. No study to date, however, has been designed to test the hypothesis that development of the functional connections between affective and cognitive circuits during the adolescent period is related to depression-onset, or to characterize the patterns of neural development that in fact confer risk for depression onset. Approach: This proposal builds on a recently completed NIMH-funded study of precursors to depression in girls, in which depression symptoms and negative life events were documented from ages 9-14. Half of the sample was selected on measures indicative of high risk for developing depressive disorders. For this PA, we propose to study this sample from ages 15-19 years and to conduct annual assessments of depression and environmental stressors and annual assessments of emotional memory and reward processing using neuroimaging. Developmental patterns in functional connectivity between amygdala-ventral-lateral prefrontal cortex (vlPFC) circuitry and striatum-medial prefrontal cortex (mPFC) circuitry during memory for emotional faces and reward processing, respectively, will be captured across four time points, as will environmental stress exposure. Environment: This proposal involves a multi-institutional investigation at the Universities of Chicago, Pittsburgh, and California-Davis. Assessments of depression, stress exposure, and brain function will be conducted in the University of Pittsburgh's Department of Psychiatry and the Neuroimaging of Emotional Disorders Lab at Western Psychiatric Institute and Clinic, which is internationally recognized for research on brain functioning and child psychopathology. PUBLIC HEALTH RELEVANCE: We propose to determine if developmental changes in how the brain responds to emotional stimuli during adolescence can inform us regarding which girls are at risk for developing depressive disorders. Adolescence appears to be a time of vulnerability in terms of developing circuits in the brain that help regulate emotional responses. By conducting a longitudinal study from ages 15-19 we will be able to examine individual differences in brain functioning from mid to late adolescence and test whether different pathways to developing mature brain circuits explains individual differences in risk for depression.

DESCRIPTION (provided by applicant): In response to RFA-AG-11-010, Basic Research on Self-Regulation, the current proposal takes an interdisciplinary approach to developing and piloting a novel functional magnetic resonance imaging (fMRI) paradigm for assessing adolescents' reward function in neural circuits implicated in reactivity and self- regulation. The overall goal of the proposed study is to develop methods for assessing the mechanisms of the development, during adolescence, of reward-related problem behaviors such as substance use, sensation- seeking, depressive symptoms, and HIV-risk behavior. Ultimately, the proposed study may have relevance to preventing these problems from developing into serious health problems such as addiction, depression, and HIV. The novel fMRI paradigm designed in the proposed study will be more ecologically valid than current fMRI reward paradigms because it will focus on personally relevant peer contexts, which create demands for the self-regulation of reward function. After development of the fMRI paradigm, the proposed study will examine 70 healthy community adolescents' neural response to the task in the striatum and medial prefrontal cortex (mPFC), as well as functional connectivity between these regions. The proposed study will investigate the association between adolescents' neural response to the novel fMRI task and their neural response to established reward tasks; behavioral response to computer tasks; behavioral response to interactions with peers; and subjective experience of positive affect during ecological momentary assessment. This strategy will allow the evaluation of how well the novel task improves on current measures of reward function. Finally, the proposed study will test the association of the novel fMRI task with adolescents' current problem behaviors relevant to the self-regulation of reward, including sensation-seeking behavior, substance use, depressive symptoms, and HIV-risk behavior. In all, the proposed study offers the opportunity to investigate how well a novel fMRI paradigm captures adolescents' reward function and predicts problem behaviors, with ultimate applications to investigating the mechanisms of the longitudinal development of serious problem behaviors.

DESCRIPTION (provided by applicant): The goal of this project is to examine biological and early developmental factors in patterns of substance use in young men from early adolescence to the transition to adulthood. The project builds on an ongoing prospective, longitudinal study of 310 high-risk young men who have been followed since infancy using multiple methods (e.g., observation, interview) and informants (e.g., parents, teachers, peers) and spanning child, family, and extra-familial risk factors. As participants undergo the transition to adulthood and face challenges in interpersonal and instrumental domains, the project will incorporate data on genetics and brain function to understand how these individual differences in underlying, emerging biology factors, separately and in combination, influence patterns of use for drugs, alcohol, and nicotine. Assessments of brain function will examine the contribution of function in mesolimbic and corticolimbic neural circuits at two time points by conducting functional MRI of participants' striatal reactivity to reward stimuli, amygdala reactivity to threat stimuli, resting cerebral blood flow, and resting functional connectivity. The inclusion of fMRI at this point in the longitudinal study will provide detailed information on the association between brain function and genetic factors, early development, social context, and substance use. The guiding hypothesis of the project is that stable characteristics such as a history of antisocial behavior and impulsivity; family and extra- familial contextual risk; brain function; and genetic variants associated with substance use- related brain function will contribute to longitudinal patterns of substance use. In addition, it is expected that the success participants have in establishing stable romantic relationships and employment/educational training during the transition to adulthood will attenuate associations between risk factors and patterns of substance use in early adulthood. The project provides an unprecedented opportunity to examine factors spanning from early childhood through early adulthood that are related to substance use and to link such data with data on genes and brain function during the transition from adolescence to adulthood using a low-income sample of ethnically diverse males at high risk for maladaptive adult functioning. Thus, the study offers the potential to advance our understanding of pathways to substance use problems and guide developmentally informed prevention and intervention efforts. PUBLIC HEALTH RELEVANCE: The goal of this project is to examine biological and early developmental factors in patterns of substance use in young men from early adolescence to the transition to adulthood. The project builds on an ongoing prospective, longitudinal study of 310 high-risk young men who have been followed since infancy using multiple methods and informants, and spanning child, family, and extra-familial risk factors. These data will be linked with data on genes and brain function during the transition from adolescence to adulthood. Thus, the study offers the potential to advance our understanding of pathways to substance use problems and guide developmentally informed prevention and intervention efforts.

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) in adults is a serious and often refractory psychiatric illness, yet little is known about underlying mechanisms that might serve as targets for the development of novel interventions. One challenge in advancing research on the pathophysiology of AN relates to the substantial within-group heterogeneity that characterizes the illness. For example, the Diagnostic and Statistical Manual of Mental Disorders includes two subtypes of AN - restricting (AN-R) and binge-eating/purging (AN-BP) that differ with respect to the presence of binge eating or purging (i.e., self-induced vomiting or the misuse of laxative, diuretics or enemas) episodes. Although there is some evidence that AN-R and AN-BP are distinct, the mechanisms that separate these groups remain elusive. Moreover, similarities and distinctions between AN-BP and bulimia nervosa (BN) underscore the need to identify processes that are shared by and unique to AN-R, AN-BP and BN. Accordingly, the overall goal of this study is to test a conceptual model linking heterogeneity in symptom presentation across the AN-BN spectrum to variations in the salience of two facets of cognitive inflexibility - attentional set-shifting (i.e., the ability to shift attention between two abstract stimulus dimensions) and reversal learning (i.e., the ability to alter behavior in response to changes in reinforcement contingencies). Importantly, attentional set-shifting and reversal learning are neurobiologically distinct, with correlates in the ventrolateral prefrontal cortex/anterior cingulate cortex and orbitofrontal cortex/ventral striatum, respectively. Cognitive inflexibility has received much attention as a putative biomarker of AN, but previous studies have relied primarily on multidimensional clinical neuropsychological measures that do not map on well to underlying neural mechanisms, and findings have been mixed. This study is guided by the hypothesis that heterogeneity in AN can be elucidated by identifying distinct aspects of altered function in fronto-cingulate circuitry mediating attentional set-shifting and fronto-striatl circuitry mediating reversal learning. Thus, this study will use both behavioral tasks outside of the scanner (i.e., Intradimensional/Extradimensional shift task from the Cambridge Neuropsychological Test Automated Battery and a probabilistic reversal learning task) and functional magnetic resonance imaging with conceptually-relevant neurocognitive probes to assess and separate behavioral and neural facets of attentional set-shifting and reversal learning across the AN-BN spectrum. Four groups of participants aged 18-55 years will be recruited: 1) AN-R with no history of binge eating or purging (n = 30); 2) AN-BP (n = 30); 3) BN with no history of AN (n = 30); and 4) psychiatrically healthy controls (n = 30). This study is innovative and significant as the first effort to examine the separate contributions of attentional set-shifting and reversal learning to phenotypic heterogeneity across the AN-BN spectrum. Findings will have important implications for neurobiological models of eating disorders and the development of novel interventions designed to target subgroup-specific pathophysiological processes.

? DESCRIPTION (provided by applicant): The proposed developmental psychopathology study examines the development of anhedonia during adolescence. Anhedonia, or difficulty experiencing pleasure in anticipation of or response to rewarding stimuli, is a coherent dimension within positive valence systems, has putative neural correlates in frontostriatal circuitry, and is relevant to several forms of serious psychopathology that emerge during adolescence. Anhedonia, a serious symptom, is likely to emerge during adolescence, and we propose that the development of anhedonia could precede the development of affective and schizophrenia-spectrum psychopathology. Specifically, the study examines developmental changes in subjective, neural, and behavioral aspects of anhedonia in 130 adolescents, age 13-17, who are either typically developing or have a first-degree relative with a history of depression, bipolar disorder, or schizophrenia-spectrum disorder. With the goal of understanding the development of anhedonia, the proposed study's aims include investigating (1) differences in anhedonia between high-risk and low-risk adolescents; (2) the development of anhedonia across adolescence; and (3) associations between anhedonia and depression, mania, and psychosis both cross-sectionally and longitudinally. Participants will complete 3 laboratory visits at annual intervals and 2 internet-based assessments, scheduled every 6 months between lab visits. Laboratory visits include self- and parent-report of anhedonia, psychopathology, and functioning; functional magnetic resonance imaging (fMRI) of frontostriatal function in response to monetary and social rewards; and behavioral tasks assessing reward motivation and reward learning. We will use longitudinal growth modeling to test our hypotheses. This study promises to advance mental health research by elucidating the development and pathophysiology of anhedonia, a dimension of psychopathology that occurs across disorders. Resulting understanding can inform the design of innovative, developmentally targeted prevention approaches.

? DESCRIPTION (provided by applicant): For more than two decades, the declining number of clinical scientists who pursue mental health research, coupled with a high rate of attrition among those who do enter the field have been threatening our nation's ability to leverage advances in basic biomedical and behavioral sciences into improvements in public health. The specific aim of this R25 application for a Research Career Development Institute for Psychiatry is to provide the necessary skill set, support, and mentoring network to a nationally- selected, broad-based group of promising young psychiatrists and PhD researchers to help them launch and maintain successful research careers in academic psychiatry. The program is geared toward individuals at the critical transition point between the completion of research training and their initial facuty appointment or very early in the initial appointment. The proposed program will help fill this training gap by providing the necessary skill set and guidance in a multi-tiered longitudinal training experience, including a comprehensive program of career and skills self-assessment, individualized career goal setting, a four-day workshop, structured long- distance career mentoring and goal tracking, webinars and tutorials, and a multi-tiered program evaluation. Targeted career skills identified as critical to beginning and maintaining a successful career in research psychiatry will include: writing, effective negotiation skills, time management, giving and receiving mentoring, responsible conduct of research, scientific project management, and enhancing statistical knowledge. Quality of the mentoring offered will be enhanced by in-person training and webinars for mentors. Career development activities will occur in four phases over a 24-month period for each annual class of up to 18 participants: online baseline career and skills self-assessment, didactic learning and preparations for four-day in-person workshop and goal setting, long-distance structured mentoring and online continued learning, and post-program career progress and process evaluation. The CDI program website will be the portal through which career goals and progress are measured and monitored, coaching and mentoring sessions take place, and virtual meetings are held throughout the 24- month training period. Consistent with the benefits of multilevel mentoring, a number of previous CDI participants will be asked to serve as junior faculty, providing two-fold added value: 1), participants will interact with colleagues who are just a few years ahead in their research career trajectory and have had similar career concerns and experiences, and 2) junior faculty members will receive an early career opportunity to provide mentoring to others and to participate at a faculty/teacher level. The proposed longitudinal program of education, training, mentoring, peer support, and communication for individuals making the transition to academic research independence will increase the number of scientists committed to research careers in mental health and provide a foundation for the field's progress toward preventing and treating mental illness.

DESCRIPTION (provided by applicant): This application seeks funding to address the opportunity at the University of Pittsburgh for a coherent training program on the neurobiology of substance use and abuse. The program will support three post- doctoral trainees and three pre-doctoral trainees at the dissertation stage. It is structured around five core areas of training faculty expertise: 1) Systems neurobiology of motivated behavior and cognition 2) Adolescent developmental biology and substance use vulnerability 3) Molecular modulation of neurotransmitter release and reuptake 4) Nicotine reinforcement and relapse 5) Stress responsive brain circuits. A didactic course will address these core areas of focus. There will also be a formal seminar series drawing prominent scientists whose work is at the cutting edge of research into these areas of focus. Extensive training in grant writing is formally incorporated through a mentored and reviewed grant writing course requirement. Presentation and analysis skills will be developed through an in-house seminar series in which works in progress will be presented by trainees or other individuals within the University of Pittsburgh substance use research community. The training program will enhance critical skills necessary for success as independent investigators, and the sum of its components will create multiple nodes of interaction between researchers, thereby increasing the breadth and quality of training of the supported individuals.

Project Summary/Abstract Depression is a chronic, impairing form of psychopathology that is one of the world's leading causes of disability. An extensive literature on the neural mechanisms of depression has documented the disruption of function in reward circuitry as part of the pathophysiology of depression. Specifically, frontostriatal function is altered, with lower ventral striatal (VS) response, greater medial prefrontal cortex (mPFC) response, and stronger functional connectivity between the two regions. Yet few neuromodulatory approaches to depression have targeted this circuitry. Noninvasive neuromodulatory techniques such as transcranial magnetic stimulation (TMS) have been applied to depression and can elucidate the pathophysiology of this disorder by focusing on function in frontostriatal circuitry. For the proposed R21 study, we will conduct a within-subject, counterbalanced study using interleaved functional MRI and TMS to examine the acute effects of theta-burst stimulation (TBS, a briefer form of TMS) to dmPFC in 35 young adults (18-25 years, 50% female) with depression. Each participant will undergo 2 sessions, one each of intermittent and continuous TBS, with the goal of increasing or decreasing dmPFC responding, respectively. Brain function, behavior, and mood will be assessed before and after each TBS session. Broadly, we predict that inhibitory TBS of the dmPFC will reduce dmPFC function and dmPFC-VS connectivity. We will also assess the potential for such change in frontostriatal circuitry to alter behavioral and subjective aspects of reward function, such as positive mood. The proposed study takes a circuit-based perspective and uses a multi-level assessment approach with the goal of identifying biomarkers of affective psychopathology. Its goal is to manipulate positive valence systems at the neural level to understand their function, and potentially reveal a source of heterogeneity relevant to future research in experimental therapeutics. Its high level of innovation and early stage of development for understanding this circuit using this method make it ideally suited for R21 funding.