Jay C. Fournier, Ph.D. - US grants

DESCRIPTION (provided by applicant): The aim of this proposed Mentored Patient-Oriented Research Career Development (K23) Award is to provide the candidate with the training in affective neuroscience necessary to examine the functional neural mechanisms associated with individual differences in response to treatments for depression. Despite abundant empirical support demonstrating the efficacy of several different treatment modalities, no treatment works equally well for all patients. The goal of the proposed award is to utilize functional neuroimaging techniques to examine whether depressed patients who differ on specific facets of personality that are strongly associated with differential treatment response also differ in the functioning of specific automatic and voluntary components of the emotion regulation neural system. The long-term goal of this research is to identify reliable, biologically based markers of individual differences among depressed patients that could lead to the development of more effective, individually tailored treatments. The candidate possesses expertise in the identification of patient variables that are associated with differential response to treatments for depression. Through the proposed career development award, the candidate is seeking to build on this skill set by learning to examine the functional neural mechanisms that may underlie the predictors of differential treatment response that he and others have reported. He will acquire these skills by receiving training in three related areas of affective and translational neuroscience: 1) functiona neuroanatomy of emotion regulation and depression; 2) advanced neuroimaging techniques, and 3) the use of neuroimaging measures to inform clinical treatment research. In order to achieve these training goals, the candidate has proposed to participate in four types of training activities: weekly meetings and didactics with mentors, directed readings and training with expert consultants, formal coursework, and participation in scientific conferences. To ensure that the candidate meets his goal of becoming an independent scientist who can utilize the tools of affective neuroscience to answer important questions about the mechanisms underlying individual differences in treatment response, he has assembled an expert team of mentors and consultants. Each of these experts has a strong record of training junior scientists and fostering their development into successful independent investigators. The candidate's mentors, Drs. Mary Phillips and Ellen Frank, have extensive and complementary sets of expertise. Dr. Phillips is an expert in the functional neuroimaging of emotion regulation in the context of mood disorders, and Dr. Frank is expert in the assessment and treatment of depression. Together, their guidance will ensure that the candidate successfully meets his research and career development goals. The proposed research and training activities will take place in the Department of Psychiatry at the University of Pittsburgh School of Medicine. This is an ideal setting for the proposed project. The department has a longstanding track record of excellence in affective neuroscience, personality, and depression research. Senior faculty from each of these research domains are represented on the proposed mentorship and consultant team. The candidate will have access to extensive resources in each of these research areas throughout the proposed award period. The candidate's training will be further advanced by the proposed study, in which individual differences in the functioning of the automatic and voluntary emotion regulation neural systems will be examined among depressed adults who are high and low on facets of personality associated with differential treatment response. The study will examine functional neuroimaging measures of neural activity and connectivity within and between key prefrontal cortical and subcortical regions associated with emotion regulation. Neuroimaging, symptom, and personality data will be acquired in a sample of 60 currently depressed adults (30 with low scores on the personality facets of interest and 30 with high scores), as well as 30 psychiatrically healthy control participants. The aims of the proposed project are to examine whether depressed patients who differ on the personality facets associated with differential treatment response also differ in the functioning of the automatic and voluntary emotion regulation neural systems. Abnormalities in the functioning of these neural systems will be assessed using tasks that target: 1) automatic emotion regulation during the processing of conflicting emotional information; 2) voluntary emotion regulation during the cognitive reappraisal of negative emotions; and 3) voluntary emotion regulation during the cognitive reappraisal of negative self-beliefs. The specific aims of the proposed project match well with the strategic goals of the National Institute of Mental Health, and the results of this study can b expected to help identify reliable markers of individual difference among patients with depression. These findings could have enormous clinical utility and could lead to future work attempting to refine existing treatment strategies to make them more effective for patients with functional deficits in the emotion regulation system.

ABSTRACT There is growing recognition that strict distinctions between clinical psychiatric disorders such as anxiety and depression, on the one hand, and more stable dispositions to experience negative emotions (negative affectivity), on the other, fail to capture the true nature of psychopathology. We argue that by examining specific dimensional phenotypes that cut across depression and anxiety disorders, we will be better able to identify the neurobiological processes that are specifically associated with an individual's distress and dysfunction ? a critical step for developing more effective, targeted treatments. Negative affectivity is a broad dimension that underlies depression and anxiety and is associated with enormous public health consequences. One of the specific facets of negative affectivity, excessive self-consciousness, may represent a dimensional phenotype that is closely aligned with a specific pattern of dysfunction in neural mechanisms that can lead to difficulties regulating emotional responses. Excessive self-consciousness refers to the tendency to feel shame, humiliation, and inadequacy. Our preliminary data suggest that it is strongly associated with altered functioning in self-related processing neural regions and in regions responsible for emotion regulation, over and above acute psychiatric symptoms. Furthermore, our findings suggest that excessive self-consciousness is strongly associated with specific types of real-world interpersonal problems. The primary goals of this project are to test a novel model of neural dysfunction during emotion regulation associated with excessive self-consciousness and to examine the real-world consequences of that dysfunction. To achieve these goals, 125 young adults (18-25 years old) with at least mild symptoms of depression or anxiety will be recruited. In addition, 75 demographically matched, psychiatrically healthy individuals will be recruited to ensure that we capture the full range for all of the dimensions of interest. Participants will complete clinical and neuroimaging assessments, as well as 6- and 12-month follow-up assessments that will include weeklong daily diary protocols of real-world functioning. The project will examine 1) whether excessive self-consciousness is associated with abnormal functioning in self-related processing regions; 2) whether excessive self-consciousness is associated with abnormalities in the functioning of the emotion regulation circuit; and 3) whether abnormalities in these neural systems prospectively predict psychiatric symptoms and poorer interpersonal and work functioning 6 and 12 months later. The aims of the project match well with the strategic goals of the National Institute of Mental Health, and the results of this study have the potential to describe specific neurobiological mechanisms associated with excessive self-consciousness ? a dimensional phenotype that cuts across anxiety and depressive disorders. Future work will aim to develop personalized treatments to target the neural mechanisms identified in this study in order to reduce distress and improve functional outcomes.

ABSTRACT Depression is the leading cause of disability worldwide, and despite the fact that several treatments have been developed, only a minority of patients (<40%) respond and sustain that response for a year, regardless of which treatment they receive. Sustained response rates beyond one year are lower still. Thus, there is a vital public health need to better target the enduring quality of depressive symptoms and to improve longer-term outcomes. Negative self-evaluations, a core characteristic of depressive illness, appear to contribute to the enduring nature of depression. Negative self-evaluations are not only linked directly to the persistence of depressive symptoms, but for many, negative self-evaluations persist even after otherwise effective treatments, increasing the risk of relapse. Although much is known about the cognitive deficits and negative information processing biases in memory and attention among adults with depression, very little is known about the specific disruptions in information processing and brain function that cause depressed adults to make overly negative self-evaluations either during or following episodes of depression. We argue that we can substantially improve longer-term outcomes by identifying the underlying pathology that leads to these negative self-evaluations so that better targeted and more enduring treatments can be developed. Building on our preliminary data, and the work of others, the goal of this short-term project is to provide the first test of a novel hypothesis about the neural mechanisms that lead to dysfunctional self-evaluations in current and remitted depressed adults and to begin to examine the real-world consequences of that pathology for future symptoms and functioning. To test our hypotheses, we will evaluate behavioral and neuroimaging markers of abnormal processing during self- evaluation in 30 currently depressed, 30 remitted depressed, and 30 healthy adults. Participants will complete baseline clinical and functional magnetic resonance imaging (fMRI) assessments, as well as three weeklong daily diary protocols (over the span of four months) that will assess symptoms, self-evaluations in daily life, and real-world functioning. The project will examine processes leading to the abnormal engagement of the autobiographical memory (Aim 1) and social-cognitive (Aim 2) networks among depressed adults when evaluating self-relevant material, and it will examine whether abnormalities in brain function during self- evaluation prospectively predict psychiatric symptoms and poorer interpersonal and work functioning in daily life (Exploratory Aim). The aims of the project match well with the strategic goals of the National Institute of Mental Health, and the results of this study have the potential to lead to new, brain-based treatment strategies to target the identified mechanisms underlying negative self-evaluations to improve longer-term outcomes.