Anna Manelis, Ph.D. - US grants

DESCRIPTION (provided by applicant): Recent studies show that neural activation during anticipation to perform cognitive or emotional tasks determines the quality of task performance. Individuals with unipolar depression (UDd) and individuals with bipolar depression (BDd) often experience impairment in emotion processing, as well as episodic and working memory. One reason for such impairment may be the inability of depressed individuals to efficiently prepare for upcoming tasks. This project will pioneer research on the relationship between anticipatory brain activation preceding episodic and working memory tasks, brain activation during task performance and behavioral performance in UDd vs. BDd vs. healthy controls (HC). Distinguishing unipolar from bipolar depression is critically important to optimizing treatments fo those who suffer from these disorders, and yet reliably differentiating them from one another remains challenging in clinical practice. For example, about 60% of BDd are initially misdiagnosed with unipolar depression, which results in inappropriate or delayed treatment and concomitant worsening of symptomatic and functional outcomes. Therefore, studying the patterns of neural activation that differentiate these two groups is a critically important step toward identifying biomarkers that can help improve diagnostic accuracy as early as possible. To examine the extent to which UDd and BDd differ in their neural activity during task anticipation, a variety of converging methods will be employed: behavioral (reaction time and accuracy), functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS). Furthermore, the use of advanced methods of neuroimaging data analysis (e.g., multi-voxel pattern classification) will improve the chances to detect the differences between the two diagnostic groups. The first aim of the proposed work is to characterize brain activity during anticipation to encode and encoding of positive emotional, negative emotional and neutral stimuli in UDd vs. BDd vs. HC. The second aim is to understand how anticipatory brain activation during preparation for emotional working memory tasks of different levels of difficulty influences neural and behavioral correlates of task performance in UDd vs. BDd vs. HC. The third aim is to explore whether and how NIRS activity during preparation to encode, encoding and retrieval of emotional stimuli characterizes UDd vs. BDd vs. HC. Given that NIRS is portable, it can potentially be used in clinical settings to help in diagnostic decision-making. Findings from the proposed research will deepen our understanding of functional abnormalities in neural systems underlying emotion and cognitive impairments in UDd and BDd. They may also ultimately help identify biomarkers that distinguish UDd from BDd, and help provide targets to tailor intervention programs to alleviate cognitive and emotion deficits, and to enhance quality of life for these individuals. As a Principal Investigator on this project I have strong commitment to health-oriented research. My research career in psychology began more than 15 years ago in Russia where I studied the role of sports career in able body and Paralympic athletes. I continued my research at Rutgers University - Newark (as a graduate student with Dr. Hanson), where I learned about fMRI research and advanced methods of the fMRI data analysis, then at Carnegie Mellon University (as a post-doctoral researcher with Dr. Reder), and finally, at the University of Pittsburgh (as a post-doctoral researcher with Dr. Phillips). My long term career goals are to develop expertise in understanding the extent to which abnormalities in neural systems supporting emotion regulation and cognitive functioning (working memory, episodic memory) underlie emotion and cognitive impairment in individuals with mood disorders, and to become an independent clinical neuroscientist specializing in multimodal neuroimaging research of mood disorders. My expertise in cognitive neuroscience and advanced methods of data analysis is well documented by the publications in peer-reviewed journals. However, to be able to conduct clinical neuroscience research and to be able to interpret findings resulting from that research, I need to develop the understanding of adult psychopathology, which requires additional training in clinical psychology, psychiatry and neuroimaging of clinical population. I propose to receive such training through formal coursework, weekly meetings and didactics with mentors, directed readings and training with expert consultants, and participation in scientific conferences. I have assembled a team of mentors and consultants who represent expertise in each of the areas in which I will need training in order to meet my career development goals: functional neuroimaging markers of unipolar and bipolar depression (Phillips, Altshuler), clinical assessment and treatment of UDd and BDd (Frank), cognitive functioning of UDd and BDd (Gildengers), near-infrared spectroscopy (Huppert). During my research and training at the University of Pittsburgh, I will have access to the Magnetic Resonance Research Center (MRRC) with a 3T neuroimaging scanner, to the NIRS equipment, to extensive computer facility at the MRRC, and the help of experienced MR technicians, trained in research-related fMRI. These resources, combined with those at the Department of Psychiatry and with the expertise provided by my mentors and consultants, create an ideal environment for both successful training and the successful completion of the proposed research project.

Abstract Mood disorders are highly disabling and affect 60 million Americans. Individuals experiencing mood symptoms and comorbid conditions (e.g., anxiety) also experience a decrement in their ability to use working memory in everyday life. Understanding neurobiological characteristics of cognitive and emotional dysfunction in distinct psychiatric disorders remains challenging because multiple psychiatric disorders share common patterns of disruption in brain functioning supporting cognitive and emotional processes. We propose to use a dimensional (RDoC) approach to analyze already collected functional magnetic resonance imaging (fMRI) to identify aberrant neurobiological mechanisms of continuous constructs of depression (ranging from no depression to sub-threshold depression to syndromal depression) and mania (ranging from no mania to sub-threshold mania to syndromal mania) symptoms and their relationship to working memory dysfunction. This 2-year study will merge clinical, behavioral and neuroimaging data from five studies (PI: Phillips) and analyze the merged large dataset across diagnoses using a dimensional approach. We will determine the relationship between behavioral and neural correlates of working memory and current and life-time symptoms of depression, mania, and comorbid anxiety in youth (8-17) and adults (18-45). We will validate these findings using an independent dataset (Aim 1). We will also examine how longitudinal improvement/worsening of depression, mania and comorbid anxiety symptoms over the 6-month period affects adult subjects? ability to perform difficult working memory tasks and engage the working memory circuitry during those tasks across diagnoses (Aim 2). The development of working memory in youth involves improvement of the ability to recruit working memory circuitry during working memory tasks. This maturation process may be disrupted by worsening of mood and anxiety symptoms. We will use longitudinal data to map working memory circuitry functioning across a range of ages and developmental time frames, and across the range of syndromal and non-syndromal depression, mania and comorbid anxiety across diagnoses (Aim 3). The proposed research will lay the foundation for understanding neural mechanisms underlying longitudinal trajectories in depression, mania and anxiety spectrum symptoms. It will provide neurobiological targets to help guide personalized treatment and facilitate development of new interventions to alleviate working memory dysfunction in affected individuals.

Abstract Mood disorders, including major depressive (MDD) and bipolar (BD), are highly disabling and affect 60 million Americans. Depressive and manic symptoms impair episodic and working memory and overall psychosocial functioning in affected individuals. We will use the mood spectrum approach and functional magnetic resonance imaging to determine the relationship among continuous constructs of depression (ranging from no depression to sub-threshold depression to syndromal depression) and mania (ranging from no mania to sub- threshold mania to syndromal mania) symptoms, brain and behavior measures of episodic and working memory, and psychosocial dysfunction across MDD and BD diagnoses. We propose that aberrant anticipatory processing preceding performance on episodic and working memory tasks may be an important factor that mediates the relationship between mood symptoms and functioning in individuals with MDD and BD. Healthy individuals and those with MDD and BD will undergo clinical evaluation at baseline, 6, and 12 months. They will be scanned at baseline and at 6 months. We expect to collect longitudinal neuroimaging and clinical data from 150 individuals (across diagnoses). We will identify brain regions whose activation during anticipation of happy, fear, and neutral faces correlates with episodic memory accuracy and lifetime and current depression and mania spectrum symptoms and psychosocial functioning (Aim 1). We will identify brain regions that differentially activate during anticipation of easy and difficult working memory tasks, and correlate with lifetime and current depression and mania spectrum symptoms and psychosocial functioning (Aim 2). Quality of life for affected individuals could be improved if it were possible to predict and prevent worsening of clinical symptoms and decline in functioning. We will use multiple regression, mixed models, classification, trajectory, and path analyses to examine the role of anticipatory processing in the relationship between longitudinal trajectories in mood symptoms and brain and behavior measures of episodic and working memory and longitudinal trajectories in psychosocial functioning (Aim 3). To compare dimensional and categorical approaches, we will compare main neuroimaging and behavioral measures in MDD vs. BD, and perform a Group-by-Symptom interaction analyses. We will also explore how anticipation strategies and affective bias contribute to clinical and functional outcomes described above (Exploratory Aims). The proposed research will lay the foundation for understanding neural correlates underlying longitudinal trajectories in mood spectrum symptoms and psychosocial functioning in mood disorders. If the mediating role of anticipatory processing for clinical and functional outcomes is confirmed, anticipatory processing may become a new treatment target for affected individuals. Addressing dysfunctional anticipatory processing may help predict occurrence of syndromal episodes of depression and mania and related psychosocial impairments leading to disability.