Yvette Sheline - US grants

DESCRIPTION (Adapted from applicant's abstract): 5-HTergic system pathology in late life major depression may distinguish patients with poor treatment outcome. Clinical studies have shown that the key distinguishing factor correlated with failure to achieve remission is late age of depression onset; the prototypical disorder of this type is VsD. In contrast, older patients with early onset recurrent major depression (EORD) have more favorable course following antidepressant treatment. Multiple lines of evidence have suggested that alterations in postsynaptic 5-HT receptors play a key role in pathophysiology. We hypothesize that 5-HT receptor-specific PET imaging will discriminate the effect of treatment on early-onset and VsD when compared with controls, and that this will demonstrate 5-HTergic abnormalities in subgroups of patients with late life depression. We propose a treatment study of patients with protypical treatment responsive and treatment refractory depression: EORD (n=18) and VsD (n=18), respectively, and controls (n=18 at baseline) using F-altanserin, a selective PET agent for imaging the 5-HT receptor: (1) to quantify 5-HT receptor binding and test for differences between patients with untreated EORD and VsD, and normal controls; (2) to quantify 5-HT receptors after treatment with an 5-HT reuptake inhibitor (SSRI) and test for differences between EORD and VsD and (3) to correlate changes in 5-HT receptor binding following SSRI treatment and clinical response to treatment. All subjects will be studied at baseline, and depressed subjects again after chronic treatment (8 weeks) with sertraline. Repeated measures ANOVA will be used to determine group differences. Pearson correlations will be used to correlate changes in 5-HT densities and clinical response (HAMD). We hypothesize: (1) that the 5-HT receptor density will be lower in medial prefrontal cortex and hippocampus in patients with both EORD and VsD than in controls will negatively correlate with baseline HAMD score; (2) that relative to patients with EORD, patients with VsD will have less change in 5-HT receptor binding in the medial prefrontal cortex and hippocampus following antidepressant treatment; and (3) that the magnitude of downregulation of 5-HT receptors in medial prefrontal cortex and hippocampus after SSRI treatment will correlate with the degree of treatment response. This information will lead to better understanding of the pathogenesis of late life depression and may contribute to improvements in antidepressants treatment design.

DESCRIPTION (Adapted from applicant's abstract): This K07 Clinical Mental Health Academic Award application in Geriatric Psychiatry has been revised based upon recommendations of the Review Committee. It will provide five years of support for special study and supervised research to prepare the applicant for a career investigating the effects of depression on aging and a faculty leadership role as Director of Research, Division of Geriatric Psychiatry. The Development Plan for nominee outlines goals and activities which will support these endeavors. The primary goal of the Award is to develop expertise in neuroimaging and apply that expertise to the study of the relationship between MRI measures of brain neuromorphometry and age-related changes in patients with early onset major depression. Secondary goals include learning about neuropsychological changes, changes in HPA axis sensitivity, and the conceptualization and measurement of course of illness variables associated with aging. The proposed research project "Age-related hippocampal volume loss in MDD" seeks to define the nature of changes in brain structures due to recurrent episodes of depression. It is hypothesized that recurrent depression may accelerate normal hippocampal aging, perhaps through neuronal glucocorticoid toxicity resulting from depression-induced hypercortisolemia. In pilot work, the applicant found hippocampal volumes to be decreased in elderly depressed patients, and a correlation between volume reduction and duration of depression. A cross-sectional study of 40 medically healthy patients, ages 30-80, with recurrent early onset major depression and 40 pair-wise matched controls will test for differences in regional brain structure volumes, cognitive function, HPA axis function, and clinical variables. Hypotheses to be tested are that, relative to controls, patients with depression will show: 1) greater age-related decreases in hippocampal and frontal lobe volumes and increases in temporal horn volumes, with no between group differences for occipital lobe and intracerebral volumes, or volume of white matter abnormalities; 2) greater age-related deficits in performance on Benton;'s Visual Retention Test, paragraph recall, verbal fluency and Stroop Color-Word Interference Test; and 3) grater increases in plasma cortisol levels following administration of dexamethasone. 4) Hippocampal and frontal lobe volume reduction will be directly correlated with cumulative burden of depression.

The project "Age-related hippocampal atrophy in recurrent major depression" seeks to define the nature of changes in brain structures due to recurrent episodes of depression. It is hypothesized that recurrent depression may accelerate normal hippocampal aging, perhaps through neuronal glucocorticoid toxicity resulting from depression- induced hypercortisolemia. A cross-sectional study of 40medically healthy patients with recurrent early onset major depression and 40 case-matched normal controls will test for differences in regional brain structure volumes, cognitive function, HPA axis function, and clinical variables. In addition, recent studies have found bone density loss in depressed women relative to controls. It is unclear whether this was caused by differences in cortisol or in estrogen status. We will ezamine both cortisol and estrogen status as well as bone density in our sample.

clinical depression; neuropsychological tests; brain imaging /visualization /scanning; human old age (65+); cerebrovascular disorders; white matter; gray matter; human therapy evaluation; sertraline; cognition; mental disorder chemotherapy; patient oriented research; bioimaging /biomedical imaging; magnetic resonance imaging; human subject; behavioral /social science research tag; clinical research;

Description (provided by applicant): This K24 Midcareer Investigator Award in Patient-Oriented Research will provide five years of support to enhance a program of research and mentoring for the applicant in Neuroimaging in Depression Treatment Studies. The treatment of major depression in late life is an important health problem with a large and growing number of affected individuals. Many investigators have found that patients with late-onset depression, particularly those with cerebrovascular disease risk factors (VRF), are likely to have a slower and less complete response to antidepressant treatment. It has been proposed VRF may predispose to occult cerebrovascular disease in the form of frontal cortex deep white matter hyperintensities (FDWMH) and subcortical gray matter hyperintensities (SCGMH), collectively referred to as T2H. This may contribute to the development of late life depression by interrupting pathways involved in mood regulation. The overall goals of the applicant's research are 1) to continue the transition from cross-sectional studies to treatment outcome studies investigating brain pathophysiological factors that predict treatment outcome and 2) to train junior investigators from a range of clinical backgrounds in the design and conduct of neuroimaging studies in assessing treatment outcome of depression. The proposal describes the applicant's current research program and the career development and mentoring activities planned for the 5-year duration of the K24. Two NIH grants are ongoing: one will determine if severity of T2H and frontal executive dysfunction predict less antidepressant treatment response; the other will determine if late life depression is associated with abnormalities in 5-HT2A receptor regulation by antidepressants. Career development activities for the PI in MRI diffusion tensor imaging are described to further delineate the prognostic value of T2H and their ischemic nature and a third project is described to use these measures in longitudinal studies of white matter ischemic changes. Trainees will engage in these projects, take coursework in neuroimaging and clinical investigation and complete a research proposal over the 2-year training period. K24 support will provide the applicant with protected time to carry out depression treatment outcome studies in late life depression and to increase the mentoring of beginning clinical investigators in neuroimaging studies in depression.

[unreadable] DESCRIPTION (provided by applicant): Patients with recurrent major depression have abnormalities in a broad array of emotional and cognitive functions. Recently functional imaging studies have developed emotional tasks to elicit brain activation responses under standardized conditions. These studies implicate a circuit including the amygdala, the affective division of the anterior cingulate (ACad) and dorsolateral prefrontal cortex (DLPFC) in emotional regulation. The amygdala detects critical emotional information, especially threats. The ACad assesses salience of motivational cues, particularly based on amygdala input, detects conflict and regulates emotional responses. The DLPFC has a critical role in supporting a wide range of cognitive control functions. The goal of the current project is to determine which elements of the emotional circuit are dysfunctional in major depression. We propose to use functional magnetic resonance imaging (fMRI) in depressed (n = 50) and matched control (n = 50) subjects studied before and after a course of antidepressant treatment. We will use two standard cognitive paradigms in which emotion is manipulated to help elucidate the cognitive-emotional interace: a 2-back emotional working memory task and a matching task producing emotional conflict. We will determine whether depression involves a primary dysfunction in amygdala, ACad, or DLPFC. In addition, we hypothesize that depressed subjects will have normalization of abnormal brain activation with treatment. The proposed study has the potential to substantially advance our understanding of the precise nature and mechanisms underlying cognitive-emotional dysregulation in major depression. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Late life depression (LLD) is a common and debilitating problem that may indicate a higher risk for developing cognitive impairment. Our current grant "Treatment Outcome of Vascular Depression" MH60697 has gathered a large sample (n=120) of LLD patients and controls (n=40) to examine white matter disease, cerebrovascular risk factors and cognitive function prospectively. However, LLD is a heterogeneous disorder with poorly understood risk factors for development; both vascular disease and incipient dementia are common comorbid syndromes. LLD depressive symptoms actually may be the presenting symptoms of incipient dementia. Alternatively, LLD may be an independent risk factor for AD. Thus, incipient dementia, perhaps years in advance of DAT, is an important factor that may contribute to poor outcome, including treatment resistance in LLD. A novel agent for imaging brain amyloid in vivo, [11C] PIB, presents the opportunity to determine whether subjects with LLD have abnormal brain amyloid binding. We have preliminary data showing a 3 fold increase in PIB+ status in LLD: 3/10 LLD patients vs. 2/20 controls were PIB+. Further 2/5 antidepressant non-responders (NR) vs. 1/5 responders (R) were PIB+. In our current proposal, we use PET imaging of [11C] P1B to gather preliminary data to investigate whether compared with control subjects, elevated brain PIB binding will be associated with LLD, especially in LLD treatment non-responders and those with longstanding depression. If this PET data shows support for our hypotheses, we will use this pilot dataset as a basis for a larger grant application to further explore these relationships. We also have a number of other key neuroimaging, cognitive and clinical data from our original "Treatment Outcome" study and will explore the extent to which they provide significant predictive effects for LLD. Nondemented LLD subjects age 65-85 y/o (n=50) who have completed a treatment study with a standard antidepressant (sertraline) will be recruited for imaging with PET and [11C] PIB, MRI, cognitive testing and ascertainment of clinical measures. Depressed subjects who did not respond to treatment (n=25) will be compared with responders (n=25) and with a non-demented non-depressed comparison sample (n=25). AIM1: Compared with controls, LLD subjects will have elevated gray matter [11C] PIB binding. AIM2: Compared with responders, a higher number of non-responders will have elevated gray matter [11C] PIB binding. AIM 3: Additional measures, including lifetime duration of depression, untreated episodes of depression, age of onset and comorbid vascular risk factors will be explored. Successful completion of this study will allow effect size and power calculations critical in designing a definitive study to determine whether LLD is associated with increased numbers of PIB+ patients. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): A significant body of research supports a role of vascular disease in the pathogenesis of late-life depression. It has been proposed that vascular disease affects white matter pathways and subcortical structures involved in mood regulation and is associated with poorer cognitive function and treatment resistance. While a number of cross-sectional observations have been described, it is not known how these abnormalities predict longitudinal course. Further, the interaction between white matter pathology and structural changes in important gray matter structures, including orbitofrontal cortex, amygdala, hippocampus and basal ganglia is not fully studied. The proposed study will follow up a well defined cohort of late life depressed (LLD) subjects recruited for the NIH-funded "Treatment Outcome of Vascular Depression" study. In that study we have found an association between baseline cognitive and structural measures and acute response to antidepressants. In the current proposal we will extend those findings to determine their impact on longitudinal course of depression. The proposed study will examine the effect of baseline neuroimaging findings and cognitive function in predicting course of illness over a five year follow-up. We propose to conduct a collaborative study with 168 elderly subjects enrolled in the previous "Treatment Outcomes of Vascular Depression" study at Duke University and Washington University. They will receive follow-up magnetic resonance imaging, neuropsychological testing, and a careful interval history focusing on their depression history, antidepressant use, and medical history to test the hypotheses that: 1) LLD individuals with more depressive episodes over the 5 year longitudinal course will have greater baseline impairment on measures of a) white matter structure b) smaller volumes of the amygdala, hippocampus, and orbitofrontal cortex and c) neuropsychological function; 2) LLD individuals with more depressive episodes over the 5 year longitudinal course will have greater changes on these MRI and neuropsychological test variables over the interim. In secondary aims we will test the effect of the interaction of the measures on depression duration, and examine the effects of connectivity in specific fiber tracts on depression course. The proposal will provide important new data on neuroradiologic and neuropsychological factors contributing to recurrent or chronic depression in older individuals. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation, and specific Challenge Topic, 03-MH-101 Biomarkers in mental disorders. The variability of treatment outcome in PTSD, the high risk of relapse and the fact that only a subset of trauma victims develop PTSD are unsolved aspects of the illness. Yet at the current time there are no tests or markers that can help guide treatment decisions about which treatment should be administered to a particular patient, how long the person should be treated or whether trauma victims at high risk can be identified early, prior to the onset of illness. We have therefore developed a model of emotional circuitry abnormalities in PTSD. With funding of the current application we propose to validate these abnormalities as biomarkers in PTSD that can be further developed to guide treatment decisions. Post Traumatic Stress Disorder (PTSD) is a common, severe psychiatric problem that occurs in some people following a traumatic event. Treatment outcomes are variable and incomplete. Relapse is common. Brain biomarkers of abnormal emotional circuitry could provide evidence of insufficient treatment and high risk for relapse. Biomarkers could identify subgroups of patients who are better suited to a particular treatment.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. While there is no currently approved treatment that modifies the underlying cause of the disease, there is intense activity towards developing anti-amyloid beta therapies. Recent trials of such treatments however have had no, or very limited, success in altering the course of AD. It is likely that these failures to benefit individuals with clinically diagnosed AD occurred because the treatments were administered too late in the disease process. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A[unreadable] plaques in the human brain. We also found that in a transgenic mouse model of AD two SSRI antidepressants acutely reduced brain A[unreadable] levels by 25% and direct infusion of serotonin reduced A[unreadable] levels by 30% in vivo without affecting A2 elimination rates, suggesting that serotonin signaling is responsible for the reduction in A[unreadable] generation. We now have data demonstrating that prospective treatment with 16 weeks of citalopram significantly reduced plaque burden in AD mice. The current proposal will test whether clinically relevant doses of an SSRI reduce A[unreadable] production in healthy human subjects. This is made possible by the recent development of a stable isotope labeling kinetic (SILK) technique by our colleagues here at Washington University. The SILK assay assesses A[unreadable] pharmacodynamics in human subjects. It uses administration of 13C6-leucine and monitors the rate of 13C6-labeled A[unreadable] appearance in the CSF to determine the rate of A[unreadable] synthesis and clearance. We propose to conduct a randomized placebo-controlled comparison in 12 subjects ages 18-40 who will undergo assessment of A[unreadable] production during a 36-hour stay in our clinical research unit. Each subject will be randomized to treatment with a 4 week course of placebo or 20 mg/day of citalopram, prior to the initiation of the 13C6-leucine administration and CSF sampling. Hypothesis: Compared to the subjects receiving placebo, subjects receiving citalopram will show significantly (p<0.05) lower A[unreadable] production as measured by SILK. Significance: If our hypothesis is supported and citalopram is associated with a substantial reduction in A[unreadable] production, we will use this data to assess the value of a prospective trial to test whether SSRIs reduce the rate of A[unreadable] plaque formation. While many factors go into the design of such a trial, the potential significance for preventing AD would be large. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating illness, projected to increase dramatically in the next decades. Currently there is no approved treatment that modifies the underlying cause of the illness. We have preliminary data in humans and animal models that SSRI antidepressants can lower the amount of Amyloid beta (A[unreadable]), the peptide that plays a critical and early role in the development of AD. This project will determine whether compared to placebo, SSRI antidepressants lower the production of A[unreadable] in human CSF.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. In the revised application we respond to PAR-11-100 Alzheimer's Disease Pilot Clinical Trials to outline a pilot clinical trial to answer critical questions before proceeding toa larger scale, definitive prospective trial. We will establish measures of drug efficacy in CSF as well as refine the target population. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A¿ plaques in the human brain. We have investigated the possible mechanism for this reduction in amyloid plaque burden by measuring the effect of SSRI antidepressants on A¿ levels in a transgenic mouse model of AD. Three common SSRI antidepressants acutely reduced brain extracellular A¿ levels by 25% in vivo. Furthermore, chronic treatment with an SSRI, citalopram, for 4 months significantly reduced hippocampal and cortical plaque burden by 42.3% and 50.7%, respectively. We will conduct a stratified, randomized placebo controlled trial of 54 cognitively normal participants, age 65- 80, (Clinical Dementia Rating scale, [CDR] = 0) recruited from the Washington University ADRC. Participants will have undergone full clinical evaluation and PET amyloid imaging. Prior to randomization they will be stratified by APOE4 status. Participants will be randomized (18 per group) to acute treatment with placebo, 20 mg citalopram or 40 mg citalopram. Participants will receive non-radioactive 13C6-leucine administration and CSF sampling with assessment of A¿ production during a 36-hour stay in our clinical research unit. To yield n = 18 participants per group with analyzable data, we will recruit n = 60 subjects, allowing for the 10% dropout rate that has been experienced in prior SILK studies. We will determine: 1) whether SSRI administration results in reduced CSF A¿ production (Aim 1); 2) whether a dose of citalopram 20 mg as well as citalopram 40 mg dose results in A¿ reduction (Aim 2); and 3) explore whether there is an effect of APOE status or age on A¿ reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in A¿ generation, we wil use this data to plan a prospective clinical trial to test whether chronic use of SSRI reduces the rate of A¿ plaque formation. While many factors go into the design of such a trial, given that SSRIs are among the best-tolerated neuroactive drug classes approved by the FDA and could be readily tested in a clinical trial, the potential significance for AD prevention would be rapid and large.

DESCRIPTION (provided by applicant): Late life depression (LLD) is an increasingly important cause of disability and mortality worldwide. Clinical studies have characterized many aspects of the phenomenology, and treatment response in LLD, but the etiology of LLD remains unclear. Few models have yielded testable hypotheses, but an emerging concept is that inflammation may have particular relevance, especially in late life depression. We have preliminary data supporting increased inflammatory cytokines in LLD compared with controls that are associated with decreased hippocampus and amygdala volumes. LLD also had specific impairment in neuropsychological function in episodic memory and executive function and decreased hippocampus and amygdala resting state functional connectivity. Antidepressant treatment improved IL-6 levels, neuropsychological testing and resting state connectivity. In the current proposal we propose to recruit patients with LLD (n = 100) and controls (n = 50) matched for vascular risk factors to characterize immune function, brain structure and connectivity and neuropsychological function. Further, we will randomize participants with LLD to 10 weeks of SSRI treatment (n=50) or no treatment (wait list) (n=50), and assess participants pre- and post-treatment with peripheral and central cytokine levels, neuropsychological tests and brain resting state functional connectivity. Aim 1: Characterize neuroanatomical and neuropsychological correlates of abnormal cytokines in LLD. Hypothesis 1: a) Compared with matched controls, LLD will have abnormalities in peripheral and CSF inflammatory cytokines, neuropsychological function (e.g., executive function, episodic memory), hippocampal, amygdala and prefrontal cortex (PFC) structure and functional connectivity; b) Peripheral/central inflammatory cytokine levels will be associated with volume loss in hippocampus, including CA2-3, PFC, and amygdala; and c) Cumulative duration of depression will correlate with volume loss in hippocampus, including CA2-3, amygdala, and PFC. Aim 2: Characterize the reversibility of brain dysfunction, including cognitive impairment, with treatment of late- life depression and its association with inflammation. Hypothesis 2: a) Subjects randomized to treatment will have greater normalization of IL-6 and IL-10, greater improvements in memory and executive function and improvements in resting state functional connectivity compared with those randomized to initial no treatment; b) Improvement in clinical depressive scores will correlate with normalizatio of inflammatory cytokines. Significance: Demonstration of hypothesized links between neurobiology, depression and inflammation should augment development of treatment strategies for this debilitating disorder.

? DESCRIPTION (provided by applicant): Every year more than 30% (2 billion) of the world's population and 75 million adult Americans suffer from disorders that have been lumped under the term anxious misery. Among patients who receive treatment, a large number remain with debilitating symptoms, often for years or decades. Recently the NIMH has led efforts to define constructs within the Negative Valence System (NVS) that cut across such disorders in order to spur research on underlying mechanisms. This application will focus on potential brain circuitry and behaviors associated with loss, and responses to sustained threat, two of the most central NVS dimensions. By considering these brain circuits jointly, we can disentangle these dimensions for more specific targeting of disabling symptoms. Recent improvements in treatment efficacy have been shown in studies that target regions by mapping individual anatomy and connectivity patterns. This application, submitted in response to PAR-14-281, by a team of investigators at the forefront of understanding NVS disorders, will comprehensively characterize NVS spectrum disorders using the RDoC framework, focusing on brain circuits important in pathophysiology across the spectrum of loss and responses to sustained threat. By implementing neuroimaging assessment on a single Prisma scanner optimized for compatibility with the Human Connectome Protocol (HCP) and by collecting demographic data, neurocognitive data using the NIH Toolbox and Penn Computerized Neurocognitive Battery (CNB), and DNA samples, along with specialized assessments pertinent to NVS disorders, we will expand the HCP database with a highly significant pathophysiology sample for human health. These goals will be achieved by recruiting 50 control participants and 200 participants with anxious misery symptoms from the Outpatient Clinics of the University of Pennsylvania, where they will undergo an extensive multi-modal assessment to characterize the cross-sectional phenomenology of these NVS domains and a one-year followup to assess subsequent symptoms. The proposed project has both objectives and hypotheses. The main objective is to acquire and make public a vast database of brain imaging and behavioral data from patients with anxious misery as well as innovative new tools to analyze brain connectome changes. This objective includes careful QA and harmonization procedures. The main hypothesis to be tested is that severity of responses to sustained threat and loss correlate with dissociable circuit abnormalities in the structural and functional connectome; further, these abnormalities will predict course of illness.

? DESCRIPTION (provided by applicant):Title: Integrated Training in Neurocircuitry of Affective Disorders The proposed revised Institutional National Research Service Award Training Program will provide basic and clinical neuroscientists with the skills and mentor-guided experiences to propel them into an interdisciplinary research career designed to further the understanding of brain circuitry and affect. We request funds for two positions in Year 1 and four positions each subsequent year. The area of brain circuitry as applied to understanding psychopathology is a rapidly growing domain with great potential to inform the understanding of the causal pathways and mechanisms of affective mental illness. The Center for Neuromodulation in Depression and Stress (CNDS), in collaboration with multiple University of Pennsylvania (PENN) departments, centers and institutes is well poised to launch this novel post-doctoral fellowship based on established innovations in imaging, as well as the range of related expertise offered by the proposed multidisciplinary mentor group. The proposed training recognizes that the tools necessary to understand brain circuitry pathology require training across psychopathology, human neuroimaging methodology, statistics, engineering, neuroscience, genetics and basic translational models with associated imaging, such as optogenetics. The program will be guided by Dr. Yvette Sheline, (neuroimaging of depression and stress). Dr. John Detre (clinical neuroscience and methods development in functional neuroimaging) will be Associate Director. They are joined by numerous investigators at PENN with a rich track record of experience in imaging of affective disorders, including a cadre of investigators at the forefront of new methods development; many of these labs will be co-located, along with trainees, in a new facility. Research taking a brain circuit approach to psychopathology using a neuroscience model is a novel approach for training. The program mentors provide a unique multidisciplinary training environment in which to pursue this exciting new approach, given the established collaborations between neuroimaging researchers in the clinical and basic departments of the Perelman School of Medicine and their interface with the Biomedical Graduate Studies program. The University's role at the forefront of neuroimaging and translational neuroscience offers an opportunity to help train the next generation of young scientists who can pursue fundamental questions about abnormalities in brain circuitry in affective illness from the perspective of core psychological, neural and translational mechanisms that can inform and span traditional boundaries of psychopathology and lead to more effective treatments and identification of new targets for prevention.

Every year more than 20% (55 million) of the adult American population suffers from major depression. (MDD). While effective treatments are available, depression remains under-diagnosed and under-treated, in part due to cost and availability of treatment. In the current application in response to NIMH NOT-14-007 we propose a clinical trial to study potential novel biomarkers of depression treatment response rather than to test efficacy of an efficient, cost-effective form of computer-augmented cognitive behavioral therapy (CCBT) which already has proven efficacy. We present pilot data supporting CBT-induced improvements in functional connectivity and task-induced activation in MDD. We also have found in previous work that this model of CCBT, known as Good Days Ahead (GDA), has efficacy for MDD that is not inferior to conventional individual CBT therapy across 8 and 16 weeks of treatment, despite reducing average therapist contact from 16 hours to less than 5 hours. We now propose that this new variation of cognitive therapy, which substitutes intensive, computer- administered skills training for hours of therapist contact, will engage the same brain targets we have previously seen with CBT. We hypothesize that it is rehearsal time during which an individual actively engages in corrective skills training that ?mends? the brain connectivity and promotes recovery. We will recruit a total of 60 patients with MDD and 40 matched comparison healthy participants from the outpatient clinics of the Hospitals of the University of Pennsylvania. To take into account the impact of nonspecific factors, half of the MDD participants will be randomized to receive CCBT immediately after baseline assessments and half will first receive 8 weeks of Depression Care Management (DCM) (a clinically responsible alternative to a traditional wait-list control group that includes support and clinical management) before subsequently receiving CCBT. Aim 1: Compare baseline resting state functional connectivity and task-induced activity between MDD and controls. Aim 2: Assess CCBT treatment effects on resting state functional connectivity and task- induced activation in MDD comparing CCBT-treated participants to DCM ?treated participants. Exploratory Aim: 1a:Predict the effects of baseline imaging measures on treatment outcomes; 1b: Predict the effects of baseline executive function on treatment outcomes.