Depression is a major public health problem. However, the heterogeneity of DSM-defined major depressive disorder (MDD) has prevented elucidating the etiology and the pathophysiology of this prevalent disorder. A core feature of MDD is impairment in reward processing, in the form of decreased reward motivation and anhedonia. The prior project periods for this grant established several key neural underpinnings of these symptoms including abnormalities in the structure and function of the medial prefrontal cortex (mPFC) and indirect evidence for dopamine (DA) abnormalities in the ventral striatum (VS). In this next phase, we propose to expand this line of work in fundamental new directions by applying these insights to a mechanistic model of how stress impacts each of these nodes. Further, we propose to determine how these effects may individually or in combination predict the severity of real-world stress-induced anhedonic symptom expression over a 1-year follow-up period. Specifically, the overarching goals of the proposed research are to investigate: stress-induced glutamatergic abnormalities and their relation to disruption within the corticostriatal valuation circuit in MDD (Aim 1); stress-induced DA signaling disruptions in MDD (Aim 2); and the predictive validity of these two pathophysiological mechanisms (Aim 3). This will be achieved through an innovative integration of (1) proton magnetic resonance spectroscopy (MRS)-based assessments of glutamatergic metabolites in the mPFC; (2) functional magnetic resonance imaging (fMRI) probes of the corticostriatal valuation circuit; (3) positron emission tomography (PET)-based measurement of striatal DA release with well-established stress manipulations and assessments (cortisol and inflammatory markers), and a naturalistic follow-up design. To differentiate between state- and trait-like markers of vulnerability to stress, currently depressed individuals (cMDD), remitted individuals with a history of MDD (rMDD), and never-depressed healthy controls will be included. Based on our extensive preliminary studies and findings from the prior project period, we hypothesize that, relative to healthy controls, cMDD and rMDD participants will show mPFC cortical thinning, decreased stress-induced glutamine/glutamate ratio in the mPFC, increased inflammatory responses, disrupted activation/connectivity within the corticostriatal valuation circuit, and decreased stress-induced DA release. Moreover, across the cMDD and rMDD groups, we expect that stress-induced changes in glutamine/glutamate ratio and inflammatory responses will predict mPFC thickness, anhedonic behavior, and striatal DA release. Finally, we expect that an empirically derived composite risk score combining the proposed pathophysiological mechanisms will predict anhedonic symptoms and general functioning following stress during follow-up. Altogether, the proposed research promises to improve our mechanistic understanding of stress-induced anhedonia and the pathophysiology of MDD, as well as our ability to identify mechanisms that prospectively predict reward deficit-related symptoms, thus opening novel avenues for improved treatment and prevention.

Public Health Relevance

Depression is a major public health problem; however, our understanding of and treatment for this prevalent disorder remain lacking. Using an integration of state-of-the-art neuroimaging techniques in conjunction with validated stress manipulations and a longitudinal design, the overarching goal of the proposed research is to investigate two pathophysiological mechanisms (stress-induced glutamatergic and dopaminergic disruptions) in the expression and prediction of anhedonic behavior, and risk for future depression. A better understanding of the neurobiological mechanisms underlying stress-induced anhedonia may contribute to identifying individuals at risk for future episodes, developing targeted therapeutic interventions, and preventing future relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37MH068376-12A1
Application #
9106361
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
2003-07-01
Project End
2021-02-28
Budget Start
2016-04-28
Budget End
2017-02-28
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
Moran, Lauren V; Stoeckel, Luke E; Wang, Kristina et al. (2018) Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia. Psychopharmacology (Berl) 235:789-802
Ironside, Maria; Kumar, Poornima; Kang, Min-Su et al. (2018) Brain mechanisms mediating effects of stress on reward sensitivity. Curr Opin Behav Sci 22:106-113
Janes, Amy C; Zegel, Maya; Ohashi, Kyoko et al. (2018) Nicotine normalizes cortico-striatal connectivity in non-smoking individuals with major depressive disorder. Neuropsychopharmacology 43:2445-2451
Kaiser, Roselinde H; Treadway, Michael T; Wooten, Dustin W et al. (2018) Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation. Cereb Cortex 28:4281-4290
Kaiser, R H; Clegg, R; Goer, F et al. (2018) Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response. Psychol Med 48:1157-1166
Belleau, Emily L; Treadway, Michael T; Pizzagalli, Diego A (2018) The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. Biol Psychiatry :
Olson, Elizabeth A; Kaiser, Roselinde H; Pizzagalli, Diego A et al. (2018) Anhedonia in Trauma-Exposed Individuals: Functional Connectivity and Decision-Making Correlates. Biol Psychiatry Cogn Neurosci Neuroimaging 3:959-967
Whitton, Alexis E; Mehta, Malavika; Ironside, Manon L et al. (2018) Evidence of a diurnal rhythm in implicit reward learning. Chronobiol Int 35:1104-1114
Webb, Christian A; Trivedi, Madhukar H; Cohen, Zachary D et al. (2018) Personalized prediction of antidepressant v. placebo response: evidence from the EMBARC study. Psychol Med :1-10
Der-Avakian, Andre; Pizzagalli, Diego A (2018) Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou. Biol Psychiatry 83:932-939

Showing the most recent 10 out of 29 publications