With a lifetime prevalence of 16%, Major Depressive Disorder (MDD) is predicted to become the second leading cause of death and disability in the United States by the year 2020. A core feature of MDD is reward- processing deficits in the form of decreased reward motivation and anhedonia. These deficits have been linked to alterations in corticostriatal networks in MDD, but less is known about the specific mechanisms that may contribute to these changes. One candidate mechanism is alterations in medial prefrontal glutamate (Glu) and GABA, both of which have recently been implicated in both MDD, as well as a key risk-factor for the development of MDD, stress. To date however, no study has provided an in vivo assessment of Glu and GABA function in response to psychosocial stress in MDD or in healthy controls. To address this question, the K99 phase of this application proposes the following training goals. First, in order to develop the technical skills needed to assess Glu and GABA in vivo, the candidate will learn MR-Spectroscopy techniques from Dr. J. Eric Jensen (K99 Co-mentor) and Dr. Dost Ong?r (Consultant). This will involve the completion of a combined MRS/fMRI study that will explore the relationships between baseline Glu and GABA function and BOLD fMRI signals during reinforcement learning in healthy participants. Second, the candidate will deepen his understanding of the role of Glu and GABA function in reward processing through directed readings with Dr. Kent Berridge (Consultant) as well as their relevance to the pathophysiology of mood disorders through readings supervised by Dr. Ong?r. Third, he will build upon his behavioral modeling skills developed in graduate school through the application of a reinforcement learning paradigm and associated Q-learning model analysis, which will be supervised by Dr. Michael Frank (Consultant);the candidate will also attend Dr. Frank's lab meetings on a monthly basis as well as his course "Computational Cognitive Neuroscience". Finally, the candidate will receive guidance and supervision from his primary mentor, Dr. Diego Pizzagalli, in the integration multimodal imaging data, design and analysis of laboratory stressors, and preparation towards the development of an independent laboratory. During the independent phase, two additional multimodal imaging studies are proposed that will combine MRS assessment of Glu and GABA function with fMRI measures of reinforcement learning both before and after a psycho-social stressor. The first of these studies will be focused on healthy controls, while the second will include a sample of patients with MDD and matched controls. Through its use of multimodal imaging focused on two major neurotransmitters, a pre-post stress manipulation and inclusion of both controls and MDD patients, the proposed research will provide important new insights into the role of Glu and GABA function in the pathophysiology of reward processing deficits in MDD.

Public Health Relevance

Major Depressive Disorder (MDD) is a debilitating mental illness that is frequently associated with symptoms of low motivation and anhedonia. Prior work suggests that these symptoms may result from alterations in medial prefrontal glutamate and GABA signaling, which may disrupt normal corticostriatal circuit function, but direct evidence is lacking. To address this gap, the proposed research will use pre- and post-stress measures of MR- Spectroscopy of medial prefrontal glutamate and GABA in combination with fMRI during a reward-learning paradigm to investigate the relationships between amino-acid neurotransmission, reward learning behavior and functional neuroimaging measures in healthy controls and MDD patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Chavez, Mark
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mclean Hospital
United States
Zip Code
Treadway, Michael T; Peterman, Joel S; Zald, David H et al. (2015) Impaired effort allocation in patients with schizophrenia. Schizophr Res 161:382-5
Barch, Deanna M; Treadway, Michael T; Schoen, Nathan (2014) Effort, anhedonia, and function in schizophrenia: reduced effort allocation predicts amotivation and functional impairment. J Abnorm Psychol 123:387-97
Treadway, Michael T; Pizzagalli, Diego A (2014) Imaging the pathophysiology of major depressive disorder - from localist models to circuit-based analysis. Biol Mood Anxiety Disord 4:5