MRI Studies of Emotion in Depression

The purpose of this study is to research the effects of ketamine on brain function in patients with Major Depressive Disorder (MDD). This study is an ancillary MRI neuroimaging study being conducted in patients with MDD who are enrolled in a separate clinical trial. Healthy control volunteers are also enrolled. No drug or other intervention is given as part of this protocol per se. To study brain activity related to emotion, the study team will use a technology called functional MRI (fMRI), which is a method for evaluating the flow of blood in the brain using a powerful magnet. fMRI does not involve exposure to radiation. Patients will be shown a sample of images on a computer screen designed to bring about an emotional reaction. The MRI machine will then take a number of pictures of your head. By computer analysis, this machine is able to create a picture of your brain's activity. There are several tasks during scanning that involve looking at various images that represent different emotions, and the study team will be monitoring brain activity during these tasks. Patients will be scanned before and 24 hours after receiving ketamine (as part of a separate study) to analyze treatments effects. These scans are compared to depressed patients who did not receive ketamine, as well as to healthy controls.

Specific Aim 1: To characterize the function of basic neural systems involved in emotion perception and regulation in TRD. * Experiment 1.1: Neural responses to emotional faces in TRD (neutral, low and high intensity sad facial expressions). o Hypothesis 1.1: Patients with TRD, relative to HC participants, will evidence increased activation in the amygdala/parahippocampal gyrus to sad compared to neutral faces. * Experiment 1.2: Neural responses during negative emotion regulation in TRD (cognitive reappraisal). * Hypothesis 1.2: Patients with TRD, relative to HC participants, will show enhanced activation of the amygdala during the generation of negative affect and will be impaired in their ability to recruit PFC/ACC regions during attempts to down-regulate negative affect. Specific Aim 2: To characterize changes in emotion-processing neural networks associated with ketamine and rapid antidepressant response. * Experiment 2.1: Neural changes in response to emotional faces associated with ketamine and rapid antidepressant response. o Hypothesis 2.1a: Ketamine, compared to midazolam, will be associated with reduced activation in the amygdala to sad compared to neutral faces. 2.1b: Antidepressant response, compared to non-response, will be specifically associated with changes in PFC/ACC function. * Experiment 2.2: Neural changes during negative emotion regulation (cognitive reappraisal) associated with ketamine and rapid antidepressant response. * Hypothesis 2.2a: Ketamine, compared to midazolam, will be associated with reduced activation in the amygdala during negative emotion generation and enhanced PFC/ACC function during down-regulation of negative affect. 2.2b: Antidepressant response, compared to non-response, will be specifically associated with enhancement of PFC/ACC function. Specific Aim 3 (Exploratory): To investigate functional and effective connectivity between emotion perception/generation neural systems and cognitive emotional regulation systems. Hypothesis 3: TRD compared to HC will be characterized by abnormal connectivity between PFC/ACC and amygdala, which will normalize with rapid antidepressant response. The setting of research will be MSSM. All research participants will be recruited and screened through the Mood and Anxiety Disorders Program (MAP) (Director: Dan V. Iosifescu, M.D.) at MSSM. MAP is one of the major clinical research programs of the Department of Psychiatry, with research funding from NIH, the Department of Defense, NARSAD, and industry.