MRI Studies of Emotion in Depression
Condition: Major Depressive Disorder
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The research plan calls for the recruitment of adult human subjects with major depressive
        disorder (MDD) or healthy control (HC) volunteers over the 5-year grant period. All
        participants are required to be medically healthy as determined by medical history,
        physical examination, ECG, screening blood laboratory tests, urine analysis, and urine
        toxicology drug screen. Participants with MDD must have demonstrated inadequate therapeutic
        response to a minimum of one adequate antidepressant trial (e.g. TRD). MDD participants who
        meet this minimum TRD threshold will be eligible for the experiments in Aim 1.

        We recruit participants from several Mount Sinai-affiliated community hospitals (North
        General Hospital, Elmhurst), mental health associations (National Alliance for the Mentally
        Ill, Mood Disorders Support Group of New York), the Mood and Anxiety Disorders Program
        (MAP) Outpatient Clinic, the Mount Sinai Hospital outpatient psychiatry clinic, and from
        media/internet advertising.
      
Keywords: depression; MRI; treatment-resistant; imaging; ketamine