Glutamatergic Adaptation to Stress as a Mechanism for Anhedonia and Treatment Response With Ketamine

The glutamate concentration in the mPFC as determined by in vivo magnetic resonance spectroscopy (MRS) at a field strength of 3 Tesla (3T) using standard MRS protocols. The levels of glutamate metabolite will be quantified using a custom quantification algorithm for modelling the background noise inherent in NMR (Nuclear Magnetic Resonance) signals. In MDD participants receiving ketamine, acute stress challenges will result in decreased glutamate in mPFC at 24 hrs that will be sustained at 2 weeks.

The AMI is an 18-item self-report index of apathy and motivation. It is used to assess the different mechanisms of sub-clinical lack of motivation. It covers motivation within three dissociable domains: cognitive, emotional/affective and behavioral. Every domain contains 6 items that is each scored from 0-4, with a higher mean score indicating greater apathy.

The mood and pleasure questionnaire is a 15-item self-report measure of severity of negative symptoms. This scale will be used to assess self-reported changes in motivational anhedonic symptoms. All items are rated on a 5-point Likert scale; higher scores reflect greater pathology. .

The DAS-SF is a self-report questionnaire containing nine items and utilizes an item-response analysis to provide an efficient and accurate assessment of dysfunctional attitudes. Subjects will rate their agreement to each of the 9 statements on a Likert scale of agreement from 1 to 5. Scores could range from 9 to 45, with higher scores reflecting more dysfunctional attitudes.

The Perceived Stress Scale (PSS) is a psychological instrument for measuring the perception of stress. It is a measure of the degree to which situations in one's life are appraised as stressful. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress.

Scores ranging from 0-13 would be considered low stress, 14-26 would be considered moderate stress and 27-40 would be considered high perceived stress.

The State-Trait Anxiety Inventory (STAI) is used measure trait and state anxiety. It consists of 20 items for assessing trait anxiety and 20 for state anxiety. State anxiety items include: "I am tense; I am worried" and "I feel calm; I feel secure." Trait anxiety items include: "I worry too much over something that really doesn't matter" and "I am content; I am a steady person." All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater levels of anxiety.

The MMSE is a 30-item interviewer-administered questionnaire widely used for the evaluation of general cognitive functioning and identification of altered mental status. A score ≤24, indicates evidence of more than mild cognitive impairment.

The RTT provides measures of simple and choice movement and reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses and providing distinction between reaction (or decision) time and movement latencies. Reaction times are typically 0.2 seconds (s) to 0.9 s. Shorter reaction times indicate better cognitive processes of perception and response execution.

Participants will be asked to perform three runs of an instrumental learning task. For each run, one pair of visual stimuli will be randomly presented, with one stimulus above and one below a fixation cross (counterbalanced). The subject will be instructed to choose the upper or lower stimulus by pressing one of two keys. After 4 seconds, the choice will be circled in red and the outcome (either "Nothing", "Gain", "Loss" or "Look") will be presented, accompanied by the image of a $1 bill in the event of gain, loss and look outcomes. In sum, to win money the subjects will have to learn, by trial and error, the stimulus-outcome associations. Higher stimulus-outcome associations made will indicate increased cognitive function.

The AES addresses characteristics of goal directed behavior that reflects apathy including behavioral, cognitive and emotional indicators. It consists of 18 items; Items are scored on 4-point Likert scale with descriptors for the "self" version (not at all true, slightly true, somewhat true, very true). The score range for the complete AES (total AES score) is 18 to 72, with a lower score indicating greater apathy.

The UCLA (University of California, Los Angeles) Loneliness Scale is a 20-item scale designed to measure one's subjective feelings of loneliness as well as feelings of social isolation. Participants rate each item on a scale from 1 (Never) to 4 (Often). Higher scores indicate higher levels of feeling lonely or isolated.

The Digit Symbol Task consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphomotor speed, visual scanning and memory, with about half of the variance being accounted for by graphomotor speed, a third by visual scanning and 4-5% by memory. Scores range from 0 to 100. Higher scores indicate higher cognitive function.

This task uses a specially adapted tapper that the subject taps as fast as possible using the index finger. The subject is given 5 consecutive 10-second trials for the preferred and non-preferred hands. The finger tapping score is the mean of 5 trials and is computed for each hand. Lower scores indicate higher levels of brain dysfunction and higher scores are indicative of better brain function.

This task will require subjects to make repeated choices between an effortful option and a no-effort option. The effortful option varies in the amount of effort required (20%, 50%, 80% and 100% of the subject's individually-calibrated maximum effort, set for each individual prior to scan), measured in speeded button presses. The reward magnitude for the no-effort option remains constant ($1.00), while the reward magnitude for the high-effort option ranges from $1.00 to $5.00. These tasks assess how much effort a person is willing to exert for a given level of reward. Higher reward scores indicate a higher input of effort.

In this task, subjects will first be asked to make a series of speeded button presses to calibrate in their rates of effortful responding. Subjects will be given three trial task choices where they will be asked to push a button as quickly as possible for a total of 20 seconds. Based on the average maximum speed, subjects will then be presented with choices between performing 100%, 80%, 50%, and 20% of this effort in exchange for various amounts of money ($1.00-$5.00), and doing nothing to win $1.00. The number of participants opting for the higher choice of reward will be recorded.

In this task, subjects will be trained on different computerized mazes with varying difficulties/lengths. There will be a group of easy mazes and a group of hard mazes. After a subject has sufficiently learned the mazes (defined as reaching the end of a maze by a specified goal time), he or she will begin the task itself. In this task, subjects will be exposed to "navigate" trial tasks. In "navigate" trials, subjects will have to reach the end of the maze for a varying known or unknown reward amount (ranging from $0-10). The number of participants who complete the task will be recorded.

In this task, subjects will be trained on different computerized mazes with varying difficulties/lengths. There will be a group of easy mazes and a group of hard mazes. After a subject has sufficiently learned the mazes (defined as reaching the end of a maze by a specified goal time), he or she will begin the task itself. In this task, subjects will be exposed to "passive viewing" trials, subjects will watch as they are navigated through the maze without needing to actively respond or move. The number of participants who complete the task will be recorded.