ON/OFF Stimulation and Reward Motivation in Patients With Deep Brain Stimulators

The study will take place at a clinical office in the Charlestown Navy Yard (CNY), and will
consist of one 4 or 4.5-hour visit. Study staff will schedule a convenient time for patients
to arrive, or the research visit may be paired with a regularly scheduled DBS programming
visit. A member of the Division of Neurotherapeutics authorized to manipulate DBS programming
will turn the device on and off during the study. The subject's therapeutic parameters of the
DBS system will not be changed. The subject will be asked to complete four self-report
questionnaires: the Temporal Experience of Pleasure questionnaire, the Chapman Anhedonia
Questionnaire, the Perceived Stress Questionnaire (PSS) and the Mood and Anxiety Symptom
Questionnaire (MASQ). Following these questionnaires, a member of the study staff will teach
the subjects to perform the following tasks on the computer:

Effort Expenditure for Rewards Task (EEfRT) To measure motivation to work for rewards, we
will use the Effort Expenditure for Rewards Task (EEfRT or "effort"). The EEfRT is a
multi-trial computer-based task that assess an individual's willingness to expend effort for
the chance to earn monetary rewards developed by Michael Treadway and David Zald at
Vanderbilt University (Treadway et al., 2009). On each trial, subjects are given an
opportunity to choose between two different task difficulty levels in order to obtain
monetary rewards. For all trials, subjects must make repeated manual button presses in a set
period of time. Each button press raises the level of a virtual "bar" viewed onscreen by the
subject. Subjects will be eligible to win the money allotted for each trial if they are able
to raise the bar to the "top" within the prescribed time period. This button-press task has
two levels of difficulty: referred to henceforth as the 'hard task' or 'easy task'.
Successful completion of hard task trials requires the subject to make 100 button presses,
using the non-dominant pinky finger within 30 seconds, while successful completion of easy
task trials requires the subject to make 30 button presses, using the dominant index finger
within 10 seconds.

For easy task choices, subjects are eligible to win the same amount on each trial if they
successfully complete the task. For hard task choices, subjects are eligible to win an amount
that varies per trial. Subjects are not guaranteed to win the stated reward if they complete
the task; some trials are 'win' trials, in which the subject receives the stated reward
amount, while others are 'no win' trials, in which the subject receives no money for that
trial. To help subjects determine which trials are more likely to be win trials, subjects are
provided with probability cues at the beginning of each trial. Trials have three levels of
probability: 88% probability of being a win trial, 50% and 12%. There are equal proportions
of each probability level across the experiment. Each level of probability appears once in
conjunction with each level of reward value for the hard task.

At the beginning of the task, subjects are provided with a detailed set of instructions, and
an opportunity to play 4 practice trials. Subjects are then told that they will have twenty
(20) minutes to play as many trials as they can. Easy Task choices take approximately 15
seconds, whereas Hard Task choices take approximately 30 seconds. Therefore, the number of
trials that the subject is able to play will depend in part on the choices that she makes.
This means that making more Hard Task trials early-on in the experiment will result in fewer
trials total, which may mean that the subject does not get a chance to play high-value,
high-probability trials that could appear towards the end of the playing time. This trade-off
is explained clearly to the subject. The goal of this trade-off is to ensure that neither a
strategy of always choosing the easy or the hard option can lead to optimal performance on
the task. Moreover, the complexity of variables (with varying monetary reward levels,
probability, and loss of time for future trials), does not lend itself to a formal
calculation of an optimal response selection, forcing Subjects to make a relatively rapid
decision, that we believe taps individual differences in the willingness to expend effort for
a given level of expected reward value.

At the end of the task, two trials are randomly selected that will be added to the subject's
compensation as a reward incentive. Subjects therefore may earn additional funds in incentive
performance compensation each time they complete the EEfRT.

Clock Task The "clock task" is an additional reward task that assesses reward learning
developed by Michael Frank and colleagues (Moustafa et al., 2008; Frank et al., 2009). For
this task, participants observe a clock arm that completes a revolution over the course of 5
seconds, and participants are instructed to press a key to stop the clock at any time in an
attempt to win points. The amount of points won varies depending on RT, and participants must
use trial-and-error strategies to learn when to stop the clock so as to maximize points
received. To prevent subjects form explicitly learning reward values associated with a
specific location on the clock face, reward values at any given point along the clock face
are randomized within +/- 5 points. At the end of the task, subjects may redeem points for a
small amount of additional compensation, each time they complete the task. This task takes
approximately 15 minutes to complete.

30 minutes after turning OFF DBS stimulation, participants will either remain in the OFF
condition or will have the DBS turned ON, depending on their counter-balanced condition
assignment. Subject assignment will alternate sequentially. Subjects will complete the tasks
above in the first condition. Following task completion, subjects will have DBS stimulation
turned OFF or ON (again, depending on condition assignment). After 30 minutes, participants
will complete the same tasks in the second condition. Following retesting, participants that
were in the OFF condition will return to ON DBS stimulation.

We will be using the implanted pulse generator, so it is not possible to deliver an unsafe
current. Because we are not changing the therapeutic parameters of stimulation, subjects
should not experience and adverse side effects. The computer will register the subject's
performance.

Electroencephalography recordings (EEG) will be acquired during performance of the
aforementioned tasks. Continuous EEG data will be sampled at a maximum of 1024Hz using a
64-electrode cap. Eye movement artifacts will be assessed using bipolar electrodes.

Patients with just major depressive disorder or obsessive compulsive disorder will also be
recruited as a control group for the patients with deep brain stimulation.

DBS Patients:

Inclusion Criteria:

- Deep brain stimulator implantation performed at least three months prior to study

Exclusion Criteria:

- Subjects unable to visualize stimulus objects with correction

- Dementia or other known cognitive deficit

Psychiatric Patients:

Inclusion Criteria:

- Right-handed (as determined by the Handedness Inventory; Oldfield, 1971)

- Normal or corrected-to normal vision and hearing

- Current diagnosis of MDD or OCD

Exclusion Criteria for Patients:

- Clinical history of bipolar disorder

- Current or past psychotic disorder

- Gross structural brain damage

- Cognitive impairment that would affect a participant's ability to give informed
consent

- Current substance abuse, or abuse within the past 3 months

- Clinical history of severe personality disorder

- Imminent risk of suicide or an inability to control suicide attempts

- Evidence of dementia or other significant cognitive impairment on neuropsychological
evaluation