Deep Brain Stimulation for Treatment Resistant Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Emory University

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 Deep Brain Stimulation for Treatment-Resistant Depression 
 
IRB# IRB00024883 
Protocol Dated: 04/24/2018 
NCT00367003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TITLE: 
Deep Brain Stimulation for Treatment-Resistant Depression 
 
PRINCIPAL INVESTIGATOR: Patricio Riva Posse, MD (Psychiatry) 
 
CO-INVESTIGATORS: 
Helen Mayberg, MD (Psychiatry and Neurology) 
Robert Gross, MD, PhD (Neurosurgery)  
 
 
Andrea Crowell, MD (Psychiatry)  
 
 
 
 
 
 
 
DRAFT DATE: 
 
4/24/2018 
 

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SCHEMA  
 
Recruitment:  
 
Telephone screening 
Screening: 
 
 
Eligibility assessment 
 
 
 
 
Informed consent and videotaping of consent process 
Pre-operative Evaluation:  
Confirmatory psychiatric interview  
(4-6 weeks pre-op) 
 
Neurosurgical evaluation 
 
 
 
 
2-4 Behavioral Activation evaluations 
Neuropsychological testing #1 
 
 
 
 
Emotional response testing #1 
 
 
 
 
Activity Monitoring and GPS Route Logging  #1 
 
 
 
 
EEG testing #1 
 
 
 
 
High-resolution anatomical MRI 
 
 
 
 
Diffusion tensor imaging 
 
 
 
 
Resting BOLD fMRI 
 
 
 
 
Weekly mood ratings 
Surgery: 
 
 
Pre-operative anatomical MRI 
 
 
 
 
Implantation of bilateral deep brain stimulators 
 
 
 
 
Intraoperative testing of DBS contacts with 
electrophysiological recordings LFP, EEG, HRV, SCR, 
EMG 
 
 
 
 
Implantation of pulse generator and lead extensions 
 
 
 
 
Post-operative anatomical MRI  
 
Post-operative evaluation: 
Stimulation OFF 
(4 weeks post-op) 
 
Weekly mood ratings for 4 weeks 
 
 
 
 
Emotional response testing #2 
 
 
 
 
Activity Monitoring, GPS Route Logging #2 
 
 
 
 
EEG #2 
 
 
 
 
High resolution computed tomography (CT) scan 
 
Open Stimulation: 
 
Bilateral, open-label chronic stimulation 
(24 weeks) 
 
 
 
 
 
Emotional response testing #3-5 (1,3,6 months) 
 
 
 
 
Activity Monitoring, GPS Route Logging  (1,3,6 mos) 
 
 
 
 
EEG #3-5 (1,3,6 months) 
 
 
 
 
 
 
 
 
Weekly mood ratings for four weeks 
 
 
 
 
Bi-weekly to monthly mood ratings for next 20 weeks 
 
 
 
 
Behavioral Activation therapy sessions (up to 30) 
 
 
Ten Year Follow-Up:  
Mood Ratings every month for 3 months, then 
 
 
 
 
Mood Ratings every 3 months for 9 months then 
 
 
 
 
Mood Ratings every 6 months 
 
 
 
 
EEG #6 
Optional EEG at 6 months and at annual visits 
 
 
 
 
Gait assessment (once) 
 
 
 
 
Emotional response testing (once) 
 
 
 
 

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INTRODUCTION 
 
Major Depression is one of the most common and costly of all psychiatric 
disorders 1. It ranks among the top causes of worldwide disease burden and is the 
leading source of disability in adults in North America under the age of 50 2.  While 
depression can be effectively treated in the majority of patients by either medication or 
some form of evidence-based psychotherapy 3, up to 20% of patients fail to respond to 
standard interventions 4, 5. For these patients, trial-and-error combinations of multiple 
medications and electroconvulsive therapy are often required 6, 7.  For patients who 
remain severely depressed despite these aggressive approaches, new strategies are 
needed. 
 
Converging clinical, biochemical, neuroimaging, and post-mortem data suggest 
depression is unlikely to be a disease of a single brain region or neurotransmitter 
system.  Rather, it is now generally viewed as a systems-level disorder affecting 
integrated pathways linking select cortical, subcortical and limbic sites and their related 
neurotransmitter and molecular mediators 8-12.  While mechanisms driving this ‘system 
dysfunction’ are not yet characterized, they are likely to be multi-factorial, with important 
and synergistic contributions from genetic vulnerability, developmental insults, and 
environmental stressors 13-15.  Treatments for depression can be similarly viewed within 
this limbic-cortical system framework, where different modes of treatment modulate 
specific regional targets, resulting in a variety of complementary, adaptive chemical and 
molecular changes that re-establish a normal mood state 12, 16, 17. 
 
Functional neuroimaging studies have played a critical role in characterizing 
these limbic-cortical pathways 17-20.  Previous studies have demonstrated consistent 
involvement of the subgenual cingulate (Cg25) in both acute sadness and 
antidepressant treatment effects, suggesting a critical role for this region in modulating 
negative mood states 21, 22.  In support of this hypothesis, a decrease in Cg25 activity is 
reported with clinical response to different antidepressant treatments including specific 
serotonin reuptake inhibitor (SSRI) antidepressant medications, electroconvulsive 
therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and ablative surgery 
23-28. In addition, Cg25 connections to the brainstem, hypothalamus, and insula have 
been implicated in the disturbances of circadian regulation associated with depression 
(sleep, appetite, libido, neuroendocrine changes) 29-33.  Reciprocal pathways linking Cg25 
to orbitofrontal, medial prefrontal, and various parts of the anterior and posterior 
cingulate cortices form the neuroanatomical substrates by which primary autonomic and 
homeostatic processes influence various aspects of learning, memory, motivation and 
reward – core behaviors altered in depressed patients 31, 34-36. 
 
Recent advances in the surgical treatment of Parkinson’s disease have 
demonstrated that chronic high frequency deep brain stimulation (DBS) in pathologically 
active brain circuits produces profound clinical benefits 37-39.  It has also been shown that 
clinically effective DBS in the basal ganglia produces both local and remote changes in 
neural activity as assessed by positron emission tomography (PET) 40, 41.  
 
Based on these observations, Dr. Mayberg has studied DBS of the white matter 
adjacent to Cg25 as a treatment for treatment-resistant depression in 13 patients. Of 
these 13 patients, 9 have mood ratings at 3 months post-surgery and 6 have mood 
ratings at 6, 9 and 12 months post-surgery. At 3 months, 3 of 9 patients met response 
criteria (>50% decrease in Hamilton Depression Rating Scale [HDRS] score). At 6 
months, 4 of 6 patients met response criteria. Of these four patients, 2 were in remission 
(HDRS less than 8) and one was near remission at the 6 month time point. Also, all of 
these 4 responders (at 6 months) maintained this response out to 12 months post-
surgery. In addition to improvements in depressive symptoms, patients with an 
antidepressant response have spontaneously reported improvements in sleep and 

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changes in visual perception. Although three patients had post-operative local wound 
infections, no other behavioral or medical adverse events were noted. 
 
This pilot study supports the hypothesis that high-frequency DBS in Cg25 white 
matter can be used to treat depression, but further data is needed to confirm these 
findings.  We propose a replication study at Emory University that will help further test the 
efficacy, safety and potential mechanisms of action of DBS for treatment-resistant 
depression (TRD). 
 
OBJECTIVES 
 
We propose to test whether high frequency DBS of the subgenual cingulate white 
matter (Cg25-DBS) is a safe and efficacious antidepressant treatment in forty TRD 
patients, and to investigate potential mechanisms of action of this intervention.  
Importantly, this study will be used to assess the need for and assist in planning a larger, 
more definitive trial of Cg25-DBS for TRD.  We will address the following specific aims. 
 
Specific Aim 1. To assess the safety and tolerability of acute and chronic Cg25-DBS.  
Rates of complications (surgical complications, hemorrhage, stroke, infections, and 
seizures) will be assessed and compared to known rates for DBS surgery in other 
disorders.  
 
Specific Aim 2.  To assess the antidepressant efficacy of active Cg25-DBS in treatment-
resistant depressed patients.  We hypothesize that 24 Weeks of open Cg25-DBS will 
yield statistically significant antidepressant effects. 
 
Specific Aim 3.  To assess the possible mechanisms mediating Cg-25 DBS effects on 
depression.  This will include behavioral and psychophysiological measures of emotional 
response and perception, motor activity and electrophysiological measurements with 
acute intra-operative testing of DBS.     
 
Secondary Aim 1.  To assess long-term effects of Cg25-DBS in patients with Major 
Depressive Disorder.  Patients will be followed naturalistically over 10 years.  
 
Secondary Aim 2. To assess for variables that predict antidepressant response, 
remission and relapse over time. 
 
Secondary Aim 3.   Changes in mood and behavior associated with DBS will have both 
immediate effects and slowly evolving, delayed effects, our experimental protocol will 
assess mood and behavior at several time points post-surgery. This will include 
behavioral and psychophysiological measures of emotional response and perception, 
motor activity and electrophysiological measurements.      
 

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PROTOCOL 
 
1.0 Clinical Care Costs 
1.1 Patients or their third party payers will be responsible for the costs of the 
following procedures: 
1.1.1 Initial surgery and any subsequent battery replacements 
1.1.2 Pre & post-operative MRI, 
1.1.3  post-op Xray CT 
1.1.4 Psychiatric screening  
1.1.5 Psychiatric follow-up visits 
1.1.6 Neuropsychological assessment 
1.1.7 Labs 
1.1.8 Behavioral activation therapy 
1.1.9 EKG (if required) 
1.2 The following procedures will be covered by the study: 
1.2.1 Research fMRI scan 
1.2.2 Research assessments 
1.2.3 Emotional Response Testing46-50 
1.2.4 Actigraphy and GPS Route Logging51-53 
1.2.5 EEG54 
1.2.6 Gait Assessment 
1.3 We currently have approval from the local CMS director for Medicare to 
cover the clinical costs associated with this study. We will pursue pre-
authorization from other third party payers as appropriate.  
 
2.0 Patient Selection 
2.1 Eligibility Criteria.  Patients can be included if they have: 
2.1.1 Age 18-70 years old. 
2.1.2 Ability to provide written informed consent. 
2.1.3 Current Major Depressive Episode (MDE), secondary to either 
Major Depressive Disorder or Bipolar Disorder (I, II or NOS), 
diagnosed by structured clinical interview for DSM IV-TR42. 
Diagnosis will be confirmed by two independent psychiatrists. 
2.1.4 Current MDE at least two years duration OR a history of more 
than 4 lifetime depressive episodes.   
2.1.5 Minimum score at study entry of 20 on the 17-item Hamilton 
Depression Rating Scale (HDRS-17)43. 
2.1.6 Average pre-operative HDRS-17 score of 20 or greater (averaged 
over four weekly pre-surgical evaluations during the four weeks 
prior to surgery) and an average pre-operative HDRS-17 score no 
more than 30% lower than the baseline screening HDRS-17 
score. 
2.1.7 A maximum Global Assessment of Functioning of 50. 
2.1.8 Treatment-resistant depression defined as: 
2.1.8.1 
Failure to respond to a minimum of four different 
antidepressant treatments, including at least three 
medications from at least three different classes, 
evidence-based psychotherapy or electroconvulsive 
therapy (ECT) administered at adequate doses and 
duration during the current episode.  We will require 

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documentation (i.e., statement from the treating 
psychiatrist) that a treatment trial has failed (either no 
response to maximum tolerable doses for a minimum 
of 4 weeks, or side-effects at sub-maximal doses) as 
coded by a revised Antidepressant Treatment History 
Form (ATHF). The study investigators will confirm each 
treatment via review of records from referring 
psychiatrists.   
2.1.8.2 
Failure or intolerance of an adequate course of 
electroconvulsive therapy (ECT) during any episode 
(confirmed by medical records), or refusal of ECT due 
to a reason considered to be valid by the study 
psychiatrist. Such reasons might include concern 
regarding the impact of cognitive side effects of ECT 
on current ability to work or function, or inability to 
obtain third-party payment for a course of ECT. 
Additionally, it is recognized that the probability that a 
patient who has failed four medications in the current 
episode will achieve a lasting response with ECT is 
about 18% (60% probability of an acute response and 
30% chance of maintaining this for at least 24 Weeks); 
patients who have refused ECT because this chance of 
benefit does not outweigh the risks associated with 
ECT will be considered eligible. 
2.1.9 A patient may remain on psychotropic medications during this 
study. However, doses must remain stable during the 4 weeks 
prior to surgery, the four weeks post-operatively, and the 24 
weeks open stimulation phase. Medications will be changed only if 
intolerable side effects clearly attributable to the medications 
develop. 
2.1.10 All patients must have an established outpatient psychiatrist 
and be willing to sign a written release to allow study 
investigators to give and receive information from this 
psychiatrist. 
 
2.2 Ineligibility Criteria. Patients will be excluded if they have: 
2.2.1 Inability to tolerate general anesthesia. 
2.2.2 Significant cerebrovascular risk factors or a previous stroke, 
documented major head trauma or neurodegenerative disorder. 
2.2.3 Other currently active clinically significant Axis I psychiatric 
diagnosis including schizophrenia, panic disorder, obsessive-
compulsive disorder, generalized anxiety disorder or post-
traumatic stress disorder.  Patients with severe Axis II personality 
disorders will also be excluded if the personality disorder is likely 
to interfere with cooperation and adherence to the study protocol. 
2.2.4 Current psychotic symptoms. 
2.2.5 Evidence of global cognitive impairment. 
2.2.6 Substance abuse or dependence not in full sustained remission 
(i.e., not active for at least one year). 

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2.2.7 Active suicidal ideation with intent; suicide attempt within the last 
six months; more than three suicide attempts within the last two 
years. 
2.2.8 Pregnancy or plan to become pregnant during the study period. 
2.2.9 General contraindications for DBS surgery (cardiac 
pacemaker/defibrillator or other implanted devices). 
2.2.10 Inability or unwillingness to comply with long-term follow-up. 
2.2.11 History of intolerance to neural stimulation of any area of the body. 
2.2.12 Participation in another drug, device or biologics trial within the 
preceding 30 days. 
2.2.13 Conditions requiring repeated MRI scans. 
2.2.14 Conditions requiring diathermy. 
2.2.15 Conditions requiring anticoagulant medication. 
2.2.16 Terminal illness associated with expected survival of <12 months. 
2.3 Final patient selection will be made by consensus of the primary study team. 
 
3.0 Pre-operative Clinical Evaluation 
3.1 Telephone screening. To increase the efficiency of the screening process, 
interested patients will first be contacted by telephone to complete an initial 
telephone screening. This screening will confirm the patient’s interest and 
review the major inclusion/exclusion criteria. Insurance status will be 
collected. Medical records will be requested and reviewed. Patients who 
continue to be eligible and interested will be scheduled for a screening visit. 
A copy of the informed consent form will be mailed to patients for careful 
review. 
3.2 Screening visit. Potentially eligible and interested patients will have an initial 
screening visit to obtain informed consent and confirm eligibility. This visit 
will last approximately 8 hours including breaks, and may occur over more 
than one day. During this visit, the patient will meet with a study psychiatrist 
and a research coordinator. The following will be performed: 
3.2.1 Informed consent (120 minutes). Patients will first be given an 
informed consent to be videotaped during the informed consent 
process for the DBS study. If patient’s agree, the entire informed 
consent discussion will be videotaped.  The patient will also be 
given the request to interview family member consent.  If the 
patient chooses to sign, we will contact the family member 
(chosen by the patient) to see if they are willing to consent to be 
interviewed regarding DBS. The DBS study will be explained in 
detail and all questions from the patient will be answered to the 
greatest degree possible. The patient will demonstrate 
understanding of the study protocol verbally and will sign the 
informed consent form if they choose to participate. As part of the 
informed consent process, questions will be asked to assess how 
well the participant understands the consent using a validated 
questionnaire (the MacArthur Competence Assessment Tool for 
Clinical Research [MacCAT-CR]). Additionally, a brief 
questionnaire assessing how well the participant understands key 
differences between research and usual clinical care, and the 
effects of these differences on their participation in this study, will 
be administered. Patients will also have the opportunity to  
consent for us to contact a family member of their choosing.  That 

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family member would then give us consent to interview them 
about their understanding and expectations of the study.  
Responses taken from the family member will be used to compare 
to those taken from the patients.  The interview will be videotaped.  
That family member will also complete an interview/questionnaire 
form.  Family members will be asked to do the 
interview/questionnaire again 7 months after their family member 
has received the DBS surgery.  As a separate part of this study, 
videotapes will be reviewed by up to three outside psychiatrists 
with expertise in decision-making capacity. Videotapes of the 
consent discussion and capacity assessment will be kept 
confidential. The outside experts will obtain separate IRB approval 
from their home institutions to review these videotapes for the 
purpose of studying capacity to consent to research involving 
deep brain stimulation. A repeat, videotaped MacCAT-CR/consent 
assessment will be done at the end of the 24 weeks open active 
stimulation phase.  As a separate part of this study, audio files will 
be extracted from the patient videos before surgery and after 24 
weeks of active stimulation and sent to collaborators at the Nathan 
Kline Institute for analysis of changes in speech and language. 
Grammatical complexity, frequency of vocabulary, and 
conversational expressions will be analyzed as part of the 
language analysis.  Audio files of the consent discussion and 
capacity assessment will be kept confidential. The outside experts 
will obtain separate IRB approval as necessary.   
3.2.2 Diagnostic interview and mood ratings (120 minutes). The 
following will be administered: 
3.2.2.1 
Structured Clinical Interview for DSM-IV Diagnoses 
(SCID-I) 
3.2.2.2 
Structured Clinical Interview for DSM-IV Diagnoses, 
Axis II (SCID-II) 
3.2.2.3 
Shedler-Westen Assessment Procedure (SWAP) 
3.2.2.4 
28-item Hamilton Depression Rating Scale (HDRS-28) 
3.2.2.5 
Hamilton Anxiety Scale (HAS) 
3.2.2.6 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
3.2.2.7 
Young Mania Rating Scale (YMRS) 
3.2.2.8 
Mini-Mental Status Examination (MMSE) 
3.2.2.9 
Edinburgh Handedness Inventory (EHI) 
3.2.2.10 
Beck Depression Inventory (BDI-2) 
3.2.2.11 
Inventory of Depressive Symptomatology – Subject 
Rated (IDS-SR) 
3.2.2.12 
Beck Anxiety Inventory (BAI) 
3.2.2.13 
NEO-PR Personality Inventory (NEO) 
3.2.2.14 
Dysfunctional Attitude Scale (DAS) 
3.2.2.15 
Revised Dimensions of Temperament Survey  
(DOTS-R) 
3.2.2.16 
Beck Hopelessness Scale (BHS) 
3.2.2.17 
Toronto Alexithymia Scale (TAS) 
3.2.2.18 
Health and Labor Questionnaire (HLQ) 

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3.2.2.19 
Quality of Life Expectation Satisfaction Questionnaire 
(Q-LES-Q) 
3.2.2.20 
Klein trauma & abuse-neglect (KLEIN)  
3.2.2.21 
Stressful Life Events Questionnaire (SLEQ)  
3.2.2.22 
Columbia Suicide Severity Scale (C-SSS) 
3.2.2.23 
Clinical Global Impression – Severity (CGI-S) 
3.2.2.24 
Patient Global Impression – Severity (PGI-S) 
3.2.2.25 
Global Assessment of Function (GAF) 
3.2.2.26 
Antidepressant Treatment History Form (ATHF) 
3.2.3 Psychiatric examination (60 minutes). If the patient continues to 
meet inclusion criteria, a study psychiatrist will perform a detailed, 
diagnostic examination. Current psychiatric and physical 
symptoms, current medications and treatments, past psychiatric 
history, past medical and surgical history and substance use 
history will be reviewed. A physical examination will be performed 
as indicated.   
3.2.4 Medications. Medications can be adjusted during the first part of 
the screening/pre-operative phase. However, doses must remain 
stable during the four weeks prior to surgery. 
3.2.5 Release of information (ROI). Patients will sign an ROI so 
that study investigators may share health-related information 
with the patient’s psychiatrist. 
3.3 Follow-up screening visits. Patients who continue to be eligible will be 
scheduled for follow-up screening visits to include: 
3.3.1 Evaluation by a second study psychiatrist to confirm psychiatric 
diagnosis and degree of treatment resistance (60 minutes). 
3.3.2 Evaluation by the study neurosurgeon including review of 
appropriateness for surgery, physical and detailed neurological 
examination (60 minutes). 
3.3.3 Labs (10 minutes). Blood and urine will be obtained for the 
following tests: complete blood count (CBC), comprehensive 
metabolic panel (CMP), thyroid screening tests, coagulation 
studies, high-sensitivity C-reactive protein, genotyping, urinalysis, 
urine drug of abuse screen, pregnancy test (if applicable). A small 
amount of blood will be stored for further genetic testing – cell 
lines will be immortalized so that blood can be stored indefinitely 
for future studies. 
3.3.4 
EKG (20 minutes). An EKG will be performed if the neurosurgeon 
determines this is necessary as part of the pre-surgical screening. 
3.3.5 Magnetic Resonance Imaging (MRI)(60 minutes). This pre-
operative scan will help rule out intracranial abnormalities that 
might explain the patient’s level of treatment resistance or 
preclude the patient from surgery. During this scan, we will also 
acquire diffusion tensor imaging (DTI) to assess white matter tract 
integrity and resting BOLD functional MRI data to assess regional 
connectivity.   
3.3.6 Neuropsychological testing (4 hours). A comprehensive 
neuropsychological battery will be administered by a trained 
psychometrist under the supervision of a board-certified 
neuropsychologist. This battery will take approximately 4 hours to 

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complete but can be done over more than one day if needed to 
prevent patient fatigue.  The study will be performed prior to 
surgery and repeated at the end of 6 months of active stimulation 
3.3.7 Behavioral Activation: In an effort to provide rehabilitation to our 
patients, behavioral activation therapy will be performed.  There 
will be 2-4 sessions pre-op to establish a relationship with the 
patient.  Therapy will begin post operatively when stimulation is 
started and will occur weekly for approximately 30 weeks. 
3.4 Mechanism of Action Studies. To help assess mechanism of action (MOA) 
of DBS for TRD, several MOA experiments will be performed throughout the 
study beginning in the pre-operative evaluation period. All of the following 
will be repeated 1 month after surgery during acute DBS testing and again 
after 1,3, and 6 months of active DBS.  : 
3.4.1 Emotional response testing with psychophysical meaures.  
Eye-Tracking and Pupilometry:  Eye-tracking will be used to measure the 
visual attention of the participant, The participant sits in front of a 
computer monitor and simply watches as pictures or sounds are 
presented. While they view the image or screen, a light beam is used to 
track the position and size of the pupil and cornea over time in order to 
estimate position of gaze.   
3.4.1.1.1 Emotional Pictures: Emotional pictures will be 
selected from the International Affective Picture 
System, a standardized, widely available 
dataset, normed for content and emotional 
valence (IAPS; Lang, Bradley, and Cuthbert, 
2008).  
3.4.1.1.2 Emotional Sounds:  The set of emotional 
sounds will include emotionally evocative and 
neutral musical excerpts (from classical and 
popular sources) as well as standard sounds 
from the International Affective Digital Sounds 
set (IADS; Bradley and Lang, 1999) which 
contains. short audio clips associated with 
pleasant (e.g., laughing) and unpleasant (e.g., 
crying, a barking dog) events. 
3.4.1.1.3 Emotional Videos: The set of emotional videos 
will include up to twelve two-minute video clips 
from movies, documentaries, and instructional 
videos.  
3.4.1.1.4 Emotional Memories: Participants will be asked 
to remember an experience that made them 
feel sad, feel happy, and feel angry for two 
minutes per experience. These emotional 
memories will be interspersed with 2 minutes 
spent imagining common, emotionally-neutral 
experiences, such as going grocery shopping. 
3.4.1.1.5 Image and sound ratings and questions:  
Participants will rate emotional valence (how 
positive or negative a stimulus is) and 
emotional arousal (strength of emotional 
response), using a numeric scale. To verify that 

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participants attended to each stimulus, memory 
for selected items will be assessed with 
standard recall (e.g., “what stimuli did you 
experience”) and recognition tests (e.g., “is this 
stimulus one that you experienced in the 
experiment?”). 
3.4.1.1.6  Psychophysiology:  Galvanic Skin Response 
(GSR) will be measured using two sensors 
placed on the palm surface of the index and 
middle finger. (Andreassi, 2000). 
Electromyography (EMG) will be measured 
using two pairs of sensors placed on two 
separate locations of the face. (above the left 
eye brow corrugator supercilli muscle—
frowning; midway between the corner of the 
mouth and the ear lobe (zygomaticus major 
muscle--smiling),  Cardiac measures (ECG): 
Heart rate acceleration, heart rate variability 
(HRV) will be used using 3 lead ECG.  Blood 
pressure will be measured simultaneously using 
a finger sensor..    
3.4.2 Motivation and activity levels. Q-Sensor mobile wrist sensor 3-
dimensional accelerometer to assess somatic activity movement), 
Garmin mobile personal GPS tracking to assess large-scale daily 
activity via tracking of routes (20). 
3.4.2.1 
Actigraphy. We hypothesize that decreased depressive 
symptoms will be associated with an increase in 
patients' average level of somatic movement, Patients 
will wear a mobile wristband-style 3-D accelerometer 
sensor that continuously logs arm and body movement 
levels. 
3.4.2.2 
 GPS logging.  We also hypothesize that decreased 
depressive symptoms will be associated with an 
increase in patients' average level of daily life activities 
including amount of travel outside the home. This will 
be assessed by a wristband-style GPS route logger, 
which periodically logs the individual's GPS location, 
forming a connected route map of daily travels.  
3.4.2.3 
Security.  Patients will be fully informed about the 
nature of the information that will be recorded, its 
purpose and use, and will be able to stop, pause, or 
start the GPS logging function whenever they wish, by 
pressing a button (patients will receive training on 
these functions).  The GPS logging information will be 
securely transmitted to a cloud server that will store the 
route logging information associated with a random 
study identification number, not the individual's name 
or other identifying information. The information on the 
server is only retrievable using a login and password. 
The route logging information will be used to determine 

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the number, length, and complexity of travel outside 
the home.  
3.4.2.4 
Gait Assessment. We hypothesize that decreased 
depressive symptoms will be associated with increased 
gait speed and endurance. Patients will engage in a 
self-paced walk for six minutes while wearing sensors 
attached to the trunk and limbs (APDM Wearable 
Technology).  
 
3.4.3.  Electroencephalography. (EEG) (1 hour). This data will be tested 
in conjunction with the resting bold fMRI as a predictive biomarker of 
antidepressant response to chronic DBS and as as index of ongoing brain 
changes with short term and chronic DBS.  This study will be performed at 
baseline, 1 month after surgery and during acute testing of optimal DBS contacts, 
after 1, 3  and 6 months of active DBS, and at one time point during the 
naturalistic follow up phase.   
3.4.3.1. 
EEG Recording and Analysis. During the EEG 
session, cortical field potentials will be continuously recorded at 
1000 Hz (1kHz) from 32-64 active electrodes distributed over the 
scalp and held in place using an elastic cap.  Electrodes will be 
placed so as to maximize scalp coverage and labeled according to 
the International 10-20 System for localizing EEG electrodes.  
Additional bipolar leads will be placed around the eyes to record 
the horizontal and vertical electrooculogram (H-EOG and V-EOG 
respectively).  All electrophysiological data will be recorded using 
a BioSemi ActiveTwo biopotential measurement system 
(Amsterdam, Netherlands) and digitized on a laptop computer.  
Raw EEG data will be collected continuously during the testing 
session and segmented and filtered offline (0.01 – 100 Hz 
bandpass) prior to analysis.  Positioning the electrodes and 
ensuring good electrical contact with the scalp will take an 
estimated 20-30 minutes for each patient.  The total EEG session, 
including set-up and clean-up time is expected to be 
approximately 1 hour in duration. 
 
3.4.3.2  
Behavioral Tasks. EEG will be recorded in two 
conditions: (1) resting state; (2) a mood induction/emotion 
regulation task;  
3.4.3.2.1 
Resting Baseline:  Previous research with 
patients receiving DBS for Parkinson’s Disease (PD) has revealed 
a significant effect of DBS on EEG coherence in a resting 
condition in which no task was required of the patients.  To 
facilitate comparison with this existing literature we will replicate 
their recording conditions.  During this recording, the patient will 
be asked to sit still and maintain visual fixation on a marker on the 
computer screen for 150 seconds (2.5 minutes).  Because DBS in 
our patients is expected to primarily influence prefrontal circuits 
we expect to find an overall increase in EEG coherence at frontal 
electrode sites and possibly between frontal and more posterior 
sites.  However, the lack of a defined task in this baseline period 
may make interpretation difficult.  To this end, we will record 
resting activity during different DBS states (ON versus OFF). 

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Additionally, we will collect EEG during an emotional behavioral  
tasks designed to explore the effects of DBS on the engagement 
of prefrontal circuits.  Preliminary data using this task and a 
previously approved protocol demonstrates feasibility and results 
in support of the current hypotheses 54 
3.4.3.2.2 
Mood Induction/Emotion Regulation Task:  
This task assesses the ability of the patients to regulate negative 
emotions.  Words describing a variety of negative (e.g., “greedy”) 
or positive (e.g., “kind”) personality traits will be presented on a 
computer monitor. In two separate task runs, the patients will be 
asked to decide: (1) whether each word describes themselves or 
not, and (2) whether it would be a desirable trait in someone else 
or not.  This task, particularly the condition in which patients make 
judgments about whether negative traits apply to themselves, 
requires patients to actively engage in mood regulation, 
presumably by engaging prefrontal circuits that may be 
compromised by depression.  Because we expect DBS to alleviate 
depression and thus to facilitate mood regulation we will compare 
patterns of EEG coherence between conditions (self vs. other; 
positive vs. negative traits) during each session.  We expect that 
successful emotion regulation will be manifested by increases in 
EEG coherence in prefrontal circuits, and that those circuits will be 
more engaged following successful DBS treatment. 
 
 
 
3.5 Weekly mood ratings. During the pre-operative phase, patients will have 
assessments every 1 to 4 weeks. Assessments will occur weekly during the 
4 weeks prior to surgery. Assessments will include: 
3.5.1 HDRS-28 
3.5.2 HAS 
3.5.3 MADRS 
3.5.4 YMRS 
3.5.5 BDI-2 
3.5.6 IDS-SR 
3.5.7 BAI 
3.5.8 PGI-S 
3.5.9 Patient Global Assessment of Improvement (PGI-I) 
3.5.10 DAS 
3.5.11 DOTS-R 
3.5.12 BHS 
3.5.13 Q-LES-Q (every 4 weeks) 
3.5.14 HLQ (every 4 weeks) 
3.5.15 TAS 
3.5.16 C-SSS 
3.5.17 CGI-S 
3.5.18 Clinical Global Assessment of Improvement (CGI-I) 
3.5.19 GAF 
3.5.20 Medication Log 
3.6 Pre-surgical visit. On the last weekly mood rating visit prior to surgery, the 
patient will again meet with a study psychiatrist and PI to confirm continued 

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interest in participation and to review the surgical and post-surgical 
procedures. 
3.7 Videotaping: Videotaping: At several time points in this study the patient will 
be briefly videotaped to document their appearance, speech and behavior.  
Additionally a more extensive videotaped interview  will be performed prior 
to surgery and at the primary endpoint date to further document overall 
change in symptoms, appearance, speech and behavior, supplementing 
quantitative measures.   
 
4.0 Surgery 
4.1 Target Identification. Patients will come to Emory University Hospital on the 
morning of surgery. A CRW stereotactic frame (Radionics, Inc., Burlington, 
MA) will be affixed to the patient's head and preoperative MRI obtained 
(Signa, 1.5 tesla; General Electric, Milwaukee, WI). The x, y, and z 
coordinates of the anterior (AC) and posterior commissures (PC) will be 
determined using axial 3D T1 MR images. To reach the intended target 
within the subgenual cingulate white matter, a midline T2 sagittal image will 
be selected and the cingulate gyrus below the genu of the corpus callosum 
identified.  A line will be traced from the most anterior aspect (genu) of the 
corpus callosum to the anterior commissure and the midpoint selected. The 
T2 coronal section corresponding to the plane of this midpoint will be 
identified and the coordinates of the transition point between the gray and 
white matter identified. 
4.2 DBS Surgery. In the operating room under local anesthesia, a burr hole will 
be drilled 2 cm from the midline immediately anterior to the coronal suture. 
The underlying dura mater will be opened, and the exposed pial surface 
coagulated. A mixture of fibrin glue and cryoprecipitate will be used to 
prevent cerebrospinal fluid egress and minimize brain shift. The CRW arc 
will be attached to the head frame and set to the pre-determined target 
coordinates. Micro-electrode recordings will commence at 10 mm above the 
target using electrodes made from parylene-C-insulated tungsten wires and 
plated with gold and platinum (FHC, Inc., Bowdoinham, ME).  Cellular 
activity will be amplified (DAM 80 WPI Instruments) with a gain of 1000 and 
initially filtered to 0.1-10 kHz. The signal will be displayed on an oscilloscope 
(Axon Instruments) and directed to an audio monitor (Grass AM 8, with 
noise clipping circuit). Microelectrode mapping will be used mainly to confirm 
the anatomic location of the gray and white matters of area 25, 
characterized respectively by the recording of neuronal activity and cell 
sparse areas. The transition between these two regions will be chosen as 
the final target for the implantation of the electrodes. DBS quadripolar 
electrodes (St. Jude Medical Neuromodulation; Plano, TX) will be implanted 
bilaterally. Each of the 4 electrode contacts will be tested for adverse effects 
and clinical benefits. These contacts will be numbered from 1-4 (left 
hemisphere) and 5-8 (right hemisphere), with 1 and 5 being the most ventral 
and 4 and 8 the most dorsal contacts. The Positive And Negative Affect 
Scale (PANAS) and visual analog scales will be used to test mood 
intraoperatively as each contact is tested. This portion of the surgery will be 
videotaped. 
4.3 Intraoperative Recording. We will record electrical activity (single cell 
recording and local field potentials) in the vicinity of the surgical target and 
along the electrode trajectory. We will also record scalp EEG, facial EMG, 

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Skin conductance (SCR), and heart rate  intraoperatively.. Recording will 
occur prior to, during and after stimulation at each DBS contact. This will 
provide comparable measures to those measured in the lab during the 
Emotional testing sessions.   
 
5.0 Post-operative care. Prophylactic antibiotics will be administered for 24 hours after 
the surgical procedures. An 1.5T MRI will confirm DBS electrode placement and 
absence of intraoperative complications (e.g., intracranial air, hemorrhage, edema),  
Patients will be discharged 1-3 days following surgery. 
 
6.0 Post-operative, Stimulation Off Phase (4 weeks) 
6.1 Patients will discharged with the DBS system off (patients will be told the 
system is off). 
6.2 Patients will be evaluated weekly for four weeks to assess for behavioral 
changes following DBS surgery but prior to receiving active, chronic 
stimulation.  
6.3 Clinical Assessments. During this phase, clinical assessments will include: 
6.3.1 HDRS 
6.3.2 HAS 
6.3.3 MADRS 
6.3.4 YMRS 
6.3.5 BDI 
6.3.6 BAI 
6.3.7 IDS-SR 
6.3.8 DAS 
6.3.9 DOTS-R 
6.3.10 BHS 
6.3.11 Q-LES-Q (every 4 weeks) 
6.3.12 HLQ (every 4 weeks) 
6.3.13 TAS 
6.3.14 C-SSS 
6.3.15 SDS 
6.3.16 PGI-S 
6.3.17 PGI-I 
6.3.18 CGI-S 
6.3.19 CGI-I 
6.3.20 Medication log 
6.4 High Resolution x-ray CT scan: this study will be used to verify the final 
location of DBS electrode contacts needed for selection of the optimal 
contact for chronic stimulation.   
6.5 Emotional response testing, actigraphy and GPS logging, EEG  #2: Patients 
will return for repeat testing (sam as 3.4.1-3).  
 
7.0 Open Stimulation Phase (4-30 weeks post-op) 
7.1 Clinical Assessments. During this phase, patients will return every two to 
four weeks for clinical assessments to include: 
7.1.1 HDRS 
7.1.2 HAS 
7.1.3 MADRS 
7.1.4 YMRS 
7.1.5 BDI 

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7.1.6 BAI 
7.1.7 IDS-SR 
7.1.8 DAS 
7.1.9 DOTS-R 
7.1.10 BHS 
7.1.11 Q-LES-Q (every 4 weeks) 
7.1.12 HLQ (every 4 weeks) 
7.1.13 TAS 
7.1.14 C-SSS 
7.1.15 PGI-S 
7.1.16 PGI-I 
7.1.17 CGI-S 
7.1.18 CGI-I 
7.1.19 Medication log 
7.2 Behavioral Activation Therapy:  Patients will begin BA with the onset of 
stimulation.  There will be a maximum of 30 sessions over the course of the 
first 6 months. 
7.3 Emotional response testing #3-4: Patients will return for repeat testing at 1 
month and 3 months of DBS.  SCR and activity will be monitored 
continuously for the first month using the Q-Sensor mobile wrist sensor, 3-D 
accelerometer and Garmin mobile GPS devices.  Weekly testing will be 
performed monthly for months 2-6. 
7.4 EEG #3 and #4:  EEG will be repeated at 1 month, 3 months of DBS. 
 
7.5 End of Phase MOA Assessment. At the end of this 24 Week phase, patients 
will be evaluated as follows (see above for details): 
7.5.1 Neuropsychological testing #2 
7.5.2 Emotional response testing, actigraphy, GPS logging and EEG #5.   
7.6 Programming Adjustments. Initial stimulation settings will be 130 Hz, 91 µs 
pulse width, 4mA monopolar bilateral stimulation (one contact per electrode 
array per side). Every 4 weeks, after the clinical evaluation, a decision will 
be made whether to continue at these settings or make an adjustment. 
Adjustments will be made based on whether a patient is considered 
IMPROVED (>10% change in the 17-item HDRS score from the previous 
assessment and/or at least minimally approved on the CGI-I), 
UNCHANGED (≤10% change in the 17-item HDRS score from the previous 
assessment and/or unchanged on the CGI-I) or WORSE (>10% increased in 
the 17-item HDRS score from the previous assessment and at least 
minimally worse on the CGI-I) using the following algorithm: 
7.6.1 If IMPROVED, make no change and re-assess in 4 weeks. 
7.6.2 If UNCHANGED or WORSE, go through the following sequence of 
steps: 
7.6.2.1 
Increase amplitude to 6 mA and reassess in 4 weeks. 
7.6.2.2 
Increase amplitude to 8 mA and reassess in 4 weeks. 
7.6.2.3 
Re-evaluate contact location and consider a contact 
switch; remain at 8 mA; re-assess in 4 weeks. 
7.6.2.4 
Re-evaluate contact location and consider adding a 
second contact; remain at 8 mA; re-assess in 4 weeks. 
7.6.3 To date, there has been no association with stimulation of this 
brain region or increased amplitude of stimulation with a 
worsening of depression. When patients have had a worsening of 

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depression, this has consistently been determined to be due to 
environmental stressors or the natural history of the patient’s 
illness (normal fluctuations). However, if a patient experiences a 
>30% increased in the 17-item HDRS score within 4 weeks of a 
stimulation setting change AND there is no other cause identified 
for this worsening, then the stimulation parameters will be 
returned to the previous settings and the patient will be re-
evaluated in 4 weeks (or sooner if clinically indicated).  
 
8.0 Ten Year Naturalistic Phase 
8.1 Rationale. The long-term effects of DBS are not known. This will be 
evaluated over ten years. 
8.2 Length. The overall length of this phase will be ten years and will begin at 
the end of the 6 month open stimulation phase. 
8.3 Clinical Assessments. During this phase, patients will return every month for 
the first three months, every 3 months for the next 9 months, then every six 
months for clinical assessments: 
8.3.1 HDRS 
8.3.2 HAS 
8.3.3 MADRS 
8.3.4 YMRS 
8.3.5 BDI 
8.3.6 BAI 
8.3.7 IDS-SR 
8.3.8 DAS 
8.3.9 DOTS-R 
8.3.10 BHS 
8.3.11 Q-LES-Q (every 4 weeks) 
8.3.12 HLQ (every 4 weeks) 
8.3.13 TAS 
8.3.14 C-SSS 
8.3.15 PGI-S 
8.3.16 PGI-I 
8.3.17 CGI-S 
8.3.18 CGI-I 
8.3.19 PANAS-X 
8.3.20 Hope Scale 
8.3.21  
8.3.22 Medication log 
8.3.23 Depressive Experiences Scale (once) 
8.3.24 Brio acceptability questionnaire 
8.3.25 CAT MH  
8.4 Medication Adjustments. Medications can be adjusted during this phase 
based on clinical judgment. 
8.5 DBS programming adjustments. DBS programming adjustments will be 
allowed based on clinical judgment. 
8.6 Assessment of long-term stable response: Patients will be invited to undergo 
a brief EEG subsequent to the 6 month study period and in conjuction with 
annual visits. After several years of stimulation, when a long-term, stable 
response has been attained, subjects will be reassessed with EEG #6, 
emotional response testing, psychophysiology, and gait assessment. 

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. 
9.0 Data Analyses and Statistical Consideration 
9.1 Definitions. Standard criteria for antidepressant response, remission, 
relapse and recurrence will be applied45. 
9.1.1 Response will be defined as a decrease in the HDRS-17 score of 
50% or greater from the average pre-surgical baseline.  
9.1.2 Non-response will be defined as a <30% decrease in HDRS-17. 
9.1.3 Partial response will be defined as a decrease in HDRS-17 >30% 
but less than 50%.  
9.1.4 Remission will be defined as an HDRS-17 score <10. 
9.1.5 Depressive relapse will defined as meeting DSM-IV criteria for a 
MDE (i.e., meeting 5 of 9 DSM-IV criteria for 2 consecutive weeks 
with at least one symptom being depressed mood or anhedonia) 
in the absence of a 2 month period of remission. Recurrence will 
be defined as meeting DSM-IV criteria for a MDE following at least 
a 2 month period of remission. 
9.1.6 Study Success will be defined by the number of patients meeting 
individual patient success criteria (HDRS-17 decrease of ≥50% 
between baseline and 24 Weeks) after 6 months of active DBS. 
The study will be considered a success if 30% or more of enrolled 
patients meet the response criteria after 6 months of active 
stimulation. This threshold would exceed that seen for Vagus 
Nerve Stimulation, the only currently approved treatment for this 
degree of treatment refractory depression.   
 
9.2 Statistical Analyses. 
9.2.1 General analysis issues. Given that this is a preliminary study of 
safety and efficacy (SE), the primary focus of the analyses is to 
determine the size of the treatment effect and its clinical relevance 
as a basis for future comparative trials. Thus, the sample size is 
expected to be small. Even so, all exploratory analyses of 
mechanisms of action will use the assumed distribution of the 
outcome variables and the appropriate analysis method that would 
be expected in the population. However, careful attention will be 
paid to outliers that may affect the validity of the estimates. This 
will be done through careful analysis of model residuals and 
influence statistics. If outliers or variance issues are apparent, we 
can substitute nonparametric procedures, and in some case 
small-sample exact methods, for those analyses outlined below. 
Multiple measures will be handled using appropriate multivariate 
analyses, or with data reduction techniques such as PCA which 
are not model dependent (i.e., do not assume a distribution and 
therefore are not as sensitive to sample size issues). 
9.2.2 Power Analysis. The sample size calculation is based on the 
demonstration of efficacy of the treatment (SA2). Our purpose is 
to estimate the response rate with a given level of precision, thus 
we used the 6 month response rate for the pilot data (4/6=0.67) 
and determined the sample size necessary to estimate a similar 
rate with specified levels of precision (i.e., the width of the 
confidence interval). For the given rate, a sample size of 11-19 
patients would be required to estimate the response rate plus or 

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minus 20-25%. For the purposes of the exploratory analyses, a 
sample size of 19 should be adequate to detect larger effect sizes 
(differences equal to 68% of the standard deviation (ES=0.68)), 
though more patients will be needed to detect smaller effect sizes 
and to evaluate for predictors of response. 
9.2.3 Specific Aim 1. We will record all surgical complications in 
addition to any other adverse events in order to get a reasonable 
estimate of the risks of the treatment. We will examine specific 
complication rates in addition to rates of “any” adverse event. We 
will separately document serious adverse event rates. If possible, 
we may also do a formal statistical comparison of these sample 
rates to those associated with DBS surgery in other disorders to 
determine if the sample rates are comparable. Rates of the first 
occurrence of all adverse events and device and procedure 
related adverse events within 24 Weeks following the initial 
bilateral implants will be summarized along with exact one-sided 
95% upper confidence bounds. Similar analyses will be conducted 
for serious adverse events.    
9.2.4 Specific Aim 2. We will estimate of the 24 Week response and 
remission rates; we will quantify the magnitude of the response 
using repeated measures analysis of variance on the depression 
scores (HDRS-17) comparing the levels at baseline with those 
after 24 Week of open DBS treatment.  
9.2.5 Specific Aim 3. This aim is exploratory and will assess for 
intraoperative electrophysiological changes associated with 
stimulation at specific DBS contacts.   
9.2.6 Secondary Aim 1. The purpose of this maintenance phase will be 
to attempt to quantify the level of treatment (dose) that is sufficient 
to sustain the antidepressant effect. 
9.2.7 Secondary Aim 2. Analyses will include evaluating a variety of 
measures, including demographics, clinical characteristics, brain 
morphology and cognitive function, as possible mediators of the 
antidepressant effect over time. This will be formally carried out in 
two ways: 1) by comparing these measures in 6 month 
responders and nonresponders using appropriate two-sample 
tests (e.g, t-tests for continuous data, chi-square for categorical 
data) and 2) by using longitudinal analysis to see if either baseline 
measures of these variables or changes in these variables with 
treatment are significantly associated with the change in 
depressive symptoms over time. This can be performed using 
repeated measures analysis of covariance, or more simply, using 
linear regression predicting the change in depression (pre-post). 
Given the nature of the study these analyses will be 
underpowered but will provide useful data for future comparative 
trials. 
9.2.8 Secondary Aim 3. Analyses will evaluate EEG, emotional 
reactivity and psychophysiological variables over time, as possible 
mediators of the antidepressant effect. This will be formally carried 
out in two ways: 1) by comparing these measures in 6 month 
responders and nonresponders using appropriate two-sample 
tests (e.g, t-tests for continuous data, chi-square for categorical 

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data) and 2) by using longitudinal analysis to see if either baseline 
measures of these variables or changes in these variables with 
treatment are significantly associated with the change in 
depressive symptoms over time. This can be performed using 
repeated measures analysis of covariance, or more simply, using 
linear regression predicting the change in depression (pre-post). 
Given the nature of the study these analyses will be 
underpowered but will provide useful data for future comparative 
trials. 
 
 
10.0 Data and Safety Monitoring 
10.1 Expected Side Effects/Potential Adverse Events. The complications of DBS 
surgery are well established and relate to surgical complications at the time 
of implantation and secondary complications due to failure of the device, 
infection or stimulation of structures adjacent to intended target structures. 
Effects of acute and chronic Cg25-DBS in depressed patients are largely 
unknown. No unanticipated psychiatric, neurological or other medical 
adverse effects have been observed in 20 patients studied to date in 
Toronto, or the 23 patients implanted thus far as part of this protocol. Three 
out of the first five patients in the Toronto series developed local wound 
infections; however, these infections occurred in the context of two separate 
surgeries separated by one week with externalization of the electrodes for 
testing. This prompted a switch to performing both surgical procedures at 
the same time and no infections have occurred since (in the next eight 
patients). Risks of general anesthesia are well-known include a less than 
1/200,000 risk of death. Based on data collected to date on DBS in 
Parkinson’s Disease patients, the rate of serious surgery-related adverse 
events (e.g., hemorrhage, seizures,  hemiparesis/hemiplegia, serious 
infection) is approximately 10%. The rate of all serious adverse events is 
approximately 53%, and the rate of all (including minor) adverse events is 
approximately 88%.  
10.2 Adverse Event Rates Leading to Study Discontinuation. Based on the DBS 
in PD event rates listed above, study discontinuation will be considered in 
the following situations: 
10.2.1 If the serious surgery-related adverse event rate is more than 
double the above rate (>20%), the study will be halted and the 
DSMB will carefully review the data to determine if the risks of the 
study outweigh benefits. 
10.2.2 If the rate of all serious adverse events is greater than the rate for 
PD (>53%), the study will be halted to allow the DSMB to carefully 
review the data to determine if the risks of the study outweigh 
benefits.   
10.2.3 If the rate of all adverse events is greater than the rate for PD 
(>88%), the study will be halted to allow the DSMB to carefully 
review the data to determine if the risks of the study outweigh 
benefits.   
10.3 Data and Safety Monitoring Board (DSMB). In light of the limited experience 
with this procedure in psychiatric patients, we will use the Data Safety 
Monitoring Board (DSMB) for the Department of Psychiatry and Behavioral 
Sciences as a third-party oversight committee. 

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10.3.1 DSMB Composition.  The DSMB for this study will consist of the 
Clinical Research Oversight Committee members including co-
chairs Larry Tune, M.D. and Boadie Dunlop, M.D., Bobbi 
Woolwine, L.C.S.W and Tanja Mletzko, M.A. Should the DSMB 
require additional specialized expertise to evaluate safety issues 
related to the performance of this study, a relevant specialist will 
be consulted. 
10.3.2 Frequency of meetings/review. The frequency of DSMB review for 
this protocol will follow recommendations from the IRB based on 
the assessed risk status of the study. Currently, it is expected that 
the DSMB will meet quarterly. 
10.3.3 This protocol will be submitted to the DSMB simultaneously with 
this initial submission to the Emory IRB. The DSMB will review the 
research protocol and plans for data and safety monitoring. Twice 
per year, the DSMB will review a report from the study’s data 
manager that includes the following information: the number of 
participants who signed consent forms for the study and were 
subsequently randomized to study arms, the number of post-
randomization dropouts, the reasons for withdrawal from the 
study, and any safety concerns, adverse events, an up-to-date 
consent form, and measures taken to protect confidentiality (e.g., 
data and tape storage, use of coded ID numbers, etc.). The DSMB 
will also review the Principal Investigator’s summary of any new 
data or evidence that might alter the risk/benefit ratio for 
participating in the study (e.g., newly published studies, etc.). After 
reviewing this information, the DSMB will issue its own report 
summarizing any serious and unexpected adverse events or other 
unanticipated problems that involve risk to study participants, and 
whether these appear related to the study-based interventions or 
research assessment protocols.  
10.3.4 There will be regular, ongoing communication between the PI, 
Emory’s IRB, and the DSMB. The PI will take responsibility for 
reporting any serious and unexpected adverse events or other 
unanticipated study problems to Emory’s IRB within 24 hours, 
according to standard regulations. A copy of each report will be 
sent to the DSMB. Actions taken by the IRB in response to 
adverse event reports will be immediately reported to the DSMB, 
which will review all serious adverse events as they arise. DSMB 
reports will be shared with the IRB. 
10.3.5 A Serious Adverse Event (SAE) in this study will be defined as an 
event that results in death, is life-threatening, requires 
hospitalization or prolongation of existing hospitalization, or results 
in persistent or significant disability or incapacity. The degree of 
probable relation between study procedures and the SAE will be 
carefully evaluated and documented. 
10.3.6 Unexpected adverse events in this study will be defined as any 
adverse events for which the nature and severity are not 
consistent with expected adverse events resulting from the 
surgery, pre- or post-operative evaluation, or deep brain 
stimulation. 
10.3.7 The DSMB will have the authority to stop the study at any point. 

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