Theta Burst Stimulation in Young Adults With Depression
Phase: NA
Conditions: Depression
Sponsor: Erika Forbes

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Study Protocol  
 
 
 
 
 
 
Official Title: 
  
Theta Burst Stimulation to Reward Circuitry in Young Adults with Depression 
 
ClinicalTrials.gov ID (NCT number): 
 
NCT03737032 
 
Protocol Date: 
 
3/31/2023 
 
Scientific Background 
 
Our work has consistently found that depression and related mood states are 
associated with high dmPFC response to reward and altered functional 
connectivity between dmPFC and ventral striatum (e.g., Healey et al., 2014; 
Morgan et al., 2016; Romens et al., 2015). The emerging literature on dmPFC as a 
target for repetitive TMS treatment for depression also focuses on this region 
(Dunlop et al., 2015), and intrinsic dmPFC connectivity has recently been 
identified as a biomarker for an anhedonic subtype of depression (Drysdale et al., 
2017). 
Innovative rodent research involving a combination of optogenetics and 
neuroimaging has indicated that mPFC plays a causal role in anhedonia, a feature 
of depression involving disrupted motivation toward and enjoyment of pleasant 
experiences (Ferenczi et al., 2016). Anhedonia includes neural, behavioral, and 
subjective components, and it is evident in reward-driven mood (e.g., low positive 
affect, low enjoyment of rewards) and behavior (e.g., low motivation, low effort to 
obtain rewards). Thus, the clinical and basic neuroscience literatures support our 
guiding hypothesis that reducing dmPFC response via TMS will increase VS 

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response, reduce strength of dmPFC-VS functional connecitivity, and increase 
reward-driven mood and behavior in adults with depression. 
Clinically and developmentally, early adulthood represents an optimal time for 
investigating the disruption of dmPFC and related circuitry in depression, as it is 
early in the clinical course of depression, close to a mature state of brain system 
organization, and a foundational period for the skills critical to healthy adult 
functioning (Arnett, 2000). TBS, a next-generation form of noninvasive brain 
stimulation, requires shorter duration of stimulation and provides perhaps stronger 
clinical efficacy than traditional repetitive TMS for depression (Chung et al., 
2015). It is thus an appropriate technique for the study. 
 
 
 
Study Objectives 
 
This study will use theta burst stimulation (TBS), a form of neuromodulation based 
on transcranial magnetic stimulation, to investigate frontostriatal brain function in 
young adults with depression. 
The goal of the study is to understand the pathophysiology of depression by taking 
an experimental approach to testing the role of dorsomedial prefrontal cortex and 
related reward circuitry in mood, behavior, and brain function. 
Aim 1. Investigate the feasibility of stimulation to decrease activity of the 
dorsomedial prefrontal cortex (dmPFC) using TBS. We will use an fMRI-TBS-
fMRI design with counterbalanced sessions of continuous (inhibitory) TBS, 
intermittent 
(excitatory) TBS, and sham TBS. 
Aim 2. Examine whether TMS targeting dmPFC will increase response in the VS 
and decrease functional connectivity between dmPFC and VS. We predict that 
circuit-level changes will occur with acute TBS to influence task-related VS 
response and dmPFC-VS functional connectivity, such that VS response will 
increase and mPFC-VS will decrease with continuous but not intermittent TBS. 
Aim 3. Examine (a) whether TMS targeting dmPFC will influence reward-related 
mood (i.e., anhedonia, positive affect) and behavior and (b) whether TMS 
influence on mood and behavior occurs through changes in dmPFC, VS, or their 
functional connectivity. We will test acute changes with TBS, with the hypothesis 
that anhedonia will decrease and positive affect and reward-motivated behavior 
will increase after continuous but not intermittent TBS. If associations are found, 
we will test the mediating effects of changes in frontostriatal function detected by 
analyses in Aims 1 and 2. We will include covariates as appropriate (e.g., COVID 

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experiences, stressful life events, age, gender) to address potential confounds or 
influences on the associations of interest. 
Depression is a chronic, impairing form of psychopathology that is one of the 
world’s leading causes of disability. An extensive literature on the neural 
mechanisms of depression has documented the disruption of function in reward 
circuitry as part of the pathophysiology of depression. Specifically, frontostriatal 
function is altered, with lower ventral striatal (VS) response, greater medial 
prefrontal cortex (mPFC) response, and stronger functional connectivity between 
the two regions. Yet few neuromodulatory approaches to depression have targeted 
this circuitry. Noninvasive neuromodulatory techniques such as transcranial 
magnetic stimulation (TMS) have been applied to depression and can elucidate the 
pathophysiology of this disorder by focusing on function in frontostriatal circuitry. 
This research fills the gap of understanding the brain networks underlying 
depression. It will investigate how frontostriatal function (especially functional 
associations between the dorsal mPFC and the VS) contribute to key symptoms of 
depression that involve altered positive emotions. The study will take an 
experimental approach to investigate how directly trying to modulate function in 
this brain circuit can influence mood, brain function, and behavior. Ultimately, this 
work can have relevance to developing or adapting treatments to improve response 
in people with depression. 
 
 
 
Study Design & Methods 
 
This experimental study examines response to theta burst stimulation (TBS) of the 
dorsomedial prefrontal cortex in a within-subjects crossover design with three 
conditions: intermittent TBS (excitatory to underlying cortex), continuous TBS 
(inhibitory to underlying cortex), and sham TBS (no cortical stimulation, with 
inactive placement of electrodes). All participants will complete all three TBS 
conditions, but in counterbalanced order and with randomization to order based on 
gender and baseline brain function. 
The main variables are mood (especially anhedonia and positive affect), reward-
related behavior, and brain function in frontostriatal reward circuitry. Brain 
function will include both BOLD response in specified brain regions (dmPFC, 
ventral striatum) and functional connectivity between those regions. 
Study duration is a minimum of 4 weeks but may be longer due to scheduling 
constraints (will allow up to 10 weeks total, or more at the discretion of the PI). 
Screening: 

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At the first lab visit, participants will go through the Core Modules of the 
Structured Clinical Interview for DSM-5, Research Version (SCID) with Research 
Associate staff. Between the subject's first visit and their second visit, the RA staff 
who completed the SCID interview will review the results of the interview with the 
Principal Investigator or one of the other clinical expert Co-Investigators (Dr. 
Ryan, Dr. Jones) to obtain their confirmation of subject eligibility prior to any TBS 
procedures. 
Female participants will undergo a urine pregnancy test at the MRRC or SBNC, 
prior to MRI scans, to confirm the absence of pregnancy at each visit involving an 
MRI 
(visits 2-5). All participants will be asked to undergo a urine drug screen at the 
SBNC on the day of their baseline MRI visit (visit 2), prior to any MRI or TBS 
procedures. At subsequent visits (3-5) the participant will be asked to self-report 
about recent drug use using a standard questionnaire. 
Participants will complete a TMS Adult Safety Screening (TASS) questionnaire 
prior to any TBS procedures. The following responses on the TASS are considered 
unacceptable and would lead to exclusion from the study: a response of "Yes" to 
items 2 (seizure), 6 (metal in the head), or 7 (implanted devices), and/or "Yes" to 
item 11 (medications) and the medications being taken are exclusionary based on 
the study. In addition if the response to any other items is "Yes" and the 
corresponding characteristic or experience is determined by the MD, after review 
of the written details and/or discussion with the participant, to be a contraindication 
to TBS they may also be excluded from the study. 
Study Procedures: 
Participants will talk to a member of the research team on the phone for screening 
of eligibility, visit the lab for further evaluation of eligibility criteria and lab 
procedures, have MRI scans, and have 3 sessions of theta burst stimulation (TBS). 
Eligibility criteria will be assessed during Visits 1 and 2, with a complete 
determination of eligibility being completed during the first half of Visit 2, prior to 
having their motor threshold measured and prior to participating in an MRI scan. 
Visit 1 will include written informed consent, during which an MD/DO, a PhD-
level licensed clinical psychologist, or a Master's-level licensed professional 
counselor explains exactly what the study involves, including risks and benefits of 
participation. During this visit, participants will also be asked about demographic 
characteristics (e.g., age and education) and clinical characteristics (e.g., 
depression symptoms). Sections of the research version of the Structured Clinical 
Interview for DSM-5 
(SCID) will be completed with participants during this visit to further confirm 
diagnostic eligibility criteria that were asked about first during the phone screening 
call. With participant approval, these interviews may be audio- or videotaped and 

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reviewed by the research team to ensure consistency and reliability, and to provide 
training. If deemed eligible by the research team, participants will then complete a 
set of questionnaires. 
Visit 2 will include a physical exam, motor threshold procedure, MRI scan, 
computer task, and questionnaires. The physical exam will include an MD 
assessing the participant's height, weight, Body Mass Index (BMI), blood pressure, 
pulse, respiration, and temperature. During the physical exam, the MD will also 
review the results of a urine drug screening test and a urine pregnancy test (for 
females). In addition, the MD will administer the TMS Adult Safety Screening 
form (TASS) and review participant's medical history by reviewing the "Medical 
History Form" and 
"Medical Update Form" filled out by the participant at Visit 1 and Visit 2, 
respectively. The MD will initial on each of the medical history forms to confirm 
their review. After the physical exam, the information collected will be used to 
make a determination of subject eligibility. If the subject is deemed eligible, an 
MD will measure the participant’s motor threshold, or the minimum amount of 
TBS power needed to make their thumb twitch. To do this, the MD will position 
the coil above the participant’s motor cortex and deliver a single pulse of 
stimulation at a time. The MD will start at 55% (a low level of stimulation and 
standard in the field for finding motor threshold) and adjust the intensity in small 
increments (i.e., beginning with 1-2% at a time and not exceeding a 5% increase at 
each increment) until a motor response is elicited in the participant’s hand. This is 
a process that is used as a basis for the TBS setting for each person, as it will be 
80% of their motor threshold. Next, the participant will complete the first MRI 
scan in the study, which lasts approximately 30 minutes and will measure brain 
structure and function, used to identify the best location to place the TBS device. 
The MRI scan at Visit 2 will also include a number-guessing task that lasts 8 
minutes and involves winning money. Participants will complete another computer 
task (outside of the MRI), and questionnaires about their mood. 
Visits 3, 4, and 5 will each involve (1) questionnaires on recent medical history, 
depression, and recent life events, (2) an MRI scan before the TBS session, (3) a 
discomfort rating before the TBS session, (4) a TBS session, (5) a discomfort 
rating after the TBS session, (6) an MRI scan after the TBS session, (7) a computer 
task and (8) questionnaires about their mood. 
An RA will review the "Medical Update Form" filled out by the participant before 
the TBS session and report any changes to an MD. An MD will review the 
"Medical Update Form" within 24 hours of each visit (3-5) to initial the document 
and provide comments on the clinical significance of any reported changes. At 
each TBS session, participants will have a magnetic coil placed on their scalp by 
carefully rained investigators, near the top of their forehead. The coil will send 

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pulses that can influence brain function in the region under that scalp location. 
There will be 3 sessions so that we can use 3 kinds of TBS: continuous (constant 
series of pulses) TBS, which tends to decrease brain function; intermittent (off and 
on) TBS, which tends to increase brain function; and sham TBS, which sounds and 
feels like TBS but doesn’t send pulses or change brain function. TBS sessions will 
last from 40 seconds to 190 seconds, and the TBS influences brain function for up 
to 1 hour. The order in which participants receive these 3 kinds of TBS will be 
randomized and counterbalanced. 
To accommodate participant schedules, activities listed under each visit may take 
place on separate days as possible and necessary. During the COVID-19 outbreak, 
written informed consent for all study activities as well as diagnostic interviews for 
eligibility, and participant completion of tasks and questionnaires may take place 
remotely. An approved video conference platform will be used to conduct and 
record diagnostic interviews to determine eligibility remotely. The study consent 
form would be emailed or mailed to the participant in advance, reviewed 
thoroughly during a phone or video call with an MD/PhD/DO, signed by the 
participant, and returned. Study activities would not begin until the signed consent 
form is received. 
Measures and Devices: 
The TBS sessions (Visits 3-5) will use the Cool-B65 Active/Placebo Coil and 
MagLink research software. The MRI scans (Visits 2-5) will be done on a Siemens 
3T Prisma scanner. MRI scans will include brain structure, resting brain function, 
and task-based brain function at the first scan (visit 2); resting brain function 
before each TBS procedure (Visits 3-5); and resting brain function and brain 
function in response to a guessing task after each TBS session (Visits 3-5). The 
guessing fMRI task is a number-guessing task that lasts 8 minutes and involves 
winning money. The computer task completed at Visit 2 and after each TBS 
session involves pressing buttons to earn money. Self-report measures will be 
completed at each visit. The following questionnaires will be completed at Visit 1: 
the Alcohol and Drug Consumption Questionnaire (Cahalan, et al., 1969); the 
Center for Epidemiologic Studies Depression Scale (Radloff, 1977); the Young 
Mania Rating Scale (Young et al., 2000); the Barratt Impulsiveness Scale (Patton, 
et al., 1995); the Zuckerman Sensation-Seeking Scale (Zuckerman, 1971); the 
Youth Risk Behavior Survey 
(CDC, 2015); the Revised Chapman Social Anhedonia Scale (Eckblad et al., 
1982); the Snaith Hamilton Pleasure Scale (Snaith et al., 1985); the Temporal 
Experience of Pleasure Scale (Gard et al., 2006); the Behavioral Inhibition 
System/Behavioral Activation System Scales (Carver & White, 1994); the Altman 
Self-Rating Mania Scale (Altman et al., 1997); the Pittsburgh Sleep Quality Index 

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(Buysse et al., 1989), and the Generalized Pain Questionnaire (Van Bemmel et al., 
2019). 
Visits 2-5 will include the following questionnaires: the Positive and Negative 
Affect Schedule (Watson et al., 1988), the Altman Self-Rating Mania Scale, a brief 
questionnaire on recent medical history, the Center for Epidemiologic Studies 
Depression Scale (Radloff, 1977), and an adapted version of the Life Events Scale 
for Students (Nikolova et al., 2012). Visit 2 will also include the TMS Adult Safety 
Screening (Keel et al., 2001). Visits 3-5 will additionally include a 0-10 discomfort 
rating. 
Safety and Comfort: 
We will conduct TBS according to the safety guidelines in our field. IFCN 
guidelines will be followed for training of the research team. Each person in the 
study will experience a much lower dose of TBS than the type of stimulation used 
to treat depression. During TBS participants will hear a series of clicking sounds 
and feel a tapping sensation under the location of the coil. Participants might 
experience a headache in the region of the coil or feel lightheaded during TBS. 
These usually end 30 seconds after TBS and feel like mild discomfort. Participants 
could also experience mood changes. Participants will stay in the lab for an hour 
after the TBS session, so we can make sure that they don’t experience any 
lingering discomfort or mood changes. 
 
 
 
 
Eligibility Criteria  
 
Inclusion criteria are as follows: 
• 
Age 18-25 
• 
DSM-5 diagnosis of Major Depressive Disorder, Persistent Depressive 
Disorder, Other Specified Depressive Disorder, or Other Unspecified 
Depressive Disorder 
• 
Eligibility confirmed by a physician associated with the study who will 
conduct a physical exam, review medical history, and conduct the TMS 
Adult Safety Screening (TASS) prior to TMS 
Exclusionary criteria include: 
• 
Bipolar disorder (lifetime diagnosis) 
• 
Obsessive-compulsive disorder (lifetime diagnosis) 
• 
History of psychosis 
• 
Daily use of nicotine 

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• 
Past- month use of cocaine, amphetamines, MDMA, Phencyclidine 
(PCP), Ketamine, or gamma-hydroxybutyrate (GHB) 
• 
Past 6 month substance use disorder 
• 
Binge drinking (using NIAAA criteria) within the past week, more than 3 
drinks/day in the past 3 days, alcohol use in the past 12 hours 
• 
More than 3 uses of cannabis in the past month 
• 
Neurological disorders: Epilepsy, Parkinson's Disease, brain tumor, brain 
injury, stroke 
• 
History of head trauma with a loss of consciousness (eg. concussion) 
• 
History of seizures 
• 
MRI contraindications: body shape/size too large to fit in scanner, 
claustrophobia, and ferromagnetic forms of metal in the body 
• 
Pregnancy 
• 
Current use of Clozapine or Bupropion or prescription stimulants 
 
 
 
Statistical Considerations 
 
Our final sample size of N=36 (i.e., those who qualify and undergo all research 
procedures) gives adequate (80%) power to detect moderate-large effects (d>.5) of 
cTBS vs. iTBS and change in frontostriatal function. Meta-analytic review of iTBS 
and cTBS on motor cortex suggest large effect sizes (ES=1.5-2.2 for active vs. 
sham; Wischnewski & Schutter, 2015). In mPFC during a cognitive task, iTBS vs. 
cTBS produces a large effect size (ES=1.0; Grossheinrich et al., 2009). 
Recommendations for neuroimaging studies and effect sizes from our previous 
studies (eg., Cohen's d=.71 for depression association with striatal response) 
support this sample size, even with a loss of 15% of data due to movement.