Intermittent Theta Burst Stimulation to Relieve Depression and Concurrent Executive Function Impairment in Older Adults: A Randomized Controlled Study
Phase: NA
Conditions: Executive Dysfunction, Depression
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Intermittent theta burst stimulation to relieve depression 
and concurrent executive function impairment in older 
adults: A Pilot Randomized Trial  
 
Principal Investigator:   
Lucia del Pilar Cristancho M.D. 
 
NCT Number: NCT03745768 
 
 
 
 
 
 
 
Version Date/Number: 10.26.18 (V5) 

 
 
 
 
 
 
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TABLE OF CONTENTS 
 
A 
INTRODUCTION ..................................................................................................................... 4 
A1 
STUDY ABSTRACT .............................................................................................................. 4 
A2 
PRIMARY HYPOTHESIS ....................................................................................................... 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .................................................................................. 5 
B 
BACKGROUND ...................................................................................................................... 5 
B1 
PRIOR LITERATURE AND STUDIES ....................................................................................... 5 
B2 
RATIONALE FOR THIS STUDY ............................................................................................... 7 
C 
STUDY OBJECTIVES ............................................................................................................. 7 
C1 
PRIMARY AIM ..................................................................................................................... 7 
C2 
SECONDARY AIM ................................................................................................................ 8 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES .................................................. 8 
D 
INVESTIGATIONAL AGENT ...................................... ERROR! BOOKMARK NOT DEFINED. 
D1 
PRECLINICAL DATA .......................................................... ERROR! BOOKMARK NOT DEFINED. 
D2 
CLINICAL DATA TO DATE .................................................. ERROR! BOOKMARK NOT DEFINED. 
D3 
DOSE RATIONALE AND RISK/BENEFITS .............................. ERROR! BOOKMARK NOT DEFINED. 
E 
STUDY DESIGN ...................................................................................................................... 9 
E1 
OVERVIEW OR DESIGN SUMMARY ....................................................................................... 9 
E2 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................. 9 
2.a 
Inclusion Criteria .......................................................................................................... 9 
2.a 
Exclusion Criteria ....................................................................................................... 10 
2.b 
Ethical Considerations ............................................................................................... 10 
2.c 
Subject Recruitment Plans and Consent Process ..................................................... 10 
2.d 
Randomization Method and Blinding ......................................................................... 11 
2.e 
Risks and Benefits ..................................................................................................... 12 
2.f 
Early Withdrawal of Subjects ..................................................................................... 13 
2.g 
When and How to Withdraw Subjects ....................................................................... 14 
2.h 
Data Collection and Follow-up for Withdrawn Subjects ............................................ 14 
E3 
STUDY DRUG ................................................................................................................... 14 
3.a 
Description ................................................................................................................. 14 
3.b 
Treatment Regimen ................................................................................................... 16 
3.c 
Method for Assigning Subjects to Treatment Groups ................................................ 18 
3.d 
Preparation and Administration of Study Drug ............ Error! Bookmark not defined. 
3.e 
Subject Compliance Monitoring ................................................................................. 18 
3.f 
Prior and Concomitant Therapy ................................................................................. 18 
3.g 
Packaging .................................................................... Error! Bookmark not defined. 
3.h 
Blinding of Study Drug ................................................. Error! Bookmark not defined. 
3.i 
Receiving, Storage, Dispensing and Return ............... Error! Bookmark not defined. 

 
 
 
 
 
 
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F 
STUDY PROCEDURES ........................................................................................................ 18 
F1 
SCREENING FOR ELIGIBILITY ............................................................................................. 18 
F2 
SCHEDULE OF MEASUREMENTS ........................................................................................ 19 
F3 
VISIT 1 ............................................................................ ERROR! BOOKMARK NOT DEFINED. 
F4 
VISIT 2 ETC. ..................................................................... ERROR! BOOKMARK NOT DEFINED. 
F5 
SAFETY AND ADVERSE EVENTS ........................................................................................ 21 
5.a 
Safety and Compliance Monitoring ............................................................................ 23 
5.b 
Medical Monitoring ..................................................................................................... 23 
i 
Investigator only ......................................................................... Error! Bookmark not defined. 
ii 
Independent expert to monitor ................................................... Error! Bookmark not defined. 
iii 
Institutional Data and Safety Monitoring Board .......................... Error! Bookmark not defined. 
iv 
Independent Data and Safety Monitoring Board ........................ Error! Bookmark not defined. 
5.c 
Definitions of Adverse Events .................................................................................... 23 
5.d 
Classification of Events.............................................................................................. 24 
i 
Relationship ............................................................................... Error! Bookmark not defined. 
ii 
Severity ...................................................................................... Error! Bookmark not defined. 
iii 
Expectedness ............................................................................. Error! Bookmark not defined. 
5.e 
Data Collection Procedures for Adverse Events ....................................................... 24 
5.f 
Reporting Procedures ................................................................................................ 24 
5.g 
Adverse Event Reporting Period ................................. Error! Bookmark not defined. 
5.h 
Post-study Adverse Event ........................................... Error! Bookmark not defined. 
F6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT .................................................. 25 
G 
STATISTICAL PLAN............................................................................................................. 25 
G1 
SAMPLE SIZE DETERMINATION AND POWER....................... ERROR! BOOKMARK NOT DEFINED. 
G2 
INTERIM MONITORING AND EARLY STOPPING ..................... ERROR! BOOKMARK NOT DEFINED. 
G3 
ANALYSIS PLAN ............................................................... ERROR! BOOKMARK NOT DEFINED. 
G4 
STATISTICAL METHODS .................................................... ERROR! BOOKMARK NOT DEFINED. 
G5 
MISSING OUTCOME DATA ................................................. ERROR! BOOKMARK NOT DEFINED. 
G6 
UNBLINDING PROCEDURES ............................................... ERROR! BOOKMARK NOT DEFINED. 
H 
DATA HANDLING AND RECORD KEEPING ...................................................................... 26 
H1 
CONFIDENTIALITY AND SECURITY ...................................................................................... 26 
H2 
TRAINING ......................................................................................................................... 26 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................................. 27 
H4 
RECORDS RETENTION ...................................................................................................... 27 
H5 
PERFORMANCE MONITORING ............................................ ERROR! BOOKMARK NOT DEFINED. 
I 
STUDY MONITORING, AUDITING, AND INSPECTING .............. ERROR! BOOKMARK NOT 
DEFINED. 
I1 
STUDY MONITORING PLAN .................................................... ERROR! BOOKMARK NOT DEFINED. 
I2 
AUDITING AND INSPECTING ................................................... ERROR! BOOKMARK NOT DEFINED. 
J 
STUDY ADMINISTRATION .................................................................................................. 27 
J1 
ORGANIZATION AND PARTICIPATING CENTERS ....................................................................... 27 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ................................................................... 27 
J3 
COMMITTEES ....................................................................... ERROR! BOOKMARK NOT DEFINED. 
J4 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................... 27 
J5 
STUDY TIMETABLE ............................................................................................................... 27 
K 
PUBLICATION PLAN ........................................................................................................... 28 
L 
ATTACHMENTS ................................................................................................................... 28 
L1 
TABLES ........................................................................... ERROR! BOOKMARK NOT DEFINED. 
L2 
INFORMED CONSENT DOCUMENTS ..................................... ERROR! BOOKMARK NOT DEFINED. 
L3 
PATIENT EDUCATION BROCHURES ..................................... ERROR! BOOKMARK NOT DEFINED. 

 
 
 
 
 
 
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L4 
SPECIAL PROCEDURES PROTOCOLS .................................. ERROR! BOOKMARK NOT DEFINED. 
L5 
QUESTIONNAIRES OR SURVEYS ......................................... ERROR! BOOKMARK NOT DEFINED. 
M 
REFERENCES ...................................................................................................................... 28 
 
A Introduction 
 
A1 Study Abstract 
Executive function deficits are common in late life depression. They are associated with 
resistance to antidepressants, poor quality of life, considerable disability and increased risk for 
suicide. No optimal treatments exist for this problem. Selective serotonin reuptake 
antidepressants do not improve executive impairments and psychotherapy is less helpful with co-
occurring executive deficits. Therefore, a safe and well-tolerated treatment is needed to improve 
executive function, depression burden and overall quality of life. This study will use a novel type 
of Transcranial Magnetic Stimulation called intermittent Theta Burst Stimulation (iTBS). iTBS uses 
very high frequency (50Hz) magnetic pulses delivered in “bursts” of 3 stimuli delivered at 50 Hz. It 
is posited that this intervention induces plasticity in the human cortex. Theoretical and empirical 
evidence from research studies informs that iTBS is can also improve depression and executive 
deficits. However such effects have not been examined in older adults.  
 
This project examines iTBS’s ability to improve depression and executive impairment in Late life 
depression (LLD). In addition the study tests the effects of iTBS on brain connectivity within the 
Cognitive Control Network (CCN). This study will enhance the understanding of LLD and will 
provide critical pilot data regarding feasibility to support the development of future randomized 
controlled clinical trial.   
 
Both active and sham (placebo) interventions will be administered sequentially to the left and right 
dorso-lateral prefrontal cortex. The total time of stimulation or sham is less than 7 minutes. Active 
or sham intervention will be administered for 6 weeks ( Monday to Friday).  A total of 20 subjects 
will ben randomized.  Changes in mood from baseline to the end of 6 weeks will be measured 
using The Montgomery-Asberg Depression scale. Executive function at baseline and end of study 
will be evaluated with the National Institutes of Health (NIH) Toolbox executive domain battery. 
Safety assessments will include: The 21 item Scale for suicidal ideation SSI. The frequency, 
intensity and burden of side effects rating ( FIBSER) and the Altman Self Rating Mania scale ( 
ASRM). Ancillary depression measures include the The self-reported Quick Inventory of 
Depressive Symptoms ( QIDS) and the Clinical Global Impression of Improvement scale.  
 
Subjects will undergo functional Magnetic Resonance Imaging (fMRI) before and after the study 
interventions to tests the effects of iTBS vs. placebo on brain’s functional connectivity.  
 
This research will provide meaningful information about the effects of the iTBS intervention on 
mood and executive function in older adults as well as information regarding the effects of the 
intervention on brain function. Results of this pilot study will inform a grant submission and allow 
us to calculate power for a definitive randomized controlled clinical trial to test the efficacy of of 
iTBS and placebo.  
 
A2 Primary Hypothesis 
Aim 1.  To assess the efficacy of iTBS in improving mood and executive dysfunction in 
older adults with depression. H1. Older adults randomized to iTBS will show significant 

 
 
 
 
 
 
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decreases in the Montgomery Asberg Depression Rating Scale consistent with 
improvement, and significant increases in scores on the NIH Toolbox executive domain 
measures5-7 consistent with executive function improvement compared to those subjects 
randomized to placebo stimulation (sham).  
 
Aim 2.  To test the effects of iTBS on functional connectivity within the Cognitive Control 
Network (CCN) in depressed older adults using resting state fMRI. H2 Depressed older 
adults randomized to iTBS versus sham will have a significant increase in functional 
connectivity within the CCN.  
 
Aim 3. To examine the association between change in clinical symptoms and 
neurocognitive assessments and changes on brain connectivity within the CCN.  H3 
Among older adults who receive iTBS, changes in connectivity within the CCN will 
correlate with changes in depression and executive function.  
 
A3 Purpose of the Study Protocol 
 
The purpose of this study protocol is to address the research question of whether 
intermittent TBS (iTBS) leads to improvement in depression and executive impairment in 
older adults when compared to placebo.   In addition the study will test the effects of 
iTBS vs. sham ( placebo) on functional connectivity within the Cognitive Control Network 
(CCN) in depressed older adults using resting state fMRI 
 
B Background 
 
B1 Prior Literature and Studies 
 
Late Life depression is associated with executive impairment:   
 
Major depression episodes occurring in older adults, known as Late Life Depression 
(LLD), are frequently associated with executive impairment. Executive functions are 
specialized cognitive processes integral to social and occupational success and overall 
quality of life. These functions involve planning, goal-directed activity, impulse inhibition 
and capacity for change and adaptation. Three main executive domains have been 
consistently described: 1. Inhibitory control; 2. working memory; and 3. cognitive 
flexibility.4 Brain regions within the Prefrontal Cortex (PFC), particularly the Dorso-
Lateral Prefrontal Cortex (DLPFC) have been proposed to orchestrate executive 
control.5 Functional neuroimaging studies have shown recruitment of PFC regions when 
subjects perform tasks related to executive domains. Meta-analytic evidence supports 
the key involvement of a superordinate Cognitive Control Network (CCN) involving 
fronto-parietal brain regions including the DLPFC (Brodmann Area 9, 46), anterior 
cingulate (Brodmann Area 32) inferior (Brodmann Areas 39, 40) and superior (Brodmann 
Area 7) parietal lobe and pre-cuneus (Brodmann Area 19) subsuming executive function. 
The CCN is involved in “top-down” control and executive tasks. Besides, dysfunction of 
this network may be responsible for deficits in attention, working memory and slowed 
processing speed in LLD.  
 

 
 
 
 
 
 
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Executive function is reduced with normal aging, but much more so in LLD, a conclusion 
from neuropsychological studies and brain imaging studies which have characterized 
executive deficits, shown volume reduction and white matter tracks ischemic changes in 
frontal and limbic brain regions and more recently connectivity changes in key cortical 
networks including the Cognitive Control Network (CCN) and the Default Mode Network. 
The resultant LLD with co-occurring executive function deficits has devastating 
consequences including a protracted and treatment-resistant depression course, poor 
quality of life and increased risk for suicide. No optimal treatments exist for this problem. 
Selective serotonin reuptake antidepressants do not improve executive impairments and 
psychotherapy is less helpful with co-occurring executive deficits. Therefore, an effective 
and well-tolerated treatment is needed to improve executive function, depression burden 
and overall quality of life.  
 
Theta Burst Stimulation (TBS) enhances neuroplasticity:  
TBS is a highly efficient form of Transcranial Magnetic Stimulation (TMS). TMS is a 
standard FDA approved treatment for depression. In TBS, magnetic stimuli are delivered 
in “bursts” of 3 stimuli at 50 Hz (i.e. 20 ms between each stimulus) given every 200 
milliseconds (i.e. 5 Hz). This pattern of stimulation has been used to probe synaptic 
efficiency of the motor cortex using in vivo slice preparations of animal tissue, but has 
been adapted for stimulation of the human brain using magnetic stimulators and has 
shown to induce faster effects on synaptic plasticity than conventional TMS. The 
excitability of the corticospinal system in humans has been probed before and after two 
main theta burst paradigms intermittent (iTBS) and continuous (cTBS). Although they 
both induce a mixture of excitatory and inhibitory effects, it is generally accepted that 
iTBS induces facilitation of the motor-evoked response indicating predominant 
excitatory, long-term potentiation (LTP) effects and cTBS decreases the motor evoked 
response indicating predominantly inhibitory, Long-Term Depression (LTD) effects. Both 
LTP and LTD mechanisms are triggered by an influx of Ca+ to the post-synaptic neuron. 
Since iTBS increases LTP indicating enhancement of the brain’s plasticity, it is 
conceivable that iTBS may lead to increase synaptic efficiency and connectivity in key 
brain networks.  
 
Rationale for the use of iTBS to relieve depression and executive 
impairment in older adults:  
The following studies provide empirical evidence of the use of iTBS in depression and in 
the improvement of executive function.  
 
Studies providing empirical evidence of rTMS and iTBS improvement of depression and/or executive 
function 
Study 
Effects of intervention  
Study and paradigm 
Barr et al.64RCT in patients with 
schizophrenia (n= 27)  
Improved working memory  
(measured by n-back task)  
High Frequency – excitatory 
rTMS over bilateral DLPCF 
Moser et al.65 RCT in healthy middle 
age and elderly (n = 19) 
Enhanced 
cognitive 
flexibility 
(measured by Trail-Making-Test 
B)  
5 sessions of (High frequency) 
rTMS 
Hoy et al.66 RCT  in healthy subjects 
(n = 20) 
Improved 
working 
memory 
measured 
by 
n-back 
task.  
Increased 
EEG’s 
theta 
connectivity.  
One session of iTBS (600 
pulses) over the DLPFC vs. 
sham  
Cheng et al./ Li Ct et al.67,68  RCT of 
iTBS in depressed subjects (n= 60) 
aged 21-70 years old.  
Depression and executive function 
improvement  
(using the Wisconsin card sorting 
test)  
Comparison or iTBS over the 
left DLPFC vs. cTBS over the 
right DLPFC vs. sham.  

 
 
 
 
 
 
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These studies demonstrate depression improvement with high frequency rTMS and 
iTBS paradigms. Previous studies also demonstrate beneficial effects on executive 
function with these paradigms. These studies provide rational for the use of iTBS to 
relieve depression and executive function impairment in older adults.  
 
Rationale to test the effects of iTBS on brain function using resting state 
functional connectivity measures:  
Resting State Functional Connectivity (rsFC) has allowed a further understanding of 
brain systems in relationship to depression. rsFC is based on the principle that 
functionally related brain regions exhibit correlated activity in intrinsic very low frequency 
(<~ 0.1 Hz) Blood Oxygen Level Dependent (BOLD) signal.34-36  Such low-frequency 
BOLD fluctuations constitute an indirect measure of spontaneous neural activity.34,37,38 
This approach proposes canonical resting state networks defined as neural systems 
exhibiting intrinsic brain activity which is temporarily correlated with widely distributed 
brain regions39-41. Networks relevant to LLD include the Cognitive Control Network 
(CCN) a fronto-parietal circuit involved in top down attention dependent executive 
control, the Default Mode network (DMN) which is involved in self-referential processes, 
and the affective fronto-limbic circuits, involved in emotion regulation.42  The CCN is the 
key network of interest of this proposal given its control of executive function.  This 
network involves fronto-parietal regions including the DLPFC (Bas 9,46), anterior 
cingulate (BA 32) inferior (BAs 39, 40) and superior (BA 7) parietal lobe and pre-cuneus 
(BA 19) subserving executive function43. Multiple lines of evidence indicate an 
association between altered CCN function and executive impairment in depression: 1) 
Dysfunction of CCN regions has been linked to executive impairment in depression42,44,45 
2) Cognitive regulation of emotions is deficient in depression46,47 3) Middle aged and 
older adults with depression exhibited low rsfMRI connectivity within the CCN48,49; which 
was linked to dysexecutive behavior and antidepressant resistance48 4) A pattern of 
decreased activity in the DLPFC during cognitive tasks and decreased connectivity 
between the DLPFC and the Dorsal Anterior Cingulate14 has been found in depression.  
 
In summary, LLD with executive dysfunction is associated with poor outcomes. Such a 
“malignant” depression variant appears to be the end result of aberrant connectivity in 
the CCN. iTBS is a novel kind of magnetic stimulation treatment, which offers the 
potential to improve mood and executive function by enhancing connectivity within the 
CCN. This intervention has the potential to provide an effective treatment approach for 
LLD with executive dysfunction and the study will compare the effects of this intervention 
against sham (placebo).  
 
B2 Rationale for this Study 
 
C Study Objectives 
 
C1 Primary Aim 
Aim 1.  To assess the efficacy of iTBS in improving mood and executive dysfunction in older 
Plewnia C. et al.69 RCT of TBS in 
depressed subjects (n- 32) 
Improved depression  
Bilateral TBS paradigm iTBS 
over the left and cTBS over the 
right.  

 
 
 
 
 
 
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adults with depression. Hypothesis 1. Older adults randomized to iTBS will show significant 
decreases in the Montgomery Asberg Depression Rating Scale consistent with improvement, and 
significant increases in scores on the NIH Toolbox executive domain measures consistent with 
executive function improvement compared to those subjects randomized to placebo stimulation 
(sham).  
C2 Secondary Aims 
Aim 2.  To test the effects of iTBS on functional connectivity within the Cognitive Control Network 
(CCN) in depressed older adults using resting state fMRI. H2 Depressed older adults randomized 
to iTBS versus sham will have a significant increase in functional connectivity within the CCN.  
 
Aim 3. To examine the association between change in clinical symptoms and neurocognitive 
assessments and changes on brain connectivity within the CCN.  H3 Among older adults who 
receive iTBS, changes in connectivity within the CCN will correlate with changes in depression 
and executive function.  
 
C3 Rationale for the Selection of Outcome Measures 
 
Depression Measure:  
The Montgomery-Asberg Depression Rating Scale, is a standardized mood rating scale, 
widely used in depression studies.  The scale is particularly sensitive to treatment 
effects, demonstrating greater sensitivity to change (between responders and non-
responders) to antidepressant treatment than other scales such as the Hamilton  
Depression Rating Scale.  
 
Executive function measures:  
The flanker inhibitory control, the Dimensional Change Card sort test and the List Sorting 
Working memory test will measure executive function.  These scales are state of the art 
scales and are recommended by the National Institutes of Health in their NIH Toolbox.  
NIH Toolbox measures are brief and standardized for assessing function from ages 3 to 
85.  The NIH toolbox monitors behavioral function over time and across developmental 
stages. This makes it possible to study changes across the lifespan, and evaluate the 
effectiveness of a treatment.   
 
Brain’s connectivity measure: Resting State Functional Connectivity (rsFC) is based on 
the principle that functionally related brain regions exhibit correlated activity in intrinsic 
very low frequency (<~ 0.1 Hz) Blood Oxygen Level Dependent (BOLD) signal. Such 
low-frequency BOLD fluctuations constitute an indirect measure of spontaneous neural 
activity. This approach has identified canonical resting state networks, defined as neural 
systems exhibiting intrinsic brain activity which is temporarily correlated with widely 
distributed brain regions. Using resting state fMRI we will measure functional 
connectivity within the Cognitive Control Network (CCN) in depressed older adults 
before and after study intervention. We will also explore functional connectivity within 
and between other networks that are relevant to depression including the Default Mode 
network  and the cingulo-opercular networks.  
 
 
 
 
 
 

 
 
 
 
 
 
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D Study Design  
D1 Overview or Design Summary 
 
 
 
 
 
 
 
Figure 1. Study Design: Subjects will receive a total of 30 session of intervention ( daily Monday –
Friday) for 6 weeks.  Executive function and mood assessments will be performed pre- and post- 
intervention.  
D2 Subject Selection and Withdrawal  
2.a 
Inclusion Criteria :   
1) Age ≥ 60 – 85 years old 
2) Diagnosis of major depressive disorder (MDD), single or recurrent, with a current 
Major depression episode as diagnosed by the Mini-international 
Neuropsychiatric Interview (MINI 6.0)  
3) Montgomery Asberg Depression Scale score greater than or equal to 15 at 
baseline. 
4) Evidence of decreased executive function as evidenced by either of the 
following conditions: a) scoring below the mean normative scaled 
score on the average of the NIH Toolbox executive function measures: 
Flanker inhibitory control and attention test and the Dimensional sort 
card test, approximate score 70 – 100 as per PI discretion. b) 
Discrepancy of at least 10 points between the average of the picture 
vocabulary score and the reading recognition test score and the average 
of the Flanker inhibitory control and dimensional card sort test score. c) 
Frontal Systems Behavior Scale (FRSBE) T scores above 60 (indicative of 
borderline to clinically significant impairment) and at least 10 points (1 
Standard Deviation) above subject’s premorbid (pre-depression) scores. 
 
 
Study Design
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
TBS sessions 5 times a week 
MRI 
MRI 
Outcomes:  
• Cognitive testing 
• Depression assessment 
Before:  
• Cognitive testing 
• Depression 

 
 
 
 
 
 
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 Exclusion Criteria 
• Exclusion criteria: 1) Inability to complete NIH tool box cognitive testing; 2) Inability to 
provide informed consent; 3) <22 score on the Montreal Cognitive Assessment MoCA 
indicative of moderate to severe cognitive impairment per PI discretion;4) Lifetime 
diagnosis of bipolar I or II disorder or psychotic disorder as per the MINI interview; 5) 
current psychotic symptoms 6) alcohol or other substance use disorder per DSM V 
criteria in the past 6 months; 7) High risk for suicide (active suicidal ideation/intent or 
plan and patient is unsafe to be in the outpatient setting), an urgent psychiatric referral 
will be made in those cases; 8) Have a diagnosis of obsessive compulsive disorder, 
post-traumatic stress disorder (current or within the last year), anxiety disorder 
(generalized anxiety disorder, social anxiety disorder, panic disorder), assessed by a 
study investigator to be primary 9) Previous history of TMS 10) history of failure to an 
adequate course of electroconvulsive therapy (ECT) such as equal or more than 7-9 
electroconvulsive therapy treatments, per PI discretion;11) Major unstable medical 
illness including advanced/uncontrolled diabetes, hypertension, renal disease or 
advanced cancer, per PI discretion 12) Psychotropic use other than antidepressants 
(e.g., Benzodiazepines [more than 2mg of lorazepam equivalent daily], anticonvulsants 
[except low dose of Neurontin approximately 600mg/day] or cognitive enhancers such as 
N-Methyl D – Aspartate (NDMA) receptor antagonists [Memantine HCL], 
psychostimulants [such as methylphenidate or modafinil]) per PI discretion; 13) Recent 
changes or initiation of antidepressant therapy approximately in the last 4 weeks prior to 
intervention delivery, per PI discretion 14) if participating in psychotherapy, must have 
been in stable treatment for at least 3 months prior to entry into the study, with no 
anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus 
over the duration of the study 15) contraindications for TMS including the presence of 
metallic objects within 30 cm of the TMS coil, intracranial implants (e.g., aneurysm clips, 
shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or 
near the head, excluding the mouth, that cannot be safely removed; presence of 
intracardiac lines, defibrillators or a cardiac pacemaker and unable to assess safety; 
presence of implanted electronic devices that control physiologic functions and unable to 
assess safety. 16) have a personal history of a primary seizure disorder or a seizure 
associated with an intracranial lesion. 17) History of severe head trauma or neurological 
disorders that substantially increase seizure risk, per PI discretion.18) non-correctable 
clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with 
interview). 
 
No exclusion criteria based on race, ethnicity, gender or HIV status. 
2.b 
Ethical Considerations  
No exclusion criteria based on race, ethnicity, gender or HIV status. 
 
2.c 
Subject Recruitment Plans and Consent Process 
Depression is common in older adults: up to 15% of older adults experience a major 
depressive episode. We will recruit Community-dwelling older adults with depression via 
advertisement as well as referring care providers. The Clinical Transcranial Magnetic 
Stimulation service directed by Dr. Cristancho as well as Dr. Lenze’s outpatient geriatric 
practice at Washington University will also provide recruitment sources. Recruitment 
strategies for subjects will involve the use of IRB approved advertisements, in the print, 
advertisement via electronic media such as facebook, referrals by word of mouth, 

 
 
 
 
 
 
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11 
referrals by clinicians in both primary care and specialty mental health sectors. 
Volunteers for health, and the formation of partnerships with community agencies and 
primary care networks. All these methods have provided ongoing access to older adults 
with depression. 
 
Consent process:  
The Pi designee will obtain participant's verbal consent prior to doing a phone screen to 
determine study eligibility. After completion of the phone screen if the subject is 
determined eligible, the PI designee will provide detailed information about the study and 
will review the consent form with them over the phone. The subject will be told that study 
participation is optional and it will not affect their care. Per subject’s request a copy of 
the consent form will be mailed, faxed or e-mailed to the subject, so he/she has time 
prior to his/her visit to review and discuss with family/friends. A screening visit will be 
scheduled.  
 
During the screening visit the PI designee will review the consent form with the subject, 
page by page and answer any questions the study subject has to their satisfaction. The 
subject will be told that study participation is optional and it will not affect their care. If 
subject agrees, his/ her signature will be obtained and both subject and PI designee will 
sign and date the consent form.  
 
A note to file will be used to document the consent process. 
 
2.d 
Randomization Method and Blinding:  
Subjects who consent to study participation will be randomized to receive six weeks of 
either iTBS or sham. Each subject enrolled in the study will have equal probability to be 
randomized in each study arm and permuted blocks of randomly varying sizes (4, 6, and 
8) will be used to generate the scheme. Each block will contain equal numbers of 
assignments to iTBS and sham providing a balanced design. Neuropsychological 
testing, mood assessments and fMRI scans will be performed pre- and post-
interventions. 
 
Blinding:  To deliver the stimulation we will use One treatment coil (B-65 A/P) capable of 
delivering iTBS and sham.  Subjects randomized to iTBS will receive iTBS and those 
randomized to sham will receive sham (placebo) stimulation.  Sham stimulation is 
ensured by an Internal shielding mechanism in the delivery coil, which reduces the 
magnetic field strength to < 5% of active field which is biologically inactive.  The coil’s 
symmetric design and identical clicking noises during both active and sham. The coil has 
a built-in position sensor to ensure that the correct (active or sham) side of the coil faces 
toward the subject’s head.  We will use synchronized gentle electrical stimulation to the 
scalp via pre-gelled surface stimulation electrodes to simulate scalp sensations on the 
sham delivery, which will mimic the active stimulation. Subject’s assignment to the 
intervention will be defined by the Maglink software according to the randomization 
schedule.  Assignments are stored on individualized USB memory devices. 
 
At intervention end, subjects will be queried about what they believed was their 
intervention assignment. 
 
 

 
 
 
 
 
 
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2.e 
Risks and Benefits 
Risks associated with TBS intervention 
 
Risk with theta burst delivery is assessed based on the risk associated with TMS therapy 
(FDA approved treatment for depression) and based on published clinical trials using 
TBS intervention.  
 
Risk of common side effects: Most frequent side effects included headaches, dizziness, 
nausea, vertigo, pressure in the head, twitching in superficial muscles of the face while 
receiving stimulation, palpitations and tremor. These have been reported to be mild and 
moderate tolerability.  
Stimulation may affect hearing due to the loud sound of the magnetic stimulator. As in 
clinical practice subjects are required to wear earplugs throughout the entire session.  
 
Risk of serious side effects: Seizure during stimulation is a potential risk. No seizures 
have been reported in TBS literature in depression studies. The largest reported 
naturalistic study (N = 87) estimated an incidence rate range of seizure or other serious 
adverse effects at 0.011 per patient (95% CI, 0-0.362). We will comply with the 
International Safety guidelines for TMS administration, and we have a written protocol to 
handle seizures at the TMS suite.  
 
Intervention emergent mania or hypomania: This is a theoretical concern, as such as 
reaction has not been reported with iTBS. The rTMS literature estimates the risk for 
intervention emergent mania or hypomania at 0.84% but this was not statistically 
different from sham 0.73%.  
 
Risk of mood worsening: Due to the clinical course of depressive illness it is conceivable 
that subject’s assigned to either iTBS or sham may experience worsening of mood 
during their participation in the trial. 
 
Suicide risk: Patients who are identified, as being acutely suicidal will be excluded from 
the study. Nevertheless, since the rate of completed suicide in the USA remains high 
(i.e., about twice the rate of homicide) and most Americans who commit suicide suffer 
from depression, all subjects eligible to participate in this study are statistically at a 
relatively higher risk for suicide than the general population. Participation in the study 
does not create or increase the risk of completed suicide. Actually, most experts believe 
that one of the most efficient ways to decrease suicidal risk in older depressed 
individuals is to treat their depression. A Recent study by the PI indicated that 
intervention emergent suicidal ideation in older adults is likely to be related to the 
underlying illness rather than being an antidepressant treatment side effect.  
 
Breach of confidentiality: this is a potential risk of clinical research due to the need to 
inquire about health related information. 
 
For protections against risk see letter F subheading, below. 
 
Risks associated with MRI 
 
Likely risks: During scan and behavioral task procedures, patients may experience 
boredom or get tired.  

 
 
 
 
 
 
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13 
 
Less likely risks: Because patients are asked to lie still during the scan they may 
experience mild muscle aches and pains. Participants are offered cushions to place at 
pressure points or beneath the knees to reduce discomfort. Participants will be exposed 
to the MRI scanner acoustic noise. They will be provided with earplugs to dampen the 
noise. Participants may feel anxious or even experience claustrophobia (fear of being in 
closed spaces) while in the scan. Participants are able to communicate with staff 
throughout the scan and are encouraged to tell the staff if they feel anxious and whether 
they want to interrupt or stop the scan.  
 
Rare risks: Because the scanner uses a high strength magnet, subjects with ferro-
magnetic metallic objects inside their bodies are at substantial risk. Metallic objects can 
be pulled by the magnetic field and cause physical harm. The following medical devices 
and body implants can be affected by the MRI field or be potentially hazardous in the 
MRI environment: cardiac pacemaker, implanted cardioverted defibrillator (ICD), 
aneurysm clip, implanted insulin/drug pump, neurostimulator (TENS unit), 
biostimulator/bone growth stimulator, hearing aid/cochlear implant, Gianturco coil 
(embolus coil), vascular clip, surgical clip or staples, heart valve prosthesis, Greenfield 
Vena Cava filter, middle ear implant, penile prosthesis, shrapnel or bullets, wire sutures, 
tattooed eye liner, body piercing jewelry, permanent contraceptive implants such as 
diaphragm/ UID and pessaries, intraventricular shunts, wire mesh, artificial limb or joint, 
any orthopedic item that is ferro-conductive (ei, pins, rods, screws, nails, clips, plates, 
wire etc) dentures, any type of dental item held in place by a magnet, dental braces or 
any type of removable dental item, any other implanted item not mentioned. There may 
be unknown risks to the unborn fetus during pregnancy. Prior to the MRI, each subject 
will be carefully screened for the presence of any of these devices or implants. 
 
Benefits of study participation: Benefits to subjects include the possibility that their 
depression improves with this intervention. There are theoretical grounds and other 
research evidence indicating that TBS has potential beneficial effects on depression and 
executive dysfunction. The side effect profile for TBS is predicated on the side effect 
profile of repetitive Transcranial Magnetic Stimulation (rTMS). TMS was cleared as a 
depression treatment by the FDA in 2008.  According to Dr. Cristancho Pimiento’s 
clinical experience (Director of the TMS clinic at Washington University), patients often 
seek alternative treatments to medications, because medications have the potential for 
systemic side effects. TMS is generally an amenable treatment to patients. 
 
Benefits to society:  Depression in older adults with co-existing executive function 
impairment has devastating consequences including a protracted and treatment 
resistant depression course, poor quality of life and increased risk for suicide.  Testing 
TBS intervention will inform research in this area of significant public health relevance.  
 
 
2.f 
Early Withdrawal of Subjects  
 
Subjects can terminate their participation at any time. 
 
Subjects will be terminated by the PI if they experience a new event that will compromise 
their safety to receive the study intervention.  For example, subject becomes sick and 

 
 
 
 
 
 
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14 
her/his new condition precludes the use of the study intervention.  Or, subject 
experiences a seizure during the intervention administration; this will preclude further 
study intervention sessions. Subjects can be withdrawn due to other medical or 
psychiatric events that in the judgment of the PI will compromise subject’s safety to 
receive iTBS.  
 
In addition, subjects may be terminated due to missing sessions.  More than four 
consecutive missed sessions will cause withdrawal from study. Missed sessions will 
have to be made up, in this way the subject will still receive the entire 20-30 
interventions, but over a longer time period (i.e. greater than 4-6 weeks). Missing more 
than six non-consecutive sessions ( 20% of the intervention), which cannot be made up 
will also lead to study withdrawal.  
 
  All missed intervention days will be recorded in a log for each participant. 
 
2.g 
When and How to Withdraw Subjects  
 
Subjects can withdraw their consent to participate at any time.  Subjects should inform 
the study team about their wish to withdraw or sent a withdrawal letter.  
 
Subject’s termination from study by PI will be documented in Case report forms.  
 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
 
All data collected from subjects up to their withdrawal date will be used for analysis.  
 
If a subject decides to withdraw, we will ask him/ her to come for a close out visit to  
complete the same mood and executive function assessments that were recorded at  
baseline.  
 
D3 Study Device:  rTMS device  
 
3.a 
Description of the rTMS device used to deliver iTBS vs sham 
(placebo)  
 
We will use the rTMS device currently available at our institution for clinical and research 
applications.  The stimulator is a MagPro R 30 magnetic stimulator manufactured by 
MagVenture A/S (Farum, Denmark) and FDA approved for treatment of major 
depressive disorder.  Equipment components include: 1) R30 magnetic stimulator 2) coil 
cooler unit 3) dedicated C-B60 butterfly coil for Motor threshold assessments only 4) 
Treatment chair with neck rest and cloth cover, subjects will recline in this comfortable 
motorized recliner during intervention delivery 5) Head Stabilizer System (Airtight Pillow 
and Evacuation Pump).  
 
The intervention will be delivered using: 

 
 
 
 
 
 
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15 
• 
A Coil- cool B65 A/P butterfly coil. This coil functions as both active and sham 
coil. The coil has a symmetrical design, one side of the coil delivers active 
treatment and the other side delivers sham. Both sides of the coil are identical.  
• 
Theta burst delivery software 
Maglink software, this software interfaces with the B65 A/P coil to deliver the 
randomization assignment.  The software provides codes assignments according 
to the randomization schedule to ensure double -blind conditions 
 
The Magpro R30 is a non-significant risk device because:  
 
- It is not an implant  
- It is not for use in supporting or sustaining human life  
- It does not present a potential for serious risk to the health, safety or welfare of study 
 
3b. Other devices used: 
 
MRI guided neuronavigation equipment:  This frameless stereotactic system 
(Brainsight; Rogue Research, Quebec, Canada), co-registers the patient's head in a 
standardized magnetic resonance imaging (MRI) space. The equipment allows for 
accurate coil targeting of the Dorsolateral Prefrontal Cortex within and between Theta 
Burst stimulation sessions.  The equipment is located at the Laboratory for Applied Brain 
Plasticity (LABP), which is also equipped with a Magstim Super Rapid and a Magstim 
BiStim² (The Magstim Company Ltd, Wales, UK) and various coil types for brain 
stimulation (TMS).   
 
 
3T Prisma MRI Scanners  
The newest-generation fMRI scanner from Siemens, the Prisma 3T Magnet Resonance 
Imaging Scanner, will be used for this project.  Washington University (WU) has 
PrismaFit at the Mallinckrodt Institute of Radiology (MIR), operational since October 
2015.  A PrismaFit upgrade to a TRIO in the Center for Clinical Imaging Research 
(CCIR) is scheduled for December of 2017. These two Prismas will be running the same 
software version and will be equipped with identical equipment and resources for the 
structural and functional sequences proposed in this application. The Prisma scaners at 
the MIR and the CCIR are fully research dedicated scanners and available for use 24 
hours a day. The Siemens Prisma is the most advanced, FDA-approved 3Tesla MR 
scanner one can buy today. This scanner is the first commercial scanner to offer 80 
mT/m gradients with a slew rate of 200 T/m/s. These gradients are the product version 
of the research gradients used in the WU Human Connectome Project (HCP) Scanner. 
The key benefit to these gradients is the ability to achieve high diffusion sensitivity at 
shorter echo times than is possible with the previous generation of gradient system. The 
Prisma platform is also notable for 64 independent RF channels. Our scanners are (or 
will be) configured with both 32 and 64 element head coils to ensure protocol 
compatibility across multiple centers. These coils enable high acceleration factors during 
traditional parallel imaging approaches as well as the more modern techniques of 
simultaneous multislice and multiband acquisitions utilized in the HCP. Together, these 
technologies enable whole brain imaging with submillimeter structural MRI, sub-second 
BOLD fMRI and high angular resolution diffusion imaging with higher signal to noise than 
is possible on traditional, widely available 3T MR scanners. The new Prisma platform 
offers parallel RF transmission that enables uniform RF excitation and thus prospective 
signal homogeneity and inner volume imaging without aliasing. These state of the art 

 
 
 
 
 
 
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16 
technologies built into the Prisma will ensure neuroimaging data of optimal quality and 
maximal compatibility with HCP data.  
MRI Scanner Peripheral Equipment: The Prisma Suites will also contain the necessary 
equipment to present experimental stimuli and acquire responses including (1) a rear 
projection system; (2) an S14 fMRI Compatible Insert Earphones system (Sensimetrics 
Corporation, Malden, MA); and (3) ergonomic subject response devices.  
Physiological Recording in the MRI Scanner: During bold EPI scans, recording of 
respiratory and pulse oximeter measurements can be conducted using the built-in 
Prisma Siemens Physiological Monitoring Unity (PMU). 
 
3.b 
Intervention Regimen  
 
iTBS delivery:  
According to Huang et al, each burst consisting of three stimuli at 50 Hz, repeated every 
200ms will be administered using a two-seconds train repeated every 10 seconds for a 
total of 190s (600 pulses). We chose this paradigm due to its excitatory effects and LTP 
properties and given the best available evidence for effects on depression and executive 
function.  iTBS will be delivered over bilateral Dorso-Lateral Prefrontal Cortex (DLPFC ) 
(600 pulses left/ 600 pulses right). TBS will be administered for a total of six weeks, one 
daily session, Monday thru Friday.  The coil (B-65 A/P) will be used to deliver the iTBS 
intervention.  
 
Sham (placebo) delivery:  To deliver sham, we will use the same B-65 A/P coil. Sham 
stimulation is ensured by an Internal shielding mechanism in the delivery coil, which 
reduces the magnetic field strength to < 5% of active field which is biologically inactive.  
The coil’s symmetric design and identical clicking noises during both active and sham. 
The coil has a built-in position sensor to ensure that the correct (active or sham) side of 
the coil faces toward the subject’s head.  We will use synchronized gentle electrical 
stimulation to the scalp via pre-gelled surface stimulation electrodes to simulate scalp 
sensations on the sham delivery, which will mimic the active stimulation. Subject’s 
assignment to the intervention will be defined by the Maglink software according to the 
randomization schedule.  Assignments are stored on individualized USB memory 
devices. 
 
Localization of the Dorso-lateral prefrontal cortex (DLPFC) for iTBS and placebo 
interventions: Subjects assigned to either iTBS or sham intervention will receive 
stimulation on the DLPFC. We will target the DLPFC because it is a key prefrontal cortex 
structure involved in orchestration of executive function.74 The DLPC is a main region of 
the CCN network which is also implicated in the pathophysiology of LLD.43,76 We will 
stimulate bilaterally given evidence from our open label study. Subject’s structural MRI 
scans will be used to localize the DLPFC stimulation target. The DLPFC target 
comprises an area between the center of Brodman area (BA) 9 and the border of BA9 
and BA 4677, the Tailarach coordinates for left DLPFC stimulation will be  [x = -45 y=45, 
z = 35] and  [x = +45 y=45, z = 35] for the right DLPFC.78,79 This neuronavigated target 
has been successfully used in previous rTMS depression studies78,79 and it is expected 
to reduce variability resulting from localization of the stimulation, which has been 
problematic with previous localization approaches such as the 5cm rule.80,81  

 
 
 
 
 
 
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17 
Neuronavigation procedures: Following randomization and baseline MRI subjects will 
undergo neuronavigation, the target locations will be specified by reverse co-registration 
from a stereotaxic coordinate on the Tailarach template brain, onto each subject’s 
anatomical MRI. Neuronavigation will proceed using the frameless stereotactic system 
Brainsight (Rogue Research, Quebec, Canada), to position the coil for maximal field 
strength at the left and right target regions of the DLPFC for each subject. 
Neuronavigated coordinates will be marked on a textile cap and subjects will wear this 
cap during each intervention session, ensuring delivery of stimulation on the DLPFC 
target. A picture of the subject will be taken with the stimulation coil on the head. This 
will help investigators get a better visualization of where the coil should be placed after 
the subject undergoes neuronavigation. 
 
Motor Threshold Determination: Each subject’s Motor Threshold (MT) will be assessed 
using a dedicated C-B60 butterfly coil before the first intervention session. The MT will 
be re-assessed at the beginning of intervention weeks 2, 4 and 6 and re-checked as 
needed according to PI instructions, for example if the subject has had any medication 
changes or other conditions that may cause fluctuations in the MT. MT is the lowest 
stimulation intensity required to induce a motor response of the Abductor Pollicis Brevis 
(APB) muscle in the contralateral hand. MT will be measured via the visualization 
method, by observing movement of the contralateral thumb or adjacent fingers. Because 
of our subjects’ age range, we will “dose” iTBS at 120% of the resting MT. This dosing is 
necessary to adjust for prefrontal atrophy in the elderly.  This dosing has been used in a 
large sample without serious adverse events.  
 
In order to ease subjects into stimulation we will begin the first intervention at the level of 
MT and titrate up to 120% of the MT during the first week of intervention.  Subjects will 
achieve 120% of MT by the end of the first week.  
 
The TMS device to be used in this study for delivery of the interventions is currently 
employed in clinical operations and is housed at the West Pavilion, suite 15340, 
Outpatient Psychiatric Clinic at 1 Barnes-Jewish Hospital Plaza. The equipment will 
remain in place once study is finished. Therefore, there is not need for maintaining 
device shipment and receipt records. 
 
The equipment used for neuronavigation procedures is located at the Laboratory for 
Applied Brain Plasticity (LABP) on the East Building located at 4525 Scott Ave., St. 
Louis, MO 63110 and it is currently used in research operations.  
 
Scanning facilities :.  
 
Scanning facilities: MRI scans will be performed at the following scanning facilities at 
Washington University:  
 
• 
Center for Clinical Imaging Research (CCIR):  The CCIR is located on the 10th 
floor of Barnes-Jewish Hospital West Pavilion. The CCIR possesses four 
dedicated research scanners, which include a 3T MRI Siemens scanner which 
will undergo PrismaFit upgrade.  
 
• 
The MRI facility at the Mallinckrodt Institute of Radiology:  located at  
4525 Scott Avenue, Rm. 1109. This facility houses 2 PRISMA 3T Systems.  

 
 
 
 
 
 
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18 
 
 
3.c 
Method for Assigning Subjects to Intervention Groups  
 
A randomization scheme generated by the study statistician will be used. Subjects who 
consent to study participation will be randomized to receive six weeks of either iTBS or 
sham. Each subject enrolled in the study will have equal probability to be randomized in 
each study arm and permuted blocks of randomly varying sizes (4, 6, and 8) will be used 
to generate the scheme. Each block will contain equal numbers of assignments to iTBS 
and sham providing a balanced design. Neuropsychological testing, mood assessments 
and fMRI scans will be performed pre- and post-intervention. 
 
3.d 
Subject Compliance Monitoring  
 
Subjects will receive a total of 30 study intervention sessions, administered once daily, 
Monday thru Friday for six weeks.  Single- day intervention sessions missed due to 
expected ( holidays) or unexpected ( eg. Inclement weather, illness, transportation 
difficulties) reasons will have to be made up, in this way the subject will still receive the 
entire 30 interventions, but over a longer time period (i.e. greater than 4-6 weeks).  
More than four consecutive missed sessions will cause withdrawal from study. Missing 
more than six non-consecutive sessions (20% of the interventions), which cannot be 
made up will also lead to study withdrawal.  
 
All missed intervention days will be recorded in a log for each participant, and reviewed 
(weekly if no adherence is detected, so that study staff can intervene) by the PI.  
 
 
3.e 
Prior and Concomitant Therapy  
 
Subjects may continue existing antidepressant treatments (which are not part of 
excluded medications). However, subjects will be asked not to make changes on 
antidepressant doses in order to maintain a consistent regimen of medications during 
TBS intervention.  Likewise, is a subject is receiving psychotherapy, this regimen should 
not be modified.  
 
 
E Study Procedures  
 
E1 Screening for Eligibility 
 
A phone screen will be performed prior to the first study visit.  Over the phone the 
participant will be given a detailed description of the study including risk/benefits. They 
will be asked to provide information to help determine eligibility. Questions include 
demographics and health questions related to subject’s history of depression, 

 
 
 
 
 
 
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19 
medications.  Other questions include those to rule out contraindications to TMS such as 
metal in the head, a personal history of seizures or severe head trauma.  Questions 
about contraindications to MRI will be asked as well. If participant meets eligibility criteria 
based on that information an appointment will be scheduled to review and discuss the 
informed consent in person. 
 
E2 Schedule of Measurements 
 
After providing informed consent the following procedures will begin.  
 
Screening visit (Visit 0)  
At this visit a psychiatric interview will be performed by PI or her designee, during the 
visit the diagnosis of major depressive disorder will be confirmed, and information about 
subject's health status and ongoing medications will be obtained. Also a safety 
assessment will be performed to rule out the presence of active suicidal ideation with 
plan and imminent danger which will preclude study participation.  
Screening assessments include:  
Montreal Cognitive Assessment (MoCA)  
TMS Adult Safety Screen (TASS)  
MINI 
FrSBE 
Montgomery Asberg Depression Rating Scale (MADRS) (Repeat it at Baseline 
Assessment Visit if screening visit is done more than a week prior to intervention) 
 
National Institute of Mental Health Tool Box will be administered using an IPAD 
application. The tests include: 
NIH Toolbox Picture Vocabulary Test (TPVT)  
NIH Toolbox Flanker Inhibitory Control and Attention Test (Flanker)  
NIH Toolbox Dimensional Change Card Sort Test (DCCS)  
NIH Toolbox Picture Sequence Memory Test (PSMT)  
NIH Toolbox List Sorting Working Memory Test (List Sorting)  
NIH Toolbox Pattern Comparison Processing Speed Test (Pattern Comparison) 
NIH Toolbox Oral Reading Recognition Test (Reading)  
NIH Toolbox Oral Symbol Digit Test 
NIH Toolbox General Life Satisfaction 
 
Screen visit will take about 145 minutes to complete. 
 
If subject qualifies for the study a baseline visit will be conducted.  
 
Baseline Assessment Visit  
 
At this visit the following assessments will be administered:  
Trail Making Test 
Semantic Fluency Test  
The Revised Observed Tasks of Daily Living (OTDL-R) 
Delis-Kaplan Excecutive Function System (D-KEFS): Color–word interference 
Quick Inventory of Depressive Symptoms Self report  
Anxiety Measure (self report)  

 
 
 
 
 
 
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20 
Ruminative Response Scale (RRS) (self report)  
NIH Toolbox – General Life Satisfaction CAT and Positive Affect CAT 
Cumulative Illness Rating Scale-Geriatric (CIRS-G) 
The Antidepressant Treatment History Form (ATHF) 
California Verbal Learning Test – second edition (CVLT-II) 
Line Orientation test from RBANS 
 
Safety and side effects assessments:  
21 item for suicidal ideation SSI  
Frequency Intensity and Burden of side effects (FIBSER)  
Altman Self Rating Mania Scale (ASRM)  
 
Baseline Assessment will take about 3 hours to complete. 
 
Pre-intervention MRI Scan Visit: 
Neuroimaging Pre-Scan Questionnaire 
Pre-intervention MRI scan (about 60 minutes) 
 
This visit will take one hour and half to complete 
 
Intervention visit 1 
Motor Threshold determination: Each subject’s Motor Threshold (MT) will be assessed 
using a dedicated C-B60 butterfly coil.  Motor Threshold for the left and the right 
hemisphere will be determined. MT will be repeated every two weeks afterwards at the 
beginning of each intervention week. MT will be re-checked in situations such as recent 
medication changes, changes in sleep habits as determined necessary by the PI.  MT is 
the lowest stimulation intensity required to induce a motor response of the Abductor 
Pollicis Brevis (APB) muscle in the contralateral hand. MT will be obtained by the 
observation method, by observing movements of the thumb and fingers on the 
contralateral hand. Motor Threshold determination takes about 20 minutes to complete.  
 
Determination of stimulation site: Stimulation will be delivered over the scalp over the 
brain area corresponding to the dorsolateral prefrontal cortex (Brodmann areas 9 and 
46). Stimulation will be bilateral, subsequent left and right. We will localize the DLPFC 
using subjects’s structural scans and the following Tailarach coordinates: [x = -45 y=45, 
z = 35] for the left DLPFC and  [x = +45 y=45, z = 35] for the right DLPFC.74,75 Following 
randomization and baseline MRI subjects will undergo neuronavigation, the target 
locations will be specified by reverse co-registration from a stereotaxic coordinate on the 
Tailarach template brain, onto each subject’s anatomical MRI. Neuronavigation will 
proceed using the frameless stereotactic system Brainsight (Rogue Research, Quebec, 
Canada), to position the coil for maximal field strength at the left and right target regions 
of the DLPFC for each subject.  
 
Intervention delivery #1:  will be delivered as follows:  
Subjects assigned to iTBS: Burst of three stimuli at 50 Hz, repeated every 200ms using 
a two-seconds train repeated every 10 seconds for a total of 190s (600 pulses). TBS will 
be delivered over the scalp over the brain area corresponding to the dorsolateral 
prefrontal cortex. We will apply stimulation bilaterally with a total of 600 pulses on the left 
and 600 pulses on the right. This protocol takes about 8 minutes to complete.  
 
Subjects assigned to Sham:  Stimulation will be delivered mimicking the pulse 

 
 
 
 
 
 
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21 
frequency, sound and sensation of the active stimulation but with not active magnetic 
pulse delivery.  
 
Intervention delivery # 2- 30: Subsequent interventions will be scheduled daily Monday 
to Friday the theta burst stimulation paradigm as described above will be used.  
 
Weekly assessments:  
We will obtain the following assessments on a weekly basis, at the end of the 
intervention week.  
Montgomery Asberg Depression Rating Scale (Week 2, Week 4, and Week 6 only*)  
Quick Inventory of Depressive Symptoms Self report  
21 item for suicidal ideation (SSI)  
Frequency Intensity and Burden of side effects (FIBSER)  
Altman Self Rating Mania Scale (ASRM)  
NIH Toolbox – General Life Satisfaction CAT and Positive Affect CAT (Baseline, Week 
2, Week 4, and Week 6 only*) 
Anxiety Measure (self-report) (Baseline, Week 2, Week 4, and Week 6 only*) 
Ruminative Response Scale (RRS) (self report) (Baseline, Week 2, Week 4, and Week 6 
only*) 
 
 
End of intervention assessments: 
At the end of 6 weeks, or 30 interventions we will repeat the NIH Tool box battery, 
Semantic Fluency, Trail Making Test, FrSBE, the Revised Observed Tasks of Daily 
Living (OTDL-R), Delis-Kaplan Executive Function System (D-KEFS): Color–word 
interference, the California Verbal Learning Test – second edition (CVLT-II), and the 
Line Orientation test from RBANS in addition to the weekly assessments. This 
assessment session will take about three hours to complete. 
 
Post-intervention MRI Scan Visit 
Neuroimaging Pre-Scan Questionnaire 
Post-intervention MRI scan (about 60 minutes) 
 
This visit will take one hour and half to complete. 
E3 Safety and Adverse Events  
 
Interventions and precautions to minimize subject’s risk during TBS intervention:  
 
• Treating personnel is trained to act as first line responder, and will have 
cardiopulmonary resuscitation (CPR) training, in case of a seizure event.  
• Intervention will be delivered in a suite equipped with necessary materials to assist the 
subject in case of a seizure (oxygen, pulsoxymetry monitor, etc.).  
Besides the suite is located in house Barnes Jewish hospital and the emergency 
response team at Barnes Jewish hospital is readily available to assist.  The TMS treater 
will call the emergency response team in case of a seizure or other event deemed an 
emergency.  
• The TMS suite has a written protocol to handle a seizure occurrence  
• Subjects with increased risk of seizure or history of head trauma that may increase 
seizure won’t be eligible for intervention.  Besides we will screen subjects with The TMS 

 
 
 
 
 
 
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22 
Adult Safety Screen (TASS) prior to iTBS intervention.  
• Cognitive function is monitored throughout the intervention.  
• Side effects of the intervention will be monitored weekly with the Frequency, Intensity 
and Burden of Side Effects rating (FIBSER).  If deemed clinically necessary side effects 
will be also monitored by the study physician. Besides, subjects will be asked about side 
effects and will be monitored on all intervention days by the staff member administering 
the interventions.  
• Hearing will be protected by the use of earplugs during intervention sessions  
 
 
Interventions to minimize risk of worsening of mood and suicide risk:  
• Depressive symptoms will be monitored weekly and every day subjects will be asked 
about how is their mood. Standardized mood scales are administered pre and post 
intervention.  
• Emergent suicidal ideation will be monitored daily during the intervention and suicidal 
ideation will be assessed weekly with the 21-item Scale for Suicidal Ideation SSI,  
• During the course of the intervention if necessary, Dr. Cristancho Pimiento will perform 
a safety assessment. If clinically indicated, severely depressed patients will be advised 
hospitalization for close monitoring of their depressive symptoms. Hospitalization will be 
reported as a serious adverse event and the participant will be terminated from the study 
protocol. 
 
Confidentiality: Subject’s confidentiality will be assured through a multi-layered 
approach, entirely compliant with HIPAA regulations. We will have the following formal 
mechanisms limiting access to information that can link data to individual participants. 
Data forms that include identifying information will be kept in locked cabinets. Only the 
unique ID number, assigned by the research assistant at the time of initial contact will 
represent participants during data entry, data transfer, data analysis, or other file 
management procedures. To facilitate tracking, a password-protected computer file will 
be maintained containing the identity of participants, their ID numbers, and information 
about how they can be reached. This file, however, will contain no clinical data. Only 
members of the investigative group will have access to secured files or to master lists for 
participant code numbers and will be well informed regarding the protection of patients’ 
rights to confidentiality. Identities of participants will not be revealed in the publication or 
presentation of any results from this project. 
 
Interventions to Minimize Risk of MRI: 
To minimize the risk of claustrophobia, participants could do a mock scan on fake 
scanner, which can help them ease this. In addition, during the scan, participants will be 
able to talk with the MRI staff through a speaker system and can tell them to stop the 
scan at any time. 
To minimize the risk of injury caused by presence of metal and other MRI 
contraindications, participants will be asked a series of questions about metal exposure 
over the course of their lifetime from work experiences and medical procedures. 
To minimize the risk of boredom, tiredness, muscle aches and anxiety, participants may 
take breaks as needed throughout the study. They will also be told they can take breaks.  
Participants are offered pillows and blankets to alleviate discomfort in the scanner.  
Participants will be able to communicate with study staff at all times during the scan and 
will be told they can stop the scan at any time for any reason. Earplugs will be offered to 
decrease the exposure to the scanner’s acoustic noise.  
 

 
 
 
 
 
 
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23 
Participants will be screened at the time of the phone screener and again before the MRI 
scan using the 3.0 T MRI Recruitment/Pre-entry Screening form and will not receive an 
MRI scan if the screen is positive. Individuals with fear of confined spaces may become 
anxious during an MRI. There are no known long-term risks or consequences of MRI 
scans. The length of scan will be about 60 mins.  
 
 
3.a 
Safety and Compliance Monitoring 
 
At each intervention session, the intervention administrator will monitor subjects for 
safety and compliance with study procedures.   
 
Compliance monitoring: All missed intervention days will be recorded in a log for each 
participant, and reviewed (weekly if nonadherence is detected, so that study staff can 
intervene) by the PI.  
 
3.b 
Medical Monitoring  
 
At each intervention session, the intervention administrator or the PI designee, will 
monitor subjects’ safety during study procedures.  
 
Dr. Cristancho Pimiento is a board-certified psychiatrist with expertise in mood disorders 
and brain stimulation treatments (TMS).  She will be overseeing all study procedures. 
Subjects will be provided with her office number and a 24-hour emergency contact 
number to cover subjects’ concerns. 
 
3.c 
Definitions of Adverse Events 
A. Definition 
 
An adverse event (AE) is any untoward medical occurrence in a subject temporally 
associated with participation in the clinical study or with use of the TMS device.  An 
adverse finding can include a sign, symptom, abnormal assessment (laboratory test 
value, vital signs, electrocardiogram finding, etc.), or any combination of these. 
 
A Serious Adverse Event (SAE) is any adverse event that results in one or more of 
the following outcomes: 
 
• Death 
• A life-threatening event 
• Inpatient hospitalization or prolongation of existing hospitalization  
• A persistent or significant disability/incapacity 
• A congenital anomaly or birth defect 
• Important medical event based upon appropriate medical judgment 
 
 

 
 
 
 
 
 
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24 
3.d 
Classification of Events 
 
AEs will be labeled according to severity, which is based on their impact on the subject. 
An AE will be termed “mild” if it does not have a major impact on the subject, 
“moderate” if it causes the subject some minor inconvenience, and “severe” if it 
causes a substantial disruption to the subject’s well being.  
Additionally they will be classified as expected or unexpected.  
 
 
AE Attribution Scale  
 
AEs will be categorized according to the likelihood that they are related to the study 
intervention or other study procedures. Specifically, they will be labeled definitely 
unrelated, definitely related, probably related, or possibly related to the study 
intervention or procedures.   
 
 
3.e 
Data Collection Procedures for Adverse Events 
 
We will systematically collect AEs and summarize them in a running table throughout the 
study, including date of onset/offset, type of AE, severity, and interventions if any. Per 
Washington University IRB policy, reportable AEs are those that are possibly, probably, 
or definitely related to the study intervention or procedures. 
 
Throughout the study interventions, each subject will be queried about any adverse 
events since the last iTBS/ placebo session to date. The study research assistant or the 
blinded intervention administrator will do the questioning of AE’s. 
 
After an adverse event occurrence, a detailed note will be generated.  Note will include 
time, point in the intervention session, subject’s symptoms or complaints, and any steps 
taken.  Steps taken may include physical examination, medical care delivered, etc.  
 
3.f 
Reporting Procedures 
 
The PI or a sub-PI will be notified of all unexpected AE’s, all severe expected AE’s, and 
all AE’s which meet the qualifications of serious (SAE’s). If an adverse event occurs then 
PI will be notified and an evaluation will be performed. Intervention (iTBS or placebo) -
related events or any safety issue will be addressed by Dr. Cristancho. 
 
A compilation on AE will be documented for the yearly HRPO renewal review. 
 
SAEs that are unanticipated, serious, and possibly related to the study intervention will 
be reported to the IRB, and NIH/NCATS in accordance with reporting guidelines.     
 
 
D. Data and Safety Monitoring Plan (DSMP) : 
  
General considerations:  

 
 
 
 
 
 
______________________________________________________________________________________ 
 
25 
The PI will have primary responsibility for the monitoring of participants throughout their 
participation, both with respect to their safety and the integrity of the research data. 
Likewise the PI will be responsible for reporting of adverse events to the IRB, FDA and 
or the National Institute of Health.  
All participants will be reviewed by the PIs at baseline; exclusion criteria (e.g., suicidality, 
contraindications to study intervention) will reduce the risk to participants. Participants 
will be carefully monitored during the study. Additionally, the study will have a 24-hour 
answering service with physician coverage.  
 
The PI Dr. Cristancho Pimiento and her designee will meet weekly for research meetings 
to focus on screening forms; inclusion/exclusion criteria; case report form review; 
adverse events and other Human Research Protection Office (HRPO) required 
monitoring and reporting activities. The PI or her designee will record each subject 
screened for study inclusion and maintain records of reasons for subject exclusions. This 
information will be included in yearly renewals with the HRPO.  
 
Dr. Eric Lenze (Professor at the Department of Psychiatry ) will be fully available to 
provide guidance regarding issues related to the safety of study participants and the 
integrity of the study. Dr. Lenze will participate in research meetings to review accuracy 
of screening, subject accrual, and all subjects who withdraw from the study. Likewise, he 
will be available to assess with issues regarding participant accrual, overall study 
progress, intervention efficacy, adverse events, ethical concerns, quality of monitoring, 
and protocol adherence. The entire investigative team with Dr. Cristancho , Dr. Lenze 
and the PI Designee will meet at least once per quarter.  
 
 
We will follow procedures pertaining to adverse events and serious adverse events as 
specified in the DSMP document 
 
E4 Study Outcome Measurements and Ascertainment 
 
Primary outcome measures:  
The effects of the study intervention depression will be measured using the Montgomery  
Asberg Depression Rating Scale. 
The effects of the study intervention on executive function will be evaluated using the 
Flanker inhibitory control, the Dimensional change sort task and the  
List Sorting Working memory test will measure executive function,  from the NIH Tool box 
executive function domain.  
 
Brain’s connectivity measure: Using resting state fMRI we will measure functional 
connectivity within the Cognitive Control Network (CCN) in depressed older adults 
before and after study intervention. We will also explore functional connectivity within 
and between other networks that are relevant to depression including the Default Mode 
network  and the cingulo-opercular networks.  
 
 
F Statistical Plan  
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
26 
 
Statistical Analyses: We will use intention-to-treat principles. We will use t-test or its 
non-parametric equivalent to compare the distribution of continuous variables and the 
changes in the main outcome measures between active and sham groups. χ2 tests will 
be used to compare categorical variables between groups. We will use a mixed general 
linear model (GLM) to accommodate data from our within- and between-participant study 
design to examine changes from baseline to post-intervention, and compare them 
between active vs. sham groups. The GLM explores estimated marginal means by 
taking into account within- and between-participant variability, adjusting for confounders 
and allowing exploration of significance of within-participant and between-group 
interaction effects. Differences between groups in behavioral outcome measures and 
network connection changes will be evaluated through 2-way interaction effect 
(time*group). Through the 2- way interaction iTBS*Fazekas score we will explore the 
modification effect of grade of white matter burden on the impact of iTBS in the observed 
network connectivity changes. Pearson’s correlation will examine the correlation 
between changes in behavioral measures with changes in network connectivity. We will 
use Hayes’ PROCESS114 macro to evaluate the role of the difference in the strength of 
connections pre-intervention minus the strength of connection post intervention as 
mediator of change for iTBS and bootstrap and Monte Carlo confidence intervals will be 
calculated. All statistical tests will be two-sided and evaluated at the alpha level of 0.05. 
SAS 9.4 (SAS Institute, Cary, NC) and R 3.2.3 statistical software packages will be used 
for all analyses. Sample size justification: For this pilot study, I plan to enroll 20 elderly 
subjects and randomized them to iTBS arm or placebo arm (10 in each group).  The 
sample size of 20 subjects is feasible for the time limit of the KL2 award. This pilot 
sample  will provide meaningful data to estimate sample size and calculate power for a 
subsequent grant application to rigorously test the effects of theta burst stimulation on 
depressed older adults.   
 
G Data Handling and Record Keeping Records 
retention:  
 
Study data will be kept for potential future analysis. Records will be maintained for at least 7 
years after completion of the study as per local HRPO requirements. 
 
G1 Confidentiality and Security 
 
Obtaining consent forms and interviews will be conducted in the private research offices 
suites of Dr. Cristancho or study staff. Intervention sessions will be conducted in a 
private office in the West pavilion 15th floor at BJH Psychiatry Department at the TMS 
clinic suite. Only the minimally necessary number of personnel will be present. MRI 
scans will be performed at scanning facilities at Washington University: The 
CCIR and the MRI facility at the Mallinckrodt Institute of Radiology.  
 
G2 Training  
 
All staff involved in TBS administration will be trained by Dr. Cristancho Pimiento 
(director of the TMS clinic).  

 
 
 
 
 
 
______________________________________________________________________________________ 
 
27 
 
G3 Case Report Forms and Source Documents 
Confidentiality Subject confidentiality will be assured through a multi-layered approach, 
entirely compliant with HIPAA regulations. We will have the following formal mechanisms 
limiting access to information that can link data to individual participants: Data forms that 
include identifying information will be kept in locked cabinets. Only the unique ID 
number, assigned by the research assistant at the time of initial contact will represent 
participants during data entry, data transfer, data analysis, or other file management 
procedures. 
 
Electronic case report forms will be created using the same confidentiality procedures 
described above.  Data will be stored into a secure data base on the university network.  
 
G4 Records Retention 
 
Records will be maintained for at least 7 years after completion of the study as per local 
HRPO requirements. 
 
H Study Administration 
 
H1 Organization and Participating Centers 
 
Washington University School of Medicine 
 
H2 Funding Source and Conflicts of Interest 
 
Support is from The National Institutes of Health and the National Center for Advancing 
translational Sciences, and the Department of Psychiatry, through the Center for Brain 
Research in Mood Disorders.  
 
H3 Subject Stipends or Payments  
 
Subjects will be compensated up to $125 for their participation in the study. Cards to 
cover the cost of parking will be provided for subjects.  
 
H4  Study Timetable 
 
Recruitment and data acquisition will take place from 2018 to 2020.   
 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
28 
I Publication Plan  
 
 
It is estimated that a primary publication will be produced reporting outcomes of this study.  
Depending on study results additional publications may result.  
 
J  Attachments  
 
Please refer to IRBS submission for all attachments.  
 
 
K References 
 
 
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