A Single Arm Study of Resting State Functional Magnetic Resonance Imaging (Rs-fMRI)-Guided Theta Burst Stimulation (TBS) in Early-Stage Alzheimer's Disease (AD)
Phase: NA
Conditions: Alzheimer Disease
Sponsor: HealthPartners Institute

  
A Single Arm Study of Resting State Functional Magnetic 
Resonance Imaging (rs-fMRI)-Guided Theta Burst 
Stimulation (TBS) in Early-Stage Alzheimer’s Disease 
(AD) 
SHORT TITLE: TMS PILOT IN EARLY AD 
  
Protocol Number: Version 3.0 
National Clinical Trial (NCT) Identified Number:  05292222 
Principal Investigator: Bhavani Kashyap, MBBS, PhD 
Study Physician/Medical Oversight: Dr. Marcel Hungs, MD, PhD 
Sponsor: HealthPartners Neuroscience Research 
Funded by: Department Donations Raised by Regions Hospital Foundation  
May 18, 2023 
 
 

  
CONFIDENTIALITY STATEMENT 
 
This document is confidential communication. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be published 
or disclosed without prior approval of the Principal Investigator or other participating study 
leadership and as consistent with the terms of the award. 
 
 
 
 

  
CONTENTS 
STATEMENT OF COMPLIANCE.............................................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE ............................................................................................................................................... 2 
1 
PROTOCOL SUMMARY............................................................................................................................................. 3 
1.1 
Synopsis......................................................................................................................................................... 3 
1.2 
Schema .......................................................................................................................................................... 4 
1.3 
Schedule of Activities (SoA) ......................................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................................................ 5 
2.1 
Study Rationale and Background ................................................................................................................ 5 
2.2 
Risk/Benefit Assessment.............................................................................................................................. 8 
2.2.1 
Known Potential Risks ............................................................................................................. 8 
2.2.2 
Known Potential Benefits ........................................................................................................ 9 
2.2.3 
Assessment of Potential Risks and Benefits........................................................................... 9 
3 
OBJECTIVES AND ENDPOINTS ...............................................................................................................................10 
4 
STUDY DESIGN........................................................................................................................................................11 
4.1 
Overall Design .............................................................................................................................................11 
4.2 
Overview – study procedures/data collection .........................................................................................11 
4.3 
End of Study Definition ..............................................................................................................................11 
5 
STUDY POPULATION ..............................................................................................................................................12 
5.1 
Inclusion Criteria.........................................................................................................................................12 
5.2 
Exclusion Criteria ........................................................................................................................................12 
5.3 
Lifestyle Considerations .............................................................................................................................12 
5.4 
Screen Failures............................................................................................................................................12 
5.5 
Strategies for Recruitment and Retention................................................................................................13 
6 
STUDY INTERVENTION...........................................................................................................................................13 
6.1 
Study Intervention(s) Administration .......................................................................................................13 
6.1.1 
Study Intervention Description.............................................................................................13 
6.1.2 
Dosing and Administration....................................................................................................14 
6.2 
Measures to Minimize Bias: Randomization and Blinding ......................................................................14 
6.3 
Study Intervention Compliance .................................................................................................................15 
6.4 
Concomitant Therapy.................................................................................................................................15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................................................................15 
7.1 
Discontinuation of Study Intervention......................................................................................................15 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................................................15 
7.3 
Lost to Follow-Up........................................................................................................................................15 
8 
STUDY ASSESSMENTS AND PROCEDURES............................................................................................................16 
8.1 
Study Schedule ...........................................................................................................................................16 
8.1.1 
SCREENING VISIT (VISIT 1) Day 0 ..........................................................................................16 
8.1.2 
Baseline visit (Visit 2) -Week 1 (± 7 days).............................................................................16 

  
8.1.3 
Treatment visit (Vists 3-5 and visits 6,7) (5 days over 2 weeks, ± 7 days 
after visit 2) 
17 
8.1.4 
follow-up/repeat visit (visit 8)(week 10, 6 weeks after visit 7 ± 7 days)............................17 
8.2 
Efficacy Assessments..................................................................................................................................17 
8.2.1 
Demographics and medical history ......................................................................................17 
8.2.2 
MMSE (Mini-mental status examination) ............................................................................17 
8.2.3 
Clinical Dementia Rating (CDR) .............................................................................................17 
8.2.4 
Neuropsychological assessments .........................................................................................18 
8.2.5 
MOOD Assessments ..............................................................................................................19 
8.2.6 
MRI Imaging ...........................................................................................................................19 
8.2.7 
connectomic Analysis ............................................................................................................19 
8.3 
Safety and Other Assessments ..................................................................................................................21 
8.3.1 
Trancranial magnetic stimulation adult safety screen (TASS) ............................................21 
8.4 
Adverse Events and Serious Adverse Events ............................................................................................21 
8.4.1 
Definition of Adverse Events (AE).........................................................................................21 
8.4.2 
Definition of Serious Adverse Events (SAE)..........................................................................22 
8.4.3 
Expectedness..........................................................................................................................22 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................................22 
8.5 
Unanticipated Problems ............................................................................................................................22 
8.5.1 
Definition of Unanticipated Problems (UP) .........................................................................22 
8.5.2 
Unanticipated Problems Reporting ......................................................................................23 
9 
STATISTICAL CONSIDERATIONS.............................................................................................................................23 
9.1.1 
Statstical plan overview.........................................................................................................23 
9.1.2 
power analysis........................................................................................................................24 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.........................................................24 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................................24 
10.1.1 
Informed Consent Process ....................................................................................................24 
10.1.2 
Study Discontinuation and Closure ......................................................................................25 
10.1.3 
Confidentiality and Privacy ...................................................................................................25 
10.1.4 
Key Roles and Study Governance .........................................................................................26 
10.1.5 
Safety Oversight .....................................................................................................................26 
10.1.6 
Clinical Monitoring.................................................................................................................26 
10.1.7 
Quality Assurance and Quality Control ................................................................................26 
10.1.8 
Data Handling and Record Keeping ......................................................................................27 
10.1.9 
Protocol Deviations................................................................................................................27 
10.1.10 
Publication and Data Sharing Policy .....................................................................................27 
10.1.11 
Conflict of Interest Policy ......................................................................................................28 
10.2 
Additional Considerations..........................................................................................................................28 
10.3 
Protocol Amendment History ....................................................................................................................29 

  
11 
REFERENCES ...........................................................................................................................................................31 
 

A21-251 TMS Pilot in Early AD 
 
Version 3 
PI: Dr. Bhavani Kashyap 
 
May 18, 2023 
 
 
1 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Council for Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46)  All personnel involved in the conduct of this study have 
completed human subjects protection training. 
 
 

A21-251 TMS Pilot in Early AD 
 
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PI: Dr. Bhavani Kashyap 
 
May 18, 2023 
 
 
2 
INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines, as described in the 
Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name:  Bhavani Kashyap, MBBS, PhD 
Title: 
Research Associate, Neuroscience Research Center, HealthPartners Institute 
 
Investigator Contact Information 
Affiliation: Neuroscience Research Center, HealthPartners Institute  
Address: 295 Phalen Blvd. 
       St. Paul, MN 55130 
   Mailstop 41200A 
Telephone: (651) 495-6358 
Email: Bhavani.X.Kashyap@HealthPartners.com 
 
 
 

A21-251 TMS Pilot in Early AD 
 
Version 3 
PI: Dr. Bhavani Kashyap 
 
May 18, 2023 
 
 
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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A Single Arm Study of Resting State Functional Magnetic Resonance Imaging (rs-
fMRI)-Guided Theta Burst Stimulation (TBS) in Early-Stage Alzheimer’s Disease 
(AD) 
IRB Number: 
 
Study Description: Alzheimer’s disease (AD) is a progressive neurodegenerative condition affecting 
6.2 million individuals in the United States, resulting in an annual cost of care of 
$305 billion. AD is functionally characterized by progressive degeneration of 
large-scale brain networks (LSBNs), including the default mode network (DMN) 
presumably from the deposition of amyloid plaques and neurofibrillary tangles.  
Available FDA-approved medications for AD such as donepezil and memantine 
offer limited benefit and modest impact on quality of life.  In combination with 
resting state functional MRI (rs-fMRI), transcranial magnetic stimulation (TMS) 
with intermittent theta burst stimulation (iTBS) offers a non-invasive alternative 
to pharmacotherapy in persons with AD.  We propose a pilot trial using rs-fMRI 
to target dysfunctional LSBNs in early stage AD.   
Objectives: 
 
Primary Aim: To estimate the effect of rs-fMRI-guided TBS on connectivity 
dysfunction within the temporal area  G dorsal (TGd) in persons with early stage 
AD. 
 
Exploratory Aim 1: To estimate the effect of rs-fMRI-guided TBS on the 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
score in persons with early stage AD. 
 
Exploratory Aim 2: To estimate the effect of rs-fMRI-guided TBS on the Geriatric 
Depression Score (GDS) in persons with early stage AD. 
Exploratory Aim 3: To identify and estimate the effect of rs-fMRI-guided 
TBS on two additional dysfunctional parcellations within the default 
modal network (DMN), central executive network (CEN), and salience 
network (SN) in persons with early stage AD. 
Endpoints: 
Primary Endpoint: Connectivity Measures of the TGd parcellations at 
baseline and post-treatment 
Exploratory Endpoints: 
• 
RBANS at baseline and post-treatment 
• 
GDS at baseline and post-treatment 
• 
Connectivity levels of other parcellations that are anomalous 
Study Population: 
The study will enroll 10 subjects with a diagnosis of early stage AD (mild 
cognitive impairment or mild AD).   
Inclusion criteria:  
1. Established diagnosis of MCI/mild AD 
2. Evidence for CNS amyloidosis (e.g., Amyloid PET or CSF biomarkers 
consistent with AD) 
3. Prior brain imaging performed 
4. MMSE >24 
5. CDR 0.5-1 

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6. Stable dose of cholinesterase inhibitors and memantine for at least one 
month 
7. Subjects are between 40-90 years of age 
Exclusion Criteria: 
1. Non-AD dementia including, but not limited to, Lewy body dementia, 
frontotemporal dementia, vascular dementia, Jakob-Creutzfeldt 
disease, etc. 
2. Inability to tolerate rs-fMRI 
3. Contraindication of rs-fMRI due to implants or metal 
4. Seizure disorder 
5. Alcoholism 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Participants will be enrolled at HealthPartners Neuroscience Center, 
located at 295 Phalen Blvd., St. Paul, MN 55130. 
Description of 
Study 
Intervention: 
All subjects will receive treatment with intermittent theta burst stimulation 
(iTBS), There will be a total of 5 iTBS sessions per treatment visit, and a total of 
5 treatment visits distributed over a two-week period (#3 during week 1 and #2 
during week 2). All patients will receive iTBS to the right TGd region.   In 
addition, we will further provide TBS treatment for two additional sites within 
the LSBNs that is found to contain the greatest number of connectivity 
anomalies. Data from the Infinitome program will be exported to the Localite 
TMS Navigator; the navigator is a device that visualizes brain regions to 
facilitate correct positioning of patient and coil based on the coordinates from 
the Infinitome analysis. 
Study Duration: 
The duration of this study is 1.5 years.  
Participant 
Duration: 
10-12 weeks 
 
 
1.2 
SCHEMA 
 
 
 
Screening 
Baseline 
 rs-fMRI/ 
RBANS & 
GDS 
1 week 
+/-7 days 
1 week 
+/-7 days 
Treatment 
TBS (5 days 
over 2 wks) 
6 weeks 
+/-7 days 
Repeat  
rs-fMRI/ 
RBANS & 
GDS 
Figure 1: Study Visit/Workflow 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Table 1: Study Visit Schedule 
Procedure 
Screening 
Baseline 
Treatment 
Follow-up 
Early 
Withdrawal 
Visit # 
Visit 1 
Visit 2 
Visits 3-7 
Visit 8 
 
 
Day 0 
Week 1  
Weeks 2-4 
Week 10 
 
Window 
 
± 7 Days 
± 7 Days 
± 7 Days 
 
Informed consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
MRI Contraindications 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
MMSE 
X 
 
 
 
 
CDR 
X 
 
 
 
 
TMS Safety 
Questionnaire 
X 
X 
 
 
 
Physical Exam 
X 
 
 
 
X 
RBANS 
 
X 
 
X 
 
GDS 
 
X 
 
X 
 
iTBS Treatment 
 
 
X 
 
 
MRI Imaging 
 
X 
 
X 
 
Adverse Events/Serious 
Adverse Events 
X 
X 
X 
X 
X 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE AND BACKGROUND 
Alzheimer’s disease is the most common cause of dementia, the 6th leading cause of death, 
and the only illness among the top ten that cannot be slowed, prevented, or cured (cite All 
Association Facts and Figures).  The condition affects 6.2 million Americans and results in $305 
billion in annual costs ("2021 Alzheimer's disease facts and figures," 2021).  The pathological 
signature of AD is the presence of cerebral amyloid plaques and neurofibrillary tangles resulting 

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in disrupted connectivity of large-scale brain networks (LSBN), including, but not limited to the 
default mode network (DMN).  Available FDA approved treatments for AD temporary alleviate 
symptoms but have no bearing on overall disease progression (Mielke et al., 2012).  
Furthermore, cholinesterase inhibitors, the most commonly prescribed drugs for AD, cause 
dose-limiting gastrointestinal side effects in 20% of patients.  Therefore, the current limitations 
of cognitively enhancing medications suggest a role for a more targeted treatment in AD.  
Transcranial magnetic stimulation (TMS) is a therapeutic tool, consisting of magnet and coil that 
utilizes Faraday’s principle to induce electric currents in specific brain regions, leading to 
cortical excitability or suppression (Janicak & Dokucu, 2015).  The treatment is relatively safe 
with the most common side effect being tension headache (to which patients frequently 
acclimate over time) and is FDA-approved for the treatment of depression (Janicak & Dokucu, 
2015).  The device is routinely used in outpatient psychiatry clinics including HealthPartners and 
Park Nicollet behavioral health.  Repetitive TMS (rTMS) has been shown to induce changes in 
cortical excitability and modulate neural network activity beyond the duration of the stimulus 
itself (Pascual-Leone et al., 2011).  Intermittent theta burst stimulation (iTBS) is a more recent 
variation of TMS that delivers longer lasting change in brain activity with less stimulation and 
has likewise been found to be safe and well-tolerated by patients (Blumberger et al., 2018; 
Gonsalvez, Baror, Fried, Santarnecchi, & Pascual-Leone, 2017).  Whereas, rTMS applied to the 
dorsolateral prefrontal cortex is an FDA approved treatment for refractory depression, TMS has 
significant potential as a targeted treatment for cognitive disorders.  A proposed mechanism is 
that persistent enhancement of cortical excitability results in long-term potentiation (Huang, 
Edwards, Rounis, Bhatia, & Rothwell, 2005) and increased expression of brain derived 
neurotrophic factors (Phillips et al., 1991). 
In addition to improving mood, TMS has demonstrated positive effects on cognitive 
performance.  TMS has been shown to improve memory in young and healthy elderly 
individuals (Manenti, Cotelli, Robertson, & Miniussi, 2012) as well as in memory impaired adults 
(Gonsalvez et al., 2017).  In mild-moderate AD, rTMS at 20 Hz applied over the DLPFC resulted 
in improvement of object naming at 8 weeks (Cotelli et al., 2011).  In addition, this frequency 
and anatomical location has improved performance in mild AD on the MMSE, the instrumental 
activities of daily living (IADL) scales, and global deterioration scale at 3 months, but no such 
benefits were noted in severe stage dementia (Ahmed, Darwish, Khedr, El Serogy, & Ali, 2012). 
An investigation targeting the precuneus, a hub within the DMN, with 20 Hz stimulation lead to 
improved episodic memory performance compared to sham (Koch et al., 2018).  In addition, 
this study was remarkable in showing that iTBS, a more efficient approach to non-invasive 
neurostimulation, was well-tolerated in prodromal AD (Koch et al., 2018) In addition to AD, 
rTMS applied to the DLPFC at 10 Hz in MCI has resulted in cognitive benefits (Marra et al., 
2015). The use of rTMS in conjunction with concurrent cognitive training has further improved 

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outcomes relative to placebo on the ADAS-Cog, MMSE, and CGIC lasting up to 4.5 months 
(Bentwich et al., 2011; Lee, Choi, Oh, Sohn, & Lee, 2016; Jose Martin Rabey & Dobronevsky, 
2016; Jose M Rabey et al., 2013). Prior areas that have been targeted by TMS treatments for 
memory impairment in AD include the left/right dorsal prefrontal cortex, left inferior frontal 
gyrus, left middle temporal gyrus, left/right temporal parietal junction, precuneus, and 
left/right superior parietal lobule (Gonsalvez et al., 2017). 
Investigation of the role of TMS in AD has been guided by anatomical landmarks, prolonged 
EEG, and structural imaging, but has yet to leverage resting state fMRI (rs-fMRI) imaging of 
LSBNs. rs-fMRI clinical tool relies on the low-frequency fluctuation in the blood-oxygen-level-
dependent contrast (BOLD) signal to interrogate LSBNs (Joo, Lim, & Lee, 2016).  In the 
behavioral health literature, rs-fMRI has been employed to better target key brain regions and 
networks responsible for mood regulation and have shown improvements in mood compared 
to standard approaches to treatment (Cole et al., 2019).  Thus, the combination of rs-fMRI with 
TMS has the potential to enhance outcomes in targeted interventions for cognitive dysfunction.   
Omniscient (Forbes Startup -30 Million), a for-profit, Sydney, Australia-based company, has designed 
the Infinitome program, which utilizes data from the Human Connectome Project (HCP) 
together with machine learning to analyze diffusion tensor and resting-state fMRI imaging data 
from remote sites.  The HCP commenced one of the most ambitious neuroscientific initiatives 
to “map the brain(Glasser et al., 2016),” identified 379 functional areas of the cerebrum, and 
discovered 97 new brain regions that had not been previously described.  The foundation for 
this imaging tool is based upon the HCP atlas, which has also informed prior publications from 
our group, including the Connectomic Atlas of the Human Cerebrum (Baker et al., 2018).  The 
Infinitome program creates a subject specific version of the Human Connectome Project 
Multimodal Parcellation (HCP-MMP1) atlas using diffusion tractography (DT).  Analytics are 
performed on both diffusion tensor imaging (DTI) and rs-fMRI (see appendix Guide to Planning 
an Infinitome Study).  Outlier detection using a tangent space connectivity matrix is performed 
by comparing results with a subset of 300 normal HCP subject fMRI samples to determine the 
range of normal correlations for each regions of interest in a LSBN.  Abnormal connectivity is 
determined as a 3-sigma outlier for that correlation.  The program includes a 15-minute 
imaging protocol that can readily be added on to structural MRI sequences and provides 
automated support for image analysis, thus simplifying the process of accessing clinically 
applicable imaging data.  Preliminary work has shown that connectomic analysis in AD subjects 
using this software is feasible and can detect functional anomalies involving regions of interest 
described by the HCP (Ren et al., 2020).  
Our preliminary research at HealthPartners using Infinitome in AD (n=4) and dementia with 
Lewy bodies (n=6) has shown temporal area G dorsal (TGd) (Figure 2) within the default mode 
network to have connectivity anomalies in persons with dementia.  We suspect this area to be 

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important in the clinical presentation of various dementia, and therefore, these regions may be 
targeted with transcranial magnetic stimulation to improve symptoms. 
  
 
2.2 
RISK/BENEFIT ASSESSMENT   
2.2.1 
KNOWN POTENTIAL RISKS  
Transcranial Magnetic Stimulation (TMS) 
The TMS device to be used in this study is the MagVenture TMS Therapy® with theta Burst  
stimulation. MagVenture is a computerized, electromechanical medical device that produces 
and delivers non-invasive, magnetic fields to induce electrical currents targeting specific regions 
of the brain. In 2018, MagVenture received FDA clearance for the 3 minute protocol which we 
market under the trademarked name Express TMS®. The Lancet: “THREE-D: a randomized non-
inferiority trial”), comparing the standard, 37 minute TMS protocol to the newer, 3 minute 
Theta Burst protocol (TBS) (Blumberger et al., 2018). The study concluded that the Theta Burst 
protocol is just as safe and effective for the treatment of major depressive disorder as standard 
TMS. Recent safety review of TMS summarizes the Theta Burst studies and concludes that TBS 
in the range of 80-100% of motor threshold is safe (Supplementary Table 5, (Rossi et al., 2020)). 
In this study, the planned motor threshold is 80%.  
 
The TMS devices are non-significant risk devices, in line with the criteria for exception from an 
IDE. Transcranial magnetic stimulation (TMS) is a therapeutic tool, consisting of magnet and coil 
that utilizes Faraday’s principle to induce electric currents in specific brain regions, leading to 
cortical excitability or suppression (Janicak & Dokucu, 2015) .  The treatment is relatively safe 
with the most common side effect being tension headache (to which patients frequently 
acclimate over time) and is FDA-approved for the treatment of depression (Janicak & Dokucu, 
2015).  The device is routinely used in outpatient psychiatry clinics including HealthPartners and 
Park Nicollet behavioral health.  Patients are generally able to drive home or return to work 
immediately after an TMS session. Rare side effects include dizziness, memory trouble, trouble 
concentrating and sudden mood changes. The long-term effects of TMS are not known.  
Magnetic Resonance Imaging (MRI) 
Figure 2: Temporal Area Gd

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Structural MRI is a routine diagnostic procedure at HealthPartners, and the resting state portion 
merely requires 15 minutes of scan time.   The patient may experience claustrophobia with the 
narrow imaging space and hearing loud noises while inside the machine. An MRI scan does not 
involve radiation like conventional X-rays.  Instead, images are generated using a magnetic field 
and radio signals.  Because an MRI scanner uses strong magnets, subjects will be screened by the 
NSC Imaging staff – as for a routine MRI.  People with artificial heart valve, metal plate, pin, or 
other metallic objects in their body (including gun shot or shrapnel) will not be eligible for this 
study. 
Neuropsychological Testing 
Neuropsychological testing may result in frustration on the part of the patient but does not 
have any other significant risks.   
 
Loss of Confidentiality 
There may be a slight possibility of breach of confidential information that was collected. 
However, the following procedures will be implemented to reduce this risk: 
• Data collection and reporting tools will be developed and stored internally. 
• Data collected and stored electronically will remain confidential and secure (e.g. secured 
server and password protected files [REDCap]).  
• Study binders will be stored in a locked file cabinet within a locked office. 
• After the study is closed, all subject identifiers will be destroyed. 
 
2.2.2 
KNOWN POTENTIAL BENEFITS  
Benefits for the patient include the ability to review imaging of their rs-fMRI imaging studies.  In 
addition, patients may experience improvements in mood or cognition with the TMS although 
this has not been well-established at this time.   
 
This research will be important to better investigate the role of non-invasive neurostimulation 
for symptoms in AD in a larger cohort and will support a future application for an NIH-
sponsored grant. 
2.2.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
We believe the potential risks to the participants in this study are minimal. 
The following measures will be taken to protect patients from risk of TMS 
• 
Transcranial magnetic stimulation is associated with a 50% risk of self-limiting headache 
and a 1/10,000 risk of seizures.  All patients will undergo the TMS Adult Safety Screen 
(TASS), which will ensure that the risk of seizure is negligible for each subject 
participating in the study.  In the event of adverse events during TMS treatment, specific 
procedures will be outlined (aligned with HealthPartners Behavioral Health) and staff 
will be trained and on-site for any assistance. In addition, all research staff will be 

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trained on the operation of device (Fried et al., 2020). Repeated exposure to TMS may 
result in sensorineural hearing loss, which is prevented by routine use of ear plugs. 
• 
Relative to most oral medications used in treatment of dementia, TMS has a very 
favorable side effect profile. 
The following measures will be taken to protect providers and patients from the risk of breach of 
confidentiality:  
• A unique study ID code unrelated to the medical record number or other study subject-
specific information will be assigned to each patient and used to link data from various 
sources and needed for analysis.  The study number will be used on the RedCap database 
and Infinitome Program.  All imaging data uploaded from the NSC research site will be de-
identified and uploaded to the Infinitome cloud-based server.   
• Infinitome program uses an industrial grade cyber security that is superior to what is 
offered at the leading medical device companies.  No personal health information is 
stored on servers and only de-identified scans are stored on a dedicated edge node on 
encrypted MinIO instances.  Patient data is only accessed through authenticated calls 
form Kubernetes pods contained in the VPC.  The web service requires user 
authentication.  Only the data related to a specific facility can be retrieved through 
authenticated calls and are restricted to their use. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
Table 2: Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To estimate the effect of rs-fMRI-
guided TBS on connectivity 
dysfunction within the temporal 
area temporal area G dorsal (TGd) 
in persons with early stage AD. 
Connectivity measures of the TGd 
parcellations at baseline and post-
treatment 
Infinitome processed rs-
fMRI data that is targeted 
with TMS 
Exploratory  
 
 
1. To estimate the effect of rs-
fMRI-guided TBS on the 
Repeatable Battery for the 
Assessment of 
Neuropsychological Status 
(RBANS) score in persons 
with early stage AD. 
2. To estimate the effect of rs-
fMRI-guided TBS on the 
Geriatric Depression Score 
(GDS) in persons with early 
stage AD 
1. RBANS at baseline and post-
treatment 
 
 
 
 
 
 
 
2. GDS at baseline and post-
treatment 
 
Provide pilot data for 
larger trials. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
3. To identify and estimate 
the effect of rs-fMRI-guided 
TBS on two additional 
dysfunctional parcellations 
within the default modal 
network (DMN), central 
executive network (CEN), 
and salience network (SN) 
in persons with early stage 
AD. 
 
3. Connectivity levels of other 
parcellations that are 
anomalous 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This investigation is a prospective single arm treatment trial in early stage AD (MCI and mild 
AD).   
Primary Aim 
 To estimate the effect of rs-fMRI-guided TBS on connectivity dysfunction within the temporal 
area temporal area G dorsal (TGd) in persons with early stage AD. 
Exploratory Aims 
1. To estimate the effect of rs-fMRI-guided TBS on the Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) score in persons with early stage AD. 
2. To estimate the effect of rs-fMRI-guided TBS on the Geriatric Depression Score (GDS) in 
persons with early stage AD. 
3. To identify and estimate the effect of rs-fMRI-guided TBS on two additional 
dysfunctional parcellations within the default modal network (DMN), central executive 
network (CEN), and salience network (SN) in persons with early stage AD. 
4.2 
OVERVIEW – STUDY PROCEDURES/DATA COLLECTION 
Early AD (MCI and Mild AD) patients will be recruited from a multidisciplinary dementia clinic. 
Patients will receive TMS treatment and data will be obtained for cognitive measures and 
imaging. This research investigation will take place at the Center for Memory and Aging at the 
HealthPartners Neuroscience Center (multidisciplinary dementia clinic).   
4.3 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed study visits 
and assessments.  

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5 
STUDY POPULATION 
 
The study will enroll 10 subjects with a diagnosis of early stage AD (mild cognitive impairment 
or mild AD).  Those patients where fMRI is contraindicated (e.g. implantable device, pacemaker, 
metallic implants, etc.) or who are unable to tolerate sitting for a one-hour fMRI will be 
excluded from the study.   
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. 
Established diagnosis of MCI/mild AD 
2. 
Evidence for CNS amyloidosis (e.g., Amyloid PET or CSF biomarkers consistent with 
AD) 
3. 
Prior brain imaging performed 
4. 
MMSE >24 
5. 
CDR 0.5-1 
6. 
Stable dose of cholinesterase inhibitors and memantine for at least one month 
7. 
Subjects are between 40-90 years of age 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Non-AD dementia including, but not limited to, Lewy body dementia, frontotemporal 
dementia, vascular dementia, Jakob-Creutzfeldt disease, etc. 
2. Inability to tolerate rs-fMRI 
3. Contraindication of rs-fMRI due to implants or metal 
4. Seizure disorder 
 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
 
5.4 
SCREEN FAILURES 
Research Referral Form: This will be filled out by PI or qualified designee to assess the 
appropriateness of TMS in these patients. Patients will be considered ineligible and not screened 
if they do not meet one or more of the criteria. 
 
Pre-screening Phone Call: All potential participants will undergo a pre-screening phone or a video 
call to determine whether they meet the inclusion/exclusion criteria. Patients will be considered 
ineligible if they do not meet one or more of the inclusion/exclusion criteria during pre-screening. 

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We will collect information on why participants are ineligible or decide not to move forward with 
the trial.  
 
Screen failures are defined as participants who are considered eligible during the pre-screening 
phone call, but it was subsequently determined that they do not meet one or more of the 
inclusion/exclusion criteria. We will collect information on why participants screen fail or decide 
not to move forward with the trial.  
 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
All subjects will be recruited from the Center for Memory and Aging clinic.  An Epic-based list 
has been created with subjects having either an MCI or early AD diagnosis.  Patients and their 
caregivers will be presented with the option of participating in the study by the PI including 
providing a brochure at the clinic visits. Participants with clinic visits will meet with research 
staff. Other patients will be mailed/e-mailed a letter and flyer/brochure.  An informed consent 
form will be provided to those individuals expressing interest in the study.  A video or phone 
encounter will be arranged to provide additional details of the study and informed consent 
  
To reach our target enrollment, we anticipate that we will need to screen 40 people.  
 
Remuneration: Participants will be provided gift cards totaling $100 per subject. The gift cards 
will be provided at the end of the study for completing all the study visits. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
All subjects will receive TMS treatment with intermittent theta burst stimulation (iTBS). The 
TMS devices are non-significant risk devices, in line with the criteria for exception from an IDE.  
 
The TMS device to be used in this study is the MagVenture TMS Therapy® (MagPror30/Theta 
Burst option) with theta Burst stimulation (See User Guide). A B65-coil – FDA cleared figure 8 
coil will be utilized for iTBS treatment. In 2018, MagVenture received FDA clearance for the 3 
minute protocol which we market under the trademarked name Express TMS® for Major 
depressive disorder (Blumberger et al., 2018), but TMS is not approved by the FDA for 
symptoms in Alzheimer’s disease.  
 

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Localite Neuro Navigator will utilized to stimulate brain regions identified by the Infinitome 
software and allows correct positioning of the patient and coil 
(https://www.magventure.com/tms-research/localite-neuronavigation).  
 
6.1.2 
DOSING AND ADMINISTRATION 
 
There will be a total of 25 intermittent theta burst sessions (iTBS) spread evenly across 5 
treatment visits (5 sessions per treatment visit), all distributed over a two-week period (#3 
treatment visits during week 1 and #2 during week 2).   Intermittent theta burst sessions will be 
administered at the following settings, which have been used in a standardized manner by our 
collaborators in their TMS clinic:  
Table 3: TMS Treatment Parameters 
Resting Motor Threshold  
80% 
# of Pulses/Session 
1200 pulses (40 cycles x 10 burst pulses x 3 
pulses per burst pulse) 
Inter-Train Interval  
8 sec 
Pulse Frequency in Burst 
50 Hz 
Session Length 
15-30 min 
Time between Sessions 
45 min to Hour 
Number of Targets 
3 
Number of Sessions per Day 5 
Treatment Days 
5 
Total Pulses per Day 
18,000 
Total Pulses for Treatment 
90,000 
 
The treatment regime above will be applied to a total of three regions of interest or 
parcellations (right TGd + two other sites found to have greatest # of anomalies).  The interval 
between treatment of separate regions of interest (target) will be 2 minutes. The interval 
between iTBS sessions within the same treatment visit will be 45-60 minutes. Details of the 
operations of TMS and intervention will be included in a SOP or User guide that will be kept on 
site. 
 
During the treatment, the TMS operator will be in the room and trained to activate the 
seizure protocol 
(https://healthpartnersconnect.sharepoint.com/:b:/r/sites/bhc/TMS%20Library/Safety/Emergency%20Management%2
0of%20Seizures%20Standing%20Order.pdf?csf=1&web=1&e=p5h4Gg.   All patients will be screened with 
the TASS screening questions. Vital signs will be monitored prior to and after treatment in 
participants. 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 

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N/A 
 
6.3 
STUDY INTERVENTION COMPLIANCE 
 
Each treatment will be recorded on CRFs developed internally and will be based on 
HealthPartners Behavioral Health Clinic workflow and documents.  
 
6.4 
CONCOMITANT THERAPY 
Medications to be reported in the Case Report Form (CRF) are concomitant prescription 
medications, over-the-counter medications and supplements. Specifically, any medication with 
that increases the risk of seizure will be documented in CRF and judged by the PI if it is allowed 
in the study.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If a clinically significant finding is identified (including, but not limited to changes from baseline) 
after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an 
adverse event (AE). 
 
If the patient develops a seizure, the PI may discontinue the TMS treatment and early 
withdrawal procedures will be performed.  
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may withdraw a participant from the study if: 
• Any medical condition, event or situation occurs such that continued participation in the 
study would not be in the best interest of the subject. 
• The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.   
• Significant study procedure non-compliance  
• Lost-to-follow up; unable to contact subject 
 
7.3 
LOST TO FOLLOW-UP 

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The reason for participant discontinuation or withdrawal from the study will be recorded on the 
relevant CRFs. Subjects who sign the  informed  consent  form and undergo only cognitive 
measures, and not imaging or TMS will not have completed participation and may be replaced.  
A participant will be considered lost to follow-up if he or she fails to attend any scheduled study 
visit and study staff are unable to contact the participant after at least 5 attempts. 
The following actions must be taken if a participant fails to attend any required study visit: 
• Study staff  will attempt  to  contact  the  participant,   reschedule  the  missed  visit,   
counsel  the  participant  on  the  importance  of  maintaining  the  assigned  visit  
schedule  and  ascertain  if the participant wishes to and/or should continue in the 
study.  
• Before a  participant  is  deemed  lost  to  follow-up,  the  investigator  or  designee  will 
make every effort  to  regain  contact  with  the  participant  (where  possible,  telephone  
calls  or  e-mail –  if  no  answer  leave  a  voicemail  on  the  first  and  last  attempt).  
These  contact  attempts  will be documented. 
• Should  the  participant  continue  to  be  unreachable,  he  or  she  will  be  considered  
to  have  withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
STUDY SCHEDULE 
See Figure 1 under protocol summary.  
8.1.1 
SCREENING VISIT (VISIT 1) DAY 0 
 
• This visit may be virtual or in-person at NSC  
• This visit will last about 90 minutes 
• Review, obtain and document consent from subject and caregiver (e-consent) 
• Administer MMSE, CDR 
• Review medical history, demographics to determine eligibility to participate 
• Review history regarding any contraindications for MRI imaging 
• Schedule study visits for individuals who are eligible and available for the duration of the 
study. 
8.1.2 
BASELINE VISIT (VISIT 2) -WEEK 1 (± 7 DAYS) 
• Verify inclusion/exclusion criteria 
• Neuropsychological battery as mentioned in Section 8.2. 
• This visit is at the clinic (HealthPartners Neuroscience Center [NSC]), is about 2 hours. 
This may be extended depending on availability of Imaging slot. 

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• Subject will undergo MRI imaging as mentioned in section 8.2 
• Subject will be screened for TMS safety 
• Review concomitant medications 
• Record any adverse or serious adverse events 
8.1.3 
TREATMENT VISIT (VISTS 3-5 AND VISITS 6,7) (5 DAYS OVER 2 WEEKS, ± 7 DAYS AFTER 
VISIT 2) 
• Verify inclusion/exclusion criteria 
• Motor threshold mapping in Visit 3. Visit 3 will be 5 -7 hours. Visits 4-7 will be 4-6 hours 
each. 
• All visits will be at NSC 
• Subject will receive 5 theta burst stimulation sessions at each of the treatment visits 
• Visits will be on alternating days (weekdays) 
• Review concomitant medications at each visit 
• Record any adverse or serious adverse events at each visit 
8.1.4 
FOLLOW-UP/REPEAT VISIT (VISIT 8)(WEEK 10, 6 WEEKS AFTER VISIT 7 ± 7 DAYS) 
• Verify inclusion/exclusion criteria 
• Neuropsychological battery as mentioned in Section 8.2. 
• This visit is at the clinic (HealthPartners Neuroscience Center [NSC]), is about 2 hours. 
This may be extended depending on availability of Imaging slot. 
• Subject will undergo MRI imaging as mentioned in section 8.2 
• Review concomitant medications 
• Record any adverse or serious adverse events 
8.2 
EFFICACY ASSESSMENTS  
8.2.1 
DEMOGRAPHICS AND MEDICAL HISTORY 
Demographic information will be collected, including: gender, age, race, ethnicity, height, weight, 
BMI, education, dementia diagnosis, co-morbidities (such as Diabetes, Hypertension) and e-mail 
address for consent. 
8.2.2 
MMSE (MINI-MENTAL STATUS EXAMINATION) 
Originally developed in 1976 by Folstein, the MMSE is a paper-based test commonly used in 
clinical and research settings (Folstein, Folstein, & McHugh, 1975). A 30 point cognitive screening 
tool that assesses orientation, working memory, short term memory, visuospatial construction, 
and language. This will be used in the screening visit for eligibility of participants in the study 
8.2.3 
CLINICAL DEMENTIA RATING (CDR) 

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The CDR is a 5-point scale used to characterize six domains of cognitive and functional 
performance applicable to Alzheimer disease and related dementias: Memory, Orientation, 
Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care 
http://alzheimer.wustl.edu/cdr/aboutcdr.htm. The necessary information to make each rating is 
obtained through a semi-structured interview of the patient and a reliable informant or 
collateral source (e.g., family member). The CDR table 
(http://knightadrc.wustl.edu/cdr/PDFs/CDR_Table.pdf) provides descriptive anchors that guide 
the clinician in making appropriate ratings based on interview data and clinical judgment. In 
addition to ratings for each domain, an overall CDR score may be calculated through the use of 
an algorithm. This score is useful for characterizing and tracking a patient's level of 
impairment/dementia:  
CDR-0.5 = very mild dementia  
CDR-1 = mild  
CDR-2 = moderate  
CDR-3 = severe  
In addition, the total CDR ratings for each of the six cognitive/functional domains can be added 
to create a CDR sum of boxes (SOB). This will be used in the screening visit for eligibility of 
participants in the study 
8.2.4 
NEUROPSYCHOLOGICAL ASSESSMENTS 
All enrolled subjects will undergo the following cognitive scales.  These will be administered by 
the research staff trained in these assessments using instructions specific for tests under the 
guidance/ supervision of the study neuropsychologist. 
8.2.4.1 
REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATE (RBANS)  
The RBANS is a brief, individually administered neurocognitive battery measuring immediate 
and delayed memory, attention, language, and visuospatial skills. The RBANS is a “pencil-and-
paper” test and requires only a stimulus booklet and record form for administration and 
scoring. It is specially designed for repeat evaluations and includes alternate forms to control 
for practice effects related to content.  The measure is broadly used for clinical diagnostic 
purposes and has also been increasingly employed as an endpoint in clinical trial investigations 
of medications believed to impact neurocognitive status. The RBANS will be administered by a 
research staff member to early stage AD subjects at baseline and 6 weeks after treatment to 
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8.2.5 
MOOD ASSESSMENTS 
8.2.5.1 
GERIATRIC DEPRESSION SCALE (GDS) 
The GDS is a screening measure for depression in older patients 
(http://neurosciencecme.com/library/rating_scales/depression_geriatric_ long.pdf).  The scale 
will be administered by research staff at baseline and 6 weeks after TBS treatment. 
8.2.6 
MRI IMAGING 
Subjects will undergo MRI imaging at HealthPartners Neuroscience Center. Subjects will be 
screened for any contraindications for MRI. Subjects will undergo a protocol based on 
recommendation by Omniscent (o8t MR Acquisition Recommendations). We anticipate 15 
minutes of scan run time using a 3T Siemens Skyra scanner and the following images will be 
obtained. 
1) High-resolution multi-scan directional diffusion scan, which is most similar to a diffusion 
tensor image (DTI) acquisition - Specifically, diffusion weighted imaging with the 
following acquisition parameters will be used: 2 mm x 2 mm x 2 mm voxels, FOV = 25.6 
cm, matrix = 128 mm x 128 mm, slice thickness = 2.0 mm, one non-zero b-value of b = 
1000, 40 directions, and gap = 0.0 mm.  
2) EPI BOLD rs-fMRI - A resting-state fMRI as a T2-star EPI sequence, with 3 x 3 x 3-mm 
voxels, 128 volumes/run, a TE = 27ms, a TR = 2.8s, a field of view – 256mm, a flip angle = 
90°  
3) Anatomical Scan –T1 Weighting 
All images will be de-identified and uploaded to the infintome cloud-based server to be 
analyzed. Internal guidelines/best practices based on infinitome user manual will be developed 
for transfer, obtaining accounts, uploading of raw images and downloading of analyzed data.  
This will be transferred to the Localite Neuro Navigator to help with target areas for TMS 
Treatment 
8.2.7 
CONNECTOMIC ANALYSIS 
All subject images will be processed using the infinitome tool. This will be used to conduct a 
connectomic analysis to identify large scale brain networks.  
The Infinitome tool creates a machine learning-based, subject specific version of the Human 
Connectome Project-Multimodal Parcellation (HCP-MMP1) atlas based upon diffusion 
tractography structural connectivity (Figure 3).  All data uploaded to the cloud is de-identified.  
This novel method was created by training a machine learning model on 200 normal subjects by 
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each brain and the structural connectivity calculated between every pair of this atlas and a set 
of ROI containing 8 subcortical structures per hemisphere and the brainstem based on the 
streamlines which terminated within an ROI.  To ensure this atlas is applicable to pathologically 
distorted brains, a machine-learning tool takes the individual’s DTI or CSD tractography and 
locates every voxel and reassigns them to an area that fits more accurately with the structural 
connection to create a personalized adjusted atlas. The personalized patient atlas is used to 
subset the resting-state and CSD tractography data to create Structural and Functional 
connectivity matrices. When these matrices are compared to other individuals using machine-
learning, an output of structural and functional anomaly matrices demonstrates the abnormal 
connectivity in this subject’s brain (Figure 4). Abnormal connectivity is determined as a 3-sigma 
outlier for that correlation, after excluding the highest variance 1/3 of pairs, to further reduce 
the false discovery rate. Assignment of parcellations to various large-scale brain networks is 
based on several previous coordinate based meta-analysis and matching the HCP-MMP1 
parcellations to the coordinates of the ALE in MNI space, which has been previously published 
(or in review presently) by our group. 
 
 

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8.3 
SAFETY AND OTHER ASSESSMENTS 
8.3.1 
TRANCRANIAL MAGNETIC STIMULATION ADULT SAFETY SCREEN (TASS) 
Screening questionnaire to assess the safety of TMS prior to treatment. This will be conducted 
at visits 1 and 2.  
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.4.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event is any symptom, sign, illness or experience which develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events 
if the abnormality:  
Figure 4: Connectomic Analysis 
Figure 3: Anomaly Matrix for LSBNs in Temporal Lobe 

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• 
Results in study withdrawal.  
• 
Is associated with clinical signs or symptoms.  
• 
Leads to treatment or to further diagnostic tests.  
• 
Is considered by the investigator to be of clinical significance.  
 
8.4.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
Adverse events are classified as either serious or non-serious. A serious adverse event is any 
event that results in: 
• 
Death. 
• 
Life-threatening situation. 
• 
Hospitalization or prolongation of hospitalization. 
• 
Disability or incapacitation. 
• 
Other events determined by investigator to be medically significant in which subject’s 
well-being is jeopardized (e.g. events that have high likelihood of escalating to the point 
of meeting criteria outlined above) 
8.4.3 
EXPECTEDNESS  
PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study 
intervention. 
8.4.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Upon consenting, a subject is considered to be a participant in the study, and until that person 
either withdraws or completes study, AEs and SAEs will be recorded. The investigational team 
will promptly report any AE/SAE as required per federal guidelines. 
 
8.5 
UNANTICIPATED PROBLEMS 
8.5.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human 
Research Protections (OHRP). OHRP considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
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2. Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.5.2 
UNANTICIPATED PROBLEMS REPORTING  
The PI will report unanticipated problems (UPs) to the reviewing IRB. The UP report will include 
the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number 
• A detailed description of the event, incident, experience, or outcome  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• UPs will be reported to the IRB as soon as possible, but no later than 10 working days 
after the investigator first learns of the event 
9 
STATISTICAL CONSIDERATIONS  
9.1.1 
STATSTICAL PLAN OVERVIEW 
The study population demographics (age, race, etc.) will be described using appropriate 
summary measures (i.e. means, standard deviations, or medians for continuous variables and 
counts or percentages for discrete variables). Disease characteristics (MMSE and CDR) will also 
be summarized to describe our population.  
The primary aim will be assessed by calculating the difference and corresponding 95% 
confidence interval between follow-up and baseline connectivity measures of the TGd 
parcellations. We will conduct a t-test to statistically test if that difference is greater than 0, 
which would indicate a non-null effect of the TBS intervention on those areas of the brain. 
Exploratory aims 1 and 2 will be analyzed similarly to the primary aim.  
For exploratory aim 3, parcellations within the DMN, CEN, or SN associated with ≧4 anomalies 
on the baseline matrix will be considered for the third TBS treatment. We will descriptively note 
whether there are shared anomalous parcellations between study patients. If one area of the 

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brain is anomalous in at least half of the subjects, we will target that area with the third TBS 
treatment for all patients and analyze it similarly the primary aim. If no such area rises to this 
level, we will simply describe changes from baseline for the individual areas treated for each 
patient. 
9.1.2 
POWER ANALYSIS 
From our 4-person pilot study of persons with Alzheimer’s Disease, we calculated the average 
HCP-standardized functional connectivity levels of right TGd with all areas that had non-zero 
functional connectivity. The mean was 0.096 with a pooled standard deviation of 0.033. Given 
this limited preliminary data, we will consider a one standard deviation (0.033) change from 
baseline to be meaningful. With 10 subjects, we have 80% power to detect a 0.033 change from 
baseline if the pooled standard deviation remains similar to our preliminary findings. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
All research study staff will maintain certification in human subject’s protection. All study 
investigators and staff will take an active role in developing procedures to protect against or 
minimize potential risks to the safety and well-being of enrolled participants. Potential research 
subjects will be informed that participation in this study is voluntary and will not be discriminated 
against if they choose not to participate. Written informed or electronic consent and assent will 
be obtained from participants, and family member/caregivers or legally authorized 
representatives (LAR). Participants will be asked to describe in their own words the study’s 
expectations. Subjects will be informed that they can withdraw from the study at any time and 
will be given a copy of the consent form. Subjects will have written assurance that while de-
identified individual subject data may be available to other researchers for research purposes, or 
used to improve the software program, only a summary of the results will ever be published or 
otherwise publicly released. Subjects will be assured that participation in the study will be strictly 
confidential, that any identifying information will be available to the study staff only, and that no 
identifying information concerning the data and results will be made known. 
 
Potential research subjects will be informed that participation in this study is voluntary and that 
their decision to participate will not reflect upon their relationships with the Center for Memory 
and Aging, Regions Hospital, or HealthPartners. Subjects will be informed that they can withdraw 
from the study at any time and will be given a copy of the consent form.   
 
With the electronic consent via REDCap the patient/caregiver providing consent will be able to 
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using a signature field in REDCap. After the individual has received the link and can view the 
consent form, the research staff member will go through the consent form with the individual as 
would be typical in person. Following the consent conversation, the staff member will sign and 
e-mail the consent and HIPPA electronically to the patient. The patient will electronically sign, 
certify, and submit the consent and HIPPA in REDCap. A fully executed PDF copy of the consent 
and HIPPA will be provided electronically to the patient for their records as well as saved via the 
auto-archiver function in REDCap. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to regulatory authorities.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB).  Study participants will 
be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, the safety and oversight monitor(s), and the sponsor(s). This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a 
specific study participant will be held in strict confidence within the research team. No 
personally-identifiable information from the study will be released to any unauthorized third 
party without prior written approval of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
All study regulatory binders will be stored in a locked file cabinet within a secure office. The 
internal study monitor, representatives of the IRB, or regulatory agencies, may inspect all 
documents and records required to be maintained by the investigator, for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor/funding agency requirements. 

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A unique study ID code unrelated to the medical record number or other study subject-specific 
information will be assigned to each patient and used to link data from various sources and 
needed for analysis.  The study number will be used on the RedCap database and Infinitome 
Program.  All imaging data uploaded from the NSC research site will be de-identified and 
uploaded to the Infinitome cloud-based server.   
 
Infinitome program uses an industrial grade cyber security that is superior to what is offered at 
the leading medical device companies.  No personal health information is stored on servers and 
only de-identified scans are stored on a dedicated edge node on encrypted MinIO instances.  
Patient data is only accessed through authenticated calls form Kubernetes pods contained in the 
VPC.  The web service requires user authentication.  Only the data related to a specific facility 
can be retrieved through authenticated calls and are restricted to their use 
 
The PI will ensure all mechanisms used to share data will include proper plans and safeguards for 
the protection of privacy, confidentiality, and security for data dissemination and reuse (e.g., all 
data will be thoroughly de-identified and will not be traceable to a specific study participant). 
Plans for archiving and long-term preservation of the data will be implemented, as appropriate.  
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Michael Rosenbloom, MD 
HealthPartners Neuroscience Center 
295 Phalen Blvd. St. Paul, MN 55130 
 
10.1.5 SAFETY OVERSIGHT 
There is no Data Safety Monitoring Board for this study, as the risks are minimal. We plan to 
have a data safety officer (DSO), who will be an independent individual and is not participating in the 
trial and have no direct affiliation with the research team. The DSO responsibilities include but are not 
limited to the following: 
• 
Monitoring the study for compliance to the protocol. 
• Stopping the study if the rate of SAE’s raises safety concerns. 
Frequency of the DSO meetings, responsibilities, and procedures will be documented prior to initiation 
of the study. 
10.1.6 CLINICAL MONITORING 
N/A, refer to next section 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 

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Study staff will perform internal quality management of study conduct, data collection, 
documentation and completion. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process 
and 10% of the completed consent documents. Feedback will be provided to study staff to ensure 
proper consenting procedures are followed. 
 
Protocol Deviations – The study team will review documented protocol deviations on an ongoing 
basis and will implement corrective actions when the quantity or nature of deviations are 
deemed to be at a level of concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all study 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
the sponsor/funding agency, and inspection by local and regulatory authorities. 
10.1.8 DATA HANDLING AND RECORD KEEPING  
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the research study staff under the supervision of the 
PI. The PI will be responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. Data collection/reporting tools will be developed internally (i.e. CRFs or 
eCRFs (RedCap Database) and source documents).  Data collected and stored electronically will 
remain confidential and secure (e.g. secured server, encrypted data, password protected file). 
10.1.8.2 STUDY RECORDS RETENTION  
Investigator records will be retained in accordance with regulatory, organizational and sponsor 
or grantor requirements.  All records will be maintained securely with limited access. Disposal of 
investigator records will be done in such a manner that no identifying information can be linked 
to research data. 
10.1.9 PROTOCOL DEVIATIONS  
Plans for detecting, reviewing, and reporting deviations from the protocol should be described. 
A This protocol defines a protocol deviation as any noncompliance with the study protocol. The 
noncompliance may be either on the part of the participant, the investigator, or the study site 
staff. As a result of deviations, corrective actions will be developed by the site and implemented 
promptly. 
10.1.10 PUBLICATION AND DATA SHARING POLICY 
This study will be registered at ClinicalTrials.gov, and results information from this study will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. 
 

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Data from the de-identified images may be utilized by Omniscent for improvement of Infinitome 
program and potential future imaging research studies. 
10.1.11 CONFLICT OF INTEREST POLICY 
The study leadership in conjunction with HealthPartners Institute has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
Sep 2 2021 
 
Initial Version 
2.0 
March 30 
2022 
Clarification of Number of Treatment 
sessions per day 
In order for subjects to receive 
the goal 6000 pulses per target 
per treatment day, they will 
require a total of 5 sessions per 
treatment day 
2.1 
April 26 
2022 
Clarification of treatment visits over 
two weeks 
The TMS treatment visits have 
been updated to reflect 
alternating days. This is to 
provide flexibility for scheduling 
visits for patients and easy 
viewing on the consent. No 
change in the number of 
treatment visits 
3 
May 18 
2023 
Change in PI -from Dr. Rosenbloom 
to Dr. Kashyap 
Dr. Rosenbloom is leaving HP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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