A Single Arm Study of Resting State Functional Magnetic Resonance Imaging (Rs-fMRI)-Guided Theta Burst Stimulation (TBS) in Primary Progressive Aphasia (PPA)
Phase: NA
Conditions: Primary Progressive Aphasia
Sponsor: HealthPartners Institute

  
A Single Arm Study of Resting State Functional Magnetic 
Resonance Imaging (rs-fMRI)-Guided Theta Burst 
Stimulation (TBS) in Primary Progressive Aphasia (PPA) 
SHORT TITLE: TMS PILOT IN PPA 
  
Protocol Number: Version 2.0 
National Clinical Trial (NCT) Identified Number:   
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 18th, 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agreement by the recipient that no unpublished information contained herein will be published 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 
CONFIDENTIALITY STATEMENT ............................................................................................................... iii 
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 ......................................................................................................................... 6 
2.1 
Study Rationale and Background ......................................................................................... 6 
2.2 
Risk/Benefit Assessment .................................................................................................... 9 
 
Known Potential Risks ....................................................................................... 9 
 
Known Potential Benefits ................................................................................ 10 
 
Assessment of Potential Risks and Benefits ......................................................... 10 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................... 11 
4 
STUDY DESIGN ........................................................................................................................ 12 
4.1 
Overall Design ............................................................................................................... 12 
4.2 
Overview – study procedures/data collection ...................................................................... 13 
4.3 
End of Study Definition .................................................................................................... 13 
5 
STUDY POPULATION ................................................................................................................ 13 
5.1 
Inclusion Criteria ............................................................................................................ 13 
5.2 
Exclusion Criteria ............................................................................................................ 13 
5.3 
Lifestyle Considerations ................................................................................................... 14 
5.4 
Screen Failures............................................................................................................... 14 
5.5 
Strategies for Recruitment and Retention ........................................................................... 14 
6 
STUDY INTERVENTION .............................................................................................................. 15 
6.1 
Study Intervention(s) Administration ................................................................................. 15 
 
Study Intervention Description ......................................................................... 15 
 
Dosing and Administration............................................................................... 16 
6.2 
Measures to Minimize Bias: Randomization and Blinding ....................................................... 16 
6.3 
Study Intervention Compliance ......................................................................................... 16 
6.4 
Concomitant Therapy ...................................................................................................... 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL .......... 17 

  
7.1 
Discontinuation of Study Intervention ................................................................................ 17 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................................ 17 
7.3 
Lost to Follow-Up ........................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 18 
8.1 
Study Schedule .............................................................................................................. 18 
 
SCREENING VISIT (VISIT 1) Day 0 ....................................................................... 18 
 
Baseline visit (Visit 2) -Week 1 (± 7 days) ............................................................ 18 
 
Treatment visit (ViSTV 3-5 and visits 6,7) (5 days over 2 weeks, ± 7 days after visit 2).. 19 
 
follow-up/repeat visit (visit 8)(week 10, 4 weeks after visit 7 ± 7 days) ..................... 19 
8.2 
Efficacy Assessments ....................................................................................................... 19 
 
Demographics and medical history .................................................................... 19 
 
MMSE (Mini-mental status examination) ............................................................ 19 
 
Neuropsychological assessments ...................................................................... 20 
 
MRI Imaging.................................................................................................. 21 
 
connectomic Analysis ..................................................................................... 22 
8.3 
Safety and Other Assessments .......................................................................................... 23 
 
Trancranial magnetic stimulation adult safety screen (TASS) .................................. 23 
8.4 
Adverse Events and Serious Adverse Events ........................................................................ 23 
 
Definition of Adverse Events (AE) ...................................................................... 23 
 
Definition of Serious Adverse Events (SAE) .......................................................... 23 
 
Expectedness ................................................................................................ 24 
 
Time Period and Frequency for Event Assessment and Follow-Up ........................... 24 
8.5 
Unanticipated Problems .................................................................................................. 24 
 
Definition of Unanticipated Problems (UP).......................................................... 24 
 
Unanticipated Problems Reporting .................................................................... 25 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 25 
 
Statstical plan overview .................................................................................. 25 
 
power analysis .............................................................................................. 25 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................................ 26 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 26 
 
Informed Consent Process ............................................................................... 26 
 
Study Discontinuation and Closure .................................................................... 26 
 
Confidentiality and Privacy .............................................................................. 27 
 
Key Roles and Study Governance ...................................................................... 28 

  
 
Safety Oversight ............................................................................................ 28 
 
Clinical Monitoring ......................................................................................... 28 
 
Quality Assurance and Quality Control ............................................................... 28 
 
Data Handling and Record Keeping .................................................................... 29 
 
Protocol Deviations ........................................................................................ 29 
 
Publication and Data Sharing Policy ................................................................... 30 
 
Conflict of Interest Policy ................................................................................. 30 
10.2 
Additional Considerations ................................................................................................ 30 
 

A23-078 TMS Pilot in PPA 
 
Version 2.0 
PI: Bhavani Kashyap, MBBS, PhD 
 
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. 
 
 

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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 
 
Investigator Contact Information 
Affiliation: HealthPartners Neuroscience Center 
Address: 295 Phalen Blvd. 
       St. Paul, MN 55130 
   Mailstop 41200A 
Telephone: (651) 495-6358 
Email: Bhavani.X.Kashyap@HealthPartners.com 
 
Signed: 
 
Date: 
 
 
Name:  Marcel Hungs, MD 
Title: 
Neurologist, HealthPartners Center for Memory and Aging 
 
 
Investigator Contact Information 
Affiliation: HealthPartners Neuroscience Center 
Address: 295 Phalen Blvd. 
       St. Paul, MN 55130 
   Mailstop 41200A 
Telephone: (651) 495-6358 
Email: Marcel.G.Hungs@HealthPartners.com 
 
 
 

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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 Primary 
Progressive Aphasia (PPA) 
IRB Number: 
 
Study Description: 
Frontotemporal degeneration (FTD) is a non-Alzheimer’s dementia that 
is the 2nd most common cause of dementia in the United States. FTD may 
present with focal language symptoms that are clinically described as 
primary progressive aphasia (PPA).  There are two types of PPA 
associated with FTD—semantic variant primary progressive aphasia (SV-
PPA) and nonfluent/agrammatic variant primary progressive aphasia 
(NFV-PPA).  Both diseases are progressive neurodegenerative disease 
processes that compromise dominant hemisphere large scale brain 
network function, ultimately resulting in mutism. There are currently no 
FDA-approved treatments for PPA and management is mostly 
supportive.  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 PPA. In our prior studies of AD and LBD subjects, we have 
determined that the anterior temporal pole (area TGd and TGv) is an 
area that is commonly dysfunctional in dementia.  We have already 
embarked upon an fMRI guided study of iTBS in early stage Alzheimer’s 
disease where subjects received a series of 5 treatments to distinct brain 
regions inclusive of area TGd.   We propose a case study of 3 PPA studies 
where rs-fMRI is applied to the large-scale language networks  
Objectives: 
 
 
Primary Aim 
1.  To describe the effect of rs-fMRI-guided TBS on connectivity 
dysfunction within the large scale language networks in persons 
with PPA. 
Exploratory Aims 
1. To describe the effect of rs-fMRI-guided TBS on Naming (Boston 
Naming Test) in PPA due to FTD 
2. To describe the effect of rs-fMRI-guided TBS on Receptive 
Language (Token Test and Peabody Picture Verbal Vocabulary 
Test) in PPA due to FTD 
3. To describe the effect of rs-fMRI guided TBS on Fluency (Animal 
naming and Controlled Oral Word Association Test [COWAT]) in 
PPA due to FTD  

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4. To describe the effect of rs-fMRI guided TBS on Repetition (WAB 
Sentence Repetition) 
Endpoints: 
Primary Endpoint: Connectivity Measures of the TGd/STV/55b 
parcellations at baseline and post-treatment 
Exploratory Endpoints: 
• 
BNT at baseline and post-treatment 
• 
Token Test at baseline and post-treatment 
• 
PPVT at baseline and post-treatment 
• 
Animal naming at baseline and post-treatment 
• 
COWAT at baseline and post-treatmnet 
• 
WAB sentence repetition at baseline and post-treatment 
Study Population: 
The study will enroll 3 subjects with a diagnosis of primary progressive aphasia 
Inclusion criteria:  
1. Established diagnosis of NFV-PPA and SV-PPA based on criteria (Gorno-
Tempini et al., 2011) 
2. Prior brain imaging performed 
3. MMSE>10 
Subjects are between 40-90 years of age 
Exclusion Criteria: 
1. Non-FTD neurodegenerative comorbidities, (eg AD, Lewy body 
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  
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 left TGd, STV, and 55b 
regions.    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 6 months 
Participant 
Duration: 
8-10 weeks 
1.2 
SCHEMA 

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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 8  
  
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  
  
  
  
  
TMS Safety Questionnaire  
X  
X  
  
  
  
Cognitive Battery  
  
X  
  
X  
  
iTBS Treatment  
  
  
X  
  
  
MRI Imaging  
  
X  
  
X  
  
Adverse Events/Serious 
Adverse Events  
X  
X  
X  
X  
X  
  
 
 
Figure 1: Study Visit/Workflow 
Screening 
Baseline 
rs-fMRI/ 
RBANS & 
GDS 
1 week 
+/-7 days 
1 week 
+/-7 days 
Treatment
TBS (5 
days over 
2 wks) 
4 weeks 
+/-7 days 
Repeat  
rs-fMRI/ 
RBANS & 
GDS 

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INTRODUCTION 
2.1 
STUDY RATIONALE AND BACKGROUND 
Frontotemporal degeneration (FTD) is a spectrum of neurodegenerative disease characterized 
by either behavioral changes or primary progressive aphasia and represents the second most 
common cause of young onset dementia.  When impacting the right hemisphere, FTD presents 
as a behavioral variant with disinhibition, apathy, loss of empathy, hyperorality, and repetitive 
motor behaviors whereas involvement of the left hemisphere results in primary progressive 
aphasia (PPA).  PPA due to FTD is characterized by two clinical phenotypes: the semantic variant 
(SV-PPA) and the nonfluent/agrammatical variant (NFV-PPA).  We are most interested in the 
application of TMS to these two conditions, which have well-established localized 
neuroanatomical localizations that correlate with clinical symptoms.  
The clinical phenotype associated with SV-PPA is marked by language impairments in naming, 
object knowledge, and single-word comprehension (Kerchner & Rosenbloom, 1999). Words 
may be at the tip of the tongue and readily recognized from a list, but a patient with svPPA 
loses not only the word itself but also the semantic knowledge surrounding the noun in 
question.  Neuroanatomically, this condition is defined by progressive neurodegeneration of 
the left anterior temporal pole (or areas TGd/TGv), an integration center for neural pathways 
from auditory, visual, and somatosensory brain regions.  With time, SV-PPA neurodegeneration 
may spread to the contralateral right anterior pole (areas R TGd/TGv), leading to symptoms of 
prosopagnosia, food fats, mental rigidity, and disinhibition (Rabinovici & Miller, 2010).  fMRI 
studies have further implicated a disconnection of the left temporal pole from large scale brain 
networks in SV-PPA (Montembeault et al., 2019).   The underlying neuropathology associated 
with SV-PPA is exclusively tar DNA-binding protein 43 [(TDP-43); (Davies et al., 2005)]. Post-
mortem evaluation typically reveals tau more frequently than TDP-43 pathology (Kerchner & 
Rosenbloom, 1999). 
Similar to SV-PPA, NFV-PPA leads to progressive neurodegeneration localized to the left 
hemisphere and results in compromise of expressive speech and language.  Patients present 
clinically with motor speech dysfunction and effortful, nonfluent speech with shortened phrase 
length, dysarthria, phonemic paraphasias, and speech apraxia. In addition to effortful speech, 
the other key clinical feature is agrammatism, with omissions of articles and other syntactic 
words, leading to speech sometimes described as telegraphic (Gorno-Tempini et al., 2011). The 

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condition localizes within the left hemisphere prefrontal-perisylvian region of the cerebral 
cortex (Gorno‐Tempini et al., 2004).  
There are no FDA-approved treatments available for either SV-PPA or NFV-PPA, both of which 
typically result in death 5+ years from diagnosis.  Treatment for these conditions is mostly 
supportive, consisting of speech therapy, psychosocial support, and management of 
neuropsychiatric symptoms.   
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). 
Omniscient is 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 

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correlations for each region 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).  
Clinical trials applying rs-fMRI-guided TMS to refractory depression have suggested that 
functional imaging may effectively target large scale brain networks of interest, thus more 
effectively treating clinical symptoms (Cole et al., 2019).  Both SV-PPA and NFV-PPA are 
dementing conditions that promote focal neurodegeneration of the large-scale language 
cortical networks within the left hemisphere. Thus, TMS represents a potential symptomatic 
treatment capable of modulating dysfunctional language networks within the frontotemporal 
lobes.  There has been a significant, but limited number of studies evaluating the impact of TMS 
treatment to the DLPFC on language symptoms in these two disease processes.   TMS to the left 
or right DLPFC improved naming accuracy in NFV-PPA subjects (Cotelli et al., 2012). A pilot trial 
of TMS to the left DLPFC in 6 patients with PPA demonstrated improved accuracy on action 
naming tasks 10 min post-treatment (Margolis et al., 2019).    A double-blinded, sham-
controlled study of 20 subjects with PPA due to either SV-PPA or NFV-PPA found that 
personalized targeted of affected language regions improved spontaneous speech and 
enhanced left fronto-parieto-temporal lobe metabolism (Pytel et al., 2021).  
Human Connectome studies have identified three major language networks based on their 
functional connectivity (Rolls, Deco, Huang, & Feng, 2022).; a ventrally based “semantic 
network” inclusive of inferior temporal regions temporal area G dorsal (TGd) and TE1a, which 
participates in semantic representation of objects based upon their visual and reward qualities.  
There is another dorsally based network that includes areas STV, TPOJ1, responsible for 
semantic representations based on auditory and facial motion characteristics.  Finally, a third 
group that largely includes frontal-based structures such as 55b participates in syntax and 
speech output.  Theoretically, TMS targeting of these three areas could be effective in treating 
conditions that result in primary progressive aphasia, regardless of the underlying cause.  Our 
preliminary research at HealthPartners using Infinitome in AD (n=4) and dementia with Lewy 
bodies (n=15) has already shown area TgD (Figure 1) to have abnormal connectivity in persons 
with dementia. 
The present study will enroll 3 subjects with either SV-PPA or NVF-PPA.  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.  TMS will be 

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utilized to target representative areas (area TGd, STV, and 55b) from the three language 
networks.  
Figure 1: Temporal Area Gd  
 
 
2.2 
RISK/BENEFIT ASSESSMENT   
 
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 

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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) 
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. 
 
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. 
 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
We believe the potential risks to the participants in this study are minimal. 

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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 
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 
 
 
1. To describe the effect of rs-
fMRI-guided TBS on 
connectivity dysfunction 
within the large scale 
Connectivity measures of the left TGd, 
55b, and STV parcellations at baseline 
and post-treatment 
Infinitome processed 
rs-fMRI data that is 
targeted with TMS 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
language networks in 
persons with PPA.  
Exploratory  
 
 
1. To describe the effect of rs-
fMRI-guided TBS on 
Naming (Boston Naming 
Test) in PPA due to FTD 
2. To describe the effect of rs-
fMRI-guided TBS on 
Receptive Language (Token 
Test and Peabody Picture 
Verbal Vocabulary Test) in 
PPA due to FTD  
3. To describe the effect of rs-
fMRI guided TBS on 
Fluency (Animal naming 
and Controlled Oral Word 
Association Test) in PPA 
due to FTD   
4. To describe the effect of rs-
fMRI guided TBS on 
Repetition (WAB Sentence 
Repetition)  
 
1. BNT at baseline and post-
treatment 
 
 
 
 
2. Token Teste/PPVT at baseline 
and post-treatment 
 
 
 
 
3. Animal naming and COWAT 
at baseline and post-
treatment 
 
 
 
4. WAB Sentence repetition at 
baseline and post-treatment 
Provide pilot data for 
larger trials. 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
This investigation is a prospective single arm treatment trial in PPA. 
Primary Aim  
1. To describe the effect of rs-fMRI-guided TBS on connectivity dysfunction within the 
large scale language networks in persons with PPA.  
 
Exploratory Aims  
1. To describe the effect of rs-fMRI-guided TBS on Naming (Boston Naming Test) in PPA 
due to FTD  
2. To describe the effect of rs-fMRI-guided TBS on Receptive Language (Token Test and 
Peabody Picture Verbal Vocabulary Test) in PPA due to FTD  
3. To describe the effect of rs-fMRI guided TBS on Fluency (Animal naming and Controlled 
Oral Word Association Test) in PPA due to FTD   

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4. To describe the effect of rs-fMRI guided TBS on Repetition (WAB Sentence Repetition) 
 
4.2 
OVERVIEW – STUDY PROCEDURES/DATA COLLECTION 
PPA patients will be recruited from community, referrals, support groups, The Center for 
Memory and Aging Clinic, or other health systems/research centers (i.e., Mayo 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.  
 
5 
STUDY POPULATION 
The study will enroll 3 subjects with a diagnosis of PPA (SV-PPA and NFV-PPA) 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 NFV-PPA and SV-PPA based on criteria (Gorno-Tempini et al., 
2011) 
2. Prior brain imaging performed 
3. MMSE>10 
4. 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: 

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1. Non-FTD dementia including, but not limited to Alzheimer’s, disease, 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. 
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 
 
CMA CLINIC 
Subjects will be recruited from the Center for Memory and Aging clinic.  An Epic-based list has 
been created with subjects having either a SV-PPA or NFV-PPA diagnosis.  Patients and their 

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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. 
 
RECRUITMENT FROM COMMUNITY/SUPPORT GROUPS/REFERRALS 
In addition, we plan to recruit from the community, support groups, referrals from other 
research/health systems, as this is a rare form of disorder. Potential participants/anyone who 
refers/ support groups will be provided with approved flyer/brochure in a mail/email. An 
informed consent form will be provided to those individuals expressing interest in the study 
and research staff will reach out to the participant via a phone call.  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 10 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 
 
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 primary progressive aphasia.  
Localite Neuro Navigator will be 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).  

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DOSING AND ADMINISTRATION 
There will be a total of 25 intermittent theta burst sessions spread evenly across 5 treatment visits (5 
sessions per treatment visit), all distributed over a two-week period.   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 (left TGd, left 55b, and left STV).  The interval between treatment of separate 
regions of interest (target) will be at least 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%20of%20Seizur
es%20Standing%20Order.pdf?csf=1&web=1&e=p5h4Gg.   All patients will be screened with the TASS 
screening questions.  
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
N/A 
6.3 
STUDY INTERVENTION COMPLIANCE 

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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 with an 
oversight by study physician 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.  
 
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 
• 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. 
 
BASELINE VISIT (VISIT 2) -WEEK 1 (± 7 DAYS) 
• Verify inclusion/exclusion criteria 

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• 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 
• Subject will be screened for TMS safety 
• Review concomitant medications 
• Record any adverse or serious adverse events 
 
TREATMENT VISIT (VISTV 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 
 
FOLLOW-UP/REPEAT VISIT (VISIT 8)(WEEK 10, 4 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  
 
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. 
 
MMSE (MINI-MENTAL STATUS EXAMINATION) 

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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 
 
 
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. 
8.2.3.1 
LANGUAGE TESTV 
Boston Naming Test (BNT):  This test introduced in 1983 by Edith Kaplan, Harold Goodglass and 
Sandra Weintraub (Goodglass, Kaplan, & Weintraub, 1983) is a widely used neuropsychological 
assessment of confrontational word retrieval in individuals with aphasia or other language 
disturbance caused by stroke, Alzheimer’s disease or frontotemporal dementia.  The BNT 
contains 60 line drawings graded in difficulty and is one of the most sensitive test for detecting 
language impairment in SV-PPA.  
Token Test: The Token Test is used to identify and evaluate receptive language dysfunction 
associated with aphasias. The evaluation consists of a series of commands involving 20 tokens 
of different shapes, size, and color is presented in increasing complexity from "touch the small 
red square" to "put the large green circle under the small yellow square, before you touch the 
white circle” (De Renzi & Vignolo, 1962). 
Peabody Picture Verbal Vocabulary Test (PPVT): The Peabody Picture Vocabulary Test measures 
listening and understanding of single-word vocabulary.  It was developed for individuals 2 years 
6 months old through greater than 90 years old and measures the lexicon of words that a 
person can understand.  Examinees see a page on an easel with four-color pictures. For each 
item, the examiner says a word, and the examinee responds by selecting one picture out of four 
that best illustrates that word’s meaning. Because the examinee points to the appropriate item, 
the test requires no reading, writing, or expressive verbal language. Thus, it can be used with 
nonreaders and those without fluent verbal abilities. The test is untimed and individually 
administered (Eigsti, 2021). 

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Animal Naming: The Animal Naming Test (ANT) is an analysis of semantic fluency consisting of 
saying as many animal names as possible within one minute.  
Controlled Oral Word Association Test: The Controlled Oral Word Association Test [COWAT; 
(Eigsti, 2021)] is a verbal fluency test that measures spontaneous production of words 
belonging to the same category or beginning with some designated letter. There are two 
commonly used forms of the test, one using the letters F, A, and S, and the other using C, F, and 
L.  
WAB Sentence Repetition: The WAB assesses fluency and information content of spontaneous 
speech, comprehension, naming, repetition, reading, and writing as well as “performance” 
tasks such as praxis, calculation, drawing, block design, and Raven's colored progressive 
matrices. Testing in this study will focus on sentence repetition. 
Raw and normative scores for each test will be reported as appropriate.  
 
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.  

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This will be transferred to the Localite Neuro Navigator to help with target areas for TMS 
Treatment 
 
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 
first processing T1 and DT images.  An HCP-MMP1 atlas in NIFTI MNI space is then warped onto 
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 
Figure 2: Connectomic Analysis 

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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. 
8.3 
SAFETY AND OTHER ASSESSMENTS 
 
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 
 
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:  
• 
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.  
 
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. 
Figure 3: Anomaly Matrix for LSBNs in Temporal Lobe 

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• 
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) 
 
EXPECTEDNESS  
PI, along with study physician 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. 
 
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 
 
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 
population being studied; 
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. 

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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  
 
STATSTICAL PLAN OVERVIEW 
The study sample demographics (age, race, etc.) and baseline measurements (e.g., MMSE) will 
be displayed in tabular form, and described using appropriate summary measures (i.e. means, 
standard deviations, or medians for continuous variables and counts or percentages for discrete 
variables).  
The primary aim will be assessed by calculating the difference and corresponding 95% 
confidence interval between baseline and follow-up connectivity measures of the TGd, STV, and 
55b parcellations.  
The exploratory aims will be analyzed by calculating a difference in pre/post scores and 
corresponding 95% confidence interval for each cognitive test.   
 
POWER ANALYSIS 
This study will include only 3 subjects and so no power analysis will be performed  

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 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 
review the consent form themselves and sign electronically with a stylus, touch screen, or cursor 
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. 
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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. 
 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. 
 
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 

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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.  
 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Bhavani, Kashyap, MBBS, PhD 
HealthPartners Neuroscience Center 
295 Phalen Blvd. St. Paul, MN 55130 
 
Study Physician 
Marcel G Hungs 
HealthPartners Neuroscience Center 
295 Phalen Blvd. St. Paul, MN 55130 
 SAFETY OVERSIGHT 
There is no Data Safety Monitoring Board for this study, as the risks are minimal. PI, and the  
study physician will oversee the safety of the study.  
 CLINICAL MONITORING 
N/A, refer to next section 
 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. 
 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. 
 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 

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staff. As a result of deviations, corrective actions will be developed by the site and implemented 
promptly. 
 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. 
 
Data from the de-identified images may be utilized by Omniscent for improvement of Infinitome 
program and potential future imaging research studies. 
 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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