Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment
Phase: NA
Conditions: Mild Cognitive Impairment, Mild Neurocognitive Disorder, Cognitive Decline, Mental Deterioration, Cognitive Dysfunction, Memory Decline, Memory Loss, Memory Impairment
Sponsor: Palo Alto Veterans Institute for Research

rTMS-MCI Study Protocol 
Study Protocol 
Noninvasive Cortical Stimulation to Improve Memory 
in Mild Cognitive Impairment (MCI) 
NCT03331796 
Principal Investigator: 
Joy L. Taylor, PhD 
Supported by: 
The National Institute on Aging 
Grant Number:   
1 R01 AG055526 
Note:  Any modification to the final, approved protocol will be annotated in an appendix.  The 
annotation will note the exact words that are changed, the location in the protocol, the date the 
modification was approved by the DSMB and NIH Program Official, and the date it became effective. 
DSMB Approval Date:  November 30, 2017
Last Updated:  September 19, 2019

rTMS-MCI Study Protocol 
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Table of Contents 
Study Protocol 
Page 
PRÉCIS .......................................................................................................................................................... 3 
Objectives, Design and Primary Outcome .............................................................................................. 3 
Interventions and Duration.......................................................................................................................... 3 
Sample Size and Population ......................................................................................................................... 3 
STUDY TEAM ROSTER ............................................................................................................................. 4 
Principal Investigator: Joy L. Taylor, Ph.D. .......................................................................................... 4 
Co-Investigators: J. Wesson Ashford MD, PhD ................................................................................... 4 
Margaret Windy McNerney, PhD ............................................................................................................... 4 
Laura C. Lazzeroni, PhD (Biostatistician) ............................................................................................... 4 
Maheen Adamson, PhD .................................................................................................................................. 4 
Other Significant Contributors .................................................................................................................... 5 
Other Personnel ................................................................................................................................................ 6 
ABBREVIATIONS ....................................................................................................................................... 7 
1 STUDY OBJECTIVES ............................................................................................................................. 10 
1.1 
Primary Objective ............................................................................................................................ 10 
1.2 
Secondary Objectives ...................................................................................................................... 10 
2 BACKGROUND AND RATIONALE .................................................................................................... 10 
2.1 
Background on Mild Cognitive Impairment .......................................................................... 10 
2.2 
Study Rationale ................................................................................................................................. 11 
3 STUDY DESIGN ...................................................................................................................................... 15 
4 SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................................. 17 
4.1 
Inclusion Criteria .............................................................................................................................. 17 
4.2 
Exclusion Criteria ............................................................................................................................. 17 
4.3 
Study Enrollment Procedures ..................................................................................................... 18 
5 STUDY INTERVENTIONS ................................................................................................................... 19 
5.1 
Intervention Device ......................................................................................................................... 19 
5.2 
Schedule and Procedures for Administering the Study Intervention .......................... 20 
5.3 
Mechanisms for Masking (i.e., blinding) Study Interventions ........................................ 22 
5.4 
Concomitant Interventions .......................................................................................................... 23 
5.4.1 Allowed Medications ................................................................................................................. 23 
5.4.2 Required Interventions ............................................................................................................ 23 
5.4.3 Prohibited Medications ............................................................................................................ 23 
5.5 
Adherence Assessment .................................................................................................................. 23 
6 STUDY PROCEDURES .......................................................................................................................... 24 
6.1 
Schedule of Assessments ............................................................................................................... 24 
6.2 
Description of Assessments and Procedures ........................................................................ 26 
6.2.1 In-Person Screening Visit ........................................................................................................ 26 
6.2.2 Enrollment, Randomization, and Baseline Assessments ............................................. 27 
6.2.3 Intervention Visits (Visits 3 – 12) ........................................................................................ 30 
6.2.4 Follow-up Visits (Visits 13, 14 and 15) .............................................................................. 33 
6.2.5 Study Completions, Withdrawals, Early Discontinuations and Terminations .... 34 
7 SAFETY ASSESSMENTS ....................................................................................................................... 35 
7.1 
Expected AEs; Safety screening; Modifications and management if an AE occurs . 35 
7.1.1 MRI ................................................................................................................................................... 35 
7.1.2 Neuropsychological testing and Questionnaires ............................................................ 36 

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7.1.3 Blood draws for analysis of biomarkers and genetics .................................................. 36 
7.1.4 rTMS ................................................................................................................................................. 37 
7.2 
Summary of Safety Assessments ................................................................................................ 38 
7.3 
Adverse Events and Serious Adverse Events ........................................................................ 38 
7.4 
Reporting Procedures .................................................................................................................... 39 
7.5 
Follow-up of Adverse Events ....................................................................................................... 41 
7.6 
Safety Monitoring and other DSMB Reporting ..................................................................... 41 
8 INTERVENTION DISCONTINUATION ............................................................................................. 42 
8.1 
Permanent discontinuation of the study intervention ...................................................... 42 
8.2 
Temporary discontinuation of the study intervention ...................................................... 43 
8.3 
Replacement Subjects and Voluntary Withdrawals ........................................................... 43 
9 STATISTICAL CONSIDERATIONS .................................................................................................... 44 
9.1 
General Design Issues ..................................................................................................................... 44 
9.2 
Sample Size and Randomization ................................................................................................ 46 
9.2.1 Treatment Assignment Procedures ..................................................................................... 46 
9.3 
Interim analyses and Stopping Rules ....................................................................................... 47 
9.4 
Outcomes ............................................................................................................................................. 47 
9.4.1 Primary outcome ........................................................................................................................ 47 
9.4.2 Secondary outcomes .................................................................................................................. 47 
9.5 
Data Analyses ..................................................................................................................................... 48 
10 DATA COLLECTION AND QUALITY ASSURANCE ................................................................... 51 
10.1 Data Management ............................................................................................................................ 51 
10.2 Data Collection Forms .................................................................................................................... 51 
10.3 Quality Assurance ............................................................................................................................ 51 
10.3.1 
Training ..................................................................................................................................... 51 
10.3.2 
Quality Control Metrics ....................................................................................................... 53 
10.3.3 
Protocol Deviations .............................................................................................................. 53 
10.3.4 
Monitoring................................................................................................................................ 53 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................................. 54 
11.1 Institutional Review Board (IRB) Review .............................................................................. 54 
11.2 Informed Consent Forms .............................................................................................................. 54 
11.3 Participant Confidentiality ........................................................................................................... 55 
11.4 Study Discontinuation .................................................................................................................... 56 
12 ETHICAL CONSIDERATIONS ........................................................................................................ 56 
13 PUBLICATION OF RESEARCH FINDINGS ................................................................................. 56 
14 REFERENCES ..................................................................................................................................... 56 
15 APPENDICES ..................................................................................................................................... 62 
Appendix I. 
Schedule of Assessments 
Appendix II. 
Informed Consent Forms 
Appendix III.  List of Exclusionary Medications 
Appendix IV.  TMS Quick Guide and TMS Operator’s Manual of Procedures 
Appendix V.  
Sample Collection, Processing, Storage and Laboratory Protocols 
Appendix VI.  Seizure Protocol 
Appendix VII.  MRI Emergency Protocol 
Appendix VIII. Resting-state functional MRI Methods 
Appendix IX. Data and Safety Monitoring 
Appendix X. 
Stanford University HRPP Guidance on Prompt Reporting to the IRB 
Appendix XI. Protocol Amendment 

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PRÉCIS 
Study Title 
Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment (MCI) 
(IRB Title of Study:  Noninvasive Brain Stimulation for Mild Cognitive Impairment) 
Objectives  
The purpose of this study is to test the efficacy of repetitive transcranial magnetic 
stimulation (rTMS) as a treatment for mild cognitive impairment (MCI).  There are 
currently no effective treatments for MCI.   
Primary Objective: Test the hypothesis that participants receiving active (“real”) rTMS 
will show more improvement in memory at the immediate post-treatment assessment than 
the placebo (sham) control group. 
Secondary Objectives (aims): 
(2a) Assess the durability of rTMS effects on memory over a 6-month follow-up 
period, which is longer than assessed in previous studies;  
(2b) Examine effects of rTMS on behavior and brain function related to the site of 
stimulation, which is a novel approach in the Alzheimer’s disease (AD) spectrum;  
(2c) Explore patient characteristics that could be useful in identifying who responds 
preferentially to rTMS or to a particular stimulation site. 
Design and Primary Outcome   
The study will use a double-blind, placebo (sham)-controlled, randomized 3-arm design.   
Different cortical stimulation-sites will be studied in the two Active arms: 
Active group 1: Bilateral dorsolateral prefrontal cortex (DLPFC);  
Active group 2: Bilateral Lateral Parietal cortex (LPC) 
Primary Outcome is the California Verbal Learning Test (CVLT-II) Trials 1-5 Total raw score 
Interventions and Duration  
Participants will be randomly assigned to one of three treatment groups:  Group 1: DLPFC 
Active rTMS; Group 2: LPC Active rTMS; and Group 3: Placebo (sham) control (evenly split 
between each coil location).  Thus, a participant has a 2/3 chance of receiving active rTMS. 
Each participant will participate in the study for approximately 7 ½ months—including a daily 
rTMS treatment phase (20 sessions in all), and post-intervention follow-up lasting 6-months. 
Sample Size and Population  
Sample Size: 99 men and women between the ages of 55 and 90 inclusive (n=33 per group).  
Target population: Individuals with a clinical diagnosis of single- or multi-domain amnestic 
MCI (aMCI).  MCI is an intermediate state between normal aging and dementia due to 
conditions such as Alzheimer’s disease (AD).  

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STUDY TEAM ROSTER  
Principal Investigator: Joy L. Taylor, Ph.D. 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
Voice: (650) 493-5000 extension 63102 
FAX: (650) 852-3297 
email:  joyt@stanford.edu and Joy.Taylor@va.gov 
Co-Investigators: 
J. Wesson Ashford MD, PhD 
(Psychiatry; Alzheimer’s Disease) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
Voice: (650) 493-5000 extension 64059 
FAX: (650) 852-3297 
e-mail: ashford@stanford.edu and Wes.Ashford@va.gov 
Margaret Windy McNerney, PhD  
(Mechanisms of TMS) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
Voice: (650) 493-5000 extension 64901 
FAX: (650) 852-3297 
email:  windymc@stanford.edu 
Laura C. Lazzeroni, PhD (Biostatistician) 
Department of Psychiatry & Behavioral Sciences 
Stanford University School of Medicine 
401 Quarry Road, 3305 
Stanford, CA 94305  
Voice: (650) 723-0947 
FAX: (650) 723-4655 
email:  lazzeroni@stanford.edu 
Maheen Adamson, PhD  
(rTMS Brain Injury Rehabilitation) 
VA Palo Alto Health Care System (PSC/117) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
Voice: (650) 493-5000 extension 62179 
FAX: (650) 650-849-0130 
email: madamson@stanford.edu and maheen.adamson@va.gov 

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Other Significant Contributors  
(Jauhtai) Joseph Cheng, MD, PhD (rTMS-Dementia) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  Jauhtai.Cheng2@va.gov 
Michael D. Greicius, MD, MS (fMRI) 
Department of Neurology & Neurological Sciences 
Stanford University School of Medicine 
300 Pasteur Drive 
Palo Alto, CA 94304 
email:  greicius@stanford.edu 
Mark George, MD (rTMS) 
Brain Stimulation Laboratory 
Medical University of South Carolina 
67 President Street, Room 502 North MSC 861 
Charleston, SC 29425 
email:  georgem@musc.edu 
Joachim Hallmayer, MD (Genetics) 
Department of Psychiatry & Behavioral Sciences 
Stanford University School of Medicine 
401 Quarry Road 
Stanford, CA 94305-5717 
email:  joachimh@stanford.edu 
Ruth O’Hara, PhD  
 
(Neurocognitive /Neuropsychiatric Disorders) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  roh@stanford.edu  
Ahmad Salehi, MD, PhD (BDNF) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  Ahmad.Salehi2@va.gov 
Jerome A. Yesavage, MD  
(Geriatric Psychiatry; rTMS Clinical Development) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  yesavage@stanford.edu and  Jerome.Yesavage@va.gov 
 

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Other Personnel  
Nicole Strossman, BS Biochem & Molecular Biology 
 
(Study Coordinator) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  Nicole.Strossman@va.gov 
Beatriz Hernandez, BS (Data Manager) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  Beatriz.Hernandez@va.gov and bhernandez@stanford.edu 
Art Noda, MS Statistics (Back-up Data Manager) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  Arthur.Noda@va.gov and artnoda@stanford.edu 
Priyanka Bhatt, MS Biomedical Engineering  
 
(Neuroimaging Data Analyst) 
VA Palo Alto Health Care System (151Y) 
3801 Miranda Avenue 
Palo Alto, CA 94304 
email:  PBhatt@pavir.org 
 
 
 

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ABBREVIATIONS  
AD 
Alzheimer’s Disease 
ADE 
Adverse Device Effects 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADRC 
Alzheimer’s Disease Research Center 
AE 
Adverse Event 
ALE 
Activation Likelihood Estimation 
aMCI 
amnestic Mild Cognitive Impairment 
ANCOVA 
Analysis of Covariance 
ANT 
Attentional Network Task 
APOE 
Apolipoprotein E 
ASL 
Arterial Spin Labeling 
BA 
Brodmann Area 
BDNF 
Brain-derived Neurotropic Factor 
BNT 
Boston Naming Test 
BVMT-R 
Brief Visuospatial Memory Test-Revised 
CDR 
Clinical Dementia Rating 
CEN 
Central Executive Network 
CNS 
Central Nervous System 
COMT 
Catechol-O-Methyltransferase 
CVLT-II 
California Verbal Learning Test, second edition 
DAN 
Dorsal Attention Network 
DLPFC 
Dorsolateral Prefrontal Cortex 
DMN 
Default Mode Network 
DSMB 
Data Safety Monitoring Board 
DSM-IV 
Fourth Edition of Diagnostic and Statistical Manual of Mental Disorders 
ECog 
Everyday Cognition Scale 
EDTA 
Ethylenediamine Tetraacetic Acid 
ELISA 
Enzyme-Linked Immunosorbent Assay  
EMG 
Electromyographic measurement 
ETOH 
Ethanol 
FAQ 
Functional Assessment Questionnaire 
FC 
Functional Connectivity 
FLAIR 
Fluid-Attenuated Inversion Recovery 

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fMRI 
functional Magnetic Resonance Imaging  
GDS 
Geriatric Depression Scale 
GRE 
Gradient Recalled Echo 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICNs 
Intrinsically Connected Networks 
III 
Individually Identifiable Information 
IRB 
Institutional Review Board 
ITI 
Inter-Train Interval 
ITT 
Intention-To-Treat 
LPC 
Lateral Parietal Cortex 
LTP 
Long-Term Potentiation 
MCI 
Mild Cognitive Impairment 
MIRECC 
Mental Illness Research, Education, and Clinical Center 
MLS-PEST 
Maximum-Likelihood Strategy using Parameter Estimation by Sequential Testing 
MNI 
Montreal Neurological Institute 
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MR 
Magnetic Resonance  
MRI 
Magnetic Resonance Imaging 
MT 
Motor Threshold 
MTL 
Medial-temporal Lobe 
NIBS 
Noninvasive Brain Stimulation 
PCC 
Posterior Cingulate Cortex 
PE/NE 
Physical/Neurological Examination 
PFC 
Prefrontal Cortex 
PHI 
Protected Health Information 
ROIs 
Regions of Interest 
ROCF 
Rey-Osterrieth Complex Figure 
rs-fMRI 
resting state functional Magnetic Resonance Imaging  
RSNs 
Resting State Networks 
RT 
Reaction Time 
rTMS 
repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event 

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SAS 
Statistical Analysis System  
sgACC 
subgenual Anterior Cingulate Cortex 
SMD 
Standardized Mean Difference 
SMS 
Simultaneous Multi-Slice 
SNP 
Single Nucleotide Polymorphism 
SP 
Study Partner 
TBI 
Traumatic Brain Injury 
TMS 
Transcranial Magnetic Stimulation 
TRMDD 
Treatment-Resistant Major Depressive Disorder 
UADE 
Unanticipated Adverse Device Effect 
VAPAHCS 
VA Palo Alto Health Care System 
 
 

rTMS-MCI Study Protocol 
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1 STUDY OBJECTIVES 
1.1 Primary Objective 
Test the hypothesis that participants who receive active (“real”) rTMS will show more 
improvement in memory at the immediate post-treatment assessment than the placebo 
(sham) control group. 
1.2 Secondary Objectives 
(2a) Assess the durability of rTMS effects.  To address Objective 2a, we will assess 
the extent to which rTMS-related improvements in memory are sustained at the 
3- and 6-month follow-up points 
(2b) Examine effects related to the site of stimulation (DLPFC vs LPC).   
To quantify effects of rTMS treatment, MCI-relevant behavioral measures and 
resting-state functional MRI (rs-fMRI, aka task-free fMRI) data will be collected.  
2.b.1. One set of analyses will be done to examine differences in behavioral 
outcomes related to the site of rTMS stimulation.   
2.b.2. The second set of analyses will focus on indices of improved brain 
functional connectivity (derived from rs-fMRI) and plasticity (assessed by levels 
of BDNF).  
(2c) Explore patient characteristics that could be useful in identifying who responds 
preferentially to rTMS or to a particular stimulation site.  To address Objective 2c, 
regarding heterogeneity of response to rTMS, baseline functional connectivity, 
genetic, and selected clinico-demographic variables will be explored as potential 
moderators of response to rTMS. 
2 BACKGROUND AND RATIONALE 
2.1 Background on Mild Cognitive Impairment 
The goal of this study is to test the efficacy of repetitive Transcranial Magnetic Stimulation 
(rTMS) as a treatment for Mild Cognitive Impairment (MCI).  MCI an important public 
health concern due to its prevalence and risk of progression to dementia.  Alzheimer’s 
Disease is the most common underlying cause of dementia. 
There are currently no effective treatments for MCI, aside from general health 
recommendations.  As discussed in the NIH/NIA R01 application, the low efficacy of 
cholinesterase inhibitors is outweighed by their adverse effects (Cooper, Li, Lyketsos, & 
Livingston, 2013; Fitzpatrick-Lewis, Warren, Ali, Sherifali, & Raina, 2015; Raschetti, 
Albanese, Vanacore, & Maggini, 2007; Russ & Morling, 2012; Tricco et al., 2013).  
Systematic reviews of other interventions for MCI (Cooper et al., 2013; Fitzpatrick-Lewis et 
al., 2015; Rodakowski, Saghafi, Butters, & Skidmore, 2015) indicated that the treatment 
investigated was ineffective; or if the treatment showed promise of efficacy, the finding still 
needs to be independently replicated; or the clinical trial was underpowered (Cooper et al., 
2013).   
This clinical interventional study, originally proposed in response to NIH/NIA PAR-16-365 
“Pilot Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive 

rTMS-MCI Study Protocol 
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Decline (R01),” is designed to provide key cognitive and other outcome data as to whether 
rTMS is a viable nonpharmacological intervention for treatment of MCI.   
2.2 Study Rationale 
Cognitive Efficacy of rTMS    
rTMS has shown promise in improving cognitive function in patients with Alzheimer’s 
disease (AD) dementia (Ahmed, Darwish, Khedr, El Serogy, & Ali, 2012; Cotelli et al., 2011; 
Cotelli et al., 2006; Cotelli, Manenti, Cappa, Zanetti, & Miniussi, 2008; Rabey et al., 2013; 
Rutherford, Lithgow, & Moussavi, 2015).  As discussed in the NIH R01 application, these 
studies had limitations including small sample sizes, non-blinded control treatments, and 
collected limited outcome data.  The limited follow-up data published so far suggests that 
five or more sessions of rTMS can produce significant benefits lasting up to 4 months 
(Ahmed et al., 2012; Cotelli et al., 2011; Rabey et al., 2013).  Two meta-analyses have been 
conducted.  One meta-analysis reported a Standardized Mean Difference (SMD) = 1.00, 
which is a relatively large effect size (based on seven rTMS studies with a total of 94 AD 
patients) (Liao et al., 2015). The second meta-analysis reported a SMD = 1.35 (Two NIBS 
methods were pooled  based on six rTMS and five transcranial direct current stimulation 
studies) (Hsu, Ku, Zanto, & Gazzaley, 2015). After adjusting for potential publication bias, 
the mean effect size was 0.78, still a large and clinically meaningful effect (Cohen, 1977; 
Kraemer, 1992).   
For MCI, we found only one rTMS experiment (Turriziani et al., 2012), one rTMS clinical trial 
(Drumond Marra et al., 2015), and one case report (Cotelli et al., 2012).   In the clinical trial, 
which was sham-controlled and involved 34 MCI patients, half the patients received 10 Hz 
rTMS, applied over the left DLPFC for 10 weekday sessions (Drumond Marra et al., 2015).  
This rTMS treatment protocol significantly improved performance on the primary efficacy 
measure, the Rivermead Everyday Memory Test (Drumond Marra et al., 2015).  The 
improvement in memory was sustained at the 1-month follow-up (p = .03; SMD = 0.78). 
Together, these scant preliminary findings suggest that rTMS may enhance cognition in 
MCI patients.  As in the case of AD dementia, it is unknown how long the effects of rTMS 
last.  A rigorous pilot trial using sensitive methods is needed to evaluate the short-term 
efficacy of rTMS and duration of effects. 
Therapeutic Rationale for rTMS as a treatment for MCI and AD spectrum disorders  
AD leads to regionally specific synaptic loss due to a neurodegenerative cascade of 
processes involving “amyloid-β facilitated tauopathy” (LaFerla, Green, & Oddo, 2007; 
Nisbet, Polanco, Ittner, & Gotz, 2015; Sadigh-Eteghad et al., 2015).  In patients with MCI, 
structural MRI studies reveal gray-matter volume loss in AD-vulnerable regions, in 
particular medial and posterior regions of the limbic lobe, and middle and inferior regions 
of the temporal lobe (Bakkour, Morris, & Dickerson, 2009; Convit et al., 2000; Desikan et al., 
2008; deToledo-Morrell et al., 2004; Driscoll et al., 2009; Fennema-Notestine et al., 2009; 
Greene & Killiany, 2010; Kaye et al., 1997; Whitwell et al., 2008).  Synaptic dysfunction or 
loss in AD-vulnerable regions plausibly underlies functional MRI abnormalities seen in 
resting-state networks (RSNs; aka intrinsically connected networks or ICNs).   
According to a meta-analysis of rs-fMRI studies comparing aMCI to healthy controls, the 
most consistently significant regions that show loss of functional connectivity in aMCI are 
the posterior cingulate cortex (PCC: medial and right), the right angular gyrus, right 

rTMS-MCI Study Protocol 
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parahippocampal gyrus, and left fusiform gyrus (Lau, Leung, Lee, & Law, 2016), regions 
that are canonically accepted to be part of posterior Default Mode Network (DMN).  As 
described in the NIH R01 application, an experiment in healthy younger adults provided 
proof of concept that rTMS can induce greater functional connectivity within the DMN (J. X. 
Wang et al., 2014) when delivered to the LPC over an area encompassing the angular gyrus.   
While much remains to be learned regarding the mechanism of action of rTMS, rTMS has 
evidence of modulating brain networks in a relatively selective fashion depending on the 
site of stimulation.  Thus, rTMS offers a neurocircuit-driven strategy for stimulating and 
targeting neural networks that likely underpin core deficits of amnestic MCI.  rTMS may 
also have restorative effects, owing to the hypothesized effects of rTMS on long-term 
potentiation (LTP) and synaptic modification.   
Pre-clinical animal and cell culture studies hold the most promising keys to understanding 
the mechanisms of action of neuromodulation.  Pre-clinical studies of transcranial EMF 
treatment, another neuromodulatory intervention for cognitive decline due to AD, have 
been conducted by Arendash and colleagues (Arendash, 2016). These studies, using AD 
transgenic mice that overproduce Aβ, were able to show positive effects of EMF on 
measures of learning and memory, on Aβ plaque burden, as well as more general positive 
effects on brain function—mitochondrial function and neuronal activity measures 
(Arendash, 2016).   
Evidence of disease-modifying actions of neuromodulation via noninvasive brain 
stimulation in human research would be a major step forward in the clinical development 
these noninvasive brain stimulation as a nonpharmacological treatment for MCI due to AD 
(Albert et al., 2011).  If the current study provides a signal that rTMS favorably modulates 
brain networks affected in MCI, the next step in clinical development would the inclusion of 
AD-neuropathological biomarkers of treatment response in a longer clinical trial.   
Scientific Motivation for studying effects of rTMS at two different cortical sites 
Only two of the controlled rTMS trials in AD dementia and MCI targeted a site that is 
functionally part of the DMN.  The majority of trials--without an explicit disease-relevant 
rationale--stimulated the DLPFC, the target site for treating major depression and likely to 
be a “node” withiin the Central Executive Network (CEN).  It is not known whether the 
stimulation site used for treatment of depression—the DLFPC—is truly the ideal 
stimulation site for MCI / AD patients.   
In younger and non-AD populations, there is experimental and clinical evidence that rTMS 
delivered to the right or left DLPFC region can improve network interactions between the 
CEN and DMN regions (Chen et al., 2013; Liston et al., 2014).  Importantly, rs-fMRI studies 
of aging and the AD spectrum have revealed altered network interactions between the 
DMN and attention-related networks such as the CEN, which in turn correlate with lower 
cognitive performance (Grady, Sarraf, Saverino, & Campbell, 2016; Ng, Lo, Lim, Chee, & 
Zhou, 2016; K. Wang et al., 2007; P. Wang et al., 2015).  Thus, stimulating the DLPFC using 
rTMS has potential to improve CEN:DMN interactions in AD and MCI.  
By manipulating what cortical site is stimulated, this pilot project aims to gain novel 
insights as to how rTMS could improve brain network function in aMCI patients, laying the 
ground work for later-stage clinical trials.  Ultimately, stimulating both cortical regions 
might provide superior clinical outcomes given the profound effects of AD on widespread 
interconnected brain regions.  However, clearer understanding of how rTMS over a cortical 

rTMS-MCI Study Protocol 
13 
site leads to changes in behavior and brain function would be important in deciding 
whether one site is ideal and sufficient, or whether stimulating multiple sites could be 
superior. 
As described below, this project is designed to provide data on the short-term efficacy of 
rTMS and its potential to improve memory, cognition and brain functioning in MCI.  
Ultimately, if rTMS treatment can be delivered optimally in a way that improves clinical 
outcomes in a sustained manner, this will be a significant advance for the treatment of MCI. 
Empirical Basis for the Stimulation Parameters and Delivery Schedule 
In this study, each participant will receive a total of 20 sessions of rTMS bilateral 10 Hz 
rTMS lasting 25 minutes per session.  The stimulation parameters of this study were 
selected on the basis of a meta-analyses of rTMS studies targeting the AD dementia 
population (Liao et al., 2015), publications that presented safety and tolerability data 
(Nahas et al., 2004), and the clinical interventional research experience of our co-
investigators and consultants to ameliorate the core symptoms of treatment-resistant 
major depressive disorder (TRMDD), mild AD dementia, and mild traumatic brain injury 
(mTBI).  The empirical basis is summarized below: 
Stimulation Frequency and Intensity.  The decisions to use10 Hz rTMS and to stimulate 
both hemispheres is based on a recent meta-analysis of AD trials, which reported that the 
cognitive efficacy of rTMS was larger when high frequency (≥ 10 Hz) rTMS was used, and 
when stimulation was bilateral or to the right hemisphere (Liao et al., 2015).  The decision 
to use an intensity of 120% magnetic field intensity relative to the participant’s resting 
motor threshold (MT) is also based on a strategy to achieve efficacy in the older population 
without compromising safety.  Early studies used lower intensity stimulation because of 
safety concerns at the time, which have now been alleviated with greater experience.  This 
intensity is safe, tolerable, and has been necessary and sufficient to overcome the effect of 
age-related cortical atrophy (Nahas et al., 2004).  Recent rTMS studies of cognitive 
enhancement that targeted the older population used intensity levels ranging from 90% 
MT to 120% MT, depending on the site selected for treatment stimulation (Hsu et al., 
2015).  120% is the intensity used in the AD, mild TBI, and depression clinical trials, 
directed by our Co-Investigators, Drs. Jauhtai Joseph Cheng, Maheen Adamson, and Jerome 
Yesavage.   
Stimulation Pattern and Session Duration: The 10 Hz pulse frequency will be patterned 
as a 4-second train (40 pulses) with an 11-second interval between trains, which is 
repeated over a period of 25 minutes (i.e. a total of 4,000 pulses per session: 40 pulses per 
train x 4 trains per minute x 25 minutes).  Prior studies generally used 1,900 pulses or less 
per session, in line with 2009 safety recommendations (Rossi, Hallett, Rossini, Pascual-
Leone, & Safety of TMS Consensus Group, 2009).  The lack of serious adverse effects seen 
with 1,900 pulses has motivated clinical investigators focused on the target population of 
treatment-resistant major depressive disorder (TRMDD) to deliver an efficacious course of 
treatment safely, but in a shorter period of time.  We note that MagVenture received 510(k) 
FDA clearance in June 2017 to use "... a range of inter-train intervals from 11 to 26 seconds” 
in delivering the 10 Hz / 3000 pulse, FDA cleared protocol for treatment of adults with 
TRMDD.  
 

rTMS-MCI Study Protocol 
14 
A 10 Hz 4-sec train, 10-sec ITI protocol that delivered a total of 4,000 pulses during a 23-
minute session was used in the VA 9-site depression trial (VA CSP #556; PI: Yesavage), 
which completed data collection in 2016.  Although detailed safety and efficacy data are not 
available as of August 2017, the CSP #556 PI and Co-Chair Mark George, MD state that no 
seizures occurred in CSP #556 (per email communicated to the PI and DSMB members).   
Study co-investigators, Drs. Cheng and Adamson, have adopted a 10 Hz 5-sec train, 10-sec 
ITI protocol for use in their currently ongoing rTMS clinical trials for treatment of cognitive 
impairment due to mild AD and mild TBI.  The DSMB of the present trial has advised 
stricter adherence to the published safety table (Rossi et al., 2009).  In summary, we have 
selected a 10 Hz 4-sec train, which is within the safety table, and an 11-sec ITI, which is 1 
sec longer than that used in CSP #556.   
Delivery schedule.  Delivery of the study intervention will be scheduled as two rTMS 
sessions per treatment visit, with 10 treatment visits scheduled M-F during two 
consecutive weeks.  This delivery schedule was documented to be safe and effective in a 
depression-treatment trial (Loo, Mitchell, McFarquhar, Malhi, & Sachdev, 2007) (10 Hz, 
110% intensity, 1,500 stimuli per session).  This “twice-daily” procedure is being used at 
our site by Co-Investigators Drs. Adamson and Cheng in two ongoing clinical interventional 
studies (10 Hz, 120% intensity, 4000 stimuli per session).  From a patient’s perspective, a 
twice-daily intervention that requires a 2-week commitment is likely to be more 
convenient than coming to a clinic M-F for 4 weeks, particularly if there is some flexibility 
for “make-up” sessions, e.g. when the participant needs to fulfill other commitments. 
In summary, the 10 Hz stimulation protocol to be used in this study will consist of 
delivering up to 8,000 magnetic pulses per day, with a total of 80,000 pulses over 2 to 2.5 
weeks.  This is within the range of 60 to 90,000 total pulses that is delivered in FDA-
approved rTMS treatment of TRMDD (e.g. 3,000 magnetic pulses per day, 5 days per week, 
for 4 to 6 weeks) and more than the 39,000 pulses delivered by the NeuroAD ™ Therapy 
System protocol (Rabey & Dobronevsky, 2016; Rabey et al., 2013).  Our experience, based 
upon clinical research involving more than 60 AD and mTBI study volunteers, is that the 
stimulation protocol to be used in this study will be a safe, tolerable, and efficient means of 
providing noninvasive brain stimulation, provided that safety screening and other 
precautions are taken to minimize the risks of rTMS. 
Summary of the known and potential risks of the rTMS study intervention:  
The serious known and potential risks of rTMS are: 
o Inadvertent induction of a seizure (less than 1 in 1000 patient exposures); 
o In the absence of careful screening, ferromagnetic implants, objects or 
electromechanical devices such as pacemakers are serious risks  
Other known and potential risks of rTMS are: 
o Discomfort at the site of rTMS stimulation (15% of patients); 
o Mild to moderate headaches (up to 30% patients), and the  
o Possibility of temporary hearing loss if ear protection is inadequate. 
For detailed information on risks of rTMS, see Study Protocol Section 7 “SAFETY 
ASSESSMENTS.”  See also, the original IRB protocol submission and informed consent form, 
approved by the Stanford IRB Panel 3, March 14, 2017. 
 
 

rTMS-MCI Study Protocol 
15 
3 STUDY DESIGN 
Our hypotheses regarding the effect of rTMS on memory in persons with aMCI will be 
tested in a randomized, 2-stimulation-site, double-blind sham-controlled, 3 parallel-arm 
design, in which bilateral rTMS is delivered as: (1) real rTMS of the DLPFC, (2) real rTMS of 
the LPC, or (3) sham rTMS (evenly split between each coil location).  
Note:  All IRB-approved materials refer to the treatment groups as active “real” rTMS and 
inactive/placebo rTMS.  In the study protocol, we use the more conventional terms, “active” 
and “sham” rTMS.  
Overview of Measures.  As shown in Table 1, behavioral and cognitive outcome measures 
will be collected at 4 timepoints:  Baseline, Immediate post-treatment, and at two 
subsequent Follow-up visits at 3 and 6 months.  Resting-state fMRI (rs-fMRI, aka task-free 
fMRI) scans will be acquired at Baseline and repeated Immediate post-treatment to examine 
the effects of rTMS on functional connectivity.  BDNF levels will be measured twice, prior to 
the first treatment session and again during the last treatment visit.  Genomic DNA will be 
collected at the first treatment session to examine heterogeneity of response to rTMS.   
Table 1.  Study Design 
 
Phase 
Screening 
Baseline 
Randomization 
Treatment 
Immediate  
Post-Treatment 
Follow-up 
6-week 
window 
Day 0 
 
Days 7 -37 
(20 sessions) 
7 ± 3 days after 
Session 20 
3 & 6 mos post 
 
 In-person 
Visit 
fMRI 
Behavioral & 
cognitive outcomes 
 
[3 Arms] 
DLPFC 
LPC 
Sham 
fMRI 
Behavioral & 
cognitive outcomes 
 
Behavioral & 
cognitive outcomes 
Primary Outcome:  
Memory performance at the end of the treatment phase, as assessed by the California Verbal 
Learning Test (CVLT-II; (Delis, Kramer, Kaplan, & Ober, 2000)) Trials 1-5 Total raw score.  
Secondary Behavioral Outcomes:   
Memory performance at the 3- and 6-month follow-up visits, as assessed by the CVLT-II Trials 
1-5 Total raw score. 
Depressive symptoms, assessed using the 15-item Geriatric Depression Scale (GDS; (Yesavage, 
Brink, & Rose, 1982)).   
Everyday function, assessed using the Everyday Cognition Scale (ECog; (Farias et al., 2008)).   
Other aspects of cognitive function will be assessed using:  (a) a measure of global cognitive 
function, (b) subscores on the CVLT-II, and (c) objective indices of the major cognitive 
domains-- visuospatial episodic memory, language, visuoconstructional ability, speed of 
processing, executive function, visual-spatial orienting of attention, specifically:   
 Montreal Cognitive Assessment (MoCA; (Nasreddine et al., 2005));   
 CVLT-II; (Delis et al., 2000) selected subscores: semantic clustering, short-delay 
free recall; long-delay free recall, and recognition discriminability 
 Brief Visuospatial Memory Test–Revised (BVMT-R) (Benedict, Schretlen, 
Groninger, Dobraski, & Sphritz, 1996) 

rTMS-MCI Study Protocol 
16 
 Rey-Osterrieth Complex Figure (ROCF).  Copy task only (2 stimulus forms: original 
ROCF form and modified Taylor figure (Hubley, 2010; Hubley & Jassal, 2006);   
 Category Fluency (Strauss, Sherman, & Spreen, 2006)  
 Boston Naming Test (BNT) (Huff et al. (1986) two-equivalent forms version) 
 Trail Making (Partington & Leiter, 1949; Reitan, 1958) 
 Attentional Network Task (ANT) (Fan, McCandliss, Sommer, Raz, & Posner, 2002; 
Posner, 2012; Y.-F. Wang et al., 2015), 
(Note:  Except for Fluency and Trail Making tests, all tests have validated alternate stimulus forms, 
in order to reduce the magnitude of practice effects.  Fluency and Trails are included because they 
are widely used tests, and their brevity should not add substantial participant burden.)  
Secondary fMRI and BDNF measures relevant to improved functional connectivity 
and plasticity.  Resting-state fMRI (rs-fMRI, aka task-free fMRI) scans will be acquired at 
the Baseline and Immediate post-treatment visits to examine effects of rTMS on functional 
connectivity.  Additionally, plasma levels of brain-derived neurotrophic factor (BDNF) will 
be measured before and at completion of treatment as a strategy to gain more information 
about mechanisms of action.  BDNF expression in the brain plays a role in synaptic 
remodeling (McAllister, Katz, & Lo, 1999).  It has been suggested that the longer-lasting 
effects of rTMS involve long-term potentiation-like (LTP-like) mechanisms (Hoogendam, 
Ramakers, & Di Lazzaro, 2010).  Although a direct link between neuromodulatory 
stimulation, such as rTMS, and synaptic plasticity remains to be demonstrated, an rTMS-
related rise in BDNF plasma levels would be consistent with an effect on brain plasticity. 
Secondary measures relevant to heterogeneity of therapeutic response.  Genomic 
DNA will be collected to examine heterogeneity of response to rTMS.  For this project, three 
genotypes will be determined--Apolipoprotein E (APOE) ε4 ε3 ε2, BDNF val66met, and 
catechol-O-methyltransferase (COMT) val158met genotypes--and used in exploratory 
analyses of heterogeneity of response to rTMS.  In addition, selected Baseline clinico-
demographic variables and summary measures of functional connectivity, will be used in 
these exploratory analyses (See Section 9.5.2).  
Study Location and Duration 
The study will be conducted in an outpatient clinic setting at the VA Palo Alto Health Care 
System.  The total duration of the study will be 5 years, with a 46-month enrollment period.  
During the first half of Year 5, follow-up visits of the last enrollees are to be completed.  
Each participant will be in the trial for a total of approximately 7 ½ months, which includes 
4 to 6 weeks to undergo screening and baseline assessments, and 2 to 2.5 weeks to receive 
20 treatment sessions.  Each participant will be followed for 26 weeks post-treatment. 
The study database will ultimately include data from 99 aMCI participants (33 per arm), 
with measures of cognitive efficacy, change in brain function, and predictors of response to 
rTMS, which will be analyzed as described in Section 9.5. 
 
 

rTMS-MCI Study Protocol 
17 
4 SELECTION AND ENROLLMENT OF PARTICIPANTS  
Participants will be eligible to enroll in the rTMS study if, based on screening assessments, 
they have a clinical diagnosis of amnestic Mild Cognitive Impairment (aMCI) (Albert et al., 
2011; R. C. Petersen, 2004) and they meet all of the following inclusion and exclusion 
criteria: 
4.1 Inclusion Criteria  
1. Age 55 – 90 years inclusive; 
2. Diagnosed with amnestic Mild Cognitive Impairment (aMCI); 
3. Stable medications (including any dementia-related meds) for at least 4 weeks prior 
to Baseline; 
4. Geriatric Depression Scale score less than 6; 
5. Ability to obtain a motor threshold, determined during the screening process; 
6. Study partner available; living situation enables attendance at clinic visits; 
7. Visual and auditory acuity adequate for neuropsychological testing; 
8. Good general health with no diseases expected to interfere with the study, as 
determined by the referring Memory Clinic Physician or the rTMS Study Physician; 
9. Participant is not pregnant or of childbearing potential (i.e. women must be 2 
years post-menopausal or surgically sterile); 
10. Modified Hachinski Ischemic score less than or equal to 4; 
11. Agree to DNA extraction for single nucleotide polymorphism (SNP) genotyping; 
12. Able to understand study procedures and comply with them for the entire length 
of the study. 
4.2 Exclusion Criteria  
A candidate will be excluded from the study if he or she meets any of the following 
exclusion criteria at Screening or Baseline: 
1. Prior exposure to rTMS within the past 12 months; 
2. Magnetic field safety concern such as a cardiac pacemaker, cochlear implant, 
implanted device in the brain (deep brain stimulation), or metal fragments or 
foreign objects in the eyes, skin or body; 
3. Any significant neurological disease other than suspected incipient Alzheimer’s 
disease; 
4. Unstable cardiac disease or recent (< 3 months previous) myocardial infarction.  
Any significant systemic illness or unstable medical condition that could lead to 
difficulty with protocol adherence;  
5. History of epilepsy or repetitive seizures, as determined by patient report or chart 
review; 
6. History of a medical condition or current use/abuse of medications and 
substances that increase the risk of a seizure, specifically: 

rTMS-MCI Study Protocol 
18 
 Traumatic brain injury within 2 months that would increase the risk for 
seizure; 
 Unable to safely withdraw, at least 4 weeks prior to Baseline, from 
medications that substantially increase the risk of having seizures (for 
example, theophylline, clozapine, and methylphenidate).  See Appendix III.  
“List of Exclusionary Medications.” 
 Current or past history of a mass lesion, cerebral infarct, or other non-
cognitive active neurological disease that would increase the risk for 
seizure. 
 Stimulant abuse within the previous 90 days.  Cocaine and abuse of 
amphetamine and methylphenidate are associated with an increased risk of 
seizures;  
7. Major depression or bipolar disorder (DSM-IV) within the past 1 year, or psychotic 
features within the last 3 months that could lead to difficulty w/protocol adherence; 
8. Taking sedative hypnotics or medications with anti-cholinergic properties and 
unable to withdraw at least 4 weeks prior to Baseline; 
9. Current alcohol or substance abuse (not including caffeine or nicotine) within the 
past 1 year, as determined by chart review, participant or study partner report, or 
greater than "moderate" alcohol use defined by the Quantity-Frequency-
Variability Index (Cahalan, Cisin, & Crossley, 1969);  
10. Any contraindications for MRI studies, e.g. severe claustrophobia, weight above 
350 lb maximum allowed by MRI scanner, pregnancy; 
11. Participation in another concurrent clinical trial; 
12. Inability or unwillingness of individual or legal representative to give written 
informed consent; 
4.3 Study Enrollment Procedures  
Recruitment strategies.  (1) We will recruit participant in collaboration with the NIA-
funded Stanford Alzheimer’s Disease Research Center (ADRC) and the California-funded 
Stanford-VA AD Center.  The two centers will enable us to minimize screen fails by 
referring participants who are likely to meet the study’s eligibility criteria.  The ADRC and 
California AD center both have ongoing outreach efforts in place to recruit participants of 
diverse ethnic and racial backgrounds.  (2) Participants will also be recruited from local 
clinics and physicians.  We estimate that the Study Coordinator will conduct 3 screens for 
every 1 that is eligible for randomization. 
To augment the AD Centers’ outreach efforts to older, ethnically diverse individuals, we 
have budgeted for direct-mail advertising that will be targeted to older ethnically diverse 
residents.  Local area marketing companies have lists of individuals by age, by minority 
status, and by geographical area.  Our collaborators at both Centers have found that these 
IRB-approved postcards are one of the most effective outreach strategies.  More general 
advertising will include IRB-approved flyers posted throughout the Stanford campus, 
VAPAHCS and AD Center newsletters.  Interested respondents will learn more about the 
study during a telephone interview.  If the respondent has never had a MCI/dementia 
work-up, they will be invited to undergo the rTMS study’s screening evaluation at the NIA 

rTMS-MCI Study Protocol 
19 
ADRC or the California AD Center to obtain a consensus diagnosis and provide educational 
services to the participant and family. 
Overview of consent procedures.  Our IRB approval includes a waiver of individual 
HIPAA authorization for recruitment and a waiver of documentation of consent for 
telephone pre-screening.  Before any in-person screening procedure is performed, written 
informed consent will be obtained.  A single consent form describes both the screening and 
study procedures.   
Enough time will be allowed for the potential participant to make an informed decision, 
including time to discuss the study with the researchers and ask any questions they may 
have.  If the prospective participant lacks adequate decision-making capacity, a designated 
legal representative will need to sign the form prior to the participant undergoing 
screening or other study procedures.  Prospective participants will need to co-sign the 
consent form to indicate assent.  Consent procedures are described more fully in Sections 
11.1 and 11.2. 
Documentation of eligibility and decision to enroll.  A Phone Screening Log will be used 
to record information on each candidate who is pre-screened by telephone prior to 
scheduling Visit 1, the in-person screening visit.  For each candidate screened in person, 
two forms will be completed to document eligibility and the participant’s decision to enroll: 
 The Inclusion-Exclusion Form will document study eligibility and reasons for 
ineligibility.  
 The Enrollment and Randomization Form will document eligibility as a binary Y/N 
outcome.  The form will also have a check-box variable for recording why an eligible 
candidate was not enrolled. 
Randomization.  Participants who meet all criteria for enrollment will be randomized in a 
2:1 ratio to double-blind active treatment or sham at Baseline.  Within the active and sham 
groups, subjects will be randomized in a 1:1 ratio to the two unmasked cortical sites.  The 
method of random assignment to treatment (active vs. sham) and to cortical site (DLPFC vs 
LPC) will be determined by a computer-generated random sequence as explained in 
“Treatment Assignment Procedures 9.2.1.”    
For the purposes of the Data Analyses, there are 3 equally sized treatment groups of interest 
in this randomized trial:  
(1) one-third of subjects will receive active DLPFC;  
(2) one-third of subjects will receive active LPC; and  
(3) one-third of subjects will receive sham (sham DLPFC and sham LPC are combined). 
5 STUDY INTERVENTIONS  
5.1 Intervention Device 
Briefly, the TMS device system used in this study is comprised of the following 
components: MagPro X100 magnetic stimulator, the C-B60 coil (for MT determination), 
Coil Cooler unit, and motorized treatment chair.  These are the major components of the 
MagVita TMS Therapy system, which is FDA cleared to market for the treatment of drug 
resistant Major Depressive Disorder. 

rTMS-MCI Study Protocol 
20 
For this double-blind controlled trial, the TMS Therapy System will be configured with 
three additional research components:  a Coil Cool-B65 A/P (Active & Sham figure-of-eight 
coil), a TMS Sham Noise generator (for masking any difference in sound between real and 
sham), and a Localite TMS Navigator Spectra Edition system (for fMRI-guided placement of 
the rTMS coil). 
5.2 Schedule and Procedures for Administering the Study Intervention  
Schedule.  The intervention will be administered as 20 weekday sessions during a period 
of 2 to 4 weeks, depending on scheduling constraints.   Typically, a participant will have a 
morning session and an afternoon session. At the study physician’s discretion and if the 
participant requests, up to three rTMS sessions can be scheduled per day with at least a 
one-hour interval between sessions. 
Intervention sessions are scheduled as a 1-hour blocks, to allow time for late arrivals, for 
assessments of adverse effects, and for the 25-minute rTMS intervention.  The intervention 
will be administered in outpatient clinic setting.  In all, the participant will receive a total of 
20 rTMS sessions. 
Procedures for administering the rTMS Intervention 
1. Motor Threshold Determination.  Prior to administering the intervention, the 
participant’s right and left motor threshold (MT) will be measured to standardize the 
stimulation intensity to be 120% of resting MT, i.e. 1.2 x MT).   The 120% intensity will be 
specific to the MT of each hemisphere.  The TMS Operator will determine the left MT at the 
end the screening visit, and the right MT at the beginning of Session 1 of the Intervention 
Phase.  The TMS Operator will record the right and left MTs—and the corresponding 
stimulation intensities equal to 120% of  right and left MT—on the participant’s TMS 
Intervention Log (described in Section 6.2.3).  The participant’s right MT will also be 
recorded within the TMS system in association with the participant’s randomization 
treatment number.  (The device software allows for one MT to be saved per participant.)   
Left and right hemisphere MT will be determined using electromyographic measurement 
(EMG) of the resting contralateral thumb (abductor pollicus brevis) using a mathematical 
algorithm (Maximum-Likelihood Strategy using Parameter Estimation by Sequential 
Testing; MLS-PEST) that efficiently and reproducibly arrives at the participant’s MTs.  As 
explained in the appended TMS Operator manual (Appendix IV.  “TMS Quick Guide and 
TMS Operator’s Manual of Procedures”), adapted from the CSP #556 Study Protocol 
(Yesavage, Fairchild, & George, 2015, November ), the EMG and MLS-PEST features are 
incorporated within the TMS device and software.  If the screening MT is so high that the 
TMS system lacks capability to deliver rTMS at an intensity of 120% MT, the participant 
will not be eligible to enroll in the study.  Fewer than five percent of participants are 
expected to be ineligible due to an excessively high MT (see Table 2 of George et al., (2010) 
for a large-sample distribution of MT values).  The remainder of this section gives an 
outline of the basic procedures for administering rTMS: 
2. Neuronavigation to guide placement of the coil.  The placement of the coil will be 
individualized to each subject, using the subject’s MRI data collected at the Baseline visit.  
By using neuronavigation, we aim to optimize subjects’ clinical responses (Bashir, 
Edwards, & Pascual-Leone, 2011; Fox, Buckner, White, Greicius, & Pascual-Leone, 2012; 
Fox, Liu, & Pascual-Leone, 2013), irrespective of whether the subject is assigned to DLPFC 
or LPC stimulation.  

rTMS-MCI Study Protocol 
21 
As discussed in the grant application, multiple sessions of rTMS, when applied to the DLPFC 
or LPC, can ultimately change DLPFC:PPC connectivity and LPC:PPC connectivity, 
respectively in TMRDD (Liston et al., 2014) and healthy young adults (J. X. Wang et al., 
2014).  Regarding aMCI, the most significant x, y, z coordinates of abnormal functional 
connectivity appear to be located near MNI coordinate: x = 6, y= -52, z=16, located in the 
PCC bilaterally.  This coordinate was derived through an ALE meta-analysis of 21 rs-fMRI 
studies comparing aMCI participants to healthy older control participants (Lau et al., 2016).  
Therefore, in the present study, each subject’s MRI data and a frameless stereotactic 
neuronavigation system will be used to position the coil where it is most likely to 
ultimately target the medial PCC, given evidence that this hub-like region of the brain is 
most consistently abnormal in aMCI.   
The present study’s procedures for neuronavigation will be performed in consultation with 
Dr. Michael Greicius and Dr. Keith Sudheimer of Stanford University School of Medicine.  
The general methods, which are based on prior work (J. X. Wang & Voss, 2015), are 
outlined in the grant submission, Section C.2.d.4 and in Appendix VIII. “Resting-state 
functional MRI Methods”).  Briefly, the first step is to generate a seed-based connectivity 
map for each subject, using the subject’s rs-fMRI Baseline data.  In this step, the fMRI 
timeseries of the bilateral PCC region will be extracted as the seeds.  Next, timeseries 
analyses will be used to locate bilateral LPC or bilateral DLPFC cortical targets, depending 
which of the two cortical site the subject has been randomly assigned to.  If the fMRI data 
are too noisy due to excessive head motion, large framewise displacement, and/or low 
temporal signal-to-noise ratio, then the T1-weighted anatomical image will be used as a 
fallback.  Review of data quality and selection of stimulation locations for individual 
subjects will be done in collaboration with Dr. Sudheimer.  Dr. Sudheimer’s image-
processing pipeline and connectivity mapping procedures are currently being used in four 
ongoing rTMS projects at Stanford, each involving unique diagnoses or unique targets.   
LPC:  To locate the left and right LPC cortical stimulation sites, we will locate the 
clusters of voxels located within the left and right angular gyri (and near Brodmann Area 
(BA) 39/40) that show local maximum connectivity (i.e. are positively correlated) with the 
PCC seeds.  The left cluster should also lie within a 15-mm radius of MNI coordinate: x= -47, 
y= -68, z=36; this coordinate is the peak location, across subjects, in the rTMS experiment 
that stimulated the left LPC to improve memory (J. X. Wang et al., 2014).  
DLPFC:  To locate the left and right DLPFC sites for stimulation, we will locate the 
clusters of voxels within left and right prefrontal gyri (near the juncture of BAs 9 and 46) 
that show local maximum negative connectivity (i.e. are inversely correlated) with the PCC 
seeds.  The left cluster within the DLPFC should also lie within a 15-mm radius of the peak 
MNI coordinate (x= -38, y=44, z=26), which was found to be predictive of how effective 
rTMS was in treating clinical depression (Fox et al., 2012).  This coordinate is also near the 
peak active cluster in fMRI studies of working memory in MDD (Fitzgerald et al., 2006), and 
shows significant inverse correlations with the PCC in resting-state fMRI (Greicius, 
Krasnow, Reiss, & Menon, 2003).   
Following localization of the stimulation site (LPC or DLPFC), the bilateral locations for that 
subject will be marked in stereotactic space, transformed into original MRI space, and 
overlaid onto the structural MRI to aid in positioning the coil for the intervention.  These 
locations will be marked on the subject’s cap.  Once the locations are marked, a coil 
template will be placed over each location to mark the location on the cap where the edge 
of the coil should be.  As described in the TMS Operator manual (Appendix IV), cap fitting 

rTMS-MCI Study Protocol 
22 
and marking provides a way of reproducibly delivering rTMS across multiple intervention 
sessions. 
3. Procedures for each intervention session.  Except for positioning the rTMS coil over 
the assigned cortical site, the intervention procedures are identical for all treatment 
groups.  The TMS Operator manual (Appendix IV) lists, step by step, the procedures for 
safety screening, for operating the rTMS device, placing scalp electrodes (see also Section 
5.3 below), cap repositioning, positioning the participant for comfort and stable head 
position, delivering the treatment and monitoring for safety and tolerance to the 
procedure.  The TMS Operator will manually set the amplitude to equal 1.2 times the MT of 
the to-be-stimulated hemisphere.  For example, if the right MT = 65 and the left MT= 70, 
then the TMS Operator will manually set the amplitude to 78 (1.2 x 65) to stimulate the 
right, and to 84 (1.2 x 70) to stimulate the left.   
As in Ahmed et al (Ahmed et al., 2012), rTMS will be applied over the right hemisphere 
first, immediately followed by rTMS over the left hemisphere. Rabey et al. (2013) also used 
a R, L order for the two bilateral regions.  In both studies, all participants will receive the 
same order.  It is beyond the scope of this study to investigate order effects.  Given the 
absence of a priori data on this point, this study will follow the methods of the two prior 
studies (Ahmed et al., 2012; Rabey et al., 2013) and stimulate the right, immediately 
followed by the left. 
TMS Stimulation Parameters for the active DLPFC and active LPC rTMS intervention 
groups will be: 10 Hz, 4-second train duration and 11-second inter-train interval. During 
each session, 2,000 pulses will be applied for each hemisphere (for a total of 4,000 pulses 
per session).  These parameters will be pre-programmed in the device at the outset of the 
clinical trial, before the TMS operator begins administering the intervention. 
Modifications and supportive care in case of difficulty tolerating the intervention.  As 
noted previously, headache, scalp discomfort at the site of stimulation are relatively 
common, although tolerance to these adverse effects generally develops over the first 5 to 
10 sessions of TMS therapy (Perera et al., 2016).   Should a headache or site discomfort 
occur, these symptoms are expected to be self-treated, e.g. with ibuprofen.  Discomfort can 
vary depending on intensity and location.  For better tolerability, intensity can be ramped 
up from 80% to 120% during the first two sessions, and study staff may be able to move 
the coil position slightly if dental pain occurs.  
5.3 Mechanisms for Masking (i.e., blinding) Study Interventions  
The mechanisms used to create matched sensations for active and sham rTMS are the same 
as those used in currently ongoing VA-funded rTMS trials at this site and are very similar to 
those used in an NIMH-funded randomized rTMS trial for patients with depression (George 
et al., 2010).   
The masking system is comprised of three components: (1) the Cool-B65-Active/Placebo 
Coil, which functions as both a real and sham coil; (2) scalp electrodes; and (3) a white-
noise generator.  The Active/Placebo coil has a symmetrical mechanical design and no 
labeling identifying the active and the sham side of the coil.  Second, the subject wears scalp 
electrodes through which, in the case of sham assignment, a low voltage, low electric 
current (2–20mA at no more than 100V) is passed to mimic the sensation of receiving 
actual rTMS.  Third, a white-noise generator is used to hide the click noise produced by 

rTMS-MCI Study Protocol 
23 
rTMS, by sending low-volume white noise to the subject’s and the TMS Operator’s 
headphones when magnetic stimulation pulses are initiated. 
5.4 Concomitant Interventions 
Currently there are no medications or interventions that have been FDA-approved or have 
proven effectiveness in MCI.  Even so, some of the participants might be taking one or more 
medications for cognition.  As listed below, FDA-approved medications for cognition will be 
permitted, as will certain types of antidepressants and other medications frequently 
prescribed to older adults.     
5.4.1 Allowed Medications 
Permitted medications* include: 
FDA-approved medications for cognition (e.g. donepezil); 
Estrogen replacement therapy 
Stable doses of antidepressants lacking significant anticholinergic side effects will be 
allow if the participant’s treatment for depressive symptoms is adequate and the 
participant does not have a history of major depression within the past 1 year; 
*Medication dosing should be stable for at least 4 weeks prior to the Baseline visit. 
5.4.2 Required Interventions  
None 
5.4.3  Prohibited Medications 
Safety is the determining factor.  Any medication that substantially increases the risk of 
having epileptic seizures will not be allowed while the participant is on study.   Therefore, 
the herbal medicine gingko biloba, sometimes used as a supplement to for memory 
function, will be prohibited (Granger, 2001; Kupiec & Raj, 2005). Other medications that 
substantially increase the risk of seizures are: amphetamines, clozapine, modafinil, 
olanzapine, phenothiazines, pseudoephedrine and theophylline.  See Appendix III.  “List of 
Exclusionary Medications.” 
The washout period for all prohibited medications is ≥4 weeks prior to the Baseline visit.  
5.5 Adherence Assessment  
Adherence will be defined as attending at least 80% of the twenty 25-min rTMS sessions 
(completed at least 16/20 sessions, or received at least 400/500 minutes of stimulation) 
 
 

rTMS-MCI Study Protocol 
24 
6 STUDY PROCEDURES 
Figure 1 provides an overview of the flow of study procedures, from the initial phone pre-
screen to a participant’s completion of the study when the 6-month Follow-up is completed.  
Figure 1.  Study Flow Diagram 
 
 
 
6.1 Schedule of Assessments 
On the following page, Table 2 lists the study assessments and their timing during the Pre-
Treatment, Treatment, and Follow-up phases of the study.  Following Table 2, we list each 
assessment that will be performed during these phases. 

rTMS-MCI Study Protocol 
25 
Table 2.  Schedule of Assessments 
 
Pre-Treatment Phase 
Treatment Phase 
Follow-up Phase 
Visit Description 
In-person 
Screening 
Randomization 
& Baseline 
Sessions  
1-10 
Sessions  
11-20 
Make-up 
sessions allowed 
through Day 37 
Immediate 
Post-Tx 
3-Month  
Post-Tx 
6-Month  
Post-Tx 
Visit Number 
1 
2 
3-7 
8-12 
 
13 
14 
15 
Timeline 
Days -42 to -35 
Day 0 
Days 7-11 
Days 14-18 
Days 21-37 
7 ± 3 days 
after S20 
90 ± 14 days 
after S20  
180 ± 14 days 
after S20  
Informed Consent Form   
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
Cognitive Change Index; 
MMSE, Logical Memory I 
X 
 
 
 
 
 
 
 
CDR (Subject and SP) 
X 
 
 
 
 
 
 
 
GDS, ETOH Questionnaire, 
Logical Memory II 
X 
 
 
 
 
 
 
 
Medical, Psychiatric & 
Seizure Hx; Hach; PE/NE; 
Diagnostic Summary 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
MRI and rTMS Safety forms; 
Motor Threshold (MT) 
Safety &  
Left MT 
Safety 
Safety & 
Right MT 
Safety 
Safety 
Safety 
 
 
Inclusion/Exclusion Criteria  
X 
 
 
 
 
 
 
 
Enrollment/Randomization 
 
X 
 
 
 
 
 
 
MRI scan 
 
X 
 
 
 
X 
 
 
CVLT-II and Secondary 
Behavioral Assessments 
 
X 
 
 
 
X 
X 
X 
Blood Sample (Genomic 
DNA and BDNF Biomarkers) 
 
 
Session 1 
DNA & BDNF 
 
Session 20 
BDNF only 
 
 
 
rTMS Intervention Log  
 
 
X 
X 
X 
X 
X 
 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 

rTMS-MCI Study Protocol 
26 
6.2 Description of Assessments and Procedures 
6.2.1 In-Person Screening Visit 
Consenting Procedure 
Before any in-person screening procedure is performed, informed consent will be obtained. 
A single informed consent form describes both the screening and study procedures.  See 
Appendix II. “Informed Consent Forms.” 
The Study Coordinator or PI, in consultation with the Study Physician will conduct the 
consent process.  The process will be implemented as described in Section 11.2 “Informed 
Consent Forms.”  To document that informed consent was obtained, a progress note will be 
entered in the participant’s binder of study documents that contain PHI.  The original 
signed consent form will be filed in a single Study Consent Binder to facilitate the annual 
audit of consent forms that are conducted by VA Research Administration.  The participant 
will receive a copy of the signed consent form. 
Note: If a change in the study procedures is required, a revised consent form will be 
submitted to the local IRB for review and approval.  At their next clinic visit, study 
participants will be reconsented using the revised, approved consent form.  
Screening Evaluation (Visit 1) 
All screening evaluations to determine eligibility must be completed within 42 days (6 
weeks) of the Baseline visit.  Typically, the screening evaluation will be completed at a 
single clinic visit and eligibility will be determined within the next 2 weeks.  The next 4 
weeks is a waiting period to obtain a time slot for the Baseline MRI. 
To assess whether an individual meets enrollment eligibility criteria, the following 
assessments will be performed: 
The Participant will complete the following questionnaires 
o Cognitive Change Index 
o Geriatric Depression Scale (GDS 15-item) 
o ETOH Use Questionnaire (note ETOH use will also be assessed during MD 
interview with SP) 
The Study Coordinator will complete: 
o Vitals Signs (Safety Measure) 
o MMSE (Mini-Mental State Examination) 
o Logical Memory I and II 
The CDR Rater will complete:  
o Clinical Dementia Rating (CDR) Scale 
The referring Memory Clinic Physician or the rTMS Study Physician will perform 
the following medical evaluations 
o Medical history form /Initial Health Assessment 
o Physical, neurological examination  
(PE and NE within the past 12 months will be acceptable) 

rTMS-MCI Study Protocol 
27 
o Modified Hachinski Ischemic Score  
o Concomitant Medications & Key Background Medications 
o MCI Diagnostic Worksheet (normal, MCI and subtype, or dementia) 
o Inclusion / Exclusion Criteria Form 
The TMS Operator will administer the following: 
o MRI (and rTMS) Safety Screening  
o Motor Threshold (Left Hemisphere) 
If the MMSE is less than 24, the Study Coordinator will alert the PI, who will decide whether 
the remaining screening evaluations should proceed, or whether to end the screening visit 
early and inform the individual that the study is not a good fit for them. 
6.2.2 Enrollment, Randomization, and Baseline Assessments 
Enrollment 
Enrollment is defined in this study as the date when all of the screening criteria have been 
met and the previously consented individual agrees to participate.  Typically, eligibility will 
be determined within 2 weeks of completing the screening evaluation; enrollment will 
occur as soon as the individual expresses willingness to participate.   
The Study Coordinator will record the participant’s eligibility status, willingness to enroll, 
and the enrollment date on the Enrollment and Randomization Form.   
Randomization 
The Data Manager/SAS Analyst will receive the Study Coordinator’s emailed copy of the 
Enrollment and Randomization Form.  The Data Manager will randomize the participant 
using the randomization method described in Section 9.2.1 “Treatment Assignment 
Procedures.”  Once the participant is assigned, the Data Manager will record the date of 
randomization on the form and return the form to the Study Coordinator for data entry.  
The Data Manager emails the following information to the TMS Operator and the MRI Data 
Analyst:  
1. TMS Operator: receives the participant ID, the randomly assigned 6-digit treatment 
code, and the randomly assigned cortical site (DLPFC or LPC).  The 6-digit code 
masks whether the assigned treatment is active or sham.  (This code maps to the 
TMS device’s pre-programmed table of treatment codes.)  The site assignment is 
unmasked. 
2.  MRI Data Analyst: receives the participant ID and the randomly assigned cortical site 
assignment for use in subject-specific fMRI-guided neuronavigation of coil 
placement.  
Randomization will occur at least 14 days before the initiation of study intervention.  
As noted above, the time window from the beginning of Screening to the completion of 
Baseline Assessments is 42 days; the time window from the completion of Baseline to the 
initiation of the intervention is 7 ±3 days.  A 7-day interval between Baseline and initiation 
of the intervention is needed to allow time for subject-specific fMRI-guided 
neuronavigation of coil placement. 

rTMS-MCI Study Protocol 
28 
Baseline Assessments (Visit 2) 
Baseline assessments are only performed for consented participants who have completed 
screening, have met all eligibility criteria, are willing, and have enrolled into the study. 
All Baseline imaging and medical/cognitive assessments must take place within a 1-week 
timeframe.  These Baseline assessments must be completed at least 7 days before initiation 
of the intervention.  Typically, the Baseline assessments will be completed during a single 
visit, lasting 4 to 5 hours. 
The following assessments will be performed at the Baseline Visit: 
The Study Coordinator will complete: 
o Concomitant Medications (update of previously recorded medications) 
o Adverse Event Monitoring (to capture a new or a worsening ongoing condition) 
o Repeat of MRI (and rTMS) Safety form 
o MRI scan: 40 minutes of scan-time, which includes: 
 Scout and calibration scans 
 3D T1-weighted anatomical scan  
 T2-weighted FLAIR (Fluid-Attenuated Inversion Recovery) T2 GRE (Gradient 
Recalled Echo)  
 ASL (Arterial Spin Labeling) perfusion MRI  
 Task-free/resting-state functional MRI (rs-fMRI) using Simultaneous Multi-
Slice (SMS) acquisition)  
 DTI (Diffusion Tensor Imaging; 25 directions) 
<Rest Break> 
o Cognitive Assessments - Order of Testing 
 Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005);   
 California Verbal Learning Test (CVLT-II) (Delis et al., 2000);  
 Brief Visuospatial Memory Test–Revised (BVMT-R) (Benedict et al., 1996) 
 Trail Making (Partington & Leiter, 1949; Reitan, 1958) 
 CVLT-II Long-Delay Free Recall and Recognition 
 BVMT-R Delayed Recall and Recognition 
<Rest Break: Snack or Lunch> 
 Boston Naming Test (BNT; Huff et al. (1986) 42 items, two equivalent forms) 
 Rey-Osterrieth Complex Figure copy task only (ROCF copy) (Hubley, 2010; 
Hubley & Jassal, 2006)  
 Category Fluency (boys’ names; girls’ names) (Strauss et al., 2006) 
 Attentional Network Task (ANT) (Fan et al., 2002; Posner, 2012; Y.-F. Wang 
et al., 2015) 
The Participant and Study Partner will independently complete the Everyday 
Cognition (ECog) questionnaire (Farias et al., 2008). 
The Study Partner will complete the Functional Assessment Questionnaire (FAQ) 
(Pfeffer, Kurosaki, Harrah, Chance, & Filos, 1982). 

rTMS-MCI Study Protocol 
29 
Brief Descriptions of Behavioral Assessments 
Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005).  The Montreal Cognitive 
Assessment test (MoCA) is, similar to the MMSE, a brief, 30-point cognitive assessment 
designed to detect participants at the MCI stage of cognitive dysfunction.  This instrument 
has been shown to have adequate sensitivity and specificity in clinical settings to detect 
suspected MCI.  The MoCA provides a brief assessment of global cognitive function. 
California Verbal Learning Test-II (CVLT-II) (Delis et al., 2000), primary efficacy measure).  
The CVLT is a list-learning task that assesses multiple aspects of verbal learning and verbal 
episodic memory.  List A of the CVLT-II contains 16 concrete words; four words each from 
four categories (animals, vegetables, ways of traveling, and furniture).  List A is presented 
for 5 learning trials.    After presentation and recall of another List (B), a short-delay free 
recall and cued recall of list A is performed.  After a 20-minute delay filled with nonverbal 
testing, long-delay free recall and cued recall are assessed, followed by yes/no recognition 
of list A. 
Brief Visuospatial Memory Test–Revised (BVMT-R) (Benedict et al., 1996)).  The BVMT-R 
assesses visual memory.  The BVMT-R has six alternate, equivalent forms.  Each test form 
consists of a) 6 sets of geometric figures, each set arranged as a 2x3 array and printed on a 
page of the Recall Stimulus Booklet; and b) 12 recognition stimuli, each printed on a page in 
the Recognition Stimulus Booklet.  
Trail Making Test, Parts A & B (Partington & Leiter, 1949; Reitan, 1958).  These two tests 
progress from a numerical connect-the-dots puzzle to a more challenging alternation 
between alpha- and numerical order.  Although both Parts A and B depend on visuomotor 
and perceptual-scanning skills, Part B also requires cognitive flexibility in shifting from 
number to letter sets under time pressure. 
Boston Naming Test (BNT) Huff et al. (1986) 42-items, two-equivalent forms.  The BNT 
assesses the ability to verbally name pictured objects.  The subject is shown a series of line 
drawings and asked to name the object.  If the correct name of the object is not produced 
within 20 seconds, then a semantic cue (e.g., “kind of a building” for “house”) is offered.  If 
the correct name of the object is not produced within the next 20 seconds, then a phonemic 
cue is provided.  The test items become progressively more difficult (items are presented in 
order of decreasing frequency of the target word). 
Rey-Osterrieth Complex Figure (ROCF) (Hubley, 2010; Hubley & Jassal, 2006); copy task 
only).  The complete Rey-Osterrieth Complex Figure Test is designed to measure 
visuospatial constructional ability and visual memory.  In this clinical trial, the Brief 
Visuospatial Memory Test–Revised (described below) has been selected for assessment of 
visual memory, and the ROCF copy task will be used to assess visuospatial constructional 
ability.  The participant will be presented with the complex figure and asked to copy it. 
Category Fluency (Strauss et al., 2006).  This is a measure of verbal fluency in which the 
participant is asked to generate examples from a semantic category during a one-minute 
period. 
Attentional Network Task (ANT) (Fan et al., 2002; Posner, 2012; Y.-F. Wang et al., 2015) 
(Y.-F. Wang et al., 2015).  The ANT was developed by Posner and colleagues to provide 
reaction-time measures of the efficiency of alerting, orienting and executive attention.  
Posner has proposed that each attentional function is subserved by anatomically distinct 
networks in the brain (S. E. Petersen & Posner, 2012; Posner, 2012).  The ANT requires 

rTMS-MCI Study Protocol 
30 
participants to determine whether a central arrow in a set of 5 arrows points left or right.  
The basic design of the ANT incorporates a combination of Posner’s cued reaction time 
(RT) task (Posner, 1980) and the flanker task (Eriksen & Eriksen, 1974). Efficiency of 
orienting, alerting, and executive attention is assessed by measuring how response times 
are influenced by alerting cues, spatial cues, and congruent or incongruent flankers.  
Overall, the task has been deliberately kept short and simple so that it can be used with 
adults, children, monkeys, and patients with mild abnormalities of attention, and so that 
reliable estimates of the three attentional networks can be obtained within a half hour. 
Everyday Cognition (ECog) (Farias et al., 2008).  This instrument assesses for very mild 
functional impairment as may occur in MCI. The ECog is an informant-rated questionnaire, 
but participants will also be asked to complete a self-reported version of the same 
questionnaire.  It looks at everyday function in seven key cognitive domains: memory, 
language, semantic (factual) knowledge, visuospatial abilities, planning, organization and 
divided attention.  ECog correlates well with well-known established measures of 
functional status and global cognition. ECog can differentiate between individuals 
diagnosed with mild impairment in memory only and those mild impairment in several 
cognitive domains. ECog correlates weakly with age and education.  
Functional Assessment Questionnaire (FAQ) (Pfeffer et al., 1982). The FAQ consists of 10 
questions to ascertain the level of performance of daily function activities, including:  
paying bills; assembling tax records or other papers; shopping alone; playing a game or 
working on a hobby; keeping track of current events; understanding a TV program, book, 
or magazine; remembering appointments, family occasions, and medications; and driving 
or arranging to take public transportation. The four levels ranging from dependence or 
preparing meals.  Each of the 10 items is scored as one of four levels of independence 
(normal=0, has difficulty=1, requires assistance=2, and dependent=3). 
Geriatric Depression Scale Short Form (GDS) (Sheikh & Yesavage, 1986).  The GDS Short 
Form is a self-report scale designed to screen for symptoms of depression in the elderly.  
Note: the GDS is collected at the Screening Visit and at all three post-intervention Follow-
up Visits. 
Clinical Dementia Rating Scale (CDR) (Morris, 1993).  The CDR is a 5-point scale used to 
characterize level of functioning in six domains of cognitive and functional performance 
applicable to Alzheimer disease and related dementias.  The six domains are:  Memory, 
Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and 
Personal Care.  The information to make each rating is obtained through a semi-structured 
interview of the participant and a reliable collateral source, the Study Partner.  In addition 
to ratings for each domain, an overall CDR score is calculated through the use of 
an algorithm; the overall scores are: 0 = Normal; 0.5 = Questionable Dementia; 1 = Mild 
Dementia; 2 = Moderate Dementia; 3 = Severe Dementia. As in ADNI, a clinical diagnosis of 
MCI requires an overall CDR score = 0.5.  Note: the CDR is rated at the Screening Visit only. 
 
6.2.3 Intervention Visits (Visits 3 – 12) 
A participant will receive a total of 20 rTMS intervention sessions within a period of 2 to 
2.5 weeks, depending on scheduling constraints.  Typically, a participant will have a 
morning session and an afternoon session during a one-day clinical visit.  Accordingly, 2 

rTMS-MCI Study Protocol 
31 
intervention sessions are recorded as a single “visit” and the visits are numbered from 
Visits 3 through Visit 12. 
The first intervention session (Visit 3) needs to take place during a window of 7 ±3 days 
after the completion of the Baseline assessments.  An Intervention session is scheduled as a 
1-hour block to allow time for late arrivals, assessment of adverse effects, and for the 20-
minute rTMS intervention.  At the study physician’s discretion and if the participant 
requests, up to three rTMS sessions can be scheduled per day with at least one hour 
between sessions. 
To be fully adherent, the participant should complete 20 sessions within 30 calendar days. 
The following assessments and procedures will be performed at the Intervention Visits: 
First Intervention Session (am, Visit 3: Overnight fasting is necessary)  
o Concomitant Medications (update of previously recorded medications) 
o Adverse Events (to capture a new or a worsening pre-existing condition) 
o Vital Signs 
o Fasting Blood Sample (Genetic and BDNF Biomarkers), followed by breakfast 
o rTMS Safety Questionnaire 
o Motor Threshold Determination (Right Hemisphere), as described in Section 5.2* 
o rTMS Intervention Log 
o  Administration of study intervention, as described in Section 5.2 
      * Motor thresholds will be rechecked at the study physician’s direction at subsequent 
intervention sessions in the event a change in medication or a change in sleep 
pattern is reported by the participant and/or study partner.  If a participant’s 
subsequent MT is greater than the capacity of the TMS device, the subject will be 
treated at the maximum device capacity and tracked as such. 
Second Intervention Session (pm, Visit 3) 
o Concomitant Medications 
o Adverse Events 
o rTMS Safety Questionnaire if more than 24 hours since the previous 
o rTMS Intervention Log  
o Administration of the study intervention 
Intervention Sessions 3-18 (Visits 4 – 11) 
o Concomitant Medications 
o Adverse Events 
o Vital Signs 
o rTMS Safety Questionnaire 
o rTMS Intervention Log 
o Administration of the study intervention 
Intervention Session 19 (am, Visit 12: Overnight fasting is necessary) 
o Concomitant Medications  
o Adverse Events 

rTMS-MCI Study Protocol 
32 
o Vital Signs 
o Fasting Blood Sample (Genetic and BDNF Biomarkers), followed by breakfast 
o rTMS Safety Questionnaire 
o rTMS Intervention Log  
o Administration of study intervention 
Final Intervention Session 20 (pm, Visit 12) 
o Concomitant Medications 
o Adverse Events 
o rTMS Safety Questionnaire if more than 24 hours since the previous 
o rTMS Intervention Log  
o Administration of the study intervention 
Brief Descriptions of Assessments During the Intervention Phase 
Concomitant medications and AE monitoring.  Concomitant medication use (prescription, 
natural food products, and “over the counter”) will be updated at each morning 
intervention session.  During the intervention phase, medication use is recorded by the 
TMS Operator.  The Study Physician will be apprised of changes in medications. 
rTMS Safety Questionnaire.  The items of the Safety Questionnaire cover changes in mental 
and physical health, sleep patterns, changes in prescribed medications, recent alcohol 
consumption, and recent use of non-prescribed drugs.  The questionnaire is completed by 
the participant, in collaboration with the participant’s study partner.  See Section 7.1.4 
“rTMS: Safety and AE Monitoring during the rTMS Study Treatment Sessions 1-20,” for 
additional information on study staff responsibilities. 
rTMS Intervention Log (adapted from VA CSP 556).  The rTMS Intervention Log has 20 
rows corresponding to 20 intervention sessions.  Across the log sheet are a total of 13 
columns.  Columns 4-8 serve the purpose of prompting the TMS Operator to elicit 
medication changes, adverse events, hours of sleep, and use of alcohol and other 
recreational drugs and to notify the Study Physician in the event of a change in medication, 
change in sleep pattern, recent consumption of more than 1 alcoholic beverage, or use of 
street drug.  Column 10 is used to record all MTs, ie., the right and left MTs determined at 
Visits 1 and 3, and all MTs determined thereafter,  Column 11 is used to record the 
corresponding stimulation intensity.  Columns 12-14 are used to record adherence-related 
information (Treatment Completed (Y/N), # of minutes of treatment completed, and 
comments as to why treatment was not completed or what adjustments were made to 
improve tolerability).  These intervention-related data will be entered in the study 
database.  See also Section 7.1.4 “rTMS: Safety and AE Monitoring during the rTMS Study 
Treatment Sessions 1-20.” 
Vital Signs.  Vital signs, including temperature and weight, will be measured at all morning 
intervention sessions.  Blood pressure, respiration, and pulse will be measured in the 
sitting position.  
Fasting Blood Samples.  Blood samples for genotyping, plasma-, and serum-derived 
biomarkers and will be collected at Intervention Session 1.  Blood for plasma and serum 
biomarkers will be collected again at Intervention Session 19. 

rTMS-MCI Study Protocol 
33 
Procedures for Sample Collection.  FASTING OVERNIGHT (MINIMUM 6 HOURS) IS 
REQUIRED.  Only water is permitted until blood draws are completed.  The study visit 
schedule includes time for breakfast after the fasting blood sample is drawn. 
CONSENT TO DRAW BLOOD:  When samples are collected, the Study Coordinator will 
confirm the subject consented to biomarker collection per prior written informed consent.  
If the participant consented to biomarker collection, but is unable to provide a blood 
sample, a saliva sample can be collected for the genetic research. 
Table 3 summarizes the timing and sequence of sample collection, and the instructions 
for the immediate handling of samples. 
Table 3.  Biological Samples: Overview of Collection Procedures 
IS 1 
Tube
Order
IS 19 
Tube
Order
Sample Uses 
Tube 
Type 
# Tubes x 
Volume 
(mL) 
Total 
Amount 
(mL) 
Instructions and  
1 
1 
Whole blood:  Genomic 
DNA banking 
Plasma: Analysis of pre- 
post levels of BDNF at 
Intervention Sess 1 &19 
Buffy coat: Analysis of 
BDNF, APOE, COMT 
genotypes (Intervention 
Sess 1 only) 
Purple 
top EDTA 
1 x 10 
10 
Gently mix each 
tube by inversion, 
10 -12 times; 
 
 
 
 
 
 
2 
2 
Serum: Tissue Banking 
Red top 
serum 
1 x 10 
10 
Keep vertical and 
allow the blood to 
clot 
* IS = intervention session  
Blood samples will be centrifuged within 1 hour of collection.  Samples of saliva, if collected 
in lieu of blood, need to be delivered within 1 week of collection. 
Genetic and plasma-derived biomarkers.  Genomic DNA will be extracted from the 
participant’s sample for genotype determination of three genetic variants:  APOE e2/e3/e4, 
BDNF Val66Met (rs6265) and COMT Val158Met polymorphism (rs4680) and for genetic 
tissue banking.  APOE, BDNF and COMT genotypes will be used in exploratory analyses of 
heterogeneity of response to rTMS.  The amounts of BDNF in plasma will be quantified 
from the participant’s two samples that are collected at Intervention Sessions 1 and 19.   
Appendix V. “Sample Collection, Processing, Storage and Laboratory Protocols” further 
describes the procedures for obtaining, processing, and storing the samples, including 
details on required temperatures, location of storage, and labeling.  
6.2.4 Follow-up Visits (Visits 13, 14 and 15) 
Immediate Post-Treatment (Visit 13)  
The Immediate Post-Treatment Visit 13 needs to occur 7 ± 3 days after the 20th and final 
intervention session. 
o Each of the assessments and procedures performed at the Baseline Visit will be 
repeated at this visit.  See Section 6.2.2. 

rTMS-MCI Study Protocol 
34 
o In addition, the participant and study partner will be asked to complete a brief 
questionnaire regarding their views on the acceptability of rTMS as a treatment. 
Follow-up at 3-Month (Visit 14) 
Visit 14 can be completed ± 2 weeks of the target date. 
o Vital Signs  
o Concomitant Medications 
o Adverse Events 
o Cognitive Assessment Battery, administered by the Study Coordinator 
o ECog and FAQ Functional Outcome Questionnaires completed by Participant 
and/or Study Partner 
6-Month Follow-up (Visit 15) 
Visit 15 can be completed ± 2 weeks of the target date. 
o Each of the assessments performed at the 3-Month Follow-up will be repeated. 
o The Study Completion/Participant Withdrawal Form will be filled out to 
document the participant’s completion of the study. 
 
6.2.5 Study Completions, Withdrawals, Early Discontinuations and 
Terminations 
Study Completions and Withdrawals  
Visit 15 serves as the participant’s final evaluation.   If a participant withdraws from the 
study before Visit 15, every attempt will be made to collect the reason for the withdrawal 
of consent.  If the withdrawal from the study is due to a Serious Adverse Event (SAE) or 
Unanticipated Adverse Device Effect (UADE), the participant will be followed by telephone 
at least every 30 days to monitor recovery or other outcome, until the SAE is resolved.  If 
the SAE or UADE is not resolved, the participant will continue to be followed until 30 days 
after the End of Study date for that participant.  The SAE form will be updated at each 
contact.  Adverse Events (AEs), SAEs, and Adverse Device Effects (ADEs) are defined and 
discussed in more detail in Section 7.3. 
Early Discontinuation of the Study Intervention 
If a participant has a seizure during the intervention phase, the intervention will be 
discontinued immediately and completely.  A VA Outpatient Neurology Outpatient Consult 
evaluation will be requested to provide an understanding of precipitating factors involved 
in the seizure, and whether follow-up care is needed.  Study staff will then follow the 
participant by telephone to monitor recovery or other outcome, and report this SAE 
promptly per the appended protocol Appendix VI.  “Seizure Protocol.” 
If it is determined that a participant is using medications or abusing substances that 
increase risk of having a seizure, the PI and study physician will evaluate the situation and 
determine if it is appropriate for the participant to continue the intervention. If the study 
physician or PI feels that it is in the participant’s best interest to discontinue intervention 
because clinical judgment is that the intervention is not safe or tolerable for the participant, 
the intervention will be discontinued.   

rTMS-MCI Study Protocol 
35 
In each of these situations that lead to early discontinuation of the intervention, the 
participant will be asked to undergo the assessments that are normally administered 
during the Follow-up Phase (i.e. all assessments for Visits 13, 14, and 15). 
Early Termination of Participation 
Study enrollees are unlikely to be terminated from the study per se, unless an SAE occurs 
prior to the first rTMS session; or, if after enrollment, the investigators determine that the 
participant is ineligible.  
Documentation of Study Status 
Whenever a participant withdraws, is terminated, or completes Visit 15, the Study 
Completion/Participant Withdrawal Form will be filled out to formally document and 
track the enrollees’ study status.  
 
7 SAFETY ASSESSMENTS  
7.1 Expected AEs; Safety screening; Modifications and management if an AE 
occurs 
Expected adverse experiences, monitoring of participant safety, and modifications or 
management in case an AE occurs are described below for each study intervention, in order 
of procedural flow, starting with the Baseline MRI: 
7.1.1 MRI 
MRI has potential risks and discomforts but with careful screening of patients and 
adherence to manufacturer’s operation instructions, many adverse events can be 
prevented (Shellock, 2001; Shellock, 2002).  
MRI Safety Screening (Telephone pre-screening; Visits 1, 2, and 13) 
Serious adverse events (SAEs) occur if ferromagnetic objects (particularly when 
implanted) or electromechanical devices such as pacemakers enter the MRI.  To assess for 
MRI Safety, all subjects will be rigorously screened by MR personnel to be certain that they 
do not have any medical contraindications for MRI which include metallic foreign bodies in 
the brain or eye, or cardiac pacemaker.  This safety screening is part of routine clinical 
practice at MRI centers and is performed before any subject is permitted to enter the 
scanning room.   
The MRI Safety Form provides screening for factors that might affect the participant’s 
comfort in the MRI environment. These factors include claustrophobia and back pain that 
interferes with their ability to lie supine for a prolonged period.  Individuals who know 
they are severely claustrophobic would be excluded from participating in the study.  People 
with weight or size above the size allowable by the manufacturer will not be scanned.  
While it is unlikely that women in this study will be of childbearing age, the formal, written 
screening form lists pregnancy as exclusion.   
Safety Procedures and Modifications during an MRI Scan Session (Visits 2 and 13) 
Anxiety.  Any participant who experiences anxiety when placed into the MR scanner will 
be pulled out of the scanner, offered reassurance by the MR tech doing the scan, and 
offered the option of continuing or terminating the scan.  There will be no attempt to 

rTMS-MCI Study Protocol 
36 
persuade participants to complete a scan that they are uncomfortable with.  No sedative or 
anxiolytic agents will be given, as this is a voluntary research protocol. 
Ear Protection.  As with a routine clinical MRI, participants will wear MR compatible ear 
protection.  
Incidental findings. The scans performed in this study are not optimized to find 
abnormalities. However, a Stanford radiologist will provide clinical reads of the anatomical 
scans and will also notify the PI whether an abnormal finding merits follow-up.  In that 
case, the study physician will contact the participant regarding follow-up with the 
participant’s physician.  Image data collected in the course of the research project will not 
be made available for diagnostic purposes because they do not comprise a full clinical MRI 
series.  
Investigational MRI.  Some of the imaging software are not FDA approved, but have been 
tested for safety and are very similar to what is used regularly in clinical MR examinations. 
The MR personnel are highly trained in the set-up, monitoring, and use of this software.  
Metal.  There is a slight risk that someone will accidently bring metal into the MRI scanner 
room, which might be pulled into the MRI magnet and injure the participant.  MR personnel 
work with the participant to make sure such objects are removed and stored in a locker 
before entering the magnet room. 
Medical emergency.  In the unlikely event of a medical emergency, the Stanford University 
Hospital’s Emergency Department is a nearby, where medical intervention can be provided 
by Stanford Health Care Emergency Department staff.  See Appendix VII.  “MRI Emergency 
Protocol”. 
7.1.2 Neuropsychological testing and Questionnaires 
The risks posed by neuropsychological testing are temporary fatigue and mild frustration. 
Fatigue.  Participants will be reminded that they are free to take a break if feeling tired.   
Frustration. If the participant appears to be excessively frustrated, they may discontinue 
that test and be offered an easier one.  If a participant is unwilling to continue a testing 
session, they will be given the option of continuing at a later time, ending the current 
session, or ending all participation.  
7.1.3 Blood draws for analysis of biomarkers and genetics 
Blood draw discomforts.  There is a small risk of pain with a blood draw when the needle 
enters the skin.  Bruising at the site of the needle stick may occur, but this is temporary.  
Some people may experience fainting or dizziness.  To minimize these risks, experienced 
personnel at the VA Outpatient Surgical Center will handle all the blood drawing 
procedures.   
Blood draw infection risk.  Sterile conditions are maintained at the VA Outpatient 
Surgical Center.  In the unlikely event of infection at the site of the needle stick, the 
participant will be treated at the study site. 
Genetic testing concerns.  It is possible that biomarker and genetic testing could cause 
some psychological stress in a few individuals.  All participants will be informed that tissue 
samples and results of the biomarker and genetic testing will be labeled using a code that 
has no individual identification.  Participants will be informed that we will not release 

rTMS-MCI Study Protocol 
37 
results of the genetic testing to them, to members of their family, physician, or other third 
party. 
7.1.4 rTMS 
TMS Safety Screening (Telephone pre-screen and Visit 1 in-person screen) 
To minimize risks and AEs related to rTMS, the same ferromagnetic safety policies and 
procedures described above for MRI will be applied to rTMS safety screening.   During the 
consenting and history taking process, we emphasize to participants that giving false 
information about their medical history, including past and present drug use, could have 
serious consequences for their health and well-being.  
Individuals who might be prone to seizures (e.g. have had a recent traumatic brain injury, 
have history of a seizure disorder, need to be on medications that substantially increase the 
risk of having seizures, or abuse medications or use illegal substances that can increase the 
chance of having a seizure) will be excluded from this study, as documented on the Medical 
History and the Inclusion/Exclusion Forms.  
Even though psychotic symptoms and suicidal ideation have been never described in 
normal subjects during or after rTMS, there is a report of one patient with major 
depressive disorder who developed delusions during rTMS treatment (Zwanzger, Ella, 
Keck, Rupprecht, & Padberg, 2002).  In the present MCI rTMS study, participants with a 
Geriatric Depression Scale score ≥ 6 will not be eligible to enroll. (They will be referred for 
evaluation and treatment of their depressive symptoms.)   
Safety and AE Monitoring during the rTMS Study Treatment Sessions 1-20 
Eligible participants will be closely monitored by the study physician and the certified TMS 
operator during the intervention phase to minimize the risks associated with the rTMS 
intervention/device and to document adverse effects.   
At the beginning of every morning treatment session, the participant will be asked about 
changes in mental and physical health, sleep patterns, changes in prescribed medications, 
recent alcohol consumption, and recent use of non-prescribed drugs, using the TMS Session 
Safety Questionnaire.  This questionnaire will be used by the TMS Operator to probe an AE 
further.  All AEs will be documented on the Adverse Event form.  
In case of a safety concern, the Study Coordinator or TMS Operator will alert the Study 
Physician before proceeding with rTMS.  If the participant reports having had less than one 
hour of sleep the previous night, the rTMS session will postponed until the participant’s 
sleep pattern improves.  During every session, the rTMS Operator will monitor the 
participant’s ear protection, coil placement, and possible seizure activity.  The log sheet 
explicitly reminds the Operator to notify the Study Physician in the event of a change in 
medication, change in sleep pattern, recent consumption of more than 1 alcoholic beverage, 
or use of street drug.  Motor thresholds (MTs) will be rechecked at the Study Physician’s 
direction. Rechecked MTs and power outputs will be documented in the participant’s 
intervention log.   
If an AE occurs:  Risk management, modifications, and assessments  
Discomfort.  Should a headache or site discomfort occur, these symptoms are expected to 
be self-treated (e.g. with ibuprofen).  Reported levels of discomfort often diminish in later 
sessions in the absence of over the counter (OTC) pain medications.  If dental pain occurs, 

rTMS-MCI Study Protocol 
38 
study staff may be able to move the rTMS coil position slightly or provide a bite block to 
reduce or prevent the pain.  
Ear Protection.  To protect against possible hearing damage, participants will wear ear 
protection during rTMS sessions.  
Syncope. Occasionally, syncope occurs with TMS, particularly in initial sessions.  Staff will 
provide reassurance and monitor the participant for level of anxiety and psycho-physical 
discomfort.  Premonitory complaints are: “I need to lie down”, or “I need air” “I think I’m 
going to black out.” Visceral distress, nausea, dizziness, pallor, and diaphoresis are other 
symptoms.  Upward eye deviation, which is common in circulatory syncope, is rare in 
partial seizures unless there is progression to generalized convulsions.  Because 
participants will be reclined in a chair during the stimulation procedure, the risk of syncope 
and a fall-related injury are lower.  Study staff will be trained to be first responders to these 
unlikely events, and will know to call the VAPAHCS facility’s E-Team as a proactive 
measure.  Uncomplicated syncope not requiring hospitalization is normally considered an 
adverse event; the seriousness of the AE is a clinical judgement of the study physician. 
Seizure.  The VAPAHCS facility where the rTMS treatment sessions are performed is fully 
equipped to safely handle a seizure.  The initial management of syncope and seizure is 
identical.  Clinically, the cardinal feature that distinguishes syncope from seizure is rapid 
recovery of consciousness within seconds and not minutes.  Delayed recovery of normal 
consciousness beyond 30 seconds mandates further evaluation and a neurological work-
up.  The participant will be treated at the study site for any medical or psychological 
consequences.  Procedures for medical care, for documenting this study-specific SAE, and 
for monitoring the outcome of a seizure-related SAE are described separately in seizure 
safety protocol (see Appendix VI.  “Seizure Protocol”). 
7.2 Summary of Safety Assessments 
Safety will be measured based on the occurrence of serious adverse events, such as 
seizures, and syncope that results in hospitalization.  Tolerability of rTMS will be based on 
the number of adverse events reported (grouped per side effect type) and number of 
dropouts due to AEs and other reasons during the intervention phase of the study.   
All AEs will be documented on the Adverse Event form.   If the AE is serious, then the SAE 
will be further documented on the SAE Form.  Briefly, the forms contain the event 
description, severity, outcome, recovery date, and other follow-up information.  
7.3 Adverse Events and Serious Adverse Events  
Definitions for Adverse Events (AEs) 
An Adverse Event (AE) is any untoward medical occurrence, including any abnormal sign, 
symptom, or disease temporally associated with study participation, whether or not 
considered related to participation in the research.   
 An AE is deemed to be associated with the use of the study device if there is “a 
reasonable possibility that the experience may have been caused by the device.”   
 Chronic problems which are unchanged from baseline are not considered AEs.  
However, worsening of an ongoing condition would be considered an AE.  
A Serious Adverse Event (SAE) is an adverse event that  
 results in death  

rTMS-MCI Study Protocol 
39 
 is life-threatening, or places the participant at immediate risk of death from the 
event as it occurred 
 requires or prolongs hospitalization 
 leads to persistent or significant disability or incapacity  
 is a seizure (Note: intervention-specific SAE definition) 
 Is another condition which investigators judge to represent significant hazards. 
An Unanticipated Adverse Device Effect (UADE) is an SAE caused by or associated with a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence, or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of patients.   
Time span of collecting AEs and SAEs 
Collection of all adverse events will begin at the time the participant signs the informed 
consent form and will continue throughout the 6-month post-intervention follow-up phase:   
 At the Baseline visit, the participant and study partner (SP) will be asked about 
changes in medications, any other health or behavior changes, and any medical 
care received since the Screening visit;  
 At each Intervention session, the participant will be asked about any side effects 
experienced.  At each morning Intervention session, the participant will 
additionally be asked about any changes in medications, any other health or 
behavior changes, and any medical care received;  
 At the Immediate Post-Intervention Follow-up visit, the participant will be asked 
about any side effects experienced since last seen, and any changes in medications, 
any or other health or behavior changes since the previous visit or phone follow-
up, and any medical care received;  
 At the 3- and 6-Month Follow-up visits, the participant will be asked about any 
changes in medications, medical care received, or other health or behavior 
changes since the previous visit or phone follow-up.  
In summary, study staff will screen for new AEs/SAEs and review any unresolved 
AEs/SAEs at each encounter with the participant.   
7.4 Reporting Procedures 
Time lines for reporting AEs and SAEs 
The PI and research team will notify the DSMB and the NIA Program Official of all SAEs 
(regardless of intervention vs. follow-up phase) by group email within 24 hours of study 
staff’s knowledge of the event. 
 The emailed, expedited report will be followed by a detailed, written initial SAE 
report as soon as possible.   
 The PI is responsible for verifying that the report has been submitted and that that 
the DSMB Chair and NIA Program Official acknowledge receipt. 
The PI and research team will report SAEs to the local IRB per Stanford University’s HRPP 
Policy Guidance “Events and Information that Require Prompt Reporting to the IRB“ GUI-
P13 1/3 (see Appendix X). 
All adverse events will be reported annually or more often to the DSMB, Stanford IRB, and 
NIA staff.   

rTMS-MCI Study Protocol 
40 
 The study’s Data Manager will generate tabulations of all AEs (including SAEs and 
non-serious AEs) and present a summary of these to the DSMB and NIA staff on a 
schedule set by the DSMB.   
 Aggregate summaries of SAEs and non-serious AEs will also be reported annually 
to the Stanford IRB.   
Procedures and forms for recording AEs 
Any new condition, recurrence of a previously resolved condition, or worsening of a pre-
existing condition will be reported as an AE.  (The Screening Visit Medical History Form 
provides a list of all pre-existing conditions and whether each condition is resolved or 
ongoing.) 
All adverse events (including adverse device effects) will be recorded on the AE report 
form (based on NIH Template AE form 9a) and, if severe, on the SAE form (based on NIH 
Template SAE form 9b).  Both SAEs and UADEs will be recorded using SAE form 9b.  All 
adverse events will be assessed as “Not related,” “Possibly related,” or “Definitely Related” 
to the intervention or to other study procedures.   
Decisions regarding AE relatedness and severity  
The Study Physician will be responsible for decisions regarding relatedness and severity.  
Assessment of study relatedness.  Relatedness involves an assessment of the degree of 
causality between the study intervention and the event. Relatedness can be assessed by 
considering the following criteria:  
 Previously reported with this treatment,  
 Occurred after treatment began,  
 Improved when treatment is withdrawn or a specific antagonist administered,  
 Reappearance upon re-challenge,  
 No alternative causes for the reaction,  
 Increased severity when dose increased or lessened when dose decreased,  
 Patient previously had similar reaction when exposed to the treatment, and  
 Reaction confirmed by objective evidence. 
Study-relatedness criteria. 
 All adverse events or effects with a clear causal relationship to the intervention or 
to the procedures involved in the research should be considered “Definitely 
related”.   
 All adverse events or effects with a possible causal relationship to the intervention 
or to the procedures involved in the research should be considered “Possibly 
related”.   
 In general, if event is determined to be caused solely by an underlying disease, 
disorder, or condition of the subject, or due to other circumstances unrelated to 
either the research or any underlying disease, disorder, or condition of the subject, 
it would be considered “Unrelated” to participation in the research. 

rTMS-MCI Study Protocol 
41 
Study Staff Responsibilities 
 During the pre- and post-intervention phase of the study, the Study Coordinator 
will be responsible for collection of initial AEs, follow-up of AEs (see Section 7.5) 
and completion of AE forms. 
 The TMS Operator will be responsible for initial AE collection, follow-up, and form 
completion during the intervention phase. 
 The Study Physician will be responsible for reviewing all AEs and for making 
decisions regarding relatedness and severity. 
 The PI will be responsible for reviewing the AE forms for completeness and 
accuracy, for monitoring the AE data to avoid double capture of AEs, and for 
monitoring charts and CRFs for documentation of the physician’s review of AEs.  
7.5 Follow-up of Adverse Events 
All AEs will be followed until resolution, or until the patient’s participation in the study 
ends.  For a participant who ends study participation prior to the 3-month follow-up visit 
(Visit 14), unresolved SAEs/UADEs will be monitored and reported for 30 days after the 
date the participant was last-seen. 
An AE will be considered “resolved” when one of the following criteria are met: 
 Health has returned to baseline status or applicable variables have returned to 
normal. 
 The event has stabilized and the study staff expect no further improvement or 
worsening of the event. 
If the Adverse Event does not resolve and it has been determined that the condition is 
stable or chronic, then the event can be considered “resolved with sequelae”. 
The study staff are also responsible for following up on AE/SAE information that was 
initially incomplete.  Whenever new information about an SAE is obtained, the staff is 
responsible for reporting the follow-up information as soon as it becomes available.  
Examples of incomplete AE/SAE information that may require follow up: 
 An event for which complete information was not available at the time of 
reporting to the DSMB or NIA Program Official. 
 Update or new information related to an event that was previously reported (e.g. 
receipt of hospitalization records, clarity from study participant on event details). 
7.6 Safety Monitoring and other DSMB Reporting 
The PI will be responsible for ensuring participants’ safety on a daily basis. The Data and 
Safety Monitoring Board (DSMB) will act in an advisory capacity to the NIA Director to 
monitor participant safety, evaluate the progress of the study, to review procedures for 
maintaining the confidentiality of data, the quality of data collection, management, and 
analyses.  The DSMB will also determine when they should be un-blinded to treatment 
assignment for the reviewing of AE data and evaluating whether the aggregate AE 
information may also qualify as a UP.  The DSMB will advise the PI concerning whether the 
study should continue or be stopped for safety reasons.  
DSMB will meet twice annually, typically by teleconference call to review study progress, 
data quality, and participants’ safety.  The DSMB may decide to meet less frequently (such 

rTMS-MCI Study Protocol 
42 
as annually) and may receive a data report for their review in-between meetings.  The 
DSMB will discharge itself from its duties when the last participant completes the study. 
Open-Session Reports to the DSMB will include information on:  (1) recruitment and 
overall study status; (2) participants descriptive information; (3) safety information, and 
(4) information on study quality.   The contents of the report will be based on the NIH 
Single-site Open DSMB Reports Templates.  Appendix IX “Data and Safety Monitoring” 
provides an outline of the various tables and charts that the PI proposes to provide to the 
DSMB.  For example, a recruitment-related table will show the reasons for screen failures, 
including any refusals to donate blood or saliva for DNA extraction.   
For Closed-Session reports, the Study’s Data manager will generate AE reports using 
modified NIA templates with information reported by blinded treatment group (A, B, C). 
The final content and format of the reports for both the open and closed sessions will be 
determined by the DSMB.  Throughout the trial, the DSMB may request changes in the 
content or format of the reports. 
Special Procedures for the Monitoring of Seizures 
As addressed in the rTMS Safety Section 7.1.1, participants will be closely monitored by the 
study physician and the certified TMS operator during the intervention phase to minimize 
the risks associated with the rTMS intervention/device.  In the unlikely event that a seizure 
occurs, the hospital where this rTMS study will be conducted is fully equipped and staffed 
to respond to a seizure.  The study staff will be trained as first responders, and trained to 
carry out the “Seizure Protocol” previously developed by the CSP 556 investigators (see 
Appendix VI).  Procedures for medical care, for documenting and reporting this study-
specific SAE, and for monitoring the outcome of a seizure-related SAE are described 
separately in the seizure safety protocol.  
8 INTERVENTION DISCONTINUATION  
8.1 Permanent discontinuation of the study intervention  
The study intervention will be discontinued if:   
 A participant has a seizure; 
 There are signs or reports of inability to tolerate the intervention.  Specifically, the 
participant will no longer continue with the intervention if the participant either 
reports or indicates upon questioning that a side effect (such as a headache) is not 
well tolerated despite self-treatment (e.g. severe in intensity and persists beyond 
the first week of treatment), or if the study physician feels it is in the participant’s 
best interest to discontinue with the intervention. 
 Or, any other health or safety concern that contraindicates continuation, based on 
the judgment of the study physician.  
Continued follow-up will occur in each of these cases.  The participant will be closely 
monitored and treated for any medical or psychological consequences.  The Study 
Coordinator will be responsible for phone follow-ups to check on the participant’s well-
being and to collect follow-up AE information.   
Such participants will be encouraged to return for all three post-intervention follow-up 
evaluations (Visits 13, 14, and 15).   Except for the MRI scan (Visit 13), all other outcome 

rTMS-MCI Study Protocol 
43 
measures, safety assessments, and AE information would be collected at the three follow-
up visits. 
8.2 Temporary discontinuation of the study intervention 
The intervention will be temporarily discontinued in case of a concern regarding safety or 
intolerability to rTMS.   
Recognized safety concerns for eligible participants during intervention are: 
 Insufficient sleep; 
 Use of substances or medications that increase seizure risk.  
Tolerability concerns include: 
 In case of headache or site application discomfort or other AE, the intervention 
can be temporarily discontinued either at the request of the participant or based 
on a physician’s recommendation. 
Modifications to the intervention schedule.  In the event of a safety concern, the Study 
Coordinator or TMS Operator will alert the Study Physician before proceeding with rTMS.  
If the participant reports having had less than one hour of sleep the previous night, the 
rTMS session will postponed until the participant’s sleep pattern improves.  If it is 
determined that a participant is using or abusing substances or medications that increase 
risk of having a seizure, the Study Physician and PI will evaluate the situation and 
determine if it is appropriate for the participant to continue. 
While a participant is temporarily discontinued from receiving the intervention, the Study 
Coordinator will be responsible for phone follow-ups to check on the participant’s well-
being and, if applicable, to collect information regarding resolution and/or occurrence of 
adverse events. 
8.3 Replacement Subjects and Voluntary Withdrawals  
Replacements.  In the event of an SAE prior to the Baseline Visit or a medical emergency 
during a Baseline MRI, (i.e. prior to randomization), the intervention and study assessments 
will be canceled.  Such a participant would continue to be followed to monitor recovery; 
however, active participation in the study would end for the participant’s safety, and because 
of unstable or uncertain health status. (See also Appendix VII. “MRI Emergency Protocol” and 
Section 7 above.)  Another subject will be enrolled to replace that participant.  
Voluntary withdrawals.  Subjects may withdraw voluntarily from participation in the 
study at any time and for any reason.   If voluntary withdrawal occurs during the 
intervention phase, the participant will be encouraged to return for all three post-
intervention follow-up evaluations (Visits 13, 14, and 15).  Except for the MRI scan (Visit 
13), all other outcome measures, safety assessments, and AE information would be 
collected at the three follow-up visits.  If an AE or SAE begins during the intervention phase 
and the participant decides to withdraw, the Study Coordinator will continue to do phone 
follow-ups to check on the participant’s well-being and to collect follow-up AE information.   

rTMS-MCI Study Protocol 
44 
9 STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
This is a double-blind, randomized, 2-stimulation-site, sham-controlled parallel group 
design of rTMS treatment to either bilateral DLPFC or LPC.  The parallel groups design 
avoids potential carryover effects of active rTMS treatment to other treatment conditions 
within the same subject.  The length of an appropriate washout period for rTMS has not 
been established for this rTMS intervention protocol in this population.   
Primary Hypothesis  
The primary hypothesis is that participants receiving active (“real”) rTMS will show more 
improvement in memory at the immediate post-treatment assessment than the placebo 
(sham) control group.  The sham group is comprised of all subjects assigned to the sham 
group, regardless of the position of the sham coil. 
Testing the primary hypothesis involves two statistical tests:  Test 1 will compare Active 
DLPFC to sham; Test 2 will compare Active LPC to sham.   
For these tests, memory is measured by the CVLT-II Trials 1-5 Total raw score.  This 
outcome measure has excellent retest reliability (Total and Delayed: r  > .75), diagnostic 
validity (Rabin et al., 2009) (Silva et al., 2012), and normative data on a representative 
sample.  The CVLT, which is comprised of 16 concrete words presented for 5 learning trials, 
helps achieve a wide range of scores that are neither at floor nor at ceiling level (Ellis et al., 
2009; Karrasch, Sinerva, Gronholm, Rinne, & Laine, 2005; Ribeiro, de Mendonca, & 
Guerreiro, 2006).  An additional advantage of the CVLT-II is the availability of alternate test 
forms. 
Secondary Analyses   
This study, was originally proposed in response to NIH/NIA PAR-16-365 “Pilot Clinical 
Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline (R01).”  In 
addition to testing the primary hypothesis to learn whether rTMS is a viable 
nonpharmacological intervention for treatment of MCI, this study was designed to address 
essential questions of durability, choice of site, and prediction of response.  Information 
gained from this study will inform efforts to optimize rTMS effectiveness and pave the way 
for further clinical development.  From this perspective, we plan to examine durability of 
rTMS over the 6-month follow-up, and to describe effects of rTMS on secondary cognitive 
and behavioral outcomes, as described below: 
 (Grant Aim 2a) Assess the durability of rTMS effects:  The primary efficacy 
measure, the CVLT-II Trials 1-5 Total raw score will be analyzed for effects of rTMS on 
memory at 3- and 6-month post-intervention.  Our working hypothesis is that an effect of 
rTMS on memory will be sustained up to 3 months. 
 (Grant Aim 2b.1) Examine behavioral differences related to the site of brain 
stimulation:  The secondary behavioral outcomes will be analyzed in longitudinal data 
analyses with respect to the site of active stimulation (DLPFC or LPC).  The secondary 
behavioral outcomes of most interest are selected sub-scores of the CVLT-II.   
 Because the DLPFC and LPC have distinct roles in memory encoding and delayed 
recall (Long, Oztekin, & Badre, 2010), our working hypothesis is that DLPFC 
stimulation could result in a higher level of semantic clustering compared to LPC 

rTMS-MCI Study Protocol 
45 
stimulation.  By contrast, LPC stimulation could result in higher recall, assessed by 
CVLT-II short- and long-delayed recall scores.  An rTMS-induced increase in 
semantic clustering would be a positive outcome in MCI because older adults who 
showed more semantic clustering on the CVLT-II were more cognitively stable 
over time (McLaughlin et al., 2014).  An rTMS induced increase in delayed recall 
would also be clinically important.  
As part of addressing secondary Aim 2b.1, effects of rTMS on other secondary outcomes 
will be described.  These outcomes include depressive symptoms, objective assessments of 
global cognitive function, visuospatial episodic memory, language, visuo-constructional 
ability, orienting of attention, information processing speed, executive function, and self- 
/partner-reported assessments of everyday cognitive functioning.  All measures have 
demonstrated re-test reliability and construct validity.  These secondary outcomes (which 
are described in Section 6.2.2) are listed in Section 9.4.2 below. 
 (Grant Aim 2b.2) Changes in brain function related to the site of brain stimulation. 
This study is designed to provide novel information about the therapeutic mechanisms of 
rTMS in the target population.  Resting-state fMRI scans will be acquired at the Baseline visit 
and the Immediate Post-Treatment visit to examine effects of rTMS on brain functional 
connectivity.  Additionally, plasma levels of brain-derived neurotrophic factor (BDNF) will be 
measured before and at completion of the rTMS intervention.     
 Our working hypothesis is that BDNF levels will increase more in either active 
rTMS group, compared to that in the sham group.   
 Our working hypothesis is that rTMS will beneficially modulate functional 
connectivity within and between large-scale networks that are abnormal in MCI. 
Two analyses will be performed: (1) The aim of one set of analyses is to learn the 
extent to which rTMS can restore connectivity within regions of the Default-Mode 
Network (DMN), especially to the hypo-connected PCC; (2) The aim of the second 
set of analyses relates to between-network connectivity.  We will examine if rTMS 
reduces abnormally strong functional connectivity between the Central Executive, 
and Default-Mode Networks (CEN and DMN), as has been found preliminarily in 
rTMS studies on ameliorating depressive symptoms in TRMDD and executive 
dysfunction in mild TBI.  Functional connectivity metrics are outlined in Section 
9.4.2 “Secondary neuroimaging outcomes.”  Analyses are outlined in Section 9.5.2 
“Secondary Analyses.” 
 As part of addressing secondary Aim 2b.2, we will explore the extent to which 
rTMS-induced changes in functional connectivity correlate with changes in 
selected behavioral variables, e.g., is the amount of reduction in functional 
connectivity between the CEN and DMN associated with improvement in executive 
function?  
(Grant Aim 2c) Heterogeneity of response to rTMS.  We expect that baseline clinico-
demographic characteristics, baseline connectivity, and genetic variants may help explain 
individual differences in responsiveness to rTMS, either generally, or to a particular rTMS 
site.  Selected baseline variables relevant to explaining heterogeneity of response are 
outlined in Data Analysis Sections 9.5.2. 

rTMS-MCI Study Protocol 
46 
9.2 Sample Size and Randomization 
Power to test the primary hypothesis.  We have powered the proposed study to detect a 
moderately large effect size (Cohen’s d = 0.80) of either rTMS treatment on the primary 
outcome.  Moderately large effect sizes of 1.0, 0.80, and 0.80 were reported in two meta-
analyses of rTMS studies in AD (Liao et al., 2015) (Hsu et al., 2015) and one rTMS trial in 
MCI (which used unilateral rTMS (Drumond Marra et al., 2015), deemed suboptimal by 
(Liao et al., 2015)).  Our proposed design is estimated to have 80% power to detect an 
effect size of 0.8, for a 5% two-tailed test., with a multiple testing penalty for 2 tests.   
Attrition and the test of the primary hypothesis.  The attrition rate in Dr. Adamson’s rTMS 
TBI trial at our site has been 0% so far.  The rate of attrition in the rTMS MCI trial (Drumond 
Marra et al., 2015) due to all reasons was 6%.  Based on these rates of attrition, we do not 
expect attrition to substantially reduce power or the interpretation of results.  If a participant 
in the present study discontinues the intervention early, we will encourage the participant to 
undergo all post-intervention assessments that are normally administered during the 
Follow-up Phase (Visits 13, 14, and 15).  If there are baselined participants who have missing 
outcome data, we will perform and report sensitivity analyses that include participants with 
missing data, and make plausible assumptions about their outcomes based on the observed 
data.  Additionally, the total minutes of rTMS received by each participant can be used as a 
covariate in the data analyses.   
Attrition and secondary data analysis of behavioral outcomes.  For the durability 
analysis of rTMS effects, mixed-effect growth curve analyses will be used, which enables 
full utilization of repeatedly measured outcomes and minimizes bias if subjects drop out 
during the extended follow-up period of the study (Singer & Willett, 2003).   
Likelihood of obtaining other useful secondary results.  In these secondary analyses, 
the proposed sample size will provide 80% power to detect a large difference (d = 1.00) 
related to the site of stimulation.  For all analyses, we will convey practical significance by 
reporting effect sizes and confidence intervals, in addition to reporting statistical 
significance. 
9.2.1 Treatment Assignment Procedures 
Participants will be randomized to one of three treatment groups: (1) active rTMS of the 
DLPFC, (2) active rTMS of the LPC, or (3) sham rTMS (evenly split between each coil 
location).  An adaptive randomization scheme will be used so that equal numbers of 
participants will be randomized to each of the 3 treatment groups within blocks of every 6 
participants.  For each block, 4 active and 2 sham treatment numbers will be randomly 
assigned.  To ensure proper allocation of participants, a block of 6 participants will consist 
of:  2 active DLPFC, 2 active LPC, 1 sham DLPFC and 1 sham LPC. 
The treatment numbers are non-sequential, and a 6-digit number is assigned to each 
participant.  This unique 6-digit number will be key entered into the TMS device interface, 
whose programming enables the device to deliver the appropriate treatment (active or 
sham) to that participant.   
Masking.  To ensure appropriate masking for the study, the Database Manager/SAS 
Programmer performs the randomization of each participant to treatment and maintains 
the randomization codes.  The Database Manager will store the randomization codes in an 
encrypted restricted-access file on the server.  Only the Database Manager will know the 
link for randomization.  To prevent unplanned breaking of randomization codes, the 

rTMS-MCI Study Protocol 
47 
Database Manager will utilize codes to refer to treatment groups, and maintain the link of 
these codes to the actual treatment groups in a separate file.   
Unmasking.  If a participant were to experience an SAE during the intervention phase, 
unmasking of that participant’s treatment is permitted only if knowledge of the 
participant’s treatment assignment is necessary to protect patient safety.  The DSMB will 
determine when they should be unmasked to treatment assignment for the reviewing of 
adverse event data. 
9.3 Interim analyses and Stopping Rules 
There is no planned interim analysis for this single-site project.  The DMSB or NIA will 
determine if a planned interim analysis should be conducted.  If the DSMB requests a 
detailed safety review of SAEs or severe AEs by group, then based on that review, the DSMB 
or NIA Officer will determine what steps will be taken.  
9.4 Outcomes  
Outcome measures will be collected by blinded staff (study coordinator, imaging analyst, 
laboratory staff), and analyzed at study completion by the Database Manager under the 
supervision of the Ph.D. biostatistician. 
9.4.1 Primary outcome   
Primary outcome is the California Verbal Learning Test (CVLT-II) Trials 1-5 Total  
raw score (possible range 0-80), assessed at Visit 13 (immediate post-treatment). 
The CVLT-II is also assessed at Visit 2 (Baseline) and at Visits 14 and 15.   As described in 
Sections 9.4.2 and 9.5. these scores will be used as the baseline covariates and secondary 
outcomes. 
9.4.2 Secondary outcomes   
a) Secondary behavioral outcomes (assessed at Visits 2*, 13, 14 & 15) 
 Depressive symptoms: 15-item Geriatric Depression Scale (GDS), Total score (0-15) 
 Everyday functional outcomes:  Everyday Cognition Scale Total score (39-156) 
and Functional Activities Questionnaire Total score (0-30) 
 Global cognition: Montreal Cognitive Assessment Total score (0 to 30) 
 Verbal episodic memory: CVLT-II Semantic clustering (chance-adjusted) Trials 1-5 
(0-80) and CVLT-II Short-delay free recall correct (0-16) 
 Visuospatial episodic memory: Brief Visuospatial Memory Test–Revised (BVRT) 
Trials 1-3 Total raw score (0-36) 
 Language:  Category Fluency Total score & 42-item Boston Naming Test Total 
score (0-42) 
 Visuoconstructional function:  Rey-Osterrieth Complex Figure, Copy score (0-36) 
 Speed of processing:  Trail Making Test, Part B, number of seconds to complete 
and the Attentional Network Task (Alerting) correct reaction time (RT) (msec) 
 Executive function:  Attentional Network Task (Executive) correct RT (msec) 
 Visuospatial orienting:  Attentional Network Task (Orienting) correct RT (msec) 
*GDS is assessed at the time of screening (Visit 1) because the GDS is an eligibility 
criterion.  The visit 1 GDS score will also be treated as a Baseline score. 

rTMS-MCI Study Protocol 
48 
b) Secondary neuroimaging outcomes (assessed at Visits 2 and 13) 
 Functional connectivity metrics (derived from the pre- and the post-intervention 
rs-fMRI scans) will be computed with respect to: 
 Connectivity within the DMN, and 
 Connectivity between the DMN and the CEN. 
 Analyses are outlined in Section 9.5.2 “Secondary Analyses.” 
c) Secondary biomarker outcome (assessed at Visits 3 and 12) 
 Plasma levels of BDNF will be measured from fasting blood samples that are 
collected at the first and last morning intervention sessions of Visits 3 and 12. 
9.5 Data Analyses 
9.5.1.  Primary Hypothesis Testing 
o Analysis:  Test the hypothesis that active rTMS (to either stimulation site) is superior to 
sham in improving memory performance, as observed at the immediate post-treatment 
visit. 
o Method:  Analysis of Covariance (ANCOVA)  
o Population:  Intention-to-treat (ITT), defined as all randomized patients who 
started at least 1 treatment session. 
o Independent variable:  rTMS Treatment group  
 ANCOVA 1:  active DLPFC vs sham  
 ANCOVA 2:  active LPC vs sham  
o Dependent variable: Primary outcome, i.e. CVLT-II Trials 1-5 Total raw score at 
Visit 13 
o Covariate:  CVLT-II Trials 1-5 Total raw score at Baseline, i.e. Visit 2 
o Results will be presented as n, mean and standard deviation of CVLT-II (Total 
Trials 1-5) scores at baseline and post-treatment.   ANCOVA model parameters 
with estimates will be provided. 
o The two tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, adjusted for two tests; 2-sided confidence intervals will be displayed with a 
95% confidence level. 
9.5.2.  Secondary Analyses  
Durability of rTMS effects (Aim 2a) 
o Analysis: Longitudinal analysis of primary efficacy measure (memory 
performance) over the entire trial period in relation to treatment group  
o Method: Mixed-effects growth curve modeling 
o Population:  ITT 
o Dependent variable:  CVLT-II Trials 1-5 Total raw score (Visits 2, 13, 14,15) 
o Independent variable:  rTMS Treatment group 
 Model 1:  active DLPFC vs sham  
 Model 2:  active LPC   vs sham  
o Results:  Mixed model parameters with estimates will be provided. 

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49 
o Contrasts:  To convey the durability of the effect of each type of rTMS stimulation 
on the primary efficacy measure, the magnitude of treatment effects at the 3-mos 
and 6-mos time points will be reported. 
 
Analysis of behavioral differences related to stimulation site (Aim 2b.1) 
o Analysis:  Longitudinal analysis of behavioral changes over the entire trial period 
in relation to treatment group.  
o Method: Method: Mixed-effects growth curve modeling.  
o Population:  ITT. 
o Dependent variables:  Behavioral measures listed in Section 9.4.2.a (Visits 2, 13, 
14 & 15).  Semantic clustering and delayed recall sub-scores of the CVLT-II are of 
most interest. 
o Independent variable:  Active rTMS Treatment group (DLPFC vs LPC). 
o Results:  Mixed model parameters with estimates will be provided. 
Analysis of effects on brain function related to stimulation site (Aim 2b.2) 
As noted above, rs-fMRI data will be acquired at baseline (Visit 2) and post-intervention 
(Visit 13) to examine effects of rTMS on brain function.  Secondly, plasma levels of brain-
derived neurotrophic factor (BDNF) will be measured at the first and last intervention 
sessions to gain information about mechanisms of action of rTMS with respect to brain 
plasticity.   
BDNF levels analysis (two time-points).  As in the primary analysis, ANCOVA will be used.  
Functional connectivity (two time-points).   
 To define the DMN and CEN networks, we will perform seed-based whole brain 
analysis of the baseline fMRI data, using the methods of Greicius (for the DMN) 
and Vincent (for the CEN).  The networks will be broadly defined (p<.01) from the 
group data to generate inclusive masks of the DMN and CEN. 
 1) Analysis of rTMS effects on PCC connectivity within the DMN.  As described in 
more detail in Appendix VIII, connectivity maps will be calculated by the 
correlating subject’s timeseries of the PCC seed-ROI with those of non-seed voxels 
in the DMN group mask, followed by Fisher’ r to z transform of the values. 
Contrasts of the connectivity maps will be made (Pre- vs. Post-Tx, for each active 
rTMS vs. sham, and for active LPC vs. DLPFC).  The aim of these analyses is to 
discover the extent to which rTMS restores connectivity of the PCC within regions 
of the DMN.  rTMS-induced increases in PCC:hippocampal, PCC:parahippocampal, 
PCC:LPC, and/or PCC:mPFC connectivity would provide indications of therapeutic 
response (J. X. Wang et al., 2014; J. X. Wang & Voss, 2015; Ward et al., 2014).   
  Analysis of rTMS effects on between-network connectivity.  As explained in 
Appendix VIII, we will define 6 a priori ROIs: bilateral PCC (posterior DMN), and 
DLPFC (key node of the CEN) and medial PFC (anterior DMN).  For each subject 
and scan session, a correlation matrix of ROI-pairwise timeseries correlations will 
be computed; next, each participant’s z-score matrix (using Fisher’s r-to-z 
transform) will be used to compute Pre-minus-Post changes in z values. These will 
be used in group-level analyses to compare each active rTMS to sham-control and 

rTMS-MCI Study Protocol 
50 
to compare active LPC to DLPFC.  The aim of these analyses is to examine the 
extent to which rTMS reduces functional connectivity between the DMN and CEN. 
Decreases in PCC:DLPFC  and mPFC:DLPFC between-network connectivity would 
provide indications of therapeutic response.  
 Finally, we will explore the extent to which rTMS-induced changes in functional 
connectivity correlate with changes in selected behavioral variables (delayed 
recall, semantic clustering, executive function, and depression).  
Heterogeneity of response to rTMS (Moderators: Aim 2c).  
To explore the extent to which one treatment is superior over another as a function of a 
moderator variable, we will fit regression models with interactions between the treatment 
group variable and a selected moderator variable, yielding estimates of the regression line 
for each group.  In addition to reporting the magnitude of the interaction as a p value, we 
will obtain predicted values of the regression lines corresponding to each group.  (From 
these, we can estimate the superiority of one treatment over another as a function of the 
moderator; confidence intervals and p-values can be readily reported).  As these are 
exploratory analyses, we would analyze individual moderators separately to avoid over-
fitting the models.   
Based on limited data from previous TMS studies, the following classes of moderators are 
most likely to account for heterogeneity of response to rTMS in patients with MCI:  
 Profiles of baseline cognitive deficits, as defined by CVLT-II clustering and 
delayed recall scores; 
 Brain endophenotypes, as defined by a baseline functional connectivity metric for 
the Language, Central Executive, and Default-mode Networks; 
 BDNF met carrier status (in other clinical populations, val/val genotype has 
predicted a better response to rTMS (Chang et al., 2014; Cheeran et al., 2008)). 
In addition, gender and racial/ethnic categorical variables will be examined to gauge the 
magnitude of any potential differences in response to rTMS in patients with MCI. 
Descriptive analyses of safety and tolerability 
Adverse events will be coded according to established Medical Dictionary for Regulatory 
Activities (MedDRA) terms and summarized by MedDRA System Organ Class and Preferred 
Term.  In most cases, aggregate safety and tolerability data (see Section 7.2) will be 
summarized with descriptive statistics (counts, percentages, mean and standard deviation) 
for all participants, by treatment group and by study phase (i.e., intervention and follow-
up).  Summaries will indicate whether events were determined to be related to the study 
device and whether the AE led to treatment discontinuation.  Inferential comparisons may 
include t-tests or chi-square tests as appropriate.  The time course of incidence of common 
treatment-related adverse effects will be examined to characterize the extent to which 
participants accommodated to the treatment. 
 

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51 
10 DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Management 
In this single-site study, the PI and study team are responsible for all data collection and 
management.  The Database Manager will monitor all data entered into the database by the 
Study Coordinator.  The PI will review data on an ongoing basis at regularly scheduled staff 
meetings.  A formal review of the accumulating data and any data integrity issues will be 
conducted at a meeting of the PI and the Data Manager every 3 months during the active 
data collection period. 
Information about adverse events will be collected at each visit.  Any potentially serious 
problem will be brought immediately to the attention of the PI and the Study Physician. 
Biomarker/genetic information will be stored in a separate password-protected file, in a 
separate database, which can only be accessed by the Study Data Manager and MIRECC 
Senior Data Manager.  Only the Data Managers can match genetic information with the 
participant ID (PID); the Data Managers are blinded as to which PID is associated with 
which study participant. The genetic data will only be used for analysis of data conducted 
by the Data Manager. 
The Participant ID (PID) will be recorded on all data collection forms and entered into 
encrypted, password-protected databases located on physically secure VA servers behind a 
firewall.  
10.2 Data Collection Forms 
Data collection forms include:  
o Original copyrighted test forms (e.g. CVLT-II);  
o Standard questionnaires (e.g. ECog form and GDS like those used in the Alzheimer’s Disease 
Neuroimaging Initiative [ADNI]);  
o Case report forms adapted from the NIH Clinical Trial Toolkit (e.g. Participant Demographic 
form, Enrollment & Randomization form, Vital Signs form, and Adverse Event Forms). 
o Forms developed specifically for this study, many of which were adapted from VA CSP #556 
(e.g. Inclusion-Exclusion Form, and rTMS Intervention Log sheet). 
No data collection forms will show an individual participant’s identifiers, such as name or 
initials.  For additional steps taken to maintain participants’ confidentiality, please see 
Section 11.3.  For information regarding which members of the study team will fill out the 
about forms, please see Section 6.2. 
10.3 Quality Assurance  
10.3.1 Training 
General Training.  All staff will have completed all VA- and Stanford-required online 
training in Human Subjects, Good Clinical Practice (GCP), Privacy, and HIPAA before 
engaging in any study-related activities.  Each member of the study staff will have 
completed training specific to their scope of practice and specific to their roles before 
performing study procedures.  These types of training include: 

rTMS-MCI Study Protocol 
52 
TMS Training.  Didactic and practical hands-on training will be provided onsite to the 
study staff at VA-Palo using the training model of the VA-funded, Mental Illness Research, 
Education, and Clinical Center (MIRECC)-led "TMS Clinical Roll-out" training program. The 
trainers will be rTMS-certified physicians and nurses.  The didactic materials include the 
MagVita TMS Therapy User Guide for use with MagVenture MagPro devices, software 
version 7.1. 
Study Staff TMS Safety training.  Multiple study personnel, including the Study 
Coordinator and TMS Operator, will be trained comprehensively in TMS safety procedures, 
including: pre-session safety screening, solicitation and recognition of AEs, and training as 
first responders per the seizure protocol.  Knowledge will be demonstrated by taking a 
written examination that includes questions on what to do if there is a TMS-induced 
seizure.  Annual drills simulating a TMS emergency will be conducted to maintain staff 
preparedness. 
TMS Operator training.  The TMS Operator will be trained to reach proficiency in all 
aspects of the rTMS intervention procedure, including: device operation, motor 
thresholding, coil placement for cortical targeting, and delivery of rTMS.  Proficiency will be 
demonstrated by both a written test and by observation-based testing of all aspects of the 
rTMS intervention procedure.  Once the TMS Operator is certified as proficient by the 
trainers, the TMS Operator’s research scope of practice will allow the operator to 
independently administer rTMS under the supervision of an rTMS-certified physician.  This 
aspect of training is the “Core” component of TMS Certification.   Following completion of 
the Core training, the TMS Operator will be trained to proficiency in the specific stimulation 
protocol of this study, and certified by the PI. 
Assessments Training.  The Study Coordinator will be trained in the administration and 
scoring of the behavioral assessments by the PI.  Training will take place in three phases:  
self-study of the test manuals; practice in administering and scoring the assessments with a 
trained study coordinator (e.g. the ADNI 3 coordinator), and finally observation by PI to 
check for adherence to the test manuals.  The PI and other staff at the study site who will 
provide training are experienced in administering these same assessments. 
Training of Specific Assessments:  CDR. The CDR rater in this study will be another 
researcher at the study site, so that the CDR—which is part of the screening visit diagnostic 
evaluation—will be collected independently of the outcome measures.  The CDR rater will 
be certified through Washington University.  If the rater has never been CDR certified, full 
certification will be required.  The training includes nine (9) reliability tapes.  The 
ratings/scores are compared to the Gold Standard and, if the rater passes, Washington 
University will issue a certificate. CDR Certification and Refresher Course can be found 
online at url: http://alzheimer.wustl.edu/cdr/application/step1.htm   
Experienced MIRECC personnel associated with the Study Protocol.  The following 
long-time study staff have worked on NIH- and VA-funded protocols that involve similar 
populations, assessments, biomarkers, and/or interventions (e.g. rTMS clinical trials, older 
adults, and cognitive outcomes): 
Beatriz Hernandez, Database Manager and SAS Programmer (15% FTE).  Ms. 
Hernandez is presently studying for a Master’s in Statistics and has used SAS professionally 
for over 9 years.  She and the PI have worked together 6+ years on cognitive and MRI 
datasets.  She has performed complex analyses, including multiple linear regression 
modeling and mixed-effects growth curve modeling under the supervision of Dr. Lazzeroni.  

rTMS-MCI Study Protocol 
53 
She has substantial experience in database management, gained under the direction of Art 
Noda, the MIRECC Senior Data Manager.  Ms. Hernandez will perform randomization of the 
subjects to treatment arms, to ensure that all other research staff are blinded.  Ms. 
Hernandez will be responsible for setting up REDCap study database for the Study 
Coordinator to enter screening and other behavioral data.  She will also be responsible for 
dataset merges in SAS and coding the data analyses and models involving the primary and 
secondary outcome measures.  
Phoebe (Chun-Ping) Liao, Laboratory Technician (effort as needed).  Ms. Liao and 
the PI have worked together 10 years.  Ms. Liao, who has Bachelor’s Degree from UC Davis, 
has over 10 years of laboratory experience.  She has performed complex protocols, 
including DNA extraction, genotyping assays, microarray genotyping, sequencing, and 
measurements of gene expression both genome-wide and targeted.   She consistently meets 
a high level of reproducibility, as demonstrated by implementing robust procedures and 
protocols that resulted in multiple publications over the past decade.   Quality control 
measures of her work have consistently shown that her results are reliable.  Ms. Liao will 
be responsible for DNA extraction and tissue banking, and for performing the laboratory 
protocols for determining BDNF, COMT, and APOE genotypes that will be used in the data 
analyses relevant to heterogeneity of response to rTMS.   
New Staff.   Any new staff who join the project will undergo all required training before 
beginning work on the project, and will be carefully trained on all necessary aspects of the 
protocol by rTMS-certified physicians, nurses, and the PI. 
 
10.3.2 Quality Control Metrics 
Outcome measures will be entered using the procedures outlined in Section 10.2 “Data 
Management” above.  Range checks and automatically computed total scores will be 
utilized in RedCAP to enhance data quality.  Double data entry will be performed on 
randomly selected records using RedCAP’s double data entry feature.  The percentage of 
errors detected will be captured and tabulated for review by the study’s biostatistician and 
members of the DSMB. 
10.3.3 Protocol Deviations 
Protocol deviations will be captured using a Protocol Deviation Log that is very similar to 
the NIH Clinical Trial Toolbox form.   
o Any serious protocol deviation (that meets the definition of an SAE or 
compromises the safety, welfare or rights of subjects or others) will be reported to 
the DSMB Chair, NIA Program Official, and IRB as soon as possible, not more than 
7 days after the PI first learns of the deviation.  
o The report will describe what steps have been taken and what steps are planned 
as a result of the event. 
The DSMB will receive a tabulation of all protocol deviations (e.g. visits out of window; 
missed assessments) at each meeting or reporting interval. 
10.3.4 Monitoring 
The Research Compliance Officer of the VA Palo Alto Health Care System conducts annual 
audits of the participants’ informed consent documents. 

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54 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
An IRB-required protocol and informed consent documents for study participants and their 
study partners were approved on March 14, 2017.  This IRB approval includes a waiver of 
individual HIPAA authorization for recruitment and a waiver of documentation of consent 
for telephone pre-screening using an approved telephone script.   
This study protocol, as well as any subsequent modifications, the informed consent documents, 
and other information for participants--will be reviewed and approved by the IRB.  
11.2 Informed Consent Forms 
The consent form describes the purpose of the study, the procedures to be followed, and 
the risks and benefits of participation.  See Appendix II.  “Informed Consent Forms.”  A 
separate consent form will be presented to the study partner (SP).  The SP’s consent form 
informs the SP of their role in the study including the kinds of information the partner will 
be asked to provide during the study. 
Procedures for obtaining informed consent.  During the consenting process, each 
prospective participant and a study partner will meet in a private interview room at the 
study site with the PI or the Study Coordinator.  The information contained in the Informed 
Consent Form (ICF) is initially described orally to the prospective participant.  Care is taken 
to inform prospective participants repeatedly that participation is entirely voluntary and 
that they may withdraw at any time and for any reason.  Any questions will be answered.  
The prospective participant is then asked to read the consent form carefully.  The 
prospective participant is asked to summarize the consent form, including the discomforts, 
risks, and confidentiality sections.   
Enough time will be allowed for the potential participant to make an informed decision, 
including time to discuss the study with the researchers and ask any questions they may 
have.  We estimate the consenting process will take between 30 minutes and one hour.  The 
potential participant may take the consent home to discuss with others, and return later to 
sign it if they desire. 
Procedures for documenting informed consent.  Only after the prospective participant 
demonstrates by stating in their own words that they understand the purposes, risks, and 
potential benefits of the study and they are willing to volunteer, will the participant be 
asked to sign and date the consent form.  If the prospective participant lacks adequate 
decision-making capacity, a designated legal representative will need to sign the ICF prior 
to the participant undergoing screening or other study procedures.  Prospective 
participants will need to co-sign the ICF to indicate assent.   
A copy of the ICF will be given to each participant and study partner or legally authorized 
representative.  This fact will be documented in the participant’s record.  All original signed 
consent forms will be stored in the Study Consent Binder in a locked file when not in use.    
Provisions for vulnerable populations.  Most participants with aMCI are expected to be 
demonstrate adequate decision-making capacity by stating in their own words that they 
understand the purposes, risks, and potential benefits of the study and they are willing to 
volunteer.  As noted above, each prospective participant is asked to summarize the consent 
form, including the discomforts, risks, and confidentiality sections.  Participants will be 

rTMS-MCI Study Protocol 
55 
given ample time to discuss the study and ask the researchers questions.  Participants will 
be given time to discuss the study with the study partner, or with any family member, 
friend, or primary care provider. 
It is possible that a volunteer who comes for an in-person screening visit may be more 
impaired than we expected, based on the phone pre-screening interview.  If the prospective 
participant lacks adequate decision-making capacity at any in-person visit, then a legally 
authorized representative will need to sign the ICF and the volunteer will need to co-sign to 
indicate assent prior to participating in screening or any other study procedures. 
We will follow the recommendations set out in the Alzheimer's Assn position paper, 
"Research Consent for Cognitively Impaired Individuals" (AD & Associated Disorders 2004, 
18:171-175), which puts forth that cognitive impairment is not always associated with the 
lack of capacity for informed consent to research.  Nevertheless, potential participants will 
be evaluated by a Stanford/VA California Alzheimer's Center physician, a Stanford 
Neurology ADRC physician, or a VA physician for competency.  In case a person lacks 
capacity, a proxy (legally authorized representative) will need to sign the consent form. 
The subject's assent will be obtained & documented by also including their signature on the 
ICF.  Using these procedures for obtaining consent, we aim to protect the rights of any 
decisionally-challenged subjects.  
We note that anyone who scores less than 24 on the MMSE at the Screening Visit will be a 
screen-fail and will not be enrolled in the study because the inclusion /exclusion criteria 
select for participants with MCI, who by definition do not meet criteria for dementia. Given 
the low risks of the proposed procedures and study's exclusion criteria, we feel that the 
risks and chance of harm to potentially vulnerable subjects are minimized. 
11.3 Participant Confidentiality  
An identification code (Participant ID, PID) will be assigned by the study staff to each 
participant. The PID will be used in lieu of the participant’s name in order to protect the 
participant’s identity:   
o All computer entry will be done using participant identification numbers (Participant ID, 
PID) only;   
o Any data, specimens, forms, reports, video recordings, and other records that leave the site 
will be identified only by PID to maintain confidentiality;   
o The PID will be used when reporting AEs and/or other trial-related data;  
o No research reports will identify any individual participant or otherwise disclose identifiers. 
Privacy.  All paper records containing individually identifiable information (III), including 
Identifiable Protected Health Information (PHI)--such as original signed consent forms, 
telephone pre-screening and study visit progress notes--will be maintained in a secure 
room, and in locked file cabinet when not in use.   
HIPAA compliance.  Information will not be shared or disclosed without written permission 
of the participant, except as necessary for monitoring by IRB, the FDA, the NIA, and the 
OHRP. 
Data security requirements.  All portable IT equipment (i.e., laptops, USB thumb drives, and 
other removable storage media) used in the research project must be encrypted.  Access to 

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56 
electronic versions of data will be limited to authorized researchers who need access to 
conduct the research. 
Record retention.  Paper data collected under the HIPAA waiver for recruitment will be 
shredded when the research has been completed and all required waiting periods have 
elapsed.  Per the VA record control schedule, research records must be maintained for 6 
years after study closure. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NIA, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
12 ETHICAL CONSIDERATIONS 
The research conducted in this study will follow the guiding ethical principles of the 
Declaration of Helsinki and The Belmont Report (Office of the Secretary, Ethical Principles 
and Guidelines for the Protection of Human Subjects of Research, The National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research 1979]). 
13 PUBLICATION OF RESEARCH FINDINGS 
Any presentation, abstract, or manuscript will be made available for review prior to 
submission, at the written request of the NIA Program Official. 
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15 APPENDICES 
Appendix I - X. Consent forms, detailed study procedures, and study manuals are 
available from the Study Investigative Team.  Contact: Joy Taylor at joyt@stanford.edu   
Appendix XI. 
Protocol Amendment 

rTMS-MCI Study Protocol 
63 
 
 
Appendix XI 
 
Protocol Amendment / Modification: 
 Attention Network Task Dropped  
 
Noninvasive Cortical Stimulation to Improve 
Memory in Mild Cognitive Impairment (MCI) 
 
NCT03331796 
 
 
Amendment: The Attention Network task (ANT) was dropped from the study 
protocol on September 19, 2019 by approval of the Data Safety and Monitoring 
Board (DSMB).   
 
DSMB meeting minutes summary: “Other assessments already require 2 hours to 
complete. Members agreed that the protocol already included enough assessments 
to answer the research question. The possibility of study drop-outs due to 
participant burden was more concerning than administering the ANT task and 
collecting data on this secondary outcome. Consensus was to drop the ANT from 
cognitive battery. 
Date of approval by the DSMB and NIH Program Official: September 19, 2019 
Effective date: Immediate 
The following pages document approval of this protocol modification by the DSMB 
and the Stanford University Administrative Panel on Human Subjects in Medical 
Research. 
 

DSMB Meeting, Teleconference, Thursday, September 19, 2019 
Study:  Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment 
Grant Number: 1 R01 AG055526-02 
Meeting attendees 
Board Members – F. Andy Kozel MD (Chair), Prasad Padala MD, Ping Luo PhD, Noah Philip MD 
NIA – Kristina McLinden PhD, Alvin McKelvy PhD 
Blinded Study Staff: Joy Taylor PhD (PI), not present: Joshua Teso (Research Coordinator) 
Unblinded study staff: Beatriz Hernandez (Data Manager) 
I. Open Session  
Opening Remarks: PI summarized the open report. 
Summary of Discussion 
1. Study Progress: 
a. Enrollment: 26 participants screened, 17 enrolled, 15 completed baseline evaluation, 14 
completed post-treatment measures, and 6 completed the study. Committee discussion: Board 
members discussed the importance of meeting recruitment milestones for the study to 
continue. From an NIA perspective, insufficient statistical power due to low recruitment raises 
ethical concerns about continuing the study; Dr. McLinden outlined a milestone of 33 
participants by the next NIA progress report on March 15, 2020.  Given that this is an under-
represented population, the committee would like the study team to provide a realistic 
recruitment rate with assessment of its impact on the study timeline.  Consensus was to 
continue the study and reassess in 6 months.  PI Actions: 1) Aim to screen 4-6 participants per 
month; 2) provide the board with a realistic recruitment rate and its impact on the study 
timeline. 
2. Protocol: 
a. Inclusion criteria: PI requested guidance about allowing exceptions to the current age range of 
55 to 90 years. Committee discussion: Board members agreed there are no safety concerns but 
discussed data integrity issues that may result from exceptions. Consensus was to recommend 
keeping the age range unchanged.  
b. Excluded medications: PI had question about safety of dextroamphetamine while receiving 
TMS. Committee discussion: board members pointed out this medication is excluded based on a 
theoretical concern, and that the motor threshold value may provide a favorable level of safety.  
That said, there is no solid evidence for contra-indication of rTMS or for safety of rTMS.  Given 
the research protocol context, recommended participant be tapered off medication before 
starting rTMS (achieve a washout period of at least 4 times the drug half-life).  PI Actions: 
proceed with screening if participant is willing to discontinue dextroamphetamine during the 
rTMS Intervention phase. 

c. Secondary outcomes: PI raised possibility of dropping the Attention Network Task (ANT) as 
other assessments already require 2 hours to complete. Committee discussion: members 
agreed that protocol already includes enough assessments to answer the research question. The 
possibility of drop-outs is more concerning given recruitment issues. Consensus is to drop the 
ANT from cognitive battery. PI Actions: submit a protocol modification to drop the ANT. 
3. Safety Assessments: Chair verified that board members had no safety assessment concerns before 
ending the open session. 
II. Closed Session  
Meeting attendees 
F. Andy Kozel MD (Chair), Prasad Padala MD, Kristina McLinden PhD, Alvin McKelvy PhD, Ping Luo PhD, Noah 
Philip MD, Beatriz Hernandez (unmasked, Data Manager); not present: Joy Taylor PhD (PI), Joshua Teso 
(Research Coordinator) 
Summary of Discussion 
1. Board members would like greater clarification about the degree of medical instability permitted before 
denying further participation. Study team should make clear the criteria and procedures to evaluate 
medical instability during study participation (post-randomization). 
2. Board chair would like to know how often beam F3 is used instead of sole reliance on the Localite 
method. 
3. There were no safety concerns raised during the closed session. 
III. DSMB Recommendations 
1. Continue the study with recruitment goal of at least 33 participants by the next DSMB meeting in March 
2020. Consider the possibility of adding a 2nd site to boost recruitment. 
2. Submit a protocol modification to drop the Attention Network Task from assessments. 
3. Clarify criteria and procedures to determine whether medical instability warrants discontinued 
participation. 
4. Next meeting will be held in 6 months (NIA requires DSMB meeting every 6 months). 
 

STANFORD UNIVERSITY
Stanford, CA 94305 [Mail Code 5579]
 David Spiegel, M.D.
CHAIR, PANEL ON MEDICAL HUMAN SUBJECTS
(650) 724-9815
(650) 725-6766
March 10, 2020
Date:
Joy Taylor, PhD, Psychiatry and Behavioral Sciences
To:
 David Spiegel, M.D., Administrative Panel on Human Subjects in Medical Research
From:
Joshua Teso B.A.,  Alesha Maree Heath PhD,  Arthur Noda,  John Wesson Ashford M.D., Ph.D. (VA),
Beatriz Hernandez,  Harlene Grewal,  Jauhtai Joseph Cheng MD, PhD,  Joachim Franz Hallmayer MD,
PhD.,  Laura Lazzeroni Ph.D,  Logan Douglas Schneider,  Maheen Mausoof Adamson,  Monica
Mercedes Nable B.S.,  Priyanka Manojkumar Bhatt M.B.E.,  Ruth O'Hara Ph.D.,  Allyson Rosen Ph.D.,
Steven Chao M.D., Ph.D.,  Timothy Durazzo Ph.D.,  Vivian Quyah Nbu Chu B.A.,  Margaret Windy
Mcnerney Ph.D.,  Jerome A Yesavage M.D.
eProtocol
eProtocol #:
IRB
Non-Invasive Brain Stimulation for Mild Cognitive Impairment
39859
350)
The IRB approved human subjects involvement in your research project on 03/10/2020.  'Prior to subject
recruitment and enrollment, if this is:  a Cancer-related study, you must obtain Cancer Center Scientific
Review Committee (SRC) approval; a CTRU study, you must obtain CTRU approval; a VA study, you must obtain
VA R and D Committee approval; and if a contract is involved, it must be signed.'
 David Spiegel, M.D., Chair
03/10/2020 - 03/10/2021
Approval Period:
REGULAR - CONTINUING REVIEW
Review Type:
NIH - Grant: R01 AG055526-01
Funding:
Includes: Attention Network Task dropped.
Documents related to DSMB Meetings 3 and 4 were submitted.
copy of Notifications to DSMB of SAEs 1 & 2 were submitted.
The expiration date of this approval is 03/10/2021 at Midnight.  If this research is to continue beyond that date,  it is
your responsibility to submit a Continuing Review application in eProtocol. Research activities must be reviewed and
re-approved on or before midnight of the expiration date. The approval period may be less than one year if so
determined by the IRB. Proposed changes to approved research must be reviewed and approved prospectively by
the IRB.  No changes may be initiated without prior approval by the IRB, except where necessary to eliminate
apparent immediate hazards to subjects.  (Any such exceptions must be reported to the IRB within 10 working
days.)  Unanticipated problems involving risks to participants or others and other events or information, as defined
and listed in the Report Form, must be submitted promptly to the IRB.  (See Events and Information that Require
Prompt Reporting to the IRB at http://humansubjects.stanford.edu.) Upon completion, you must report to the IRB
within 30 days.
Please remember that all data, including all signed consent form documents, must be retained for a minimum of
three years past the completion of this research.  Additional requirements may be imposed by your funding agency,
your department, HIPAA, or other entities.  (See Policy 1.9 on Retention of and Access to Research Data at
http://doresearch.stanford.edu/policies/research-policy-handbook)
This institution is in compliance with requirements for protection of human subjects, including 45 CFR 46, 21 CFR 50
and 56, and 38 CFR 16.
Certification of Human Subjects Approvals
Waiver of Individual Authorization for recruitment under 45 CFR 164.512(i)(2)(ii)(A),(B),(C), pursuant to information
provided in the HIPAA section of the protocol application.
(Registration
3

FWA00000935 (SU), FWA00000929 (VA), FWA00000937 (PAVIR)
Assurance #: