Intra-Individual Variability in Cognitive Performance as a Marker of Prodromal Disability in MS
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: NYU Langone Health

Official Title: 
Intra-Individual Variability in Cognitive Performance as a Marker of 
Prodromal Disability in MS  
NCT Number:
NCT05543915
Study Number:
21-01385 
Document Type:
Study Protocol and Statistical Analysis Plan
Date of the 
Document: 
 
April 4, 2023 

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Intra-Individual Variability in Cognitive Performance as a Marker of Prodromal 
Disability in MS
Principal Investigator:
Dr. Leigh Charvet, Ph.D.
Department of Neurology, NYU Langone Health
222 East 41 Street, New York, NY, 10017
(929) 455-5141
Leigh.Charvet@nyulangone.org
Additional Investigators:
Dr. Lauren Krupp, M.D.
Department of Neurology, NYU Langone Health
222 East 41st Street, 10th floor
New York, NY 10016, USA
Lauren.Krupp@nyulangone.org
Dr. Yulin Ge, M.D. 
Department of Radiology, NYU Langone Health
660 First Avenue, New York, NY 10016
Yulin.ge@nyulangone.org  
(212) 263-3784
Dr. Giuseppina Pilloni, Ph.D.
Department of Neurology, NYU Langone Health
222 East 41 Street, 10th Floor
New York, NY, 10017
(929) 455-5568
Giuseppina.pilloni@nyulangone.org  
Dr. Hyein Cho, Ph. D. 
Department of Neurology, NYU Langone Health
222 East 41 Street, 10th Floor
New York, NY, 10017
(212) 263-7744
Hyein.Cho@nyulangone.org
NYULMC Study Number:
s21-01385
Funding Sponsor:
NYU Multiple Sclerosis Comprehensive Care Center
Study Product
MRI: Siemens PRISMA 3T MRI scanner
tDCS: 1x1 tDCS Model 1300A Low-Intensity Stimulator (Soterix 
Medical, Inc)
Runscribe or G-Sensor wearable gait sensors
IND/IDE Number
ClinicalTrials.gov 
Number                
Initial version (version 1): 12.14.2021
Amended (version 7.1): 3.15.2023

Study number: s21-01385
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Statement of Compliance 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), any other applicable US government research regulations, and 
institutional research policies and procedures. The Principal Investigator will assure that no deviation from, 
or changes to the protocol will take place without prior agreement from the sponsor and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the study participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection Training. 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................................. 1
1 
KEY ROLES ......................................................................................................................................... 3
2
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE.......................3
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 3
2.2 
RATIONALE.................................................................................................................................... 4
3
POTENTIAL RISKS & BENEFITS....................................................................................................... 4
3.1.1 
Known Potential Risks ............................................................................................................. 4
3.1.2 
Known Potential Benefits ........................................................................................................ 6
4
OBJECTIVES AND PURPOSE ........................................................................................................... 6
4.1 
PRIMARY OBJECTIVE ...................................................................................................................... 6
4.2 
SECONDARY OBJECTIVES............................................................................................................... 6
5
STUDY DESIGN AND ENDPOINTS.................................................................................................... 6
5.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................... 6
6 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................... 7
6.1 
INCLUSION CRITERIA ...................................................................................................................... 7
6.2 
EXCLUSION CRITERIA ..................................................................................................................... 7
6.3 
VULNERABLE SUBJECTS................................................................................................................. 7
6.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................................................ 7
6.4.1 
Use of Epic Information for Recruitment Purposes ................................................................. 8
6.5 
DURATION OF STUDY PARTICIPATION.............................................................................................. 8
6.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES .................................................................................. 8
6.7 
PARTICIPANT WITHDRAWAL OR TERMINATION.................................................................................. 8
6.7.1 
Reasons for Withdrawal or Termination .................................................................................. 8
6.7.2 
Handling of Participant Withdrawals or Termination ............................................................... 8
6.7.3 
Premature Termination or Suspension of Study ..................................................................... 8
7 
STUDY SCHEDULE............................................................................................................................. 9
7.1 
ELIGIBILITY PRE-SCREENING ........................................................................................................... 9
7.2 
STUDY VISIT .................................................................................................................................. 9
8 
STUDY PROCEDURES ....................................................................................................................... 9
8.1 
BASELINE PROCEDURES................................................................................................................. 9
8.2
COGNITIVE ASSESSMENTS............................................................................................................10
8.3 
MRI SEQUENCES ......................................................................................................................... 11
8.4 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 11
9 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12
9.1 
DEFINITIONS ................................................................................................................................ 12
9.2 
RECORDING OF ADVERSE EVENTS................................................................................................ 13
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 13
9.3.1 
Investigator reporting: notifying the IRB ................................................................................ 13
9.4 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 14
9.4.1 
Severity of Event ................................................................................................................... 14
9.4.2 
Relationship to Study Intervention......................................................................................... 14
9.4.3 
Expectedness ........................................................................................................................ 14
9.5 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP.................................... 14
9.6 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 15
9.6.1 
Adverse Event Reporting ...................................................................................................... 15

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9.6.2 
Serious Adverse Event Reporting ......................................................................................... 15
9.6.3
Unanticipated Problem Reporting .........................................................................................15
9.6.4 
Reporting of Pregnancy ......................................................................................................... 16
10
STUDY OVERSIGHT ......................................................................................................................... 16
10.1
SAFETY OVERSIGHT.....................................................................................................................16
10.2
MEDICAL MONITORING.................................................................................................................. 16
10.3
STUDY HALTING RULES................................................................................................................ 16
10.4
CLINICAL MONITORING .................................................................................................................16
11
STATISTICAL CONSIDERATIONS .................................................................................................. 16
11.1
STUDY HYPOTHESES .................................................................................................................... 16
11.2
SAMPLE SIZE DETERMINATION......................................................................................................16
11.3
STATISTICAL METHODS ................................................................................................................ 17
11.3.1 
Agency for Healthcare Research and Quality (AHRQ) Indicator ...................................... 17
12
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS.................................17
13
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 18
13.1
ETHICAL STANDARD ..................................................................................................................... 18
13.2
INSTITUTIONAL REVIEW BOARD..................................................................................................... 18
13.3
INFORMED CONSENT PROCESS .................................................................................................... 18
13.3.1 
Consent Procedures and Documentation ......................................................................... 18
13.3.2 
Posting of Clinical Trial Consent Form .............................................................................. 19
13.4
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 19
13.4.1 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 19
14
DATA HANDLING AND RECORD KEEPING. .................................................................................. 19
14.1
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 19
14.2
STUDY RECORDS RETENTION ....................................................................................................... 20
14.3
PROTOCOL DEVIATIONS ............................................................................................................... 20
14.4
PUBLICATION AND DATA SHARING POLICY..................................... ERROR! BOOKMARK NOT DEFINED.
15
STUDY FINANCES ............................................................................................................................ 20
15.1
FUNDING SOURCE ........................................................................................................................ 20
15.2
COSTS TO THE PARTICIPANT ......................................................................................................... 20
15.3
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 20
16
STUDY ADMINISTRATION ............................................................................................................... 20
16.1
STUDY LEADERSHIP .....................................................................................................................20
17
CONFLICT OF INTEREST POLICY .................................................................................................. 20
18
REFERENCES ................................................................................................................................... 21
19
ATTACHMENTS ..................................................................... ERROR! BOOKMARK NOT DEFINED.
 

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List of Abbreviations
AE
Adverse Event/Adverse Experience
AHRQ
Agency for Healthcare Research Quality
BICAMS
Brief International Cognitive Assessment in MS
CBB
Cogstate Brief Battery
CBF
Cerebral Blood Flow
CBI
NYU Center for Biomedical Imaging
CFR 
Code of Federal Regulations 
CIS
Clinically isolated syndrome 
CMRO2 
Cerebral Metabolic Rate of Oxygen
CRF 
Case Report Form
CSOC 
Clinical Study Oversight Committee 
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services
DLPFC
Dorsolateral Prefrontal Cortex
 
PDDS 
Patient Determined Disease Step
FFR 
Federal Financial Report
fMRI 
Functional MRI
FWA 
Federalwide Assurance
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
IIV 
Intra-individual variability
IRB
Institutional Review Board
MOP 
Manual of Procedures
MRI
Magnetic Resonance Imaging 
MS
Multiple Sclerosis
MSCCC
Multiple Sclerosis Comprehensive Care Center
N 
Number (typically refers to participants)
NIH
National Institutes of Health
OHRP 
Office for Human Research Protections
OHSR 
Office of Human Subjects Research
pCASL
Pseudo-Continuous Arterial Spin Labeling 
PHI
Protected Health Information 
PI 
Principal Investigator

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QA
Quality Assurance
QC
Quality Control
RAVLT 
Rey Auditory Verbal Learning Test
RIS
Radiologically isolated syndrome
RS-fMRI 
Resting State-fMRI
RT
Reaction Time 
SAE
Serious Adverse Event/Serious Adverse Experience 
SDMT
Symbol Digit Modalities Test
SES
Socioeconomic Status
SOP 
Standard Operating Procedure 
tDCS 
Transcranial Direct Current Stimulation 
UAP 
Unanticipated Problem
US
United States
ISD
Intraindividual Standardized Deviations 

IIV Cognitive Biomarkers in Early MS
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writing by the study sponsor 
Drug/Device Template Version: 8 February 2019 
Protocol Summary
Title 
Intra-Individual Variability (IIV) in Cognitive Performance as a Marker of 
Prodromal Disability in MS
Short Title 
IIV Cognitive biomarkers in early MS 
Funding Sponsor 
National Multiple Sclerosis Society (NMSS) 
Brief Summary
We recently received notice of award for the proposed study. The focus of this 
work is the evaluation of a measure of cognitive functioning- intra-individual 
variability (IIV) – derived from a computer-based continuous reaction time (RT) 
task (Cogstate) as an early marker of prodromal MS.  
This study is a prospective observational clinical study, where we will recruit 
adults with early MS (n=60) to complete a cognitive assessment and an 
optional gait assessment using Runscribe and G-sensor. Thirty-five [35] 
participants will also have a single 60-minute investigational MRI combined 
with 20 minutes of simultaneous tDCS. The MRI will repeat the protocol from 
our current study (ClinicalTrials.gov Identifier: NCT03564496, IRB i18-00548) 
using simultaneous transcranial direct current stimulation (tDCS) during the 
imaging acquisition.  
 
Objectives 
To evaluate cognitive IIV as marker of prodromal MS   
Methodology 
Observational study  
Endpoint 
- Primary outcomes: Cogstate Brief Battery (CBB) measures of reaction 
time/accuracy/IIV and Cerebral metabolic rate of oxygen (CMRO2) 
 
- Secondary outcomes: Brief International Cognitive Assessment for MS 
(BICAMS) and IIV in gait measured with inertial wearable sensors (optional)
Study Duration 
24 months  
Participant Duration 
Participation will include one that will last approximately 1.5-3.5 hours and will 
include a cognitive assessment, optional gait assessment. 35 participants will 
have a 60-minute MRI combined with simultaneous tDCS after the cognitive 
assessment. Participants may complete the MRI during a second visit. 
Population
We will recruit 50 adults with early (prodromal) MS (e.g., clinically isolated 
syndrome (CIS),radiologically isolated syndrome (RIS), or subjects with a MS 
diagnosis of less than 5 years).
Study Sites 
222 E 41st street, 10th Floor, NY, NY 10017 – NYU Dept. of Neurology
 
240 East 38th Street, 13th Floor, NY, NY 10016 – NYU Multiple Sclerosis 
Comprehensive Care Center 
 
NYU Langone Bernard and Irene Schwartz Center for Biomedical Imaging 
(CBI): 660 First Avenue, New York, NY 10016
Number of participants 
N= 60 
Statistical Analysis 
Descriptive statistics, repeated measures ANOVA, simple correlations, and 
regression

Study number: s21-01385
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Schematic of Study Design
Eligibility pre-screen to determine general 
eligibility
Obtain informed consent
Confirm eligibility criteria 
Complete the self-reported questionnaire PDDS
Cognitive assessment
Optional gait assessment
tDCS-MRI scan (for 35 participants only)
Visit 1
Prior to
Enrollment
Analyses: Summarizing baseline patient and disease 
characteristics, cognitive IIV is calculation using CogState, 
and CMR02 measure from MRI.

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1
Key Roles
 
Dr. Leigh Charvet, PhD 
Department of Neurology, NYU Langone Health 
222 East 41st Street, 10th floor 
New York, NY 10016, USA 
(929)455-5141 
Leigh.Charvet@nyulangone.org 
 
Dr. Lauren Krupp, M.D. 
Department of Neurology, NYU Langone Health 
222 East 41st Street, 10th floor 
New York, NY 10016, USA 
(646)501-7500 
Lauren.Krupp@nyulangone.org 
Yulin Ge, M.D. 
NYU Langone Health —Radiology  
660 First Avenue, New York, NY 10016 
(212)263-3784 
Yulin.ge@nyumc.org 
 
Giuseppina Pilloni, PhD 
Department of Neurology, NYU Langone Health 
222 East 41 Street, 10th Floor 
New York, NY, 10017 
(929) 455-5568 
Giuseppina.pilloni@nyulangone.org 
 
Hyein Cho, PhD 
Department of Neurology, NYU Langone Health 
222 East 41 Street, 10th Floor 
New York, NY, 10017 
(929) 455-5319 
Hyein.Cho@nyulangone.org  
2 Introduction, Background Information and Scientific Rationale 
2.1
Background Information and Relevant Literature 
 
 
The goal of this project is to evaluate intra-individual variability (IIV) in cognitive performance, measured 
across response time (RT) on a computer task, as a marker of potential cognitive decline. We currently identify 
a patient’s advancing neurological decline when it reaches the threshold for clinical detection of change. There 
remains an urgent need to identify patients before the onset of decline and disability1. Our scientific premise is 
that the initial neuronal dysfunction that defines prodromal neurodegeneration2–5 can be reliably identified by 
subtle inconsistencies in cognitive processes6–8. We therefore propose using a clinically applicable approach 
to evaluate cognitive consistency as an indicator of prodromal neurological disability1. 
 
Cognitive consistency can be readily measured using simple computer-based psychomotor tasks9–12, 
capturing intra-individual variability13–15 (IIV) across an individual’s repeated reaction times (RTs). IIV, compared 
to the conventional measures of accuracy or speed16, is a highly sensitive marker of future health status at the 
population level8,17 as well as in prodromal neurological disease18–21.  

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For this project, we propose to develop the measurement of IIV towards its clinical application as 
prodromal marker in MS. We will utilize an innovative and accessible approach to measure IIV in patients that 
provides an age-normative score to represent cognitive consistency interpreted at the individual level. We will 
measure IIV measured with the simple and choice RT tasks in the computer-based Cogstate9 platform. This 
brief (~7 min), practical, and widely available IIV measurement is clinically validated and with an extensive 
(n=95,162) normative data points for interpretation at the individual level. The cognitive IIV value will be 
compared to real time neuronal responses to tDCS as prodromal MS marker via a tDCS-MRI scan. This work 
will develop a clinical measure of IIV as behavioral measure of prodromal neurodegeneration that can guide 
early detection and, ultimately, prevention of disability.  
2.2
Rationale
 
While we can detect cognitive impairment once it reaches the level of clinical impairment, there remains an 
urgent need for a measure that can identify patients at risk for impairment before the onset of disability. Our 
scientific premise is to measure risk in the prodromal/early stage- before disability occurs- by subtle 
inconsistencies in cognitive processes measured on simple computer-based reaction time tests. We will 
compare the IIV measure to neuroimaging markers of early disease. This work will advance us towards a 
clinical screening measure that can be used to detect the patients most at risk for near-term neurological 
disability in the context of MS. 
 
3 Potential Risks & Benefits 
3.1.1 Known Potential Risks 
 
Risks associated with cognitive assessments and questionnaires: Completing questionnaires may produce 
some emotional distress in some participants. While we don’t anticipate this will be a significant issue, 
participants will be allowed to take breaks as needed and may stop answering questions at any time without 
affecting their enrollment. 
 
Risks associated with tDCS: There are no major risks associated with tDCS. Some people report head 
tingling, itchiness at the site of anodal stimulation, and a mild heating sensation. These irritations are usually 
mild and tolerable.  
 
As in our previous MRI-tDCS study, we will use a Soterix Medical tDCS device 
(https://soterixmedical.com/research/1x1/tdcs) to administer ~20 minutes of stimulation during the MRI scan. 
The Soterix 1x1 tDCS device is outside of the MRI suite in the MRI control area. The cables used to connect 
the tDCS device to the tDCS headset/electrodes (which will be inside the MRI suite) are MRI-certified carbon 
cables. In addition, between the MRI control room and the MRI suite is a patch panel with an MRI filter. So 
far, no tDCS sessions delivered during the MRI scan were aborted due to safety or tolerability concerns. The 
most commonly reported side effects were skin tingling, sensations of warmth, and skin itching. 
 
For the reasons referenced above, tDCS meets the criteria for an abbreviated IDE (non-significant risk medical 
device): 
1. It is not intended as an implant and does not present a potential for serious risk to the health, safety, 
or welfare of a subject 
2. It is not purported or represented to be for a use in supporting or sustaining human life and does not 
present a potential for serious risk to the health, safety, or welfare of a subject. 
3. It is not for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise preventing impairment of human health and does not present a potential for serious risk to 
the health, safety, or welfare of a subject: the device will not be used for subject treatment and 
subjects standard medical treatment will continue regardless of their participation in the study 
4. It does not otherwise present a potential for serious risk to the health, safety, or welfare of a 
subject23-25. 
 

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Risks associated with MRI
Magnetic Field and Imaging Risks: MRI scanning involves the use of a magnet and radio frequency waves 
(much like an ordinary short-wave radio). There are no known risks or adverse effects resulting directly from 
exposure to magnetic fields and radio frequency signals used in this study, other than the potential risks 
associated with the scanning procedure summarized below. These potential risks are present with any MRI 
procedure.
Implanted Devices: Subjects, who have pacemakers, certain aneurysm clips, or shrapnel fragments or persons 
with metal in the eye, are at risk for injury from MRI examinations.
Collision Hazard: Because of the strong magnetic field associated with the scanner, one risk is that of a metallic 
object flying through the air toward the scanner and hitting you. To reduce this risk, all people involved with this 
study will remove all metal from their clothing and all metal objects from their pockets when in the scanning 
environment.
Hearing Protection: The MRI scanner produces tapping sounds during operation, which may reach very loud 
levels. To minimize any discomfort from this noise, the subject will be provided with disposable earplugs that 
suppress external noise levels but do not eliminate voice communication with the scanner operator. 
Alternatively, in some cases, they will have headphones instead of earplugs, which will deliver other sounds.
Claustrophobia (Fear of confined spaces): Some people feel claustrophobic (fear of small spaces) in the MRI 
scanner. If this happens, the scan will be stopped immediately and the subject will be removed from the scanner.
Quench Hazard (MR system failure): The MR scanner uses liquid nitrogen and liquid helium. It is remotely 
possible that the liquid nitrogen and helium will boil off rapidly and fill the magnet room with extremely cold 
dense gaseous nitrogen and helium, which can be dangerous if breathed for more than a few moments. The 
scanner operator will obviously detect this and immediately provide assistance to anyone inside the magnet 
room.
During the MRI, subjects will be in visual and verbal contact with the experimenter throughout the scan through 
a video monitoring system and can be removed quickly. In addition, participants are given a squeeze ball so 
they can signal the scanner operator in the event of an emergency. Some subjects have experienced dizziness 
or a metallic taste if they move their heads rapidly in the magnet. This, however, is only temporary and does 
not occur if the head is still. Acoustical noise is generated by the charging and discharging of the gradient coils 
which create the magnetic fields used to generate an image. Subjects will be wearing hearing protection that 
reduces acoustic noise by approximately 30dB. All possible measures will be taken to educate research 
personnel concerning the dangers of metallic projectiles in the magnet room and any individuals entering the 
magnet room will be thoroughly screened for ferromagnetic material. 
Risks associated with optional gait assessments
Completing the optional gait assessment is associated with minimal risks. To minimize these potential risks, we 
will ask the participant to perform only tests that are familiar with (walking, standing from sitting position). 
Other risks
There is minimal risk of breach of confidentiality. All data will be obtained on paper CRF and kept strictly 
confidential and stored in locked cabinets located at 222 East 41st Street, 10th Floor.  Participants will be 
assigned a unique ID that will be used on all data collection instruments. The identifying link will be stored in a 
separate file and saved on password-protected NYU servers.
Unforeseeable Risks: While not expected, there may be risks associated with tDCS that are not known at this 
time.

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3.1.2
Known Potential Benefits
There is no direct benefit to the participants expected from participating in this study. It is hoped that developing 
a method for early identification of cognitive decline in MS can help patients and clinicians develop clinical 
treatment plans in the future. 
Incidental findings
Incidental findings on MRI scans are possible health abnormalities that are found during the course of subjects’ 
participation in this study and are unrelated to the research topic but may be important for subjects and their 
physician to know about. Incidental findings that are identified by licensed radiologists may or may not have 
clinical significance as determined by the health professionals conducting this study will be communicated to 
Dr. Krupp, Sub-I for this study, who will also review the neuroimaging reports. 
If clinically useful information is uncovered, Dr. Krupp will contact the subject on the telephone regarding the 
new information within 7 business days. Incidental findings reported to the subject will be recorded in the 
subject’s medical record. A copy of the original image report will be provided upon patient request and 
participants will be encouraged to follow up with their treating physician outside of the study.
4
Objectives and Purpose
4.1
Primary Objective
The primary objectives are to characterize IIV and evaluate its underlying neuropathological mechanisms using 
neuroimaging techniques in prodromal/early MS. This work will develop a clinical measure of IIV as behavioral 
biomarker of prodromal MS that can guide early detection and, ultimately, prevention of disability.
4.2
Secondary Objectives 
The secondary objective is to collect additional data to explore potential relationship among changes in IIV and 
cognitive function and in relation to gait variability. 
5
Study Design and Endpoints
5.1
Description of Study Design
We will recruit 60 participants over a two-year period to assess the feasibility of developing the measurement 
of IIV towards its clinical application as prodromal marker of MS, and to test the association between IIV and 
the real-time neuronal responses to tDCS as prodromal MS marker via a tDCS-MRI scan. 
Thirty-five (35) participants will complete 1 visit that will last approximately 3.5 hours. The visit will include 
consent, a cognitive assessment, an optional gait assessment, and a 1-hour MRI brain scan combined with 20 
minutes of simultaneous tDCS. Participants may also complete the MRI on a separate visit.
Twenty-five (25) participants will complete 1 visit that will last approximately 1.5 hours (consent, cognitive 
assessment, and optional gait assessment). Procedures are exactly the same except that the tDCS-MRI will 
not be completed.
Group assignment will depend on eligibility, enrollment space (e.g. if one group reaches its target), and 
participant choice. The only difference between the two groups is that 1 group will have the MRI-tDCS 
procedure.

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6
Study Enrollment and Withdrawal
6.1
Inclusion Criteria for All Participants
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ages 21-59 years old (inclusive) 
2. Prodromal MS (defined by radiologically isolated syndrome 
 from first MRI or clinically 
isolated syndrome 
 from first clinical event)  
3. MS diagnosis of than 5 years 
6.2
Exclusion Criteria (All Participants)
An individual who meets any of the following criteria will be excluded from participation in this study:  
 
1. Below average estimated premorbid cognitive functioning (based on WRAT-4 reading recognition 
standard z-score < 85). 
2. Presence of severe cognitive impairment (based on SDMT age normative z-score <-3.0). 
3. Primary psychiatric disorder that would influence ability to participate. 
4. Current uncontrolled seizure disorder. 
5. Current substance abuse disorder. 
6. History of head trauma in the past year (e.g., head injury, brain surgery) or medical device 
implanted in the head (such as Deep Brain Stimulator) or in the neck (such as a Vagus Nerve 
Stimulator). 
7. Pregnant or breastfeeding 
6.2.1 Additional Exclusion Criteria for tDCS-MRI Participants 
 
1. Extreme claustrophobia 
2. Any skin disorder/sensitive skin (e.g., eczema, severe rashes), blisters, open wounds, burn 
including sunburns, cuts or irritation, or other skin defects which compromise the integrity of the 
skin at or near stimulation locations (where electrodes are placed) 
3. Treatment for a communicable skin disorder currently or over the past 12 months 
4. Have any irremovable piercings, metallic based-tattoos, or MRI-contraindicated implants (e.g. 
pacemakers and defibrillators) 
 
6.3
Vulnerable Subjects
N/A. Vulnerable subjects will not be recruited for this study.  
6.4
Strategies for Recruitment and Retention 
Research participants will be recruited from the NYU Langone Health MS Comprehensive Care Center 
(MSCCC) patient database. Additionally, an IRB approved study description will be posted on the website of 
the National Multiple Sclerosis Society and shared with the appropriate list-service. Moreover, IRB approved 
flyers will be posted in the clinic of the MS Comprehensive Care Center. Interested participants who learned of 
the study through word of mouth may reach out directly to the research team members. Patients who are seen 
by medical staff at NYU Langone Health, who fit eligibility criteria, will be referred by the study PI and sub-
investigators. All recruiting division neurologists and medical staff will be presented with the study description. 
A patient who is seeing one of these medical staff members as their treating physician will be introduced to the 
study by that medical staff member. If the patient is interested and agrees, then a member of the research study 
staff will contact them. An IRB-approved phone script will be used to inform the patient about the study and to 
ask eligibility questions. Verbal responses will be recorded on a separate pre-screen verbal checklist. 

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If a potential subject is ineligible or does not provide written consent the information collected including all PHI 
collected for the purposes of this study will be destroyed immediately.   
6.4.1
Use of Epic Information for Recruitment Purposes
N/A 
6.5
Duration of Study Participation
Study participation involves 1 visit that will last approximately 1.5-3.5 hours. The study visit will include:  
 
Consent (~25 minutes), 
 
Eligibility clearance by study clinician (e.g. Neurologist or Nurse Practitioner), eligibility can be 
confirmed either over the phone, research video visit, or review of medical record from an external 
provider (30 minutes) 
 
Cognitive assessment (30 minutes) 
 
Optional gait assessment (20 minutes) 
 
[MRI-tDCS group only] tDCS tolerability test (2 min) 
 
*[MRI-tDCS group only] MRI scan with simultaneous tDCS (60 minute scan plus an additional 40 
minutes to walk to CBI, change clothes, complete MRI safety form, etc.). 
 
*Participants in the MRI-tDCS  group may opt to complete the scan on a separate visit. 
6.6
Total Number of Participants and Sites  
This study will recruit a total of 60 participants (target for participants who complete the tDCS-MRI is n=30 and 
target for participants who complete the cognitive assessment only is n=20 for total target of n=50, plus 10 to 
account for screen fails and withdrawals) at NYU Langone Health. 
6.7
Participant Withdrawal or Termination 
6.7.1 Reasons for Withdrawal or Termination 
Participation in the study is voluntary and participants are free to withdraw from the study at any time upon 
request. An investigator may terminate participation in the study if: 
 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the participant. 
 
The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation.  
6.7.2 Handling of Participant Withdrawals or Termination 
If a participant wishes to withdraw from the study, they may do so at any point without adversely effecting any 
standard-of-care treatment. Participants will be provided with study team e-mail and contact number and can 
withdraw at any time. 
 
Data of participants who withdraw or are terminated from the study may be kept for analysis if the data is usable 
(as determined PI).   
6.7.3 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. If 
the study is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants.  

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Demonstration of inefficacy that would warrant stopping 
 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy 
the IRB. 
7 Study Schedule 
7.1
Eligibility Pre-screening
 
Eligibility pre-screen to determine general eligibility.  
 
Obtain medical records.  
7.2
Study Visit 
 
Obtain written informed consent (approximately 25 minutes or however much time is needed) 
 
Study clinician confirms patient’sdiagnostic eligibility based on inclusion/exclusion criteria in-person at 
the research visit. Alternatively, this can be done via phone, Zoom or Webex, prior to the baseline visit. 
Patients seen clinically at the NYU MSCCC may have their diagnostic eligibility confirmed without 
speaking to the study clinician prior to the baseline visit.  
 
Complete self-reported questionnaire-- Patient Determined Disease Steps26 (PDDS, 5 minutes) 
 
Complete cognitive assessment (Cogstate and BICAMS, 30 minutes) 
 
Complete self-report questionnaire (paper form) (15 minutes). 
 
(Optional for all participants) Gait assessment (approximately 20 minutes) 
 
[tDCS-MRI group only] Perform tDCS tolerability test (2 minutes) 
 
[tDCS-MRI group only] Complete tDCS-MRI scan (40 minutes to prepare for scan, change, etc. and 60 
minutes for scan [including 20-minutes of tDCS]).  
8 Study Procedures 
8.1
Baseline Procedures
After the participant provides written informed consent, the following research procedures will take place: 
8.1.1
All Participants
 
A study clinician will meet with the participant to confirm their eligibility according to the MS or prodromal 
MS inclusion criteria. Depending on patient and clinician availability, the clinician can either meet the patient 
in-person on the day of the research visit in a private room at NYU MSCC (222 East 41st Street, 10th floor, 
or 240 East 38th Street, 13th floor). Alternatively, the clinician can speak to the patient via phone, Zoom, or 
Webex prior to the baseline visit to confirm eligibility. Patients who are known to the NYU MSCCC can have 
their eligibility confirmed by a study clinician without meeting with the patient. Patients who have been 
diagnosed with MS less than five years and who receive their care from an external provider can provide 
their medical record or a letter from their neurologist indicating the date and nature of their MS diagnoses 
to confirm eligibility.  
 
 
Participants will complete a cognitive assessment (measures described in section 8.2).   
 
 
Optional gait assessment: Participants will have the option to complete a brief gait assessment 
administered by a trained study team member. Participants will be asked to walk at their self-selected speed 
back and forth for 2 minutes along a 30 meter hallway (222 East 41st Street, 10th floor, or 240 East 38th
Street, 13th floor) in order to collect at least 30 steps to calculate the motor IIV. The gait assessment will be 

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repeated twice. During one walking task, participants will wear an inertial sensor around their waist (G-
Sensor, BTS Bioengineering), while during the other will wear the inertial sensor on their shoe (Runscribe). 
The inertial sensor used will depend on availability. Both devices connect to a study iPad via Bluetooth and 
obtain data such as walking speed, balance, and stride length, etc. Identifying information will not be saved 
to the iPad or the sensors. 
8.1.2 MRI-tDCS group only 
 
tDCS tolerability test: In a private room at CBI, a study team member will place the tDCS headset on the 
participant (dorsolateral prefrontal cortex montage, left anodal) and administer a 60-second tDCS 
stimulation test, with a 30-second ramp up to target 2.0mA, followed by a 30-second ramp down. 
Participants who cannot tolerate 2.0mA will be excluded from the study. 
 
 
MRI scan with simultaneous tDCS: At CBI, participants will be asked to complete an MRI Safety 
Questionnaire per standard protocol for radiology procedures. Participants who cannot confirm their 
pregnancy status will be given a urine pregnancy test and may only continue in the study if the test is 
negative. Participants will be asked to change into an MRI compatible patient robe in a private room and 
place their belongings in a locker for safe keeping.  
Next, they will be taken to the MRI suite and asked to lie down on the MRI table. A team member will 
place the MRI-compatible tDCS headset on the participant’s head). Participants will be given a squeeze 
ball which can be used to alert the MRI technicians at any time during the scan should they need 
assistance. Participants will also be monitored by a study team member for the entirety of the MRI-tDCS 
scan. The set-up of the device and administration of stimulation will be done by an onsite study team 
member. 
The tDCS-MRI scan will last approximately one hour. The first 20 minutes of the MRI will not include 
tDCS stimulation. After 20 minutes, the tDCS device will ramp up to 2.0mA and deliver 2.0mA for 20 
minutes. Then the tDCS will ramp down (30 seconds) and the final 20 minutes will be without stimulation. 
At the conclusion of the MRI, the participant will be paid for their participation.  
8.2
Cognitive Assessments
 
Wide Range Achievement Test- 4th Edition (WRAT-4) Reading Recognition Subset: The WRAT-4 is a 
brief test of single word reading recognition that provides a proxy of literacy and general intellectual 
ability. 
 
Symbol Digit Modalities Test (SDMT): The SDMT is 90-second cognitive task in which the participant 
is shown a sheet containing rows of symbols. Each symbol corresponds to a specific number. The 
participant’s task is to say out loud the number associated with each symbol. The SDMT is used as a 
general cognitive screen to detect severe cognitive impairment. 
 
Brief International Cognitive Assessment for MS (BICAMS): this battery tests mental processing 
speed and memory. BICAMS includes the following tests: Brief Visuospatial Memory Test (BVMT, 
requires the participant to look at a sheet with 6 shapes on it for 10 seconds and then draw as many 
shapes as they can from memory); the Rey Auditory Verbal Learning Test (RAVLT, requires the 
participant to recite back a list of words from memory as best they can), and SDMT described above. 
 
Cogstate Brief Battery (CBB): The core Cogstate RT tasks involve a deck of cards on a green 
background screen and the participant answers “yes” or “no” by hitting a keyboard key (“D” or “K”) 
across repeated trials. Each task first includes instructions and practice period before the test begins 

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and takes approximately 3-4 minutes to complete (for a total of ~7 minutes). The representative timed 
RT scores are provided by the Detection task (indicating when a card is revealed; DET/simple RT),
Identification task (“is the card revealed black or red?”; IDN/choice RT), and One-Back (“Is this the card 
that you just saw?”). Performance is characterized by near complete accuracy (i.e. all, or almost all,
items are answered correctly), and validity checks are built into the scoring. The primary IIV outcome 
measure is calculated as intraindividual standardized deviations (ISD) in RTs across both tasks, 
measured in milliseconds and with log10 transformation.
8.3
MRI Sequences
Cerebral metabolic rate of oxygen (CMRO2) MRI:  To quantify absolute CMRO2, both TRUST MRI for 
quantification of venous oxygenation (Yv) and phase contrast (PC) MRI for quantification of total blows are 
needed. The imaging details were described in our previous paper22. The total scan time for CMRO2 MRI is 
approximately 4 minutes.  
Resting-state functional MRI (RS-fMRI): The sequence parameters for the RS-fMRI scans follow the ADNI 
protocol. We will use a 2D EPI sequence with SENSE partial-parallel imaging acceleration to obtain 3.3 × 3.3 
mm (64 by 64 voxels) in plane resolution in forty-eight 3.3 mm transverse slices. An ascending slice order 
with TR/TE = 3000/30 ms, flip angle of 75°, and SENSE acceleration factor of 2 will be used. SPIR will be 
used for fat suppression. We will record 140 time points, for a scan time of 7 min.
Regional brain perfusion -Pseudo-Continuous Arterial Spin Labeling (pCASL): Increased neural activity 
is known to increase local cerebral blood flow through neurovascular coupling, which can also be monitored 
with Arterial Spin Labeling (ASL)147 technique before and after tDCS. The CBF measured with pCASL in the 
current study will be used as an exploratory marker of regional integrity of neurovascular coupling (i.e., CBF 
and CBF in the PFC substrate) and its association with clinical and neuropsychological outcomes.
MRI session includes 2 conditions: tDCS off (immediately before and after tDCS) and active tDCS (in red 
frame) (refer to Figure 3). The RS-fMRI is performed before the active tDCS (with device turned off) to assess 
the network connectivity changes without any current influence. The pCASL is performed before and after the 
active tDCS (with device turned off) to assess the integrity of the brain regional perfusion. CMRO2 scans 
include PC MRI for CBF and TRUST MRI for Yv estimation; both sequences are not sensitive to the current-
induced field inhomogeneity.
8.4
Laboratory Procedures/Evaluations
N/A
Figure 3. tDCS-MRI Timing, Protocol and Sequences 

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9
Safety and Adverse Events
9.1
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e., possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm).
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would typically 
be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 

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All unresolved adverse events should be followed by the investigator until the events are resolved, the subject 
is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  The investigator should notify 
the study sponsor of any death or adverse event occurring at any time after a subject has discontinued or 
terminated study participation that may reasonably be related to this study.  The sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  
9.2
Recording of Adverse Events
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded 
in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to study participation should be recorded and reported 
immediately. 
9.3
Reporting of Serious Adverse Events and Unanticipated Problems
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association 
between the event and study treatment 
9.3.1 Investigator reporting: notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, though 
Investigators at participating sites are responsible for meeting the specific requirements of their IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 

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Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 Protocol deviations or violations (includes intentional and accidental/unintentional deviations from 
the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
 Breach of confidentiality 
 Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
 New Information indicating a change to the risks or potential benefits of the research, in terms of 
severity or frequency. (e.g., analysis indicates lower-than-expected response rate or a more severe or 
frequent side effect; Other research finds arm of study has no therapeutic value; FDA labeling change 
or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using a Reportable New Information 
submission and will include a description of the event with information regarding its fulfillment of the above 
criteria, follow-up/resolution, and need for revision to consent form and/or other study documentation. Copies 
of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s study 
file. 
9.4
Classification of an Adverse Event 
9.4.1 Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to describe 
severity. 
 
 Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
 Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
 Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. 
9.4.2 Relationship to Study Intervention 
The study PI, in conjunction with CO-I and clinicians, will determine the relationship of any adverse events or 
unanticipated problems to study procedures and equipment. 
9.4.3 Expectedness 
The study PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
9.5
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate 

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RF. Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study intervention (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system throughout 
the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained 
until participant completes study.  Dr. Krupp will be informed of the occurrence of SAEs, review the SAE with 
the PI and study team, and assess the event based on institutional guidelines regarding relatedness to the 
study, harm to the patient, or if it is expected. Events will be followed for outcome information until resolution 
or stabilization.  
 
All unresolved adverse events should be followed by the PI as well as MD-Co Investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. The investigator should 
notify the study sponsor of any death or adverse event occurring at any time after a subject has discontinued 
or terminated study participation that may reasonably be related to this study. 
9.6
Reporting Procedures – Notifying the IRB 
9.6.1 Adverse Event Reporting 
All adverse events will be reported to IRB per NYU policy.  
9.6.2 Serious Adverse Event Reporting 
All serious adverse events will be reported to IRB per NYU policy. Presence of an SAE will be included on 
data safety monitoring reports to the IRB and an immediate report (SAE that is related to study) will be 
submitted to the IRB within 48 hours of the event occurring. Dr. Krupp will review all SAE reports prior to their 
submission and follow up with each patient. 
9.6.3
Unanticipated Problem Reporting
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report 
form. It is the site investigator’s responsibility to report UPs to their IRB. The UP report will include the 
following information: 
 
 Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
 A detailed description of the event, incident, experience, or outcome; 
 An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP; 
 A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
 UPs that are SAEs will be reported to the IRB within 10 days of the investigator becoming aware of the 
event. 

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 All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and OHRP within10 days of the IR’s 
receipt of the report of the problem from the investigator. 
9.6.4 Reporting of Pregnancy 
In the case of a positive pregnancy test, the participant will be informed of the test results and excluded from 
participating in the study.  
10 Study Oversight 
10.1 Safety Oversight 
It is the responsibility of the Principal Investigator and Dr. Krupp to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well 
as the construction and implementation of a site data and safety-monitoring plan.  
 
Data safety monitoring will occur at least on a tri-annual (3 times a year) basis and will include PI and Dr. Krupp 
review of safety and efficacy data including reports of tDCS side effects including skin irritation, itching, warming, 
and discomfort, potential distress from completing cognitive assessments and questionnaires, protocol 
adherence, regulatory documentation, enrollment (e.g. rate of enrollment, screen fails, withdrawals, etc.), 
unanticipated problems, and any issues that may arise during the course of research. Data safety monitoring 
reports will be submitted to the IRB on an annual basis at the time of continuing review. There are no predefined 
stopping rules.  
10.2 Medical monitoring  
Dr. Lauren Krupp, MD, Director of the NYU MSCCC, will serve as medical monitor for this study. Dr. Krupp will 
be responsible for assessing the severity and relatedness of SAEs. In addition, Dr. Krupp will be responsible 
for communicating incidental findings that have clinical significance found on the MRI scans to the patient. 
10.3 Study Halting Rules 
There are no predefined study halting rules.  
10.4 Clinical Monitoring 
Not Applicable 
11 Statistical Considerations 
11.1 Study Hypotheses
For the first aim with a cross-sectional representative cohort data, we hypothesized that higher IIV predicts a 
clinical classification of early cognitive impairment. For the second aim with longitudinal observational early MS 
cohort, we predict that higher IIV at baseline will predict greater decline. For the last aim with prospective 
recruitment of a prodromal cohort, we predict that that CMRO2 response to tDCS to DLPFC will differentiate at-
risk patients with high vs. low IIV. 
11.2 Sample Size Determination
We aim to enroll 60 participants with prodromal MS to have n=50 evaluable participants (30 evaluable for the 
tDCS-MRI group and 20 evaluable for cognitive assessment group). As this is an exploratory protocol that is 
collecting data for future power analyses, the designation of recruiting 60 human subjects is arbitrary. Showing 
the feasibility of using Cogstate by this initial sample of participants, future studies can be conducted with 
properly powered samples to build a larger database. Recruitment of 60 participants would allow for enough 
data for assessing feasibility.  

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11.3 Statistical Methods
For the cognitive measures, the scores will be transformed to z scores to adjust for age: Each individual IIV 
value will be transformed into an age-normative z score using the Cogstate normative database (n=95,162). 
This will result in an age-adjusted IIV z score for use in all analyses described below.  
 
BICAMS tests of SDMT, RAVLT and BVMT-R will be similarly converted to age-normative z scores using the 
most recently available databases133–136. A single BICAMS score will be computed as the average of z scores 
across the three measures49. 
 
Baseline patient and disease characteristics will be summarized for the 60 participants enrolled into this cohort. 
The primary focus in this cohort is to evaluate IIV along with changes in CMRO2 during stimulation as described 
above as predictors of disease status. Distributions of IIV values and CMRO2 at baseline and during stimulation, 
along with changes in CMRO2 will be summarized descriptively and graphically with BICAMS classes. Bivariate 
scatterplots will display the baseline, during, and changes with IIV levels. Pairwise correlations will be estimated 
as measures of association between these variables (with transformations of values if required). Based on prior 
data, the mean change from baseline in CRMO2 in 31 patients =7.91, sd=10.17 (mean % change =5.61%, 
sd=6.72). Here, we will predict IIV based on the CMRO2 measurements at baseline and in response to tDCS. 
Other covariates will be incorporated into these exploratory models. For the binary BICAMS classes, again 
AUCs for the ROC curves from logistic models will be used to evaluate the roles of CRMO2 changes and IIV. 
Sample size. With 50 evaluable participants, we can detect an R2
and of 0.225 with 5 independent variables. The collected data for this prodromal cohort will serve as the basis 
for future longitudinal follow-up of this cohort.  
11.3.1 Agency for Healthcare Research and Quality (AHRQ) Indicator 
 
An additional feature of our analyses is the inclusion of environmental adversity represented by socioeconomic 
status (SES). For all participants, using the zip code of their home residence, we will use the AHRQ indicator 
as a single linear value of SES and quality of healthcare access. This indicator will provide secondary and 
exploratory testing of the role of SES in IIV and clinical disability benchmarks. 
12 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a study 
necessary for the reconstruction and evaluation of the study.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the study.  
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 

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Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
13 Ethics/Protection of Human Subjects
13.1 Ethical Standard
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects of Research codified in 45 CFR Part 46. 
13.2 Institutional Review Board
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether previously consented participants need to be re-consented. 
13.3 Informed Consent Process 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting intervention. The 
following consent materials are submitted with this protocol: informed consent form. 
13.3.1 Consent Procedures and Documentation 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Participants will be asked to read the ICF in a private 
room at an approved study location (MSCCC or CBI). Extensive discussion of risks and possible benefits of 
participation will be provided to the participants and their families. Alternatively, participants can be emailed a 
PDF version of the consent form via SendSafe and the phone number of a study team member to contact 
after they have reviewed the form. The study team member will then explain the consent to the subject, and 
ask if the subject has any questions. If the subject agrees to participate, they will electronically sign the 
informed consent document and email it back to the study team. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. A study team member will explain the research 
study to the participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and potential risks of the 
study and of their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the opportunity to 
discuss the study with their family or think about it prior to agreeing to participate. The participant will sign the 
informed consent document prior to any procedures being done specifically for the study. The participants 
may withdraw consent at any time throughout the course of the study. A copy of the signed informed consent 
document will be given to the participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The consent 
process, including the name of the individual obtaining consent, will be thoroughly documented in the 
subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, consent 
document presented orally, etc.) and the justification for such alteration will likewise be documented.  
 

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13.3.2 Posting of Clinical Trial Consent Form
N/A
13.4 Participant and Data Confidentiality
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information  
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the sponsor (NMSS). In addition, only raw data 
will be shared with the study sponsor and the study sponsor will not have access to the identifying link which 
is stored on secure, password-protected NYU Langone servers. 
 
The study monitor or representatives of the IRB may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at the clinical site for internal use during the 
study. Only IRB-approved members of the NYU research team will have access to the linked data. At the end 
of the study, all records will continue to be kept in a secure location for as long a period as dictated by local 
IRB and Institutional regulations. 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data 
N/A 
14 Data Handling and Record Keeping. 
14.1 Data Collection and Management Responsibilities
 
Data collection is the responsibility of the study staff at the site under the supervision of the site PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out 
the original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Paper CRF will be provided for use as source documents and maintained for recording data for each 
participant enrolled in the study. 

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14.2 Study Records Retention
 
Study documents will be retained for the longer of 3 years after close out or 5 years after final 
reporting/publication. These documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be retained. 
14.3 Protocol Deviations
 
A protocol deviation is any noncompliance with the study protocol or MOP requirements. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations as soon as 
practicably possible after identification of the protocol deviation. All deviations will be addressed in study 
source documents. Protocol deviations must be reported to the local IRB per their guidelines. The site 
PI/study staff is responsible for knowing and adhering to their IRB requirements. 
15 Study Finances 
15.1 Funding Source
This study will be funded by the National Multiple Sclerosis Society. 
15.2 Costs to the Participant 
 Participants will not be responsible for any costs associated with this study. 
15.3 Participant Reimbursements or Payments
Participants will be compensated $50 for completing the cognitive assessment and optional gait assessments 
and an additional $75 for completing the MRI-tDCS. 
16 Study Administration 
16.1 Study Leadership
Dr. Leigh Charvet (study neuropsychologist) and Dr. Lauren Krupp (MS neurologist) will oversee the cognitive 
data collection and collaborate with the NYU Langone Health Neurology divisions for the recruitment. Dr. 
Charvet will be responsible for the scientific aspects of the cognitive and optional measurement data 
collection and analyses. Dr. Yulin Ge, MD, NYU radiologist, will oversee the radiology aspects of the study.  
17 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, conduct, 
analysis, publication, or any aspect of this study will be disclosed and managed. Furthermore, persons who 
have a perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the study. The study leadership in conjunction with the NYU IRB and CIMU 
has established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has been 

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reviewed and approved by the study sponsor prior to participation in this study.  All NYULMC investigators will 
follow the applicable conflict of interest policies. 
 
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