Cognitive Remediation Augmented With Transcranial Direct Current Stimulation (tDCS)
Phase: NA
Conditions: Multiple Sclerosis, Neurological Disorder
Sponsor: NYU Langone Health

Cognitive remediation augmented with tDCS  
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Cognitive remediation augmented with transcranial direct current stimulation (tDCS) 
Principal Investigator: Leigh Charvet 
 
Version: December 30, 2019 
 
  
I. 
PURPOSE OF PROTOCOL 
The proposed study will test the feasibility and tolerability of transcranial direct current stimulation 
(tDCS) added to a cognitive remediation program in n=100 adults.  For up to 60 cognitive remediation 
sessions, participants will receive 20 minutes of active tDCS stimulation (up to 4.0 mA,  montage 
dependent on specific  area of deficits to be targeted) while they complete the cognitive training tasks.   
 
After initial assessment and training, participants will be assigned to complete the cognitive training and 
tDCS sessions at home using a remotely-supervised tDCS (RS-tDCS) protocol to provide telerehabilitation.   
If a participant does not meet criteria for at-home treatment, the sessions will be delivered in clinic. 
 
We have extensively developed both our cognitive remediation and tDCS methods including the RS-tDCS 
protocol (initially at our former institution, Stony Brook Medicine), alone and in combination in adults 
with multiple sclerosis (MS) and Parkinson’s disease (PD).  In MS, we have demonstrated that a program 
of adaptive cognitive remediation (that will be used clinically in this study) leads to significant cognitive 
gains [2, 3]. We then demonstrated the feasibility of tDCS combined with cognitive remediation, using 
our RS-tDCS for at-home treatment [2]. As described below, we have used this protocol in >1000 
sessions, finding very high rates of compliance and tolerability.  
 
 
II. 
BACKGROUND 
 
Cognitive remediation can lead to improved cognitive functioning across disorders.  Cognitive 
training is an attractive alternate therapeutic option, especially in its online home-use format. Our 
group has demonstrated efficacy of this type of program for improving cognitive functioning in 
individuals with MS, training for 60 sessions across 12 weeks [3]. Preliminary data from our recently-
completed randomized double-blind active-placebo controlled trials show that CT leads to greater gains 
in a neuropsychological testing composite z-score when compared to playing ordinary computer games 
(n=135, program by Posit Science[5], p=0.02, report in preparation; and n=20, program by Lumos Labs, 
0.46 ± 0.59 improvement vs.−0.14 ± 0.48 decline, p = 0.02 [6]). However, the difference in average 
improvement of the composite z-score is relatively modest (n=135, z-score 0.20±0.36 vs. 0.05±0.31, 
p=0.02, Cohen’s d =0.43). Further, we have developed a protocol to allow participants to cognitively 
train from home and shown its feasibility to use in a Multiple Sclerosis patient population [6]. The 
remote access has resulted in rapid enrollment of >160 patients in two years; in comparison, the largest 
published CT trial in MS (an outpatient memory training program with 10 sessions in five weeks) 
required >7 years to enroll n=86 participants[7]. Using our protocol we have found very high 
compliance (with no loss of study equipment). Such rapid enrollment emphasizes the tremendous 
unmet treatment need for people living with MS and other debilitating conditions, and has led to the 
established procedures to be used in this study to deliver remotely-supervised cognitive remediation.  
 
 
 
 

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Transcranial Direct Current Stimulation (tDCS) is a novel, safe, well-tolerated, and low-cost 
treatment approach that may enhance the benefits of cognitive remediation. The application of 
tDCS is a relatively recent therapeutic development that utilizes low amplitude direct currents to induce 
changes in cortical excitability [8-10]. tDCS is expected to produce neuronal polarization of less than one 
mV[11] and leads to relatively diffuse current flow, as demonstrated by imaging studies and 
computational models [12]. Most of the studies in healthy and clinical populations have used electrode 
montages that produce some current flow across the frontal lobe (including any montage with a supra-
orbital “return”). A broad neuromodulation of the frontal pole may be consistent with a general 
mechanism of action for its activating effects, along with a general increase in large-scale network 
connectivity [13]. 
 
Though various non-invasive neuromodulation technologies are available (e.g., transcranial magnetic 
stimulation), tDCS has many advantages compared to other stimulation methods including ease of use, 
lower cost, and better tolerability (e.g., it has not been associated with development of seizures [14, 15]). 
tDCS produces current intensities in the brain orders of magnitude below other stimulation techniques 
such as transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT) [16]; thus tDCS has 
none of the significant side-effects reported with these more intensive interventions.  Many subjects feel 
nothing or only mild sensation during the main course of tDCS. Across studies, the most common side 
effect reported from this technique is a mild tingling sensation [9, 17, 18]. With an extensive record of 
safety and tolerability a recent safety review demonstrates that across trials, no serious adverse events 
have been reported and throughout the literature the most common side effects are specific to the 
electrode site and include mild itching, tingling, and burning [16, 18]. Initial studies have found tDCS to 
be effective in a variety of uses in healthy participants as well as in a range of clinical conditions [19-28] 
and may be preferred to drug treatment in special populations (such as pregnant women [29]) due to its 
safety advantages.  
 
tDCS is considered especially promising for symptomatic treatment of neurological disease for its 
tolerability and, based on our innovative remotely-supervised approach, 
easy at-home use.  
While there is emerging study of the cellular mechanisms of tDCS[30-33], 
what is established is that sustained (minutes) of tDCS can produce lasting 
changes in brain excitability[8-10] and  that these changes are plastic and 
cumulative with repeated sessions [33]. One of the largest and more 
reproducible effects in healthy volunteers is enhanced vigilance with an 
increased ability to engage selective attention [17, 27, 34, 35], a finding 
which may indirectly underpin the cognitive benefits of tDCS.  
 
Pairing tDCS with cognitive remediation can improve training 
outcomes. While the programs in our studies were broadly successful, the 
training focused heavily on attention and working exercises (e.g., vigilance, 
n-back and span exercises) and we found the greatest benefits in this 
domain. Specifically isolating the working memory exercises, levels 
achieved within the CT system transfers to improvement on the 
representative working memory task, Paced Auditory Serial Addition Test 
(PASAT[36]) r=.33, p=.04, lending further support that targeted WM CT training boosts WM performance.  
 
To meet this study’s objectives, we will focus specifically on WM in both training and outcome. Limiting 
training to WM exercises will provide the opportunity to test proof of concept for the combined therapies 
Working Memory Cognitive Training 
+ DLPFC tDCS (OLE) 
Fig,1 :WM CT associated with increased perfusion of left 
precentral gyrus/frontal middle gyrus/superior frontal gyrus 
(from Buschkuehl et al. 2014)[1] 
Fig. 2 :The OLE DLPFC tDCS montage is optimized to 
targets similar regions for synergistic benefit (from Seibt et 
al. 2015)[4] 

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within this eight week frame, and maximize the synergistic effect by engaging the same regions as targeted 
by the tDCS (figures 1 and 2). Also, cognitive training targeted to specific domain of impairment vs. broad 
spectrum may have utility in MS to ultimately tailor to a patient’s specific needs[37].  
 
Training will be comprised of traditional training tasks that have been demonstrated to lead to benefit, 
both with and without adjunctive tDCS (dual n-back, auditory and visual span, simple arithmetic, and 
match-to sample [1, 38-46]). Designed and customized for research, we will use classic working 
exercises through a platform designed by Lumos Labs[47], due to our experience with their high level 
graphics, high user engagement[6], ease of administration, and ease of data extraction. Based on our 
experience using this with MS participants, we have found these games to be the best-designed with the 
highest compliance rates (e.g., reaching 80% or more of target playing time in a sample of 10 pilot 
participants[6]). 
 
We have developed a telemedicine tDCS protocol that will facilitate recruitment, increase 
compliance, and enable designs with multiple sessions to evaluate benefits of a cumulative effect. 
tDCS urgently requires further study to fully leverage this treatment modality for maximal clinical benefit. 
Repetitive sessions are necessary to produce cumulative effects as shown in neurophysiology studies and 
clinical trials for neuropsychiatric disorders and rehabilitation [25, 48-50]. For the treatment of 
depression, a clinical application that has received extensive study, some patients have required 20 to 30 
sessions or more for optimal improvement [28, 51-53].  
 
We believe that studies of tDCS have been limited by sample size and number of treatment sessions due 
to the barrier of access for many patients to participate in studies requiring multiple consecutive clinic 
visits for treatment. Daily travel to a treatment facility is a real-world limitation because it is not feasible 
for those with a full work and family schedule (requiring time taken from meeting these other 
obligations), and/or limited mobility and/or restricted transportation options (which can be especially 
burdensome for caregivers). To study multiple applications of tDCS, participants must have the option to be 
able to access these treatments from home. 
 
To address this need, we have developed a remotely-supervised telemedicine protocol to provide access 
to tDCS treatment to participants in their homes (Remotely Supervised tDCS or RS-tDCS). Our protocol 
was developed following our group’s extensive experience with a remotely-supervised cognitive 
remediation program [6], and meets collaborative guidelines and standards that we established working 
with a diverse group of tDCS clinical investigators [54]. As detailed below, our protocol is opposed to 
self-directed home use, where a patient is given a device without parameters and real-time supervision, 
which is not advisable due to both safety concerns as well as problems with uniformity and 
reproducibility of results. Instead, we maintain clinical trial standards for safety and consistency with a 
specially-designed tDCS device (that “unlocks” one “dose” per code, controlled by a study technician) with 
extensive checkpoints and built-in safety features for study using remote supervision through a 
telemedicine videoconferencing platform (VSee). 
 
Feasibility and safety study for the RS-tDCS protocol Consistent with the demonstrated safety and 
tolerability across hundreds of clinical trials in tDCS [17, 18] , including a total of eight published trials 
in MS [20, 22, 25, 26], we found very high tolerability in our feasibility study. In approximately one year, 
and at two institutions,
We have administered 1000 RS-tDCS sessions, including >700 active sessions in n=62MS 
participants (approaching the combined published experience of tDCS in MS) and n=12 PD 
participants. Participants have ranged in age from 19 to 74 years and included individuals with a 
range of disability from mild to severe or wheelchair dependent disability.  No adverse effects or 

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side effects of severe intensity have been reported in any session, and no session has been 
discontinued. As seen in Figure 1, the most common adverse event reported was skin tingling, 
and this did not exceed an intensity of “moderate.”  
 
We have experienced rapid enrollment, limited only 
by device and staff availability (53 patients on a 
waitlist over a three-month period). Compliance has 
been near-universal and all but three participants 
(95%) completed study sessions (this study 
discontinuation was due to personal family events 
unrelated to tDCS or the study). Further, the majority 
of participants have reported benefit from tDCS and 
requested to continue past study participation.  
 
From our high rate of tolerability and great interest from patients and physicians in previous 
studies, we believe expanding our tDCS protocol to open-label trials for general neurological 
disease offers the potential for direct clinical benefit.   
 
While we have focused the development of our methods in participants with MS and PD, both 
cognitive remediation along and in combination tDCS treat the symptom of cognitive impairment 
as it occurs across a wide range of disorders [23, 25, 43]. 
 
 
III. 
SPECIFIC AIM 
Specific Aim: To test the feasibility and tolerability of augmenting cognitive remediation 
with tDCS. Once referred to receive cognitive remediation, eligible and interested 
participants (n=100) will receive up to sixty daily 20-minute sessions of active (up to 4.0 
mA) tDCS paired with their completion of the cognitive tasks.   
We will determine the dosing parameters for optimal treatment across individual 
participants, depending on the nature and severity of baseline deficits. 
The primary outcome for feasibility will be the number of participants completing at least 80% of 
the targeted number of sessions. Secondary outcomes will be analysis of tolerability and 
participant-reported side effects. 
 
IV. 
DESCRIPTION OF THE PROTOCOL                                                                                                                                           
A baseline neurological and neuropsychological assessment will be completed in-clinic before 
patients begin the cognitive remediation program. Pending the results of these assessments, 
participants who are eligible for cognitive remediation will be referred to the study. For the 60 
cognitive remediation sessions, eligible participants will receive 20 minutes of active tDCS 
stimulation (up to 4.0 mA, montage to be determined based on clinician input) while they complete 
the cognitive training tasks. Once the participant has completed his/her 60 sessions a follow-up 
neuropsychological assessment will be completed. 
V. 
SUBJECT SELECTION 
 
Characteristics of the Research Population 
We will enroll a total of n=100 adults (ages 18 and over) with a clinician referral to receive cognitive 
mediation.  
 
0
50
100
150
Skin tingling
Skin itching
Skin burning
Nausea
Localized head pain
Headache
Blurred vision
Forgetfulness
Difficulty Concentrating
Dizziness
Figure 1: Tolerability across >500 active RS-tDCS sessions 

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Eligibility Criteria 
While expected to have cognitive impairment, based on our extensive experience with cognitive 
remediation studies and tDCS, we will exclude participants with an estimated premorbid level of 
cognitive functioning in the below average range (estimated by reading recognition on the Wide Range 
Achievement Test-4th Edition or WRAT-4 [55]) and a Symbol Digit Modalities Test or SDMT [56] score 
≥3.0 SD published age-referenced normative means will be excluded to ensure basic cognitive capacity to 
participate. In the case of the potential participant having either speech, motor or vision impairment 
secondary to their condition that will limit the completion of the SDMT and WRAT-4 screening measures, 
we will use the following substitution: 
• For the WRAT-4 word reading test, using reading recognition and vocabulary as an estimate of 
general and premorbid intellectual functioning, we will use the following alternate tests: Peabody 
Picture Vocabulary Test- 4th edition (PPVT-4) that is a nonverbal alternative or the Wechsler 
Abbreviated Scale of Intelligence-2nd Edition (WASI-2) expressive vocabulary test (that does not 
require vision). 
As with the WRAT-4, the cutoff for these substitute tests will remain less than 1 SD below age normative 
means. 
• For the SDMT measure, used to estimate information processing and degree of cognitive 
impairment, we will substitute with the following alternate tests: Written condition of the SDMT for 
a nonverbal alternative or the Wechsler Adult Intelligence Scale-fourth edition (WASI-IV) Digit Span 
(that does not require vision) combined with either the a) WASI-2 Matrix Reasoning subtest 
(nonverbal reasoning that does not require motor function) or b) WASI-2 Similarities subtest 
(verbal reasoning that does not require motor functioning). 
As with the SDMT, for these measures, we will continue to use the cutoff of less than -3 SD below age 
normative means.   
 
Exclusion criteria will include any health condition contraindicated with the use of a tDCS device 
(including skin disorders, head trauma or medical device in the head or neck).  
 
 
Inclusion Criteria 
 
Exclusion Criteria 

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• 
At least 18 years of age 
• 
Clinician Referral for cognitive remediation. 
• 
Have undergone a neurological examination 
and neuropsychological examination as part of 
standard of care. 
• 
Has access to internet service at home 
compatible with the study laptop (Wi-Fi or 
ethernet cable) 
• 
Able to commit to the designated period of 
study training sessions with baseline and 
follow-up visits. 
• 
Able to understand the informed consent 
process and provide consent to participate in 
the study 
 
• Visual, auditory and motor deficits that would 
prevent full ability to understand study 
instructions or operate the tDCS device or study 
laptop, as judged by treating clinician or study staff 
• Primary, uncontrolled psychiatric disorder 
that would influence ability to participate 
• Poorly controlled epilepsy 
• Medical device implanted in the head (such as 
Deep Brain Stimulator) or in the neck (such as a 
Vagus Nerve Stimulator) 
• 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) 
• Treatment for a communicable skin disorder 
currently or over the past 12 months 
• Other serious uncontrolled medical condition (e.g., 
cancer or acute myocardial infarction)  
• Wide Range Achievement Test-4th Edition (WRAT-4) 
Reading Recognition score <85* 
• Symbol Digit Modalities Test (SDMT) ≥3.0 SD 
below published norms* 
• Learned English language after 12 years of age 
• Pregnant or breastfeeding  
 
 
 
*In the case of the potential participant having either speech, motor 
or vision impairment secondary to their condition that will limit the 
completion of the SDMT and WRAT-4 screening measures the 
substitutions as mentioned above will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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   Gender and Minority Inclusion of Subjects 
Subjects will be enrolled into the study regardless of gender or minority status. 
 
 
Vulnerable Subjects 
Some participants referred may have cognitive impairment or other debilitating symptoms and could be 
considered a vulnerable population; however, those who lack capacity to consent will not be enrolled in 
this study. For all participants, we will confirm capacity to consent with their referring clinician before 
the visit. We will also screen those with estimated overall cognitive impairment and reading ability by 
administering a reading measure Wide Range Achievement Test 4 (WRAT-4). It will be clearly explained 
and written for all potential participants that the study is entirely optional and there will be no negative 
consequences if their decision is not to participate. 
 
 
VI. 
METHODS AND PROCEDURES 
a) Study Design: Participants will be referred by their treating physician to receive cognitive 
remediation. Following this referral, participants will be screened for general eligibility before 
completing a baseline neurological and neuropsychological assessment to determine eligibility for 
the study. Subjects will receive the type of neuropsychological evaluation for which they were 
originally referred. Once participants are found eligible they will complete up to 60 sessions of 
cognitive remediation while receiving 20 minutes of up to 4.0 mA tDCS using a montage based on 
presenting cognitive deficits. Subjects will not be required to complete additional sessions for 
research. The first session is completed at baseline with the option for the remaining sessions to be 
completed at home using the RS-tDCS protocol.  If for some reason participants are not able to 
complete the training from their home, they will have the option to receive treatment at clinic.   
Screening: 
Participants will primarily be recruited from the NYU Langone Medical Center. Once a participant is 
deemed generally eligible following their neurological and neuropsychological evaluations, the 
individual will be scheduled for a visit at NYU to review and sign consent and complete screening 
procedures. For those interested in study participation, once eligibility is confirmed by the study PI, their 
cognitive remediation and tDCS training will be scheduled.  
Baseline Visit: 
*Note PI assessment for eligibility may occur either before or at the baseline visit 
 
Prior to tDCS training, the tests and evaluations detailed in Table 2 will be administered. 
 
tDCS aptitude screen and tolerability test: 
• tDCS Aptitude: Participants will first complete an aptitude test to confirm that they have the 
cognitive and motor skills required for headset placement.  
With instruction of the study technician, participants will be asked to insert the sponges onto the headset 
and place the electrodes into the sponges. The technician will determine whether or not the participant is 
qualified to proceed. Participants will not be allowed to proceed if they are not able to correctly either 1) 
attach sponges to headset or 2) place electrodes into the sponges. 
tDCS Tolerability: The study technician will next directly place the headset and then initiate a one-minute 
test session, with 30 seconds of ramp-up to target, following by 30-second ramp down. The tolerability test 
will first take place using 2.5 mA stimulation. If the participant tolerates and agrees, 3.0 will be tested; again 

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if the participant tolerates and agrees, the next increment of 3.5 mA will be tested; as follows, increases will 
be made to 3.5 and 4.0 mA respectively (note: the option for increase is device-dependent; some current 
devices have a maximum of 2.5 mA programming).  Alternatively, if the participant cannot tolerate 2.5 mA, 
stimulation will be based on highest amplitude tolerated, following 0.5 mA decrements (with 2.0, 1.5., and 
1.0 mA stimulation offered). Once the tolerable dose is established, it will remain constant throughout the 
study.  If the participant cannot tolerate any offered stimulation levels, they are excluded from the study. 
 
• 
A total of 20 x 20 minute sessions is targeted, with the option for up to 60 x 20 minute 
sessions to be completed. The minimal goal of 20 sessions completed will continue up to 60 treatment 
sessions if jointly agreed between the study participant and referring clinician. 
 
Remotely Monitored Study Sessions: 
Study Equipment: For the remotely-supervised sessions, participants will be given the specially- 
designed tDCS device and headset, study laptop computer for secure video monitoring with study 
technician (must have internet access) and a training video. The Soterix mini-CT is uniquely 
designed for remotely-supervised delivery and requires a one-time use code provided by the 
study technician to unlock the device for one stimulation session at a time. The device will not 
operate without correct headset placement and has a single-button option to abort the session. 
The device will also automatically abort the session if optimal conditions are not maintained. It 
reports and records a completion code for each session. 
These sessions will be completed from home with remote monitoring by the study technician.  
Participants will schedule times during which they are certain they can self-administer the tDCS while 
they are being remotely monitored by study staff. They will be observed using a secure internet-based 
video chat program that will be installed in the laptop they will use for the study. To start their session, 
the participant will connect to study staff via VSee. VSee is a HIPAA compliant teleconferencing software 
that encrypts data before sending, creating a secure connection between two computers. 
They will put on the tDCS headgear while being monitored, and tell study staff if the device feedback 
indicates that the electrodes are acceptably placed. The participant will then receive the activation code 
from the tDCS device. If the study staff observes the participant making any errors that may cause the 
latter discomfort they can intervene with instructions for correction. 
Montage: 
We currently use the dorsolateral prefrontal cortex (DLPFC; left anodal) montage.  We will expand to the 
other commonly-used tDCS montages to be matched depending on referring clinician’s input. Most 
participants will receive the montage with the standard DLFPC cortex (left anodal) montage.  However, in 
some cases, with clinician input a different montage may be used for current delivery[18, 57].  For instance, if 
there are primary visuomotor integration problems, the M1-S0 montage may be used instead.  Or, if there are 
primary visual processing difficulties, an occipital lobe montage may be used.  All montages will follow the 
standard placement systems[58] as available through the device company Soterix, and with no safety or 
tolerability issues noted between differing montages[18]. 
 
 
Safety notes: 
• The tDCS device can only operate if: 1) the headset is correctly placed for adequate connection, 
and 2) the study technician provides a session code that unlocks the device for a one-time only 20 
minute period of use. 

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• If the device loses adequate contact for any reason, the device will automatically discontinue the 
session. The session can only be reestablished if another unlock code is provided by the study 
technician. 
• If the participant wishes to discontinue the session at any time, they will be instructed to press the 
“abort” key which ramps down the current within 30 seconds to allow for headset removal. 
 
 
Figure 2. Study stop criteria 
 
 
 
Study End Visit: 
Within three days of their last session (including same day), participants will have their final study end 
visit in clinic. The tests and evaluations administered at baseline will be given to the participant again 
(Table 1).  The equipment that had been provided to the participant for this study will be returned on 
this visit. 
 
Outcome Measures: Before and after each session, participants will complete brief measures to 
monitor for any stimulation-related events. Brief measures will also be given to monitor any 
therapeutic or behavioral effect of the tDCS stimulation. To further inform tolerability of 
stimulation sessions, a pain scale will be administered before, during, and after each session. 
Participants will also complete baseline and study-end inventories of cognitive and behavioral 

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measures to help guide power estimates for the future trials. A summary of outcome measures 
can be found in Table 2. 
All remotely-supervised sessions will be completed while connected to a video session with the 
study technician. The protocol is designed to have a decision-tree series of checkpoints that must 
be met in order to proceed at each step (Figure 2). These checkpoints address compliance 
(attendance, ability to complete the procedures as instructed, following the study guidelines) and 
tolerability (at any time, if any predefined events are reported, or if pain crosses a threshold the 
participant will be discontinued). 
 
Table 2. Study Outcome Measures 
 
 
Test 
Screening 
Baseline Daily 
Study 
Sessions 
Study 
End/Follow-up 
Visit 
Post Study Survey 
(at least 1 month 
after study end) 
Medical Clearance 
x 
x 
 
 
 
Wide Range 
Achievement Test 
(WRAT-4) 
x 
 
 
 
 
Symbol Digit 
Modalities Test 
(SDMT) 
x 
x 
 
x 
 
tDCS Aptitude Test 
 
x 
 
 
 
tDCS Tolerance Test 
(4.0, 3.5, 3.0. 2.5, 2.0, 
or , 1.5, or 1.0 mA) 
 
x 
 
 
 
PROMIS Measure of 
Fatigue, Mood and 
Health-Related 
Quality of Life 
 
x 
 
x 
x 
Cogstate 
 
x* 
 
x* 
 
Test of Everyday 
Cognitive Ability 
 
x* 
 
x* 
 
King Devick 
 
x* 
 
x* 
 
Hand grip and pinch 
strengths  
 
x* 
 
x* 
 
Symptom Specific 
Measures (Cognitive 
and behavioral)  
 
 
x 
x 
x 
 
Cognitive Linguistic 
 
x* 
 
x* 
 

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Quick Test, The 
Communicative 
effectiveness Index, 
Western Aphasia 
Battery Part 2 
Positive and Negative 
Affect Scale (PANAS) 
 
x 
x 
x 
x 
Visual analog scale 
for pain (pre-, mid- 
and post-session) 
 
x 
x 
 
 
Tolerability 
questionnaire  
administered by 
study staff (pre- 
and post-session) 
 
x 
x 
 
 
Safety and 
tolerability 
questionnaire - 
self-report (pre- 
and post-session) 
 
x 
x 
 
 
Score for 
Computerized 
cognitive games 
(daily) 
 
 
x 
 
 
Participant 
evaluation 
of 
study 
procedures and 
report of their 
experience 
 
 
 
x 
x 
Count of 
successful tDCS 
sessions 
(confirmation 
code by session 
days) 
 
 
 
x 
 
 
*- Optional measure 
 
VII. 
STUDY LOCATION 
Participants screening, baseline and study end visits will be completed at the NYU Langone MS 
Comprehensive Care Center, 240 East 38th Street, 18th Floor, NY NY 10016, or the satellite location for the  
MS Center: NYU Langone Huntington Medical Center, 789 Park Ave, Huntington, NY 11743. For 
participants with limited mobility, visits can be completed from the participant’s home. 
Additionally, 222 East 41st Street, 10th Floor is a third available study location. 

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VIII. 
DATA ANALYSES AND DATA MONITORING 
 
Database and Patient Information 
Data will be entered in the HIPAA- compliant NYU REDCap database designed specifically for this study. 
An anonymous database number will be assigned to each participant and will be used for both the Data 
Entry Sheet and the Patient Follow-up Sheets. The original front sheet, which includes the patient name 
and ID number, will be stored separately in a locked filing cabinet in a locked office. Access to this data 
will be restricted to study personnel only. Research data will be entered online through the secure NYU 
database software REDCap and source documents will be kept in a locked filing cabinet in a locked office. 
Patient clinical data will be entered directly into the Patient Registry (on-line entry). Participant data will 
be coded by the assigned ID and identifying information will not be presented or published to maintain 
participant privacy and confidentiality. 
 
Additional Quality Assurance Measures 
• Development of standard protocols to perform all data collection and follow-up activities. 
• Use of standardized forms. 
• Uniform criteria for patient recruitment. 
• Standardized data processing. 
• Regular communications between study staff and study investigators to resolve questions. 
• Performance monitoring of data collection and data processing activities, as well as preparation of 
periodic reports and analyses on performance monitoring. 
• Monthly monitoring of recruitment statistics. 
 
Data and Safety Monitoring Plan 
We will utilize operating procedures for reviewing patient safety data and source data generated from   
this study. This will include weekly meetings between the PI, the Co-I (Dr. Lauren Krupp), and study 
coordinators. At these meetings, the entire research team will review the clinical ratings, assessments, 
clinical course, and medical records for each subject. Consideration of dropping any patient from the study 
for any reason will be discussed. If after the completion of the first 20 subjects the compliance is 
significantly low, the study will be put on hold and reviewed. Based on the extensive body of literature 
using tDCS across a range of conditions, and our initial participants studied to date (completed at Stony 
Brook Medicine), we have had >94% compliance in the active condition. Due to our success with 
compliance in previous studies, we do not expect severe compliance issues. Still, we are prepared to deal 
with compliance problems, if there is significantly poor compliance, we will be able to identify reasons 
including tolerability as well as symptom experiences.  Tolerability is measured before, during and after 
each session and all participants will be monitored for all sessions. Safety is carefully addressed in our 
protocol with a series of stop criteria and clearly defined action items. 
 
Specific attention will be given to data quality and timeliness, HIPAA-complaint, safe storage of data, and 
data backup of electronic source data. Attention will also be given to participant recruitment, accrual and 
retention, participant risk versus benefit, adverse events, and other factors that can affect study outcome, 
including scientific or therapeutic developments that may have an impact on the safety of the participants 
or the ethics of the study. 
 
 

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Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of 
the study.  Inter current 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 
Definition of Serious Adverse Events (SAE) 
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 
 
We will submit study data safety monitoring reports to the IRB after 10 participants are enrolled, and 
follow with reports for each further increment of 10 active enrollees. 
 
Statistical Analyses 
Analyses will be completed with IBM SPSS v. 23. Means, medians, standard deviations (SD) will be 
compared between subgroups on the measures using conventional cut-off points for each of the 
symptoms will be compared. Our sample size (n=100) was determined by a power analysis indicating 
over 90%in determination of feasibility and tolerability. 
Specific Aim 1 will be tested by assessing the compliance (<80% sessions completed) of study 
participants within groups established by disease, age, EDSS scores etc. We will also assess any reported 
side effects of active tDCS treatment to determine general tolerability  
Secondary outcomes will be used to compare the groups in change in performance on the additional 
measures listed in Table 2. In addition, performance on the WM CT will be analyzed across training 
sessions, including time to advance to a new level and overall levels achieved. Similar analysis as what have 
been planned for the primary outcome will be performed for comparing the change in these secondary 
outcomes between before and after the completed sessions. 
 
Neurological clinical features (age, gender, disease, treatment, disease duration) will be compared by 
correlational analysis. 
 
IX. 
SUBJECT RECRUITMENT AND CONSENT/ASSENT 
 
Subject Identification, Recruitment and Consent/Assent 
Method of Subject Identification and Recruitment 
NYU Langone Medical Center has an extensive recruitment base. Patients who are seen by medical staff at 
NYU Langone Medical Center, who fit the eligibility criteria, will be referred for the study by the study PI, 
Co-I, and sub-investigators. If the patient is interested and agrees, then a member of the study staff will 
contact them. Once a patient is identified, study staff will meet with the patient or call them to provide 
additional information regarding study participation. After the patient has reviewed the consent form and 
asked all questions, and provides consent to participate, the patient will be enrolled in the study. 

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Advertisements 
An IRB approved flyer will be posted in local physician offices and waiting rooms and throughout NYU, 
the surrounding community, and on Long Island. A description of the study will be posted on sites 
related to neurological disorder. 
 
 
Process of Consent 
All potential participants will complete a screening interview to ensure general eligibility. The study staff 
member speaking to the subject will provide the subject with an overview of the study and verbally 
receive their permission, under a waiver of documentation of consent, to complete the general eligibility 
screening. The pre-screening measures will include reading recognition on the Wide Range Achievement 
Test-4th Edition or WRAT-4 [55] and a Symbol Digit Modalities Test or SDMT [56]. In the case of the 
potential participant having either speech, motor or vision impairment secondary to their condition that 
will limit the completion of the SDMT and WRAT-4 screening measures the substitutions as mentioned 
above will be used. If a participant is not eligible, they will be considered a screen fail. No additional 
information will be collected. PHI will be destroyed immediately if a participant is not eligible or does not 
return to sign written consent/authorization to participate. Only study staff will have access to these 
records.  
Once the participant is generally eligible, the PI, or one of the trained study team members will review 
the consent form with the subject and explain the purpose of the study, the procedures, as well as risks 
and benefits. All questions will be addressed before acquiring the participant’s signed consent.  Subjects 
must have capacity to consent in order to be enrolled in the study. 
Referring clinicians and NYU clinicians doing the medical screening will be responsible for assessing the 
capacity to consent. An independent assessor will not be utilized. There is a large body of literature 
indicating no known safety or tolerability risk for use of tDCS. Further, tDCS is currently being studied as 
an alternative to relatively higher risk treatments (such as medication) in special populations such as 
pregnant women and developmentally disabled children. 
 
Published studies in MS, including the work in our lab at Stony Brook Medicine, show tDCS to be a 
tolerable and safe treatment approach. Members of the core physician group and team at the MS Center 
are Neurology specialists with extensive experience in the assessment of neurology patients, including 
capacity to consent for numerous clinical drug trials where there is a substantially greater potential risk 
posed than what are the known risks for tDCS. Therefore, taken together, we do not believe that the use 
of tDCS represents a situation where an independent party would be needed. 
Process to Document Consent in Writing 
After review of the consent form and prior to the start of the first session, the PI or one of the trained study 
staff members will obtain written consent with a signature of the patient on the consent form. All original 
signed consent forms will be maintained in the study file, separate from the participant data. 
 
 
Subject Capacity 
All participants will be confirmed to have the capacity to provide consent by a member of the core 
physician group as described above.  Further, those participants with estimated premorbid intellectual 
functioning and/or impaired reading ability (as determined by the WRAT-4 Reading Subtest), and those 
with severely impaired information processing speed (as determined by the SDMT) will be excluded. 
 
Debriefing Procedures 
No information will be purposely withheld from the subjects. A clinical neuropsychologist (PI) and the 
treatment team will be available to answer any questions concerning the tests and results, and provide 
initial feedback as warranted, including referral for clinical neuropsychological assessment. 

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Consent Forms 
Participants will receive a NYU consent form to review and sign prior to participating in the study. 
 
Documentation of Consent 
The PI is responsible for ensuring that valid consent is obtained and documented for all subjects. An 
enrollment log will be maintained and consent forms will be kept in secure location separate from the 
participant’s data. 
 
Costs to the Subject 
If subjects choose to participate, the cognitive remediation sessions will be provided to them without cost 
for that care. The MS Center medical secretary who oversees billing authorization for clinical 
neuropsychological service will perform insurance authorizations.  Following procedures for clinic 
appointments, prior authorization will be obtained and the participant will be informed of any potential 
costs prior to scheduling and enrollment. Both the cognitive remediation and tDCS will be covered by the 
research team, further no additional sessions will be required for research purposes. If subjects have been 
referred for other clinical services in addition to cognitive remediation or if the clinical review of their case 
indicates that other treatments would be appropriate, these treatments would be provided at a cost to 
subjects based upon their insurance coverage. Subjects will be informed of their payment responsibilities 
before they are enrolled in the study during the pre-screening phone conversation (see Section IX, Process 
of Consent). 
 
Payments to the Subject 
Subjects will not be compensated for their participation in the study. 
 
Risk to Participants 
As described above, tDCS poses low risks to participants and our protocol is well-tolerated 
[18].To our  knowledge, hundreds of tDCS studies in the US have all been designated Non-Significant-
Risk (NSR) the  lowest risk level (devices that are not: intended as an implant with potential for serious 
risk to health,  safety, or welfare of subject; purported or represented to be for use in supporting or 
sustaining human  life with a potential for serious risks; for use of substantial importance in diagnosing 
curing, mitigating, treating disease or otherwise preventing impairment of human health with potential 
for significant risk; otherwise presents significant risk to the health, safety, or welfare of a subject). For 
these reasons, the Soterix Mini CT, as used in this study, also qualifies as a NSR device. While tDCS 
remains an investigational technique (simply because no company has applied to the FDA for approval 
to market tDCS for any given indication), tDCS is a broadly reproduced and tested techniques that is 
considered effective in modulating brain excitability in a manner that may support learning and with 
adverse events (different than sham) limited to tingling, itching, and redness that dispel after stimulation 
stops. In a prior study of use in a vulnerable population (developmentally disabled children), the FDA 
issued a NSR for tDCS device (see attached letter). The letter provided as an example of the FDA’s 
designation of tDCS devices as having abbreviated-IDE. Because of its prior designation of tDCS devices 
as abbreviated-IDE, trials do not typically seek further declaration. In the letter provided, Dr. Wasserman 
specifically sought FDA review of the trial due to the use of tDCS in a vulnerable population 
(developmentally disabled children). To date, hundreds of trials have been designated as non-
significant-risk by IRB review which provides its abbreviated IDE status. Results of completed trials, 
including our own work in MS using this protocol, have supported the risk designation provided by IRBs. 
The Stony Brook Medicine IRB confirmed the NSR and abbreviated IDE status of tDCS for our study. 

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and others at the institution. We have learned that the NYU IRB has also confirmed tDCS devices 
(including those manufactured by Soterix) as having an abbreviated-IDE for current ongoing studies at 
this institution for other indications. 
 
The safety of this technique has been addressed and tested by multiple researchers (Fregni, et. al. [59];  
Nitsche, et al. [60]; Priori, et al. [15]) who have concluded that tDCS, as applied in a manner similar to 
our proposed protocol, induces only temporary mood, cognitive / motor effects, and no negative side 
effects..  For example, researchers at the National Institute of Neurological Disorders and Stroke 
(NINDS), Iyer et al. [17] conducted a safety study on tDCS, investigating 20-minute sessions of 1 mA and 
2 mA current stimulation with healthy controls (n=103). No negative effects were identified. Nitsche and 
colleagues found no measurable structural changes in brain tissue due to tDCS [61]. In a meta-analysis of 
over 200 tDCS studies conducted from 1998 to 2010, 56% of studies mentioned adverse events, which 
were generally minor. The most commonly reported side effects included itching, tingling, headache, 
burning sensation and discomfort limited to the scalp site where the tDCS electrodes were applied. To 
date, there have been no reports of seizures induced by tDCS14. Importantly this is the case in normal 
volunteers, but also in different populations of patients, including patients with disorders where there 
might be an increased risk of seizures (e.g. Alzheimer’s disease, recent stroke, epilepsy). A study from 
NYU on the use of tDCS in patients with epilepsy [62] encountered no increase in complications of tDCS 
in the patients as compared with controls. Specifically, there were no instances of seizures induced by 
tDCS. 
Participants in all groups may find the questionnaires time consuming and potentially bothersome. 
Neuropsychological testing and the computer training sessions may, in some individuals, be stressful or 
anxiety producing. There is a small risk of loss of confidentiality. Participants will be assigned a study ID 
and their name will not be used on any of the information collected. The program used for brain training 
games will not collect any personally identifiable information. The results of these data collected may be 
used for publication but will not include the participants’ names. Hardcopies of the data files will be kept 
in secure, locked files and data will be entered in a secure, NYU approved database. 
 
Benefits to Participants 
Participants may have some benefit from this study. The therapeutic techniques used may, on their own, 
be of benefit to the participant. Cognitive remediation can have an increase in cognitive functioning 
through the use of the tDCS device. We hope the knowledge gained from this study will help others in 
the future. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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