Remotely Supervised Transcranial Direct Current Stimulation for Slowing Disease Progression in Amyotrophic Lateral Sclerosis (ALS)
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Sponsor: University of Illinois at Chicago

Cover Page 
 
Official Study Title 
Remotely Supervised Transcranial Direct Current Stimulation for Slowing Disease 
Progression in Amyotrophic Lateral Sclerosis (ALS) 
 
NCT Number 
NCT04866771 
 
Document Type 
Study Protocol and Statistical Analysis Plan 
 
Document Date 
January 1, 2023 
 
Sponsor 
University of Illinois at Chicago 
 
Principal Investigator 
Dr. Sangeetha Madhavan, PT, PhD 
Professor, Department of Physical Therapy 
University of Illinois at Chicago 
 

Remotely Supervised tDCS as an intervention in ALS  
 
Remotely Supervised Transcranial Direct Current Stimulation for Slowing Disease 
Progression in Amyotrophic Lateral Sclerosis (ALS) 
 
TABLE OF CONTENTS 
Page 
Table of Contents .......................................................................................................... 3 
List of Abbreviations ..................................................................................................... 4 
1.0 Project Summary/Abstract ................................................................................... 5 
2.0 Background/Scientific Rationale ......................................................................... 6 
3.0 Objectives/Aims .................................................................................................... 9 
4.0 Eligibility .............................................................................................................. 10 
4.1 Inclusion Criteria ........................................................................................... 10 
4.2 Exclusion Criteria .......................................................................................... 10 
4.3 Excluded or Vulnerable Populations ........................................................... 11 
5.0 Subject Enrollment.............................................................................................. 11 
6.0 Study Design and Procedures ........................................................................... 11 
7.0 Expected Risks/Benefits ..................................................................................... 18 
8.0 Data Collection and Management Procedures ................................................. 20 
9.0 Data Analysis ....................................................................................................... 21 
10.0 Quality Control and Quality Assurance ............................................................. 21 
11.0 Data and Safety Monitoring ................................................................................ 22 
12.0 Statistical Considerations .................................................................................. 23 
13.0 Regulatory Requirements ................................................................................... 23 
13.1 
Informed Consent ..................................................................................... 23 
13.2 
Subject Confidentiality ............................................................................. 24 
13.3 
Unanticipated Problems .......................................................................... 24 
13.3.1 Table 1:  tDCS related adverse effects …………………………………25 
14.0 References ........................................................................................................... 26 
 
 
 
 
 
 
 
 
 

Remotely Supervised tDCS as an intervention in ALS  
 
 
 
LIST OF ABBREVIATIONS  
 
10MWT 
 
10-meter walk test (10MWT) 
AE 
 
 
Adverse Event 
ALS  
 
Amyotrophic Lateral Sclerosis 
ALSFRS-R  
ALS Functional Rating Scale-Revised 
ANOVA 
 
Analysis of Variance 
BBS  
 
Berg’s Balance Scale 
EMG  
 
Electromyogram 
FDA  
 
Food and Drug Administration 
HIPAA 
 
Health Insurance Portability and Accountability Act 
IRB  
 
Institutional Review Board 
LMN  
 
Lower Motor Neuron 
M1 
 
 
Primary Motor Cortex 
MEP  
 
Motor Evoked Potential 
MS 
 
 
Multiple Sclerosis 
NSE  
 
Neuron Specific Enolase 
NIBS  
 
Non-invasive Brain Stimulation 
PI 
 
 
Principal Investigator 
PNS   
 
Peripheral Nerve Stimulation 
RCT  
 
Randomized Control Trial 
RPE  
 
Rate of Perceived Exertion 
RS-tDCS 
 
Remotely Supervised Transcranial Direct Current Stimulation 
TA 
 
 
Tibialis Anterior 
tDCS  
 
Transcranial Direct Current Stimulation 
TMS  
 
Transcranial Magnetic Stimulation  
UMN  
 
Upper Motor Neuron 
UIC  
 
University of Illinois at Chicago 
 
 
 
 
 
 

Remotely Supervised tDCS as an intervention in ALS  
 
 
 
 
1.0 
Project Summary/Abstract 
ALS affects as many as 30,000 individuals in the United States, with 5,600 new cases diagnosed 
each year. Riluzole and edaravone, the only drugs approved by the U.S. FDA for ALS, slow 
ALS progression; however, they do not demonstrate marked improvement in ALS symptoms and 
increase survival time only by a few months. Hence, most of the care is centered on patient 
support and symptom management, making rehabilitation an integral aspect for slowing disease 
progression, prolonging life span and increasing quality of life. Our long-term goal is to develop 
neuromodulation therapies for easy clinical management of ALS. Transcranial direct current 
stimulation (tDCS) has been increasingly explored as a promising neuromodulatory tool to prime 
motor function in several neurological disorders. Despite the emerging importance of cortical 
dysfunction as a pathophysiological biomarker in disease progression, the study of tDCS in ALS 
is limited. Here we propose a novel mechanism using remotely supervised tDCS (RS-tDCS) to 
target hypoexcitable neural pathways to preserve motor function in individuals with ALS. Due to 
its low risk, ease of use, and portability, tDCS is a candidate neuromodality to be administered in 
a home-based environment with remote supervision from qualified personnel. Remote 
supervision would ensure that the stimulation is delivered optimally in the comfort of a patient’s 
home, reducing burden on patients and caregivers to travel to the clinic or research facility and 
encourage protocol adherence. We aim to investigate the effectiveness and feasibility of long-
term RS-tDCS in individuals with ALS. In a delayed-start design, 100 participants with ALS will 
be randomized into remotely supervised tDCS or delayed-start control group. The intervention 
group will receive 24 weeks of anodal tDCS (3 times/week; 72 sessions). The delayed-start 
group will first receive sham tDCS for 12 weeks followed by a switch to anodal tDCS for 12 
weeks. Aim 1 will investigate the safety and feasibility of long-term treatment with anodal RS-
tDCS in ALS. Aim 2 will determine the effects of 24-weeks of RS-tDCS on disease progression 
in individuals with ALS, using the ALS Functional Rating Scale (Change in Revised ALS 
Functioning Rating Scale (ALSFRS-R). Scores range from 0 to 48, with higher scores indicating 
more function retained. 
 As a secondary aim, we will explore the effectiveness of RS-tDCS on upper and lower motor 
neuron mechanisms in individuals with ALS, quantified using Upper and lower motor neuron 
mechanisms will be assessed using single-pulse transcranial magnetic stimulation (TMS). 
 Successful completion of this project will trigger future studies that will test the clinical 
translation of tDCS as a home-based neuromodulatory adjuvant to slow disease progression in 
ALS and create a paradigm shift in the clinical management of ALS.  
 
 
Hence, the objectives of this pilot study are:  
• Aim 1: To investigate the safety and feasibility of long-term treatment with anodal RS-
tDCS in ALS. 
• 
Aim 2: To determine the effects of 24-weeks of RS-tDCS on disease progression in individuals 
with ALS, using the ALS Functional Rating Scale (Change in Revised ALS Functioning Rating Scale 
(ALSFRS-R). Scores range from 0 to 48, with higher scores indicating more function retained. 
 

Remotely Supervised tDCS as an intervention in ALS  
 
• 
Aim 3: To determine the effects of RS-tDCS on upper (UMN) and lower motor neuron (LMN) 
mechanisms in individuals with ALS, quantified using Upper and lower motor neuron mechanisms 
will be assessed using single-pulse transcranial magnetic stimulation (TMS). 
 
 
 
2.0 
Background/Scientific Rationale 
Amyotrophic Lateral Sclerosis (ALS): ALS is a rapidly progressive neurodegenerative disorder 
that causes muscle weakness, and eventually death from respiratory failure (Borasio & Miller, 
2001). Glutamate mediated excitotoxicity has been implicated as a predominant cause for 
neuronal cell death in ALS (Steve Vucic, Ziemann, Eisen, Hallett, & Kiernan, 2012). Integrity of 
the glutamatergic circuits can be non-invasively assessed via TMS. Several lines of evidence 
have implicated the degeneration of corticospinal neurons via glutamate excitotoxicity, followed 
by that of lower motor neurons as the pathophysiological site of disease onset in ALS (Attarian, 
Pouget, & Schmied, 2009; Floyd et al., 2009; Geevasinga, Menon, Kiernan, & Vucic, 2014; 
Steve Vucic et al., 2012). Few TMS studies have established motor cortical and corticospinal 
dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of 
ALS and preceding the clinical onset of familial ALS (S. Vucic, Cheah, Yiannikas, & Kiernan, 
2011; Steve Vucic et al., 2012). Other non-invasive therapeutic adjuncts such as repetitive TMS 
or Transcranial Direct Current Stimulation (tDCS) are currently being investigated based on the 
evidence garnered from TMS based studies.  
tDCS: tDCS is a therapeutic adjunct that has emerged as a promising tool to modulate neural 
excitability and enhance motor learning and motor behaviour ALS (Boggio et al., 2007; Fleming, 
Pavlou, Newham, Sztriha, & Teo, 2016; Lefaucheur, 2016; M. A. Nitsche et al., 2008; Michael 
A Nitsche, Kuo, Paulus, & Antal, 2015; Schlaug & Renga, 2008; Ziemann & Eisen, 2004). tDCS 
involves the application of low intensity direct current to the scalp, and although it does not 
directly induce action potentials, it alters the membrane potentials that affect neuronal 
excitability (Stagg & Nitsche, 2011). Stimulation with the anode over the motor cortex 
contralateral to the target muscles and the cathode over the ipsilateral orbit (anodal tDCS) 
increases the excitability of the corticospinal projections to the target muscle (Stagg & Nitsche, 
2011). In contrast, with the cathode over the motor cortex and the anode over the orbit (cathodal 
tDCS), corticospinal excitability is decreased. tDCS has been shown to be effective as a 
neuromodulatory adjunct in stroke, Parkinson’s disease, Multiple Sclerosis and several other 
neurological disorders (Palm, Ayache, Padberg, & Lefaucheur, 2014) 
Transcranial direct current stimulation (tDCS) is one of the technically uncomplicated NIBS 
protocols to apply. During tDCS, electrodes are placed and secured to the scalp over the desired 
areas and currents are delivered to the underlying cortical tissue. The stimulation elicits minimal 
discomfort and only a mild tingling sensation that usually disappears after a few seconds (M. A. 
Nitsche & Paulus, 2000). By varying the position and polarity of the electrodes, tDCS has been 
adapted to produce a wide variety of effects (Kantak et al., 2010; Kessler, Turkeltaub, Benson, & 
Hamilton, 2012; Reis et al., 2009). There is evidence that anodal (facilitatory) tDCS applied over 
M1 during skilled task performance in healthy subjects enhances hand motor skill acquisition 
with persistence of the beneficial effect 3-months after training (Reis et al., 2009). tDCS has 
been evaluated as a viable clinical adjuvant therapy in those with ALS (Munneke et al., 2011; 
Quartarone et al., 2007). tDCS session are typically administered for four weeks (3 times/week 

Remotely Supervised tDCS as an intervention in ALS  
 
for 12 sessions). The number of sessions are dictated in part by patient convenience as patient 
adherence to the study drops if longer time periods are necessitated. Also, many participants are 
unable to travel to the laboratories to obtain the benefits of lab based tDCS. Given that tDCS is a 
safe procedure, tDCS treatment can be administered outside the laboratory under remote 
supervision. The participants would be educated and trained by the research team in tDCS 
treatment and electrode preparation techniques. A remotely supervised tDCS treatment would 
potentially increase patient compliance.  
Safety of tDCS: The relatively low cost of tDCS devices along with the potential beneficial 
effects combined with its safe, simple, painless application and easy portability, makes it an ideal 
candidate to be used as a clinical adjuvant before or during therapy to enhance neuroplastic 
changes and improve function. Numerous clinical trials have demonstrated tDCS to be a safe and 
tolerable device without any major adverse events (Fregni et al., 2005; Fregni et al., 2006; 
Hummel et al., 2005; Kantak et al., 2010). Studies from our lab have also shown tDCS to have 
minimal or no adverse effects (Devanathan & Madhavan, 2016; Madhavan & Stinear, 2010; 
Madhavan, Weber II, & Stinear, 2011; Sriraman, Oishi, & Madhavan, 2014). A recent review 
concluded that human studies that evaluate the parameters of neuronal damage, such as neuron 
specific enolase (NSE), electroencephalography (EEG) and neurophysiological tests support the 
safety of tDCS (Antal et al., 2017; Iyer et al., 2005; M. A. Nitsche et al., 2003) Tadini et al. 
2011). Typically, tDCS related dosage parameters include a current intensity of 0.5 – 2 mA with 
most stimulation electrode sizes of 5 x 7 cm. This electrode configuration creates a net current 
density of approximately 0.029 mA/cm2 when currents are applied for 20 minutes. M. A. Nitsche 
et al. (2003) reviewed tDCS induced adverse events from studies that included approximately 
500 healthy subjects from 2000 to 2003 with dosage parameters as mentioned above. The major 
common adverse events (AE) reported were mild tingling sensations that occurred under the 
electrodes during stimulation. Another study (Poreisz, Boros, Antal, & Paulus, 2007) examined 
the adverse events (AE) from 567 tDCS sessions that were administered to healthy volunteers 
and patients with migraine, stroke and tinnitus. The most common AEs were mild tingling 
sensation (70.6 %), moderate fatigue (35.3 %), slight itching under the stimulating electrode 
(30.4 %), headache (11.8 %), nausea (2.9 %) and insomnia (0.98%) (Poreisz et al., 2007) (Please 
refer to Table 1). Transient redness and contact dermatitis following tDCS has also been reported 
in a few studies (Riedel, Kabisch, Ragert, & von Kriegstein, 2012). Contributing factors to these 
AEs include electrode position, pre-existing conditions such as skin allergies, high skin-electrode 
impedance (dry electrode, solution salinity of electrode sponges, incorrect electrode fixation), 
prolonged duration, high current density (high current, small electrode) (Dundas, Thickbroom, & 
Mastaglia, 2007; McFadden, Borckardt, George, & Beam, 2011; Palm et al., 2014) The 
occurrence of AEs can be prevented by careful adherence to protocol and necessary precautions 
(such as screening for hypersensitivity and monitoring). Skin irritation can be prevented by 
adequate preparation of the skin and stimulating electrode. Several studies have also evaluated 
possible AEs of tDCS in perceptual and cognitive domains by testing performance on 
neurocognitive tests following tDCS. tDCS does not appear to cause apparent perceptual or 
cognitive AEs in healthy subjects (Iyer et al., 2005).  
To summarize, when adhering to standard stimulation parameters (1 – 2 mA) and 15 – 20 min 
duration, single and repeated sessions of tDCS show benign study effects such as mild to 
moderate, tingling or itching and/or a burning but not painful sensation that do not outlast the 
stimulation period. Although headache, fatigue and light headedness may also be occasionally 
reported, they are typically transient and rarely require medical management.  

Remotely Supervised tDCS as an intervention in ALS  
 
Need for remotely delivered tDCS: Several clinical trials have shown that multiple tDCS 
sessions are required to produce greater benefits in clinical outcomes, especially in clients with 
limited motor recovery, where tDCS related effects are thought be cumulative (Acler et al., 2013; 
Ferrucci et al., 2014; Meesen, Thijs, Leenus, & Cuypers, 2014; Mori et al., 2010; Mori et al., 
2013; Rosso et al., 2014). Most tDCS based studies thus far have been conducted in a laboratory-
based setting. There are several barriers for accessing tDCS based studies. Repeated tDCS 
application requires participants to travel to the lab for each treatment session, which can be 
burdensome to patients and their caregivers. Especially because the tDCS sessions last only for 
20 minutes and the participants have to spend anywhere between 2-3 hours to travel for this 
session (Brunoni, Ferrucci, et al., 2012; Brunoni, Nitsche, et al., 2012; Ferrucci et al., 2014; 
Holland & Crinion, 2012; Meesen et al., 2014; Vaseghi, Zoghi, & Jaberzadeh, 2014). Some 
studies have reported significant drop-out rates when participants were treated with tDCS 
sessions that were administered over 6 months (Loo et al., 2012; Martin et al., 2013). Moreover, 
when the target population has a progressive neurological disorder such as ALS, there is a higher 
drop out as reported in several intervention-based studies (Bello-Haas et al., 2007; Sanjak, 
Bravver, Bockenek, Norton, & Brooks, 2010). Patients receiving palliative care often rely on 
their caregiver and may not comply with traditional research protocols. This causes ineffective 
data collection and underpowered tDCS studies which reduce the generalizability of this 
promising device.  
tDCS suitability for remote supervision: A possible solution to ameliorate the feasibility problem 
is remotely supervised self-administration of tDCS, with a protocol that is safe, well-tolerated, 
easy to administer and reproducible. A recent study (L. E. Charvet et al., 2015) provided 
recommendations for staff and end user training, assessment of the participant’s capability for 
self-administration of tDCS, and guidelines to formulate device usage and training manuals. Of 
particular importance in their recommendations, is a specially designed tDCS equipment that 
carefully regulates use by the patient. In addition, extensive training procedures that include 
safety checks at each step that are remotely monitored by study staff can guide safe and 
reproducible tDCS application. Study ‘stop’ criteria are also provided that need to be reviewed at 
several time-points (screening, baseline, study sessions and follow-up visit) during the course of 
the study for each subject. The subjects need to be initially trained by research staff to monitor 
their aptitude and tolerability to stimulation.  
L. E. Charvet et al. (2015) also emphasize strict dose control for each session. The device 
suggested is a pre-programmed tDCS device that is dependent on a code for activation for a 
single session (where the dosage would be pre-determined by the researcher) at a time. After a 
single use, the device would be inert until a new code is provided. Study staff would provide the 
unlock code, once safety and tolerability checks have been established, including correct 
placement of the device, headset and electrodes via a teleconferencing platform. Finally, research 
staff need to be trained for preparation and testing of the device and its accessories (electrodes) 
prior to release to subjects and adequate documentation. Training will also include remote 
monitoring of subjects for any unexpected adverse events (discomfort experienced with the 
device) or misuse of the device. At the end of the study, staff would also be trained on evaluating 
the device materials and downloading the stored data from the device. Adverse effects will be 
monitored, and subjects would be required to report any atypical pain/discomfort during/after 
stimulation. If the adverse effects cross the study stop criteria, the session should be stopped in 

Remotely Supervised tDCS as an intervention in ALS  
 
order to prevent further risks and research staff will assess if the AE has occurred due to device 
factors (improper electrode placement) or subject factors (low threshold for pain).  
 
The authors conclude that remotely supervised tDCS could be incorporated as an extension to 
tDCS administered in a clinical setting. Careful consideration of staff training, user aptitude and 
compliance need to be ensured to maintain the same level of safety and tolerability that is 
typically experienced in a lab/clinic-based setting. Other study protocols following these 
guidelines are currently ongoing for exploring the effectiveness of home based tDCS in patients 
with Multiple Sclerosis (Kasschau et al., 2016; O'Neill, Sacco, & Nurmikko, 2015). In a pilot 
study on MS, Kasschau et al. (2016) proposed 10 remotely supervised tDCS sessions over 2 
weeks. The first two sessions of the study were in-person training sessions and the remaining 
eight were remotely supervised. In the second session, study personnel went to the participant’s 
home to determine appropriate device setup and environmental suitability. Thus far, 20 
participants have completed a total of 192 sessions without any adverse event or discontinuation 
of treatment. All remotely supervised sessions (n = 152) were executed successfully with optimal 
electrode placement, device operation and adequate tolerability to stimulation. By including 
comprehensive training and ongoing supervision of participants, the study has achieved high 
compliance and tolerability. As portable tDCS devices have become available, 
patients/caregivers can be easily trained in its application and patients may safely use the device 
at home without the need for regular visits to the laboratory. These authors discuss the use of 
specially designed devices for supervised tDCS with instruction manuals, and real time 
monitoring through video conferencing platforms. Taken together, these studies emphasize the 
feasibility for remotely supervised tDCS devices for patients with progressive neurological 
disorders (such as ALS, MS) who cannot frequently commute to a lab-based setting because of 
their impairments.  
 
3.0 
Objectives/Aims 
The purposes of this pilot study are: 
1. To determine the safety and feasibility of long-term treatment with remotely supervised 
anodal tDCS (RS-tDCS) in individuals diagnosed with ALS. We will evaluate safety and 
feasibility via the occurrence of adverse events and participant dropout rate. Secondary 
outcomes will include corticospinal excitability measures, walking function and other 
clinical measures of balance, gait and strength which will be described subsequently. 
2. To determine the effects of 24-weeks of RS-tDCS on disease progression in individuals with 
ALS. Subjects will be randomized into one of two groups: remotely supervised tDCS or 
delayed-start control group. The intervention group will receive 24 weeks of anodal tDCS (3 
times/week; 72 sessions). The delayed-start group will first receive sham tDCS for 12 weeks 
followed by a switch to anodal tDCS for 12 weeks. Secondary outcomes will include the 
ALS Functional Rating Scale (Change in Revised ALS Functioning Rating Scale (ALSFRS-
R). Scores range from 0 to 48, with higher scores indicating more function retained. 
 
3. To determine the effects of RS-tDCS on upper (UMN) and lower motor neuron (LMN) 
mechanisms in individuals with ALS, quantified using Upper and lower motor neuron 
mechanisms will be assessed using single-pulse transcranial magnetic stimulation (TMS). 
 Subjects will be randomized into one of two groups: remotely supervised tDCS or delayed-
start control group. The intervention group will receive 24 weeks of anodal tDCS (3 

Remotely Supervised tDCS as an intervention in ALS  
 
times/week; 72 sessions). The delayed-start group will first receive sham tDCS for 12 weeks 
followed by a switch to anodal tDCS for 12 weeks. Secondary outcomes will include 
corticospinal excitability measures which will be described subsequently. 
4.0 
Eligibility 
4.1 Inclusion Criteria 
The general inclusion criteria will be approximately 100 males and females of any race or ethnic 
status with the following characteristics:  
• Age between 18 – 80 years 
• Diagnosis of possible, probable, or definite amyotrophic lateral sclerosis according to El 
Escorial revised criteria  
• Spinal onset ALS with initial weakness in the upper or lower extremity. 
• Diagnosed with ALS within the past 5 years 
• 1-2 point change in pre-slope of the ALSFRS-R at time of enrollment (ratio of drop in 
score from 48 to the duration in months from onset of weakness) 
• Score ≥ 2 for “swallowing” of the ALSFRS-R 
• Score ≥ 2 for “walking” of the ALSFRS-R 
• Able to provide informed consent 
• Stable dose of riluzole, edaravone, AMX0035 (Relyvrio) or no medications 
• 
Availability of a caregiver for remote administration of tDCS 
4.2 Exclusion Criteria 
 
Our general exclusion criteria for all subjects will include: 
• Subject has bulbar onset ALS 
• Any neurological diagnosis other than ALS 
• Psychiatric disorders  
• Any other concomitant disease that affects prognosis of ALS inclusive of systemic 
disease, cardiovascular disease, hepatic or renal disorder 
• Tracheostomal or noninvasive ventilation for more than 12 hours per day 
• Enrollment in an on-going ALS pharmaceutical trial 
• Subject plans on moving within 6 months. 
 
As necessitated by the risks of TMS, the exclusion criteria for all subjects will include 1) 
implanted cardiac pacemaker, 2) metal implants in the head or face, 3) unexplained, recurring 
headaches, 4) history of seizures or epilepsy, 5) currently under medication that could increase 
motor excitability and lower seizure threshold: antidepressants such as maprotiline and 
clomipramine, and antipsychotics such as chlorpromazine and clozapine (Pisani, Oteri, Costa, Di 
Raimondo, & Di Perri, 2002), 6) skull abnormalities or fractures, 7) concussion within the past 
six months, and 8) currently pregnant:  
Other than the TMS exclusion criteria, tDCS exclusion criteria will also include 
• Extreme skin hypersensitivity 
• History of contact dermatitis 
• History of allodynia and/or hyperalgesia 
• Any other skin/scalp condition that could potentially be aggravated by tDCS  

Remotely Supervised tDCS as an intervention in ALS  
 
Participant eligibility will be confirmed upon completion TMS and tDCS safety questionnaire on 
the phone as well as on the day of screening. Females of childbearing age will be screened with 
an instant urine pregnancy test that the lab will provide to confirm negative pregnancy. Subjects 
would be required to inform the research personnel immediately if they are pregnant after 
beginning the study. If subjects become pregnant during the study, we will exclude them from 
participating in the study and ask them to surrender their tDCS device. Subjects will not be 
excluded if they do not have access to videoconferencing capabilities. Instead, tablets with 
prepaid data will be provided to these participants. 
 
4.3 Excluded or Vulnerable Populations:  N/A 
 
5.0  
Subject Enrollment 
Individuals with ALS will be recruited through the use of an email script (Supplement_E-mail 
Announcement) and flyer (Supplement_Flyer ALS RStDCS) which will be posted at UIC, 
University of Chicago as well as via the web (UIC Announcements, UIC-AHS labs webpage, 
UIC Massmail, ALS Association support groups and outpatient clinics). Individuals will also be 
recruited through online postings on a College of Applied Health Sciences subject recruitment 
page (https://ahs.uic.edu/research/participate-in-research/) and on our lab webpage 
(https://bpl.ahs.uic.edu/participate/). Text to be displayed on these webpages is shown in the 
supplemental document (Supplement_Online Study Recruitment Text). The flyer 
(Supplement_Flyer ALS RStDCS) and email script (Supplement_E-mail Announcement) will 
provide contact information for interested individuals to directly contact a member of the 
research team. Research personnel will explain the study and answer all questions. If the 
individual is interested, they will be screened over the phone. If the individual is eligible, they 
will be scheduled for a visit to the research sight.   
Furthermore, individuals with ALS will also be recruited by physician referral from the 
Department of Neurology at UIC and the University of Chicago. Physicians will inform eligible 
patients about the study during their routine visits to the clinic, and if the patient seems interested 
physicians will provide a flyer (Supplement_Flyer ALS RStDCS) containing the Brain Plasticity 
Lab contact information. To minimize potential coercion, co-investigators will not be involved in 
obtaining informed consent from the patients. It will be made clear that the study is solely being 
conducted for research purposes and will in no way provide treatment for their symptoms. If the 
patient is interested in knowing more about the study, the patient will initiate contact with key 
research personnel. Screening and informed consent will be conducted by key research personnel 
only and not by the referring physician (to avoid possible coercion by the treating neurologist 
who may be the patient’s primary care physician).   
Patients who have been previously seen in the ALS clinic will be contacted by mail and/or 
telephone. A letter informing patients about the research will be sent by the ALS clinic. Dr. 
Abrams and/or his staff members will also contact previous patients by phone to ascertain if 
patients have an interest to be contacted by the research team to participate in the study.  If a 
patient expresses an interest to participate in research, their name and contact information will be 
provided to the research team for future contact. 

Remotely Supervised tDCS as an intervention in ALS  
 
To aid recruitment, we will also use the UI Health EPIC electronic health record system. 
Specifically, we will use EPIC to identify potential participants who have been diagnosed with 
ALS and have been treated at UI Health. Individuals who have ALS and meet other study 
inclusion criteria will be contacted first with one email (Supplement_E-mail Announcement). 
After 7 days, if the research team has not received a response to the email, we may contact the 
individual with one phone call (attached phone script). No additional attempts will be made to 
contact potential participants if no response is received to the email or phone call. If a response is 
received from the individual indicating interest in the study, they will undergo screening 
procedures. 
 
6.0 
Study Design and Procedures 
General Overview  
Subjects will attend 1 tDCS tolerability test and training visit, 7-10 testing sessions (2-3 at T0, 2-
3 at T1, 2-3 at T2, and 1 follow-up at T3) and 72 remotely supervised tDCS sessions. Testing 
sessions at four timepoints will involve two to three visits (depending on availability and 
capacity of the participant). Visit 1: obtain informed consent and administer a pregnancy test, 
complete the Medical Screening Questionnaire and the TMS and tDCS Safety Questionnaire, 
measure blood pressure, and perform clinical assessments (1-2 hours). Visit 2: Upper and lower 
motor neuron mechanisms will be assessed using single-pulse transcranial magnetic stimulation 
(TMS). 
 Visit 3: tDCS tolerability testing (30 minutes) will be performed and subjects will be asked to 
return to the lab with their caregivers for a training session on the use of the Soterix tDCS Mini-
CT device (1.5 - 2 hours.). The visits maybe combined if the patient wishes to reduce their travel 
time. Remotely supervised tDCS sessions are expected to last for 45 minutes which will include 
up to 20 minutes of stimulation with RS-tDCS and an additional 25 minutes for setting up video 
conferencing and RS-tDCS equipment. The follow-up testing session will be combined into one 
visit (up to 4 hours) consisting of the same outcome measures recorded at T0, T1, and T2. If 
subjects are in the delayed start group, they will receive 24 sessions of sham stimulation 
followed by 24 sessions of anodal tDCS. 
 
 
Randomization: Stratified treatment assignment of participants into the two groups will be based 
on baseline ALFSRS-R score and the pre-slope. Group assignment will be randomized within 
each category using sequential randomization to achieve study arm balance. Participants and 
assessors will be masked to the type of stimulation they receive.  

Remotely Supervised tDCS as an intervention in ALS  
 
Safety: Participants will make two interim visits to the lab after every 6 weeks for a safety check 
(scalp integrity and Change in Revised ALS Functioning Rating Scale (ALSFRS-R). Scores 
range from 0 to 48, with higher scores indicating more function retained. 
 The number of adverse events (AE) will be actively monitored using structured questionnaires 
that enquire for AEs related to tDCS during training and lab visits. Key AEs of interest will 
include 12 symptoms including clinical seizures, skin injury and neurological deterioration. The 
safety of each participant will be assessed on an individual basis throughout his or her 
involvement with the study.  
Feasibility: Recruitment and randomization will be assessed using frequency approached for 
screening and enrollment. Retention will be assessed using proportion of participants enrolled 
after screening eligibility and number who completed the study. Acceptability of treatment will 
be examined using semi-structured patient, caregiver and clinician feedback questionnaires 
regarding perceived satisfaction, perceived ease-of-use, strengths and weaknesses 
(Supplement_Final Survey Questions). All participants will be required to complete feedback 
questionnaires. These questionnaires will contain close-ended questions which use a Likert scale 
and open-ended questions on treatment perception and attitudes. Adherence will be measured by 
rate of patient dropouts. Tolerability will be measured by pleasant/unpleasant ratings using a 
visual analog scale for each session.  
All subjects will continue with their standard-of-care treatment while participating in the 
research.   
Screening and clinical examination testing visit 
Subjects will report to the Brain Plasticity Lab at UIC located at 1919 W. Taylor St, #810, 
Chicago, IL 60612. All subjects will sign a written informed consent. Females of childbearing 
age will undergo a urine pregnancy test. Subjects who test positive will not be eligible to 
participate. Female participants of childbearing age will also be informed that the effects of 
tDCS on pregnancy are still unknown. If participants of childbearing age are planning to get 
pregnant or may be pregnant during the 24-week period, they will be instructed to stop the tDCS 
immediately and will be excluded from the study. All subjects will be asked to complete a 
medical screening questionnaire and TMS and tDCS safety questionnaires. The medical 
screening questionnaire will include questions about age, gender, race, medical history, 
medications and personal habits (such as smoking). The TMS and tDCS safety questionnaire will 
include questions pertaining to the TMS and tDCS exclusion criteria. Blood pressure will be 
measured prior to conducting clinical assessments. The first testing visit will last for 1 – 2 hours. 
 
Clinical assessments 
Clinical testing will take approximately 60 minutes to complete. The battery of functional 
measures are listed below, and will include tests of walking and balance. The tests have 
been validated and are commonly used, non-invasive clinical measures.  
• 
Revised ALS Functional Rating Scale (Change in Revised ALS Functioning Rating 
Scale (ALSFRS-R). Scores range from 0 to 48, with higher scores indicating more 
function retained. 
91. This will be conducted every two weeks over the phone or Zoom PHI. 
• 
Gait speed will be measured using the average speed over two trials of the 10MWT. 
 Change in Revised ALS Functioning Rating Scale (ALSFRS-R). Scores range from 

Remotely Supervised tDCS as an intervention in ALS  
 
0 to 48, with higher scores indicating more function retained. 
 Self-selected and fast walking will be measured as the average walking speed from 
2 trials of the 10-m walk test, a reliable and sensitive marker for function in patients 
with ALS.  
• 
10-meter walk: The 10-meter walk test (10MWT) is a performance measure used to 
assess walking speed in meters per second over a short distance. It can be employed 
to determine functional mobility, gait and vestibular function. We will also employ 
the use of APDM wearable sensors during the test to assess outcome measures of 
functional mobility. 
• 
Ankle motor control will be assessed using a sinusoidal tracking task. 
 A custom-built ankle-tracking device will be used to quantify the participant’s 
ability to track a computer-generated sinusoidal target with ankle movement  
• 
Other measures: We will examine patient perspective on health outcomes using the 
Health Related Quality of Life scale, EuroQual-Visual Analog Scale and fatigue 
using the Fatigue Severity Scale (FSS), 9-item measure from 1 to 7, higher scores = 
more severe fatigue. 
 
Safety and Feasibility: The number of adverse events (AE) will be actively monitored using 
structured questionnaires that enquire for AEs related to tDCS during training and lab visits. Key 
AEs of interest will include 12 symptoms including clinical seizures, skin injury and 
neurological deterioration (tDCS adverse event questionnaire). The safety of each participant 
will be assessed on an individual basis throughout his or her involvement with the study. 
Recruitment and randomization will be assessed using frequency approached for screening and 
enrollment. Retention will be assessed using proportion of participants enrolled after screening 
eligibility and number who completed the study. We will collect reasons for study refusals and 
withdrawals. Acceptability of treatment will be examined using semi-structured patient, 
caregiver and clinician feedback questionnaires regarding perceived satisfaction, perceived ease-
of-use, strengths and weaknesses  
 
Transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) testing visit 
 
TMS procedures 
The TMS procedure will be conducted in the UIC Brain Plasticity Lab. This is the same TMS 
procedure that has been successfully used in our other research studies (e.g., IRB #2015-0764, 
#2011-0676, # 2015-1127, # 2011-0284). TMS is a safe, non-invasive method of brain 
stimulation that has been widely used to study the physiology of the representations of muscles 
in the motor cortex in healthy and neurologically disordered individuals (Anand & Hotson, 
2002). Very short duration (< 1 ms) magnetic pulses are applied via an insulated wire coil placed 
on the intact scalp overlaying the motor cortical area projecting to a target muscle. Each pulse 
induces a motor evoked potential (MEP) in a target muscle that can be readily monitored by 
recording EMG from that muscle. A figure-of-eight or double cone coil is typically used to 
deliver focal magnetic pulses to a number of scalp sites over the cortical area representing a 
muscle of interest. Self-adhesive disposable electrodes (Suretrace) with an inter-electrode 
distance of 2 cm will be applied over the muscle bellies of the tibialis anterior (TA) in the lower 

Remotely Supervised tDCS as an intervention in ALS  
 
extremity. A ground electrode will be applied over a proximal bony prominence. Standard skin 
preparation techniques (light abrasion and cleansing with alcohol) will be completed prior to 
application of the electrodes. EMG recordings will be amplified (Delsys Bagnoli system), band-
pass filtered (10-1000 Hz), and sampled at 5000 Hz.  
 
Subjects will be seated, and magnetic stimuli will be delivered via a figure of eight or double 
cone coils connected to a Magstim 200 unit (Magstim Company, Boston MA). Resting motor 
threshold for the muscle of interest will be defined as the stimulator output intensity that can 
elicit a MEP with peak-to-peak amplitude of at least 0.075 mV in four out of eight trials. It will 
be determined by increasing stimulus intensity in steps of 1% stimulator output. Active 
thresholds will be determined with the same protocol and defined by the lowest stimulus 
intensity required to elicit a MEP with a peak-to-peak amplitude of at least 0.1 mV in four out of 
eight trials with the subject contracting the muscle of interest to about 10% of maximum 
voluntary contraction. TMS measurements will involve generating MEPs for each muscle. Short 
intracortical inhibition (SICI) was measured at an interstimulus interval of 2.5 ms. A 
subthreshold pulse (80% active threshold) was set as the conditioning stimulus and a 
suprathreshold pulse was set (130% active threshold) as the testing stimulus. To assess 
corticospinal excitability of the M1, the figure of eight or double cone coil will be placed over 
the M1 cortical area (near the vertex of the head) and the subject will then receive 15 - 30 stimuli 
at intensities corresponding to 80% to 130%of rest and active threshold. These measures will 
assist the investigators to assess the contribution of the motor cortex to the upper and lower limb 
muscles. The entire procedure should take about 2 hours. 
 
PNS procedures 
The PNS procedure will be conducted in the UIC Brain Plasticity Lab under the supervision of 
Dr. Rezania. Peripheral nerve stimulation (PNS) will be used to assess lower motor neuron 
integrity. 
 Very short duration (1ms) electric pulse is applied to the skin overlying the peripheral nerve that 
projects to a target muscle. Each pulse induces two evoked potentials in a target muscle that can 
be readily monitored by recording EMG from that muscle. The first evoked potential is the M-
wave and the second is referred to as the H-reflex. The M wave arises from direct stimulation of 
the motor nerve serving the muscle and its amplitude is used as an estimate of the stimulus 
intensity delivered to the sensory nerve whose excitation generates the H-reflex. The maximum 
amplitude M wave that can be obtained in an individual is referred to as the M max, and the 
stimulus intensities used expressed as a percentage of that needed to produce M max.   
Stimulating electrodes will be placed on the lower limb on the skin over the fibular head, 
longitudinal to the estimated path of the common peroneal or tibial nerve. For upper limb 
stimulation, stimulating electrodes will be placed on the skin 2cm above the elbow on the lateral 
part of arm, longitudinal to the estimated path of the radial nerve or on the skin above the wrist 
joint, longitudinal to the estimated path of the ulnar nerve.  
Peripheral nerve stimulation (PNS) will be used to assess lower motor neuron integrity. 
 Similar to TMS, Peripheral nerve stimulation (PNS) will be used to assess lower motor neuron 

Remotely Supervised tDCS as an intervention in ALS  
 
integrity. 
 The resting and active threshold for eliciting H-reflexes will be determined for each muscle.   
H-reflexes will be evoked using a 1-ms square wave pulse, via a Cadwell Sierra Summit 
EMG/NCV/EP machine (Cadwell Laboratories, Inc., Kennewick, WA). As outlined in the TMS 
procedure above, resting motor threshold for the muscle of interest will be defined as the 
stimulator output intensity that can elicit H-reflex waveforms with peak-to-peak amplitude of 
more than 50 µV in four out of eight trials. Active thresholds will be determined with the same 
protocol, however with the subject contracting the muscle of interest to about 10% of maximum 
voluntary contraction. The magnitude of the M wave, which arises from direct stimulation of the 
motoneuron axons serving the autogenic muscle, will be used as an estimate of the stimulus 
intensity delivered to the large diameter afferent fibers.   
The subjects will receive 6 stimulations at each of 7 intensities ranging from 70% of H-reflex 
active threshold to 110% M max.  
Pairing the magnetic and peripheral nerve stimuli allows investigators to assess the cortical 
contributions to spinal mechanisms underlying changes in the H-reflex. TMS delivered at 
intensities below motor threshold will be specifically timed to arrive at the spinal cord just before 
the afferent volley from Peripheral nerve stimulation (PNS) will be used to assess lower motor 
neuron integrity. 
 This is called a TMS conditioned H-reflex. TMS conditioned H-reflex recruitment curves will 
be elicited, using the same Peripheral nerve stimulation (PNS) will be used to assess lower motor 
neuron integrity. 
 Six paired stimuli will be delivered at each of 7 intensities ranging from 70% of H-reflex active 
threshold to 110% M max. 
 
tDCS procedures 
tDCS is a safe and painless technique to increase or decrease motor system excitability. This 
involves the application of weak electrical currents to the scalp and has been widely used to 
improve motor function in neurologically disordered individuals without any adverse effects  
(30). 2mA Anodal tDCS (anodal electrode over the motor cortex and cathode over the 
contralateral orbit) enhances cortical excitability, which increases the amplitude of motor evoked 
potentials. Saline soaked sponge electrodes will be attached over the scalp to the target area and 
to the skin above the contralateral orbit. Transcranial current will be induced using a Soterix 
Medical 1X1 tDCS mini-CT Stimulator (Soterix Inc., New York, New York, USA). Current will 
be increased slowly over a 30 second period which will help the subjects get accustomed to the 
tingling sensation associated with the current.  
 
Remotely Supervised tDCS sessions 
Remotely supervised tDCS sessions will take place at the participant’s home three times a week 
for 24 weeks for a total of 72 sessions. These sessions are expected to last for 45 minutes which 
will include up to 20 minutes of stimulation with tDCS and an additional 25 minutes for setting 
up video conferencing and RS-tDCS equipment. The sham stimulation will be programmed into 
the device for those in the delayed start group. Previous studies have shown that participants 

Remotely Supervised tDCS as an intervention in ALS  
 
typically do not know the difference between sham and real stimulation, enabling the study to 
remain blinded. 
 
tDCS tolerability test and training visit  
All subjects will report to the lab for a tDCS tolerability test. Lab personnel will test the subject’s 
tolerability to stimulation with tDCS. tDCS electrodes will be placed on the subject’s scalp and 
stimulation will be performed for 20 minutes. Subjects will be assessed for side effects. Subjects 
will also complete a RS-tDCS training session which will last for 1.5 – 2 hours.  
 
Device information and training of study personnel  
A portable tDCS device (Soterix Medical 1X1 tDCS mini-CT Stimulator) will be issued to the 
subject upon completion of training. All subjects will be directly trained by research personnel. 
Research personnel will be trained by the device manufacturer (Soterix Inc.) in the preparation 
and testing of the tDCS device and electrodes prior to providing it to participants, as well as 
appropriate documentation of the device release. This device has built in programmable codes 
which allows for strict dosage control which can be monitored remotely. The device would be 
deactivated until a code is provided by the research staff to the subject for every session. The 
code unlocks a single session with a pre-set duration and intensity that would be pre-
programmed. After a single discharge, the device is inert until a new code is provided. This 
allows the remote supervisor to control tDCS application, as the code may not be provided until 
the researcher is satisfied with the placement of the electrodes via video conference. The subject 
or caregiver cannot change stimulation intensity or treatment duration which enhances safety and 
reproducibility.  
 
Study staff will be familiarized on the usage of the device and the location of headset placement. 
In addition, selected research staff (who are not blinded to the study) will be trained with and 
have access to the device manual that enlists in a step-by-step fashion, the procedures that are 
required to program the device prior to release to subjects, for example programming device 
unlock codes for one-time use to be provided prior to each session. Prior to releasing a device to 
a subject, study staff will program the intensity, duration, and condition of each planned session, 
along with a code that limits the number and frequency of sessions. This will be double checked 
by the Principal Investigator prior to release of the device to the subject. Through the duration of 
the study, study staff will be trained to monitor subjects for any unexpected adverse events (e.g., 
atypical discomfort) or misuse of the device. At the end of the study, study staff will evaluate 
retrieved device materials (e.g., headgear/stimulator condition, gel) and download any data 
stored on the device (e.g. completion codes for each subject’s study sessions, stimulation history 
of each code issued) as relevant to confirm compliance. 
 
Training of subject/ caregiver: 
At the training visit, study personnel will complete a tDCS checklist (Supplement _tDCS 
checklist) to screen subjects for at home RS-tDCS. In the training session, the participant and 
caregiver will be familiarized to the device, electrode positioning and placement on the scalp. 
The subject/caregiver will be trained to properly apply the headset and correctly operate the 
device.  
At the training visit, subjects will be measured for individually fitted and engineered headband 
locators for electrode placement. Headbands are measured and marked relative to ear tragi, the 

Remotely Supervised tDCS as an intervention in ALS  
 
nose and midline of scalp. A separate occipital band ensures the locator headband cannot slip 
from its position. The headgear will allow consistent placement of electrode at the lower limb 
motor cortex area on the scalp (1 cm posterior and 1 cm lateral to the vertex, Cz). The headgear 
will be marked with “RED” and “BLACK” to confirm that color coded leads are properly 
placed, ensuring Anode (Red) and Cathode (Black) and the subject is shown how the electrodes 
are placed (see figure). Once fitted, subjects are shown how to position the headbands 
reproducibly and instructed on how to position the band markers relative to the anatomical 
landmarks described. The subject/caregiver will then demonstrate tDCS application and 
electrode placement under the supervision of the researcher. The research personnel will use a 
checklist to identify if the participant/caregiver has understood device operating instructions.  
 
 
 
 
 
 
          
 
 
  
 
 
 
 
 
 
 
 
Photographs and measurements will be taken in case the subject needs for reference at home and 
all instructions are given in an information guide as well. The investigators will then confirm that 
the subject and caregiver /partner have understood all details of the stimulation. We will provide 
study training materials i.e. an information guide (Supplement_Information guide and 
Stimulation Manual), a RS-tDCS session log [to record the number of treatment sessions] 
(Supplement_tDCS session log), and RS-tDCS equipment (headgear and 12 electrode sets) along 
with other supplies for the entire study. We will also provide a RS-tDCS side effects survey 
(Supplement_tDCS side effects survey) in which subjects are informed of potential side effects 
such as tingling, burning sensation, dizziness, headache, nausea and phosphenes while switching 
the device on or off abruptly. Subjects will also be provided a RS-tDCS ease of use form 
(Supplement_tDCS ease of use) for reporting their experience of equipment use, including 
convenience. 
 
Following the training visit, the subject would be provided a schedule for RS-tDCS sessions 
(monitored via Zoom PHI). The researcher will remotely observe the placement of the electrodes 
and the headset and supervise each of the 72 sessions. The subject will also be asked to report 
adverse effects at the beginning and end of every session. Participants will be instructed to 
contact the Emergency Department in the event of experiencing serious side effects.  
 
Study stop criteria (Supplement_study stop checklist) will be reviewed at each stage of the study: 
baseline, study sessions and post study completion. Throughout the study, we will monitor 
compliance via the stop criteria to exclude participants who fail to set up the device properly. We 
will monitor each session and dosage of current using codes. If any participant reports 
discomfort, pain or a desire to withdraw, their participation may be terminated. The session log 
will be reviewed by the study staff every 2 weeks until the end of the study.  
 
Study stop criteria (adapted from Charvet et al. 2015) 
 
• Does not pass tDCS aptitude test  
• Does not tolerate tDCS  
• Three reschedules/ failures to initiate video conferencing 
• Failure to place headset correctly within 15 minutes at more than one session  

Remotely Supervised tDCS as an intervention in ALS  
 
• Subject experiences any severe adverse event such as an event resulting in death, life-
threatening event, initial or prolonged hospitalization, disability or permanent damage, or 
event requiring intervention to prevent permanent impairment or damage   
 
In addition, a pre-specified interim analysis for the continuation of the entire study will be 
completed after the first 6 participants complete the study. The adverse events and mean change 
in Change in Revised ALS Functioning Rating Scale (ALSFRS-R). Scores range from 0 to 48, 
with higher scores indicating more function retained. 
 The stopping criteria will be defined as a mean difference between groups exceeding 2 standard 
deviations. If this occurs, the study will be stopped for full review by the medical monitor or 
revising the protocol before proceeding. 
 
7.0 Expected Risks/Benefits 
 
7.1 Risks  
Risks associated with the TMS procedure:  
1) Seizures: Rare cases have reported the development of seizures during or immediately after 
magnetic brain stimulation. Individuals who have a history of seizures or have been diagnosed 
with epilepsy will be excluded from this research study (by thoroughly screening subjects we 
hope to minimize this risk). Single pulse TMS that we use in this study has been deemed to carry 
little risk beyond occasionally causing local discomfort. Our stimulation procedures follow 
published safety guidelines. Seizure activation is extremely unlikely with the single pulse low 
numbers of stimulation proposed in the current investigation. 
2) Discomfort: A small number of people find TMS uncomfortable, particularly at high 
intensities of stimulation. If individuals report feelings of discomfort, stimulation intensity will 
be reduced or, if not feasible, testing will be terminated.  
3) Muscle Twitching: Subjects may feel twitches in the muscles of the arm, leg or face during the 
magnetic stimulation.  
4) Noise: A loud click during magnetic stimulation may be heard. Subjects will be provided with 
foam earplugs that can effectively prevent this discomfort.  
5) Skin Irritation: There is a risk of mild skin irritation at the location where the electrode sensors 
have been placed, but this usually consists of minor redness that will go away quickly after they 
are removed. 
 
Risks associated with clinical assessments and balance testing: 
1) There is a possibility that subjects may lose balance while getting up from sitting or walking 
or performing the balance test. An authorized research personnel will be present at all times to 
ensure safety of the subject. A gait belt will be used when the subjects are performing the clinical 
tests and a safety harness will be used when necessary for balance testing. 
2) Muscle Soreness or Fatigue: During or following testing subjects may feel temporary muscle 
aching or general fatigue. Individuals with ALS who are in the treatment group may feel muscle 
soreness or fatigue associated with training. Risks of both muscle soreness and muscle fatigue 
will be minimized by terminating training if greater than moderate muscle soreness occurs.  
 
Risks associated with RS-tDCS:   

Remotely Supervised tDCS as an intervention in ALS  
 
1) Discomfort: Subjects may feel tingling or itching when tDCS is being delivered or at the spot 
where the electrodes are placed. This usually goes away in a minute or so. In a low percentage of 
people, there is a side effect of nausea or insomnia. If subjects report any symptoms that make 
the stimulation not tolerable, they can be excused from participating at any time.   
2) Pain: Participants will be provided a list of standard safety precautions to minimize any risk of 
harm to themselves or damaging the device. The participants will be informed of typical tDCS 
side effects such as tingling or itching, which should never be painful. If they feel any pain 
concentration in one area, they would be asked to abort the stimulation, remove the headband 
and check the skin for any redness or discoloration. Study personnel would then evaluate if 
treatment can be continued. 
3) Light headedness/ phosphene flash: tDCS will automatically stop if the electrode-skin contact 
is poor. The current intensity will drop to zero, and it is possible that the participant may feel 
transient light headedness or even see a phosphene flash. Although these symptoms are unusual, 
they must inform the study personnel so that they can investigate the cause of poor electrode 
contact. 
4) Skin redness/burns: The participants will also be instructed not to administer tDCS over skin 
that is damaged including any cuts, scratches or scars as this could lead to current concentration 
in that area, causing skin burns. In the event of an accidental application, the participant must 
notify the study personnel immediately. 
5) Remaining still: Subjects will need to remain still during the tDCS procedure. The tDCS 
device must be kept on a flat, secure surface during the stimulation procedure. Subjects will need 
to avoid any head movements that could jerk the cables or cause the tDCS device to fall on the 
floor and potentially disconnect the electrodes. 
6) Worsening of pre-existing medical condition: If the participant notes a worsening of a pre-
existing medical condition, such as migraines or balance because of treatment with tDCS, the 
team must be notified immediately. Although the exact safety plan may be specific to the 
subject’s underlying medical condition, information regarding an emergency contact number and 
contact details for the nearest clinic/hospital will be provided.  
7) Feeling anxious: Subjects will be responsible for administering the tDCS procedure 
themselves so they may feel a little nervous or anxious. 
8) Device malfunction: tDCS is a low risk procedure and is not expected to cause serious adverse 
events. To avoid undue risk of tDCS being delivered at a higher intensity, codes will be used to 
monitor dosage. It is possible that the device may malfunction or have technical issues. In the 
event of such a problem, subjects will be instructed to switch off the device and inform the 
research personnel immediately. In addition, as an added safety feature, the device will not work 
(discharge) unless the electrodes are correctly applied to the scalp and the electrode contact is 
adequate. The device will prompt subjects to adjust the placement of electrodes, if necessary.    
 
Other Risks: 
1) Subjects will feel a squeezing sensation on their arm when the cuff is inflated during the blood 
pressure measurement.  
2) A risk of this research is a loss of privacy or confidentiality. To minimize this risk, subject 
study data will be stored and coded. Only authorized research personnel will have access the 
subject master code and all data. 
3) Subjects may feel uncomfortable providing personal information in the questionnaires. They 
will be instructed to skip any questions that they do not wish to answer. 

Remotely Supervised tDCS as an intervention in ALS  
 
4) Pregnancy testing: Females of childbearing age who test positive during the testing may be 
surprised or experience distress if they were unaware. If they are not comfortable taking the 
pregnancy test, they will not be enrolled in the study. 
 
7.2 Benefits 
There is no direct benefit to the individual from participating in this research project.   
 
8.0 Data Collection and Management Procedures 
The research will be conducted in compliance with state and federal laws, including the Health 
Insurance Portability and Accountability Act (HIPAA) which require researchers to protect an 
individual’s health information.   
Data will be stored and analyzed in the Brain Plasticity Lab located at 810/834, 1919 W. Taylor 
St. in Chicago. To minimize breach of privacy and confidentiality, subject data will be stored and 
coded. Members of the research team will process the data and it will be stored on computer 
disks on which the subject’s data will be referred to by a participant number that will be assigned 
based on the date of his/her participation. This will ensure that anyone who views the data will 
not have access to the subject’s personal information. The key to the code, which links the 
subject’s participant number to his/her identity will be stored separate from the data and 
destroyed ten years after study completion.  
The Principal Investigator and the research coordinator will have access to the device key for 
release of treatment (activation) codes.  
The primary investigator and co-investigators will have access to the raw data. The raw data will 
not be made available to any other individuals. When requested by the subject, we will share the 
results of the experiments. 
Study information from this study may be reviewed by representatives of the study group at 
University of Illinois at Chicago, the Institutional Review Board (IRB) at the University of 
Illinois at Chicago, and perhaps, the U.S. Food and Drug Administration (FDA). Study records 
will be kept confidential to the extent provided by the law. The name of individual subjects or 
other identifying data will not be used in any report or publication of this study. 
 
9.0 Data Analysis 
We will look at pre and post changes in our primary and secondary outcomes measures. A one-
way ANOVA will be used to examine changes in adverse events, subject dropouts, and TMS and 
clinical assessments. A two-way repeated measures ANOVA with groups and time as the two 
factors will be used to analyze change scores on adverse events, TMS and clinical assessments. 
10.0 Quality Control and Quality Assurance 
We will employ several quality control procedures namely written protocols, training, objective 
evaluation of tDCS protocols and training research personnel thus maximizing validity and 
reliability of the protocol delivery and outcome assessments.   
As a part of the subject’s tDCS kit, a tDCS side effects survey checking for typical side effects 
that may arise during or after tDCS will be included. Subjects would be instructed to record the 
presence/absence of each side effect, the severity and duration. Any side effect that is rated very 

Remotely Supervised tDCS as an intervention in ALS  
 
severe and atypical of tDCS, regardless of whether the subject attributes to tDCS or not, should 
be reported and assessed by study personnel before further treatment is continued. Guidelines 
provided to participants can help identify and document adverse events that may be useful in 
managing any potential risks. In addition, the information guide provided to the subject will 
minimize any risk of harming themselves or damaging the tDCS device. 
To monitor compliance, we will also ensure that participants are familiar with basic functioning 
of a smart phone/laptop/computer/iPad and how to connect the device to internet via a computer 
aptitude checklist (Supplement_technical aptitude checklist). We will also ensure that 
participants have the aptitude to setup the tDCS device. We will choose a secure video 
conferencing software such as Zoom PHI to allow for remote supervision of the proper setup of 
the device, optimal electrode-skin contact, and that the intender user is receiving the treatment.  
Assessors who are performing the clinical assessments will be blinded to the intervention. Dr. 
Madhavan will be actively involved with supervising and monitoring the study on a day-to-day 
basis. She will meet with all study personnel at least once a week to ensure that there is strict 
adherence to study protocol and outcome assessments. Dr. Madhavan will also hold bi-monthly 
journal club meetings to ensure that all key personnel are abreast of the scientific literature in the 
area and the importance of the current research and thereby motivate staff to ensure their best 
performance during training and assessment. All key research personnel will be provided the 
adequate training and equipment needed to carry out the study. Training will be repeated as 
necessary. Dr. Madhavan will check and regularly review any adverse events or deviations from 
protocol. Study personnel will monitor subject compliance to the protocol and losses to follow 
up. 
11.0 
Data and Safety Monitoring 
The PI will be primarily responsible for monitoring the safety of participants, and the safety and 
confidentiality of data. This will be done by following the best practices to ensure that we strictly 
adhere to the inclusion and exclusion criteria, and protections against risks outlines. The safety of 
each participant will be assessed on an individual basis throughout his or her involvement with 
the study, regardless of group assignment. Any decline in function or participant responses that 
indicates a potential adverse effect will be reviewed individually. 
A member of the research team will be available to the subject throughout testing and will be 
monitoring subject safety throughout. We will ask the subject to provide us with a phone number 
of a caregiver (or friend or family member) to contact in case of emergency. For the RS-tDCS, 
the stimulation sessions will be supervised remotely from the research lab using video 
conferencing. The RS-tDCS device has built in programmable codes which allows for strict 
dosage control which can be monitored remotely. The device would be deactivated until a code 
is provided by the research staff to the subject for every session. The code unlocks a single 
session with a pre-set duration and intensity. After a single discharge, the device is inert until a 
new code is provided. This allows the remote supervisor to control RS-tDCS application, as the 
code may not be provided until the researcher is satisfied with the placement of the electrodes via 
video or phone conference. The subject or caregiver cannot change stimulation intensity or 
treatment duration which enhances safety and reproducibility. The subject will also be asked to 
report adverse effects at the beginning and end of every session. The subject cannot operate the 

Remotely Supervised tDCS as an intervention in ALS  
 
device unless there is another adult present at home in case they are alone and an AE occurs and 
they are unable to call for help. Participants will be instructed to contact the Emergency 
Department in the event of experiencing serious side effects.  
Before sending the device home, at the training visit, study personnel will complete a tDCS 
checklist to screen subjects for suitability of RS-tDCS. This will be double checked by the 
Principal Investigator prior to release of the device to the subject. If the subject qualifies, we will 
ensure a rigorous training session for the subject and if necessary, the caregiver. We will instruct 
the subjects to maintain a RS-tDCS log which will be reviewed by staff every 2 weeks until the 
end of the study. We have many different stops inserted into the protocol for the safety of the 
participant. The STOP criteria are summarized below: 
 
• 
tDCS tolerability test – Stop 1: Does not pass tDCS tolerability test, has pain or other adverse effects 
• 
tDCS training visit – Stop 2: Does not understand tDCS 
• 
RS-tDCS sessions:  
o 
Zoom PHI video call – Stop 3: Three reschedules/ failure to initiate conference 
o 
Placement of headset: Stop 4: Failure to place headset correctly within 30 minutes at more 
than one study session 
o 
Adverse event – Stop 5: Subject reports experiencing any of the critical events 
o 
Pain- Stop 6: Reporting of a pain score of 7/10 or more at any point 
• 
In addition, a pre-specified interim analysis for the continuation of the entire study will be 
completed 
after the first 6 participants complete the study. The adverse events and mean change in ALSFRS-R 
between the 2 groups will then be compared. The stopping criteria will be defined as a mean 
difference between groups exceeding 2 standard deviations. If this occurs, the study will be stopped 
for full review by the medical monitor or revising the protocol before proceeding 
 
 
Dr. Rezania will serve as the medical monitor of the study. A DSMB will be established to 
monitor the study in terms of timely subject enrollment, integrity of data acquisition and storage, 
and patient safety. There will be three members who will not be a part of the study team, and 
who will have no conflicts of interest. The DSMB will include a physician, a scientist with 
clinical trials experience, and a physical or occupational therapist with experience in working 
with patients with neurological conditions. Adverse events and unanticipated problems will be 
reported within 24 hours to the IRB and documented on an Adverse Event Log Sheet in the 
research records. 
12.0 
Statistical Considerations 
Subjects and their caregivers face difficulties in participating in randomized controlled trials. 
Some of the issues that limit participation include travel arrangements, travel associated costs, 
caregiver’s time and scheduling of multiple appointments. Hence it is critical to perform a 
thorough assessment of the potential benefits of RS-tDCS before considering a randomized 
controlled trial (RCT). We have powered the study to demonstrate safety of RS-tDCS in terms of 
adverse events. We will study 100 subjects with ALS. For Aim 2, we will be testing 50 subjects 
per group. For each comparison of 50 subjects with RS-tDCS compared to 50 in the other group, 
if the true adverse event rates are really equal, we will have 80% power to reject the null of a 

Remotely Supervised tDCS as an intervention in ALS  
 
higher event rate in the RS-tDCS group. This power will also obtain an estimate of the variance 
of the treatment effect for use in power calculations for a future study. We have estimated a total 
of 100 subjects to be included in the study. 
13.0 
Regulatory Requirements 
13.1 
Informed Consent   
Oral consent will be obtained by phone during the initial telephone screen. Upon determination 
of eligibility, the initial meeting will take place in Room 810 in the Applied Health Science 
Building (1919 W Taylor St.) Subjects will meet with Dr. Madhavan and/or key research 
personnel who will explain the research study. Subjects and/or family will then review the 
informed consent document and all questions will be answered by the investigator. Informed 
consent will be obtained in English using lay language. The subject will receive a copy of the 
signed informed consent document and the investigator will keep the original in the research 
records. A preparatory to research waiver will be secured by the IRB according to 45 CFR 46 
164.512(i)(1)(ii). A waiver of informed consents for the screening, recruiting, and determining 
eligibility will be secured by the IRB according to 45 CFR 46.116(g). 
13.2 
Subject Confidentiality  
Screening and testing of participants will be conducted in private rooms. Subject’s privacy will 
be protected at all times by ensuring that only key research personnel are present during testing 
and training. An alphanumeric code will be used to identify each subject. Authorized research 
personnel will maintain a master sheet which has the subject's name linked to his/her code 
(initials followed by a number). This sheet will be maintained on the lab computer in a password 
protected file that only the research team directly working on the project has access to. The other 
data will be maintained on the lab computers which only authorized personnel have access to. 
Security of these computers are maintained by the College of Applied Heath Science IT 
personnel. The key linking the code to the subject's identity will be destroyed 10 years after 
study completion. Results published will not include names of subjects. 
13.3 
Unanticipated Problems 
Any unexpected experience, adverse events or outcomes related to the research will be closely 
monitored by the research personnel and reported to Dr. Madhavan immediately. Dr. Madhavan 
will take necessary action according to the nature of unforeseen problem which will suspension 
of research procedures in currently enrolled subjects; modification of research procedures for 
new subjects; changes of the informed consent document/process to ensure subject safety and 
privacy, modification of inclusion or exclusion criteria to mitigate the newly identified risks; 
implementation of additional procedures for monitoring subjects; and/or suspension of 
enrollment of new subjects.