Accelerated High-Dose tDCS for Depression: An Open-Label Outpatient Pilot Study
Phase: NA
Conditions: Major Depression, Major Depression Disorders
Sponsor: Medical University of South Carolina

Medical University of South Carolina 
 
 
Accelerated High-Dose Transcranial Direct Current 
Stimulation (tDCS) for Depression: 
An Open-Label Outpatient Pilot Study 
 
 
ClinicalTrials.gov Identifier (NCT Number): NCT 
 
 
SPONSOR / COLLABORATORS: 
• Medical University of South Carolina (MUSC) 
• City College of New York (Collaborating Investigator: Marom Bikson, PhD) 
 
 
PRINCIPAL INVESTIGATOR: 
Mark S. George, MD 
Distinguished Professor, Psychiatry, Radiology, and Neuroscience 
Medical University of South Carolina 
 
                                               Study Lead: Clayton Olash, MD 
 
 
 
 
 
Psychiatry Resident 
 
 
 
 
 
      DART Fellow  
 
 
PROTOCOL VERSION: Version 2.1 
Date of Document: November 4, 2025 
 
DOCUMENT TYPE: Full Study Protocol 
 
 

PRINCIPAL INVESTIGATOR:  Mark George, MD 1 
CO-INVESTIGATORS: Clayton Olash, MD,1 Danyal Smani, MD,1 Stewart Cox, MD, PhD1, 
Marom Bikson, PhD2, Kyle Donnery, PhD, Jean-Philippe Miron, MD, PhD3, John Freedy, MD, 
PhD4, Mark George, MD1 
 
1 Brain Stimulation Laboratory, Medical University of South Carolina 
2 City College of New York (CCNY) Neural Engineering Group 
3 Interventional Psychiatry Program, UC San Diego Health 
4 Medical University of South Carolina, Department of Family Medicine  
 
1.0 Objectives / Specific Aims 
Aim 1:  Evaluate the Safety, Feasibility, and Tolerability of High-Dose Repeated tDCS in 
Adults with Major Depressive Disorder 
Aim 1: 
To evaluate the safety, tolerability, and feasibility of delivering high-dose transcranial direct 
current stimulation (tDCS) at 6 mA, administered twice daily for five consecutive days in an 
outpatient brain stimulation laboratory setting. Safety will be assessed by the absence of device-
related serious adverse events (SAEs) (Protections (OHRP), 2010) requiring hospitalization or 
emergency care, and by skin assessments at each visit. Tolerability will be operationalized using 
the standardized tDCS Adverse Event Questionnaire (A. Brunoni et al., 2011). We hypothesize 
that ≥80% of participants will meet the “tolerated” classification, no device-related SAEs will 
occur, and the independent Safety Review Committee will not recommend stopping the study 
after reviewing safety/tolerability data from the first three participants in the run-in cohort. 
 
Aim 2: Collect Preliminary Outcome Data on Depression Symptom Improvement and 
Mindfulness Following High-Dose Repeated tDC 
This aim will explore whether high-dose, twice-daily transcranial direct current stimulation 
(tDCS) administered over five consecutive days leads to measurable improvements in depressive 
symptoms and state mindfulness. All participants (n = 20) will complete validated pre- and post-
treatment clinical assessments, including the Patient Health Questionnaire-9 (PHQ-9)  and the 
Snaith-Hamilton Pleasure Scale (SHAPS), to evaluate changes in mood and anhedonia. 
Additionally, participants will complete the Cognitive and Affective Mindfulness Revised 
(CAMS-R) before and after the intervention to assess changes in state mindfulness. Finally, we 
will also assess potential cognitive effects—both positive and negative—on working memory, 

attention, and processing speed using the PROMIS Cognitive Function measure and the Trail 
Making Test. While this study is not powered to test efficacy, these exploratory data will help 
estimate effect sizes and inform the design of a future randomized controlled trial. We 
hypothesize that participants will show reductions in depressive symptoms, improvements in 
hedonic tone, and increases in state mindfulness following the stimulation protocol. 
Aim 3: E-Field Modeling  
All participants will undergo a structural MRI to enable individualized retrospective E-field 
modeling. This modeling will estimate intracerebral current flow and assess the relationship 
between predicted dose and tolerability or symptom change. E-field modeling is exploratory and 
will serve to inform potential future dose-response modeling and precision targeting in follow-up 
studies. 
2.0 Background 
Major Depressive Disorder (MDD) is a highly debilitating condition characterized by persistent 
sadness, impaired functioning, and significant morbidity, profoundly impacting individuals' 
quality of life and societal productivity (Stringaris, 2017). Despite advances in pharmacological 
and psychotherapeutic treatments, current estimates suggest that about 20-40% of patients 
continue to experience inadequate symptom relief (Touloumis, 2021). 
Neuromodulation techniques, including transcranial direct current stimulation (tDCS), have 
emerged as effective alternatives or adjuncts for managing depressive symptoms. Numerous 
randomized controlled trials and meta-analyses have shown tDCS to be effective in alleviating 
acute depressive episodes, demonstrating moderate effect sizes across many studies (A. R. 
Brunoni et al., 2016; Couture et al., 2025; Moffa et al., 2020; Palm et al., 2016; Zheng et al., 
2024). However, in spite of these findings listed above, tDCS has yet to achieve widespread 
clinical adoption or FDA approval, likely due to several high-profile randomized controlled trials 
that failed to differentiate either active treatment from sham stimulation (Blumberger et al., 2012; 
Loo et al., 2010, 2018) or noninferiority from the gold standard of antidepressant treatment (A. R. 
Brunoni et al., 2017). Contributing factors to these failed studies likely include: insufficient dose 
or short course length (Loo et al., 2010), treatment-resistant populations (Blumberger et al., 
2012), active sham designs (Loo et al., 2018), and multisite variability with protocol 
heterogeneity (Loo et al., 2018). Furthermore, a review of the literature indicates that, in general, 
higher tDCS intensities — for example, 2 mA compared to 1 mA — are associated with greater 
clinical effects across a range of neuropsychiatric conditions (A. R. Brunoni et al., 2016; Evans et 
al., 2020; Moffa et al., 2020; Salehinejad et al., 2020; Zheng et al., 2024).  In addition, recent 
studies employing accelerated protocols, higher cumulative total duration/dosing, and repeated 
daily sessions have demonstrated superior clinical outcomes (Couture et al., 2025; Moirand et al., 
2022; Woodham et al., 2025), echoing innovations seen in TMS research with the high-dose 
SAINT protocol (Cole et al., 2022).  
Nevertheless, the vast majority of clinical studies to date have limited stimulation intensity to ≤2 
mA, despite substantial variability in the actual internal dose delivered to cortical tissue due to 

individual differences in anatomy, scalp, and skull conductivity (Evans et al., 2020). This 
variability means that two individuals receiving the same applied current may experience 
markedly different effective brain doses, leaving the safety, tolerability, and potential efficacy of 
higher intensities largely untested. To address this gap, this study will look to establish the safety, 
tolerability, and feasibility of delivering repeated dosing at 6 mA stimulation using a modified 
Soterix Medical HC-1x1 tDCS system with high-capacity hydrogel electrodes in patients with 
MDD. 
Recent dose-escalation studies in brain injury populations have confirmed safety and tolerability 
at 4 mA (Chhatbar et al., 2017; Nitsche & Bikson, 2017), while recent assessments tested with 
healthy volunteers indicate minimal discomfort and no significant skin injury even at 6 mA 
(Donnery et al., 2025). However, this device and dose have not been tested in a clinical or 
depressive patient population. Establishing feasibility and safety under these clinical conditions is 
critical to progressing toward a definitive efficacy randomized controlled trial (RCT) and 
expanding the therapeutic reach of tDCS for treating Major Depressive Disorder. 
3.0 Intervention to be Studied 
The intervention we are studying is called high-dose transcranial direct current stimulation 
(tDCS). tDCS is a non-invasive form of neuromodulation that delivers a low-intensity electrical 
current through electrodes placed on the scalp to modulate cortical excitability. The device used 
in this trial is a modified version of the Soterix Medical 1x1 tDCS system, a platform with a 
strong safety record and use in hundreds of clinical trials worldwide. The modified “High 
Capacity” (HC-1x1) version in this study will be configured to deliver up to 6 mA of current with 
a ramp-up period extended from 60 seconds to 120 seconds to enhance comfort. In addition, the 
maximum voltage will be reduced approximately fivefold to improve tolerability further. 
Stimulation will be delivered using self-adhesive hydrogel electrodes manufactured in the 
laboratory of Dr. Marom Bikson, connected to the output of the modified 1x1 device. Electrodes 
will be positioned in a bifrontal montage, with the anode over the left frontal region and the 
cathode over the right frontal region. The device will be activated for 20 minutes per session, with 
twice-daily sessions separated by at least 30 minutes during the main protocol phase. 
 
4.0 Study Endpoints 
Aim 1 Primary Endpoint: Safety, Feasibility, and Tolerability 
The proportion of participants meeting the “tolerated” classification as defined in Aim 1, based 
on data from the standardized tDCS Adverse Event Questionnaire and skin integrity assessments. 
“Tolerated” is defined as: 
1. Completion of all scheduled tDCS sessions without discontinuation due to adverse events 
 

2. No device-related serious adverse events (SAEs) requiring hospitalization or emergency 
care 
 
3. No more than one transient Severe/Extreme symptom (score 4–5 on Likert scale) lasting 
≤30 minutes without intervention 
 
4. No clinically significant skin irritation, defined as skin redness ≥3 persisting >24 hours or 
requiring medical treatment. 
 
Secondary Endpoints: 
● Determination by the independent Safety Review Committee, after review of 
safety/tolerability data from the first three participants in the safety run-in cohort, to 
proceed with full enrollment. 
 
● Recruitment rate from primary care referrals 
 
● Proportion of participants completing all scheduled sessions 
 
● Average symptom severity scores from the tDCS Adverse Event Questionnaire across all 
participants 
 
 
Aim 2 Primary Endpoint: Neuropsychiatric Assessments with a focus on depression, anxiety, 
cognitive function, and mindfulness.A neuropsychiatric battery will be collected at baseline, 
immediately post-intervention (Day 5), and at four-week follow-up. This battery will include the 
following validated measures: 
● Patient Health Questionnaire-9 (PHQ-9) – for self-reported depression severity. 
– to examine state mindfulness and experiential changes. 
● Cognitive and Affective Mindfulness Revised (CAMS-R) 
● Snaith-Hamilton Pleasure Scale (SHAPS) – to measure anhedonia 
● Trail Making Test (TMT) Parts A & B- To measure objective changes in cognitive 
processing, such as working memory, attention, and concentration 
● PROMIS Cognitive Function Test 4a- to measure subjective changes in cognitive 
function such as memory  
 
Aim 3 Primary Endpoint: MRI and Retrospective E-field Modeling 
Participants will undergo MRI scanning for retrospective electric field (E-field) modeling 
analyses, conducted in collaboration with Dr. Bikson's laboratory at CCNY. This secondary 
outcome will provide important mechanistic insight into electric field distribution and dose-
response relationships relevant to clinical outcomes. 

 
5.0 Inclusion & Exclusion Criteria / Study Population 
This study seeks to recruit from a broad range of individuals to ensure generalizability, though 
some exclusion criteria are required to ensure participant safety. Participants will be screened. 
The recruited sample will be 50% female. No racial or ethnic groups will be excluded during 
recruitment, nor will any other individuals with diverse backgrounds. However, participants must 
be English-speaking, as the study consent and other assessments are presented in English. Risks 
of tDCS to a fetus are currently unknown. Thus, women of childbearing age will be screened for 
pregnancy during the screening assessment and will be provided a pregnancy test prior to 
stimulation to confirm they are not pregnant. 
Inclusion Criteria  
●  Ages 18–70.  
● Current MDD diagnosis (MINI v7).  
●  Baseline PHQ-9 > 9.  
●  Capacity to consent 
●  Fluent English. 
Exclusion Criteria   
● Current or past diagnosis of treatment-resistant depression, defined as failure of ≥2 
adequate antidepressant trials at any point. If on an antidepressant: Must be on a stable 
dose for ≥4 months prior to enrollment. No medication changes (dose or agent) during 
the study period. 
●  Bipolar or psychotic disorder 
● Primary anxiety disorders without concomitant major depression as defined above 
● Current significant suicidal ideation or behaviors require a higher level of care. 
● Diagnosis of personality disorder  
● Use of neuromodulation therapies (e.g., ECT, TMS, VNS) within the past 6 months. 
● History of seizures, implanted cranial/ cardiac metal, or neurosurgery.  
● Frequent and or severe headache 
● Must be not have any contraindication to MRI (e.g. metals, implants, etc.) 
● Personal history of head trauma, concussion, or TBI 
●  Current alcohol or substance‑use disorder (moderate‑severe).  
●  Any non-uniformities in the skin under the electrode site, including eczema, severe 
rashes, hyperhidrosis, communicable skin disorders, sensitive skin (ex., eczema, severe 
rashes), blisters, open wounds, burns, including sunburns, cuts or irritation (e.g., due to 
shaving), or other skin defects or lesions, as determined by clinical personnel 
●  Pregnancy (urine test required for women of childbearing potential). 
6.0 Number of Subjects 
A total of N = 20 participants will be enrolled in a structured, two-phase study evaluating safety, 
tolerability, feasibility, and exploratory efficacy of a novel high-dose transcranial direct current 
stimulation (tDCS) protocol. We will recruit and aim to enroll 20 participants for an expected 12 
total completed participants.  

7.0 Setting 
Study activities will occur in two primary settings: the MUSC Brain Stimulation Laboratory 
Space and the MRI scanner at MUSC. The stimulations will take place in the Brain Stimulation 
Lab (5th Floor, MUSC Institute of Psychiatry), a secure outpatient neuromodulation suite 
equipped with adjustable treatment chairs, video monitoring, crash cart access, and on-site 
clinical supervision. Participants check in through the IOP outpatient research desk and are 
escorted to the badge-secured lab, where licensed research staff will be present. 
For participants undergoing E-field modeling, MRI scans will be performed at the MUSC Center 
for Biomedical Imaging (CBI) located at 30 Bee Street, 29425, and de-identified for retrospective 
analysis by Dr. Bikson’s lab at CCNY. 
8.0 Recruitment Methods 
Recruitment for this study will be conducted through the Family Medicine Primary Care Clinics 
at MUSC, under the management of Dr. John Freedy. Primary care physicians in these clinics 
will identify patients with a diagnosis of depression who may be appropriate for participation. 
Physicians will conduct an initial screen against the study’s inclusion and exclusion criteria. If a 
patient appears to meet preliminary eligibility requirements, and expresses interest in the study, 
the physician will notify the Principal Investigator and study collaborators. The research team 
will then follow up with the patient to confirm eligibility, provide study information, and obtain 
informed consent prior to enrollment. 
In addition, we will also be recruiting through paper flyers and advertisements on social media 
such as Instagram, targeting patients in the Charleston community who may meet our inclusion 
and exclusion criteria. The advertisement will have information on how to reach out to a member 
of our team, who will then thoroughly screen them before, if applicable, consenting the 
participant. 
9.0 Consent Process 
Written informed consent will be obtained either in a private room at MUSC, or in a secure 
location of their choosing. For patients that are unable to arrive at the lab prior to the start of the 
study, electronic “eConsent” will also be available. Participants will receive a copy of the consent 
form, either paper or electronic. Consent covers procedures, time commitment, risks/benefits, 
confidentiality, voluntary participation, and right to withdraw, of which the study team will 
describe thoroughly 
In addition, participants will be prompted to ask questions throughout the consent process to 
further ensure understanding. Participants will be given ample time to ask questions and consider 
participation. After signing the consent form, they will also be offered a hard copy.  
10.0 Study Design / Methods 
At the initial study visit, participants will undergo the informed consent process with a co-
investigator. After providing written consent, participants will complete baseline 

neuropsychological assessments, including the standardized tDCS Adverse Event Questionnaire, 
the PHQ-9, the SHAPS, and the CAMS-R. A pregnancy screening will also be conducted when 
applicable. Following these assessments, participants will be escorted to a room in the brain 
stimulation lab on the 5th floor to undergo their first tDCS stimulation session. Since MRI is 
being obtained for E-field modeling, and not pre vs post, the MRI can be scheduled at any point 
and does not have to be obtained before or during the study.  
 
Day 1 (dose-escalation safety assessment cohort: first 3 patients enrolled): 
● 20-minute stimulation at 2 mA → 30-minute rest period (extendable to 60 minutes if 
needed) 
 
● 20-minute stimulation at 4 mA → 30-minute rest period (extendable to 60 minutes if 
needed) 
 
● 20-minute stimulation at 6 mA 
 
Day 2 (skin integrity and safety check): 
● Visual inspection of electrode sites for erythema, burns, or other skin reactions, and 
completion of the tDCS Adverse Event Questionnaire 
 
● If no serious adverse event (SAE) requiring emergency department evaluation or 
hospitalization is observed, and skin integrity is deemed acceptable by clinical evaluation 
by on-site MD, participants will proceed to: 
 
○ Two 20-minute stimulation sessions at 6 mA, separated by a 30-minute-60 to 60-
minute rest period for the remaining 4 days.  
 
○ Main Protocol (remaining 9 participants): Progression beyond the initial 
safety run-in cohort will occur only after the Safety Review Committee has 
reviewed the adverse event data, skin integrity assessments, and tolerability 
questionnaire responses from the first three participants and determined that 
continuation at 6 mA is acceptable. 
 
■ Same procedure as above, including consent, neuropsychological testing, 
pregnancy testing (if applicable), and MRI 
■ Instead of starting at 2 mA, participants will start at 2 sessions/day at 
6 mA (20 min each, 30-minute interval), 
 
■ Conducted in-lab over 5 consecutive weekdays. After each session, skin 
and safety checks will be completed by study staff or trained personnel.  
 
 
● Post-Treatment Assessment: 
 

○ Conducted in-person after the last stimulation session 
 
○ Virtual follow-up at 4 weeks to assess durability. Pt’s will answer the same 
neuropsychological questions as above.  
 
12.0 Data Management 
All data will be stored in the REDCap database. Information about the participant (including their 
identifiable private information) may have all their identifiers removed and used for future 
research studies or distributed to other researchers for future research without additional informed 
consent. After participation, REDCap data will be downloaded in Excel format to the secure 
MUSC server. In terms of publication, data will be published in aggregate form, so individual 
participants will not be identifiable in the final manuscript. No identifying information will be 
published. 
Confidentiality and Quality Control: All study personnel will complete Social-Behavioral-
Educational research CITI training, and also complete in-lab training regarding data security 
practices. Study personnel will be trained in the IRB protocol. The investigator and co-
investigators will be available to monitor data collection to ensure quality, confidentiality, and 
adherence to the IRB protocol. 
 
13.0 Provisions to Monitor Data & Ensure Safety 
The Principal Investigator (PI), or a designated Co-Investigator (Co-I) if the PI is unavailable, 
will be responsible for reporting all unanticipated problems or adverse events (AEs) promptly to 
the Institutional Review Board (IRB). The PI or designated study team member will be present 
during each stimulation session to document any AEs in real-time. Screening data collected from 
participants will be securely stored in REDCap. Data from participants who do not qualify for the 
study will be securely destroyed. 
The PI or Co-I will oversee device testing and the technical use of the High-Capacity tDCS (HC-
tDCS) device. Participants will remain in the lab throughout the stimulation protocol, monitored 
continuously by study personnel and research staff. Co-Investigators will be present for all 
administration sessions, and participants will be closely monitored around the clock for any 
adverse events and tolerability concerns. 
Informed consent will be obtained by the PI or Co-I, ensuring participants are fully informed 
about the research procedures, time requirements, potential risks and benefits, their rights to 
refuse or withdraw from participation at any time without prejudice, and providing contact details 
for the principal investigator. 
Participant confidentiality will be rigorously maintained, with access to collected data strictly 
limited to authorized research staff. Participants' identities in databases will be protected using 

alphanumeric codes, and all data will be securely stored in locked file cabinets or on secure 
servers accessible only by designated members of the study team. 
14.0 Withdrawal of Subjects 
Subjects may withdraw at any time without penalty. Reasons and partial data will be documented. 
Participants who withdraw due to AEs will receive appropriate medical evaluation. 
15.0 Risks to Subjects 
Transcranial direct current stimulation (tDCS) has been shown to safe when used within standard 
parameters (up to 4 mA, sessions under 40–60 minutes), with no evidence of serious or 
irreversible adverse effects reported across tens of thousands of sessions, including in vulnerable 
populations such as children, the elderly, and patients with neurological conditions (Bikson et al., 
2016; Grossman et al., 2019; Ko, 2021). Furthermore,  this newly invented High-Capacity tDCS 
device was recently studied in healthy volunteers and found to be tolerated and safe up to 6 mA 
for 30 minutes, with minimal discomfort and no skin injury (Donnery et al., 2025). The most 
commonly reported side effects in tCDS research are mild and transient, including itching, 
tingling, headache, burning sensations, and discomfort at the site of electrode placement, with 
these effects occurring at similar rates in both active and sham (placebo) groups (Aparicio et al., 
2016; A. Brunoni et al., 2011; Nikolin et al., 2017). There is no evidence that repeated sessions 
increase the risk of adverse events, nor that any specific patient group is at higher risk under 
standard protocols (Chhatbar et al., 2017; Russo et al., 2017). Animal studies suggest that the 
electrical doses used in tDCS are far below levels that could cause brain tissue damage (Bikson et 
al., 2016; Ko, 2021).  
 
1. Transient Skin Erythema / Redness 
Local redness or mild warmth is common beneath the stimulation pads. This reaction is 
expected to resolve within 30–60 minutes. Participants will be advised to apply vitamin E 
or an aloe‐based cream if erythema persists longer than 2 hours. Any Grade ≥ 2 skin event 
will be documented and reviewed prior to the next stimulation day. 
2. Skin Irritation, Dermatitis, or Superficial Burns 
Prolonged or repeated sessions at higher current density may produce focal irritation, 
itching, or—rarely—superficial burn/necrosis. All electrode sites will be inspected before 
and after each session.  
3. Tingling, Itching, or Pressure Sensation 
Mild paresthesia under the pads (described as tingling, itching, or pressure) is typical and 
generally subsides shortly after the current is offset. 
4. Headache, Dizziness, or Facial Pain 
Low‑intensity electrical stimulation of the scalp can occasionally provoke a headache or 
transient dizziness. These symptoms usually resolve within minutes. Participants will be 
seated during stimulation to minimize fall risk; fluids and rest will be offered if 
symptoms persist. 
5. Mood Destabilization or Induction of Mania 
Although rare, neuromodulation studies in depression have reported emergent hypomanic 
or manic symptoms.  Systematic reviews and meta-analyses have documented a small 

number of cases—six instances of affective switching (from depression to mania or 
hypomania) were observed in studies of tDCS for bipolar depression, and a total of 11 
cases have been reported in patients with depression across the literature, though the 
overall incidence is very low and a direct causal relationship is difficult to establish due 
to the limited number of subjects and events (Antal et al., 2017; A. R. Brunoni et al., 
2017; Dondé et al., 2017; Matsumoto & Ugawa, 2016). Participants will complete brief 
mood screens daily; any sign of treatment‑emergent mania will prompt psychiatric 
evaluation and possible withdrawal from the study. 
6. Seizure 
The delivered current (≤ 6 mA) and charge density are well below established seizure 
thresholds; nonetheless, a new‑onset seizure is considered a Serious Adverse Event 
(SAE). In our review of the literature, there is only one case report of a tCDS being 
associated with seizure, and this was in a child with epilepsy (Ekici, 2015). Emergency 
response equipment and ACLS‑trained personnel will be immediately available; the IRB 
will be notified within 24 hours of any seizure. 
7. Cardiovascular Changes 
Transcranial direct current stimulation is not typically associated with heart‑rate 
variability, but autonomic shifts cannot be ruled out. Vital signs will be obtained 
pre‑session and once hourly during Days 1–7. Clinically significant 
hypotension/bradycardia (≥ 20 % decline from baseline) will lead to dose reduction or 
discontinuation. 
8. Device Malfunction 
Unintended rapid discharge or incomplete current delivery could result from device 
failure. Any malfunctioning of the device will be uploaded to RedCaps. Malfunctioning 
devices will be removed and quarantined for engineering review. 
9. Unknown Risks 
HC-tDCS is a novel, higher‑dose form factor; unanticipated AEs are possible. New 
information that could alter the risk–benefit profile will be promptly communicated to 
participants and the IRB. 
10. Loss of Confidentiality 
As with any study collecting personal data, there is a small risk of a privacy breach. Data 
protections (encrypted REDCap, coded identifiers, limited‑access servers) are in place, 
and any breach would be reported per MUSC policy. 
11. Questionnaire‑Related Distress 
Some survey items address depressive symptoms and suicidal ideation. Participants may 
skip any item or discontinue assessments; immediate clinical support from study 
psychiatrists is available. 
 
16.0 Potential Benefits 
To the Participant: Participants may experience improvement in depressive symptoms as a 
result of receiving high‑dose transcranial direct current stimulation (tDCS). While the primary 
purpose of this study is to evaluate safety, tolerability, and feasibility, tDCS has been shown in 
prior research to produce clinically meaningful reductions in depressive symptoms, particularly in 
non‑treatment‑resistant populations. Participants will receive repeated, structured stimulation 
sessions under close clinical supervision, and their mood, anxiety, and related symptoms will be 
regularly monitored. This may allow for earlier identification of symptom changes and facilitate 
appropriate clinical follow‑up if needed. Although symptom improvement cannot be guaranteed, 

participants may benefit from access to a novel, non‑pharmacologic intervention that is not yet 
widely available in clinical settings. 
To Society: If shown to be safe, tolerable, and feasible, this study could lay the groundwork for a 
scalable, accessible brain stimulation intervention for Major Depressive Disorder. Current 
neuromodulation treatments are generally limited to treatment‑resistant populations and require 
in‑clinic administration, restricting their accessibility. The findings from this study could inform 
larger efficacy trials and ultimately contribute to the development of a first‑line, 
non‑pharmacologic treatment option that could be deployed in primary care and outpatient 
psychiatry settings. Such a treatment could expand the therapeutic toolkit for depression, reduce 
reliance on medications with systemic side effects, and improve the quality of life for a broad 
range of patients. 
 
17.0 Sharing of Results with Subjects 
Aggregate results will be posted on ClinicalTrials.gov and shared upon request. Clinically 
actionable incidental findings will be communicated individually. 
18.0 Drugs or Devices 
The device used in this trial is a modified version of the Soterix Medical 1x1 tDCS system, a 
platform with a strong safety record and use in hundreds of clinical trials worldwide. The 
modified “High Capacity” (HC-1x1) version in this study will be configured to deliver up to 6 
mA of current with a ramp-up period extended from 60 seconds to 120 seconds to enhance 
comfort. In addition, the maximum voltage will be reduced approximately fivefold to further 
improve tolerability. 
Stimulation will be delivered using self-adhesive hydrogel electrodes manufactured in the 
laboratory of Dr. Marom Bikson, connected to the output of the modified 1x1 device. Electrodes 
will be positioned in a bifrontal montage, with the anode over the left frontal region and the 
cathode over the right frontal region. The device will be activated for 20 minutes per session, with 
twice-daily sessions separated by at least 30 minutes during the main protocol phase. 
tDCS is a non-significant risk method that has been approved in many studies by the MUSC IRB, 
of which Dr. Mark George has been a co-author (Borckardt et al., 2012; George & Aston-Jones, 
2010; Glaser et al., 2016). The intervention under investigation involves the use of a tDCS 
hydrogel electrode (High Capacity, HC). Compared to the typical sponge electrodes, HC 
electrodes are designed for superior delivery of current across the skin, which in turn reduces the 
sensations felt at the skin, allowing the use of higher current, for example, 6 mA. Based on tDCS 
safety studies and standards, while most trials use 2 mA, this is not a safety limit but rather 
related to skin sensations. 6 mA remains well below safety limits reported (~50 mA) (Bikson et 
al., 2016). In regard to electrode current density and charge density, HC-tDCS with 6 mA is less 
than “High Definition tDCS,” which is also well established to be safe, including trials at MUSC 

(Borckardt et al., 2012).  Based on the prior work in healthy subjects, we expect 6 mA HD-tDCS 
to be well tolerated in a clinical population of MDD. 
The device used for this study is the Soterix Medical 1x1 HC-tDCS device, which is a medical-
grade investigational device (ie, not approved by the FDA for treatment of any disease). The 1x1 
HC-tDCS device is based on the Soterix Medical 1x1 tDCS platform, which has been used in 
hundreds of clinical trials under NSR, is CE marked, and broadly considered a quality standard in 
tES.  The standard models have been modified to allow the higher current needed in the trial, 
along with a slower ramp and reduced voltage compliance to further enhance tolerability.  
 
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