Supervised Home-based Transcranial Direct Current Stimulation (tDCS) for Major Depressive Disorder
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Hebrew SeniorLife

 
 
 
Title: Home-based tDCS in Major Depressive Disorder (MoodStim) 
NCT04799405 
01/13/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title: Home-based Transcranial direct current stimulation (tDCS) in Major Depressive Disorders 
IRB #:  HSL # 2020-3, Advarra Protocol # PRO00044198 
Creation Date: 4-10-2020, version 2 01132021 
 
 
 
Principal Investigator: Alvaro Pascual-Leone 
Marcus Institute for Aging Research 
Address: 1200 Centre Street, Boston, MA 02131-1101 
Phone: 617-971-5372 
Email: apleone@hsl.harvard.edu 
  
Co-Investigators: 
Name: Bradley Manor 
Organization: Marcus Institute for Aging Research  
Address: 1200 Centre Street, Boston, MA 02131-1101 
Phone: 617-971-5339 
Email: BradManor@hsl.harvard.edu 
 
Name: Lewis Lipsitz 
Organization: Marcus Institute for Aging Research  
Address: 1200 Centre Street, Boston, MA 02131-1101  
Phone: 617-971-5318 
Email: Lipsitz@hsl.harvard.edu 
 
Name: Eran Metzger 
Organization: Hebrew SeniorLife 
HealthCare Services and HRC 
Email:  metzger@hsl.harvard.edu
  

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 Purpose of the study   
Major depressive disorder (MDD) is highly prevalent and the main cause of global disability worldwide (Kupfer 
et al., 2012). About 20–40% of patients do not benefit sufficiently from the existing antidepressant interventions, 
including trials of medication and psychotherapy (Greden, 2001). Pharmacological treatments have limited 
efficacy, side effects are common (Carvalho et al., 2016), and one-third of patients are medication-resistant failing 
to achieve remission after using three or more antidepressants (Rush et al., 2006) and experiencing recurrent 
depressive episodes (Nemeroff, 2007). 
For patients with medication-resistant MDD, a number of neuromodulation strategies are available, including 
electro-convulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). These are effective 
interventions, which nonetheless present relatively high costs, may have side-effects and risks (e.g. complications 
of anesthesia in the case of ECT or risk of seizure induction in the case of rTMS), and require specialized 
equipment, trained personnel and suitable clinic facilities. This can pose a challenge for some patients as ready 
access to specialized clinics or treatment centers is not available in all areas of the US or worldwide. The 
challenge is particularly acute among seniors who have additional limitations in mobility and need help and 
support to make it to outpatient clinics. And yet, it is estimated that approximately 15% of the elderly (aged > 65) 
living in the community suffer from clinically significant depressive symptoms (Blazer 2003). Depression in the 
elderly is a cause of particularly high morbidity and early mortality (Schulz et al. 2002), and older age is a 
significant predictor of an unfavorable course of depression (Mitchell & Subramanian 2005), reduced likelihood 
of treatment response (Licht-Strunck et al 2007; Tedeschini et al. 2011), diminished chance of functional recovery 
(Little et al 1998), and increased risk of relapse (Beekman et al 2002). 
At present, given the COVID-19 pandemic and the required and appropriate restrictions on individual mobility 
and outpatient medical encounters and procedures, access to rTMS, ECT, or similar in-clinic treatments is much 
more limited. These added difficulties to access ECT and rTMS are occurring at a time when the risk of mental 
health problems and of decompensation from pre-existing depression is extremely high due to the uncertainties, 
fears, and stressors caused by the COVID-19 pandemic and the social distancing. The risk of mood and mental 
health decompensation in the setting of social isolation and loneliness is particularly high among the elderly, who 
in turn are at a particularly high risk of serious complications of an infection with COVID-19 and thus are faced 
with particularly high stress, fears, and strict isolation regulations. 
Therefore, the current COVID-19 pandemic makes the need for a safe, effective, home-based intervention for an 
acute, medication-resistant episode of uni- or bi-polar MDD particularly urgent. Transcranial direct current 
stimulation (tDCS) offers a suitable and readily available solution.  
Study design and purpose:     We propose a safety/feasibility study designed to determine whether it is possible 
for transcranial direct current stimulation (tDCS) interventions to be successfully delivered by a caregiver at the 
homes of  adults who have medication-resistant MDD.    
Study objectives: 
Primary objective:  Demonstrate that remote tDCS sessions applied by a caregiver are feasible, complied and 
adhered to, and are safe in individuals with severe depression  
Secondary objective: Gather pilot data on the potential of home-based tDCS to induce clinically meaningful 
improvements in the severity of depression in individuals who would otherwise be offered rTMS or ECT 
treatment. 
 

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The ultimate goal of this work is to prepare the path for a subsequent randomized clinical trial to assess the 
antidepressant therapeutic efficacy of home-based tDCS. We thus propose a study of tele-health supervised, 
caregiver-delivered, home-based tDCS for antidepressant treatment of patients with a medication-resistant 
depression episode of uni- or bi-polar Major Depression who would otherwise qualify for rTMS or ECT. 
Specifically, in the present protocol we seek to offer participation to: 
 Patients with medication-resistant MDD who have undergone rTMS or ECT and responded to it but whose 
benefit has lapsed, and they need repeat a rTMS or ECT course that they cannot access 
 Patients with medication-resistant MDD who are undergoing rTMS or ECT and responding, but cannot 
continue to get the rTMS or ECT course due to COVID-19 pandemic-related regulations or other access 
concerns 
 Patients with medication-resistant MDD who are referred to rTMS or ECT and are found well qualified 
but cannot access rTMS or ECT due to COVID-19 pandemic-related regulations or other access concerns. 
 
The benefits of this project address a present need due to the COVID-19 pandemic, but also go beyond the present 
situation and address a larger, pre-existing need. 
Across all these potential groups of participants, prospective participants will: 
1. Need to have a primary psychiatrist who agrees to their participation in the study and is willing to continue 
to follow the patient and work collaboratively with the study team 
2. Need to be assessed by their primary psychiatrist to be stable enough to be able to remain at home and 
participate in the present study without undue risk to their safety 
3. Need to be living with an adult willing and capable to provide oversight and learn to deliver the home-
based tDCS 
4. Have the capability to connect with the study team for daily supervision of the intervention sessions and 
close safety monitoring, and be willing to commit to doing so 
 
Background 
Transcranial direct current stimulation (tDCS)  tDCS is a painless method for focal brain stimulation. tDCS is 
based on decades-old observations that neuronal firing is modulated by low amplitude electrical direct current 
(DC). Specifically, when applied to the cerebral cortex, cathodal DC inhibits neuronal firing (Creutzfedt, 1962, 
Nitsche, 2000). The mechanisms by which cathodal DC reduces neuronal firing likely relate to hyper‐polarization 
of the soma membrane which occurs when the apical dendrites neurons are oriented toward the cathode in a 
constant electric field. The practical application of tDCS is simple: low amplitude DC is administered via scalp 
electrodes such that the cerebral cortex is exposed to cathodal DC beneath one of the electrodes, and the return 
(anodal) electrodes can be placed anywhere else on the body, or in more complex arrangements to minimize 
currents at any site. tDCS methods have also recently been adapted to rats for work with disease models (Kabakov 
2012, Rotenberg, 2014). Hundreds of tDCS trials have demonstrated the technique to be well tolerated and safe. 
Direct electrical current stimulation is presently FDA-approved for extracranial use, and FDA applications for 
cranial stimulation (tDCS) for management of mood disorder and chronic pain are in progress. tDCS units are also 
inexpensive and lightweight. The electrical supply can be derived from conventional 9-volt batteries.  The scalp 
electrodes can be fastened in seconds. tDCS can be combined easily with other therapies, such as those that may 
be required for resuscitation of an acutely injured patient. tDCS is presently under investigation as a treatment for 
epilepsy (IDE attached to this one), where excess cortical excitability is a prominent feature of the disease 

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process, and where neuronal inhibition may be beneficial. The tDCS stimulator used in this clinical study is the 
STARSTIM device (Neuroelectrics, Inc). Starstim has an associated software that allows to personalize treatment 
per pathology and target different brain region.  
tDCS and Depression 
Transcranial direct current stimulation (tDCS) delivers weak currents into the brain through two or more 
electrodes placed on the scalp. When appropriate guidelines are followed, tDCS is safe and extremely well 
tolerated (Antal et al., 2017). The mechanisms of action remain insufficiently understood but appear to involve 
polarity-dependent shifts in neuronal membrane potentials, thus leading to purely neuromodulatory effects that 
modify likelihood of neuroplasticity effects (potentiating or suppression plasticity depending on anodal versus 
cathodal effects). Notably tDCS effects spread across functional brain networks and thus enable modulation of 
brain connectivity related to mood disorders and MDD. 
There has been a fairly large number of studies, including randomized, sham-controlled clinical trials (RCTs) on 
the effects of tDCS in MDD. Results have been variable and in part discrepant. For example, Brunoni et al., 
(2017) found tDCS to have similar efficacy to antidepressant medications, while Loo et al., (2018) found no 
efficacy of real tDCS over sham in MDD. Nonetheless, several meta-analyses have concluded that tDCS is 
effective for MDD (Mutz et al., 2018; Brunoni et al., 2016). Most recently, Razza et al. (2020) completed a 
systematic review of all studies of tDCS for treatment of acute major depressive episodes completed up to January 
2020. They included all randomized, sham‐controlled clinical trials (RCTs) enrolling participants with an acute 
depressive episode, a total of 23 RCTs with 1,092 participants. They found that active tDCS was superior to sham 
regarding endpoint depression scores, response and remission rates. Moreover, active tDCS was safe with a side-
effect profile comparable to sham. Moffa et al. (2020) also recently published an individual patient data (IPD) 
meta-analysis evaluating the efficacy and acceptability of tDCS for treatment of acute major depressive episodes. 
The IPD meta-analysis is more accurate in estimating the efficacy of an intervention and also superior to the 
aggregated data approach for obtaining predictors of treatment outcome since it uses the raw data of each 
participant collected from each study (Riley et al., 2010). Moffa et al. included data from all published placebo-
controlled trials on tDCS as only intervention in MDD conducted until December-2018. This included 9 eligible 
studies with a total of 572 participants. They found active tDCS to be significantly superior to sham for an 
antidepressant response (30.9% vs. 18.9% respectively; OR = 1.96), remission (19.9% vs. 11.7%, OR = 1.94), and 
depression improvement (effect size β = 0.31). Moreover, they found a consistent continuous clinical 
improvement after the end of the tDCS treatment course. It is noteworthy that the clinical efficacy was 
substantially higher in the studies where the tDCS course was longer (3-4 weeks versus 1-2 weeks). 
The variability in the literature on the antidepressant effects of tDCS may reflect differences in patient selection as 
well as in the tDCS protocol. Longer courses of treatment seem particularly important to ensure sustained, lasting 
benefits. Consistent with current understanding of mechanisms of action, tDCS antidepressant effects may involve 
long-term neuroplastic changes that take time to develop and may in fact continue to evolve and mature even after 
the tDCS treatment course has ended. This makes long treatment courses with maintenance phases important, and 
home-based interventions appealing. Importantly, across all studies, active tDCS has been well tolerated and there 
have been no significant adverse or side effects. 
Home Use of tDCS 
tDCS, as a relatively simple and portable technology, is particularly well suited for remotely-supervised, home-
based treatment, which would facilitate longer periods of treatment as well as offer a suitable therapeutic option at 
the present time as we aim to deal with the COVID-19 pandemic. 

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Several equipment manufacturers have developed tDCS systems for remotely-supervised, home-based use, where 
the treatment is administered by the patient or a caregiver. 
Treatment parameters, scheduling and outcomes can be monitored remotely by clinic or research staff. To date, 
this has been piloted for treatment of a number of conditions including neuropathic pain (Garcia-Lorrea et al., 
2019), auditory hallucinations in schizophrenia (Andrade, 2013), multiple sclerosis (Charvet et al., 2017; Charvet 
et al., 2018; Kasschau et al., 2016; Kasschau et al., 2015), Mal de Debarquement Syndrome (Cha et al., 2016), 
Parkinson's disease (Agarwal et al., 2018; Dobbs et al., 2018), trigeminal neuralgia (Hagenacker et al., 2014), 
vascular dementia (André et al., 2016) and Prader-Willi syndrome (Azevedo et al., 2017) with promising results. 
Palm et al. (2018) completed a systematic review of all available evidence on home use of tDCS until May 2017. 
They identified 22 original research papers, trial protocols or trial registrations involving home-use tDCS, mostly 
as an add-on intervention to cognitive or physiotherapeutic intervention. Study samples were small, and many 
were single-blinded studies focused on feasibility and safety. Nonetheless, Palm et al. were able to show that 
treatment adherence was high and side-effects minimal, and thus they concluded that remotely controlled and 
supervised home-used tDCS was feasible and promising. The experience with home-use tDCS has continued to 
grow since then. 
In the setting of depression, Clayton et al., (2018) reported a case of one patient with comorbid multiple sclerosis 
and recurrent depressive episodes who received a course of remotely supervised tDCS following ECT treatment. 
Fatigue and mood ratings improved. More recently, Alonzo et al. (2019) completed a proof-of-principle, open-
label trial in 34 participants who were taught to self-administer 20–28 tDCS sessions (2 mA, 30 min, F3-anode 
and F8-cathode montage according to 10–20 EEG placement) over 4 weeks followed by a taper phase of 4 
sessions 1 week apart. Participants were initially monitored via video link for a few days, and then through 
completion of an online treatment diary. Participants met criteria for a diagnosis of MDD according to the DSM-
IV-TR, as determined via an interview with a study psychiatrist, and confirmed with the Mini International 
Neuropsychiatric Interview (MINI; Version 5.0.0) (Sheehan et al., 1998). Inclusion criteria included a current 
major depressive episode of at least four weeks duration as part of a uni- or bipolar depression; and a score of at 
least 20 on the Montgomery–Asberg Depression Rating Scale (MADRS) at trial entry. Exclusion criteria were any 
DSM-IV-TR psychotic disorder; drug or alcohol abuse or dependence in the preceding 3 months; concurrent 
benzodiazepine medication; high suicide risk; history of clinically defined neurological disorder or insult; metal in 
the cranium or skull defects; skin lesions on the scalp at the proposed electrode sites; and pregnancy. Participants 
on antidepressant medication were permitted to enter the trial provided the medication dose was unchanged for 4 
weeks prior to trial entry and during the acute treatment phase of the study. One participant was withdrawn from 
the study due to too many missed sessions. The remaining 33 participants completed 93% of the scheduled 
sessions in the initial 4-week phase. Ten of thirteen participants (77%) who qualified for the maintenance phase 
opted to continue. Mood improved significantly from baseline (27.5 on MADRS) to 1 month after the end of 
acute treatment (MADRS 15.5; p < 0.001). Side effects reported across a total of 1,149 sessions were minimal, 
primarily mild to moderate tingling or burning/heat sensation during stimulation and redness at the electrode sites. 
This study provides clear, initial evidence that home-based, remotely supervised tDCS treatment is feasible for 
depressed patients and offers a potentially effective intervention. 
 
 
 
 

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Process of Consent 
Potentially eligible individuals (Participants with MDD and their participant caregiver-administrators) will each 
be emailed or snail-mailed (per request, and according to their preference) a copy of the informed consent for 
them to review at their own pace prior to the telephone screening call. Written or verbal  informed consent will be 
obtained by study personnel at the beginning of this in-person screening call, depending on the ability of the 
research team to have personal contact due to the restrictions imposed by COVID-19 precautions. 
Home-use device and training to caregivers 
Alonzo et al. (2019) used a tDCS device that required the placement of individual, large sponge electrodes onto 
the scalp in positions defined by the 10-20 EEG electrode placements (F3 and F8) The large sponge electrodes 
needed to be held in place by elastic bands. The procedure posed substantial challenges and precluded some 
caregivers from achieving appropriate level of competency. In addition, the interface with a programmable device 
for specification of stimulation parameters was challenging and again represented a hurdle for some patient-
caregiver pairs. 
Neuroelectrics has developed a system for home-based tDCS that effectively overcomes these challenges and is 
being used in several studies, e.g. Garcia-Lorrea 2019  https://clinicaltrials.gov/ct2/show/NCT02346396). The 
Starstim Home Kit® (Neuroelectrics Corp) is commercially available and approved in Canada for use in treating 
chronic pain, depression and addictive disorders. It utilizes the company’s industry leading Starstim system, with 
additional features that enable researchers and clinicians to “prescribe” and monitor home-based tDCS to end 
users. Briefly, the Starstim system resembles a swimming cap that fits loosely on the head, but with small 
electrodes that lie on the scalp and deliver low-level electrical currents to targeted brain regions. Within the Home 
Kit, the relevant electrode positions are marked on the headcap with different colors and numbers, and the 
corresponding electrode leads (cables) from the tDCS device are marked with the same colors and numbers. This 
ensures that the user places the electrodes in the correct position and secures the correct lead to each electrode. 
The Home Kit also utilizes a tablet that provides the user with step-by-step instructions to set up the Starstim 
device, check electrode impedance, and record side effects. The user may also videoconference with remote staff 
in real-time. The researcher uses Neuroelectrics online Portal (NE Portal) to remotely schedule sessions and 
monitor in real-time specific treatment events to ensure safety. 
At the Marcus Institute we have developed a training and in-home supervision program to accompany the 
Starstim Home Kit and have established its feasibility in two ongoing studies (one focused on gait and balance 
and the other on episodic memory in dementia). In these studies, to date we have completed the assessments of 
eight participant ‘pairs;’ that is, an individual to receive tDCS along with a family member, friend, or care-giver 
willing and able to administer tDCS. Each potential administrator was initially screened to ensure that they would 
be available throughout the intervention period and to ensure they had at least minimal computer proficiency. 
They were then trained by staff to administer tDCS to the study participant and did so under the supervision of 
staff until they self-reported comfort in the process and were deemed proficient as determined with a custom-
developed checklist. For all eight participant-pairs, the administrators, who ranged in age from 44 to 87, achieved 
proficiency by the third session of tDCS. All but one pair completed at least eight sessions of the 10-session 
intervention. No adverse events were reported. Transient skin redness and tingling sensations under the electrode 
were the only reported side effects and the frequency and severity of these side effects were similar to that 
reported in published staff-administered interventions. Upon exit interview, all administrators—and the 
participants who received the stimulation—stated that the Home Kit and training materials were easy to use, that 

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they were satisfied with the experience and training they received, and that they would be willing to use to system 
again in the future. 

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The above studies utilize in-person training methods until the participant administrator achieves proficiency. For 
the current proposal, a video telemedicine-based training program is available to ensure minimal staff-participant 
contact. Moreover, a pre-configured Starstim system will be shipped directly to the participants with all the 
required supplies and documentation.
Eligibility Criteria:  Patients meeting one of the following criteria may be eligible to participate in 
this study. 
1. Patients with medication-resistant MDD who have undergone rTMS or ECT and responded to it but whose 
benefit has lapsed, and they need repeat a rTMS or ECT course that they cannot access 
 
2. Patients with medication-resistant MDD who have undergone rTMS or ECT and responded to it but whose 
benefit has lapsed, and they need repeat a rTMS or ECT course that they cannot access 
 
3. Patients with medication-resistant MDD who are undergoing rTMS or ECT and responding, but cannot 
continue to get the rTMS or ECT course due to COVID-19 pandemic-related regulations or other access 
concerns 
 
4. Patients with medication-resistant MDD who are referred to rTMS or ECT and are found well qualified 
but cannot access  rTMS or ECT due to COVID-19 pandemic-related regulations or other access concerns. 
 
The benefits of this project address a present need due to the COVID-19 pandemic, but also go beyond the present 
situation and address a larger, pre-existing need.  Across all these potential groups of participants, prospective 
participants will: 
 need to have a primary psychiatrist who agrees to their participation in the study and is willing to continue 
to follow the patient and work collaboratively with the study team 
 
 need to be assessed by their primary psychiatrist to be stable enough to be able to remain at home and 
participate in the present study without undue risk to their safety 
 
 need to be living with an adult willing and capable to provide oversight and learn to deliver the home-
based tDCS 
 
 have the capability to connect with the study team for daily supervision of the intervention sessions and 
close safety monitoring, and be willing to commit to doing so 
 
  

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Inclusion criteria -  Individuals with MDD  
Participants will be men and women who: 
 Are aged 50 or older 
 Able to read, write, and communicate in English 
 Have a caregiver who is willing and able to provide the home tDCS sessions. 
 Participants must be under the care of a treating psychiatrist who approves of the study participation and 
believes that TMS or ECT is indicated for his/her patient but that 
o it would not endanger the patient to participate in the present study rather than pursue such 
alternative, or 
o the patient could not gain access to TMS or ECT due to COVID-19 
(The depression phase of bi-polar disorder is not a reason for exclusion if the treating psychiatrist believes TMS 
or ECT would be indicated). 
 
Participants with MDD must fit into one of the following 3 groups (medication-resistant MDD defined as 1) 
participant’s condition has not responded to prescribed antidepressant medication; 2) participant is medication 
intolerant, or 3) some other underlying reason): 
 Patients with medication-resistant Major depressive disorder (MDD) who have undergone repetitive 
transcranial magnetic stimulation (rTMS) or electroconvulsive therapy (ECT) and responded to it but 
whose benefit has lapsed and they need repeat rTMS or ECT course that they cannot access; 
 Patients with medication-resistant MDD who are undergoing rTMS or ECT and responding, but cannot 
continue to get the rTMS or ECT course due to COVID-19 pandemic-related regulations or other access 
concerns 
 Patients with medication-resistant MDD who are referred to rTMS or ECT and are found well qualified 
but cannot access rTMS or ECT due to COVID-19 pandemic-related regulations or other access concerns. 
 
Further, participants must: 
 Meet criteria for a diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental 
Disorders (DSM-IV-TR) (American Psychiatric Association, 2000), as determined via an tele-health 
interview with a study psychiatrist, and confirmed with the Mini International Neuropsychiatric Interview 
(MINI; Version 5.0.0) (Sheehan et al., 1998) and the prospective participant’s primary psychiatrist. 
 Currently experiencing a major depressive episode of at least four weeks’ duration as part of a unipolar or 
bipolar depression. Score will need to be at least 20 on the MADRS. 
 
Participant caregiver-administrators:
Caregiver-administrators will be men and women, who may be a spouse, family member or friend who is 
 At least 21 years of age 
 Able to read, write, and communicate in English 
 Self-reported computer proficiency and willingness to learn how to use tDCS as defined by "yes" answers 
to the questions "Do you feel comfortable using a computer?" and "are you willing to learn 
 How to administer tDCS?" Stated availability throughout the study period to administer tDCS sessions to 

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the participant with MDD. 
 
Exclusion criteria for participants with MDD will be: 
 Any DSM-psychotic disorder 
 Drug or alcohol abuse or dependence in the preceding three months;  
 Concurrent benzodiazepine medication; 
 High suicide risk (Utilizing the Beck Depression Inventory and the Hamilton Depression Scale, suicide 
risk will be assessed at baseline by the study psychiatrist) ; 
 History of clinically defined neurological disorder or insult; Metal in the cranium or skull defects; 
 Skin lesions on the scalp at the proposed electrode sites;  
 Pregnancy. 
 Medical devices (i.e. cardiac pacemaker, deep brain stimulator, medication infusion pump, cochlear 
implant, vagus nerve stimulator). 
 Previous skull surgery with resultant skull defects 
 Inability to understand study procedures following review of the Informed Consent form.  
 
Understanding will be assessed by asking the participant with MDD to answer the following three 
questions: 
 
1) What is the purpose of this study? 
 
2) What are the risks of study involvement?  
 
3) If you decide to participate, are you allowed to withdraw from the study at any time?  
 
Answers will be recorded by study personnel on the "Assessment of Protocol Understanding" form.   
 
Insufficient understanding will be defined by one or more incorrect answers, as determined at the 
 
discretion of the investigator. 
Exclusion criteria for Participant caregiver-administrators: 
 Poor eyesight,  
 Severe arthritis in the hands, pain, deformity or other condition that interferes with successful 
administration of tDCS. 
 Inability to understand study procedures following review of the Informed Consent form.  
 
 
Understanding will be assessed by asking the participant caregiver-administrator to answer the following 
 
three questions: 
 
 1) What is the purpose of this study?  
 
2) What are the risks of study involvement?  
 
3) If you decide to participate, are you allowed to withdraw from the study at any time?  
 
Answers will be recorded by study personnel on the "Assessment of Protocol Understanding" form (see 
 
attached). Insufficient understanding will be defined by one or more incorrect answers, as determined at 
 
the discretion of the investigator
 

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 Adverse Events 
An adverse event is any untoward medical occurrence in a participant, whether or not is is causally related to the 
study. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease temporally associated with the study. 
Adverse events will be recorded on the appropriate case report forms and source documents. The investigator 
and/or trained staff member will evaluate all adverse events as to their severity and relation to the test article. The 
severity of adverse events will be graded as follows: 
Mild: Awareness of a sign or symptom but easily tolerated. 
Moderate: Discomfort sufficient to cause interference with usual activity or to affect clinical status. 
Severe: Incapacitating with inability to do usual activity or to significantly affect clinical status. 
Life Threatening: The participant was at immediate risk of death from the adverse event as it occurred. 
The Investigator will also assess the relationship of any adverse event to study, based upon available information, 
using the following guidelines: 
0 = Unlikely: No temporal association, or the cause of the event has been identified. 1 = Possible: Temporal 
association, but other etiologies are likely to be the cause; however, involvement of the study procedures cannot 
be excluded. 
2 = Probable: Temporal association, other etiologies are possible, but not likely.  
 
A serious adverse event is any experience that results in any of the following outcomes: death,is life threatening, 
results in inpatient hospitalization or prolongation of hospitalization, a persistent or significant 
disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the 
patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
Side effects associated with tDCS according to the most recent data available (Brunoni, Fregni, & Pagano, 2011; 
Nitsche et al., 2008; Antal et al, 2007; Moliadze, Antal, & Paulus, 2010; Brignani, Ruzzoli, Mauri, & Miniussi, 
2013) are: 
Sensations reported by subjects under the electrodes: (These sensations can sometimes continue throughout and 
for a brief period following completion of the tDCS but usually resolve shortly after the initiation of tDCS) 
Mild tingling (20-70% 
Light itching (30-40%) 
Slight burning (10-22%) Discomfort or mild pain (10-18%) 
Other effects that can occur both during and after tDCS include: Skin redness (20%) 

Page 13 of 22 
 
Mild fatigue (15%) 
Headache (10-15%) 
Difficulties in concentration (11%) 
Additionally the following rare side effects have been described: Nausea (<1%) 
Nervousness (<1%) 
Although it has never been reported in tDCS, seizures are a theoretical risk. Individuals with a history of seizures 
and/or a diagnosis of epilepsy will therefore be excluded from this study. EEG has not associated adverse events 
and is considered safe and painless. 
 
All adverse events, Serious Adverse Events and Unanticipated Problems will be reported to the Advarra IRB 
according to its policies. 
References: 
Antal, A., Brepohl, N., Poreisz, C., Boros, K., Csifcsák, G. & Paulus, W. Transcranial direct current stimulation 
over somatosensory cortex decreases experimentally induced acute pain perception. Clin J Pain 2008; 24(1):56-
63. http://doi.org/10.1097/AJP.0b013e318157233b Brignani, D., Ruzzoli, M., Mauri, P., & Miniussi, C. (2013). Is 
transcranial alternating current stimulation effective in modulating brain oscillations? PloS One, 8(2), e56589. 
http://doi.org/10.1371/journal.pone.0056589 Brunoni, A. R., Fregni, F., & Pagano, R. L. (2011). Translational 
research in transcranial direct current stimulation (tDCS): a systematic review of studies in animals. Reviews in 
the Neurosciences, 22(4), 471â481. http://doi.org/10.1515/RNS.2011.042 Moliadze, V., Antal, A., & Paulus, W. 
(2010). Boosting brain excitability by transcranial high frequency stimulation in the ripple range. The Journal of 
Physiology, 588(Pt 24), 4891â4904. http://doi.org/10.1113/jphysiol.2010.196998 Nitsche, M. A., Cohen, L. G., 
Wassermann, E. M., Priori, A., Lang, N., Antal, A., & Pascual-Leone, A. (2008). Transcranial direct current 
stimulation: State of the art 2008. Brain 
Stimulation, 1(3), 206â223. http://doi.org/10.1016/j.brs.2008.06.004 
Risks 
The medical risks are described in the adverse event section. Other risks related to the loss of confidentiality are 
described in the confidentiality section with steps we will take to mitigate any such risk. 
Participant Burden: Participation in this protocol will require moderate subject time and effort. Therefore, in 
addition to recommended safety measures described below, additional efforts will be taken to minimize subject 
burden and maximize retention throughout the study. It is of note that our study team has a strong track record of 
successful clinical research requiring similar participation and retention has been high in these efforts. 
Several strategies will be employed to minimize subject burden and maximize adherence to the protocol. 
Specifically we will: 
 Develop a personal relationship between subjects and members of the staff by matching research assistants 
with individual participants. 
 Schedule appointments at convenient times with familiar staff. 
 Explain to subjects all aspects of their participation. 

Page 14 of 22 
 
 Provide reminders of all appointments. 
 Include personal notes in the subject's data file to remember events in the life of the participant; these can 
be commented on at future visits (e.g. birth of a grandchild)
Any participant who suffers an adverse event during the conduct of study protocols will be triaged immediately 
by the medical investigators, and the study psychiatrist.  The study PI and study psychiatrist will monitor and 
manage all study related A/E’s.  If follow up care is needed to treat an A/E, the investigators will arrange to have 
this care provided at a nearby institution, convenient to the study participant. . The treating provider will bill the 
insurance company or other third parties, if appropriate, for the care a participant receives for any injury. We will 
try to have these costs paid for, but the participant may be responsible for some of them. For example, they may 
be responsible for payment of any deductibles and co-payments required by the insurer. There are no plans to 
provide any compensation for an injury beyond what is described above, should one occur. 
If there is a change in the clinical condition of the participant, the study psychiatrist will contact the subject’s 
treating/primary psychiatrist so that appropriate primary clinical care can be provided. 
If, during the course of this study, the participant experiences an urgent medical need, he/she will be advised to seek 
immediate medical care, including contacting their primary care physician/psychiatrist as indicated. 
 
There is no cost to the participant or insurer for the device. 
 
Benefits 
While there are no definitive benefits to participants as a result of participation in this study, MDD participants 
who received tDCS interventions in prior studies showed improvement of symptoms.
Most recently, Razza et al. (2020) completed a systematic review of all studies of tDCS for treatment of acute 
major depressive episodes completed up to January 2020. They included all randomized, sham‐controlled clinical 
trials (RCTs) enrolling participants with an acute depressive episode, a total of 23 RCTs with 1,092 participants. 
They found that active tDCS was superior to sham regarding endpoint depression scores, response and remission 
rates. Moreover, active tDCS was safe with a side-effect profile comparable to sham. 
Moffa et al. (2020) also recently published an individual patient data (IPD) meta-analysis evaluating the efficacy 
and acceptability of tDCS for treatment of acute major depressive episodes. The IPD meta-analysis is more 
accurate in estimating the efficacy of an intervention and also superior to the aggregated data approach for 
obtaining predictors of treatment outcome since it uses the raw data of each participant collected from each study 
(Riley et al., 2010). Moffa et al. included data from all published placebo-controlled trials on tDCS as only 
intervention in MDD conducted until December-2018. This included 9 eligible studies with a total of 572 
participants. They found active tDCS to be significantly superior to sham for an antidepressant response (30.9% 
vs. 18.9% respectively; OR = 1.96), remission (19.9% vs. 11.7%, OR = 1.94), and depression improvement 
(effect size β = 0.31). Moreover, they found a consistent continuous clinical improvement after the end of the 
tDCS treatment course. It is noteworthy that the clinical efficacy was substantially higher in the studies where the 
tDCS course was longer (3-4 weeks versus 1-2 weeks). 

Page 15 of 22 
 
The ultimate goal of this work is to identify the potential of tDCS as a home therapy to induce improvements of 
MDD for patients with the disease. We anticipate that this specific study will demonstrate that remote tDCS 
sessions are feasible in this population, and offer an important and convenient alternative for multi-session tDCS 
administration in adults with MDD. 
 
Visits (All visits will be conducted remotely) 
For this study, participant caregiver administrators will be provided remote step-by-step training to administer the 
tDCS sessions to the participants with MDD. Participant caregiver-administrators will be directly supervised 
remotely, until they demonstrate proficiency, without coaching by the study team. We have developed a step by 
step training manual, and have successfully trained older adult caregivers to administer the tDCS. 
 
 
Visit 
Purpose 
Procedures 
Study 
personnel 
Duration 
Location 
Pre-ICF  Advance 
review  
Informed consent pre-review by 
potential participants 
RA will send 
As needed 
for review 
Mailed/emailed 
to P 
Visit 1 
Remote 
screen and 
assessment 
visit 
Informed consent 
[P with MDD] 
 Mental Health/Medical health 
history; medications; Cognitive 
Assessment;   Interview with 
study psychiatrist 
[Participant 
caregiver-administrators] 
Health history; computer 
proficiency questionnaire 
[Both participants] tDCS 
overview and training 
Study research 
assistant; 
Study 
psychiatrist 
~ 1 hour 
Remote  
Home tDCS administration Treatment period – Daily tDCS sessions over 4 weeks *Participant ratings of 
suicidality will be completed each day, and responses will be monitored and immediately be reviewed in 
real time by the study RA and study psychiatrist. Any changes from baseline will result in an immediate 
contact to the participant by the study psychiatrist. 
 
Week 
(Wk)1; 
Day (D) 
1 
Home-based 
tDCS 
At-home tDCS equipment set-
up; tDCS administration by 
caregiver-administrator with 
step-by- step remote training by 
study staff Daily diary 
Study research 
assistant 
1 hour total 
(tDCS 
session=30 
mins) 
Video 
conference 
Wk1, 
tDCS 
session 
Home-based 
tDCS once a 
day 
tDCS admin by the caregiver-
administrator with remote staff 
oversight and coaching Daily 
Study research 
assistant 
1 hour total 
(tDCS 
session=30 
Video 
conference 

Page 16 of 22 
 
D 2-4 
diary 
mins) 
Wk 1, 
tDCS 
session 
D 5 
Home-based 
tDCS 
tDCS admin by the caregiver-
administrator with remote staff 
oversight and coaching; Staff 
administered skills test for 
caregiver-administrators Daily 
diary 
Study research 
assistant 
1 hour total 
(tDCS 
session=30 
mins) 
Video 
conference 
Wk 1-4; 
D6-28 
Home-based 
tDCS once a 
day 
The caregiver-administrator 
will administer the in-home 
tDCS session with remote staff 
monitoring and video 
conferencing if necessary Daily 
diary 
Study research 
assistant 
1 hour 
Participant’s 
Home 
Wks 1-
4,  
D 7, 14, 
21, and 
28 
Weekly 
assessments 
Participants with MDD only 
Week 1-4 Assessment 
completion (Day 7, 14,21, and 
28); depression symptoms and 
quality of life assessments 
Study research 
assistant 
30 minutes 
Phone 
Home tDCS administration Treatment taper period – weeks 5-8 Participant ratings of suicidality will be 
completed each day, and responses will be monitored and immediately be reviewed in real time by the 
study RA and study psychiatrist. Any changes from baseline will result in an immediate contact to the 
participant by the study psychiatrist. 
 
Wk 5, D 
30,32,34 
Home-based 
tDCS 
Total of 3 
sessions, one 
every other 
day over a 6 
day period. 
The caregiver-administrator 
will administer the in-home 
tDCS session with remote staff 
monitoring and video 
conferencing if necessary Daily 
diary 
Study research 
assistant 
1 hour 
Participant’s 
Home 
Wk 6-7, 
D 37,40, 
43 
Home-based 
tDCS Total of 
3 sessions, 
one every 
third day over 
a 9 day period 
The caregiver-administrator 
will administer the in-home 
tDCS session with remote staff 
monitoring and video 
conferencing if necessary Daily 
diary 
Study research 
assistant 
1 hour 
Participant’s 
Home 
Wk 8 
D 47,51, 
55 
Home-based 
tDCS Total of 
3 sessions, 
one every 
fourth day 
over a 12 day 
The caregiver-administrator 
will administer the in-home 
tDCS session with remote staff 
monitoring and video 
conferencing if necessary Daily 
diary 
Study research 
assistant 
1 hour 
Participant’s 
Home 

Page 17 of 22 
 
period 
Wks 5-8 
D35, 42, 
49, 56 
Weekly 
assessments 
Participants with MDD only 
Weeks 5-8 Assessment 
completion (Day 35, 42,49, and 
56); depression symptoms and 
quality of life assessments 
Study research 
assistant 
30 minutes 
Phone 
Home tDCS administration completed after Week 8, Day 55 session. Return of Home tDCS 
equipment to research team in the provided shipping materials and label. 
Four week follow-up period – weeks 9-12 
Wks 9-
12 
D57-84 
Four week 
follow-up 
period 
Participants with MDD only 
The study research assistant 
will maintain weekly contact 
with the participant over the 4 
week follow-up period 
Study research 
assistant 
20 minutes 
Phone 
Week 
12, Day 
84 
Final study 
assessment 
Both participants: Final 
assessment completion, 
depression symptoms, quality 
of life assessments, cognitive 
assessment 
Study research 
assistant 
1 hour 
Phone 
End of study: Results sent to participant with MDD and treating psychiatrist 
Daily sessions (28 daily sessions): The device will be used to apply 20 minutes of tDCS to the participant 
with MDD's scalp in each of 28 daily sessions.   
 
Thereafter, participants with MDD will undergo a taper phase of an additional 9 sessions of tDCS applied in 
progressively decreasing frequency until day #60 of the study as follows: 
(1) First taper phase: three 30 minutes tDCS sessions applied every other day; 
(2) Second taper phase: three 30 minutes tDCS sessions applied one every third day; 
(3) Third and final taper phase: three final 30 minutes tDCS sessions applied one every fourth day. 
 
The study team will predetermine, with the participant team, their most convenient two hour window for the 
home administration.  During remote tDCS administration, the study team will be notified electronically by 
email when the tDCS session has been started and also when it has been completed, or if the tDCS session 
was aborted, or not completed during the predetermined two hour window. 
 
The device will contain a sequence of simplified screen prompts for the participant,. To move to the next 
screen the participant will press a circle on the screen to continue (or to stop) 
For example: 
1. Hello 
2. Battery status is GOOD 
3. Today is Monday (date) It is now ( ) o'clock 
4. Wear the Cap 

Page 18 of 22 
 
5. Check the electrodes - 1 green is in the 1 green hole and secure, 2 yellow is in the 2 yellow hole and 
secure. 
6. Are you ready for your 30 minutes session? If yes, press continue 
7. Session has started, please stay in place until session is over [clock appears on screen to count down 
the minutes] 
8. Session has ended, please stay in place while the device powers off. 
9. Session is now completed! You may turn off the tablet, and remove the cap and  electrodes 
 
Daily sessions (28 daily sessions): The device will contain a block that will only allow one session to be 
administered within a 24 hour period. If a session is started and aborted, the participant will not be able to 
administer a new session until the next day, 24 hours later. 
 
During the taper phase - the device block will only allow: 
 
First taper phase: Three sessions, one every other day. If a session is started and aborted, the participant 
will not be able to administer a new session until 48 hours later. After the 3 sessions have been 
administered, (which will include any session that was started and aborted), a new session will not be 
available until the next scheduled session. The study team will monitor participant study adherence through 
completed sessions and through video conferencing and telephone contact. 
 
Second taper phase: Three sessions, once every third day. If a session is started and aborted, the participant 
will not be able to administer a new session until 72 hours later. After the 3 sessions have been 
administered, (which will include any session that was started and aborted), a new session will not be 
available until the next scheduled session. The study team will continue to monitor participant study 
adherence through completed sessions and through video conferencing and telephone contact. 
 
Third and final taper phase: Three sessions, once every fourth day. If a session is started and aborted, the 
participant will not be able to administer a new session until 96 hours later. After the 3 sessions have been 
administered, (which will include any session that was started and aborted), the sessions will be completed. 
 
Statistical Methods and Analysis 
 
Primary  
Feasibility and tolerability/safety will be evaluated using home-based data as it is collected by reported number 
of aborted sessions. 
 
The primary outcome will be change in the observer rated MADRS score from baseline to the 1-month follow-
up.  
 
Clinical response is defined as ≥ 50% improvement in MADRS score from baseline to the 1-month follow-up.
Remission is defined as a MADRS score ≤ 10. 
 
The secondary outcome measures will include the participant-rated Quick Inventory of Depressive 
Symptomatology (QIDS-SR) (Rush et al., 2003) and the Quality of Life Enjoyment and Satisfaction 
Questionnaire Short Form (Q-LES-Q-SF) (Endicott et al., 1993), both administered at the same time points as 
the MADRS. A computer-based cognitive test battery, CogState (https://www. cogstate.com), will provide an 
additional safety outcome measure. This battery includes tests designed to assess verbal learning and memory 
(International Shopping List Task), attention and psychomotor function (Detection Task), visual attention 
(Identification Task), visual learning and memory (One Card Learning Task), working memory (Two Back 
Task), and executive function (Set Shifting Task). 
 
Statistics 

Page 19 of 22 
 
 
Primary Analysis Plan for efficacy 
The primary outcome measure is the median percentage change (across study subjects) in s MADRS from 
baseline to 1 month follow up. The significance of changes will be assessed using the non-parametric Wilcoxson 
signed-rank test; however, since this is a pilot study to determine effect sizes, demonstration of a significant 
effect is not a defined goal of the study. 
 
Sample Size 
The samples size of 50 is well within the sample size of previous published studies. 
Withdrawal and Stopping the study 
 
The criteria for discontinuing a participant's participation include the participant's request, as well as any 
unexpected life-threatening or potentially disabling event. 
 
A study subject may be withdrawn from the study at any time if the study subject, the investigator, or the 
Sponsor feels that it is not in the study subject’s best interest to continue. 
 
All study subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
Reasonable attempts will be made by the investigator to provide a reason for study subject withdrawals. The 
reason for the study subject’s withdrawal from the study will be specified in the study subject’s source 
documents. 
Stimulation Stopping criteria
Subject stimulation will be stopped if any of the following occur during the 8-week treatment period: 
 
 Clinician impression of substantial worsening of medical condition  
 If the study subject misses more than 10 stimulation visits. 
 
Study subjects will be withdrawn from the study for the following: 
 
 If the study subject is not compliant with the study procedures as determined by the 
investigator. 
 
 If, in the investigator’s opinion, it is not safe for the study subject to continue with participation in the 
study. 
 
 If the study subject is withdrawn from the study, the subjects treating psychiatrist will be notified 
so that arrangements can be made for continued treatment of his/her MDD. 
 
 The study team will be notified by email immediately if the subject reports any adverse events during 
any tDCS stimulation session, and immediate follow up will occur. 
 
 Any adverse events that take place during testing will be reported to the PI (Dr. Alvaro Pascual-
Leone )and recorded in the database. Drs. Pascual-Leone, Metzger and Lipsitz will have primary 
responsibility for monitoring participant safety in the trial. The investigators will be responsible for 
reviewing each adverse event in a timely fashion and preparing a summary report for submission to 
the IRB. 
 
 

Page 20 of 22 
 
Data storage and confidentiality  
Data will be kept on a secure, password protected HSL server in a REDCap Database. Only study members 
at the HSL site will have access to the HSL REDCap database. All hard copy forms will be kept in a locked 
filing cabinet that only study members will be able to access.  All policies and procedures of Hebrew Senor 
LIfe with regard to data storage will be followed.   
Data collected will be stripped of identifiers. Data will be assigned a code number and no personal 
identifying information will be associated with study data in any format, including electronically. Only the 
investigators will know information about a particular subject. Identifying information about a subject will 
be stored in locked computer files and cabinets and will not be used during the discussion, presentation, or 
publication of any research data. 
Results of the study will be shared with the participant’s psychiatrist if the participant has given study staff 
permission to do so.
 
 
 
 
 

Page 21 of 22 
 
 
List of Assessments and forms: 
 
Sociodemographic form_2 8619.docx 
 
Medical History Questionnaire_1 92718.docx 
 
Medication Review Form_1 92818.docx 
 
Q_LES_Q_SF.docx 
 
QIDS_SR.pdf 
 
Suicide Risk Assessment Protocol.pdf 
 
tDCS Eligibility Questionnaire_41220.docx 
 
001_Coverletter-Depression.docx 
 
002_HOME_tDCS_MDD_STUDY_04_07_2020_v1.0.docx 
 
003_Annex I- Safety Analysis of tDCS in Craniotomies.docx 
 
004_Annex II-Home based tDCS for MDD Training Manual.docx 
 
005_Annex III-Caregiver tDCS Competency Checklist.docx 
 
006_Annex IV-SPR0157_lDLPFC_DepressionHome.pdf 
 
Assessment of Understanding Protocol_mdd.docx 
 
tDCS Side Effects Questionnaire_mdd.docx 
 
FDA IDE approval letter G160208-S003.Letter.NEWS.APPR (002).pdf 
Evaluation Form Home based tDCS in MDD_Caregiver-administrator.docx 
 
Revised CPQ_v1.docx 
 
Proxy and Medical care Info.792019.docx 
 
Evaluation Form Home based tDCS in MDD_v2PMDD.docx 
 
PhoneScreenQuestionnaire_Caregiver-administrator_clean.docx 
 
PhoneScreenQuestionnaire_PMDD_v2_5420.docx 

Page 22 of 22 
 
 
tDCS Eligibility Questionnaire_41220.docx 
 
Home based tDCS MDD Training Manual v5 5120.docx 
 
MADRS.pdf 
 
Evaluation Form Home based tDCS in MDD_v2PMDD.docx 
 
Caregiver-administrator tDCS Competency Checklist_1 5120