The authors would like to thank collaborators at City College of New York and Soterix Medical for their assistance and support.

All procedures and device protocols have been approved for human subjects by institutional review boards at both Stony Brook University and New York University Langone Medical Center.
1. Participant Recruitment and Screening
<ol>
	<li>Recruit potential participants via referrals from IRB approved study physicians.</li>
	<li>Contact participants and perform a pre-screening to confirm basic eligibility before the baseline study visit (see Supplemental File 1).
	<ol>
		<li>Assess cognitive competency via remote administration of a cognitive functioning test, (e.g. the symbol digit modalities test or SDMT)14. Exclude participants who score below three standard deviations of the healthy normative mean in their age group due to concerns regarding their cognitive capacity to comply with the study protocol.</li>
		<li>Briefly assess the potential participant&#39;s medical history over the phone. Assess inclusion and exclusion criteria. Exclusion criteria can be broad based on a recent consensus safety paper1. Assess the following portion of the inclusion criteria, including that patients must be 18 years or older and have the following: the understanding and ability to give consent, adequate home facilities to store equipment and perform RS-tDCS sessions, clearance for all study procedures by a study physician, and stable internet access at home. 
		NOTE: Allot sufficient time for the baseline visit so that the study physician may clear the potential participant. At least 3 hours are typically needed to complete all baseline procedures, questionnaires, and neuropsychological tests in the current iteration of this study protocol.</li>
		<li>Rate each patient&#39;s disease related disability (e.g., the Expanded Disability Status Scale (EDSS)15 score for MS patients only). Participants with severe disability (e.g. an EDSS score above&#160;6.5) will complete daily tDCS sessions with the aid of a healthcare proxy. The healthcare proxy will complete, on behalf of the participant, the device and headstrap preparation steps that require more advanced ambulation.</li>
		<li>In sham-control studies, randomize the participant to either the active or sham condition, as dictated by the blocked stratification table. The table stratifies participants based on the cognitive functioning and disability ratings collected during pre-screening16. Any study using sham should be double-blinded and have an un-blinded study technician, who will not supervise the participant&#39;s daily sessions, assign the condition, and prepare study devices for participants and study personnel.</li>
	</ol>
	</li>
</ol>
2. Baseline Study Visit
<ol>
	<li>Administer neuropsychological assessments and self-report questionnaires.
	<ol>
		<li>Choose relevant neuropsychological assessments (such as the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)17, based on the respective patient population. Administer measures and assess the motor and cognitive abilities of participants.</li>
		<li>Administer self-report questionnaires relevant to symptoms that are specific to the patients&#39; disease. For example, the Unified Parkinson&#39;s Disease Rating Scale (UPDRS)18 is a widely used clinical self-assessment questionnaire measuring Parkinson&#39;s specific symptoms. Likewise, the Multiple Sclerosis Neuropsychology Questionnaire (MSNQ) is designed and validated to measure neuropsychological competence in daily living specifically in patients with multiple sclerosis19,20. Administer universal symptom rating inventories (such as the Patient-Reported Outcomes Measurement Information System (PROMIS)21 and the Positive and Negative Affect Schedule (PANAS)22) to allow for comparison between patient populations.</li>
	</ol>
	</li>
</ol>
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/56211/56211fig1.jpg" /> 
Figure 1: Left anodal DLPFC montage used in both studies.&#160;The red and blue patches are modeled representations of the left anode and right cathode, respectively, placed upon a scalp. <a href="//cloudfront-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/56211/56211fig1large.jpg">Please click here to view a larger version of this figure.</a>
<ol start="2">
	<li>Instruct and train participants to self-administer tDCS.
	<ol>
		<li>Show participants an instructive tDCS training video that details the entire step-by-step process of administering the stimulation.</li>
		<li>Ask participants to prepare the headstrap with guidance from study personnel. The headstrap holds the sponge electrodes in position throughout the duration of the stimulation session.
		<ol>
			<li>Have participants attach the sponges, which are pre-moistened with 5-mL of saline solution, to the cable electrodes.</li>
			<li>Instruct participants to place the headstrap upon their head, taking care to align the nasion marker on the front of the headstrap with the bridge of their nose.</li>
			<li>Have participants pull the back the headstrap towards the posterior end of their heads so the back of the headstrap rests over their inion. The Dorsolateral Prefrontal Cortex (DLPFC), left anodal tDCS montage is used23,24,25,26,27.</li>
			<li>Confirm that the participant has achieved optimal or moderate contact quality before continuing. 
			NOTE: The device dynamically adjusts its voltage depending on the entire resistive path between the anodal and cathodal electrodes (including skin and skull impedance) to deliver consistent amperage. The device will not unlock to release the stimulation if the contact quality is poor or the impedance is too high.</li>
			<li>If a participant has a poor or moderate contact quality then suggest methods to improve contact quality, such as adding saline to the sponges, adjusting headstrap placement, or brushing hair away from electrode sites. The participant can monitor their own contact quality by looking at the device&#39;s interface screen.</li>
			<li>Assess the participant&#39;s aptitude to complete study procedures to determine whether they understand and can replicate the procedures competently at home.</li>
		</ol>
		</li>
		<li>Participants complete a tolerability test lasting 90 seconds to determine whether they are able to comfortably tolerate 2.0 mA of direct current. If a participant finds they are unable to handle 2.0 mA, lessen the amperage to 1.5 mA, and further to 1.0 mA if deemed necessary. If a participant finds 1.0 mA intolerable, they must be discontinued from the study.</li>
	</ol>
	</li>
	<li>Conducting the first tDCS session in-clinic.
	<ol>
		<li>Ask the participant, after preparing the headstrap and prior to beginning the stimulation session, to report the duration of sleep from the previous night as well as any pain experienced due to the stimulation, disease specific pain, fatigue, and mood before the session with the aid of visual analogue scales.</li>
		<li>Confirm that the contact quality is still optimal or moderate. Provide the device unlock code to begin the participant&#39;s stimulation session.</li>
		<li>Begin stimulation and deliver a tolerable amount of stimulation (as detailed above) for an intended twenty minutes. The stimulation&#39;s length depends upon the parameters set by the study; for all studies presented herein, the stimulation length was twenty minutes. Should the participant be randomized to the sham condition, the participant receives only one minute of stimulation at the beginning of the session and at the end of the session, during which the amperage ramps up to the target tolerable amount of stimulation during the first thirty seconds and then ramps back down to 0 mA in the final thirty seconds, in order to convince participants that they are receiving stimulation. Aside from the first and last minute, sham participants receive no stimulation for 18 minutes.</li>
		<li>Participants complete cognitive remediation with guidance from the study technician. The cognitive remediation may be swapped out for a different remediation strategy depending on the intended goals of the study. Similarly, the length of the remediation strategy may be modified. 
		NOTE: Stimulation can be halted at any time by pressing &#34;zero&#34; on the device which immediately begins to abort stimulation by ramping down to 0 mA. Study technicians instruct participants to abort the session and end stimulation when any pain is reported above a 7 on a 1-10 visual analogue scale or if any other emergency situation occurs.</li>
		<li>After ten minutes, ask the participant whether they are experiencing any pain from the stimulation. Study technicians monitor placement through the videoconferencing software to determine that electrode placement does not shift and remains acceptable during the stimulation session.</li>
		<li>After an additional ten minutes, the pre-programmed tDCS device powers down and stimulation ceases. The device makes a loud beeping noise to notify the participant that the stimulation has ended. Should the participant have the sham condition, then the device ramps up once again during the final minute of the twenty-minute session to provide thirty seconds of the target stimulation current and then ramps down to 0 mA during the final thirty seconds of the session.</li>
		<li>Ask the participant once more to report their pain due to the device, disease specific pain, fatigue, and mood following the session, as well as any adverse events that may have been experienced during the course of the session.</li>
		<li>Plan a regular time for the remaining study sessions to ensure daily consistency for standardization purposes. Additionally for PD patients, coordinate session times so that stimulation takes place within 1-3 hours of their last dose of PD medication - a time window that study-approved physicians determined would provide maximum benefit in accordance with previous evidence showing greater improvement among Parkinson&#39;s patients in cognitive and motor dimensions (as measured by the Unified Parkinson&#39;s Disease Rating Scale, or UPDRS) when tDCS was delivered during participants&#39; &#34;on&#34; drug state vs. &#34;off&#34; drug state11.</li>
	</ol>
	</li>
</ol>
3. At-home tDCS Sessions
<ol>
	<li>Participants complete computer preparation prior to study sessions.
	<ol>
		<li>Participants connect to the internet in their homes prior to any further study procedures. Participants without stable internet in their homes are excluded from all study procedures.</li>
		<li>Connect to a participant&#39;s computer with the use of remote desktop software28 and engage in HIPAA-compliant video conferencing with the participant29.</li>
		<li>Study technicians administer study outcome measures wherein participants report the amount of sleep they received the previous night and rate pain due to the device, disease specific pain, fatigue, and mood before the stimulation session with the aid of visual analogue scales. Ask the participant to report any adverse events that may have occurred following the previous day&#39;s session (see supplemental files 2 and 3).</li>
	</ol>
	</li>
	<li>Participants remotely activate the stimulation.
	<ol>
		<li>Participants prepare the headstrap by attaching the pre-moistened sponges to the electrodes on the inside of the frontal headstrap. The sponge electrodes easily snap into the headstrap to minimize preparation.</li>
		<li>Participants place the headstrap upon their heads as study technicians monitor placement. Participants report the contact quality, which is tested by the device and assesses the sponge placement and sponge saturation measured by the tDCS device. As previously described, moderate and poor contact quality is remedied by suggestions from study personnel such as adding additional saline solution or checking sponge placement.</li>
		<li>Verbally state the stimulation code that unlocks the device to the participant and allow administration of the stimulation for twenty minutes.</li>
		<li>Should a participant have an EDSS score above 6.5, the healthcare proxy completes the above steps in lieu of the participant.</li>
	</ol>
	</li>
	<li>Participants complete computerized cognitive remediation during the twenty-minute stimulation period. The remediation includes cognitive training tasks that specifically target working memory systems. A previous publication of ours details the cognitive results concerning our first pilot study8.
	<ol>
		<li>After 10 min of stimulation, ask participants to report any pain they may be experiencing.</li>
	</ol>
	</li>
	<li>Participants complete post-session procedures.
	<ol>
		<li>Participants take off the headstrap and dispose of study sponges.</li>
		<li>Ask participants to report any pain due to the device, disease specific pain, fatigue, and mood after the session as well any adverse events that they may have experienced during the session. Record any adverse events that occurred along with their intensity and duration.</li>
		<li>Plan the session for the following day.</li>
	</ol>
	</li>
</ol>
4. Post-stimulation Visit
<ol>
	<li>Administer neuropsychological assessments and self-report questionnaires.
	<ol>
		<li>Schedule the final study visit as soon as possible after the final stimulation session.</li>
		<li>Administer study outcome measures that were completed during the baseline visit a second time to assess whether patients experienced benefit as a result of the stimulation17.</li>
		<li>Obtain and sanitize all study equipment.</li>
	</ol>
	</li>
	<li>Offer participants who were assigned the sham condition the option to complete an additional ten active, open-label, RS-tDCS sessions. This open label study period is modeled after our first tDCS pilot study6.</li>
</ol>
5. One Month Follow-up Survey
<ol>
	<li>Reach out to participants about a month after their study end to ask if they would remotely complete an online survey asking whether they believe benefits received from the stimulation persisted.</li>
</ol>

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The authors have nothing to disclose.

This study employed the DLPFC left anodal montage24, but this could easily be interchanged for another montage and the effects of stimulation may change accordingly. Depending on the location of stimulation, the brain effects and side effects experienced may change1. Stimulation type, such as intended inhibition instead of excitement may influence effects as well. Similarly, the form of remediation paired with stimulation may influence the results of the study31. Future experiments need to be conducted with different remediation strategies paired with RS-tDCS to identify its specific affects.
While the RS-tDCS protocol focuses on providing tDCS to patients in their homes, there may still be a place for stimulation provided in a clinical setting. For example, more complex montages, such as those used by HD-tDCS, may not be feasible at home even with proper training32. The RS-tDCS protocol provides a detailed procedure to ensure clinical trial standards of treatment sessions and dosing control while delivering the stimulation at home using a tele-rehabilitation protocol. Uniform electrode preparation and placement as well as simplified procedures, including the incorporation of simpler sponge electrode techniques, ensure consistency across participants. The RS-tDCS protocol allows for the completion of stimulation sessions by cognitively and physically impaired individuals who otherwise would have great difficulty reaching the clinic daily.
All troubleshooting can be immediately addressed by the study personnel who are live video-conferencing with participants during at-home stimulation sessions. In the case that the study laptop is malfunctioning, a simple restart of the computer can resolve technical issues. In the case that study equipment malfunctions from a laptop or the tDCS device are not resolved following technical support, then study personnel should arrange for the delivery of new, properly functioning equipment.
The protocol is inherently reliant upon internet access, which is the method&#39;s greatest limitation. Currently, those without internet cannot be enrolled in any trial using RS-tDCS. The internet utilized in conjunction with our protocol enables the remote supervision in our RS-tDCS protocol.
RS-tDCS remains one of the few recognized and feasible protocols for at-home delivery of tDCS33. The large volume of sessions completed with the protocol (748 in little over a year), speaks to the effectiveness of the protocol, as other centers have reported smaller and underpowered studies. The RS-tDCS protocol has been effective in providing tDCS directly to patients with a wide range of disabilities. By enabling clinical trials with the RS-tDCS protocol, rapid recruitment and swift trial completion are possible.
The RS-tDCS protocol is generalizable to other neurologic conditions. As demonstrated here, we have already generalized our protocol to PD and plan to demonstrate the applicability of the protocol to other conditions. Both the parameters of stimulation and the remediation strategy can be adjusted to target specific treatment outcomes.

Transcranial direct current stimulation (tDCS) is a type of noninvasive brain stimulation with a wide range of potential therapeutic uses. A mild electrical current (typically &#8804;2.5 mA) is directed through electrodes placed on the scalp to influence brain activity by altering neuronal polarization1. tDCS is typically paired with a rehabilitation strategy in efforts to increase training outcomes. Other popular forms of neuromodulation, such as repetitive transcranial magnetic stimulation, are used to similar ends, but lack key advantages of tDCS such as its portability, simple applicability, and relative inexpensiveness1,2.
Multiple tDCS sessions are required for cumulative clinical benefit1,3. Behavioral effects, such as reductions in fatigue or depressive symptoms, rely upon repeated, consecutive sessions. For instance, studies have only observed such treatment effects after twenty or more sessions4,5.
Typically, tDCS is administered in clinic by a trained clinician or study personnel familiar with the facets and operations of the device and stimulation method. This is costly to both the patient and clinician as significant time, clinic space, and travel are required. As a solution to the need for daily, in-clinic tDCS, we have developed remotely supervised tDCS (RS-tDCS)6. This protocol enables at-home tDCS sessions to be completed through controlled supervision and guidance as provided by study personnel via a study laptop and has the benefit of only requiring two in-clinic visits (baseline and study-end visits) by the participant.
The patient populations chosen to pilot the methodology of this protocol include patients with multiple sclerosis (MS) and Parkinson&#39;s disease (PD). Both diseases impose distinct deficits on the patient, such as symptoms of fatigue in patients with MS and dyskinesia in patients with PD. tDCS presents a unique opportunity to improve symptoms of fatigue7 and cognitive dysfunction8,9,10 as well as to promote motor learning and control11,12. Participants representing a spectrum of disease severity were included in this study with steps taken, as permitted by RS-tDCS, to accommodate their respective disability.
Among these populations, people with MS or PD may have distinct obstacles that prevent them from conveniently reaching the clinic. Motor impairments such as confinement to a wheelchair or cognitive deficits that result in loss of autonomy can limit their inclusion in clinical trials or other cognitive studies. Additionally, familial and professional obligations reduce the time available to attend clinic, limiting availability for cognitive remediation trials confined to the clinic13. These patient populations, due to their diverse range of impairment, serve as model populations to test the limits and feasibility of RS-tDCS.
The RS-tDCS protocol marks a major step in the tDCS field, since it studies the use of stimulation, as it will be administered in a patient&#39;s care at home. The protocol strengthens the rate of recruitment, trial completion rate, relieves patient burden, and minimizes clinical costs. Herein we report the specific details of the protocol as well as preliminary findings regarding the feasibility, safety, and tolerability of the device when remotely administered.

<table><tbody><tr><td>tDCS Mini-CT device</td><td>Soterix</td><td></td><td>Provides direct current stimulation</td></tr><tr><td>EASYstrap with conducting cables</td><td>Soterix</td><td></td><td>Sponges attach to the strap and the strap lays on the head</td></tr><tr><td>EASYpad sponges</td><td>Soterix</td><td></td><td>Premoistened sponges with 5mL of saline. Snaps into electodes.</td></tr><tr><td>Stream laptop</td><td>Hewlett Packard</td><td></td><td>Used for videoconferencing and cognitive remediation.</td></tr><tr><td>Device Charger</td><td>Soterix</td><td></td><td>Recharges the Mini-CT.</td></tr><tr><td>TeamViewer Software</td><td>Teamviewer</td><td></td><td>Remote desktop software that enable remote control of participant&#039;s computers.</td></tr><tr><td>Vsee Software</td><td>VSee Lab, Inc.</td><td></td><td>Enables HIPAA compliant video-conferencing</td></tr><tr><td>Lumosity</td><td>Lumos Labs</td><td></td><td>Online platform used for cognitive remediation</td></tr></tbody></table>

remotely supervised transcranial direct current stimulation: an update on safety and tolerability

The remotely supervised tDCS (RS-tDCS) protocol enables participation from home through guided and monitored self-administration of tDCS treatment while maintaining clinical standards. The current consensus regarding the efficacy of tDCS is that multiple treatment sessions are needed to observe targeted behavioral reductions in symptom burden. However, the requirement for patients to travel to clinic daily for stimulation sessions presents a major obstacle for potential participants, due to work or family obligations or limited ability to travel. This study presents a protocol that directly overcomes these obstacles by eliminating the need to travel to clinic for daily sessions.
This is an updated protocol for remotely supervised self-administration of tDCS for daily treatment sessions paired with a program of computer-based cognitive training for use in clinical trials. Participants only need to attend clinic twice, for a baseline and study-end visit. At baseline, participants are trained and provided with a study stimulation device, and a small laptop computer. Participants then complete the remainder of their stimulation sessions at home while they are monitored via videoconferencing software.
Participants complete computerized cognitive remediation during stimulation sessions, which may serve a therapeutic role or as a &#34;placeholder&#34; for other computer-based activity. Computers are enabled for real-time monitoring and remote control by study staff.
Outcome measures that assess feasibility and tolerance are administered remotely with the aid of visual analogue scales that are presented onscreen. Following completion of all RS-tDCS sessions, participants return to clinic for a study end visit in which all study equipment is returned.
Results support the safety, feasibility, and scalability of the RS-tDCS protocol for use in clinical trials. Across 46 patients, 748 RS-tDCS sessions have been completed. This protocol serves as a model for use in future clinical trials involving tDCS.

One pilot study has been completed using the RS-tDCS protocol at Stony Brook University and a second is currently ongoing at NYULMC. Respective institutional review boards approved all study procedures at both sites.
Since the presented studies were both intended to pilot the RS-tDCS methodology, participants were not selected on the basis on symptoms but instead using broad eligibility criteria for both patients with MS and PD. Similarly, patients who could not tolerate the target amperage of the stimulation were given an option of lower amperage (detailed further below).
Study 1: 
MS participants were recruited through the Lourie Center for Pediatric MS at Stony Brook between the dates of March 2015 and February 2016. This trial was an open-label RS-tDCS study to pilot the feasibility of the protocol in MS. All participants knowingly received 20 minutes x 1.5 mA (or 1.0 mA if 1.5 mA was not initially tolerated) open-label tDCS applied to the DLPFC (left anodal)23,24,25,26,27. During the stimulation, cognitive training games30 targeting attention, information speed, and working memory were completed. The first session was completed at the end of the baseline visit in clinic and the remaining sessions were completed at-home, daily, five days per week (M-F) over the course of two weeks, for a total of nine sessions at home. In total, 26 participants were recruited for this study.
Study 2: 
MS Arm - Participants with MS were recruited through the NYULMC&#39;s MS Comprehensive Care Center between the dates of January 2016 and October 2016. This arm of the study was a randomized, double-blinded, sham-controlled trial using 2.0 mA (or 1.5 mA if 2.0 mA was not initially tolerated) of RS-tDCS applied to the DLPFC (left anodal) for twenty minutes daily. The first stimulation session was completed at the end of the baseline visit in clinic while the remaining nineteen at-home sessions were completed over the following four weeks (M-F). This study is ongoing and we report the findings of 20 MS participants that have been recruited and completed the study.
PD Arm - Participants with PD were recruited through the NYULMC&#39;s Fresco Institute for Parkinson&#39;s and Movement Disorders between the dates of June 2016 and December 2016. This arm&#39;s focus was to pilot the RS-tDCS protocol in patients with PD, similar to the pilot study conducted with MS. The study was open-label, and all participants knowingly received 2.0 or 1.5 milliamps of tDCS applied to the DLPFC (left anodal). Similar to Study 1, the first session was completed at the end of the baseline clinic visit and the remaining nine sessions were completed at the participant&#39;s home remotely (M-F). This study is ongoing and we report the completed findings from 6 PD participants that have been recruited.
To assess the feasibility and tolerability of the RS-tDCS protocol, we measured the percentage of completed sessions, adverse event rates, and the average intensity of the most common adverse events.
A total of 748 RS-tDCS sessions have been successfully completed across 46 participants in approximately a year. This supports the feasibility of the RS-tDCS protocol. In Study 1, 2 participants discontinued tDCS: one participant discontinued due to personal obligations and the other participant discontinued due to study stop criteria of uncomfortable sensations of skin burning greater than a score of 7 (albeit without physical burns). In Study 2, 2 participants were discontinued: one was discontinued due to an abnormal adverse event of &#34;tongue tingling&#34; and the other was discontinued due to a pain rating of 7 (on the 1-10 analog scale) from headaches. From the PD cohort, no patients have been discontinued. In total, 4 patients were discontinued from the study and none of them were discontinued due to an inability to complete the RS-tDCS sessions.
The numbers of adverse events per stimulation type were tallied and their rates of occurrence were calculated. The stimulation types have been placed into four different categories: 1.5 mA open-label, 2.0 mA blinded, 2.0 mA open-label, and the sham condition. The rationale for division into these categories is that participants may have differing interpretations of their sensations depending on what they expected during stimulation. As seen in Figure 1, the three most common adverse events were sensations of skin tingling, itching, and burning (no participants received physical burns).
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56211/56211fig2.jpg" /> 
Figure 2: Rates of adverse events experienced with tDCS.&#160;1.5 mA OL refers to sessions in which participants knowingly received 1.5 mA of open-label tDCS. 2.0 mA BL refers to sessions in which participants were blinded to the stimulation they were receiving which was 2.0 mA tDCS. 2.0 mA OL refers to sessions in which participants knowingly received 2.0 mA of open-label tDCS. Sham refers to sessions in which participants were blinded to the stimulation they were receiving but only received 60 s of stimulation at the beginning and end of the 20 min session in order to simulate active tDCS.&#160;<a href="https://cloudflare-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/56211/56211fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
The average intensity of the most common adverse events has been calculated. As shown in Table 1, the average intensity of the most common adverse events did not exceed a score of 3 (on a 1-10 visual analog scale, 1 being mild and 10 being extreme) for any of the adverse events in any of the stimulation conditions.
<table>
	<tbody>
		<tr>
			<td>Session Condition</td>
			<td>Total Sessions</td>
			<td>Tingling (SD, n)</td>
			<td>Itching (SD, n)</td>
			<td>Burning Sens. (SD, n)</td>
		</tr>
		<tr>
			<td>2.0 mA Blinded</td>
			<td>201</td>
			<td>1.6 (0.8, 75)</td>
			<td>2.2 (0.9, 36)</td>
			<td>2.5 (1.3, 59)</td>
		</tr>
		<tr>
			<td>2.0 mA Open-Label</td>
			<td>104</td>
			<td>1.9 (1.2, 43)</td>
			<td>1.8 (1.1, 8)</td>
			<td>2.0 (1.4, 32)</td>
		</tr>
		<tr>
			<td>1.5 mA Open-Label</td>
			<td>268</td>
			<td>2.4 (2.2, 161)</td>
			<td>2.0 (1.6, 65)</td>
			<td>2.9 (2.0, 79)</td>
		</tr>
		<tr>
			<td>Sham</td>
			<td>175</td>
			<td>1.9 (1.2, 72)</td>
			<td>1.7 (0.9, 17)</td>
			<td>1.6 (1.2, 46)</td>
		</tr>
	</tbody>
</table>
Table 1: Average intensity of commonly experienced adverse events on a visual analog scale (1-10, mild-intense).
The stimulation also shows promise for symptom management as can be seen in Figure 3. Cohen&#39;s d values were calculated for change in mood, fatigue, and pain from baseline to study end for MS patients in studies 1 and 2. PD patients were not included in this analysis due to the small cohort completed to date (n=6). An effect size analysis was employed due to the small sample sizes in each study to identify signals suggesting efficacy. The active sessions in Studies 1 and 2 showed far greater average effect sizes for improvement. On average, participants who received active tDCS reported greater positive effects, and had less negative effects, fatigue, and pain by study end compared to the sham tDCS group.
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/56211/56211fig3.jpg" /> 
Figure 3: Cohen&#39;s d for symptomatic outcome measures. Positive effects were shown by the participants receiving 20 active sessions of rtDCS while the participants in sham group had negligible effects. <a href="https://cloudflare-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/56211/56211fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Remotely Supervised Transcranial Direct Current Stimulation: An Update on Safety and Tolerability at JoVE.com

Remotely Supervised Transcranial Direct Current Stimulation: An Update on Safety and Tolerability

This manuscript provides an updated remote supervision protocol that enables participation in transcranial direct current stimulation (tDCS) clinical trials while receiving treatment sessions from home. The protocol has been successfully piloted in both patients with multiple sclerosis and Parkinson&#39;s disease.

The remotely supervised tDCS (RS-tDCS) protocol enables participation from home through guided and monitored self-administration of tDCS treatment while ...

remotely-supervised-transcranial-direct-current-stimulation-an-update

Universidad San Sebastian

Research

JoVE Journal

Neuroscience

8.0K Views.  Langone Medical Center. This manuscript provides an updated remote supervision protocol that enables participation in transcranial direct current stimulation (tDCS) clinical trials while receiving treatment sessions from home. The protocol has been successfully piloted in both patients with multiple sclerosis and Parkinson's disease.

Video: Remotely Supervised Transcranial Direct Current Stimulation: An Update on Safety and Tolerability

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that delivers weak electric currents through the scalp. This constant electric current induces shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Although tDCS has most of its neuromodulatory effects on the underlying cortex, tDCS effects can also be observed in distant neural networks. Therefore, concomitant EEG monitoring of the effects of tDCS can provide valuable information on the mechanisms of tDCS. In addition, EEG findings can be an important surrogate marker for the effects of tDCS and thus can be used to optimize its parameters. This combined EEG-tDCS system can also be used for preventive treatment of neurological conditions characterized by abnormal peaks of cortical excitability, such as seizures. Such a system would be the basis of a non-invasive closed-loop device. In this article, we present a novel device that is capable of utilizing tDCS and EEG simultaneously. For that, we describe in a step-by-step fashion the main procedures of the application of this device using schematic figures, tables and video demonstrations. Additionally, we provide a literature review on clinical uses of tDCS and its cortical effects measured by EEG techniques.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has shown initial therapeutic effects in several neurological conditions. The main mechanism underlying these therapeutic effects is the modulation of cortical excitability. Therefore, online monitoring of cortical excitability would help guide stimulation parameters and optimize its therapeutic effects. In the present article we review the use of a novel device that combines simultaneous tDCS and EEG monitoring in real time.

Transcranial  direct current stimulation (tDCS) is a technique that delivers weak electric  currents through the scalp. This constant electric current ...

Behavior

Transcranial Direct Current Stimulation and Simultaneous  Functional Magnetic Resonance Imaging

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses weak electrical currents administered to the scalp to manipulate cortical excitability and, consequently, behavior and brain function. In the last decade, numerous studies have addressed short-term and long-term effects of tDCS on different measures of behavioral performance during motor and cognitive tasks, both in healthy individuals and in a number of different patient populations. So far, however, little is known about the neural underpinnings of tDCS-action in humans with regard to large-scale brain networks. This issue can be addressed by combining tDCS with functional brain imaging techniques like functional magnetic resonance imaging (fMRI) or electroencephalography (EEG).
In particular, fMRI is the most widely used brain imaging technique to investigate the neural mechanisms underlying cognition and motor functions. Application of tDCS during fMRI allows analysis of the neural mechanisms underlying behavioral tDCS effects with high spatial resolution across the entire brain. Recent studies using this technique identified stimulation induced changes in task-related functional brain activity at the stimulation site&#160;and also in more distant brain regions, which were associated with behavioral improvement. In addition, tDCS administered during resting-state fMRI allowed identification of widespread changes in whole brain functional connectivity.
Future studies using this combined protocol should yield new insights into the mechanisms of tDCS action in health and disease and new options for more targeted application of tDCS in research and clinical settings. The present manuscript describes this novel technique in a step-by-step fashion, with a focus on technical aspects of tDCS administered during fMRI.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique. It has successfully been used in basic research and clinical settings to modulate brain function in humans. This article describes the implementation of tDCS and simultaneous functional magnetic resonance imaging (fMRI), to investigate the neural basis of tDCS effects.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses weak electrical currents administered to the scalp ...

Electrode Positioning and Montage in Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability2. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation6. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders &#x2013; especially when applied over several consecutive sessions4. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks3,5. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex7. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.

Transcranial direct current stimulation (tDCS) is an established technique to modulate cortical excitability1,2. It has been used as an investigative tool in neuroscience due to its effects on cortical plasticity, easy operation, and safe profile. One area that tDCS has been showing encouraging results is pain alleviation 3-5.

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a ...

Technique and Considerations in the Use of 4x1 Ring High-definition Transcranial Direct Current Stimulation (HD-tDCS)

High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes.
Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.

Technique and Considerations in the Use of 4x1 Ring High-definition Transcranial Direct Current Stimulation HD-tDCS

High-definition transcranial direct current stimulation (HD-tDCS), with its 4x1-ring montage, is a noninvasive brain stimulation technique that combines both the neuromodulatory effects of conventional tDCS with increased focality. This article provides a systematic demonstration of the use of 4x1 HD-tDCS, and the considerations needed for safe and effective stimulation.

High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases ...

Medicine

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS)

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical excitability. With well-established safety and tolerability, tDCS has been found to have the potential to ameliorate symptoms such as depression and pain in a range of conditions as well as to enhance outcomes of cognitive and physical training. However, effects are cumulative, requiring treatments that can span weeks or months and frequent, repeated visits to the clinic. The cost in terms of time and travel is often prohibitive for many participants, and ultimately limits real-world access. 
Following guidelines for remote tDCS application, we propose a protocol that would allow remote (in-home) participation that uses specially-designed devices for supervised use with materials modified for patient use, and real-time monitoring through a telemedicine video conferencing platform. We have developed structured training procedures and clear, detailed instructional materials to allow for self- or proxy-administration while supervised remotely in real-time. The protocol is designed to have a series of checkpoints, addressing attendance and tolerability of the session, to be met in order to continue to the next step. The feasibility of this protocol was then piloted for clinical use in an open label study of remotely-supervised tDCS in multiple sclerosis (MS). This protocol can be widely used for clinical study of tDCS.

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation tDCS in Multiple Sclerosis MS

The goal of this pilot study is to describe a protocol for the remotely-supervised delivery of transcranial direct current stimulation (tDCS) so that the procedure maintains standards of in-clinic practice, including safety, reproducibility, and tolerability. The feasibility of this protocol was tested in participants with multiple sclerosis (MS).

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical ...

The Combined Use of Transcranial Direct Current Stimulation and Robotic Therapy for the Upper Limb

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of daily activities due to lower and upper limb impairments. Intensive physical and occupational therapy are still considered main treatments, but new adjunct therapies to standard rehabilitation that may optimize functional outcomes are being studied.
Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that polarizes underlying brain regions through the application of weak direct currents through electrodes on the scalp, modulating cortical excitability. Increased interest in this technique can be attributed to its low cost, ease of use, and effects on human neural plasticity. Recent research has been performed to determine the clinical potential of tDCS in diverse conditions such as depression, Parkinson&#39;s disease, and motor rehabilitation after stroke. tDCS helps enhance brain plasticity and seems to be a promising technique in rehabilitation programs.
A number of robotic devices have been developed to assist in the rehabilitation of upper limb function after stroke. The rehabilitation of motor deficits is often a long process requiring multidisciplinary approaches for a patient to achieve maximum independence. These devices do not intend to replace manual rehabilitation therapy; instead, they were designed as an additional tool to rehabilitation programs, allowing immediate perception of results and tracking of improvements, thus helping patients to stay motivated.
Both tDSC and robot-assisted therapy are promising add-ons to stroke rehabilitation and target the modulation of brain plasticity, with several reports describing their use to be associated with conventional therapy and the improvement of therapeutic outcomes. However, more recently, some small clinical trials have been developed that describe the associated use of tDCS and robot-assisted therapy in stroke rehabilitation. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

The combined use of transcranial direct current stimulation and robotic therapy as an add-on for conventional rehabilitation therapy may result in improved therapeutic outcomes due to modulation of brain plasticity. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of ...

Transcranial Direct Current Stimulation (tDCS) in Mice

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique proposed as an alternative or complementary treatment for several neuropsychiatric diseases. The biological effects of tDCS are not fully understood, which is in part explained due to the difficulty in obtaining human brain tissue. This protocol describes a tDCS mouse model that uses a chronically implanted electrode allowing the study of the long-lasting biological effects of tDCS. In this experimental model, tDCS changes the cortical gene expression and offers a prominent contribution to the understanding of the rationale for its therapeutic use.

Transcranial Direct Current Stimulation tDCS in Mice

Transcranial direct current stimulation (tDCS) is a therapeutic technique proposed to treat psychiatric diseases. An animal model is essential for understanding the specific biological alterations evoked by tDCS. This protocol describes a tDCS mouse model that uses a chronically implanted electrode.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique proposed as an alternative or complementary treatment for ...

Home-Based Transcranial Direct Current Stimulation Device Development: An Updated Protocol Used at Home in Healthy Subjects and Fibromyalgia Patients

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the cerebral cortex by a low-intensity direct current. tDCS is a low-cost technique with minimal adverse effects and easy application. This neurostimulation method has a promising future to improve pain therapy, treatment of neuropsychiatric disorders, and physical rehabilitation.
Current studies demonstrate the benefits of using tDCS over consecutive multiple sessions. However, the daily displacement to the specialized centers, travel costs, and disruptions to daily activities are some of the difficulties faced by patients. Thus, to be more comfortable, easy-to-use, and not disrupt daily commitments, a home-based tDCS was designed. Therefore, the objective of this study was to evaluate the feasibility of a portable tDCS device for home use in healthy subjects and fibromyalgia patients.
Despite increased tDCS use and a reasonably large body of research on the effects across a range of clinical conditions, there is a limited amount of research on developing secure devices that guarantee the dose and contain a block system to avoid excessive use. Therefore, we used a tDCS device with a security system to permit daily use for 20 minutes with a minimal interval of 12 hours between sessions. A programmer preconfigures the equipment, which has a neoprene cap that allows the electrode positions in any assembly, according to individualized protocols for treatments or research. After, researchers can assess the effectiveness of treatment, and its adherence using information kept in the device software.
Results suggest that the device is feasible for home use, with proper monitoring of adherence and contact impedance. There were reports of a few adverse effects, which do not differ from those reported in the literature in studies with the treatment under direct supervision.

This study provides an updated home-based tDCS protocol that enables subjects to receive the beneficial effects of tDCS at home with an easy to use device with settings to control the use and dosage, enhancing the feasibility for long-term use at home.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the ...

Stimulation Location Determination using a 3D Digitizer with High-Definition Transcranial Direct Current Stimulation

The abundance of neuroimaging data and rapid development of machine learning has made it possible to investigate brain activation patterns. However, causal evidence of brain area activation leading to a behavior is often left missing. Transcranial direct current stimulation (tDCS), which can temporarily alter brain cortical excitability and activity, is a noninvasive neurophysiological tool used to study causal relationships in the human brain. High-definition transcranial direct current stimulation (HD-tDCS) is a noninvasive brain stimulation (NIBS) technique that produces a more focal current compared to conventional tDCS. Traditionally, the stimulation location has been roughly determined through the 10-20 EEG system, because determining precise stimulation points can be difficult. This protocol uses a 3D digitizer with HD-tDCS to increase accuracy in determination of stimulation points. The method is demonstrated using a 3D digitizer for more accurate localization of stimulation points in the right temporo-parietal junction (rTPJ).

Presented here is a protocol to achieve higher accuracy in determination of stimulation location combining a 3D digitizer with high-definition transcranial direct current stimulation.

The abundance of neuroimaging data and rapid development of machine learning has made it possible to investigate brain activation patterns. However, ...

Updated Technique for Reliable, Easy, and Tolerated Transcranial Electrical Stimulation Including Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of brain stimulation presents several potential advantages compared to other techniques, as it is noninvasive, cost-effective, broadly deployable, and well-tolerated provided proper equipment and protocols are administered. Even though tDCS is apparently simple to perform, correct administration of the tDCS session, especially the electrode positioning and preparation, is vital for ensuring reproducibility and tolerability. The electrode positioning and preparation steps are traditionally also the most time consuming and error-prone. To address these challenges, modern tDCS techniques, using fixed-position headgear and pre-assembled sponge electrodes, reduce complexity and setup time while also ensuring that the electrodes are consistently placed as intended. These modern tDCS methods present advantages for research, clinic, and remote-supervised (at home) settings. This article provides a comprehensive step-by-step guide for administering a tDCS session using fixed-position headgear and pre-assembled sponge electrodes. This guide demonstrates tDCS using commonly applied montages intended for motor cortex and dorsolateral prefrontal cortex (DLPFC) stimulation. As described, selection of the head size and montage-specific headgear automates electrode positioning. Fully assembled pre-saturated snap-electrodes are simply affixed to the set position snap-connectors on the headgear. The modern tDCS method is shown to reduce setup time and reduce errors for both novice and expert operators. The methods outlined in this article can be adapted to different applications of tDCS as well as other forms of transcranial electrical stimulation (tES) such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). However, since tES is application specific, as appropriate, any methods recipe is customized to accommodate subject, indication, environment, and outcome specific features.

When administering transcranial direct current stimulation (tDCS), reproducible electrode preparation and placement are vital for a tolerated and effective session. The purpose of this article is to demonstrate updated modern setup procedures for the administration of tDCS and related transcranial electrical stimulation techniques, such as transcranial alternating current stimulation (tACS).

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of ...