All procedures were conducted under institutionally approved protocols with patient consent. See Figure 1 for an image of the intervention kit and main components and Figure 2 for the RS-tDCS session structure.
1. Pre-intervention procedures
<ol>
	<li>Perform recruitment pre-screening according to inclusion and exclusion criteria. Include patients who are adult amputees, who regularly experience phantom pain once a week or more with an intensity level of at least 4 on a Visual analog scale (VAS), and who do not have contra-indications to tDCS or unstable comorbidities. 
	NOTE: The sample size was calculated according to a calculation on our preliminary results from a previous RCT and our meta-analysis on tDCS effects, considering the minimally clinically significant difference of an effect size of 0.5 (80). We assumed a type I error of 5% and type 2 of 20% using a t-test calculation for differences and expanded to account for a 10% attrition rate. Reaching 145 subjects per group, 290 total.</li>
	<li>Enroll the subject in the research study by filling out the registration, including the informed consent form, date of birth, gender, and questions about medical history and amputee profile.
	<ol>
		<li>Perform the screening during the consent visit.</li>
		<li>Set up a date for the baseline and randomization process.</li>
	</ol>
	</li>
	<li>Baseline visit and training
	<ol>
		<li>Have the patients go through a series of questionnaires regarding pain, sleep, quality of life, cognition, and mental health.</li>
		<li>Randomize the subjects (according to their treatment expectancy) into two groups: either RS-tDCS of the M1 with somatosensory testing (intervention) or usual care (control group).</li>
		<li>Have the patients receive their training according to the randomization, so they can familiarize themselves with the provided materials and practice for the real-time remote supervised procedure.
		<ol>
			<li>Conduct this step in person but do it remotely if the distance and the patient&#39;s literacy dictate this. In this case, perform the same described procedures using the same materials but explain how to operate the devices during a Zoom meeting.</li>
		</ol>
		</li>
		<li>Train the patients from the usual care group in the use of the wearable HRV monitor and its corresponding App installed in a provided tablet, as well as the Zoom platform integrated into a laptop.</li>
		<li>Introduce the subjects to the password-protected laptop, where key features will be explained (including password, switching on/off, and USB webcam connection).</li>
		<li>Show the participants how to join the meeting through a personalized and secured call ID meeting and password via the Zoom platform. Have the participants practice with the researcher at least once.</li>
		<li>To guarantee activity success, ensure that the participants are able to trial a real-in-time session recording of HRV.
		<ol>
			<li>Guide the patients on the correct placement of the HRV wearable device (in the middle of the sternum line).</li>
			<li>Once the sensors have been checked for placement, introduce the participants to the password-protected tablet. Show the participants how to pair the devices, change the record name, start, end the recording, and save it. 
			NOTE: Ensure that all these previous steps will be performed by the patient with researcher guidance once and then repeated without guidance to guarantee information retention.</li>
		</ol>
		</li>
		<li>Stimulation group, RS-tDCS
		<ol>
			<li>Show an instructional video and repeat this video content with the patient step-by-step.</li>
			<li>Show the tDCS device to the patient while placed on a mannequin head. Explain the various parts of this device, and give the patient a chance to correctly clip the SNAPpads to the SNAPstrap and into the device.</li>
			<li>Using a mirror, ask the patients to put the SNAPstrap on themselves, as it was on the mannequin&#39;s head, until they achieve a comfortable level and make sure the participant is correctly aligning the cathode and the anode as well as the back strap to ensure correct placement.</li>
			<li>Turn on the RS-tDCS device and show the steps to follow until stimulation, how to access the stimulation menu, enter the stimulation code, and what to do in case they need to abort a session.</li>
			<li>Finally, ask the participants to go over all the steps again, either practicing or verbally based on self-assessed competency. Go over the visiting schedule and explain the normal flow of every visit.</li>
		</ol>
		</li>
		<li>To guarantee training success, fill out a comprehensive checklist covering all essential aspects of training (Table 1).</li>
	</ol>
	</li>
</ol>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always" fo:text-align="left">
	<tbody>
		<tr>
			<td>1) Computer&#160;</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; REDCap</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Open surveys</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Filling and submitting forms</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Zoom Log in and out</td>
		</tr>
		<tr>
			<td>2) Heart rate monitor&#160;</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Heart rate monitor app</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Correct placement</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Recording of the heart rate</td>
		</tr>
		<tr>
			<td>3) Home-Based tDCS&#160;</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Head and electrode preparation</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Gather the materials: sponges, head strap, the stimulator device, the saline solution, syringes, and the laptop provided by the Lab.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Find the stimulation area (the central line of your head and your ear) &#8211; identified correctly the M1.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Check the skin for redness or any sign of damage.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Open the pre-soaked sponges and attach the electrodes (located inside the pre-soaked sponges) to the head strap.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; If the sponges are not wet enough, prepare with the correct amount of saline solution (approx. 6ml on each side).</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; The sponge in the M1 area.</td>
		</tr>
		<tr>
			<td>4) Device preparation and Stimulation&#160;</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Connect the electrode cable to the tDCS device, according to the matched colors (red cable into the red entrance and the black cable into the black entrance).</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Before starting, turn on the computer and open the conference call.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Follow the instructions provided by the research team.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Turn on the device.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Press any button to get the main menu screen.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Press the button to start stimulation.</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Check the quality of the setup ( If the quality is not good, tell the team and wait for instructions).</td>
		</tr>
		<tr>
			<td>&#183;&#160;&#160;&#160;&#160;&#160;&#160; Press the pound button and correctly enter the activation code to start the stimulation.</td>
		</tr>
	</tbody>
</table>
Table 1: Training checklist.
2. Study intervention visits
NOTE: The study consists of a total of 23 visits, with 20 sessions involving either stimulation or usual care. Throughout the intervention part, regardless of group allocation, both will be connected to the trained researcher staff via Zoom.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/66006/66006fig01.jpg" /> 
Figure 1: Intervention kit and main components. Abbreviation: tDCS = transcranial direct current stimulation. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/66006/66006fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<ol>
	<li>When the patients are at home, connected via Zoom meeting, begin the session by asking the patient about their levels of PLP, phantom limb sensations (PLS), residual limb pain (RLP), and telescoping experienced within the past 24 h by using the VAS score, which is the primary outcome.</li>
	<li>Have the patient begin recording their HRV (measured for the secondary outcome).
	<ol>
		<li>Ensure the correct positioning of the device (middle of the sternum line), as well as its pairing with the tablet to guarantee accurate recordings.</li>
		<li>Remind the patients at the beginning of each session about their research ID and the visit number.</li>
		<li>Have the patients show the tablet screen through the webcam to ensure the recording is being performed accordingly.</li>
		<li>After 5 min, have the patient stop and save the recording by the patient in the App. When questions arise, guide the patients throughout by remaining connected with the patient for the total duration of the session.</li>
	</ol>
	</li>
	<li>For patients in the intervention group, check their scalp condition prior to stimulation via webcam. If the skin is intact, perform the session. For that, have the patients place the SNAPstrap as shown on the training visit.
	<ol>
		<li>Always position the anode SNAPpad situated on the motor cortex (C3 or C4) contralateral to the amputated limb. Ensure that the cathode SNAPpad is located on the supraorbital space, ipsilateral to the amputation side. Encourage the patients to always use a mirror to facilitate collocation and then, turn on the RS-tDCS device.
		<ol>
			<li>Once they are on the stimulation menu, observe that the screen will show the connection quality rated as poor, moderate, or good. When a connection is poor, the device will beep, indicating that no current can be delivered. In that case, have the patients either rearrange the SNAPpads, check for cable connectivity to the device, or add saline solution. Have the patients press the sponges against their skin for 20 s, thus enhancing contact to solve most cases of poor connectivity and start the stimulation when good connectivity appears.</li>
			<li>Provide a code for single-time use to the patients to avoid non-supervised stimulations. During the training session, follow the study protocol with 2 mA intensity for 20 min with a ramp of 30 s to create the stimulation codes on the patient&#39;s device. Ensure that these codes remain blinded to the participant to ensure stimulation is delivered within the study context only.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Once stimulation has been started, complete a 5 min guided meditation consisting of a body scan technique. Begin somatosensory training by following simple and slow movements of the limbs, including movement of the phantom limb until stimulation is complete. 
	NOTE: Due to safety reasons, to ensure study protocol adherence, this research protocol warrants constant supervision. When possible, the same researcher will be assigned throughout the study for the same participant.</li>
	<li>At the end of each session, administer a questionnaire asking about possible side effects and pain levels on a VAS score to the patient (Supplementary File 1). If a patient&#39;s pain level is increased by at least 2 points in the VAS scale, (pre-stimulation vs post-stimulation) in two consecutive visits, stop the intervention completely.</li>
	<li>If at any moment of the stimulation, the patient is experiencing severe discomfort or wants to stop the stimulation, ask the subject to abort the session (previously explained during the training session).</li>
</ol>

Treatment of Phantom Limb Pain by Remote Transcranial Direct Current Stimulation

<ol>
	<li>Gunduz, M. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+combined+and+alone+transcranial+motor+cortex+stimulation+and+mirror+therapy+in+phantom+limb+pain:+A+randomized+factorial+trial.">Effects of combined and alone transcranial motor cortex stimulation and mirror therapy in phantom limb pain: A randomized factorial trial.</a> Neurorehabilitation and Neural Repair. 35 (8), 704-716 (2021).</li><li>Pacheco-Barrios, K., Meng, X., Fregni, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neuromodulation+techniques+in+phantom+limb+pain:+A+systematic+review+and+meta-analysis.">Neuromodulation techniques in phantom limb pain: A systematic review and meta-analysis.</a> Pain Medicine. 21 (10), 2310-2322 (2020).</li><li>Segal, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Additive+analgesic+effect+of+transcranial+direct+current+stimulation+together+with+mirror+therapy+for+the+treatment+of+phantom+pain.">Additive analgesic effect of transcranial direct current stimulation together with mirror therapy for the treatment of phantom pain.</a> Pain Medicine. 22 (2), 255-265 (2021).</li><li>Fregni, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evidence-based+guidelines+and+secondary+meta-analysis+for+the+use+of+transcranial+direct+current+stimulation+in+neurological+and+psychiatric+disorders.">Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders.</a> International Journal of Neuropsychopharmacology. 24 (4), 256-313 (2021).</li><li>Silva-Filho, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Factors+supporting+availability+of+home-based+neuromodulation+using+remote+supervision+in+middle-income+countries;+Brazil+experience.">Factors supporting availability of home-based neuromodulation using remote supervision in middle-income countries; Brazil experience.</a> Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 15 (2), 385-387 (2022).</li><li>Pacheco-Barrios, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Methods+and+strategies+of+tDCS+for+the+treatment+of+pain:+current+status+and+future+directions.">Methods and strategies of tDCS for the treatment of pain: current status and future directions.</a> Expert Review of Medical Devices. 17 (9), 879-898 (2020).</li><li>Brunoni, A. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Digitalized+transcranial+electrical+stimulation:+A+consensus+statement.">Digitalized transcranial electrical stimulation: A consensus statement.</a> Clinical Neurophysiology. 143, 154-165 (2022).</li><li>Sandran, N., Hillier, S., Hordacre, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Strategies+to+implement+and+monitor+in-home+transcranial+electrical+stimulation+in+neurological+and+psychiatric+patient+populations:+a+systematic+review.">Strategies to implement and monitor in-home transcranial electrical stimulation in neurological and psychiatric patient populations: a systematic review.</a> Journal of Neuroengineering and Rehabilitation. 16 (1), 58 (2019).</li><li>Palm, U., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Home+use,+remotely+supervised,+and+remotely+controlled+transcranial+direct+current+stimulation:+A+systematic+review+of+the+available+evidence.">Home use, remotely supervised, and remotely controlled transcranial direct current stimulation: A systematic review of the available evidence.</a> Neuromodulation. 21 (4), 323-333 (2018).</li><li>Van Den Houte, M., Van Oudenhove, L., Bogaerts, K., Van Diest, I., Vanden Bergh, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endogenous+pain+modulation:+association+with+resting+heart+rate+variability+and+negative+affectivity.">Endogenous pain modulation: association with resting heart rate variability and negative affectivity.</a> Pain Medicine. 19 (8), 1587-1596 (2018).</li><li>Cousins, M. J., Lynch, M. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Declaration+Montreal:+access+to+pain+management+is+a+fundamental+human+right.">The Declaration Montreal: access to pain management is a fundamental human right.</a> Pain. 152, 2673-2674 (2011).</li><li>Maceira-Elvira, P., Popa, T., Schmid, A. -. C., Hummel, F. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Feasibility+of+home-based,+self-applied+transcranial+direct+current+stimulation+to+enhance+motor+learning+in+middle-aged+and+older+adults.">Feasibility of home-based, self-applied transcranial direct current stimulation to enhance motor learning in middle-aged and older adults.</a> Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 13 (1), 247-249 (2020).</li><li>Tsapkini, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Home-based+transcranial+direct+current+stimulation:+Are+we+there+yet.">Home-based transcranial direct current stimulation: Are we there yet.</a> Stroke. 53 (10), 3002-3003 (2022).</li></ol>

The authors have no conflicts of interest.

Aspects of training, challenges, and solutions 
Given the nature of this research study and the type of intervention, being home-based, some challenges have risen; among them were day-to-day issues such as internet connection, contact quality of the operated device, and getting familiar with the devices. The potential challenges presented by RS-tDCS research have been overcome through several creative solutions. Prior to every session, the internet connection is checked on both ends to minimize interruptions. In the case of unstable connectivity, the visit must either be re-scheduled or completed over the phone when safe to do so (usual care visits only). For the first remote visit, a refresher checklist on the devices and their functions is completed by the researcher. Moreover, when a patient has difficulties completing certain tasks, another refresher session is offered. The flexibility of schedules is an important aspect of guaranteeing participants&#39; engagement.
Considering that there are limited therapies used for treating PLP such as pain medications, anticonvulsants, and antidepressants, and that the use of M1-targeted tDCS has helped in chronic pain conditions and rehabilitation settings, tDCS has been explored as a possible therapy for treating PLP to induce significant plasticity changes in the M1. However, further research needs to be conducted to prove effectiveness in reducing PLP as suggested in previous studies by Gunduz et al.1. The relationship between PLS and PLP needs to be studied so we can understand the implications for motor cortex excitability and cortical mapping.
Moreover, it is of essence to try and implement this technique in real-life settings to assess its efficacy, feasibility, and mid-term or long-lasting effects. For this, it is important to develop not only new targeted therapies for treating PLP but also aid patients who are experiencing chronic pain who struggle to enroll in physical therapy programs or do not have access to clinical research due to commuting or accessibility issues for disabled patients11.
In a world that is constantly evolving in terms of technology, being able to perform this type of neuromodulatory techniques in remote settings with experts supervising the visits, we could be addressing not only a possible solution for gaps in accessibility to research for PLP patients, but this could expand into other types of chronic pain conditions, motor dysfunction, and neuropsychiatric conditions. Additionally, the approach presented in this paper can be easily adapted to combine therapies with behavioral interventions such as mindfulness, at-home exercise, and online psychotherapy. This would also help disabled patients who would benefit from this type of research and home-based trials, with this assuring not only inclusion but adherence and retention12.
Supervised versus non-supervised tDCS home-based sessions have been discussed13. In our study, we chose the supervised method and we felt that this was a wise choice for this population of patients with PLP as we had several subjects who are older and thus have a few more challenges with new technological procedures. Furthermore, frequently, the subjects in our study do not have a caregiver to help them during the procedures. This is a challenge to the field: how to improve the design of the stimulator and electrodes to make more feasible unsupervised sessions? In addition, we feel that supervising sessions will help to control other aspects such as adherence and safety of applications. We also hope that the design of stimulators will improve in the future and thus, would be easier for all subjects to have it in an unsupervised manner.
This new approach to neuromodulation needs more work. It proposes solutions for addressing a vast gap in chronic pain management but when this point is reached, stronger evidence would be required in real-life settings. Only such evidence could help establish guidelines for treating PLP and other types of chronic pain management, as well as for outpatient rehabilitation settings, home-based rehabilitation, or programs to continue rehabilitation at home.

The sensation of pain and discomfort experienced in an amputated limb and referred to as phantom limb pain (PLP) is a complex condition, challenging to treat, consisting of a refractory nature that contributes to the difficulty in achieving complete and long-lasting pain relief and management. The lack of effective treatment owing to its neuropathic nature, resulting from abnormal nerve activity, or signaling, neural plasticity, psychological factors, and limited understanding and research, influences the complexity of the phenomenon in the pain presentation and the treatment outcomes. From all available treatments, recent studies using transcranial direct current stimulation (tDCS) have reported positive results when combining stimulation of the primary motor cortex (M1) with motor representation techniques1,2,3,4. As Kikkert et al. published in 2019, the long-term effects of the combined stimulation resulted in significant, maintained pain reduction after intervention and a follow-up period of 3 months, with meaningful improvements and large effect sizes in lower-limb amputees.
Although the effects are promising, the clinical translations of these results are limited due to geographical constraints and disabilities related to amputations, which delay and affect the access to adequate post-amputation rehabilitation5. One solution is to deploy these interventions in remote environments using digital technologies and telehealth approaches6. A recent international consensus reported the requirements to successfully implement digitalized electrical stimulation7, including a support team available at all times to manage medical emergencies, cost optimization strategies, implementation of insurance coverage for further field development, specialized teams or third-party services for undertaking the development of software and hardware for the remote use of devices, digital marketing strategies to enhance publicity among potential patients, and front-end interfaces for user experience enhancement.
The adequate implementation of remotely supervised transcranial direct current stimulation (RS-tDCS) protocols has the potential to accelerate the clinical application of this safe and effective intervention4 and facilitate its combination with behavioral modalities that can be performed at home (e.g., physical therapy, mindfulness). Recent studies have shown feasibility and equivalent results with RS-tDCS compared to previous on-site tDCS studies for the same condition8,9. However, practical details and guidance on how to implement RS-tDCS for clinical trials in chronic pain are still limited in the literature. There are open questions on RS-tDCS such as the need for online supervision performed by a trained specialist in the technique compared to the self-administered tDCS therapy after receiving proper coaching. Furthermore, questions remain unanswered regarding metadata registration, adherence to the treatment guidelines, the use of technology such as apps to track contact quality and time of usage, avoiding the misuse of devices related to non-scheduled stimulation sessions, and topics associated with &#34;internet issues&#34;-protection of personal information, recording of health records, rules of sharing, and password protection for access.
Therefore, our goal is to provide a visual guideline on how to perform an RS-tDCS session, as well as a description of the logistics and challenges of its implementation for treating phantom limb pain (PLP) in the context of a pragmatic clinical trial.

<table><tbody><tr><td>1 x 1 tDCS mini-CT stimulator</td><td>Soterix&amp;nbsp;</td><td></td><td>parameters preset to two milliamps of stimulation for 20 min</td></tr><tr><td>Lenovo Laptop&amp;nbsp;</td><td>Lenovo</td><td></td><td>It contains a headstrap and disposable clip-on sponges for stimulation. A computer with Zoom access, to conduct the RS-tDCS sessions. The Zoom videocalls will be addressed to a secured account by Mass General Brigham (MGB)&amp;nbsp;&amp;nbsp;</td></tr><tr><td>Lenovo Smart Tab M8 8&#039;&#039;</td><td>Lenovo</td><td></td><td>We also record the heart rate variability (HRV) and therefore, we provide a tablet with the Polar app installed and the chest HR monitor.</td></tr><tr><td>Polar H10 Heart Rate Monitor</td><td></td><td></td><td>POLAR device, in addition to the materials for the RS-tDCS intervention, we also record the heart rate variability (HRV) and therefore we provide a tablet with the Polar app installed and the chest HR monitor.</td></tr><tr><td>Saline solution with a syringe for application over the sponges</td><td></td><td></td><td></td></tr><tr><td>SNAP Headgear accessories</td><td></td><td></td><td></td></tr><tr><td>&amp;nbsp; SNAPstrap, motor left (anode: C3, cathode: supraorbital) or motor right (anode: c4, cathode: supraorbital) according to the side of amputation (contralateral to stimulation)</td><td></td><td></td><td></td></tr><tr><td>&amp;nbsp;&amp;nbsp; SNAPpads, 5 x 7 CMS with pre-inserted carbon rubber snap electrode sites located on the SNAPstrap</td><td></td><td></td><td></td></tr><tr><td>Webcam</td><td></td><td></td><td>to ensure a proper visualization of the electrode placement</td></tr></tbody></table>

using home-based, remotely supervised, transcranial direct current stimulation for phantom limb pain

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants.
Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.

Our home-based and remotely supervised protocol is currently being tested in a large, pragmatic, randomized, clinical trial of patients with PLP. Based on previous clinical trial testing in-clinic tDCS in PLP patients, we expect a reduction in the level of PLP, PLS, and RLP compared to the usual care group. This reduction is expected to reach an effect size of at least 0.5, namely a clinically important difference.
Regarding safety outcomes, our initial exploration has shown a similar safety profile to in-site tDCS applications. The most common side effects reported are tingling, itching, and skin redness. Therefore, we expect higher rates of adherence and acceptability in the ongoing study. Moreover, in this protocol, we highlight the feasibility of combining a behavioral intervention with RS-tDCS (e.g., somatosensory training), also combining a home-based biomarker recording such as HRV. We expected that RS-tDCS would significantly modify the HRV compared to the usual care group and hypothesized that the analgesic effect of RS-tDCS in PLP patients would be correlated to an increase in the high-frequency band of the HRV. This modification can be interpreted as an increase in the vagal tonus related to the activation of the endogenous pain modulation system10.
We tested this protocol in two patients with PLP. In this pilot study, twenty sessions were performed, and PLP levels and HRV metrics were measured at home before and after the protocol. Our study showed a significant reduction in PLP intensity levels (p = 0.001, Table 2). This pain reduction is larger than the minimally clinically important difference for chronic pain conditions (reductions of 2 points in a VAS), supporting the analgesic power of this protocol. Similarly, HRV-related variables were modified. As expected, high-frequency HRV significantly increased after the remote protocol (p = 0.003, Table 2) but low-frequency HRV was not. These results suggest an increase in the parasympathetic tonus of patients with PLP.
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Outcome</td>
			<td>Pre-treatment</td>
			<td>Post-treatment</td>
			<td>Difference</td>
			<td>p-value</td>
		</tr>
		<tr>
			<td>PLP VAS</td>
			<td>6.25 &#177; 0.35</td>
			<td>2.70&#160; &#177; 0.42</td>
			<td>-3.55&#160; &#177; 0.77</td>
			<td>0.001</td>
		</tr>
		<tr>
			<td>HF-HRV</td>
			<td>6.19&#160; &#177; 0.73</td>
			<td>9.57&#160; &#177; 0.60</td>
			<td>3.38&#160; &#177; 0.13</td>
			<td>0.003</td>
		</tr>
		<tr>
			<td>LF-HRV</td>
			<td>8.05&#160; &#177; 0.35</td>
			<td>6.9&#160; &#177; 0.14</td>
			<td>-1.15&#160; &#177; 0.21</td>
			<td>0.13</td>
		</tr>
	</tbody>
</table>
Table 2: Changes in PLP intensity and heart rate variability (n = 2). Abbreviations: HRV = heart rate variability; PLP = phantom limb pain; HF = High Frequency; LF = Low Frequency; VAS = Visual analog scale.
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/66006/66006fig02.jpg" /> 
Figure 2: RS-tDCS session structure. Abbreviations: tDCS = transcranial direct current stimulation; RS-tDCS = remotely supervised tDCS. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/66006/66006fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Supplementary File 1: tDCS side effects questionnaire. Abbreviation:&#160;tDCS = transcranial direct current stimulation. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/66006/supplementary1.zip" target="_blank">Please click here to download this File.</a>

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Author Spotlight: Insights into Remotely Supervised Neuromodulation Procedure for Phantom Limb Pain

The goal of this study is to describe a protocol for the home-based delivery of remotely supervised transcranial direct current stimulation (RS-tDCS) conserving the standard procedures of in-clinic practice, including safety, reproducibility, and tolerability. The participants included will be patients with phantom limb pain (PLP).

Using Home-based, Remotely Supervised, Transcranial Direct Current Stimulation for Phantom Limb Pain

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

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Nanyang Technological University

Research

JoVE Journal

Neuroscience

823 Views.  Massachusetts General Hospital, Harvard Medical School. Van alle beschikbare behandelingen hebben recente onderzoeken met behulp van transcraniële gelijkstroomstimulatie, tDCS, positieve resultaten gerapporteerd bij het combineren van stimulatie van de primaire motorische cortex, M1, met motorische representatietechnieken. De langetermijneffecten van de gecombineerde stimulatie resulteerden in een significante, aanhoudende pijnvermindering na interventie en een follow-upperiode van drie maanden. Ons doel is om een visuele richtlijn te geven voor ...

Video: Auteur in de schijnwerpers: inzicht in op afstand gecontroleerde neuromodulatieprocedure voor fantoompijn in ledematen

Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest."1,2,3 It is thought the default mode network corresponds to self-referential or "internal mentation".2,3
It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia 4,5,6 and autism spectrum disorders 7 whilst hypo-activation of the network has been linked to Alzheimer's and other neurodegenerative diseases 8). As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.9
In order to explore the default mode network's propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools.

In this article, we examine the methodology and considerations relevant to the combination of TMS and fMRI to examine the effects of brain stimulation on the default network.

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful ...

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 ...

Direct-current Stimulation and Multi-electrode Array Recording of Seizure-like Activity in Mice Brain Slice Preparation

Cathodal transcranial direct-current stimulation (tDCS) induces suppressive effects on drug-resistant seizures. To perform effective actions, the stimulation parameters (e.g., orientation, field strength, and stimulation duration) need to be examined in mice brain slice preparations. Testing and arranging the orientation of the electrode relative to the position of the mice brain slice are feasible. The present method preserves the thalamocingulate pathway to evaluate the effect of DCS on anterior cingulate cortex seizure-like activities. The results of the multichannel array recordings indicated that cathodal DCS significantly decreased the amplitude of the stimulation-evoked responses and duration of 4-aminopyridine and bicuculline-induced seizure-like activity. This study also found that cathodal DCS applications at 15 min caused long-term depression in the thalamocingulate pathway. The present study investigates the effects of DCS on thalamocingulate synaptic plasticity and acute seizure-like activities. The current procedure can test the optimal stimulation parameters including orientation, field strength, and stimulation duration in an in vitro mouse model. Also, the method can evaluate the effects of DCS on cortical seizure-like activities at both the cellular and network levels.

Studies have shown that cathodal transcranial direct-current stimulation can produce suppressive effects on drug-resistant seizures. In this study, an in vitro experimental setup was devised in which the direct-current stimulation and multielectrode array recording of seizure-like activity were evaluated in mice brain slice preparation. The direct-current stimulation parameters were evaluated.

Cathodal transcranial direct-current stimulation (tDCS) induces suppressive effects on drug-resistant seizures. To perform effective actions, the ...

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 ...

Medicine

Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific frequency and in turn modulate ongoing cortical oscillatory activity. This neurotool allows the establishment of a causal link between endogenous oscillatory activity and behavior. Most of the tACS studies have shown online effects of tACS. However, little is known about the underlying action mechanisms of this technique because of the AC-induced artifacts on Electroencephalography (EEG) signals. Here we show a unique approach to investigate online physiological frequency-specific effects of tACS of the primary motor cortex (M1) by using single pulse Transcranial Magnetic Stimulation (TMS) to probe cortical excitability changes. In our setup, the TMS coil is placed over the tACS electrode while Motor Evoked Potentials (MEPs) are collected to test the effects of the ongoing M1-tACS. So far, this approach has mainly been used to study the visual and motor systems. However, the current tACS-TMS setup can pave the way for future investigations of cognitive functions. Therefore, we provide a step-by-step manual and video guidelines for the procedure.

Transcranial Alternating Current Stimulation (tACS) allows the modulation of cortical excitability in a frequency-specific fashion. Here we show a unique approach which combines online tACS with single pulse Transcranial Magnetic Stimulation (TMS) in order to "probe" cortical excitability by means of Motor Evoked Potentials.

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific ...

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.

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 ...

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 ...

Real-time Video Projection in an MRI for Characterization of Neural Correlates Associated with Mirror Therapy for Phantom Limb Pain

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). However, establishing the neural correlates associated with MT therapy have been challenging given that it is difficult to administer the therapy effectively within a magnetic resonance imaging (MRI) scanner environment. To characterize the functional organization of cortical regions associated with this rehabilitative strategy, we have developed a combined behavioral and functional neuroimaging protocol that can be applied in participants with a leg amputation. This novel approach allows participants to undergo MT within the MRI scanner environment by viewing real-time video images captured by a camera. The images are viewed by the participant through a system of mirrors and a monitor that the participant views while lying on the scanner bed. In this manner, functional changes in cortical areas of interest (e.g., sensorimotor cortex) can be characterized in response to the direct application of MT.

We present a novel combined behavioral and neuroimaging protocol employing real-time video projection for the purpose of characterizing the neural correlates associated with mirror therapy within the magnetic resonance imaging scanner environment in leg amputee subjects with phantom limb pain.

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). ...

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 ...

Using Home-based, Remotely Supervised, Transcranial Direct Current Stimulation for Phantom Limb Pain

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