We would like to thank Sydney Brigido, Hannah Hallett, Emily Aiken, Victoria Larson, Margy Bowker, Christiana Faucher, and Alexis Harle for their dedicated effort on this project. This work was supported by a Merit Award (I01 RX002450) from the United States (U.S.) Department of Veterans Affairs, Rehabilitation Research and Development Service and the Center for Neurorestoration and Neurotechnology (N2864-C) at the Providence VA (VA Rehabilitation Research and Development Service). The views expressed in this article are those of the authors and do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. We thank all the participants.

<ol>
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The authors have nothing to disclose.

The protocol detailed above describes the concurrent application of tDCS and VR, as opposed to the serial application of either technique. With respect to existing methods, the simultaneous application of tDCS with VR is important. While the VR provides a contextually rich and immersive environment for fear-related processing, the subthreshold stimulation provided by tDCS allows for the modulates of intrinsic neural activation associated with this fear-related processing. There are multiple critical steps in this protocol that can be divided into those that relate to tDCS+VR implementation and those related to psychophysiological data capture for analyses. With respect to tDCS+VR, it is of critical importance to ensure correct randomization and simultaneous application of tDCS throughout the entire VR session. Another blinded staff member can perform further confirmation of randomization.
As for ensuring simultaneous tDCS+VR two aspects are important; 1) the impedance achieved during tDCS set-up and 2) starting the tDCS device in close proximity to starting VR. The latter issue is relatively straightforward and should ensure that tDCS is continuously applied throughout the VR presentation while remaining well within the safety limits of tDCS when a 2 mA intensity is applied over a 25-minute duration20. With respect to impedance, low impedance is desirable. Knowing whether adequate impedance, or contact quality, is achieved depends on the tDCS device that is used. Some devices will display impedance in Ohms, where lower is better, whereas other devices use a 10- or 20-point display scale representing contact quality, where higher is better. Regardless of the specific device, the use of normal saline, 0.9% NaCl solution, as opposed to regular tap water to moisten the electrode sponges improves impedance35. The use of regular tap water should further be avoided because it associated with the occurrence of small skin lesions35,36, one of the more serious possible side-effects of tDCS. Skin lesions can also occur if the skin under the electrodes is vigorously abraded prior to tDCS37 or if a conductive gel is used, which can dry out35,38, and should therefore also be avoided. Finally, a high impedance prior to starting tDCS can result in reaching or surpassing the prescribed safety parameters of the device, which will trigger the device to shut down mid VR administration. Although it is important to sufficiently moisten the electrodes sponges to ensure adequate impedance, this should be balanced by not excessively soaking the electrodes, as this may result in leaking, or dripping, of saline when the VR headset is placed. Leaking of saline may allow the electrical current to &#8216;spread&#8217; over a larger area resulting in a lower, but unknown current density39, which depends on tDCS intensity (in mA) and size of electrodes (in cm2). Likewise, it is important that the VR head mounted display does not physically touch the sponges/electrodes in order to avoid disruption of current flow and shifting of electrodes as participants move their head.
In this protocol, skin conductance is considered a primary outcome measure. Skin conductance is a psychophysiological measure of sympathetic nervous system activity40. Typical factors associated with skin conductance acquisition, such as effects of environmental temperature and humidity, aging, smoking status, caffeine use, and use of medications with anticholinergic effects41, will need to be considered, but cannot always be eliminated. For example, it is possible to ask participants to abstain from using caffeine-containing products prior to VR sessions, but it is not ethical to ask them to discontinue antidepressant medications. Moreover, for reasons that are not always clear, a portion of individuals demonstrate very low or unmeasurable skin conductance levels and/or skin conductance responses, which is highlighted in Figure 4. It is therefore important to enroll a sufficient sample size to tolerate the loss, or absence, of data. Specific to the implementation of this protocol, it should also be mentioned that event markers are currently entered manually during the psychophysiological data capture. Although this is a limitation, it is not uncommon in hospital systems that a non-hospital managed computer, in this case the computer that runs the VR environment, cannot be connected to the encrypted hospital information technology network. This means that it is not possible to have the computer that runs the VR environment send signals (e.g. through a TTL pulse) to the psychophysiological data capture computer that is on the hospital network. Although less elegant, one solution is to have two research team members be present during each VR session; one that controls the VR administration and one that manually enters event markers to the psychophysiological tracing, as can be seen at the top of each figure (see Figure 1, Figure 2, Figure 3 and Figure 4). However, this does not address the presence of a slight time difference, less than half a second, from when VR events are initiated by the VR controller and entering the event marker by the second person. Future studies might want to mitigate this so that event markers can automatically be registered. Yet, the presence of a second research team member &#8211; different from the person who operates the VR environment &#8211; who can observe the participant throughout sessions is highly recommended. It should be expected that some participants might have strong emotional reactions during the study or experience cyber sickness-related side effects. The ability of the research team to quickly respond to these situations ensures the best possible care.
In summary, this protocol uses simultaneous tDCS during VR to augment habitation to trauma-related scenarios. The principal advantage of this approach is the use of an immersive trauma-related context and the application of a non-invasive brain stimulation technique during a clinically relevant cognitive process, as opposed to doing either consecutively. While the protocol described here uses in-office application in a veteran sample with PTSD, this approach of simultaneous non-invasive brain stimulation and virtual reality can translate to other fear-based and anxiety disorders as well as at-home applications of exposure-based approaches.

Posttraumatic stress disorder (PTSD) is a chronic and disabling condition that is especially prevalent among veterans. Despite its prevalence and devastating impact, many who receive evidence-based psychotherapy for PTSD have significant residual symptoms1. The synergistic application of non-invasive brain stimulation together with PTSD-focused principles of psychotherapy presents an opportunity to improve therapeutic gains and lower PTSD-related burdens.
A core component of PTSD is the inability to inhibit a maladaptive fear response2,3. Pathologically elevated activity in the amygdala and dorsal anterior cingulate cortex, regions that facilitate the fear response, has been consistently reported in PTSD. This is alongside reduced activity in the ventromedial prefrontal cortex (VMPFC), a region thought to down-regulate the fear response3,4,5,6,7. Accordingly, increasing endogenous VMPFC activity during the processing of fear-inducing stimuli may be a promising method to improve inhibition of fear and the effectiveness of exposure-based treatments.
Exposure-based psychotherapies, a first-line treatment for PTSD, aim to facilitate corrective learning by teaching patients that the hazardous experience (i.e., the cause of their PTSD) is no longer present or threatening in their current environment8,9. Emotional engagement in PTSD therapy is a crucial component of success10 but is hampered by patients wanting to avoid experiencing distressing emotions and the presence of comorbid psychiatric disorders. One appealing approach to maximize and track emotional engagement over sessions is using immersive and contextually relevant virtual reality (VR) environments11,12. VR implementation is supported by prior data indicating that VR could generate efficacy rates comparable to those observed with standard cognitive-behavioral interventions11,13,14. VR has the additional benefit of providing a standardized environment for treatment development for specific hypothesis testing.
The VR environment furthermore allows for the integration of adjunctive non-invasive brain stimulation methods, such as transcranial direct current stimulation (tDCS). tDCS alters cortical excitability via subthreshold modulation of neuronal resting membrane potentials using a weak (typically 1 &#8211; 2 mA) constant electrical current15. Stimulation is typically provided over a 20 &#8211; 30-minute period. Effects of tDCS are dependent upon the current polarity. Although an oversimplification, in theory, positive current flow (i.e., anodal stimulation) increases the likelihood of neuronal depolarization, whereas negative current flow (i.e. cathodal stimulation) decreases the likelihood of neuronal action potentials16,17. As such, tDCS readies the brain for subsequent responses to external stimuli to facilitate learning and memory18.
tDCS has a favorable safety profile as a low risk technique that is well tolerated and associated with minimal side effects19,20. tDCS is also inexpensive; tDCS devices cost around $9,000 compared to &#62;$70K for clinically available non-invasive brain stimulation methods, such as transcranial magnetic stimulation. tDCS devices are also portable, as they are battery powered, as opposed to needing a dedicated electrical circuit. This portability allows use in any office location or room, including at home. These factors enable tDCS to be used in combination with therapeutic interventions including VR and existing models of PTSD treatment. Flexible use may be particularly important in the new landscape delivering psychiatric care and non-invasive brain stimulation in the post-COVID19 world.
The protocol detailed below is designed to integrate tDCS during VR administration (tDCS+VR) in individuals with warzone-related PTSD in order to augment anxious habituation. The VR sessions allow for the exposure to trauma-related events to be standardized across participants to ensure a consistent content for this habituation. Participants undergo six sessions of tDCS+VR over the course of two to three weeks, with each session consisting of three identical VR drive-throughs. Six sessions were selected to approximate the duration of VR in Rothbaum et al.14 and Difede &#38; Hoffman21. This number of sessions showed efficacy in typical, non-VR treatment studies (e.g. Bryant et al.22) and was further informed by feasibility data from the prior pilot study23. Throughout each session, psychophysiology (i.e. skin conductance) is measured. This allows for testing of within and between session changes in hyperarousal to virtual reality events and adjunctive effects of tDCS. tDCS intensity is set at 2 mA and is delivered through a built-in rechargeable battery-driven stimulator that provides a constant, direct current using a 1 (anode) x 1 (cathode) unilateral electrode set-up. Each electrode is placed in a 3 x 3 cm (current density 2.22 A/m2) reusable sponge pocket saturated with 0.9% normal saline. Sponges with electrodes are attached to the participant&#8217;s skull using a rubber headband with the anode placed over Fp1 and AF3 regions and the cathode over PO8 of the 10 &#8211; 20 EEG electrode coordination system in order to target the ventromedial prefrontal cortex while preventing cathodal stimulation over the prefrontal cortex. Similar electrode montages, aimed to target the VMPFC, have been used to modulate the extinction of conditioned fear responses by our lab24,25 as well as others26. The virtual reality headset is placed over the tDCS montage in such a way as to avoid interference with tDCS electrodes. tDCS should start during the initiation of VR23 and continue throughout. Participants return for 1- and 3-month post-treatment assessment visits to assess longer-term effects of tDCS+VR on changes in symptoms of PTSD, depression, anxiety, and anger as well as improvements in sleep and quality of life. Hypotheses to be tested are 1A) the prediction that active tDCS+VR, compared to sham+VR, results in greater change on PTSD symptoms and quality of life/social function at end of treatment, and 1B) sustained change at 1- and 3- months post-treatment, and 2) that change in psychophysiological responses, reflective of habituation, relates to changes in PTSD symptoms and quality of life/functioning differently after active tDCS+VR versus sham+VR. This clinical trial is registered under ClinicalTrials.gov Identifier: NCT03372460.

<table>
	<tbody>
		<tr>
			<td>ECG data acquisition module</td>
			<td>Biopac</td>
			<td>Part #: ECG100C</td>
			<td>ECG100C Electrocardiogram Amplifier records electrical activity generated by the heart to record ECG.</td>
		</tr>
		<tr>
			<td>ECG electrode patches</td>
			<td>Biopac</td>
			<td>Part #:&#160;EL503, EL503-10</td>
			<td>These pre-gelled disposable electrodes have a circular contact and are most suitable for short-term recordings, including surface EMG, ECG, EOG, etc</td>
		</tr>
		<tr>
			<td>ECG leads</td>
			<td>Biopac</td>
			<td>2 x Part #: LEAD110</td>
			<td>These electrode leads are used with the EL500 series disposable snap electrodes.</td>
		</tr>
		<tr>
			<td>EDA/GSR acquisition module</td>
			<td>Biopac</td>
			<td>Part #:&#160;EDA100C</td>
			<td>The EDA100C Electrodermal Activity Amplifier measures both the skin conductance level (SCL) and skin conductance response (SCR) as they vary with sweat gland (eccrine) activity due to stress, arousal or emotional excitement.</td>
		</tr>
		<tr>
			<td>EDA/GSR electrode patches</td>
			<td>Biopac</td>
			<td>Part #:&#160;EL507, EL507-10</td>
			<td>These disposable snap electrodes are designed for electrodermal activity studies and are pre-gelled with isotonic gel. The latex-free electrodes conform and adhere well to fingers/hands. Use with LEAD110A or SS57L unshielded electrode lead.</td>
		</tr>
		<tr>
			<td>EDA/GSR leads</td>
			<td>Biopac</td>
			<td>2 x Part #:&#160;LEAD110, LEAD110A, LEAD110S-R, LEAD110S-W</td>
			<td>These electrode leads are used with the EL500 series disposable snap electrodes.</td>
		</tr>
		<tr>
			<td>HD/tDCS-Explore Neurotargeting Software</td>
			<td>Soterix Medical</td>
			<td>Contact Soterix Medical</td>
			<td>Software to assist in electrical field modeling and optimization of electrode montages for brain targeting. Free available options include ROAST and SIMNibs that run in Matlab.</td>
		</tr>
		<tr>
			<td>Psychophysiology (ECG &#38; EDA/GSR) analysis software</td>
			<td>Biopac</td>
			<td>Part #:&#160;ACK100W, ACK100M</td>
			<td>Biopac AcqKnowledge software data acquisition and analysis software allows for waveform analysis and instantly view, measure, analyze, and transform data.</td>
		</tr>
		<tr>
			<td>Psychophysiology measuring equipment for ECG and EDA/GSR</td>
			<td>Biopac</td>
			<td>Part #:&#160;MP160WSW, MP160WS</td>
			<td>MP160 data acquisition system; needs connected EDA/GSR and ECG modules ordered separately, see next two entries.</td>
		</tr>
		<tr>
			<td>Randomization and data capture software</td>
			<td>Redcap</td>
			<td>https://www.project-redcap.org/</td>
			<td>REDCap software and consortium support&#160;are available at no charge&#160;to non-profit organizations that join the REDCap consortium. Joining requires submission of a standard, online license agreement.</td>
		</tr>
		<tr>
			<td>Saline - 0.9% NaCi</td>
			<td>e.g Vitality Medical</td>
			<td>e.g. #37-6280</td>
			<td>Regular saline can be purchased from different vendors.</td>
		</tr>
		<tr>
			<td>tDCS electrodes and sponges</td>
			<td>Jali Medical (USA)</td>
			<td>Contact Jali Medical</td>
			<td>tDCS electrodes and sponges sold separately - contact vendor to order correct size (e.g. 5x5 cm)</td>
		</tr>
		<tr>
			<td>Transcranial direct current stimulator (tDCS)</td>
			<td>Jali Medical (USA)</td>
			<td>Contact Jali Medical</td>
			<td>The neuroConn DC-STIMULATOR PLUS* is a single-channel programmable direct and alternating Current Stimulator.</td>
		</tr>
		<tr>
			<td>Virtual reality system</td>
			<td>Virtually Better</td>
			<td>Contact Virtually better</td>
			<td>PTSD Suite from Virtually better &#34;Bravemind&#34; is an application for clinicians specializing in treating Posttraumatic Stress Disorder (PTSD).</td>
		</tr>
	</tbody>
</table>

simultaneous application of transcranial direct current stimulation during virtual reality exposure

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that changes the likelihood of neuronal firing through modulation of neural resting membranes. Compared to other techniques, tDCS is relatively safe, cost-effective, and can be administered while individuals are engaged in controlled, specific cognitive processes. This latter point is important as tDCS may predominantly affect intrinsically active neural regions. In an effort to test tDCS as a potential treatment for psychiatric illness, the protocol described here outlines a novel procedure that allows the simultaneous application of tDCS during exposure to trauma-related cues using virtual reality (tDCS+VR) for veterans with posttraumatic stress disorder (NCT03372460). In this double-blind protocol, participants are assigned to either receive 2 mA tDCS, or sham stimulation, for 25 minutes while passively watching three 8-minute standardized virtual reality drives through Iraq or Afghanistan, with virtual reality events increasing in intensity during each drive. Participants undergo six sessions of tDCS+VR over the course of 2-3 weeks, and psychophysiology (skin conductance reactivity) is measured throughout each session. This allows testing for within and between session changes in hyperarousal to virtual reality events and adjunctive effects of tDCS. Stimulation is delivered through a built-in rechargeable battery-driven tDCS device using a 1 (anode) x 1 (cathode) unilateral electrode set-up. Each electrode is placed in a 3 x 3 cm (current density 2.22 A/m2) reusable sponge pocket saturated with 0.9% normal saline. Sponges with electrodes are attached to the participant&#8217;s skull using a rubber headband with the electrodes placed such that they target regions within the ventromedial prefrontal cortex. The virtual reality headset is placed over the tDCS montage in such a way as to avoid electrode interference.

Representative results presented here reflect individual psychophysiological data tracings from four participants who completed the above outlined protocol. Enrolled participants are veterans with a diagnosis of PTSD and &#8211; in line with trial inclusion criteria &#8211; are between the ages of 18 and 70 years old. Given that this a currently ongoing double-blind, randomized sham-controlled trial (NCT03372460), it is not possible to present data pertaining to effectiveness of active tDCS versus sham. Therefore, individual raw, non-processed, skin conductance data tracings collected as part of this ongoing clinical trial are presented. This will provide preliminary insight into what could be expected, including obstacles when collecting psychophysiological data and skin conductance recordings in particular. Data on twelve veterans with warzone-related PTSD using the above protocol as part of a separate pilot study have previously been published23.
Based on visual inspection of the skin conductance traces, participant A (Figure 1) appears to show signs of between-session habituation from the first VR session to midpoint of protocol, during the third VR session, to the last, sixth VR session.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/61795/61795fig01.jpg" /> 
Figure 1: Example of raw skin conductance data tracing from participant A.&#160;Figure 1 shows screenshots of raw skin conductance data obtained during VR session 1 (top), VR session 3 (middle), and VR session 6 (bottom). Reductions in skin conductance reactivity indicate between-session habituation. VR sessions 2, 4, and 5 are not pictured to allow for better visual comparison of skin conductance tracings. <a href="https://www.jove.com/files/ftp_upload/61795/61795fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Visual inspection of participant B raw skin conductance tracing (Figure 2) appears to indicate within-session habituation when comparing the first drive-through (red square) to the third drive-through (green square). Prior studies suggest that although within-session habituation is important, between-session habituation may be a better predictor of prolonged exposure-based treatment success for PTSD33,34.
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/61795/61795fig02.jpg" /> 
Figure 2: Example of raw skin conductance data tracing from participant B.&#160;Figure 2 shows screenshots of raw skin conductance data obtained during the first drive (red square) and third drive (green square) of one VR session. Data represented in this figure may indicate within-session habituation from the first drive-through to the third drive-through. <a href="https://www.jove.com/files/ftp_upload/61795/61795fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Visual inspection of participant C raw skin conductance data (Figure 3) appears to show a less stark habituation profile compared to participant A (Figure 1), this participant nonetheless demonstrates both between- and within-session habituation. Furthermore, and similar to participant A, the skin conductance level is numerically higher during the first VR session as compared to the remaining five sessions.
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/61795/61795fig03.jpg" /> 
Figure 3: Example of raw skin conductance data tracing from participant C.&#160;Figure 3 shows raw skin conductance data screenshots from participant C for VR sessions 1 through 6 ordered from top to bottom. Participant C appears to demonstrate both between- and within-session habituation. <a href="https://www.jove.com/files/ftp_upload/61795/61795fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Raw skin conductance data from participant D (Figure 4) demonstrate a skin conductance level that can be considered too low for proper analyses with an absence of visually detectable skin conductance responses. As such, these data represent data collection failure. Although the raw data also reveal the presence of artifacts and electrode signal loss, the persistently low skin conductance levels and absence of visually detectable skin conductance responses across all six VR sessions is apparent for this individual.
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/61795/61795fig04.jpg" /> 
Figure 4: Example of raw skin conductance data tracing from participant D.&#160;Figure 4 shows raw skin conductance data screenshots from participant D during VR sessions 1 through 6, ordered from top to bottom, demonstrating unmeasurable skin conductance levels and responses, as well as artifacts (blue ovals) and EDA electrode signal loss (green square). <a href="https://www.jove.com/files/ftp_upload/61795/61795fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Simultaneous Application of Transcranial Direct Current Stimulation during Virtual Reality Exposure at JoVE.com

Simultaneous Application of Transcranial Direct Current Stimulation during Virtual Reality Exposure

This manuscript outlines a novel protocol to allow the simultaneous application of transcranial direct current stimulation during exposure to warzone trauma-related cues using virtual reality for veterans with posttraumatic stress disorder.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that changes the likelihood of neuronal firing through ...

simultaneous-application-transcranial-direct-current-stimulation

Research

JoVE Journal

Neuroscience

3.8K Views.  Providence VA Medical Healthcare System. This manuscript outlines a novel protocol to allow the simultaneous application of transcranial direct current stimulation during exposure to warzone trauma-related cues using virtual reality for veterans with posttraumatic stress disorder.

Video: Simultaneous Application of Transcranial Direct Current Stimulation during Virtual Reality Exposure

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 ...

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 ...

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, ...

In Vivo Intracellular Recording of Type-Identified Rat Spinal Motoneurons During Trans-Spinal Direct Current Stimulation

Intracellular recording of spinal motoneurons in vivo provides a &#8220;gold standard&#8221; for determining the cells&#8217; electrophysiological characteristics in the intact spinal network and holds significant advantages relative to classical in vitro or extracellular recording techniques. An advantage of in vivo intracellular recordings is that this method can be performed on adult animals with a fully mature nervous system, and therefore many observed physiological mechanisms can be translated to practical applications. In this methodological paper, we describe this procedure combined with externally applied constant current stimulation, which mimics polarization processes occurring within spinal neuronal networks. Trans-spinal direct current stimulation (tsDCS) is an innovative method increasingly used as a neuromodulatory intervention in rehabilitation after various neurological injuries as well as in sports. The influence of tsDCS on the nervous system remains poorly understood and the physiological mechanisms behind its actions are largely unknown. The application of the tsDCS simultaneously with intracellular recordings enables us to directly observe changes of motoneuron membrane properties and characteristics of rhythmic firing in response to the polarization of the spinal neuronal network, which is crucial for the understanding of tsDCS actions. Moreover, when the presented protocol includes the identification of the motoneuron with respect to an innervated muscle and its function (flexor versus extensor) as well as the physiological type (fast versus slow) it provides an opportunity to selectively investigate the influence of tsDCS on identified components of spinal circuitry, which seem to be differently affected by polarization. The presented procedure focuses on surgical preparation for intracellular recordings and stimulation with an emphasis on the steps which are necessary to achieve preparation stability and reproducibility of results. The details of the methodology of the anodal or cathodal tsDCS application are discussed while paying attention to practical and safety issues.

This protocol describes in vivo intracellular recording of rat lumbar motoneurons with simultaneous trans-spinal direct current stimulation. The method enables us to measure membrane properties and to record rhythmic firing of motoneurons before, during and after anodal or cathodal polarization of the spinal cord.

Intracellular recording of spinal motoneurons in vivo provides a &#8220;gold standard&#8221; for determining the cells&#8217; electrophysiological ...

Transcranial Direct Current Stimulation (tDCS) for Memory Enhancement

Memory enhancement is one of the great challenges in cognitive neuroscience and neurorehabilitation. Among various techniques used for memory enhancement, transcranial direct current stimulation (tDCS) is emerging as an especially promising tool for improvement of memory functions in a non-invasive manner. Here, we present a tDCS protocol that can be applied for memory enhancement in healthy-participant studies as well as in aging and dementia research. The protocol uses weak constant anodal current to stimulate cortical targets within cortico-hippocampal functional network engaged in memory processes. The target electrode is placed either on the posterior parietal cortex (PPC) or the dorsolateral prefrontal cortex (DLPFC), while the return electrode is placed extracranially (i.e., on the contralateral cheek). In addition, we outline a more advanced method of oscillatory tDCS, mimicking a natural brain rhythm to promote hippocampus-dependent memory functions, which can be applied in a personalized and non-personalized manner. We present illustrative results of associative and working memory improvement following single tDCS sessions (20 minutes) in which the described electrode montages were used with current intensities between 1.5 mA and 1.8 mA. Finally, we discuss crucial steps in the protocol and methodological decisions that must be made when designing a tDCS study on memory.

Transcranial Direct Current Stimulation tDCS for Memory Enhancement

A protocol for memory enhancement by using transcranial direct current stimulation (tDCS) targeting dorsolateral prefrontal and posterior parietal cortices, as core cortical nodes within hippocampo-cortical network, is presented. The protocol has been well evaluated in healthy-participant studies and is applicable to aging and dementia research as well.

Memory enhancement is one of the great challenges in cognitive neuroscience and neurorehabilitation. Among various techniques used for memory enhancement, ...

Treatment of Phantom Limb Pain by Remote Transcranial Direct Current Stimulation

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.

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).

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

Neuronavigated tDCS for Enhanced Electrode Placement Accuracy in fMRI Studies

Neuronavigated Focalized Transcranial Direct Current Stimulation Administered During Functional Magnetic Resonance Imaging

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that allows the modulation of the excitability and plasticity of the human brain. Focalized tDCS setups use specific electrode arrangements to constrain the current flow to circumscribed brain regions. However, the effectiveness of focalized tDCS can be compromised by electrode positioning errors on the scalp, resulting in significant reductions of the current dose reaching the target brain regions for tDCS. Electrode placement guided by neuronavigation based on the individual&#39;s head and brain anatomy derived from structural magnetic resonance imaging (MRI) data may be suited to improve positioning accuracy.
This protocol describes the method of neuronavigated electrode placement for a focalized tDCS setup, which is suitable for concurrent administration during functional MRI (fMRI). We also quantify the accuracy of electrode placement and investigate electrode drift in a concurrent tDCS-fMRI experiment. Critical steps involve the optimization of electrode positions based on current modeling that considers the individual&#39;s head and brain anatomy, the implementation of neuronavigated electrode placement on the scalp, and the administration of optimized and focal tDCS during fMRI.
The regional precision of electrode placement is quantified using the Euclidean norm (L2&#160;Norm) to determine deviations of the actual from the intended electrode positions during a concurrent tDCS-fMRI study. Any potential displacement of electrodes (drift) during the experiment is investigated by comparing actual electrode positions before and after the fMRI acquisition. In addition, we directly compare the placement accuracy of neuronavigated tDCS to that achieved by a scalp-based targeting approach (a 10-20 Electroencephalography (EEG) system). These analyses demonstrate superior placement accuracy for neuronavigation compared to scalp-based electrode placement and negligible electrode drift across a 20 min scanning period.

This protocol describes the method of neuronavigated electrode placement for focal, transcranial direct current stimulation (tDCS) administered during functional magnetic resonance imaging (fMRI).

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that allows the modulation of the excitability and plasticity ...