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.

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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 #:&amp;nbsp;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 #:&amp;nbsp;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 #:&amp;nbsp;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 #:&amp;nbsp;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 &amp;amp; EDA/GSR) analysis software</td><td>Biopac</td><td>Part #:&amp;nbsp;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 #:&amp;nbsp;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&amp;nbsp;are available at no charge&amp;nbsp;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 &quot;Bravemind&quot; 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

4.0K 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

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

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

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

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

Behavior

Transcranial Direct Current Stimulation and Simultaneous  Functional Magnetic Resonance Imaging

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

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

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

Modulating Cognition Using Transcranial Direct Current Stimulation of the Cerebellum

Numerous studies have emerged recently that demonstrate the possibility of modulating, and in some cases enhancing, cognitive processes by exciting brain regions involved in working memory and attention using transcranial electrical brain stimulation. Some researchers now believe the cerebellum supports cognition, possibly via a remote neuromodulatory effect on the prefrontal cortex. This paper describes a procedure for investigating a role for the cerebellum in cognition using transcranial direct current stimulation (tDCS), and a selection of information-processing tasks of varying task difficulty, which have previously been shown to involve working memory, attention and cerebellar functioning. One task is called the Paced Auditory Serial Addition Task (PASAT) and the other a novel variant of this task called the Paced Auditory Serial Subtraction Task (PASST). A verb generation task and its two controls (noun and verb reading) were also investigated. All five tasks were performed by three separate groups of participants, before and after the modulation of cortico-cerebellar connectivity using anodal, cathodal or sham tDCS over the right cerebellar cortex. The procedure demonstrates how performance (accuracy, verbal response latency and variability) could be selectively improved after cathodal stimulation, but only during tasks that the participants rated as difficult, and not easy. Performance was unchanged by anodal or sham stimulation. These findings demonstrate a role for the cerebellum in cognition, whereby activity in the left prefrontal cortex is likely dis-inhibited by cathodal tDCS over the right cerebellar cortex. Transcranial brain stimulation is growing in popularity in various labs and clinics. However, the after-effects of tDCS are inconsistent between individuals and not always polarity-specific, and may even be task- or load-specific, all of which requires further study. Future efforts might also be guided towards neuro-enhancement in cerebellar patients presenting with cognitive impairment once a better understanding of brain stimulation mechanisms has emerged.

Transcranial direct current stimulation (tDCS) over the cerebellum exerts a remote effect on the prefrontal cortex, which can modulate cognition and performance. This was demonstrated using two information-processing tasks of varying complexity, whereby only cathodal tDCS improved performance when the task was difficult, but not easy.

Numerous studies have emerged recently that demonstrate the possibility of modulating, and in some cases enhancing, cognitive processes by exciting brain ...

Simultaneous Transcranial Alternating Current Stimulation and Functional Magnetic Resonance Imaging

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs frequency-specific stimulation of the human brain through current applied to the scalp with surface electrodes. Most current knowledge of the technique is based on behavioral studies; thus, combining the method with brain imaging holds potential to better understand the mechanisms of tACS. Because of electrical and susceptibility artifacts, combining tACS with brain imaging can be challenging, however, one brain imaging technique that is well suited to be applied simultaneously with tACS is functional magnetic resonance imaging (fMRI). In our lab, we have successfully combined tACS with simultaneous fMRI measurements to show that tACS effects are state, current, and frequency dependent, and that modulation of brain activity is not limited to the area directly below the electrodes. This article describes a safe and reliable setup for applying tACS simultaneously with visual task fMRI studies, which can lend to understanding oscillatory brain function as well as the effects of tACS on the brain.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations, though its effects are not completely understood. This article describes a safe and reliable setup for applying tACS simultaneously with functional magnetic resonance imaging, which can increase understanding oscillatory brain function and effects of tACS.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs ...

Transcranial Direct Current Stimulation for Online Gamers

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that applies a weak electric current to the scalp to modulate neuronal membrane potentials. Compared to other brain stimulation methods, tDCS is relatively safe, simple, and inexpensive to administer.
Since excessive online gaming can negatively affect mental health and daily functioning, developing treatment options for gamers is necessary. Although tDCS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated promising results for various addictions, it has not been tested in gamers. This paper describes a protocol and a feasibility study for applying repeated tDCS over the DLPFC and neuroimaging to examine the underlying neural correlates in gamers.
At baseline, individuals who play online games report average weekly hours spent on games, complete questionnaires on addiction symptoms and self-control, and undergo brain 18F-&#64258;uoro-2-deoxyglucose positron emission tomography (FDG-PET). The tDCS protocol consists of 12 sessions over the DLPFC for 4 weeks (anode F3/cathode F4, 2 mA for 30 min per session). Then, a follow-up is conducted using the same protocol as the baseline. Individuals who do not play online games receive only baseline FDG-PET scans without tDCS. Changes of clinical characteristics and asymmetry of regional cerebral metabolic rate of glucose (rCMRglu) in the DLPFC are examined in gamers. In addition, asymmetry of rCMRglu is compared between gamers and non-gamers at baseline.
In our experiment, 15 gamers received tDCS sessions and completed baseline and follow-up scans. Ten non-gamers underwent FDG-PET scans at the baseline. The tDCS reduced addiction symptoms, time spent on games, and increased self-control. Moreover, abnormal asymmetry of rCMRglu in the DLPFC at baseline was alleviated after tDCS.
The current protocol may be useful for assessing treatment efficacy of tDCS and its underlying brain changes in gamers. Further randomized sham-controlled studies are warranted. Moreover, the protocol can be applied to other neurological and psychiatric disorders.

We present a protocol and a feasibility study for applying transcranial direct current stimulation (tDCS) and neuroimaging assessment in online gamers.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that applies a weak electric current to the scalp to modulate ...

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 ...

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 ...

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

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

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

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

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

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

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

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

Medicine

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 ...