Name: simultaneous application of transcranial direct current stimulation during virtual reality exposure
Uploaded: 2021-01-18T13:00:00
Duration: 8 min 20 s
Description: Watch this Scientific Journal Video about Simultaneous Application of Transcranial Direct Current Stimulation during Virtual Reality Exposure at JoVE.com

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>
	<li>Watts, B. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Meta-analysis+of+the+efficacy+of+treatments+for+posttraumatic+stress+disorder.">Meta-analysis of the efficacy of treatments for posttraumatic stress disorder.</a> Journal of Clinical Psychiatry. 74 (6), 541-550 (2013).</li><li>Rothbaum, B. O., Davis, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Applying+learning+principles+to+the+treatment+of+post-trauma+reactions.">Applying learning principles to the treatment of post-trauma reactions.</a> Annals of the New York Academy of Sciences. 1008 (1), 112-121 (2003).</li><li>VanElzakker, M. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=From+Pavlov+to+PTSD:+the+extinction+of+conditioned+fear+in+rodents,+humans,+and+anxiety+disorders.">From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.</a> Neurobiology of Learning and Memory. 113, 3-18 (2014).</li><li>Quirk, G. J., Garcia, R., Gonz&#225;lez-Lima, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prefrontal+mechanisms+in+extinction+of+conditioned+fear.">Prefrontal mechanisms in extinction of conditioned fear.</a> Biological Psychiatry. 60 (4), 337-343 (2006).</li><li>Etkin, A., Wager, T. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Functional+neuroimaging+of+anxiety:+a+meta-analysis+of+emotional+processing+in+PTSD,+social+anxiety+disorder,+and+specific+phobia.">Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.</a> American Journal of Psychiatry. 164 (10), 1476-1488 (2007).</li><li>Milad, M. R., Quirk, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fear+extinction+as+a+model+for+translational+neuroscience:+ten+years+of+progress.">Fear extinction as a model for translational neuroscience: ten years of progress.</a> Annual Review of Psychology. 63, 129-151 (2012).</li><li>Koch, S. B. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Aberrant+resting-state+brain+activity+in+posttraumatic+stress+disorder:+a+meta-analysis+and+systematic+review.">Aberrant resting-state brain activity in posttraumatic stress disorder: a meta-analysis and systematic review.</a> Depression and Anxiety. 33 (7), 592-605 (2016).</li><li>Foa, E. B., Kozak, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Emotional+processing+of+fear:+exposure+to+corrective+information.">Emotional processing of fear: exposure to corrective information.</a> Psychological Bulletin. 99 (1), 20-35 (1986).</li><li>Foa, E. B., Keane, T. M., Friedman, M. J., Cohen, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Effective treatments for PTSD: practice guidelines from the International Society for Traumatic Stress Studies. , (2008).</li><li>Foa, E. B., Huppert, J. D., Cahill, S. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Emotional+processing+theory:+An+update.">Emotional processing theory: An update.</a> Pathological anxiety: Emotional processing in etiology and treatment. , 3-24 (2006).</li><li>Opris, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Virtual+reality+exposure+therapy+in+anxiety+disorders:+a+quantitative+meta-analysis.">Virtual reality exposure therapy in anxiety disorders: a quantitative meta-analysis.</a> Depression and Anxiety. 29 (2), 85-93 (2012).</li><li>Wiederhold, B. K., Rizzo, A. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Virtual+reality+and+applied+psychophysiology.">Virtual reality and applied psychophysiology.</a> Applied Psychophysiology and Biofeedback. 30 (3), 183-185 (2005).</li><li>Sherman, J. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+psychotherapeutic+treatments+for+PTSD:+a+meta-analysis+of+controlled+clinical+trials.">Effects of psychotherapeutic treatments for PTSD: a meta-analysis of controlled clinical trials.</a> Journal of Traumatic Stress. 11 (3), 413-435 (1998).</li><li>Rothbaum, B. O., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+randomized,+double-blind+evaluation+of+D-cycloserine+or+alprazolam+combined+with+virtual+reality+exposure+therapy+for+posttraumatic+stress+disorder+in+Iraq+and+Afghanistan+War+veterans.">A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans.</a> American Journal of Psychiatry. 171 (6), 640-648 (2014).</li><li>Nitsche, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+direct+current+stimulation:+state+of+the+art+2008.">Transcranial direct current stimulation: state of the art 2008.</a> Brain Stimulation. 1 (3), 206-223 (2008).</li><li>Datta, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gyri+-precise+head+model+of+transcranial+DC+stimulation:+improved+spatial+focality+using+a+ring+electrode+versus+conventional+rectangular+pad.">Gyri -precise head model of transcranial DC stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.</a> Brain Stimulation. 2 (4), 201-207 (2009).</li><li>Lafon, B., Rahman, A., Bikson, M., Parra, L. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Direct+Current+Stimulation+alters+neuronal+input/output+function.">Direct Current Stimulation alters neuronal input/output function.</a> Brain Stimulation. 10 (1), 36-45 (2017).</li><li>Coffman, B. A., Clark, V. P., Parasuraman, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Battery+powered+thought:+enhancement+of+attention,+learning,+and+memory+in+healthy+adults+using+transcranial+direct+current+stimulation.">Battery powered thought: enhancement of attention, learning, and memory in healthy adults using transcranial direct current stimulation.</a> Neuroimage. 85, 895-908 (2014).</li><li>Poreisz, C., Boros, K., Antal, A., Paulus, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+aspects+of+transcranial+direct+current+stimulation+concerning+healthy+subjects+and+patients.">Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients.</a> Brain Research Bulletin. 72, 208-214 (2007).</li><li>Bikson, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+of+transcranial+direct+current+stimulation:+evidence+based+update+2016.">Safety of transcranial direct current stimulation: evidence based update 2016.</a> Brain Stimulation. 9, 641-661 (2016).</li><li>Difede, J., Hoffman, H., Jaysinghe, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Innovative+use+of+virtual+reality+technology+in+the+treatment+of+PTSD+in+the+aftermath+of+September+11.">Innovative use of virtual reality technology in the treatment of PTSD in the aftermath of September 11.</a> Psychiatric Services. 53 (9), 1083-1085 (2002).</li><li>Bryant, R. A., Moulds, M. L., Guthrie, R. M., Dang, S. T., Nixon, R. D. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Imaginal+exposure+alone+and+imaginal+exposure+with+cognitive+restructuring+in+treatment+of+posttraumatic+stress+disorder.">Imaginal exposure alone and imaginal exposure with cognitive restructuring in treatment of posttraumatic stress disorder.</a> Journal of Consulting and Clinical Psychology. 71 (4), 706-712 (2003).</li><li>van't Wout, M., Shea, M. T., Larson, V., Greenberg, B., Phillip, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Combined+transcranial+direct+current+stimulation+with+virtual+reality+exposure+for+posttraumatic+stress+disorder:+feasibility+and+pilot+results.">Combined transcranial direct current stimulation with virtual reality exposure for posttraumatic stress disorder: feasibility and pilot results.</a> Brain Stimulation. 12 (1), 41-43 (2019).</li><li>van't Wout, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Can+transcranial+direct+current+stimulation+augment+extinction+of+conditioned+fear.">Can transcranial direct current stimulation augment extinction of conditioned fear.</a> Brain Stimulation. 9 (4), 529-536 (2016).</li><li>van't Wout, M., Longo, S. M., Reddy, M. K., Philip, N. S., Bowker, M. T., Greenberg, B. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+direct+current+stimulation+may+modulate+extinction+memory+in+posttraumatic+stress+disorder.">Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder.</a> Brain and behavior. 7 (5), 00681 (2017).</li><li>Vicario, C. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anodal+transcranial+direct+current+stimulation+over+the+ventromedial+prefrontal+cortex+enhances+fear+extinction+in+healthy+humans:+A+single+blind+sham-controlled+study.">Anodal transcranial direct current stimulation over the ventromedial prefrontal cortex enhances fear extinction in healthy humans: A single blind sham-controlled study.</a> Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 13 (2), 489-491 (2020).</li><li>First, M., Williams, J., Karg, R., Spitzer, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Structured+Clinical+Interview+for+DSM-5+Disorders-Research+Version+(SCID-5-RV).">Structured Clinical Interview for DSM-5 Disorders-Research Version (SCID-5-RV).</a> American Psychiatric Assocation. , (2014).</li><li>Weathers, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+clinician-administered+PTSD+scale+for+DSM-5+(CAPS-5).">The clinician-administered PTSD scale for DSM-5 (CAPS-5).</a> National Center for PTSD. , (2013).</li><li>Weathers, F. W., Litz, B. T., Keane, T. M., Palmieri, P. A., Marx, B. P., Schnurr, P. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+PTSD+checklist+for+dsm-5+(pcl-5).">The PTSD checklist for dsm-5 (pcl-5).</a> National Center for PTSD. , (2013).</li><li>Rush, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+16-Item+Quick+Inventory+of+Depressive+Symptomatology+(QIDS),+clinician+rating+(QIDS-C),+and+self-report+(QIDS-SR):+a+psychometric+evaluation+in+patients+with+chronic+major+depression.">The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.</a> Biological Psychiatry. 54 (5), 573-583 (2003).</li><li>van't Wout, M., Silverman, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modulating+what+is+and+what+could+have+been:+The+effect+of+transcranial+direct+current+stimulation+on+the+evaluation+of+attained+and+unattained+decision+outcomes.">Modulating what is and what could have been: The effect of transcranial direct current stimulation on the evaluation of attained and unattained decision outcomes.</a> Cognitive, Affective, &amp; Behavioral Neuroscience. 17 (6), 1176-1185 (2017).</li><li>Brunoni, A. R., Amadera, J., Berbel, B., Volz, M. S., Rizzerio, B. G., Fregni, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+systematic+review+on+reporting+and+assessment+of+adverse+effects+associated+with+transcranial+direct+current+stimulation.">A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.</a> International Journal of Neuropsychopharmacology. 14 (8), 1133-1145 (2011).</li><li>van Minnen, A., Hagenaars, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fear+activation+and+habituation+patterns+as+early+process+predictors+of+response+to+prolonged+exposure+treatment+in+PTSD.">Fear activation and habituation patterns as early process predictors of response to prolonged exposure treatment in PTSD.</a> Journal of Traumatic Stress: Official Publication of The International Society for Traumatic Stress Studies. 15 (5), 359-367 (2002).</li><li>Sripada, R. K., Rauch, S. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Between-session+and+within-session+habituation+in+prolonged+exposure+therapy+for+posttraumatic+stress+disorder:+a+hierarchical+linear+modeling+approach.">Between-session and within-session habituation in prolonged exposure therapy for posttraumatic stress disorder: a hierarchical linear modeling approach.</a> Journal of Anxiety Disorders. 30, 81-87 (2015).</li><li>Palm, U., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+role+of+contact+media+at+the+skin-electrode+interface+during+transcranial+direct+current+stimulation+(tDCS).">The role of contact media at the skin-electrode interface during transcranial direct current stimulation (tDCS).</a> Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 7 (5), 762-764 (2014).</li><li>Palm, U., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+direct+current+stimulation+in+treatment+resistant+depression:+A+randomized+double-blind,+placebo-controlled+study.">Transcranial direct current stimulation in treatment resistant depression: A randomized double-blind, placebo-controlled study.</a> Brain stimulation. 5 (3), 242-251 (2012).</li><li>Loo, C. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Avoiding+skin+burns+with+transcranial+direct+current+stimulation:+preliminary+considerations.">Avoiding skin burns with transcranial direct current stimulation: preliminary considerations.</a> International Journal of Neuropsychopharmacology. 14 (3), 425-426 (2011).</li><li>Lagopoulos, J., Degabriele, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Feeling+the+heat:+the+electrode-skin+interface+during+DCS.">Feeling the heat: the electrode-skin interface during DCS.</a> Acta Neuropsychiatrica. 20 (2), 98-100 (2008).</li><li>Horvath, J. C., Carter, O., Forte, J. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+direct+current+stimulation:+five+important+issues+we+aren't+discussing+(but+probably+should+be).">Transcranial direct current stimulation: five important issues we aren't discussing (but probably should be).</a> Frontiers in systems neuroscience. 8, 2 (2014).</li><li>Boucsein, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Electrodermal activity(2nd ed). , (2012).</li><li>Boucsein, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Publication+Recommendations+for+Electrodermal+Measurements.">Publication Recommendations for Electrodermal Measurements.</a> Psychophysiology. 49 (8), 1017-1034 (2012).</li></ol>

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 ...

Research

JoVE Journal

Neuroscience

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 ...

Extracting Visual Evoked Potentials from EEG Data Recorded During fMRI-guided Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation (TMS) is an effective method for establishing a causal link between a cortical area and cognitive/neurophysiological ...

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

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

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 ...

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 ...

Transcranial Electrical Brain Stimulation in Alert Rodents

Transcranial electrical brain stimulation can modulate cortical excitability and plasticity in humans and rodents. The most common form of stimulation in ...

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 ...

Transcranial Direct Current Stimulation (tDCS) in Mice

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 ...

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, ...