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Randomized Single Blind Sham Controlled Trial of Adjunctive Home-Based tDCS after rTMS for Mal De Debarquement Syndrome: Safety, Efficacy, and Participant Satisfaction Assessment

Open AccessPublished:March 30, 2016DOI:https://doi.org/10.1016/j.brs.2016.03.016

      Highlights

      • A home-based tDCS treatment program can be safely administered by non-medical or research professionals given adequate teaching, ongoing communication, frequent feedback, and controlled device settings.
      • Real tDCS after an induction period of five days of rTMS leads to better maintenance of rTMS induced benefits than sham tDCS after four-weeks of treatment for MdDS.
      • The rate of skin irritation and overall side effect profile was low with self-administered tDCS.
      • tDCS may be a reasonable primary or adjunctive treatment in MdDS and may avoid the need for travel, which can potentially exacerbate this syndrome.

      Abstract

      Background

      Mal de debarquement syndrome is a medically refractory disorder characterized by chronic rocking dizziness that occurs after exposure to passive motion. Repetitive transcranial magnetic stimulation (rTMS) can acutely suppress the rocking dizziness but treatment options that extend the benefit of rTMS are needed.

      Objectives

      1) To determine whether transcranial direct current stimulation (tDCS) added after rTMS can extend the benefit of rTMS; 2) to determine whether participants can safely perform tDCS at home.

      Methods

      Participants were given five days of rTMS (1 Hz right DLPFC/10 Hz left DLPFC in right-handers, vice versa in left-handers), according to a previously piloted protocol. They received three days of training on tDCS self-administration and were then randomized to either real or sham tDCS for four-weeks (anode left DLPFC/cathode right DLPFC for right-handers, vice versa for left-handers).

      Results

      Twenty-three participants completed the study. Those who received real tDCS after rTMS showed significant improvements in the degree of rocking perception as measured by the MdDS Balance Rating Scale and anxiety ratings by Week 4 of tDCS and a trend for improvement on the Dizziness Handicap Inventory. Two rTMS non-responders responded well to subsequent open-label tDCS. Side effects were mild and not different between real and sham tDCS. There were no episodes of skin burns in a group total of 556 sessions of tDCS. Satisfaction was rated high.

      Conclusions

      Home-based tDCS can be performed safely and may be beneficial in selected individuals. Adequate teaching, automatic device safety features, and a good communications infrastructure are components of successful home therapy.

      Keywords

      Introduction

      Neuromodulation therapies that involve low levels of current applied transcranially represent a powerful new option for treating a growing number of neurological and psychiatric disorders [
      • Fregni F.
      • Freedman S.
      • Pascual-Leone A.
      Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques.
      ,
      • Brunoni A.R.
      • Ferrucci R.
      • Fregni F.
      • Boggio P.S.
      • Priori A.
      Transcranial direct current stimulation for the treatment of major depressive disorder: a summary of preclinical, clinical and translational findings.
      ,
      • Schlaug G.
      • Renga V.
      Transcranial direct current stimulation: a noninvasive tool to facilitate stroke recovery.
      ,
      • Vanneste S.
      • De Ridder D.
      Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity.
      ]. One form, transcranial direct current stimulation (tDCS), involves directionally applied current through one or more anodes and cathodes [
      • Paulus W.
      Transcranial electrical stimulation (tES–tDCS; tRNS, tACS) methods.
      ,
      • Been G.
      • Ngo T.T.
      • Miller S.M.
      • Fitzgerald P.B.
      The use of tDCS and CVS as methods of non-invasive brain stimulation.
      ]. Scientific interest in expanding neuromodulation programs into the home environment has been gaining traction as larger scale studies have shown safety and tolerability of transcranially applied electrical current when monitored by investigators [
      • Paneri B.
      • Khadka N.
      • Patel V.
      • Thomas C.
      • Tyler W.J.
      • Parra L.
      • et al.
      The tolerability of transcranial electrical stimulation used across extended periods in a naturalistic context by healthy individuals.
      ,
      • Cabrera L.Y.
      • Reiner P.B.
      Understanding public (mis)understanding of tDCS for enhancement.
      ,
      • O'Neill F.
      • Sacco P.
      • Nurmikko T.
      Evaluation of a home-based transcranial direct current stimulation (tDCS) treatment device for chronic pain: study protocol for a randomised controlled trial.
      ]. Currently, there is both a need to invest in studies that fine tune the application of these cranial electrical therapies as well to bring some of the more promising benefits into the clinical realm, especially for patients who have been otherwise deemed to be “medically refractory.” However, one obstacle in transitioning these therapies into clinical care has been in the development of infrastructure and methods to ensure safety and compliance of treatment given outside of controlled research settings [
      • Charvet L.E.
      • Kasschau M.
      • Datta A.
      • Knotkova H.
      • Stevens M.C.
      • Alonzo A.
      • et al.
      Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols.
      ]. The excellent safety record of tDCS sessions within research settings suggests that, with appropriate safeguards, these treatments might be safely administered by patients at home [
      • Poreisz C.
      • Boros K.
      • Antal A.
      • Paulus W.
      Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients.
      ]. Public perception of tDCS has been shifting toward growing acceptance of brain stimulation for either treatment of symptoms or for personal enhancement, but there are still challenges in striking a balance between freedom and control in making these treatments more generally accessible [
      • Fitz N.S.
      • Reiner P.B.
      The challenge of crafting policy for do-it-yourself brain stimulation.
      ]. Herein we describe our experience with administering a home-based tDCS program for a disorder called mal de debarquement syndrome (MdDS), a disorder induced and exacerbated by travel with high morbidity and limited treatment options [
      • Cha Y.H.
      Mal de debarquement.
      ]. The exploration of a home-based tDCS program for MdDS represents a unique opportunity from a benefit to risk standpoint of translating transcranial electrical therapy into the home environment and can serve as a case study in how a home-based program can be managed.
      MdDS is characterized by chronic rocking dizziness that occurs after prolonged exposure to oscillating motion, such as occurs on a boat, plane, or automobile [
      • Cha Y.H.
      Mal de debarquement.
      ]. Short periods of self-motion perceptions that occur after exposure to passive motion have been described in over 70% of healthy young individuals, but they rarely last more than two days [
      • Gordon C.R.
      • Spitzer O.
      • Doweck I.
      • Melamed Y.
      • Shupak A.
      Clinical features of mal de debarquement: adaptation and habituation to sea conditions.
      ,
      • Cohen H.
      Mild mal de debarquement after sailing.
      ,
      • Gordon C.R.
      • Shupak A.
      • Nachum Z.
      • Hain T.C.
      Mal de debarquement.
      ]. However, in some individuals, the symptoms can last for months or years leading to significant disability [
      • Cha Y.H.
      • Brodsky J.
      • Ishiyama G.
      • Sabatti C.
      • Baloh R.W.
      Clinical features and associated syndromes of mal de debarquement.
      ,
      • Macke A.
      • Leporte A.
      • Clark B.C.
      Social, societal, and economic burden of mal de debarquement syndrome.
      ]. Re-exposure to passive motion, such as when the individual is driving a car, flying in a plane, or getting back on the boat, temporarily relieves the internal feeling of rocking motion [
      • Cha Y.H.
      Mal de debarquement.
      ,
      • Hain T.C.
      • Hanna P.A.
      • Rheinberger M.A.
      Mal de debarquement.
      ]. Unfortunately, once the external motion stops the internal motion perception returns and is often worse than baseline. Treatment options for MdDS are extremely limited and symptoms that last longer than six months only occasionally resolve on their own [
      • Cha Y.H.
      • Brodsky J.
      • Ishiyama G.
      • Sabatti C.
      • Baloh R.W.
      Clinical features and associated syndromes of mal de debarquement.
      ,
      • Cha Y.H.
      Mal de debarquement syndrome: new insights.
      ]. Prior efforts of applying different forms of neuromodulation by either repetitive transcranial magnetic stimulation (rTMS) or a vestibular-ocular reflex re-adaption paradigm have been confounded by treatment effects being reversed by the participant traveling back home [
      • Dai M.
      • Cohen B.
      • Smouha E.
      • Cho C.
      Readaptation of the vestibulo-ocular reflex relieves the mal de debarquement syndrome.
      ].
      In a prior study, we determined that 10 Hz repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) opposite the dominant hand, or 1 Hz rTMS to the DLPFC ipsilateral to the dominant hand, could temporarily reduce the rocking dizziness of MdDS [
      • Cha Y.H.
      • Cui Y.
      • Baloh R.W.
      Repetitive transcranial magnetic stimulation for mal de debarquement syndrome.
      ]. In this study, the lateralization of treatment response was quite pronounced in that left-handed participants were worsened by l0 Hz left DLPFC stimulation but were significantly benefitted by 10 Hz right DLPFC stimulation. Both open-label and sham-controlled studies using a modified version of this rTMS protocol have shown efficacy in acutely reducing the rocking perception [
      • Pearce A.J.
      • Davies C.P.
      • Major B.P.
      Efficacy of neurostimulation to treat symptoms of Mal de Debarquement Syndrome. A preliminary study using repetitive transcranial magnetic stimulation.
      ,
      • Ding L.
      • Shou G.
      • Yuan H.
      • Urbano D.
      • Cha Y.H.
      Lasting modulation effects of rTMS on neural activity and connectivity as revealed by resting state EEG.
      ]. Finally, a double-blind placebo controlled trial of five days of 10 Hz left DLPFC stimulation in right-handed individuals has shown efficacy significantly beyond the treatment period but with eventual return of symptoms (Cha et al. in press Otol Neurotol [
      • Cha Y.H.
      • Deblieck C.
      • Wu A.
      Double-blind sham-controlled cross-over trial of repetitive transcranial magnetic stimulation for Mal de Debarquement Syndrome.
      ]).
      Because MdDS is a travel related disorder, we were faced with the challenge of providing a neuromodulation treatment that may extend the benefit of rTMS but be manageable in the home environment. Our goals in this study therefore were to determine the following: 1) whether the addition of tDCS after an induction treatment with five days of rTMS could prolong the improvement seen with rTMS, 2) whether participants could apply the tDCS sessions on themselves safely, and 3) what user interface issues are important in treatment compliance and user satisfaction. We used our previously determined rTMS protocol, switching the sides of stimulation for left-handed participants [
      • Cha Y.H.
      • Cui Y.
      • Baloh R.W.
      Repetitive transcranial magnetic stimulation for mal de debarquement syndrome.
      ,
      • Pearce A.J.
      • Davies C.P.
      • Major B.P.
      Efficacy of neurostimulation to treat symptoms of Mal de Debarquement Syndrome. A preliminary study using repetitive transcranial magnetic stimulation.
      ,
      • Ding L.
      • Shou G.
      • Yuan H.
      • Urbano D.
      • Cha Y.H.
      Lasting modulation effects of rTMS on neural activity and connectivity as revealed by resting state EEG.
      ]. This was an exploratory single-blind sham-controlled study designed to determine feasibility for remotely supervised tDCS treatments that could be used for larger scale studies. The main outcome measure was the Dizziness Handicap Inventory [
      • Jacobson G.P.
      • Newman C.W.
      The development of the dizziness handicap inventory.
      ] with the MdDS Balance Rating Scale, and the Hospital Anxiety and Depression Scale [
      • Zigmond A.S.
      • Snaith R.P.
      The hospital anxiety and depression scale.
      ] being secondary measures.

      Methods

      IRB and consent

      Study procedures were completed according to Declaration of Helsinki guidelines and were approved by Western Institutional Review Board (www.wirb.com). Participants provided written informed consent. The original approval number for this study was 1140088 and the follow-up study to this trial is listed with Clinical Trials identifier: NCT02540616. The study was conducted from September 2013 to June 2015 and all on-site study procedures were performed at the Laureate Institute for Brain Research in Tulsa, OK. The investigators have no ethical or financial conflict of interests with respect to the manufacturers of any of the equipment used in the study.

      Participant characteristics

      Participants were recruited through web based postings on the MdDS Balance Foundation website (www.mddsfoundation.org). Inclusion criteria included the following: 1) a chronic perception of rocking dizziness that started within two days after disembarking from sea, air, or land based travel; 2) symptoms lasting at least six months; 3) no other diagnosis determined after evaluation by a neurologist or otolaryngologist with appropriate testing to rule out peripheral inner ear or other central nervous system cause for symptoms. Potential participants were excluded for the following: 1) unstable medical or psychiatric condition (e.g. mania or psychosis), 2) pregnant or planning to become pregnant during study enrollment, and 3) contraindications to receiving rTMS or undergoing a structural MRI scan (ferromagnetic or coiled metal implants), and 4) any skin disorder that compromised skin integrity over the scalp. In order to maximize the benefit-to-risk ratio of participation, participants who were not aware of other medical alternatives were informed of these alternatives before being consented.
      Because of the rarity of the disorder, participants either drove in from over four hours or flew in from at least two hours away to receive rTMS treatment and tDCS teaching in our laboratory. Participants were required to identify a “Study Buddy” to provide back-up communication with the study staff if communication was lost and who would aid in observing the stimulation site for irritation during the home tDCS phase.

      MRI and rTMS

      Participants underwent a magnetization-prepared rapid acquisition with gradient echo scan on a GE Discovery MR750 3T whole-body scanner (GE Healthcare, Milwaukee WI, USA) for the purposes of neuronavigation during the TMS sessions. Each participant underwent five sessions of rTMS on consecutive days. The Localite TMS Navigator (Localite GmBH, Germany) frameless stereotaxy system was used for neuronavigation to identify the center of the DLPFC in the middle frontal gyrus. rTMS was performed with the Magventure MagPro X100 stimulator with a cooled figure-of-eight coil in biphasic mode and the handle back at a 45 degree angle relative to the mid-sagittal plane. Motor thresholds (MT) were determined each day with independent measurements made for both the right and left M1 hand areas. MTs were defined as the percent intensity of the stimulator output that generated a 50 µV motor evoked potential in the contralateral abductor pollicis brevis muscle in 50% of trials. rTMS sessions consisted of 1 Hz right DLPFC stimulation at 110% of MT for 1200 pulses followed by 10 Hz left DLPFC stimulation at 110% MT for 2000 pulses for right-handed participants, but the opposite for left-handed participants (i.e. 1 Hz left DLPFC followed by 10 Hz right DLPFC) according to our previous protocol determined for left-handed participants [
      • Cha Y.H.
      • Cui Y.
      • Baloh R.W.
      Repetitive transcranial magnetic stimulation for mal de debarquement syndrome.
      ,
      • Ding L.
      • Shou G.
      • Yuan H.
      • Urbano D.
      • Cha Y.H.
      Lasting modulation effects of rTMS on neural activity and connectivity as revealed by resting state EEG.
      ]. The 10 Hz protocol was administered as trains of 40 pulses over four-seconds followed by 26 seconds of rest.

      tDCS machine

      The Transcranial Technologies tDCS machine (www.trans-cranial.com) was used for the study. Password protected settings were as follows: maximum current = 1 mA, ramp up time = 30-seconds, duration = 20-minutes, maximum resistance = 15k ohms. The sham mode consisted of 60 seconds of real stimulation given at the beginning of the session with a ramp down. Pseudo current and resistance outputs were presented on the screen in the sham mode to simulate real stimulation.

      tDCS capping

      Each participant was custom fit with a neoprene cap that had snap electrodes placed over the region of the DLPFC as determined from their MRI (Fig. 1). A second elastic band was placed over the sponges if needed to help maintain good scalp contact, which was often needed for participants with thick hair. Participants were instructed to center the headband so that the midline locators were on the vertex and in the middle of the forehead and the horizontal band was just above the eyebrows and over the ears. All anode related connections were labeled red and all cathode related connections were labeled black. Electrode housings of 5 × 7 cm were designed by the investigator with die-cut Spontex sponges (Industrial Commercial Supply, Cleveland, OH) held together by plastic snaps. Anode and cathode sponges had opposite male and female connections so that they could not be reversed. Participants were provided with saline solution (contact lens solution buffered to physiologic pH and salt level) from a major manufacturer to wet the sponges at home. Anodes were placed over the left DLPFC and cathodes over the right DLPFC in right-handed participants, and vice versa for left-handed participants.
      Figure thumbnail brs876-fig-0001
      Figure 1Cap model. A neoprene cap was custom fit to each participant with electrodes placed over the DLPFC as determined from the participant's MRI. Anode connections were in red; cathode connections were in black. Anode and cathode electrodes were created with opposite cap attachments that could not be reversed.

      tDCS teaching

      During their visit, the participants engaged in at least three face-to-face teaching sessions of tDCS application (30–60 minutes each) and were required to show that they could properly prepare and apply the cap, start and stop the stimulation, troubleshoot, attach and detach the cables, and store the device in the box. They were instructed to not let any saline drip down the face or to excessively wet the hair. Since they were receiving rTMS during the same week, they only completed about two-minutes of tDCS stimulation each time they practiced. Written instructions with pictures either in print form or through access to an electronic version on the study server was provided as backup.

      Randomization

      All rTMS sessions were open label. tDCS sessions were randomized in a single-blind manner to real and sham stimulations. Twenty-four tDCS machines were set to real or sham settings at a ratio of 1:1 and placed in individual identical black boxes. The participants chose the boxes themselves to assure them of the randomization. They performed their training sessions with the machine that they selected. The devices themselves were labeled with a code and only the research staff knew the key to the device settings and the codes. After receiving five sessions of rTMS, participants returned home and were instructed to complete five sessions of tDCS per week for four weeks (20 sessions), not going more than two days without a completing a session. After a four-week washout period, the two groups were un-blinded and the sham group was given the option of trying open label real tDCS for 4–12 weeks preceded by a new baseline assessment period and followed by another washout period. Cap position was verified with either the participant sending pictures of herself with the cap on or via a webcam session with the study staff, whichever was possible for the participant.

      Online tracking

      Participants were given unique study identifications and a set of personalized web links through SurveyMonkey®. A daily check-in was required to report symptoms, e.g. “Today was a good day because I got a lot of rest.” Data were time stamped and tracked by the study staff daily. If two daily “check ins” were not done, the participant was either emailed or called on the phone. The main purpose of the daily check-in was to determine participant compliance with the hypothesis that if they were conscientious in doing the small things, they would be conscientious in doing the bigger things. These notes also increased our understanding of symptom modifying factors. The plan was for the Study Buddy to be contacted if the participant did not respond to the study staff's communication efforts. A set of questionnaires was completed each weekend with the main measures being the Dizziness Handicap Inventory (DHI) [
      • Jacobson G.P.
      • Newman C.W.
      The development of the dizziness handicap inventory.
      ], MdDS Balance Rating Scale (MBRS), and the Hospital Anxiety and Depression Scale (HADS) [
      • Zigmond A.S.
      • Snaith R.P.
      The hospital anxiety and depression scale.
      ]. If the questionnaires were not completed by the following Monday, a reminder was sent.
      The DHI is a well-validated 25-item scale of dizziness with a total possible score of 100 points in which a score of 16–34 = mild handicap, 36–52 = moderate handicap, and 54+  = severe handicap [
      • Jacobson G.P.
      • Newman C.W.
      The development of the dizziness handicap inventory.
      ]. The HADS is a well-validated 14-item standard scale for measuring depression and anxiety with each subcomponent scoring a maximum of 21-points in which a score of 0–7 = normal, 8–10 = borderline, and 11–21 = abnormal [
      • Zigmond A.S.
      • Snaith R.P.
      The hospital anxiety and depression scale.
      ]. The MBRS is a 10-point scale that solely assesses rocking perception designed so that scores six and higher indicate impaired walking (Supplementary Table S1). This scale was created by the lead investigator because there are no published scales that specifically query about rocking dizziness. These diaries were started 1–2 weeks before arrival to the study site as a run-in phase to assess participant baseline and compliance.

      Participant payment, side effects assessment, and survey

      In order to probe the sensitivity of compliance of reporting to study payment, the first 12 participants (Group 1) recruited were paid for each session of tDCS reported ($4/session) while the second group of 12 participants (Group 2) was guaranteed payment for 20 sessions, regardless of how many they reported. Participants reported each session of tDCS performed through their web links, rating each side effect on a scale of 0–10, in which “0” was none and “10” was intolerable. At the conclusion of the study, the participants were asked to complete an anonymous non-compensated survey of their experiences.

      Statistical analysis

      Data were analyzed with Stata IC version 14 (www.stata.com). Mixed-effects repeated measures ANOVA analyses were performed for each outcome measure with the between subject factor being allocation to real versus sham tDCS and the within subject factor being time. Data were fit with a linear model with mean change and predicted 95% confidence intervals determined. Data were not corrected for multiple comparisons since response at each time point was highly correlated with response at subsequent time points and did not meet criteria for independence. The main effect of treatment allocation to real or sham for the 4-weeks of tDCS and 4-weeks of the washout period is reported. The interaction of time-by-allocation is reported only if the main effect was significant. Significance is considered for a two-tailed alpha of 0.05.

      Results

      Twenty-four women with the following characteristics participated in the study: 21 right-handed, three left-handed, mean age ± s.d. =  52.9+ /12.2 years, range = 28–76 years; duration of symptoms ± s.d. = 33.8 ± 23.0 months, range = 8–96 months; triggers: 15 = water based travel (e.g. cruise), five = air travel, five = land travel (train or car ride) (1 participant had combined boat/plane triggers). Baseline symptom scores of participants allocated to real vs sham tDCS are provided in Table 1, which showed no statistical differences. Twenty-three of the 24 participants completed all five sessions of rTMS. The remaining participant found rTMS too painful even at <50% of her MT so she was removed from the study. The very first participant who completed rTMS was given open-label tDCS as our test subject for the online reporting set-up; her data were analyzed with the open-label data. Of the remaining participants, 12 received real tDCS and 10 received sham tDCS. All 10 participants who had initially received sham stimulation were enrolled in the open-label phase of which nine finished. Side effects of tDCS are reported for all 23 participants who had performed any home tDCS.
      Table 1Baseline symptom scores of participants randomized to real or sham tDCS.
      ScaleBaseline (s.d.)p-Value
      DHI
       Real49.67(19.10)0.578
       Sham53.80(13.80)
      MBRS
       Real5.00(1.04)0.634
       Sham5.30(1.83)
      HADS-Depression
       Real9.25(3.62)0.588
       Sham8.50(2.55)
      HADS-Anxiety
       Real6.67(5.42)0.710
       Sham7.40(3.17)

      DHI

      Scores on the DHI decreased but were not significantly below baseline immediately after rTMS (Fig. 2A). DHI scores increased after travel for both real and sham tDCS groups but then normalized to baseline with a non-significant trend toward improvement noted by Week 3 and 4 after real tDCS but not for sham tDCS. The four week main effect of treatment allocation averaged over all post-TMS time points was non-significant, F(1,7) = 1.35, p = .247).

      MBRS

      Improvement in the MdDS Balance Rating Scale was noted immediately after rTMS for both groups allocated to real or sham tDCS (Fig. 2B). After an expected travel related exacerbation, the scores gradually improved in the real tDCS group but gradually worsened and plateaued in the sham group. There was a trend toward decreasing MBRS scores between Weeks 2 and 3 and a significant decrease at Weeks 4 in the real tDCS group. The four week main effect of treatment allocation averaged over all post-TMS time points had a trend toward significance, F(1,7) = 3.76, p = .054).

      HADS

      The Hospital Anxiety and Depression scores were divided into the depression and anxiety components (Fig. 2C and D). Depression scores worsened in the week after travel home but plateaued to baseline with real tDCS. During sham tDCS, the depression scores worsened and remained elevated until the washout phase. There were no significant improvements in depression over baseline in either group. The main effect of treatment allocation was non-significant, F(1,7) = 0.77, p = .380). Anxiety scores decreased in the real tDCS groups by Week 4 but not in the sham tDCS group. The four week main effect of treatment allocation averaged over all post-TMS time points was non-significant, F(1,7) = 1.72, p = .192).

      Open label tDCS

      All ten participants who underwent sham stimulation elected to try real tDCS for at least four weeks followed by a four-week washout period. In order to directly compare the responses against the randomized real and sham group, only the first four weeks of responses to open-label tDCS were analyzed if the participant did more than four-weeks of open-label tDCS,
      One participant who had had progressively worsening symptoms while she was on sham tDCS felt worse several hours after one session of real tDCS so further sessions were stopped. Her symptoms continued to worsen for many months despite no further tDCS. Her data were not included in the analysis because she had only done one session of tDCS. For the participant who completed only three weeks of tDCS, we performed a last observation carried forward analysis using her Week 3 scores as her Week 4 scores. She completed all four-weeks of the washout phase.
      There was a greater immediate decrease in the DHI and MBRS scores at tDCS Week 2 with open-label tDCS compared to treatment after rTMS, perhaps owing to the lack of a preceding travel related exacerbation (Fig. 2, green lines). On a group level the improvements were modest. However, one participant, who had not responded to sham tDCS, went into complete remission within one week of starting real tDCS. A second participant noted gradual improvement in her symptoms representing a five-point drop on the MBRS scale over the course of eight-weeks with cyclical exacerbations during the premenstrual phase of her menstrual cycle. Neither of these two participants had responded to open-label rTMS despite having strong responses to tDCS.
      Figure thumbnail brs876-fig-0002
      Figure 2Change in clinical outcome scores. Change in total DHI (A), MBRS (B), HADS Depression (C) and Anxiety (D) subscales relative to baseline immediately after rTMS and during the four-week treatment and four-week washout periods. Real tDCS = blue line, sham tDCS = red line, open-label real tDCS = green line. Mixed-effects ANOVA with a linear model and 95% confidence interval for the mean predicted change at each time point was modeled with our data. Significant reductions in scores at p < 0.05 at each time point are noted with an “*.”

      Compliance

      Group 1 was asked to perform one-week of daily pre-TMS “check-in” reporting, amounting to 68 possible daily reports. They reported an average of 65.4 [s.d. 6.5, range 51–68, median 66.5] reports. After Group 1 completed the study, we increased the pre-TMS reporting requirements to two-weeks, i.e. 75 possible daily reports. Group 2 participants reported an average of 74.7 [s.d. 3.2, range 69–78, median 75] daily reports.
      A total of 245 sessions of real tDCS and 186 sessions of sham tDCS were reported in the randomization phase. An additional 311 sessions were reported by the sham participants when they crossed-over to open-label real tDCS. One participant allocated to real stimulation stopped after 12 sessions because of feeling “revved up,” and two participants were allowed to do an extra 1-week and 2- weeks of stimulation because they had to undergo unavoidable travel during the post-TMS period. These three participants were removed in the analysis of the effect of payment on stimulation sessions reported.
      There was a trend toward a difference in the number of sessions reported when payment was guaranteed, but only when the participants had been randomized to sham tDCS. Group 1 sham participants reported a mean of 20.6 ± 1.1 sessions; Group 2 sham a mean of 16.6 + /3.8 sessions, two tailed (p = 0.056, d.f. = 8). Though only 20 sessions were required, some participants had performed some extra tDCS sessions because of starting on a weekend. There was no difference in sessions reported for real stimulation (Group 1 real reported 19.8 ± 1.8 sessions; Group 2 real 19.8 ± 1.5, two tailed, p = 0.60, d.f. = 8).
      Postage paid boxes had been provided to the participants when they had first arrived for their rTMS sessions. All stimulators and accessories were returned undamaged at the end of the study.

      Adequacy of blinding

      The overall correct guess rate for the allocation was 12/22 (3 of 12 guessed correctly for real; 7 of 10 guessed correctly for sham). The only reason for guessing “sham” regardless of actual allocation was because of a lower than expected treatment effect, even if there had been some symptom improvement. This is because, despite counseling, most participants had harbored some hope of becoming completely symptom free. The reasons for guessing “real” included treatment intensity and improved symptoms.

      Side effects

      Percentages of side effects at each level (0–10) were tabulated for real and sham tDCS sessions (Table 2). These percentages were entered into a two-sample Kolmogorov–Smirnov test for equality of distributions. There were no differences between real and sham stimulation in the general side effect profiles (all p values for comparisons were >0.479).
      Table 2Percentage of ratings for each side effect and intensity level.
      TinglingItchingRednessHeadacheTirednessConfusionNauseaOther
      RatingRealShamRealShamRealShamRealShamRealShamRealShamRealShamRealSham
      0202367979698908173859595999595100
      141241922184113451420
      2122691101485100020
      3111620010132100000
      46210011121000000
      57220100521000100
      64610000321000000
      70000000101000000
      80100000002000000
      90000000000000000
      100000000000000000

      Skin burns and equipment failures

      There were no instances of skin irritation or skin burns in either the randomized or cross-over phases when stimulation was limited to 1.0 mA, even after 60 sessions of tDCS over 12 weeks in one participant. However, one participant who had had no improvement at 1.0 mA in the randomization phase was gradually ramped up to 2.0 mA in the open-label phase with guidance from the study staff to determine whether treatment intensity was a limiting factor. After 11 days of stimulation at 2.0 mA (total 31 sessions), she noticed a painless area of skin irritation under the anode. She was instructed to stop stimulation due to the risk of current shunting through the lesion. She recovered without any other incidents.

      Participant survey

      Twenty-two of the 23 participants completed the post study survey. Questionnaires were asked in both a positive manner and the inverse asked in a negative manner with a random presentation. For the purposes of data reporting, questions about related features are grouped (Table 3). The overall sense of convenience, confidence, and adequacy of instruction was high with three people expressing that more instruction would have been helpful but 14 participants expressing that more instruction would not have been helpful and possibly burdensome. We specifically queried how comfortable the participants would be in performing tDCS without the guidance of a physician, and the majority felt quite comfortable. Both of the participants who indicated that they would be “very uncomfortable” were in the 60–69 year age range. Eight participants felt benefited by tDCS while 11 did not. The others remained neutral. Most participants expressed a likelihood of participating in future brain stimulation studies.
      Table 3Participant survey.
      StatementStrongly agreeAgreeNeither agree nor disagreeDisagreeStrongly disagreeN/A
      The online diaries were convenient.1074000
      It was difficult for me to use mobile and online tools.0321150
      I felt confident setting up the stimulation sessions.1192000
      The stimulation sessions were difficult to set up.031791
      I could find a convenient time to do the stimulation sessions.6141100
      The stimulation sessions interfered with my everyday life.036751
      I felt that I had enough in-person one-on-one instruction.1182100
      It would have helped to have more in-person one-on-one instruction.1241131
      I felt that I was paid enough for my time.5124100
      I would have participated without getting paid.1172200
      More instruction through Facetime/Skype would have been helpful.014826
      More instruction through Facetime/Skype would have been burdensome.028237
      I felt that the Facetime/Skype sessions were helpful.860008
      Overall, I felt that transcranial electrical stimulation treatment benefited me.2641010
      How comfortable would you be doing transcranial stimulation on your own without having a physician overseeing your use?Very comfortableSomewhat comfortableNeutralSomewhat uncomfortableVery uncomfortable
      116022
      How likely are you to participate in a future brain stimulation study?Very likelyLikelyNot sureUnlikelyVery unlikely
      134311
      Six of the study participants eventually purchased their own stimulators directly from the manufacturer and continued to perform either regular or intermittent stimulation on themselves with either guidance from their own physicians or through continued contact with the study staff.

      Discussion

      Our study explored the feasibility of administering a remotely monitored tDCS treatment program for a balance disorder. Overall, the compliance level was high and safety was excellent. As treatment effects increased with longer treatment duration, it is possible that if we had extended the initial treatment phase to beyond four weeks, more substantial effects may have been noted. Treatment with open-label tDCS did not suffer from the travel related exacerbation that occurred after the rTMS portion. However, participants who received open-label tDCS after un-blinding did not benefit from an induction treatment with rTMS that was immediately followed by maintenance treatment with tDCS. Therefore, our study design also revealed the efficacy of tDCS without an rTMS induction. Though the group effects were modest, the individual effects could be quite substantial. Given the safety and ease of this form of neuromodulation, either primary or adjunctive tDCS treatment for MdDS may be reasonable especially because so few treatment options that do not involve travel exist for this disorder.
      We included several assurances within the study design to minimize inadvertent harm to the participant. These measures included 1) stimulation with a personally fitted cap, 2) password protected tDCS device settings, 3) regular symptom reporting and communication with study staff, 4) enlisting backup help from a ‘Study Buddy.’ Though it was never necessary to contact the Study Buddy, we have included the Study Buddy in the formal consent process in future iterations of this project, and 5] the online reporting tool which was instrumental in allowing the investigators to receive timely feedback.
      There were several factors that aided in our high compliance rate. Primarily, MdDS is an intractable disorder with very limited treatment options. This increased the sense of personal investment by the participants. Second, the research staff spent a significant amount of time (~20-hours) with each participant during their visits. This led to the recognition of mutual commitment to the reliability of the data, participant safety, and care for the equipment. Third, the participants and study staff maintained close communication throughout the stimulation period with occasional cues to complete data forms. This acted as a gentle reminder that the staff was following the participant's clinical course despite being at a distance.
      Three tDCS training sessions were more than adequate for the majority of the participants, with more potentially being burdensome. However, occasional participants anonymously expressed needing more guidance even if they had initially demonstrated competence and expressed feeling confident with the procedure. A few participants did express frustration with getting just the area under the sponges wet with saline noting that the devices would not let them start stimulation without adequate dampness. This is a common issue even with supervised tDCS sessions but participants, who have far less experience than researchers, have a lower frustration tolerance for devices when they do not launch. We tried to address some of these issues by initiating webcam or Facetime® sessions with the participants when we received some of this feedback. We were able to initiate “face-to-face” trouble-shooting over a webcam for participants in Group 2, which helped address some of these issues.
      In this pilot study we were concerned about adequate blinding and safety and thus limited the treatment intensity to 1 mA, an intensity level that is conducive to blinding [
      • Gandiga P.C.
      • Hummel F.C.
      • Cohen L.G.
      Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation.
      ]. Theoretically more robust treatment effects may have been attained with higher treatment intensity, however. The password protected locked settings on the tDCS device prohibited the participants from tinkering with the controls making inadvertent dosage increases unlikely. Through our educational sessions, we tried to instill in the participants an understanding that even if a little stimulation is good, more is not always better and may contribute to more side effects. With good participant screening, any suggestion of skin irritation requiring stopping treatment was communicated immediately. Other side effects were well within the realm of what have been typically reported for cranial electrical stimulation sessions [
      • Paneri B.
      • Khadka N.
      • Patel V.
      • Thomas C.
      • Tyler W.J.
      • Parra L.
      • et al.
      The tolerability of transcranial electrical stimulation used across extended periods in a naturalistic context by healthy individuals.
      ,
      • Poreisz C.
      • Boros K.
      • Antal A.
      • Paulus W.
      Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients.
      ].
      Because we had made personalized caps for the participants, they could not let anyone else use the caps. Additionally, our participant population was an educated group of middle-aged women, most of whom had professional careers, were free from major psychiatric disorders, and were generally in supportive relationships within their families. Application of home-based tDCS within a larger field of clinical syndromes would have to be done with additional precautions when using “one size-fits-all” cap designs, treatment of younger individuals, those with less stable medical conditions, cognitive challenges, or who do not have good family or peer support. In the clinical realm, face-to-face follow-up appointments, enlisting additional help from a Study Buddy to remove the device if abused, and establishing methods to remotely deactivate the devices may be additional safeguards when home-based cranial electrical therapy becomes more widely administered. We note that the left anodal/right cathodal tDCS montage is being used in a study of bipolar disorder which will test whether this montage might unmask mania in individuals who have an underlying vulnerability to mood fluctuations [
      • Pereira Junior Bde S.
      • Tortella G.
      • Lafer B.
      • Nunes P.
      • Benseñor I.M.
      • Lotufo P.A.
      • et al.
      The bipolar depression electrical treatment trial (BETTER): design, rationale, and objectives of a randomized, sham-controlled trial and data from the pilot study phase.
      ].
      A limitation to our study was that since we could not track the actual use of the device, we could not be certain that the devices were actually being used. Since most cranial electrical stimulation work still lies within the realm of research, we did try to determine whether extraneous factors like payment would affect compliance with reporting. Deception could not be ruled (report a session but not actually do the session) but we felt that this was unlikely given the modest payment level. Compliance of reporting during the run-in phases was extremely high indicating a fairly high level of conscientiousness.

      Conclusion

      Our study shows that many stimulation sessions of tDCS can be performed safely and effectively by non-professionals when they are adequately trained, have reasonable safeguards in place, and are closely followed. Although the treatment effects were modest and confounded by the travel effect, about a third of the participants felt benefited from tDCS and a quarter continued to use tDCS post study, even intermittently. This is a large proportion considering that MdDS symptoms are quite resistant to treatment particularly when they pass six-months of duration [
      • Cha Y.H.
      • Brodsky J.
      • Ishiyama G.
      • Sabatti C.
      • Baloh R.W.
      Clinical features and associated syndromes of mal de debarquement.
      ]. Some advantages of this therapy are its relative ease of use, flexibility, low cost, and the promotion of a sense of self-efficacy in actively participating in treatment. Ongoing assessment of competence and incorporation of participant feedback may promote effective long-term usage. We also note that two people who did not have a response to rTMS did have a significant response of tDCS, despite the caveat that it was in the open-label phase. Presently in the United States, tDCS is used off-label, through an ethics committee approved compassionate care pathway, or through the auspices of a clinical trial [
      • Fregni F.
      • Nitsche M.A.
      • Loo C.K.
      • Brunoni A.R.
      • Marangolo P.
      • Leite J.
      • et al.
      Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): review and recommendations from an expert panel.
      ]. The relative benefit to risk ratio will be unique to each particular patient group but advancing technology may alter this ratio for patients in general. Although self-administered tDCS may not be appropriate for all individuals, careful selection and monitoring may allow this therapy to become more widely available and help redefine the concept of medical refractoriness.

      Acknowledgements

      The investigators wish to thank the participants who had traveled to participate in this study. This study was funded by a grant from the Oklahoma Center for the Advancement of Science and Technology , NIDCD-NIH grant R03-DC010451 , the MdDS Balance Disorders Foundation Early Career Investigator Award , and by pilot funds from the Laureate Institute for Brain Research for imaging . The funding sources played no role in the design, data collection, analysis, interpretation, or in writing of this report.

      Appendix. Supplementary material

      The following is the supplementary data to this article:

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