NeuroRehabilitation xx (20xx) x–xx 1

DOI:10.3233/NRE-192851
IOS Press

1 Remotely supervised transcranial direct

2 current stimulation: A feasibility study
for amyotrophic lateral sclerosis

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4 Anjali Sivaramakrishnana,b , Abhishek Dattac , Marom Biksond and Sangeetha Madhavana,∗
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a Department of Physical Therapy, Brain Plasticity Laboratory, College of Applied Health Sciences,

University of Illinois, Chicago, IL, USA

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6

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b Graduate Program in Rehabilitation Sciences, College of Applied Health Sciences,

8 University of Illinois, Chicago, IL, USA

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c Soterix Medical, New York, USA

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d Department of Biomedical Engineering, Grove School of Engineering, The City College of New York (CUNY),

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11 New York, NY, USA

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12 Abstract.
13 BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated as a therapeutic neuromodulation tool
14 in several neurological disorders. However, evidence supporting its efficacy in disorders such as amyotrophic lateral sclerosis
15 (ALS) is limited possibly due to limited patient accessibility for research, particularly for individuals with advanced disease
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16 progression. Telerehabilitation using home-based protocols allows for remote supervision of tDCS over longer durations,
17 thereby increasing participation, compliance and adherence. In this study, we explored the safety, feasibility and preliminary
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18 effects of a remotely supervised tDCS (RS-tDCS) protocol in ALS.

19 MATERIAL AND METHODS: In this pre-post case series study, two individuals with ALS completed 24 remotely
20 supervised anodal tDCS sessions (20 minutes, 2 mA). Outcomes included adherence, compliance, disease progression,
21 walking speed, risk of fall, endurance, fatigue and depression.
22 RESULTS: Both participants successfully completed the study without any major adverse effects. Minor side effects included
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23 mild sensations of itching and throbbing under the electrodes during stimulation. Clinical outcomes showed minimal to no
24 change for any of the measures.
25 CONCLUSIONS: Preliminary findings suggest that the RS-tDCS protocol is safe and feasible in individuals with ALS. Our
26 protocol serves as a model for future long-term studies to evaluate the clinical and neurophysiological effects of tDCS using
a telerehabilitation protocol in ALS.
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27

28 Keywords: Transcranial direct current stimulation, telerehabilitation, amyotrophic lateral sclerosis, remotely supervised tDCS,
29 home-based tDCS
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1. Introduction 30

Telerehabilitation is a relatively new approach 31

∗ Address
to broaden access to rehabilitation services in a 32
for correspondence: Sangeetha Madhavan, Depart-
ment of Physical Therapy, University of Illinois, 1919 West Taylor
cost-effective manner, particularly for those with 33

Street, Chicago, IL 60612, USA. Phone: +1 312 355 2517, fax: +1 limited mobility who live in remote areas or have 34

312 996 4583; E-mail: smadhava@uic.edu. transportation barriers. Telerehabilitation utilizes a 35

ISSN 1053-8135/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved
 2 A. Sivaramakrishnan et al. / Remote tDCS in ALS

36 combination of audio and video-based technologies muscle weakness, limited mobility, and impaired 88

37 to deliver health care services (Laver et al., 2013; activities of daily living. ALS causes significant 89

38 Peretti, Amenta, Tayebati, Nittari, & Mahdi, 2017). burden and economic strain on patients and their 90

39 Transcranial direct current stimulation (tDCS), a non- caregivers with increasing need for assisted care 91

40 invasive brain stimulation technique, is one such with disease progression. (Gladman & Zinman, 92

41 modality that can be easily integrated in telehealth 2015) Current therapies for ALS are limited and 93

42 to optimize its benefits. tDCS has been promisingly are focussed on symptomatic management. As ALS 94

43 explored as a therapeutic adjunct for several neu- is primarily associated with cortical dysfunction, 95

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44 rological and neuropsychiatric disorders (Gandiga, interventions aimed at restoring and preserving the 96

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45 Hummel, & Cohen, 2006; Hummel et al., 2005; integrity of cortical circuits are beginning to be exam- 97

46 Kalu, Sexton, Loo, & Ebmeier, 2012; Kantak, Sul- ined as novel therapeutic targets in ALS (Eisen et al., 98

47 livan, Fisher, Knowlton, & Winstein, 2010). tDCS 2017; Madhavan, Sivaramakrishnan, Bond, & Jiang, 99

48 utilizes low intensity currents that are applied through 2018; Ziemann & Eisen, 2004). A few single session 100

49 saline soaked sponge electrodes for modulating neu- tDCS studies have been conducted in ALS but have 101

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50 ronal membrane potential to induce changes in neural not reported any benefits after tDCS. (Munneke et 102

51 excitability of the targeted site. Several clinical trials al., 2011; Quartarone et al., 2007) Currently, there 103

52 have shown that multiple tDCS sessions are needed are no clinical trials that have investigated multiple 104

53 to produce beneficial effects on neuroplasticity and sessions of tDCS for ALS. We recently demonstrated 105

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54 impact behavioural outcomes (Acler et al., 2013; the safety, feasibility, and effectiveness of 12 ses- 106

55 Ferrucci et al., 2014; Mori et al., 2010). Adher- sions of laboratory-based tDCS in ALS. (Madhavan 107

56 ence to multiple treatment sessions can be difficult et al., 2018) In order to establish the clinical utility 108

57 for various reasons some of which include receiving of tDCS as a neuromodulatory adjunct for ALS, a 109

58 other healthcare services, low self-efficacy, monetary longer treatment duration is necessary, and this may 110
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59 issues and burden on caretakers. Failure to complete be sustainable in this population if tDCS is admin- 111

60 multiple sessions has resulted in ineffective data col- istered remotely. As a first step towards this goal, 112

61 lection and underpowered studies limiting the clinical in this study we explored the safety, feasibility and 113

62 effectiveness and utility of tDCS (Brunoni et al., effects of an 8-week facilitatory RS-tDCS protocol 114

63 2012). for individuals with ALS. 115

Due to its low risk, ease of use, and portability,

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65 tDCS is a candidate neuromodality to be administered

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66 in a home-based environment with remote supervi- 2. Materials and Methods 116

67 sion from qualified personnel. Remote supervision

68 would ensure that the stimulation is delivered opti- 2.1. Participants 117

69 mally in the comfort of a patient’s home, thereby

70 reducing burden on patients and caregivers to travel Two individuals with spinal-onset ALS partici- 118
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71 to the clinic or research facility and encourage pro- pated in this case series. The diagnosis of ALS 119

72 tocol adherence. Recent studies have demonstrated was established by a neurologist according to the 120

73 the feasibility of tDCS for home use in neurological revised version of the El Escorial World Federation 121

74 disorders such as multiple sclerosis, stroke, vascu- of Neurology criteria. Our inclusion criteria included 122
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75 lar dementia, depression etc (Agarwal et al., 2018; individuals with a diagnosis of possible, probable, or 123

76 Alonzo et al., 2019; André et al., 2016; L. Charvet et definite ALS and the ability to walk with or without an 124

77 al., 2018; Kasschau et al., 2016; Martens et al., 2018; assistive aid for 10 meters. Participants were required 125

78 Palm et al., 2018; Shaw et al., 2017; Van de Winckel et to have access to internet and video calling soft- 126
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79 al., 2018) and provided guidelines and recommenda- ware with either a smartphone or a laptop. Our tDCS 127

80 tions for using tDCS at home which include adequate related exclusion criteria included concomitant cog- 128

81 safety checks that are remotely monitored by study nitive deficits that would prevent a full understanding 129

82 personnel ensuring participant safety (Charvet et al., of the study protocol and device usage, a history of 130

83 2015). seizure disorder, the presence of metal implants in the 131

84 The remotely supervised tDCS protocol (RS- skull or face, extreme skin hypersensitivity and any 132

85 tDCS) may particularly be relevant for those with other skin/scalp condition that could potentially be 133

86 amyotrophic lateral sclerosis (ALS), a progres- aggravated by tDCS. ALS related exclusion criteria 134

87 sive fatal neurodegenerative disorder that results in included the presence of any other neurological dis- 135
 A. Sivaramakrishnan et al. / Remote tDCS in ALS 3

136 orders and any severe cardiac, pulmonary, orthopedic personnel. Research personnel preset the stimula- 185

137 or other medical condition precluding participation. tion parameters for anodal tDCS with a dosage of 186

138 Both participants were informed about the study pro- 2 mA for 20 minutes. The participant or caregiver 187

139 cedure and risks, and a written informed consent was could not change the current intensity or duration 188

140 obtained from them. The study was approved by the which ensured the safety and reproducibility of the 189

141 institutional review board at the University of Illinois stimulation. If the electrodes were placed incor- 190

142 at Chicago and all study procedures adhered to the rectly and if the device sensed inadequate contact, 191

143 Declaration of Helsinki. a visual and an audio alert regarding the contact 192

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settings were displayed to the user and stimulation 193

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144 2.1.1. Study protocol paused for 30 seconds to enable the user to fix the 194

145 We incorporated a protocol that was based error. If the contact was still poor during stimula- 195

146 on Charvet et al. (2015) study which provided tion, the device was programmed to automatically 196

147 guidelines for self-administration of tDCS with a shut down. 197

148 pre-programmed device (Charvet et al., 2015). These

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149 guidelines provide recommendations for research 2.2.1. Training visit 198

150 personnel and user training, assessment of the par- During the training visit, we first tested the par- 199

151 ticipant’s capability for self-administration of tDCS, ticipant’s tolerability to stimulation with tDCS. The 200

152 and guidelines to formulate device usage and train- electrodes were placed on the participant’s scalp at 201

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153 ing manuals. In addition, the protocol also provides the target site and stimulation was performed for 10 202

154 safety checks that are remotely monitored by research minutes. At the end of stimulation, we assessed the 203

155 personnel to ensure safe and reproducible tDCS participant for tDCS related adverse effects. If the 204

156 application. The study stop criteria included the fol- subjects were able to tolerate the stimulation, we 205

157 lowing – i) participant did not pass tDCS aptitude proceeded with the device training. During the train- 206
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158 test, ii) participant did not tolerate tDCS, iii) three ing, the participant and caregiver were familiarized to 207

159 reschedules/failures to initiate video conferencing, the device, electrode positioning, and placement on 208

160 iv) participant reported experiencing severe adverse the scalp. We ensured that the participant/caregiver 209

161 event and v) failure to place the headset and elec- applied the head strap properly and operated the 210

162 trodes within 15 minutes for more than one session. device according to provided instructions. The head 211

The study stop criteria was reviewed at each stage of strap was adjusted to allow for fixed placement of the
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163 212

164 the study: baseline, during the study, and following anode at the targeted location and the anode/cathode 213
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165 study completion. locations were color coded. The lower limb motor 214

cortex location was considered to be 1 cm lateral 215

166 2.2. Intervention and description of the device and 1 cm posterior to Cz on the 10–20 interna- 216

tional electroencephalogram system and the weaker 217

167 tDCS was administered using the Soterix Medical leg representation was targeted (Sivaramakrishnan, 218
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168 1X1 tDCS mini-CT Stimulator. The mini-CT sys- Tahara-Eckl, & Madhavan, 2016). The stimulation 219

169 tem consists of a stimulator and a head strap with site was additionally marked on the scalp using a 220

170 marked positions for electrode placement. The anode permanent marker pen. Participants and their care- 221

171 was attached to an 8 sq. cm oblong saline-soaked givers were instructed to re-mark the spot with the 222
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172 surface sponge electrode (Iogel® Iontophoresis; 2.5 permanent marker pen after every session to ensure 223

173 cc) and the cathode was attached to a 35 sq. cm consistency of stimulation. We also asked that partic- 224

174 adhesive electrode. The head strap (EASYstrap) was ipants mark the spot with a permanent marker pen 225

175 customized to allow placement of electrodes at fixed before washing the hair. The participant/caregiver 226
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176 locations (anode over the lower limb motor cortex then demonstrated the tDCS application and head 227

177 representation (M1) and cathode over the left supraor- strap placement back to the research personnel. They 228

178 bital region). The mini-CT tDCS device has built were also familiarized with the device panel for elec- 229

179 in programmable codes that allow for strict dosage trode contact alerts. In case of poor or moderate 230

180 control. The device remains deactivated until a code contact alerts, participant/caregiver were instructed 231

181 is provided by the research staff to the participant to add more saline to the electrode or reposition the 232

182 for every session. Random codes were generated head strap. 233

183 for each participant. Each code unlocked a single Required steps were verified by our research per- 234

184 session that was pre-programmed by the research sonnel with an aptitude checklist that ensured that 235
 4 A. Sivaramakrishnan et al. / Remote tDCS in ALS

236 the participant was proficient with device operations 2.3. Remotely supervised tDCS sessions 259

237 (Charvet et al., 2015). The participant/caregiver were

238 encouraged to schedule additional training visits if Study personnel initiated the video call via Face- 260

239 the caregiver changed or if they needed further review. time/Skype for each session using a prearranged 261

240 The participant and caregiver were educated on schedule. Under the supervision of the research per- 262

241 potential adverse effects such as tingling, itching, dis- sonnel, the caregiver was required to attach the saline 263

242 comfort, pain, phosphene flashes, skin redness/burns soaked sponge electrode to the headset and then 264

243 etc. If the device were to malfunction during the place it on the head. When the location of the spot 265

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244 remote sessions (due to technical problems), the par- was visually confirmed by the researcher, the partic- 266

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245 ticipant/caregiver was instructed to turn off the device ipant turned on the device and confirmed adequate 267

246 and inform research personnel immediately. Compe- contact quality (good or moderate). The study per- 268

247 tency for use of Skype or Facetime for remote video sonnel provided the participant the five-digit code 269

248 conferencing was also assessed. After we ensured to unlock the device and start stimulation. After the 270

249 that the participant passed all items on the aptitude stimulation was complete (the device would beep 271

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250 list, we then provided them with the required study and alert the participant), the participant turned off 272

251 materials – which included an information guide, the device and removed the head strap. tDCS related 273

252 training schedule, session log, side effects survey side effects were monitored verbally by the researcher 274

253 form (Table 1) and the tDCS equipment (headgear, before, during, and after the session and noted by the 275

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254 device, electrode sets, saline solution, and alcohol researcher and participant using the side effects sur- 276

255 wipes). At the end of the study, research personnel vey form. The participant was reminded to re-mark 277

256 retrieved all study materials and checked the device the stimulation location after the stimulation. The RS- 278

257 (i.e. completion codes for sessions, stimulation his- tDCS sessions were administered three times a week 279

258 tory) to confirm compliance. for 8 weeks and the time was chosen according to 280
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Table 1
Side effects survey. This survey was used to report possible side effects that participants experienced with the
stimulation with details regarding time of discomfort (i.e. beginning, middle or end of stimulation), the duration
and location of the experienced side effect. Adapted from Fertonani et al. (2010). (Fertonani et al., 2010)
Side effect experienced None Mild Moderate Considerable Strong
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Itching
Tingling
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Pain
Burning
Warmth/heat
Pinching
Metallic/ Iron taste
Fatigue
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Headache
Skin redness
Other sensation (describe here):
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Table 2
Ease of use of tDCS device survey: This survey was used to obtain information
regarding participants experience with the device on a scale of 1 (strongly disagree) to 6 (strongly agree)
Perceived experience 1 2 3 4 5 6
Strongly disagree Neutral Strongly agree
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1. It is easy to use
2. It is user-friendly
3. The instructions were easy to understand.
4. There were no inconsistencies during use.
5. I/we were able to use it successfully every time
6. I/we easily remembered how to use it.
7. The headset was easy to place.
8. The electrodes were easy to attach.
9. I/we can use it without written instructions.
10. The codes worked for every session.
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Table 3 2.4. Safety and feasibility 303

Clinical outcome measurements
Pre-tDCS Post-tDCS Compliance was recorded based on the frequency 304

ALSFRS-R (out of 48) of sessions completed in total. Adverse events related 305

Participant 1 36 37 to tDCS were monitored using a side effects survey 306

Participant 2 43 41 adapted from a previous study (Table 1) (Fertonani, 307

Gait speed (Self-selected speed, m/s) Rosini, Cotelli, Rossini, & Miniussi, 2010). Partic- 308

Participant 1 0.71 0.75 ipants were asked whether they experienced any of 309

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Participant 2 1.17 1.31 the following sensations during or after the electrical 310

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Gait speed (Fast speed, m/s) stimulation: itching, tingling, pain, burning, warmth, 311
Participant 1 0.82 0.77 pinching, metallic/iron taste, fatigue, headache, skin 312
Participant 2 1.8 1.87 redness or other symptoms. Participants were asked 313
TUG (seconds) to rate the intensity of symptoms on a scale of 0 314
Participant 1 13.85 14.5
to 4 where 0 = none, 1 = mild, 2 = moderate, 315

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Participant 2 6.45 6.69
3 = considerable and 4 = strong. The survey also 316
6MWD (m)
included a visual analogue scale for pain that ranged 317
Participant 1 180 180
from 0 (no pain) to 10 (worst possible, unbearable 318
Participant 2 555 471
pain). Device usability was measured with a ques- 319
FSS (out of 63)

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Participant 1 52 43
tionnaire that was administered at the end of the study 320

Participant 2 38 51
(Table 2). 321

BDI (out of 63)

Participant 1 7 4
Participant 2 14 12
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3. Results 322
Abbreviations: ALSFRS-R, ALS functional rating scale-revised;
TUG, timed up and go test (seconds); 6MWD, six-minute walk dis-
tance (meters); FSS, fatigue severity scale; BDI, Beck depression Two individuals with ALS completed the study. 323

inventory. Participant 1 was a 50-year-old Hispanic female 324

diagnosed with atypical spinal onset ALS with an 325

11-year history of progressive weakness. Her symp-

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326
281 the participant’s convenience (between 9 : 00 am and toms included muscle weakness (greater in legs 327
6 : 00 pm). This time was kept consistent as far as
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282
versus arms), joint stiffness, difficulty walking, falls, 328
283 possible throughout the study. Participants made an and tremors. She was ambulatory with assistance 329
284 interim visit to the lab after 4 weeks for a clinical (walker). Her ALSFRS-R score was 36. Participant 330
285 check, restocking supplies and re-programming the 2 was a 68-year old Hispanic male diagnosed with 331
286 device for additional codes. spinal onset ALS with a 1-year history of muscle 332
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weakness. His symptoms included muscle weakness 333

287 2.3.1. Clinical outcomes (greater in arms versus legs), joint stiffness, muscle 334

288 At baseline, we collected demographic informa- twitching, and back pain. He was ambulatory with- 335

289 tion and administered screening questionnaires for out any aid or assistive device. His ALSFRS-R score 336
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290 medical information and tDCS safety. Clinical assess- was 43. Both participants were not on any medica- 337

291 ments were performed before and after the 8-week tions for ALS. Both participants and their caregivers 338

292 intervention by a physical therapist. We used the did not report any difficulties with the training visit 339

293 ALS Functional Rating Scale-Revised (ALSFRS- and initial familiarization with the device. Care- 340
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294 R) to measure disease progression (Brooks et al., givers of both patients demonstrated competency 341

295 1996). We measured gait speeds with the 10-meter with the tDCS training within the first visit. Par- 342

296 walk test, risk of fall with the timed up and go test ticipants received fitted headbands for stimulation 343

297 (TUG), (Podsiadlo & Richardson, 1991) endurance of the lower limb M1 (right hemisphere (partici- 344

298 with the 6-minute walk distance,(Laboratories, 2002) pant 1) and left hemisphere (participant 2). The side 345

299 global fatigue with the fatigue severity scale (FSS), for stimulation was chosen according to the partic- 346

300 (Krupp, LaRocca, Muir-Nash, & Steinberg, 1989) ipant’s perception of greater weakness which was 347

301 and depression with the Beck Depression Inventory confirmed by the researcher using a manual muscle 348

302 (BDI) (Beck, Steer, & Brown, 1996). test. 349

 6 A. Sivaramakrishnan et al. / Remote tDCS in ALS

increase in gait speed at the post assessment (i.e. 377

5% in Participant 1 and 12% in Participant 2). The 378

6MWD showed a decrease of 45 meters in the post 379

assessment for the second participant. 380

4. Discussion 381

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In this study our primary objective was to exam- 382

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ine the safety, feasibility, and preliminary effects of 383

remotely supervised tDCS in persons with ALS. We 384

Fig. 1. Adverse events experienced with tDCS reported as fre- were able to complete 24 sessions of training in two 385

quencies. Other symptoms refer to pulsating sensation as reported individuals with ALS under remote supervision. No 386
by Participant 2. adverse events were reported, and both participants 387

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completed the 8-week study protocol with 100% 388

350 3.1. Safety and feasibility adherence. The participant and researcher supervis- 389

ing the treatment did not report any concerns using the 390

351 A total of 48 sessions were completed by both par- RS-tDCS protocol. Any troubleshooting problems 391

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352 ticipants (24 sessions each, 100% compliance). Both with the device were addressed immediately by study 392

353 participants were able to perform the remote sessions personnel, such as inadequately moistened electrodes 393

354 with assistance from their caregivers. The frequency or poor electrode contact with scalp, thus ensuring 394

355 of adverse effects per session was recorded (Fig. 1). full compliance. Participants and caregivers reported 395

356 Participant 1 reported mild itching in 21/24 sessions adequate satisfaction with the device and training pro- 396
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357 and Participant 2 reported mild to moderate burn- tocol. Overall the RS-tDCS protocol implemented in 397

358 ing sensation in 19/24 sessions. As seen in Figure, this study provides a comprehensive guideline for 398

359 the three most common adverse events were itching, long term sessions of RS-tDCS that can be compara- 399

360 burning and pulsating sensation (other sensation). ble to laboratory or clinical standards while reducing 400

361 The average intensity of the common adverse events burden of travel for participants. 401
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362 is reported in Table 4. The average intensity ranged Our two participants were clinically heterogenous 402

363 from 0.12 to 0.95 (i.e. none to mild on a scale of 4) for in terms of muscle groups affected, stages of ALS, 403
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364 the reported symptoms. At the end of the study, both and disease onset. Despite the heterogeneity, both 404

365 participants reported on the tDCS usability survey participants completed the protocol with assistance 405

366 that the device was user friendly and were comfort- from their caregivers supporting that the study pro- 406

367 able with the device and remote supervision. None tocol allows for completion of stimulation sessions 407

368 of the 48 sessions recorded poor or critical electrode by individuals with a range of impairments. Our fea- 408
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369 contact and no serious adverse events occurred due sibility related findings concur with other RS-tDCS 409

370 to device malfunction or the intervention. No paused studies in multiple sclerosis, Parkinson’s disease, 410

371 events or critical events were recorded by the device. stroke, vascular dementia, pain and other disorders 411

372 Each session was recorded to last 20 minutes. suggesting its applicability in several populations. 412
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(Agarwal et al., 2018; André et al., 2016; Martens 413

373 3.2. Clinical measures et al., 2018; Mattioli, Bellomi, Stampatori, Capra, & 414

Miniussi, 2016; Mori et al., 2010; Van de Winckel 415

374 Table 3 shows the pre-post results for all clinical et al., 2018) The protocol we used in this study 416
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375 measures. No change was observed in the ALSFRS- was established by Charvet et al. (2015) for remote 417

376 R, TUG, FSS or BDI. Both participants showed an tDCS application in multiple sclerosis with the mini- 418

Table 4
Adverse event report. Values are means and standard deviations for 24 sessions. Adverse events (sensations) were rated on a scale from 0 to
4 (none – strong). *Participant 2 described a pulsating sensation (i.e. other sensation) as an adverse event
Participant Itching Tingling Pain Burning Metallic/ Iron taste Fatigue Skin Redness Other*
1 0.043 (0.2) 0.29 (0.46) 0.45 (0.72) 0.95 (0.62) 0.12 (0.33) 0.16 (0.48) 0.16 (0.38) 0
2 0.95 (0.46) 0 0 0 0 0 0 0.62 (0.49)
 A. Sivaramakrishnan et al. / Remote tDCS in ALS 7

419 CT device targeting the dorsolateral prefrontal cortex ease progression within this study timeframe of 471

420 (DLPFC) incorporating a dosage of 1.5 – 2 mA over 8 weeks (Rutkove, 2015). Incorporating tDCS as 472

421 10 – 20 sessions (L. Charvet et al., 2018; L. E. Charvet a longer term intervention for at least 12 weeks 473

422 et al., 2018; Kasschau et al., 2016). The participants or more may be required to establish meaningful 474

423 in these studies were provided with laptops which change in the ALSFRS-R and other clinical out- 475

424 were configured with video-conferencing software. comes. 476

425 Barring minor side effects, the researchers reported There are a few barriers to participation we need 477

426 good compliance with the protocol in general. Studies to consider for clinical implementation of RS-tDCS. 478

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427 have also used RS-tDCS in combination with cogni- One of the barriers we encountered was schedul- 479

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428 tive training for individuals with Parkinson’s disease ing conflicts with the second participant’s caregiver 480

429 and MS. (Agarwal et al., 2018; L. Charvet et al., which was resolved through flexible availability by 481

430 2018) These studies have reported excellent compli- the researcher. Another concern that the researcher 482

431 ance with improvements in motor/cognitive function. noted during one of the sessions was that the loca- 483

432 Our study adds to these findings suggesting that tel- tion of the stimulating electrode varied slightly on 484

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433 erehabilitation using RS-tDCS is feasible and can be visual inspection in one of the sessions for Par- 485

434 suited for long term treatment in ALS. ticipant 1. To ensure that the stimulation occurred 486

435 We also explored the effects of facilitatory tDCS on over the targeted site, the participant reported to 487

436 clinical function in ALS. After 8-weeks of training, the lab and the spot was measured and marked 488

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437 participants did not improve or worsen with tDCS. again by the researcher. Another participation bar- 489

438 Other ALS studies utilizing non-invasive brain stimu- rier to consider would be the requirement of a 490

439 lation protocols have used inhibitory stimulation (i.e. caregiver for tDCS administration. In our study, 491

440 cathodal tDCS or inhibitory repetitive transcranial both participants as were unable to self-administer 492

441 magnetic stimulation protocols) to target the gluta- tDCS due to upper limb weakness but were able 493
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442 mate induced hyperexcitability in ALS. While few to participate as they had adequate assistance from 494

443 studies have reported small, significant effects of supportive caregivers. 495

444 inhibitory neuromodulation on disease progression, The adverse effects reported by both participants 496

445 others showed no change in corticomotor excitabil- were minor and comparable with traditional lab- 497

446 ity, disease progression, or brain derived neurotrophic based tDCS protocols (Iyer et al., 2005). Careful 498

growth factor levels in ALS (Angelucci et al., 2004; monitoring of adverse effects is needed to ensure
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447 499

448 Vincenzo Di Lazzaro et al., 2006, 2009, 2010; Vin- safe tDCS application. Electrode contact quality was 500
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449 cenzo Di Lazzaro, Ranieri, Capone, Musumeci, & reported as moderate/good for all sessions which was 501

450 Dileone, 2013; Munneke et al., 2011; Quartarone ensured by instructing the caregivers to use 5 ml of 502

451 et al., 2007) Here for the first time we report the saline for pre-soaking the sponge electrode. Thus, 503

452 preliminary effects of facilitatory tDCS on individ- careful remote supervision from the researcher along 504

453 uals with ALS. We have established that facilitatory with adequate caregiver training ensured that tDCS 505
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454 RS-tDCS protocol can be safely implemented in was administered in a standardized manner. 506

455 individuals with ALS with assistance from their Several lines of evidence suggest that responses to 507

456 caregivers. We observed a small improvement in tDCS may be longer lasting with multiple treatment 508

457 self-selected gait speed in both participants possi- sessions (Acler et al., 2013; Ferrucci et al., 2014; Mori 509
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458 bly due to the neurophysiological effects of anodal et al., 2010). Currently, tDCS has not been imple- 510

459 tDCS, which has been shown to boost synaptic plas- mented as a tool for motor rehabilitation in outpatient 511

460 ticity and function in other neurological disorders setups due to issues such as intra-individual and inter- 512

461 (Flöel, 2014). These findings however cannot con- individual variability in responses (Horvath, Carter, 513
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462 firm efficacy due to the case series nature of this & Forte, 2014). Once these barriers are overcome, 514

463 study and lack of control. These findings are in line multiple treatment sessions will likely be imple- 515

464 with our previous case report where we adminis- mented in a clinical environment possibly spanning 516

465 tered 4 week lab based anodal tDCS to the lower days or several months. Such scenarios call for using 517

466 limb M1 (Madhavan et al., 2018). Although we the RS-tDCS protocol where trained professionals 518

467 observed a small increase in gait speed in the current monitor the remote sessions to ensure high standard- 519

468 study, we did not notice meaningful changes in dis- of-care. The RS-tDCS protocol has been used for 520

469 ease progression. It is possible that the ALSFRS-R individuals with various neurological and neuropsy- 521

470 may not be sensitive to capture change in dis- chiatric disorders which speaks to the generalizability 522
 8 A. Sivaramakrishnan et al. / Remote tDCS in ALS

523 of the protocol. However, there are certain caveats for Acknowledgments 571

524 rigorous use of this protocol. Correct implementation

525 of the RS-tDCS protocol requires for research person- We would like to thank Sonia Pradhan and Emily 572

526 nel to be aware of tDCS related dosage parameters Buxton from the Brain Plasticity Lab for their assis- 573

527 such as current intensity, duration of stimulation, and tance towards data collection in this study. 574

528 current density. In addition, electrode preparation and

529 positioning are vital for achieving the desired effects.
530 Incorrect electrode positioning on areas other than the Conflict of interest 575

f
531 target area would result in current spread to an unin-

roo
532 tended cortical area. The participant and/or caregiver None to report. 576

533 should also demonstrate adequate understanding of

534 the protocol and knowledge of common tDCS related
535 adverse effects for ensuring safety. Access to the References 577
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539 participant retention. for sleep disturbances and fatigue in patients with post- 580

540 This study shows that remotely supervised tDCS polio syndrome. Restor Neurol Neurosci, 31(5), 661-668. 581

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541 using the mini-CT device can be safely used for per-
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551
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