Transcranial electrostimulation with special waveforms enhances upper-limb motor function in patients with chronic stroke: a pilot randomized controlled trial

Shih-Ching Chen, Ling-Yu Yang, Muhammad Adeel, Chien-Hung Lai, Chih-Wei Peng, Shih-Ching Chen, Ling-Yu Yang, Muhammad Adeel, Chien-Hung Lai, Chih-Wei Peng

Abstract

Background: Transcranial direct current stimulation (tDCS) and intermittent theta burst stimulation (iTBS) were both demonstrated to have therapeutic potentials to rapidly induce neuroplastic effects in various rehabilitation training regimens. Recently, we developed a novel transcranial electrostimulation device that can flexibly output an electrical current with combined tDCS and iTBS waveforms. However, limited studies have determined the therapeutic effects of this special waveform combination on clinical rehabilitation. Herein, we investigated brain stimulation effects of tDCS-iTBS on upper-limb motor function in chronic stroke patients.

Methods: Twenty-four subjects with a chronic stroke were randomly assigned to a real non-invasive brain stimulation (NIBS; who received the real tDCS + iTBS output) group or a sham NIBS (who received sham tDCS + iTBS output) group. All subjects underwent 18 treatment sessions of 1 h of a conventional rehabilitation program (3 days a week for 6 weeks), where a 20-min NIBS intervention was simultaneously applied during conventional rehabilitation. Outcome measures were assessed before and immediately after the intervention period: Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Jebsen-Taylor Hand Function Test (JTT), and Finger-to-Nose Test (FNT).

Results: Both groups showed improvements in FMA-UE, JTT, and FNT scores after the 6-week rehabilitation program. Notably, the real NIBS group had greater improvements in the JTT (p = 0. 016) and FNT (p = 0. 037) scores than the sham NIBS group, as determined by the Mann-Whitney rank-sum test.

Conclusions: Patients who underwent the combined ipsilesional tDCS-iTBS stimulation with conventional rehabilitation exhibited greater impacts than did patients who underwent sham stimulation-conventional rehabilitation in statistically significant clinical responses of the total JTT time and FNT after the stroke. Preliminary results of upper-limb functional recovery suggest that tDCS-iTBS combined with a conventional rehabilitation intervention may be a promising strategy to enhance therapeutic benefits in future clinical settings.

Trial registration: ClinicalTrials.gov Identifier: NCT04369235. Registered on 30 April 2020.

Keywords: Functional recovery; Intermittent theta burst stimulation (iTBS); Stroke; Transcranial direct current stimulation (tDCS); Upper limb.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The experimental flowchart of this study. CR conventional rehabilitation, tDCS transcranial direct current stimulation, iTBS intermittent theta burst stimulation
Fig. 2
Fig. 2
The combined DC-iTBS protocol was iTBS of 1.5-mA intensity superposed on continuous 1-mA DC. The basic pattern of iTBS consisted of bursts containing three biphasic pulses at 50 Hz repeated at 200 ms intervals; and a 2 s train of iTBS was repeated every 10 s. For each stimulation, current intensity was ramped up to 1 mA over 30 s at the beginning, applied for 20 min and then ramped down to 0 mA over 30 s at the end of stimulation

References

    1. Faralli A, Bigoni M, Mauro A, Rossi F, Carulli D. Noninvasive strategies to promote functional recovery after stroke. Neural Plast. 2013 doi: 10.1155/2013/854597.
    1. Donaldson C, Tallis R, Miller S, Sunderland A, Lemon R, Pomeroy V. Effects of conventional physical therapy and functional strength training on upper limb motor recovery after stroke: a randomized phase II study. Neurorehabil Neural Repair. 2009;23(4):389–397. doi: 10.1177/1545968308326635.
    1. Chen H, Epstein J, Stern E. Neural plasticity after acquired brain injury: evidence from functional neuroimaging. PM&R. 2010;2:S306–S312. doi: 10.1016/j.pmrj.2010.10.006.
    1. Sadeghi Movahed F, Alizadeh Goradel J, Pouresmali A, Mowlaie M. Effectiveness of transcranial direct current stimulation on worry, anxiety, and depression in generalized anxiety disorder: a randomized, single-blind pharmacotherapy and sham-controlled clinical trial. Iran J Psychiatry Behav Sci. 2018 doi: 10.5812/ijpbs.11071.
    1. Lapenta OM, Marques LM, Rego GG, Comfort WE, Boggio PS. tDCS in addiction and impulse control disorders. J ECT. 2018;34(3):182–192. doi: 10.1097/YCT.0000000000000541.
    1. Cioato SG, Medeiros LF, Marques Filho PR, Vercelino R, de Souza A, Scarabelot VL, et al. Long-lasting effect of transcranial direct current stimulation in the reversal of hyperalgesia and cytokine alterations induced by the neuropathic pain model. Brain Stimul. 2016;9(2):209–217. doi: 10.1016/j.brs.2015.12.001.
    1. Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul. 2016;9(5):641–661. doi: 10.1016/j.brs.2016.06.004.
    1. Triccas LT, Burridge J, Hughes A, Pickering R, Desikan M, Rothwell J, et al. Multiple sessions of transcranial direct current stimulation and upper extremity rehabilitation in stroke: a review and meta-analysis. Clin Neurophysiol. 2016;127(1):946–955. doi: 10.1016/j.clinph.2015.04.067.
    1. Nowak DA, Grefkes C, Ameli M, Fink GR. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair. 2009;23(7):641–656. doi: 10.1177/1545968309336661.
    1. Klomjai W, Aneksan B, Pheungphrarattanatrai A, Chantanachai T, Choowong N, Bunleukhet S, et al. Effect of single-session dual-tDCS before physical therapy on lower-limb performance in sub-acute stroke patients: a randomized sham-controlled crossover study. Ann Phys Rehabil Med. 2018;61(5):286–291. doi: 10.1016/j.rehab.2018.04.005.
    1. Kang N, Summers JJ, Cauraugh JH. Transcranial direct current stimulation facilitates motor learning post-stroke: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016;87(4):345–355. doi: 10.1136/jnnp-2015-311242.
    1. Li Y-T, Chen S-C, Yang L-Y, Hsieh T-H, Peng C-W. Designing and implementing a novel transcranial electrostimulation system for neuroplastic applications: a preliminary study. IEEE Trans Neural Syst Rehabil Eng. 2019;27(5):805–813. doi: 10.1109/TNSRE.2019.2908674.
    1. Li CT, Huang YZ, Bai YM, Tsai SJ, Su TP, Cheng CM. Critical role of glutamatergic and GABAergic neurotransmission in the central mechanisms of theta-burst stimulation. Hum Brain Mapp. 2019;40(6):2001–2009. doi: 10.1002/hbm.24485.
    1. Huang Y-Z, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201–206. doi: 10.1016/j.neuron.2004.12.033.
    1. Diekhoff-Krebs S, Pool E-M, Sarfeld A-S, Rehme AK, Eickhoff SB, Fink GR, et al. Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients. NeuroImage Clin. 2017;15:559–571. doi: 10.1016/j.nicl.2017.06.006.
    1. Long H, Wang H, Zhao C, Duan Q, Feng F, Hui N, et al. Effects of combining high-and low-frequency repetitive transcranial magnetic stimulation on upper limb hemiparesis in the early phase of stroke. Restor Neurol Neurosci. 2018;36(1):21–30.
    1. Maizey L, Allen CP, Dervinis M, Verbruggen F, Varnava A, Kozlov M, et al. Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Clin Neurophysiol. 2013;124(3):536–544. doi: 10.1016/j.clinph.2012.07.024.
    1. Huang Y-Z, Rothwell JC, Edwards MJ, Chen R-S. Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cereb Cortex. 2008;18(3):563–570. doi: 10.1093/cercor/bhm087.
    1. Huang Y-Z, Chen R-S, Rothwell JC, Wen H-Y. The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol. 2007;118(5):1028–1032. doi: 10.1016/j.clinph.2007.01.021.
    1. Doeltgen SH, Ridding MC. Modulation of cortical motor networks following primed theta burst transcranial magnetic stimulation. Exp Brain Res. 2011;215(3–4):199–206. doi: 10.1007/s00221-011-2886-6.
    1. Talelli P, Wallace A, Dileone M, Hoad D, Cheeran B, Oliver R, et al. Theta burst stimulation in the rehabilitation of the upper limb: a semirandomized, placebo-controlled trial in chronic stroke patients. Neurorehabil Neural Repair. 2012;26(8):976–987. doi: 10.1177/1545968312437940.
    1. Talelli P, Greenwood R, Rothwell J. Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke. Clin Neurophysiol. 2007;118(2):333–342. doi: 10.1016/j.clinph.2006.10.014.
    1. Chen Y-J, Huang Y-Z, Chen C-Y, Chen C-L, Chen H-C, Wu C-Y, et al. Intermittent theta burst stimulation enhances upper limb motor function in patients with chronic stroke: a pilot randomized controlled trial. BMC Neurol. 2019;19(1):1–10. doi: 10.1186/1471-2377-2-1.
    1. Zhang L, Xing G, Fan Y, Guo Z, Chen H, Mu Q. Short-and long-term effects of repetitive transcranial magnetic stimulation on upper limb motor function after stroke: a systematic review and meta-analysis. Clin Rehabil. 2017;31(9):1137–1153. doi: 10.1177/0269215517692386.
    1. Stokes MG, Chambers CD, Gould IC, English T, McNaught E, McDonald O, et al. Distance-adjusted motor threshold for transcranial magnetic stimulation. Clin Neurophysiol. 2007;118(7):1617–1625. doi: 10.1016/j.clinph.2007.04.004.
    1. Fregni F, Thome-Souza S, Nitsche MA, Freedman SD, Valente KD, Pascual-Leone A. A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia. 2006;47(2):335–342. doi: 10.1111/j.1528-1167.2006.00426.x.
    1. Polanía R, Paulus W, Antal A, Nitsche MA. Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study. Neuroimage. 2011;54(3):2287–2296. doi: 10.1016/j.neuroimage.2010.09.085.
    1. Polanía R, Nitsche MA, Paulus W. Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation. Hum Brain Mapp. 2011;32(8):1236–1249. doi: 10.1002/hbm.21104.
    1. Pellicciari MC, Brignani D, Miniussi C. Excitability modulation of the motor system induced by transcranial direct current stimulation: a multimodal approach. Neuroimage. 2013;83:569–580. doi: 10.1016/j.neuroimage.2013.06.076.
    1. Gamboa OL, Antal A, Laczo B, Moliadze V, Nitsche MA, Paulus W. Impact of repetitive theta burst stimulation on motor cortex excitability. Brain Stimul. 2011;4(3):145–151. doi: 10.1016/j.brs.2010.09.008.
    1. Fugl-Meyer AR, Jääskö L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance. Scand J Rehabil Med. 1975;7(1):13–31.
    1. Hsieh Y-w, Wu C-y, Lin K-c, Chang Y-f, Chen C-l, Liu J-s. Responsiveness and validity of three outcome measures of motor function after stroke rehabilitation. Stroke. 2009;40(4):1386–1391. doi: 10.1161/STROKEAHA.108.530584.
    1. Maki T, Quagliato E, Cacho E, Paz L, Nascimento N, Inoue M, et al. Estudo de confiabilidade da aplicação da escala de Fugl-Meyer no Brasil. Braz J Phys Ther. 2006;10(2):177–183. doi: 10.1590/S1413-35552006000200007.
    1. Cacho EWA, de Melo FRLV, de Oliveira R. Avaliação da recuperação motora de pacientes hemiplégicos através do protocolo de desempenho físico Fugl-Meyer. Revista Neurociências. 2004;12(2):94–102. doi: 10.34024/rnc.2004.v12.8877.
    1. Jebsen RH. An objective and standardized test of hand function. Arch Phys Med Rehabil. 1969;50(6):311–319.
    1. Hackel ME, Wolfe GA, Bang SM, Canfield JS. Changes in hand function in the aging adult as determined by the Jebsen Test of Hand Function. Phys Ther. 1992;72(5):373–377. doi: 10.1093/ptj/72.5.373.
    1. Rodrigues MR, Slimovitch M, Chilingaryan G, Levin MF. Does the Finger-to-Nose Test measure upper limb coordination in chronic stroke? J Neuroeng Rehabil. 2017;14(1):1–11. doi: 10.1186/s12984-016-0213-y.
    1. Hummel F, Celnik P, Giraux P, Floel A, Wu W-H, Gerloff C, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005;128(3):490–499. doi: 10.1093/brain/awh369.
    1. Hsu Y-F, Huang Y-Z, Lin Y-Y, Tang C-W, Liao K-K, Lee P-L, et al. Intermittent theta burst stimulation over ipsilesional primary motor cortex of subacute ischemic stroke patients: a pilot study. Brain Stimul. 2013;6(2):166–174. doi: 10.1016/j.brs.2012.04.007.
    1. Watanabe K, Kudo Y, Sugawara E, Nakamizo T, Amari K, Takahashi K, et al. Comparative study of ipsilesional and contralesional repetitive transcranial magnetic stimulations for acute infarction. J Neurol Sci. 2018;384:10–14. doi: 10.1016/j.jns.2017.11.001.
    1. Kuo H-I, Bikson M, Datta A, Minhas P, Paulus W, Kuo M-F, et al. Comparing cortical plasticity induced by conventional and high-definition 4× 1 ring tDCS: a neurophysiological study. Brain Stimul. 2013;6(4):644–648. doi: 10.1016/j.brs.2012.09.010.
    1. Datta A, Bansal V, Diaz J, Patel J, Reato D, Bikson M. Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad. Brain Stimul. 2009;2(4):201–7.e1. doi: 10.1016/j.brs.2009.03.005.
    1. Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P, et al. The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol. 2008;586(16):3871–3879. doi: 10.1113/jphysiol.2008.152736.
    1. Oberman L, Edwards D, Eldaief M, Pascual-Leone A. Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol. 2011;28(1):67. doi: 10.1097/WNP.0b013e318205135f.
    1. Suppa A, Huang Y-Z, Funke K, Ridding M, Cheeran B, Di Lazzaro V, et al. Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul. 2016;9(3):323–335. doi: 10.1016/j.brs.2016.01.006.
    1. Devi M, Arumugum N, Midha D. Combined effect of transcranial direct current stimulation (tDCS) and functional electrical stimulation (FES) on upper limb recovery in patients with subacute stroke. J Neurol Stroke. 2019;9(3):140–145. doi: 10.15406/jnsk.2019.09.00364.
    1. Di Lazzaro V, Pilato F, Saturno E, Oliviero A, Dileone M, Mazzone P, et al. Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol. 2005;565(3):945–950. doi: 10.1113/jphysiol.2005.087288.
    1. Nitsche MA, Nitsche MS, Klein CC, Tergau F, Rothwell JC, Paulus W. Level of action of cathodal DC polarisation induced inhibition of the human motor cortex. Clin Neurophysiol. 2003;114(4):600–604. doi: 10.1016/S1388-2457(02)00412-1.
    1. Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. Neuroscientist. 2011;17(1):37–53. doi: 10.1177/1073858410386614.
    1. Cooper LN, Bear MF. The BCM theory of synapse modification at 30: interaction of theory with experiment. Nat Rev Neurosci. 2012;13(11):798–810. doi: 10.1038/nrn3353.
    1. Anderkova L, Pizem D, Klobusiakova P, Gajdos M, Koritakova E, Rektorova I. Theta burst stimulation enhances connectivity of the dorsal attention network in young healthy subjects: an exploratory study. Neural Plast. 2018 doi: 10.1155/2018/3106918.
    1. Di Lazzaro V, Dileone M, Pilato F, Capone F, Musumeci G, Ranieri F, et al. Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation. J Neurophysiol. 2011;105(5):2150–2156. doi: 10.1152/jn.00781.2010.
    1. Liu X-B, Zhong J-G, Xiao X-L, Li Y-X, Huang Y-J, Liu Y-G, et al. Theta burst stimulation for upper limb motor dysfunction in patients with stroke: A protocol of systematic review and meta-analysis. Medicine. 2019 doi: 10.1097/MD.0000000000017929.
    1. Wolf SL, Catlin PA, Ellis M, Archer AL, Morgan B, Piacentino A. Assessing Wolf motor function test as outcome measure for research in patients after stroke. Stroke. 2001;32(7):1635–1639. doi: 10.1161/01.STR.32.7.1635.
    1. Chhatbar PY, Chen R, Deardorff R, Dellenbach B, Kautz SA, George MS, et al. Safety and tolerability of transcranial direct current stimulation to stroke patients–A phase I current escalation study. Brain Stimul. 2017;10(3):553–559. doi: 10.1016/j.brs.2017.02.007.
    1. Horvath JC, Forte JD, Carter O. Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: a systematic review. Neuropsychologia. 2015;66:213–236. doi: 10.1016/j.neuropsychologia.2014.11.021.
    1. Liebetanz D, Koch R, Mayenfels S, König F, Paulus W, Nitsche MA. Safety limits of cathodal transcranial direct current stimulation in rats. Clin Neurophysiol. 2009;120(6):1161–1167. doi: 10.1016/j.clinph.2009.01.022.
    1. Ardolino G, Bossi B, Barbieri S, Priori A. Non-synaptic mechanisms underlie the after-effects of cathodal transcutaneous direct current stimulation of the human brain. J Physiol. 2005;568(2):653–663. doi: 10.1113/jphysiol.2005.088310.
    1. Islam N, Aftabuddin M, Moriwaki A, Hattori Y, Hori Y. Increase in the calcium level following anodal polarization in the rat brain. Brain Res. 1995;684(2):206–208. doi: 10.1016/0006-8993(95)00434-R.
    1. Stagg CJ, Best JG, Stephenson MC, O'Shea J, Wylezinska M, Kincses ZT, et al. Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009;29(16):5202–5206. doi: 10.1523/JNEUROSCI.4432-08.2009.
    1. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron. 2010;66(2):198–204. doi: 10.1016/j.neuron.2010.03.035.
    1. Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain. 2002;125(10):2238–2247. doi: 10.1093/brain/awf238.
    1. Yi YG, Chun MH, Do KH, Sung EJ, Kwon YG, Kim DY. The effect of transcranial direct current stimulation on neglect syndrome in stroke patients. Ann Rehabil Med. 2016;40(2):223. doi: 10.5535/arm.2016.40.2.223.
    1. Fierro B, Brighina F, Bisiach E. Improving neglect by TMS. Behav Neurol. 2006;17:169–176. doi: 10.1155/2006/465323.
    1. Schweid L, Rushmore R, Valero-Cabre A. Cathodal transcranial direct current stimulation on posterior parietal cortex disrupts visuo-spatial processing in the contralateral visual field. Exp Brain Res. 2008;186(3):409–417. doi: 10.1007/s00221-007-1245-0.
    1. Hummel FC, Cohen LG. Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? Lancet Neurol. 2006;5(8):708–712. doi: 10.1016/S1474-4422(06)70525-7.
    1. Kinsbourne M. Hemi-neglect and hemisphere rivalry. Adv Neurol. 1977;18:41–49.

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