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

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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 

Journal of NeuroEngineering and Rehabilitation volume 18, Article number: 106 (2021) Cite this article

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.

Introduction

Neuromodulation is an evolving therapy for rehabilitation after a stroke and is also used to improve motor function in the lesioned cortex. Recently, studies indicated that neuromodulation could enhance neuroplasticity, the ability of the brain to reorganize or relearn in response to a new stimulus, resulting in facilitation of motor sensory recovery in stroke patients [1,2,3]. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation (NIBS) technique, is contemporarily important as it can modulate neuroplasticity in advanced rehabilitation medicine, such as pain, depression and, addictive diseases [4,5,6]. tDCS can selectively change the excitability of the regional cortex non-invasively and safely [7]. In addition, tDCS has been explored as a treatment option for stroke, particularly for upper/lower-limb motor function [8,9,10,11]. However, studies reported only 10% ~ 30% improvement in forearm motor function after stroke rehabilitation. Optimal stimulation strategies of tDCS to improve plasticity and enhance motor learning need to be determined.

Recovery as a result of traditional stroke rehabilitation often has poor outcomes and long rehabilitation times. Therefore, developing a more-effective therapeutic device is an important issue for stroke rehabilitation. To develop an optimal tDCS protocol to improve motor function, we designed and implemented a prototype of a novel transcranial electrostimulation device that can flexibly output an electrical current waveform by combining DC and theta burst waveforms [12]. Theta burst stimulation (TBS) was originally a novel waveform of repetitive transcranial magnetic stimulation (rTMS) that is more rapid and efficacious than rTMS [13]. Numerous studies determined that TBS has more advantages than other traditional waveforms of rTMS, such as long-lasting effects on motor-evoked potentials (MEPs) and neuronal excitability after a shorter stimulation duration [14,15,16], and it was associated with fewer adverse events [17]. It is well known that the most widely used TBS patterns are intermittent (i)TBS and continuous (c)TBS. iTBS consists of a 2-s train of TBS repeated every 10 s for a total of 190 s which produces long-term potentiation (LTP)-like effects, whereas cTBS consists of three-pulse bursts at 50 Hz repeated every 200 ms for 40 s, which induces long-term depression (LTD)-like cortical plasticity [14, 18,19,20].

Use of an rTMS protocol with iTBS in chronic stroke patients was shown to significantly increase ipsilesional M₁ excitability, enhanced MEP amplitudes, and improve upper-limb motor functions [15, 21,22,23]. One recent meta-analysis showed that the standardized mean difference (SMD) of iTBS was 0.60 (p = 0.018), whereas that for cTBS was 0.35 (p = 0.138) for the recovery of upper-limb motor outcomes in stroke patients, indicating that iTBS was more beneficial than cTBS in motor recovery after a stroke [24]. Therefore, modulation of cortical plasticity induced by iTBS may have therapeutic potential for patients with post-stroke motor disorders.

Both rTMS and tDCS can cause physiological effects and indirectly modulate deep-brain locations via neural circuits [25, 26]. In general, rTMS therapy is usually applied before undertaking occupational therapy for patients with motor function deficits, due to the bulky size of the rTMS device. On the contrary, the lightweight, portable tDCS device can be directly worn on a patient's head during active rehabilitation exercises, which was associated with augmentation of synaptic plasticity [27,28,29]. However, most traditional transcranial stimulators have only a DC waveform mode at present. Thus, our novel transcranial burst electrostimulator was designed to develop an effective and optimal therapeutic system for patients who need rehabilitation therapy. We previously demonstrated that compared to conventional anodal tDCS, the combined DC-iTBS electrostimulator induced LTP-like plasticity as evident from significantly enhanced MEP amplitudes for at least 30 min in animal experiments [12].

With the excellent efficacy of previously combined stimulation, we report a pilot randomized controlled study to examine the combined effects of DC-iTBS and conventional rehabilitation (CR) on upper-limb motor function as measured by the Fugl-Meyer Assessment upper extremity (FMA-UE), Finger-to-Nose test (FNT), and Jebsen-Taylor hand function test (JTT) in patients with chronic stroke compared to a sham intervention. To our knowledge, this is the first randomized controlled trial (RCT) to apply tDCS with iTBS to facilitate upper-limb motor function in chronic stroke patients. We also expected that the novel DC-iTBS stimulation combined with rehabilitation of the upper extremities would result in greater improvements and have potential to become a routine treatment strategy for stroke patients at hospitals and residential rehabilitation facilities.

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