Previous longitudinal studies have reported that between 30% and 66% of patients experience upper limb paralysis 6 months after suffering from a stroke.1–3 Recent studies have demonstrated the efficacy of various treatments for patients with chronic stroke, who experience upper limb paralysis, including botulinum toxin A (BTX-A) treatment, functional electrical stimulation therapy, and robotic therapy for functional motor recovery.4–6 In addition, repetitive transcranial magnetic stimulation and transcranial direct current stimulation (tDCS), have been reported to induce long-term effects on cortical excitability, lasting for months after the intervention.7,8
tDCS modulates cortical excitability which influences neural plasticity.9 Anodal tDCS (anodal electrode placed over standard scalp coordinates for motor ipsilesional M1, the cathodal electrode over the contralesional supraorbital ridge) also modulates cortical excitability in motor areas within affected hemisphere.9,10 Furthermore, bilateral tDCS, which stimulates both hemispheres simultaneously, could affect excitatory and inhibitory synaptic transmission in the bilateral motor cortex in patients with chronic stroke.9,11–13 By modulating cortical excitability, tDCS may alter maladaptive neural plasticity after stroke.9 Moreover, peripheral neuromuscular electrical stimulation (PNMES) enhances the effects of tDCS on cortical excitability, relative to tDCS alone.14,15 Furthermore, rehabilitation therapy using PNMES combined with BTX-A has been shown to be an effective treatment in chronic stroke or spinal cord injury.16
However, no studies have examined the efficacy of the use of bilateral tDCS with PNMES and BTX-A therapy in patients with stroke and upper limb paralysis. Therefore, based on the results of each combination therapy effect from previous studies, we predicted that a new multiple combination of adding BTX-A to existing tDCS and PNMES combination therapy would result in more effective results. In addition, tDCS may help improve upper limb paralysis in pediatric patients with chronic stroke. Since tDCS alone has been rarely used in pediatrics, our pilot study aimed to investigate the safety and efficacy of tDCS in adult and pediatric patients with chronic stroke. We also aimed to verify the efficacy of BTX-A and PNMES combined therapy involving bilateral tDCS in adult patients with chronic stroke.
We conducted a pilot study applying an unblinded, non-randomized design. This study included patients with chronic stroke (>6 months from stroke onset) experiencing paralysis in an upper limb. Patients between 6 and 85 years old were included. We also excluded patients with epilepsy, complete paralysis, and/or severe pain, as well as those who were unable to follow directions due to cognitive impairment and/or aphasia. All participants provided written informed consent. Our institutional review board approved the study. Patient characteristics are summarized in Table 1.
We included 11 patients (four males and seven females; mean age 43.5 ± 5.1 years) including 7 cases of hemorrhagic stroke and 4 cases of ischemic stroke. All study participants were right handed. There were six cases of right upper limb paralysis and five cases of left upper limb paralysis. All of four ischemic stroke cases had a lesion in the middle cerebral arterial territtory, and three hemorrhagic stroke patients had a lesion in the putamen, two stroke patients had a lesion in the subcortical, and other two patients had lesions were in the thalamus and pontine. These treatment programs were initiated on 54.9 ± 23.2 days from stroke onset. Of the included cases, data from 1 patient (Case 1) was published previously.13
Five patients, included in Group I, underwent bilateral tDCS therapy alongside intensive occupational therapy (OT) (Group I-a: two adults; Group I-b: three children). Group II included six adult patients in chronic stroke who underwent BTX-A and PNMES combined therapy involving bilateral tDCS.
Each rehabilitation session lasted 60 min. Sessions were performed twice daily for 10 days so that all patients completed 20 sessions for the 2-week intervention period in the hospital. In Group I, tDCS started at the same time as the intensive OT for 25 min; and a 45-min only intensive OT was performed after the tDCS. In Group II, patients were given a BTX-A injection. Following this, patients simultaneously underwent intensive OT for 25 min using tDCS, and PNMES (25 min). Meanwhile, intensive OT was continued as well, and finally alone intensive OT (10 minutes) was performed (Figure 1). Intensive OT involved task-oriented training. The content of the task-oriented training mainly consisted of the task on the desk. The difficulty of the task was adjusted for each patient depending on the extent of their upper limb paralysis and their rehabilitation goals. Examples of activities included gripping or picking up blocks or pegs, varying in size; as well as using a keyboard and playing cards. The activities performed by each patient were recorded. In addition, patients were instructed to increase their use of upper limb paralysis. After the 2-week intervention period, patients presented as outpatients and were given exercises to complete at home. Patients were encouraged to use their paralyzed upper limbs depending on their individual rehabilitation needs. Daily activities involved tasks related to their own rehabilitation goals from the activities of daily living (ADL) and instrumental activities of daily living (IADL) tasks.
Clinical evaluations were performed at baseline and in 2-week and 4-month follow-up visits conducted after the intervention. We used the following clinical outcome measures to evaluate upper limb function, including the Fugl–Meyer Assessment Upper Extremity (FMA-UE; range: 0–66) and the Action Research Arm Test (ARAT; range: 0–57).17,18 Limb functioning used during daily activities were assessed using the Motor Activity Log (MAL; range: 0–5).19 The severity of spasticity symptoms were evaluated using the Disability Assessment Scale (DAS; range: 0–12).20 DAS evaluations were conducted with patients who had received BTX-A injections. The questionnaire included questions regarding the presence of tDCS side effects, such as headache, redness, pain, itching, and fever.
The effective change in this pilot study was defined as the minimal clinically important difference (MCID) for endpoints with established values, and the MCID for FMA-UE, ARAT and MAL were 4.25, 5.7 and 0.5 points, respectively.21,22 Furthermore, the statistically significant difference in the amount of change from the baseline within the group and the presence or absence of serious adverse events were used as reference indicators of feasibility.
Within-group comparisons were conducted to investigate changes in clinical symptoms (FMA-UE, ARAT, and MAL) before and after treatment using the Wilcoxon signed-rank test. All analyses were performed using SPSS, version 21.0 (IBM Corp., Armonk, NY, USA). The significance threshold was set to p < 0.05.
We used the DC-STIMULATOR PLUS system (neuroConn GmbH, Germany) to perform tDCS. The anodal electrode was placed over standard scalp coordinates for the ipsilesional M1; whereas the cathodal electrode was placed over standard scalp coordinates for the contralesional M1 (C3 or C4 points according to the 10–20 system). Bilateral tDCS using electrodes (size of 5 × 7 cm; 35 cm2) using a constant current intensity of 2.5 mA for 25 min (Figure 2). Our protocol used current densities below 25 mA/cm2 which should not induce damage even when high-frequency stimulation is applied for several hours.23,24 The tDCS protocol that we used has been described previously (Figure 3).13,25