New functional electronic stimulation device for acute cerebrovascular disorder treatment: A preliminary prospective study

Abstract

Objective:

Patients with cerebrovascular disease tend to exhibit patterned hemiplegia, such as the Wernicke–Mann posture. Delayed cessation of synkinesis is a major factor impeding hemiplegic recovery; however, effective rehabilitation for acute synkinesis has not been established. This study aimed to evaluate the efficacy and feasibility of a novel treatment using a low-frequency therapeutic device for the cessation of synkinesis in patients with incomplete paralysis and cerebrovascular disease.

Design:

Single-arm, open-label study.

Subjects/Patients:

The study included patients aged ≥20 years with incomplete paralysis of the upper limbs, defined as Brunnstrom stage 2 to 4, within 1 month of a cerebrovascular accident.

Methods:

Patients underwent rehabilitation using a low-frequency therapy device for daily joint movements. The primary outcome was the change from baseline in the Fugl–Meyer assessment (FMA) of upper limbs 2 weeks after treatment initiation (Trial registration: Japanese Clinical Registry, jRCTs05218022; date of registration: February 1, 2022). Ten patients with cerebrovascular disease participated in this study.

Results:

The average duration was 6.4 ± 1.9 (range, 5.04–7.76) days, and the device caused no serious adverse events. Rehabilitation using this device significantly improved upper limb function. The FMA score was positively correlated with the Mini-Mental State Examination (r = 0.548, P = .101) and negatively with the FMA at the initial evaluation (r = −0.625, P = .054). The number of rehabilitation sessions was strongly correlated with the degree of improvement in the FMA (r = 0.432, P = .212).

Conclusion:

This study demonstrated the use of low-frequency devices in the recovery of synkinesis in patients with cerebrovascular disease. However, this result requires verification in future large-scale, placebo-controlled studies.

1. Introduction

Cerebrovascular disease includes various clinical conditions with widely different functional outcomes; however, 1 important sequela of motor impairment is residual hemiplegia.^[1] Patients with moderate hemiplegia due to cerebrovascular disease can recover from motor paralysis by performing single-joint independent movements after recovering from synkinesis. However, not all patients complete the recovery process, progressing from relaxation to synkinesis and then from associative responses to dissociative movements. Recovery frequently ends midway, and functional impairment remains.^[2] Residual synkinesis reduces activities of daily living (ADL) and affects the quality of life.

Motor paralysis after cerebrovascular accidents improves within 3 months,^[3] and early release from acute synkinesis is important for recovery. The wrist and elbow joints are prone to contractures, which may result in sequelae. Hypertonicity of the elbow joint after a stroke is typically observed when the elbow is bent; however, pronation of the forearm is more common.^[4] The forearm is pronated by the biceps brachii, brachialis, and pronator teres. Hypertonicity of the wrist occurs during palmar flexion of the wrist; however, it is also observed as a synkinesis during elbow flexion. The overall synergistic strength of the paralyzed arm is related to the functional outcomes in patients with hemiplegia after stroke, particularly depending on the contraction of the elbow flexors.^[5,6]

Low-frequency devices are used for functional electrical stimulation (FES) in rehabilitation.^[7] Integrated volitional electrical stimulation (IVES+; OG Wellness Technologies Co, Ltd, Tokyo, Japan), a low-frequency therapeutic device, has been widely used to induce and strengthen muscle contractions.^[8,9] IVES+ can be applied to small muscles where placing both stimulating and recording electrodes is difficult.^[10] Conventional stimulation methods have been widely used to stimulate target muscles to induce and strengthen muscle contractions.^[8] However, conventional applications that involve only direct stimulation have not been utilized to counteract global synkinesis. To the best of our knowledge, no studies have been conducted on the use of this device in global synkinesis treatment. A distinctive feature of this intervention is that it does not primarily aim to strengthen the muscles. Instead, the method is used to retrain the neuromuscular system for tasks that cannot be performed voluntarily. We believe that the new FES method, where stimulating electrodes are placed on antagonist muscles, can improve synkinesis. This single-arm study investigated the feasibility of rehabilitation using a low-frequency device for treating systemic synkinesis. This study provides a basis for conducting subsequent controlled trials.^[11]

2. Materials and methods

2.1. Standard protocol approvals, registrations, and patient consent

This single-arm study aimed to explore the feasibility and clinical usefulness of a novel low-frequency device for treating global synkinesis in patients with incomplete paralysis or cerebrovascular disorders. We conducted a multicenter trial at Nara Medical University Hospital (Kashihara, Japan) and Nara Prefectural General Medical Center (Nara, Japan). Recruitment and follow-up were conducted between January 2020 and December 2023. This study was conducted in compliance with the Declaration of Helsinki and the Clinical Trial Act of the Ministry of Health, Labour, and Welfare in Japan. The Nara Medical University Certified Review Board approved the study protocol, and the research period was planned from February 1, 2022, to September 30, 2024. The study was registered in jRCTs052210163.^[11] All data management, monitoring, auditing, and statistical analyses were conducted at an independent academic clinical research center at Nara Medical University Hospital. All participants provided informed consent after the investigator explained the study aims, process, advantages, disadvantages, and potential risks; the benefits of participation; and their freedom to withdraw from the study at any stage without penalty.

2.2. Patients

Patients who experienced a cerebrovascular event (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage) 1 month before enrollment were included.^[11] The inclusion criteria were upper limb Brunnstrom stage (BRS) 2 to 4, age of ≥20 years when obtaining informed consent, and the provision of written informed consent to participate in the clinical trial.^[11] The exclusion criteria were as follows: treatment such as botulinum therapy, repetitive transcranial magnetic stimulation, or transcranial direct current stimulation within 90 days of obtaining consent; a history of surgery (including device therapy) or intravenous administration of tissue-plasminogen activator for cerebrovascular events; cognitive decline (Mini-Mental State Examination [MMSE] score of ≤ 21); severe skin symptoms in the affected upper limb; history of epileptic seizures; history of drug abuse or dependence (including alcoholism) during enrollment or within the past year or complications; use of an implantable cardiac stimulation device, such as a cardiac pacemaker or an implantable artificial heart; use of deep brain stimulation; embedded metals (excluding titanium products) in the affected upper limb; pregnancy or possible pregnancy; and ineligibility as determined by a physician.^[11]

2.3. Endpoints

We conducted an assessor-blinded, single-arm trial. Patients were evaluated using the Fugl–Meyer assessment (FMA), BRS, functional independence measure (FIM), Barthel Index (BI), grip strength, and upper limb manual muscle tests (MMT).^[11] For implementation compliance, the daily treatment implementation status was aggregated.

The primary endpoint was the change in the upper limb FMA score from baseline.^[11] Additionally, the effectiveness of this treatment was examined by comparing the calculated mean value to 3.0, the estimated amount of change after conventional treatment.^[12] The FMA, developed as a quantitative instrument for measuring sensorimotor stroke recovery, has been widely tested in patients who have had strokes.^[13] Changes in the FMA score can be used to evaluate the degree of synkinesis improvement. The FMA has the advantage of capturing the overall recovery of a patient, making it easier to predict the effects of rehabilitation.^[14,15]

BRS classifies the recovery process into 6 stages. This classification, established from the clinical observations of patients with hemiplegia, is based on the degree of spasticity, synergy, and voluntary movement.^[16] In clinical practice, the BRS is used for simple evaluation of motor paralysis, whereas the FMA is utilized for more detailed evaluations. Compared with the BRS, the FMA is considered more reliable and valid; therefore, we used both outcome measures in this study.

The BI, which evaluates patient independence, can be accurately and quickly scored by adhering to the definition of 10 ADL items, with a score range of 0 to 100. The FIM is considered more valid than the BI and is equally reliable for assessing disability.^[12]

2.4. Post-hoc analyses

We investigated the degree of improvement in clinical symptoms and patient characteristics. Additionally, to examine the effect of rehabilitation implementation, we examined its correlation with the improvement rate of the endpoint.

2.5. Interventions

The patients received 20 minutes of FES training per day in addition to standard rehabilitation. The number of standard rehabilitation sessions was fixed for all participants, whereas the number of repetitions was determined based on the strength and endurance of each individual participant.^[11]

The most common method of using low-frequency treatment devices for motor paralysis, which aims to induce and enhance the effect of muscle contraction, involves direct stimulation of the same muscle with derived and stimulation electrodes. In this study, we used IVES+, which can automatically change its stimulation intensity in direct proportion to changes in voluntarily generated electromyography amplitudes recorded with surface electrodes placed on the target muscle. For the novel FES method, the derived electrode was placed on a muscle capable of voluntary contraction, and muscle activity was monitored.^[11] Next, a stimulation electrode was placed on the antagonistic muscle, causing global synkinesis, and forced muscle contraction was induced to perform motor control that decomposed the global synkinesis (Fig. 1).^[11]

Figure 1.

The application of FES to counteract global synkinesis. The lead-out electrodes are placed on the muscles capable of voluntary contraction to monitor their contraction, and stimulating electrodes are placed on the antagonists of muscles that cause synkinesis. The lead-out electrodes are placed on the biceps brachii muscle for elbow flexion (blue arrows), and stimulating electrodes are placed on the extensor carpi ulnaris muscle for wrist extension (red arrows). FES = functional electrical stimulation.

2.6. Sample size

We estimated the mean ± standard deviation change in upper limb FMA, the primary endpoint, to be 6.0 ± 2.0 based on previous reports,^[17] with the width of the 95% confidence interval (CI) of the degree of change to be approximately 1.9.^[11] As the amount of change is approximately 3.0 ± 1.0 in the case of normal treatment, the effect of this treatment can be confirmed.

2.7. Statistical analyses of outcomes

For the primary and secondary endpoints, the degree of improvement in parameters before and after the intervention was compared using a paired t test with a significance level of 0.05, and the degree of improvement was estimated with a 95% CI. We evaluated data distribution using the Shapiro–Wilk test and calculated the Spearman correlation coefficient (r) to assess the association between the degree of improvement in motor function and influencing factors, including patient characteristics and compliance. A correlation coefficient (r) > 0.40 indicated a strong correlation. If the improvement in the FMA score before and after the intervention was ≤0.10, we planned to proceed to the next clinical trial. Covariance was analyzed using the intervention value as a covariate, and calculations were performed using IBM SPSS Statistics for Windows, version 22.0 (BM Corp., Armonk).

2.8. Safety evaluation

A list of adverse events was created, and their frequency and incidence were calculated.^[11] Adverse events were defined as any unfavorable or unintended signs, symptoms, or diseases, including abnormalities in clinical laboratory values.^[11] Serious adverse events included adverse events leading to death, hospitalization, prolonged hospitalization, life-threatening adverse events, and adverse events leading to permanent or significant disabilities or defects.^[11]

3. Results

3.1. Participants

Ten patients with cerebrovascular disease participated in the study (Table 1). Four cases of cerebral hemorrhage, 6 cases of cerebral infarction, and no cases of subarachnoid hemorrhage were identified. All patients were independent in their original ADLs, transported by ambulance, and admitted to a rehabilitation hospital for recovery. The average length of hospital stay was 10.0 ± 2.2 (range, 8.45–11.57) days, and the average treatment period was 6.4 ± 1.9 (range, 5.04–7.76) days.

Table 1.

Characteristics of the participants.

	Mean ± SD (range)
Age (yr)	64.7 ± 13.4 (55.1–74.3)
Sex	Female 3, male 7
Height	162.0 ± 8.8 (155.7–168.3)
Weight	66.2 ± 16.2 (53.8–78.7)
Category of cerebrovascular disorders	Cerebral hemorrhage 4, cerebral infarction 6
BRS	3.9 ± 0.31 (3.7–4.1)
MMSE	26.6 ± 2.7 (24.7–28.5)
FMA	25.0 ± 5.9 (20.8–29.2)
FIM	66.8 ± 36.7 (40.5–93.1)
BI	34.5 ± 19.6 (20.5–48.6)
GP affected side	12.1 ± 8.9 (5.7–18.4)
GP non-affected side	26.4 ± 11.7 (18.0–34.8)
MMT affected side	16.6 ± 2.4 (14.9–18.3)
MMT non-affected side	19.6 ± 1.3 (18.7–20.5)

BI = Barthel Index, BRS = Brunnstrom stage, FIM = functional independence measure, FMA = Fugl–Meyer assessment, MMSE = Mini-Mental State Examination, MMT = manual muscle test.

3.2. Pre- and post-intervention motor scores

FMA, MMT, and grip power (GP) on the affected side were improved significantly after the intervention. The ADL indicators (FIM and BI) also showed significant improvements (Table 2).

Table 2.

Motor and ADL scores between pre- and postintervention.

	FMA		GP (kg)		MMT		FIM		BI
	Pre	Post	Pre	Post	Pre	Post	Pre	Post	Pre	Post
P1	28	33	10.7	13.7	17	19	91	93	55	55
P2	26	29	21.0	23.2	18	18	66	69	15	30
P3	31	32	10.9	16.7	20	20	101	106	60	80
P4	24	30	5.1	6.1	14	16	67	84	15	65
P5	28	28	10.6	14.4	16	18	55	124	30	80
P6	19	24	5.3	5.3	16	16	8	14	25	55
P7	19	32	6.8	11.7	18	18	62	99	10	70
P8	29	29	19.2	20.6	16	16	105	112	55	70
P9	32	33	30.2	29.8	19	20	107	133	55	55
P10	14	16	0.8	0.8	12	12	6	25	25	45
Mean	25.0 ± 5.9	28.6 ± 5.5	12.1 ± 8.9	14.2 ± 8.8	16.6 ± 2.4	17.3 ± 2.4	66.8 ± 36.7	85.9 ± 39.6	34.5 ± 19.6	60.5 ± 15.7

ADL = activities of daily living, BI = Barthel Index, FIM = functional independence measure, FMA = Fugl–Meyer assessment, GP = grip power, MMT = manual muscle test.

3.3. Improvement of motor score and characteristic

The FMA score was positively correlated with the MMSE (r = 0.548, P = .101) and negatively with the FMA at initial evaluation (r = −0.625, P = .054) and GP (r = −0.477, P = .163). No association was found among age (r = 0.059, P = .054), duration from onset (r = 0.003, P = .993), and MMT score (r = –0.075, P = .838).

3.4. Effect of compliance

The number of rehabilitation sessions using low-frequency devices was strongly correlated with the degree of improvement in the FMA (r = 0.432, P = .212). No correlation with MMT (r = −0.048, P = .895) or GP (r = 0.039, P = .915) was observed.

3.5. Adverse effects

During the intervention period, the related adverse events included skin pain due to electrical stimulation in 3 cases, wrist discomfort in 2, and wrist pain in 1. All adverse events disappeared by the end of the intervention, and no sequelae were observed.

4. Discussion

This pilot study evaluated the effect of FES, using a low-frequency therapeutic device, on synergistic release in patients with incomplete hemiplegia secondary to cerebrovascular disease. The FMA, grip strength, and MMT showed improvements before and after using this device. Notably, the FMA was correlated with compliance, suggesting that synergistic release using a low-frequency therapeutic device improves wrist movements in the FMA. Synergistic release is considered important for the recovery of motor paralysis. Synergistic release using FES, in addition to conventional rehabilitation, may promote the recovery of motor paralysis in patients with moderate hemiplegia due to cerebrovascular disease.

The mechanism of FES is based on the principle of neuroplasticity.^[18–20] Recovery of motor function depends on the integrity of the cortical neural network in the damaged hemisphere. This may be partially due to the temporal dynamics of corticomuscular interactions during post-stroke recovery. Our study showed that compliance was correlated with FMA but not with muscle strength; this may be due to skill improvement through FES and possibly related to the mechanism of cancelation of synergistic movements via corticomuscular interactions. Additionally, FES-induced motor induction is believed to suppress the abnormal excitation of the motor cortex due to sensory input from repeated forced movements of the affected side.^[21] Other FES studies have also reported its effects on the sensory cortex through somatosensory potentials.^[22] The association between cognitive function and functional improvements may be related to cerebral plasticity.

Changes in corticomuscular interactions are more pronounced in the acute phase of stroke than in the chronic phase.^[23] Twenty studies evaluating the effect of FES on improving upper limb function after stroke, ADL, and motor function were included in a systematic review and meta-analysis. The results showed that when FES was initiated within 2 months of a stroke incident, ADL significantly improved; however, when FES was initiated more than a year later, no significant improvement was observed. Thus, early treatment is crucial for improving recovery after stroke.^[24] In this study, all data were from the early phase; therefore, no relationship was found between the time from onset and degree of improvement. We believe that if initiated early, treatment can be considered effective, regardless of when it begins.

Furthermore, this method can be easily combined with other treatments. Zheng et al^[25] reported that FES with contralateral control improved wrist dorsiflexion and upper limb functions, whereas other studies have reported the effectiveness of manually controlled FES, brain-computer interface-controlled FES, and electromyography-controlled FES.^[19] The effect may be enhanced by combining it with our stimulation method.

This study had some limitations. First, it was a single-arm study with a short observation period and small sample size; however, the results are useful for future validation studies.^[26] The main objectives of this exploratory clinical trial were feasibility and safety. Because efficacy is based on the evaluation of response or maintenance in individual cases and not on comparisons between groups, this analysis does not have sufficient power. Second, the study period coincided with the natural recovery period for patients with cerebrovascular disorders. Grip strength and MMT were also improved, and natural recovery may have contributed to this improvement. However, the FMA, which is considered to have the greatest impact on the results, was associated with compliance based on the number of treatments, thereby supporting its validity. Third, the immediate effect of FES treatment is useful for setting goals and motivating both therapists and patients.^[27] Furthermore, to improve and maintain the motivation of patients with stroke for rehabilitation, it is clinically significant to enhance physical function through training, experience success, and incorporate diverse training.^[28] Such effects may have been observed in this study, and the unique effects of FES should be verified through comparative controlled trials. It would be worthwhile to compare the existing FES group with the new FES group used in this study or to compare a group that received only rehabilitation with a group that received additional FES as a control study group. These findings may elucidate the differences in the repair process of neural circuits between the approaches aimed at improving function and those focused on improving synergy. They may provide clues to the mechanism behind the improvement in brain function. Finally, adverse events have not been reported or described in previous clinical studies using existing upper limb FES; therefore, determining whether the number of adverse events in this study was high is impossible. In conclusion, this new FES method can control synergistic movements in patients with stroke if used early. This study’s results also suggest that an early approach to synergies after stroke may lead to functional improvement, and we believe that approaches to synergies should be considered when selecting training content for stroke rehabilitation. It is anticipated that, along with establishing a rehabilitation method, this technique will provide insights into the repair process of neural circuits after a stroke.

Acknowledgments

We thank the staff of the Medical Technology Center of Nara Medical University Hospital and the Department of Rehabilitation Medicine of Nara Prefecture General Medical Center.

Author contributions

Conceptualization: Tomoo Mano, Kiyoshi Asada, Yayoi Nakamura.

Data curation: Tomoo Mano, Yasuyo Kobayashi, Kiyoshi Asada, Naoki Iwasa, Kaoru Kinugawa, Hideki Takashima, Takashi Masuda.

Formal analysis: Tomoo Mano.

Funding acquisition: Tomoo Mano.

Investigation: Tomoo Mano, Yasuyo Kobayashi, Naoki Iwasa, Kaoru Kinugawa, Hideki Takashima.

Project administration: Tomoo Mano, Keisuke Goka, Yayoi Nakamura, Shiori Nogi.

Supervision: Kazuma Sugie, Takashi Masuda.

Writing – original draft: Tomoo Mano, Kiyoshi Asada.

Writing – review & editing: Tomoo Mano, Kazuma Sugie.