Evaluating the Effectiveness and Safety of the Electroencephalogram-Based Brain-Machine Interface Rehabilitation System for Patients With Severe Hemiparetic Stroke: Protocol for a Randomized Controlled Trial (BEST-BRAIN Trial).

BACKGROUND: We developed a brain-machine interface (BMI) system for poststroke patients with severe hemiplegia to detect event-related desynchronization (ERD) on scalp electroencephalogram (EEG) and to operate a motor-driven hand orthosis combined with neuromuscular electrical stimulation. ERD arises when the excitability of the ipsi-lesional sensorimotor cortex increases. OBJECTIVE: The aim of this study was to evaluate our hypothesis that motor training using this BMI system could improve severe hemiparesis that is resistant to improvement by conventional rehabilitation. We, therefore, planned and implemented a randomized controlled clinical trial (RCT) to evaluate the effectiveness and safety of intensive rehabilitation using the BMI system. METHODS: We conducted a single blind, multicenter RCT and recruited chronic poststroke patients with severe hemiparesis more than 90 days after onset (N=40). Participants were randomly allocated to the BMI group (n=20) or the control group (n=20). Patients in the BMI group repeated 10-second motor attempts to operate EEG-BMI 40 min every day followed by 40 min of conventional occupational therapy. The interventions were repeated 10 times in 2 weeks. Control participants performed a simple motor imagery without servo-action of the orthosis, and electrostimulation was given for 10 seconds for 40 min, similar to the BMI intervention. Overall, 40 min of conventional occupational therapy was also given every day after the control intervention, which was also repeated 10 times in 2 weeks. Motor functions and electrophysiological phenotypes of the paretic hands were characterized before (baseline), immediately after (post), and 4 weeks after (follow-up) the intervention. Improvement in the upper extremity score of the Fugl-Meyer assessment between baseline and follow-up was the main outcome of this study. RESULTS: Recruitment started in March 2017 and ended in July 2018. This trial is currently in the data correcting phase. This RCT is expected to be completed by October 31, 2018. CONCLUSIONS: No widely accepted intervention has been established to improve finger function of chronic poststroke patients with severe hemiparesis. The results of this study will provide clinical data for regulatory approval and novel, important understanding of the role of sensory-motor feedback based on BMI to induce neural plasticity and motor recovery. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000026372; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi? recptno=R000030299 (Archived by WebCite at http://www.webcitation.org/743zBJj3D). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12339.

Change in Reciprocal Inhibition of the Forearm with Motor Imagery among Patients with Chronic Stroke.

We investigated cortically mediated changes in reciprocal inhibition (RI) following motor imagery (MI) in short- and long(er)-term periods. The goals of this study were (1) to describe RI during MI in patients with chronic stroke and (2) to examine the change in RI after MI-based brain-machine interface (BMI) training. Twenty-four chronic stroke patients participated in study 1. All patients imagined wrist extension on the affected side. RI from the extensor carpi radialis to the flexor carpi radialis (FCR) was assessed using a FCR H reflex conditioning-test paradigm. We calculated the "MI effect score on RI" (RI value during MI divided by that at rest) and compared that score according to lesion location. RI during MI showed a significant enhancement compared with RI at rest. The MI effect score on RI in the subcortical lesion group was significantly greater than that in the cortical lesion group. Eleven stroke patients participated in study 2. All patients performed BMI training for 10 days. The MI effect score on RI at a 20 ms interstimulus interval was significantly increased after BMI compared with baseline. In conclusion, mental practice with MI may induce plastic change in spinal reciprocal inhibitory circuits in patients with stroke.

Hybrid Assistive Neuromuscular Dynamic Stimulation Therapy: A New Strategy for Improving Upper Extremity Function in Patients with Hemiparesis following Stroke.

Hybrid Assistive Neuromuscular Dynamic Stimulation (HANDS) therapy is one of the neurorehabilitation therapeutic approaches that facilitates the use of the paretic upper extremity (UE) in daily life by combining closed-loop electromyography- (EMG-) controlled neuromuscular electrical stimulation (NMES) with a wrist-hand splint. This closed-loop EMG-controlled NMES can change its stimulation intensity in direct proportion to the changes in voluntary generated EMG amplitudes recorded with surface electrodes placed on the target muscle. The stimulation was applied to the paretic finger extensors. Patients wore a wrist-hand splint and carried a portable stimulator in an arm holder for 8 hours during the daytime. The system was active for 8 hours, and patients were instructed to use their paretic hand as much as possible. HANDS therapy was conducted for 3 weeks. The patients were also instructed to practice bimanual activities in their daily lives. Paretic upper extremity motor function improved after 3 weeks of HANDS therapy. Functional improvement of upper extremity motor function and spasticity with HANDS therapy is based on the disinhibition of the affected hemisphere and modulation of reciprocal inhibition. HANDS therapy may offer a promising option for the management of the paretic UE in patients with stroke.

A new therapeutic application of brain-machine interface (BMI) training followed by hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy for patients with severe hemiparetic stroke: A proof of concept study.

BACKGROUND: Hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy improved paretic upper extremity motor function in patients with severe to moderate hemiparesis. We hypothesized that brain machine interface (BMI) training would be able to increase paretic finger muscle activity enough to apply HANDS therapy in patients with severe hemiparesis, whose finger extensor was absent. OBJECTIVE: The aim of this study was to assess the efficacy of BMI training followed by HANDS therapy in patients with severe hemiparesis. METHODS: Twenty-nine patients with chronic stroke who could not extend their paretic fingers were participated this study. We applied BMI training for 10 days at 40 min per day. The BMI detected the patients' motor imagery of paretic finger extension with event-related desynchronization (ERD) over the affected primary sensorimotor cortex, recorded with electroencephalography. Patients wore a motor-driven orthosis, which extended their paretic fingers and was triggered with ERD. When muscle activity in their paretic fingers was detected with surface electrodes after 10 days of BMI training, we applied HANDS therapy for the following 3 weeks. In HANDS therapy, participants received closed-loop, electromyogram-controlled, neuromuscular electrical stimulation (NMES) combined with a wrist-hand splint for 3 weeks at 8 hours a day. Before BMI training, after BMI training, after HANDS therapy and 3month after HANDS therapy, we assessed Fugl-Meyer Assessment upper extremity motor score (FMA) and the Motor Activity Log14-Amount of Use (MAL-AOU) score. RESULTS: After 10 days of BMI training, finger extensor activity had appeared in 21 patients. Eighteen of 21 patients then participated in 3 weeks of HANDS therapy. We found a statistically significant improvement in the FMA and the MAL-AOU scores after the BMI training, and further improvement was seen after the HANDS therapy. CONCLUSION: Combining BMI training with HANDS therapy could be an effective therapeutic strategy for severe UE paralysis after stroke.

The effects of anodal transcranial direct current stimulation and patterned electrical stimulation on spinal inhibitory interneurons and motor function in patients with spinal cord injury.

Supraspinal excitability and sensory input may play an important role for the modulation of spinal inhibitory interneurons and functional recovery among patients with incomplete spinal cord injury (SCI). Here, we investigated the effects of anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) on spinal inhibitory interneurons in patients with chronic incomplete SCI and in healthy individuals. Eleven patients with incomplete SCI and ten healthy adults participated in a single-masked, sham-controlled crossover study. PES involved stimulating the common peroneal nerve with a train of ten 100 Hz pulses every 2 s for 20 min. Anodal tDCS (1 mA) was simultaneously applied to the primary motor cortex that controls the tibialis anterior muscle. We measured reciprocal inhibition and presynaptic inhibition of a soleus H-reflex by stimulating the common peroneal nerve prior to tibial nerve stimulation, which elicits the H-reflex. The inhibition was assessed before, immediately after, 10 min after and 20 min after the stimulation. Compared with baseline, simultaneous application of anodal tDCS with PES significantly increased changes in disynaptic reciprocal inhibition and long-latency presynaptic inhibition in both healthy and SCI groups for at least 20 min after the stimulation (all, p < 0.001). In patients with incomplete SCI, anodal tDCS with PES significantly increased the number of ankle movements in 10 s at 20 min after the stimulation (p = 0.004). In conclusion, anodal tDCS combined with PES could induce spinal plasticity and improve ankle movement in patients with incomplete SCI.

Modulation of cortical and spinal inhibition with functional recovery of upper extremity motor function among patients with chronic stroke.

PURPOSE: We hypothesized that recovery of upper extremity motor function is associated with reduction of intracortical inhibition and improved reciprocal inhibition. This study examines the relationships of functional recovery in chronic stroke with the intracortical inhibition and spinal reciprocal inhibition. METHODS: Participants were 61 patients with chronic hemiparetic stroke. The participants were applied hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy for 3 weeks. The Fugl-Meyer test upper extremity motor score (FM) and modified Ashworth scale (MAS) were assessed before (T0), immediately after (T1) and 3 months after (T2) the end of HANDS therapy. A paired pulse TMS paradigm was applied to assess short intracortical inhibition (SICI). Reciprocal inhibition (RI) was assessed with H reflex conditioning-test paradigm. RESULTS: FM and MAS were improved until T2. The change of FM from T0 to T2 was positively correlated with the change in affected SICI from T0 toT1. The change of wrist MAS from T0 to T1 was positively correlated with the change of RI. CONCLUSIONS: In chronic stroke patients with moderate or severe hemiparesis, well-recovered patients showed disinhibition of ipsilesional hemisphere and increased resiprocal inhibition of forearm.

A pilot study of contralateral homonymous muscle activity simulated electrical stimulation in chronic hemiplegia.

OBJECTIVE: For the recovery of hemiparetic hand function, a therapy was developed called contralateral homonymous muscle activity stimulated electrical stimulation (CHASE), which combines electrical stimulation and bilateral movements, and its feasibility was studied in three chronic stroke patients with severe hand hemiparesis. METHODS: Patients with a subcortical lesion were asked to extend their wrist and fingers bilaterally while an electromyogram (EMG) was recorded from the extensor carpi radialis (ECR) muscle in the unaffected hand. Electric stimulation was applied to the homonymous wrist and finger extensors of the affected side. The intensity of the electrical stimulation was computed based on the EMG and scaled so that the movements of the paretic hand looked similar to those of the unaffected side. The patients received 30-minutes of therapy per day for 2 weeks. RESULTS: Improvement in the active range of motion of wrist extension was observed for all patients. There was a decrease in the scores of modified Ashworth scale in the flexors. Fugl-Meyer assessment scores of motor function of the upper extremities improved in two of the patients. CONCLUSIONS: The results suggest a positive outcome can be obtained using the CHASE system for upper extremity rehabilitation of patients with severe hemiplegia.

Modulation of event-related desynchronization during motor imagery with transcranial direct current stimulation in a patient with severe hemiparetic stroke: a case report.

Recently, surface electroencephalogram (EEG)-based brain-machine interfaces (BMI) have been used for people with disabilities. As a BMI signal source, event-related desynchronization of alpha-band EEG (8-13 Hz) during motor imagery (mu ERD), which is interpreted as desynchronized activities of the activated neurons, is commonly used. However, it is often difficult for patients with severe hemiparesis to produce mu ERD of sufficient strength to activate BMI. Therefore, whether it is possible to modulate mu ERD during motor imagery with anodal transcranial direct-current stimulation (tDCS) was assessed in a severe left hemiparetic stroke patient. EEG was recorded over the primary motor cortex (M1), and mu ERD during finger flexion imagery was measured before and after a 5-day course of tDCS applied to M1. The ERD recorded over the affected M1 increased significantly after tDCS intervention. Anodal tDCS may increase motor cortex excitability and potentiate ERD during motor imagery in patients with severe hemiparetic stroke.

Effectiveness of hybrid assistive neuromuscular dynamic stimulation therapy in patients with subacute stroke: a randomized controlled pilot trial.

BACKGROUND AND OBJECTIVE: Hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy was devised to facilitate the use of the hemiparetic upper extremity in daily life by combining assistive neuromuscular electrical stimulation, referred to as the integrated volitional electrical stimulator (IVES), with a splint. The aim of this study is to assess the effectiveness of HANDS therapy for patients with subacute stroke. METHODS: The participants were 24 inpatients receiving rehabilitation for hemiparetic stroke within 60 days of onset. Entry criteria included inability to individuate finger extension. Patients were randomly assigned to 2 groups. The HANDS group (n = 12) used the IVES combined with a wrist splint for 8 hours a day for 3 weeks, and the control group (n = 12) wore a wrist splint alone. All patients received the same daily dose and length of standard poststroke multidisciplinary rehabilitation. Outcome measures were the upper extremity portion of the Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), and Motor Activity Log-14 (MAL). RESULTS: In all, 10 patients in each group completed the interventions. Compared with the control group, the HANDS group showed significantly greater gains in distal (wrist/hand) portion of the FMA (P < .01) and improvement of the ARAT (P < .05). The gains in the MAL did not differ. No adverse effects occurred and the HANDS therapy was well accepted. CONCLUSION: HANDS therapy in addition to conventional therapy may improve hand function in patients with moderate to severe hand impairment during early rehabilitation.

Motor improvement and corticospinal modulation induced by hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy in patients with chronic stroke.

BACKGROUND AND OBJECTIVE: We devised a therapeutic approach to facilitate the use of the hemiparetic upper extremity (UE) in daily life by combining integrated volitional control electrical stimulation with a wrist splint, called hybrid assistive neuromuscular dynamic stimulation (HANDS). METHODS: Twenty patients with chronic hemiparetic stroke (median 17.5 months) had moderate to severe UE weakness. Before and immediately after completing 3 weeks of training in 40-minute sessions, 5 days per week over 3 weeks and wearing the system for 8 hours each day, clinical measures of motor impairment, spasticity, and UE functional scores, as well as neurophysiological measures including electromyography activity, reciprocal inhibition, and intracortical inhibition were assessed. A follow-up clinical assessment was performed 3 months later. RESULTS: UE motor function, spasticity, and functional scores improved after the intervention. Neurophysiologically, the intervention induced restoration of presynaptic and long loop inhibitory connections as well as disynaptic reciprocal inhibition. Paired pulse transcranial magnetic stimulation study indicated disinhibition of the short intracortical inhibition in the affected hemisphere. The follow-up assessment showed that improved UE functions were maintained at 3 months. CONCLUSION: The combination of hand splint and volitional and electrically induced muscle contraction can induce corticospinal plasticity and may offer a promising option for the management of the paretic UE in patients with stroke. A larger sample size with randomized controls is needed to demonstrate effectiveness.