Functional electrical stimulation-facilitated proliferation and regeneration of neural precursor cells in the brains of rats with cerebral infarction

Previous studies have shown that proliferation of endogenous neural precursor cells cannot alone compensate for the damage to neurons and axons. From the perspective of neural plastici- ty, we observed the effects of functional electrical stimulation treatment on endogenous neural precursor cell proliferation and expression of basic fibroblast growth factor and epidermal growth factor in the rat brain on the infarct side. Functional electrical stimulation was performed in rat models of acute middle cerebral artery occlusion. Simultaneously, we set up a placebo stimulation group and a sham-operated group. Immunohistochemical staining showed that, at 7 and 14 days, compared with the placebo group, the numbers of nestin （a neural precursor cell marker）-positive cells in the subgranular zone and subventricular zone were increased in the functional electrical stimulation treatment group. Western blot assays and reverse-transcription PCR showed that total protein levels and gene expression of epidermal growth factor and basic fibroblast growth factor were also upregulated on the infarct side. Prehensile traction test results showed that, at 14 days, prehension function of rats in the functional electrical stimulation group was significantly better than in the placebo group. These results suggest that functional electrical stimulation can promote endogenous neural precursor cell proliferation in the brains of acute cerebral infarction rats, enhance expression of basic fibroblast growth factor and epidermal growth factor, and improve the motor function of rats.

A novel functional electrical stimulation-control system for restoring motor function of post-stroke hemiplegic patients

Hemiparesis is one of the most common consequences of stroke. Advanced rehabilitation techniques are essential for restoring motor function in hemiplegic patients. Functional electrical stimulation applied to the affected limb based on myoelectric signal from the unaffected limb is a promising therapy for hemiplegia. In this study, we developed a prototype system for evaluating this novel functional electrical stimulation-control strategy. Based on surface electromyography and a vector machine model, a self-administered, muki-movement, force-modulation functional electrical stimulation-prototype system for hemiplegia was implemented. This paper discusses the hardware design, the algorithm of the system, and key points of the self-oscillation-prone system. The experimental results demonstrate the feasibility of the prototype system for further clinical trials, which is being conducted to evaluate the efficacy of the proposed rehabilitation technique.

Therapeutic effectiveness of a single exercise session combined with WalkAide functional electrical stimulation in post-stroke patients:a crossover design study

A growing body of evidence has suggested that the imbalance of epigenetic markers and oxidative stress appears to be involved in the pathophysiology and progression of stroke.Thus,strategies that modulate these biomarkers might be considered targets for neuroprotection and novel therapeutic opportunities for these patients.Physical exercise has been reported to induce changes in these epigenetic markers and improve clinical outcomes in different populations.However,little is reported on this in post-stroke patients.The purpose of this study was to investigate the effect of a single exercise session with WalkAide functional electrical stimulation(FES)on cognitive performance,clinical functional parameters,oxidative stress and epigenetic modulation in post-stroke individuals.In this crossover design study,12 post-stroke individuals aged 54–72 years of either sexes were included and subjected to a single session of exercise(45 minutes)without WalkAide functional electrical stimulation(EXE alone group),followed by another single session of exercise(45 minutes)with WalkAide functional electrical stimulation(EXE+FES group).The clinical functional outcome measures,cognitive performance and blood collections for biomarker measurements were assessed pre-and post-intervention.After intervention,higher Berg Balance Scale scores were obtained in the EXE+FES group than in the EXE alone group.There was no significant difference in the Timed Up and Go test results post-intervention between EXE alone and EXE+FES groups.After intervention,a better cognitive performance was found in both groups compared with before the intervention.After intervention,the Timed Up and Go test scores were higher in the EXE+FES group than in the EXE alone group.In addition,the intervention induced lower levels of lipid peroxidation.After intervention,carbonyl level was lower,superoxide dismutase activity and superoxide dismutase/catalase activity ratio were higher in the EXE+FES group,compared with the EXE group alone.In each group,both histone deacetylase(HDAC2)and histone acetyltransferase activities were increased after intervention compared with before the intervention.These findings suggest that a single exercise session with WalkAide FES is more effective on balance ability and cognitive performance compared with conventional exercise alone in post-stroke patients.This is likely to be related to the regulation of oxidative stress markers.The present study was approved by the Research Ethics Committee of the Methodist University Center-IPA(approval No.2.423.376)on December 7,2017 and registered in the Brazilian Registry of Clinical Trials—ReBEC(RBR-9phj2q)on February 11,2019.

Rebuilding motor function of the spinal cord based on functional electrical stimulation

Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience.The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology.In this study,the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology.A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn.Based on the individual experimental parameters and normalized coordinates of the motor function sites,the motor function sites that control a certain muscle were calculated.Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension,hip flexion,ankle plantarflexion,and ankle dorsiflexion movements were successfully achieved.The results show that the map of the spinal cord motor function sites was valid.This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.

Real-time and wearable functional electrical stimulation system for volitional hand motor function control using the electromyography bridge method

Voluntary participation of hemiplegic patients is crucial for functional electrical stimulation therapy.A wearable functional electrical stimulation system has been proposed for real-time volitional hand motor function control using the electromyography bridge method.Through a series of novel design concepts,including the integration of a detecting circuit and an analog-to-digital converter,a miniaturized functional electrical stimulation circuit technique,a low-power super-regeneration chip for wireless receiving,and two wearable armbands,a prototype system has been established with reduced size,power,and overall cost.Based on wrist joint torque reproduction and classification experiments performed on six healthy subjects,the optimized surface electromyography thresholds and trained logistic regression classifier parameters were statistically chosen to establish wrist and hand motion control with high accuracy.Test results showed that wrist flexion/extension,hand grasp,and finger extension could be reproduced with high accuracy and low latency.This system can build a bridge of information transmission between healthy limbs and paralyzed limbs,effectively improve voluntary participation of hemiplegic patients,and elevate efficiency of rehabilitation training.

A Survey of Lower Limb Rehabilitation Systems and Algorithms Based on Functional Electrical Stimulation

Functional electrical stimulation is a method of repairing a dysfunctional limb in a stroke patient by using low-intensity electrical stimulation.Currently,it is widely used in smart medical treatment for limb rehabilitation in stroke patients.In this paper,the development of FES systems is sorted out and analyzed in a time order.Then,the progress of functional electrical stimulation in the field of rehabilitation is reviewed in details in two aspects,i.e.,system development and algorithm progress.In the system aspect,the development of the first FES control and stimulation system,the core of the lower limb-based neuroprosthesis system and the system based on brain-computer interface are introduced.The algorithm optimization for control strategy is introduced in the algorithm.Asynchronous stimulation to prolong the function time of the lower limbs and a method to improve the robustness of knee joint modeling using neural networks.Representative applications in each of these aspects have been investigated and analyzed.

Novel Walking Stability-Based Gait Recognition Method for Functional Electrical Stimulation System Control

Gait recognition is the key question of functional electrical stimulation (FES) system control for paraplegic walking. A new risk-tendency-graph (RTG) method was proposed to recognize the stability information in FES-assisted walking gait. The main instrument was a specialized walker dynamometer system based on a multi-channel strain-gauge bridge network fixed on the walker frame. During walking process, this system collected the reaction forces between patient's upper extremities and walker and converted them into RTG morphologic curves of dynamic gait stability in temporal and spatial domains. To demonstrate the potential usefulness of RTG, preliminary clinical trials were done with paraplegic patients. The gait stability levels of two walking cases with 4- and 12-week FES training from one subject were quantified (0.43 and 0.19) from the results of temporal and spatial RTG. Relevant instable phases in gait cycle and dangerous inclinations of patient's body during walking process were also brought forward. In conclusion, the new RTG method is practical for distinguishing more useful gait stability information for FES system control.

Observation of the Effect of Gait-induced Functional Electrical Stimulation on Stroke Patients with Foot Drop

Objective:To explore the effects of functional electrical stimulation and functional mid frequency electrical stimulation on lower limb function and balance function in stroke patients.Methods:20 cases of stroke patients with foot drop after admission were randomly divided into the observation group and the control group,10 cases in each group.On the basis of the two groups of patients,the observation group used the gait induced functional electrical stimulation to stimulate the peroneal nerve and the pretibial muscle in the observation group.The control group used the computer medium frequency functional electrical stimulation to stimulate the peroneal nerve and the anterior tibial muscle for 2 weeks.Before and after treatment,the lower extremity simple Fugl-Meyer scale(FMA),the Berg balance scale(BBS)and the improved Ashworth scale were evaluated respectively,and the comparative analysis was carried out in the group and between the groups.Results:After 2 weeks of treatment,the scores of FMA and BBS in the two groups were significantly higher than those before the treatment(P<0.05),and the scores of FMA and BBS in the observation group were higher than those in the control group(P<0.05),and the flexor muscle tension of the ankle plantar flexor muscle of the observed group was lower than that of the control group(P<0.05).Conclusions:Exercise therapy combined with gait induced functional electrical stimulation or computer intermediate frequency functional electrical stimulation can significantly improve lower limb function and balance function in patients with ptosis,and the therapeutic effect of functional electrical stimulation combined with gait is better.

Functional electrical stimulation increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of rats with stroke

Background Functional electrical stimulation （FES） is known to promote the recovery of motor function in rats with ischemia and to upregulate the expression of growth factors which support brain neurogenesis.In this study,we investigated whether postischemic FES could improve functional outcomes and modulate neurogenesis in the subventricular zone （SVZ） after focal cerebral ischemia.Methods Adult male Sprague-Dawley rats with permanent middle cerebral artery occlusion （MCAO） were randomly assigned to the control group,the placebo stimulation group,and the FES group.The rats in each group were further assigned to one of four therapeutic periods （1,3,7,or 14 days）.FES was delivered 48 hours after the MCAO procedure and divided into two 10-minute sessions on each day of treatment with a 10-minute rest between them.Two intraperitoneal injections of bromodeoxyuridine （BrdU） were given 4 hours apart every day beginning 48 hours after the MCAO.Neurogenesis was evaluated by immunofluorescence staining.Wnt-3 which is strongly implicated in the proliferation and differentiation of neural stem cells （NSCs） was investigated by Western blotting analysis.The data wera subjected to oneway analysis of variance （ANOVA）,followed by a Tukey/Kramer or Dunnett post hoc test.Results FES significantly increased the number of BrdU-positive cells and BrdU/glial flbrillary acidic protein doublepositive neural progenitor cells in the SVZ on days 7 and 14 of the treatment （P 〈0.05）.The number of BrdU/doublecortin （DCX） double-positive migrating neuroblast cells in the ipsilateral SVZ on day 14 of the FES treatment group （（522.77±33.32） cells/mm2） was significantly increased compared with the control group （（262.58±35.11） cells/mm2,P 〈0.05） and the placebo group （（266.17±47.98） cells/mm2,P 〈0.05）.However,only a few BrdU/neuron-specific nuclear protein-positive cells were observed by day 14 of the treatment.At day 7,Wnt-3 was upregulated in the ipsilateral SVZs of the rats receiving FES （（0.44±0.05）%） compared with those of the control group rats （（0.31±0.02）%,P 〈0.05） or the placebo group rats （（0.31±0.04）%,P 〈0.05）.At day 14,the corresponding values were （0.56±0.05）% in the FES group compared with those of the control group rats （（0.50±0.06）%,P 〈0.05） or the placebo group rats （（0.48±0.06）%,P 〈0.05）.Conclusion FES augments the proliferation,differentiation,and migration of NSCs and thus promotes neurogenesis,which may be related to the improvement of neurological outcomes.

EEG-controlled functional electrical stimulation rehabilitation for chronic stroke:system design and clinical application

Stroke is one of the most serious diseases that threaten human life and health.It is a major cause of death and disability in the clinic.New strategies for motor rehabilitation after stroke are undergoing exploration.We aimed to develop a novel artificial neural rehabilitation system,which integrates brain--computer interface(BCI)and functional electrical stimulation(FES)technologies,for limb motor function recovery after stroke.We conducted clinical trials(including controlled trials)in 32 patients with chronic stroke.Patients were randomly divided into the BCI-FES group and the neuromuscular electrical stimulation(NMES)group.The changes in outcome measures during intervention were compared between groups,and the trends of ERD values based on EEG were analyzed for BCI-FES group.Results showed that the increase in Fugl Meyer Assessment of the Upper Extremity(FMA-UE)and Kendall Manual Muscle Testing(Kendall MMT)scores of the BCI-FES group was significantly higher than that in the sham group,which indicated the practicality and superiority of the BCI-FES system in clinical practice.The change in the laterality coefficient(LC)values based onμ-ERD(ΔLCm-ERD)had high significant positive correlation with the change in FMA-UE(r=0.6093,P=0.012),which provides theoretical basis for exploring novel objective evaluation methods.

Artifacts of Functional Electrical Stimulation on Electromyograph

The purpose of this study is to investigate different factors of the artifact in surface electromyography(EMG) signal caused by functional electrical stimulation(FES). The factors investigated include the size of stimulation electrode pads, the amplitude, frequency, and pulse width of the stimulation waveform and the detecting electrode points. We calculate the root mean square(RMS) of EMG signal to analyze the effect of these factors on the M-wave properties. The results indicate that the M-wave mainly depends on the stimulation amplitude and the distribution of detecting electrodes,but not on the other factors. This study can assist the reduction of artifact and the selection of detecting electrode points.

Low-Power CMOS IC for Function Electrical Stimulation of Nerves

A low-power IC for function electrical stimulation （FES） of nerves is designed for an implantable system and fabricated in CSMC＇s 0.6μm CMOS technology. The IC can be used for stimulating animals＇ spinal nerve bundles and other nerves connected with a cuff type electrode. It consists of a pre-amplifier,a main amplifier,and an output stage. According to the neural signal spectrum,the bandwidth of the FES signal generator circuit is defined from 1Hz to 400kHz. The gain of the circuit is about 66dB with an output impedance of 900. The 1C can function under a single supply voltage of 3-5V. A rail-to-rail output stage helps to use the coupled power efficiently. The measured time domain performance shows that the bandwidth and the gain of the IC agree with the design. The power consumption is lower than 6mW.

Early application of percutaneous neuromuscular electric stimulation in interfering motor function of limbs and difference in temperature of axilla of patients with ischemic stroke

BACKGROUND： Temperature of axilla could be affected due to motor dysfunction of limbs and neural changes of vessel after ischemic stroke. OBJECTIVE： To observe the effect of percutaneous neuromuscular electric stimulation （PNES） on difference in temperature of axilla and analyze the relationship between function of limbs and difference in temperature of axilla. DESIGN： Randomized grouping and controlled observation SETTING： Department of Neurology, General Hospital of Shenyang Military Area Command of Chinese PLA PARTICIPANTS： Sixty patients with ischemic stroke were selected from Neurological Department of General Hospital of Shenyang Military Area Command of Chinese PLA from January to June 2003. All cases were diagnosed with clinical diagnosis criteria of ischemic stroke established by the Fourth Chinese Classification of Cerebrovasular Disease and CT examination and received neuromuscular electric stimulation （NES）. Patients were randomly divided into control group and treatment group with 30 in each group. METHODS： Control group： Patients received routinely neurological therapy. Treatment group： Except routine therapy, patients suffered from NES at 48 hours after hospitalization. NMT-91 NES equipment was used to stimulated injured limbs with low frequency once 30 minutes a day in total of 10 times a course, especially extensor muscle of upper limb and flexor muscle of lower limb. Prescription of hemiplegia was internally decided by equipment with the output frequency of 200 Hz. Intensity of electric output could cause muscle contraction. The therapy needed two or three courses. Temperature of bilateral axilla was measured every day to calculate the difference with the formula of （temperature of axilla on the injured side - temperature of axilla on the healthy side）. Motor function of limbs was measured with FugI-Meyer Motor Assessment （FMA） during hospitalization and at 2 and 4 hours after hospitalization. Among 90 points, upper and lower limb function was 54, equilibrium function 10, sensory function 10, and motion of joint 16. The higher the scores were, the better the function was. Correlation of data was dealt with linear correlation analysis. MAIN OUTCOME MEASURES ： Assessment and correlation between difference in temperature of axilla and motor function of injured limbs during hospitalization and at 2 and 4 weeks after hospitalization. RESULTS： All 60 patients with ischemic stroke were involved in the final analysis. ① Difference in temperature： Difference of 2 and 4 weeks after hospitalization was lower than that in control group and at just hospitalization [treatment group： （0.056±0.000）, （0.024±0.003） ℃; control group： （0.250±0.001）, （0.131 ±0.001）℃; hospitalization; （0.513±0.001） ℃, P 〈 0.05-0,01]. ② FMA scores： Scores of 2 and 4 weeks after hospitalization were higher than those in control group and at just hospitalization [treatment group; （43.50±15.09）, （67.97 ±18.21） points; control group： （33.33 ±13.54）, （40.87±19.34） points; hospitalization： （26.43 ±11.87） points, P 〈 0.05-0.01]. ③ Correlation： Difference in temperature of axilla was negative correlation with FMA scores （c=- -0.255 1, P 〈 0.05）. CONCLUSION： ① PNES can accelerate recovery of limb function and decrease temperature of axilla of patients with ischemic stroke. ② The lower the difference in temperature is, the better the functional recovery is.

Multi-channel neural signal stimulating module and in-vivo experiments

The module for function electrical stimulation （FES） of neurons is designed for the research of the neural function regeneration microelectronic system, which is an in-body embedded micro module. It is implemented by using discrete devices at first and characterized in vitro. The module is used to stimulate sciatic nerve and spinal cord of rats and rabbits for in-vivo real-time experiments of the neural function regeneration system. Based on the module, a four channel module for the FES of neurons is designed for 12 sites cuff electrode or 10 sites shaft electrode. Three animal experiments with total five rats and two rabbits were made. In the in-vivo experiment, the neural signals including spontaneous and imitated were regenerated by the module. The stimulating signal was used to drive sciatic nerve and spinal cord of rats and rabbits, successfully caused them twitch in different parts of their bodies, such as legs, tails, and fingers. This testifies that the neural function regeneration system can regenerate the neural signals.

Integrated circuit for single channel neural signal regeneration

Based on the 4-channel neural signal regeneration system which is realized by using discrete devices and successfully used for in-vivo experiments on rats and rabbits, a single channel neural signal regeneration integrated circuit （IC）is designed and realized in CSMC ＇ s 0. 6 μm CMOS （ complementary metal-oxide-semiconductor transistor ） technology. The IC consists of a neural signal detection circuit with an adjustable gain, a buffer, and a function electrical stimulation （FES） circuit. The neural signal regenerating IC occupies a die area of 1.42 mm × 1.34 mm. Under a dual supply voltage of ±2. 5 V, the DC power consumption is less than 10 mW. The on-wafer measurement results are as follows： the output resistor is 118 ml）, the 3 dB bandwidth is greater than 30 kHz, and the gain can be variable from 50 to 90 dB. The circuit is used for in-vivo experiments on the rat＇ s sciatic nerve as well as on the spinal cord with the cuff type electrode array and the twin-needle electrode. The neural signal is successfully regenerated both on a rat＇ s sciatic nerve bundle and on the spinal cord.

Dynamical Measurement Method of Handle Reaction Vector for FES-Assisted Paraplegic Walking

To analyze the use of upper limb support during paraplegic walking assisted by functional electrical stimulation ( FES), a new dynamical measurement for handle reaction vector (HRV) ap- plied by patient to walker was proposed. To avoid the discomfort of direct monitoring, the dyna- mometer system was designed based on 12 string-gauge bridges instrumented on a standard walker frame. The detailed positions of these bridges were determined according to the deformation distri- butions of the walker frame under different directional components of HRV. To adapt the system to quantitative and reliable measurement, a redundant-optimized technique was developed in calibra- tion. The measurement accuracy, nonlinearity. and crosstalk of the designed system were investi- gated, which were better than 1.01%. 2.91%, and 3.19% respectively. Clinical trials were done with 6 paraplegic subjects using the system and one case was given as the example of actual mea- surement. All experiment and clinical trial results show that this method is reliable and practicable.

Microelectronic neural bridge for signal regeneration and function rebuilding over two separate nerves

According to the feature of neural signals,a micro-electronic neural bridge（MENB）has been designed. It consists of two electrode arrays for neural signal detection and functional electrical stimulation（FES）,and a microelectronic circuit for signal amplifying,processing,and FES driving.The core of the system is realized in 0.5-μm CMOS technology and used in animal experiments.A special experimental strategy has been designed to demonstrate the feasibility of the system.With the help of the MENB,the withdrawal reflex function of the left/right leg of one spinal toad has been rebuilt in the corresponding leg of another spinal toad.According to the coherence analysis between the source and regenerated neural signals,the controlled spinal toad＇s sciatic nerve signal is delayed by 0.72 ms in relation to the sciatic nerve signal of the source spinal toad and the cross-correlation function reaches a value of 0.73.This shows that the regenerated signal is correlated with the source sciatic signal significantly and the neural activities involved in reflex function have been regenerated.The experiment demonstrates that the MENB is useful in rebuilding the neural function between nerves of different bodies.

Model-based optimization of adaptive external counterpulsation therapy

External counterpulsation therapy(ECP)is a non-invasive method to assist the circulatory system.The main principle of ECP is to initiate a diastolic pulse wave in the arterial system by squeezing the inner leg vessels.Superficial and low veins are compressed due to muscle contractions,which are triggered by functional electrical stimulation(FES).In this work,a new trigger method for the stimulation is proposed.Blood flow is determined by measuring the pulsatile change of conductivity in the observed segment by impedance plethysmography.The proposed“adaptive stimulation”allows the automatic adjustment of the start and duration of the stimulation to improve transport of venous blood.For this purpose,a mathematical circulation model was developed for optimization of the adaptive functional electrical stimulation.The model takes into account the effects of gravity,muscle pump with or without FES,and venous regurgitation.The model was shown to have a behavior similar to that of clinical measurements.The simulation showed a flow enhancement of up to 14%and,furthermore,that the start of the stimulation is less important than the duration of each stimulation phase.Therefore,an adaptation of the heart rate seems necessary,as the expulsion and refill times must remain relatively constant for an optimal pumping result.For a practical approach,it is reasonable to adapt the duration of stimulation to 56%of the cardiac cycle in order to reach a maximum flow.

Design and Implementation of a Wearable Body Area Sensor Network for Distributed FES System

A wearable body area sensor network(WBASN) was designed and implemented to monitor movement information of stroke patients in real time. The sensor system was combined with a previously developed distributed functional electrical stimulation(d FES) system, which is a promising technology for motor rehabilitation of stroke patients. Movement information could be useful in outcome assessment of rehabilitation, or for closed-loop adaptive stimulation during rehabilitation. In addition,a short-latency, low-power communication protocol was developed to meet the clinical requirements of energy efficiency and high rate of data feed-through. The prototype of the WBASN was tested in preliminary human experiments. Experimental results demonstrate the feasibility of the proposed wearable body area sensor network in monitoring arm movements on healthy subjects.