Effectiveness of Repetitive Transcranial Magnetic Stimulation Combined With Transspinal Electrical Stimulation on Corticospinal Excitability for Individuals With Incomplete Spinal Cord Injury: A Pilot Study.

Repetitive Transcranial Magnetic Stimulation (rTMS) and transspinal electrical stimulation (tsES) have been proposed as a novel neurostimulation modality for individuals with incomplete spinal cord injury (iSCI). In this study, we integrated magnetic and electrical stimulators to provide neuromodulation therapy to individuals with incomplete spinal cord injury (iSCI). We designed a clinical trial comprising an 8-week treatment period and a 4-week treatment-free observation period. Cortical excitability, clinical features, inertial measurement unit and surface electromyography were assessed every 4 weeks. Twelve individuals with iSCI were recruited and randomly divided into a combined therapy group, a magnetic stimulation group, an electrical stimulation group, or a sham stimulation group. The magnetic and electric stimulations provided in this study were intermittent theta-burst stimulation (iTBS) and 2.5-mA direct current (DC) stimulation, respectively. Combined therapy, which involves iTBS and transspinal DC stimulation (tsDCS), was more effective than was iTBS alone or tsDCS alone in terms of increasing corticospinal excitability. In conclusion, the effectiveness of 8-week combined therapy in increasing corticospinal excitability faded 4 weeks after the cessation of treatment. According to the results, combination of iTBS rTMS and tsDCS treatment was more effective than was iTBS rTMS alone or tsDCS alone in enhancing corticospinal excitability. Although promising, the results of this study must be validated by studies with longer interventions and larger sample sizes.

Designing and pilot testing a novel high-definition transcranial burst electrostimulation device for neurorehabilitation.

Objective.Non-invasive brain stimulation has been promoted to facilitate neuromodulation in treating neurological diseases. Recently, high-definition (HD) transcranial electrical stimulation and a novel electrical waveform combining a direct current (DC) and theta burst stimulation (TBS)-like protocol were proposed and demonstrated high potential to enhance neuroplastic effects in a more-efficient manner. In this study, we designed a novel HD transcranial burst electrostimulation device and to preliminarily examined its therapeutic potential in neurorehabilitation.Approach.A prototype of the transcranial burst electrostimulation device was developed, which can flexibly output a waveform that combined a DC and TBS-like protocol and can equally distribute the current into 4 × 1 HD electrical stimulation by automatic impedance adjustments. The safety and accuracy of the device were then validated in a series ofin vitroexperiments. Finally, a pilot clinical trial was conducted to assess its clinical safety and therapeutic potential on upper-extremity rehabilitation in six patients with chronic stroke, where patients received either active or sham HD transcranial burst electrostimulation combined with occupational therapy three times per week for four weeks.Main results.The prototype was tested, and it was found to comply with all safety requirements. The output parameters were accurate and met the clinical study needs. The pilot clinical study demonstrated that the active HD transcranial burst electrostimulation group had greater improvement in voluntary motor function and coordination of the upper extremity than the sham control group. Additionally, no severe adverse events were noted, but slight skin redness under the stimulus electrode immediately after stimulation was seen.Conclusions.The results demonstrated the feasibility of incorporating the HD electrical DC and TBS-like protocol in our device; and the novel neuromodulatory device produced positive neurorehabilitation outcomes in a safe fashion, which could be the basis for the future clinical implementation for treating neurological diseases.Trial registration:ClinicalTrials.gov Identifier: NCT04278105. Registered on 20 February 2020.

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

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.

Human platelet lysate biotherapy for traumatic brain injury: preclinical assessment.

Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at ∼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment.

Effects of Genital Nerve Stimulation Amplitude on Bladder Capacity in Spinal Cord Injured Subjects.

BACKGROUND/PURPOSE: Few studies have investigated the effects of changing the amplitude of dorsal genital nerve stimulation (GNS) on the inhibition of neurogenic detrusor overactivity in individuals with spinal cord injury (SCI). The present study determined the acute effects of changes in GNS amplitude on bladder capacity gain in individuals with SCI and neurogenic detrusor overactivity. METHODS: Cystometry was used to assess the effects of continuous GNS on bladder capacity during bladder filling. The cystometric trials were conducted in a randomized sequence of cystometric fills with continuous GNS at stimulation amplitudes ranging from 1 to 4 times of threshold (T) required to elicit the genitoanal reflex. RESULTS: The bladder capacity increased minimally and maximally by approximately 34% and 77%, respectively, of the baseline bladder capacity at 1.5 T and 3.2 T, respectively. Stimulation amplitude and bladder capacity were significantly correlated (R = 0.55, P = 0.01). CONCLUSION: This study demonstrates a linear correlation between the stimulation amplitude ranging from 1 to 4T and bladder capacity gain in individuals with SCI in acute GNS experiments. However, GNS amplitude out of the range of 1-4T might not be exactly a linear relationship due to subthreshold or saturation factors. Thus, further research is needed to examine this issue. Nevertheless, these results may be critical in laying the groundwork for understanding the effectiveness of acute GNS in the treatment of neurogenic detrusor overactivity.

Effects of Interactive Video Game-Based Exercise on Balance in Diabetic Patients with Peripheral Neuropathy: An Open-Level, Crossover Pilot Study.

Purpose. This study evaluated the effects of interactive video game-based (IVGB) exercise on balance in diabetic patients with peripheral neuropathy. Materials and Methods. Twenty-four patients were randomly assigned to two groups (12 participants per group). Group A received IVGB training for the first 6 weeks, with no exercise in the subsequent 6 weeks. Group B had no exercise for the first 6 weeks and then underwent IVGB training in the subsequent 6 weeks. For all participants, the Modified Falls Efficacy Scale (MFES), Time Up and Go (TUG) test, Berg Balance Scale (BBS), and Unipedal Stance Test (UST) were employed at weeks 0, 6, and 12 of the experiment. Results. BBS, right-leg UST, and TUG test scores significantly improved after IVGB intervention, whereas MFES and left-leg UST tended to improve after IVGB intervention. Conclusions. This study revealed that 6-week balance-based exercise training using the IVGB system exerted positive effects on functional balance in patients with diabetic peripheral neuropathy (DPN).

Designing and Implementing a Novel Transcranial Electrostimulation System for Neuroplastic Applications: A Preliminary Study.

Recently, a specific repetitive transcranial magnetic stimulation (rTMS) waveform, namely, the theta burst stimulation (TBS) protocol, has been proposed for more efficiently inducing neuroplasticity for various clinic rehabilitation purposes. However, few studies have explored the feasibility of using the TBS combined with direct current (dc) waveform for brain neuromodulation; this waveform is transcranially delivered using electrical current power rather than magnetic power. This study implemented a prototype of a novel transcranial electrostimulation device that can flexibly output a waveform that combined dc and the TBS-like protocol and assessed the effects of the novel combinational waveform on neuroplasticity. An in vivo experiment was conducted first to validate the accuracy of the stimulator's current output at various impedance loads. Using this transcranial stimulator, a series of transcranial stimulation experiments was conducted on the brain cortex of rats, in which electrode-tissue impedance and motor evoked potentials (MEPs) were measured. These experiments were designed to assess the feasibility and efficacy of the new combinational waveforms for brain neuroplasticity. Our results indicated that the transcranial electrostimulation system exhibited satisfactory performance, as evidenced by the error percentage of less than 5% for current output. In the animal experiment, the dc combined with intermittent TBS-like protocol exerted a stronger neuroplastic effect than the conventional dc protocol. These results demonstrated that the combination of electrical dc and TBS-like protocols in our system can produce a new feasible therapeutic waveform for transcranially inducing a promising neuromodulatory effect on various diseases of the central nervous system.

Chronic pudendal neuromodulation using an implantable microstimulator improves voiding function in diabetic rats.

Objective: Few studies have investigated the feasibility of using chronic pudendal neuromodulation for improving voiding function in patients with diabetes who are also experiencing urinary retention. The present study investigated the effects of chronic electrical stimulation (ES) of the sensory branch of the pudendal nerve on voiding function in diabetic rats. Approach: A custom-made implantable microstimulation system was designed and manufactured for chronic implantation in normal control (NC) and diabetic rats. After three or six weeks of pudendal neuromodulation, the intravesical pressure, external urethral sphincter electromyograms (EUS-EMGs), and urine flow rate (UFR) of all rats were simultaneously recorded to assess the effects of chronic pudendal ES on voiding function. Morphological changes in pudendal axons were assessed through hematoxylin and eosin (H&E) staining. Significance: This study demonstrated the feasibility of using chronic pudendal neuromodulation for improving voiding function in diabetic rats. These results may facilitate the development of an advanced neural prosthesis for restoring bladder function in clinical settings.

Effects of pudendal neuromodulation on bladder function in chronic spinal cord-injured rats.

BACKGROUND/PURPOSE: Few studies have investigated the feasibility of using pudendal neuromodulation to regulate bladder function in spinal cord-injured (SCI) animals. The present study aimed to determine the effects of electrical activation of the pudendal sensory branch on improving voiding functions in rats 6 weeks after a spinal cord injury and to explore the underlying neuromodulatory mechanisms. METHODS: Two urodynamic measurements were used to assess the effects of electrical stimulation (ES) on bladder and urethral functions: simultaneous recordings of the intravesical pressure (IVP) during continuous isotonic transvesical infusion (i.e., isotonic IVP) and external urethral sphincter (EUS) electromyography (EUS-EMG), and simultaneous recordings of transvesical pressure under isovolumetric conditions (i.e., isovolumetric IVP) and urethral perfusion pressure (UPP). RESULTS: Six weeks after the SCI, the rats showed voiding dysfunction, as indicated by abnormal cystometric measurements (e.g., increased volume threshold, increased contraction amplitude, and increased residual volume, and decreased voided volume). The voiding efficiency (VE) decreased to 13% after the SCI, but increased to 22-34% after applying pudendal afferent stimulation. In addition, pudendal stimulation significantly increased the EUS burst period and increased the difference between the UPP and the high-frequency oscillation (HFO) baselines, and changed the time offset between bladder and EUS activities. These findings suggest that pudendal afferent stimulation improved the VE by prolonging the micturition interval, decreased the urethral resistance, and recovered detrusor-sphincter dyssynergia during the voiding phase. CONCLUSION: This study demonstrates the feasibility of using pudendal neuromodulation in chronic SCI rats. These results could aid in developing an advanced neural prosthesis to restore bladder function in clinical settings.

Effects of far-infrared irradiation on myofascial neck pain: a randomized, double-blind, placebo-controlled pilot study.

OBJECTIVES: The objective of this study was to determine the relative efficacy of irradiation using a device containing a far-infrared emitting ceramic powder (cFIR) for the management of chronic myofascial neck pain compared with a control treatment. DESIGN: This was a randomized, double-blind, placebo-controlled pilot study. PARTICIPANTS: The study comprised 48 patients with chronic, myofascial neck pain. INTERVENTION: Patients were randomly assigned to the experimental group or the control (sham-treatment) group. The patients in the experimental group wore a cFIR neck device for 1 week, and the control group wore an inert neck device for 1 week. MAIN OUTCOME MEASUREMENT: Quantitative measurements based on a visual analogue scale (VAS) scoring of pain, a sleep quality assessment, pressure-pain threshold (PPT) testing, muscle tone and compliance analysis, and skin temperature analysis were obtained. RESULTS: Both the experimental and control groups demonstrated significant improvement in pain scores. However, no statistically significant difference in the pain scores was observed between the experimental and control groups. Significant decreases in muscle stiffness in the upper regions of the trapezius muscles were reported in the experimental group after 1 week of treatment. CONCLUSIONS: Short-term treatment using the cFIR neck device partly reduced muscle stiffness. Although the differences in the VAS and PPT scores for the experimental and control groups were not statistically significant, the improvement in muscle stiffness in the experimental group warrants further investigation of the long-term effects of cFIR treatment for pain management.

Pudendal neuromodulation improves voiding efficiency in diabetic rats.

AIMS: Diabetic cystopathy is typically manifested as bladder voiding dysfunction, and numerous patients are refractory to standard therapy. In this study, we determined whether electrical stimulation (ES) of the sensory branch of the pudendal nerve could engage an augmenting reflex and thereby improve bladder emptying in a diabetic animal model with cystopathy. METHODS: The efficiency of bladder emptying with ES of the sensory branch of the pudendal nerve at different stimulation intensities was measured in rats at 8 or 18 weeks after the induction of diabetes with streptozotocin. RESULTS: The voiding efficiency (VE) was reduced from 74 ± 4% to 30 ± 8% in rats with diabetes for 8 weeks and from 73 ± 6% to 20 ± 6% in rats with diabetes for 18 weeks. ES at lower intensities (0.025-0.05 mA) applied to the pudendal sensory nerve did not affect the VE in rats with diabetes for 18 weeks but increased the VE in rats with diabetes for 8 weeks. Subsequently, when the stimulation intensity was elevated to 0.1-0.3 mA, the VEs in rats with diabetes for both 8 and 18 weeks increased to 40-50%. CONCLUSIONS: The results of the present study are consistent with the essential role for pudendal sensory feedback in efficient bladder emptying, and electrical activation of the sensory branch of the pudendal nerve was efficient restoring the voiding function in diabetic animals with cystopathy. This could provide an approach to improve bladder emptying in diabetic patients with voiding dysfunction.

Effects of functional electrical stimulation cycling exercise on bone mineral density loss in the early stages of spinal cord injury.

OBJECTIVE: To determine whether bone mineral density loss after spinal cord injury can be attenuated by an early intervention with functional electrical stimulation cycling exercises (FESCE) and to ascertain whether the effect persists after FESCE is discontinued. DESIGN: A prospective study. SUBJECTS: Twenty-four individuals with spinal cord injury, 26-52 days after spinal cord injury, were divided into FESCE or control groups. METHODS: FESCE was applied in the initial 3 months and then suspended in the subsequent 3 months. Bone mineral density in the femoral neck and distal femur was measured using dual energy X-ray absorptiometry before training, immediately after the initial 3 months of training, and at the end of the subsequent 3 months. RESULTS: The bone mineral density decrease rate in the distal femur in the FESCE group was significantly less than that in the control group during the initial 3 months. However, there was no significant difference in the subsequent 3 months. CONCLUSION: FESCE in the early stages of spinal cord injury can partly attenuate bone mineral density loss in the distal femur. However, bone mineral density loss in the distal femur cannot be ameliorated completely by FESCE. In addition, the effect on the attenuation of bone loss in the distal femur faded once FESCE was discontinued.