Increased Transcranial Direct Current Stimulation After Effects During Concurrent Peripheral Electrical Nerve Stimulation

In this study we tested the hypothesis whether a lasting change in the excitability of cortical output circuits can be obtained in healthy humans by combining a peripheral nerve stimulation during a concomitant depolarization and/or hyperpolarization of motor cortex. To reach this aim we combined two different neurophysiological techniques each of them able to induce a lasting increase of cortical excitability by them self: namely median nerve repetitive electrical stimulation (rEPNS) and transcranial direct current stimulation (tDCS). Ten normal young volunteers were enrolled in the present study. All subjects underwent five different protocols of stimulation: (1, 2) tDCS alone (anodal or cathodal); (3) Sham tDCS plus rEPNS; (4, 5) anodal or cathodal tDCS plus rEPNS. The baseline MEP amplitude from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscle, the FCR H-reflex were compared with that obtained immediately after and 10, 20, 30, 60 min after the stimulation protocol. Anodal tDCS alone induced a significant transient increase of MEP amplitude immediately after the end of stimulation while anodal tDCS + rEPNS determined MEP changes which persisted for up 60 min. Cathodal tDCS alone induced a significant reduction of MEP amplitude immediately after the end of stimulation while cathodal tDCS + rEPNS prolonged the effects for up to 60 min. Sham tDCS + rEPNS did not induce significant changes in corticospinal excitability. Anodal or cathodal tDCS + rEPNS and sham tDCS + rEPNS caused a lasting facilitation of H-reflex. These findings suggest that by providing afferent input to the motor cortex while its excitability level is increased or decreased by tDCS may be a highly effective means for inducing an enduring bi-directional plasticity. The mechanism of this protocol may be complex, involving either cortical and spinal after effects.     

Transcutaneous Electrical Nerve Stimulation in Nerve Regeneration: A Systematic Review of In Vivo Animal Model Studies

ObjectiveTranscutaneous electrical nerve stimulation (TENS) is a noninvasive electrical stimulation therapy indicated for pain control that has been applied for the regeneration of nerves. This systematic review aimed to analyze the evidence on TENS effectiveness on nerve regeneration.Materials and MethodsA systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria: PubMed/MEDLINE, Web of Science, ScienceDirect, and SciELO data bases. Primary research that evaluated TENS on nerve regeneration was considered.ResultsSeveral studies have investigated the use of TENS for pain treatment. A total of six animal studies analyzed TENS for nerve regeneration. The selected articles showed high quality (Animal Research: Reporting of In Vivo Experiments guidelines), with many unclear points related to bias opportunities (Systematic Review Center for Laboratory Animal Experimentation Risk of Bias tool). In general, TENS accelerated functional and motor recovery and increased axon quantity and diameter. More specifically, the application of low-frequency TENS resulted in a continuous basal lamina; a higher density of fibers with normal diameters, indicating normal myelination, showed signs of deterioration and delayed nerve regeneration. In contrast, the high-frequency TENS application stimulated motor regeneration and increased the diameter of the regenerated axons but revealed a small number of axons, demyelination, dark axoplasm, and an increase in the predisposition of neuropathic pain.ConclusionsAlthough there is some heterogeneous evidence in animal research, TENS seems to be a promising treatment for nerve injury that should be better explored. It is still necessary to improve the analysis of its application parameters, which can lead to the most satisfactory regeneration results and improve the understanding of its mechanisms on peripheral nerve regeneration.     

Repetitive Electrical Stimulation of Peripheral Nerve and Spinal Cord Activity

Abstract

Spinal cord neuron and dorsal column fiber responses to electrical stimulation of the sciatic nerve in anesthetized cats were recorded before, during, and after periods of repetitive electrical stimulation of the sciatic nerve through an implantable nerve cuff stimulator device of the type and method used in human patients for pain relief. In previous publications from this laboratory using similar experimental conditions, we reported that repetitive electrical stimulation of the peripheral nerve suppressed all components of the compound action potential of nerves. The present study corrfmns that 5 percent of the spinal cord units studied showed facilitated discharge, 46 percent showed inhibited or depressed discharge, 36 percent underwent no change, and 13 percent showed equivocal responses to repetitive electrical stimulation. Inhibition of dorsal column fiber activity following repetitive electrical stimulation of peripheral nerve is not consistent with the Melzack-Wall gate hypothesis in which suppression of small fiber nociceptive input is mediated by large fiber activity. Our work suggests that the most commonly observed effect 9f electroanalgesia is to cause a more diffuse depreSSIon of nociceptive as well as nonnociceptive spinal cord activity.     

Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity

BackgroundVagus nerve stimulation (VNS) is currently used to treat refractory epilepsy and is being investigated as a potential therapy for a range of conditions, including heart failure, tinnitus, obesity and Alzheimer's disease. However, the invasive nature and expense limits the use of VNS in patient populations and hinders the exploration of the mechanisms involved.ObjectiveWe investigated a non-invasive method of VNS through electrical stimulation of the auricular branch of the vagus nerve distributed to the skin of the ear – transcutaneous VNS (tVNS) and measured the autonomic effects.MethodsThe effects of tVNS parameters on autonomic function in 48 healthy participants were investigated using heart rate variability (HRV) and microneurography. tVNS was performed using a transcutaneous electrical nerve stimulation (TENS) machine and modified surface electrodes. Participants visited the laboratory once and received either active (200 μs, 30 Hz; n = 34) or sham (n = 14) stimulation.ResultsActive tVNS significantly increased HRV in healthy participants (P = 0.026) indicating a shift in cardiac autonomic function toward parasympathetic predominance. Microneurographic recordings revealed a significant decrease in frequency (P = 0.0001) and incidence (P = 0.0002) of muscle sympathetic nerve activity during tVNS.ConclusiontVNS can increase HRV and reduce sympathetic nerve outflow, which is desirable in conditions characterized by enhanced sympathetic nerve activity, such as heart failure. tVNS can therefore influence human physiology and provide a simple and inexpensive alternative to invasive VNS.     

Involvement of CAPON and Nitric Oxide Synthases in Rat Muscle Regeneration After Peripheral Nerve Injury

Carboxy-terminal PDZ ligand of nNOS (CAPON) protein, as an adaptor, binds to nNOS via the PDZ domain helping regulate neuronal nitric oxide synthase (nNOS) activity at post-synaptic sites in neurons (Jaffrey et al., Neuron, 20, 115–124, 1998). Recently, it has been reported that CAPON is present in mouse muscle and may be involved in mouse muscle growth, injury, and repair possibly by regulating the stability, activity, or position of nNOS (Segalat et al., Experimental Cell Research, 302, 170–179, 2005). The present study was to explore the expression patterns and roles of CAPON as well as NOS in rat muscle regeneration after nerve injury. Normal Sprague–Dawley rats were subjected to right sciatic nerve crush injury. Walking track analysis, real time polymerase chain reaction, Western blotting, in situ hybridization, immunocytochemistry, and co-immunoprecipitation techniques were used. It revealed that CAPON mRNA increased, which peaked on days 1 and 28, whereas nNOS mRNA underwent a downregulation in the ipsilateral gastrocnemius muscles after sciatic nerve injury. Their proteins approximately paralleled the mRNA expression. CAPON and nNOS were identified in the activated satellite cells or myotubes and their in vivo interaction was verified. However, eNOS and iNOS proteins suffered an upregulation and were detected in activated satellite cells or myotubes. These data suggest that CAPON and all these three isoforms of NOS might be involved in muscle regeneration after nerve injury. Further study is necessary for a better understanding of the potential functional link between CAPON, NOS, and muscle regeneration, with possible application to therapy for skeletal muscle repair from nerve injury. M. Chen and C. Cheng contribute equally to this work.     

Vagus Nerve Stimulation in Humans: Neurophysiological Studies and Electrophysiological Monitoring

Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters behavioral and electrographic seizure activity. We report on effects of electrical stimulation of the vagus nerve in five patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and it is hoped that analysis of electrophysiological effects of vagal nerve stimulation will help elucidate which brain areas are affected. Stimulation of the left vagus nerve in the neck was accomplished with a programmable implanted stimulator. Effects of stimulus amplitude, duration, and rate were studied. Noncephalic reference recording of the vagus-nerve-evoked potential showed some unusual properties: a scalp negative component occurred with latency of 12 ms, very high amplitude (up to 60 μV), and widespread scalp distribution. Field distribution studies indicate that this potential is generated in the neck, in the region of the stimulating electrodes. Muscle paralysis confirms this observation. Stimulation at various frequencies had no noticeable effect on electroencephalographic (EEG) activity regardless of whether the patient was under general anesthesia, awake, or asleep.     

The Predictive Value of Transcutaneous Electrical Nerve Stimulation for Patient Selection in Peripheral Nerve Field Stimulation for Chronic Low Back Pain: A Prospective Study

ObjectivePeripheral nerve field stimulation (PNFS) is an effective alternative treatment for patients with chronic low back pain. Transcutaneous electrical nerve stimulation (TENS) is frequently used in pain therapy. Aim of this prospective study was to examine the predictive value of TENS for later PNFS treatment.Materials and MethodsBetween 2014 and 2019, a prospective cohort study of 41 patients with chronic lumbar pain was conducted. Pain intensity (NRS) was assessed before and after TENS use, preoperatively/postoperatively and in the follow-up after three and six months, SF12v2 questionnaires with physical (PCS) and mental component summary (MCS) scores, and Oswestry disability index (ODI) questionnaire at baseline as well as three and six months after PNFS implantation. Implantation of the PNFS-system with two percutaneous leads was performed after four to seven days of positive testing. Statistical analysis was performed using depending t-test, ANOVA, and Spearman correlation.ResultsThe cohort consisted of 41 patients (19 females, 22 males) with a median age of 60.5 years (IQR^25-75 52–67). Two patients were lost to follow-up. After positive PNFS testing a pulse generator (IPG) was implanted in 15 patients with positive TENS effect and 15 patients without TENS effect. Leads were explanted in nine patients after negative PNFS trial phase. TENS positive patients showed significant correlation to a positive effect in the PNFS trial phase in NRS reduction (p = 0.042) indicating that TENS responders will also respond to PNFS (94% patients). After three and six months follow-up median NRS and SF12v2 (PCS) improved significantly in both cohorts, SF12v2 (MCS) and ODI only in the TENS positive cohort, respectively.ConclusionTENS can be predictive for patient selection in PNFS, as TENS positive patients showed significant correlation with a positive PNFS trial period. Therefore, TENS positive patients might be justifiable to be directly implanted with leads and IPG. TENS positive patients further tend to show a better improvement in the follow-up.     

1102/异种神经脱细胞移植物桥接大鼠坐骨神经缺损

目的　探讨异种神经脱细胞移植物桥接大鼠坐骨神经缺损后的神经再生及其再生过程中免疫排斥反应。 方法　用脱细胞兔周围神经作为移植物桥接大鼠坐骨神经1cm缺损;术后3、5、8、11、15天检测血液中淋巴细胞占白细胞百分比;3个月后取移植物及腓肠肌,用甲苯胺蓝、乙酰胆碱酯酶(AchE)、琥珀酸脱氢酶(SDH)组化染色,光、电镜观察神经再生及腓肠肌运动终板的恢复情况。　 结果　术后大鼠血液中淋巴细胞占白细胞的百分比与正常大鼠相比较无显著性差异,3个月后大鼠术侧下肢足趾能分开,行走时后蹬动作有力,针刺足底有逃避反应,桥接物内见有大量再生的坐骨神经纤维,腓肠肌肌纤维上见有呈AchE阳性的运动终板和神经纤维。　 结论　异种神经脱细胞移植物桥接大鼠坐骨神经缺损具有促进其再生的作用。     

Extent and Duration of Recovered Pupillary Light Reflex Following Retinal Ganglion Cell Axon Regeneration through Peripheral Nerve Grafts Directed to the Pretectum in Adult Rats

The functional reinnervation of the olivary pretectal nucleus (OPN) was studied in adult rats with peripheral nerve (PN) grafts bridging the interrupted retinopretectal pathway. Functional recovery was assessed quantitatively using established pupillometry techniques. The effect of intravitreal tuftsin fragment 1–3 (tuftsin 1–3) injections during the grafting procedure was also studied. A total of 53 adult rats received autologous PN grafts connecting the ocular stump of the transected optic nerve to the ipsilateral OPN. The contralateral eye was enucleated to remove the input from that eye to the OPN. A pupillary light reflex was elicited from 35 of the 53 PN-grafted animals and in the best cases, a response was obtained which compared closely to that recorded from control animals. Tuftsin 1–3 was found to increase the rate of recovery of the response. The response amplitude of PN-grafted rats was generally found to diminish with repeated stimulus presentation and also appeared to deteriorate with age. This was in contrast to control animals' responses. However, a PLR could still be elicited in 3 of the 6 animals studied 15 months after PN-grafting. These findings indicate that a near-normal PLR function can be restored using a peripheral nerve graft, but there are a number of factors that are likely to compromise optimal outcome.     

Psychophysical Responses to Experimentally Induced Heat and Cold Pain Before,During, and After Transcutaneous Electrical Nerve Stimulation

Objective. The outcomes of different modes of TENS (transcutaneous electrical nerve stimulation) in relieving experimental heat and cold pain were studied. Materials and methods. Three modes of stimulation, conventional, burst, and high rate frequency modulation (HRFM) including placebo, were trancutaneously applied to 20 right handed healthy volunteers (10 males and 10 females). Stimulation was carried out using two pad electrodes placed over the median nerve for 120 s in each case. Heat pain was induced to the right and left hands of each subject by means of a hot water bath and cold pain by means of frozen bottles. Pain scores based on Verbal Rating Scale (VRS) were recorded at 60 s intervals before, during, and after stimulation. Results. All stimulation modes except placebo decreased VRS values down to statistically significant levels in each case (p < 0.05). HRFM was the most effective mode of TENS causing a decrease of 53.1% to perception of heat pain during its application and 43.8% after HRFM in the right hand. In the left hand, these values were recorded as 46.8% and 40.3%, respectively. HRFM also decreased the perception of cold pain by 47.2% during stimulation and 44.5% after stimulation in the right hand. In the left hand, cold pain scores were reduced by 52.8% and 45.1%, respectively. There were no statistically significant sexual differences and no recorded statistically significant difference between the right or left sided stimulation. Conclusions. All modes of stimulation statistically decreased both heat and cold pain when compared to placebo. HRFM was the most effective mode of TENS. It might be worthwhile to test the patterns of stimulation in chronic pain patients.     

Axon Myelination and Electrical Stimulation in a Microfluidic,Compartmentalized Cell Culture Platform

Axon demyelination contributes to the loss of sensory and motor function following injury or disease in the central nervous system. Numerous reports have demonstrated that myelination can be achieved in neuron/oligodendrocyte co-cultures. However, the ability to selectively treat neuron or oligodendrocyte (OL) cell bodies in co-cultures improves the value of these systems when designing mechanism-based therapeutics. We have developed a microfluidic-based compartmentalized culture system to achieve segregation of neuron and OL cell bodies while simultaneously allowing the formation of myelin sheaths. Our microfluidic platform allows for a high replicate number, minimal leakage, and high flexibility. Using a custom built lid, fit with platinum electrodes for electrical stimulation (10-Hz pulses at a constant 3 V with ~190 kΩ impedance), we employed the microfluidic platform to achieve activity-dependent myelin segment formation. Electrical stimulation of dorsal root ganglia resulted in a fivefold increase in the number of myelinated segments/mm² when compared to unstimulated controls (19.6 ± 3.0 vs. 3.6 ± 2.3 MBP⁺ segments/mm²). This work describes the modification of a microfluidic, multi-chamber system so that electrical stimulation can be used to achieve increased levels of myelination while maintaining control of the cell culture microenvironment.     

Peripheral Nerve Stimulation in Treatment of Intractable Postherpetic Neuralgia

Objective. This case report presents an application of peripheral nerve stimulation to a patient with intractable postherpetic neuralgia that conventional treatment failed to ameliorate. Methods. The patient underwent an uneventful peripheral nerve stimulator trial with placement of two temporal eight‐electrode percutaneous leads (Octrode leads, Advanced Neuromodulation Systems, Plano, TX, USA) into the right subscapular and right paraspinal area of the upper thoracic region. Results. Upon experiencing excellent pain relief over the next two weeks, the patient underwent implantation of permanent leads two weeks later and reported sustained pain relief. Conclusion. Peripheral nerve stimulation offers an alternative treatment option for intractable pain associated with postherpetic neuralgia, especially for elderly patients where treatment options are limited due to existing comorbidities. Further studies are warranted.     

Three-Year Outcomes After Dorsal Root Ganglion Stimulation in the Treatment of Neuropathic Pain After Peripheral Nerve Injury of Upper and Lower Extremities

ObjectivesTraumatic peripheral nerve injuries (PNI) often result in severe neuropathic pain which typically becomes chronic, is recalcitrant to common analgesics, and is associated with sleep disturbances, anxiety, and depression. Pharmacological treatments proven to be effective against neuropathic pain are not well tolerated due to side effects. Neuromodulative interventions such as peripheral nerve or spinal cord stimulation have generated mixed results and may be limited by reduced somatotopic specificity. Dorsal root ganglion (DRG) stimulation may be more effective in this etiology.Materials and MethodsTwenty-seven patients were trialed with a DRG neurostimulation system for PNI; trial success (defined as ≥50% pain relief) was 85%, and 23 patients received a permanent stimulator. However, 36-month outcome data was only available for 21 patients. Pain, quality of life, mental and physical function, and opioid usage were assessed at baseline and at 3-, 6-, 12-, 18-, 24-, and 36 months post-permanent implant. Implant-related complications were also documented.ResultsCompared to baseline, we observed a significant pain relief (p < 0.001) at 3 (58%), 12 (66%), 18 (69%), 24 (71%), and 36 months (73%) in 21 patients (52.5 ± 14.2 years; 12 female), respectively. Mental and physical function showed immediate and sustained improvements. Participants reported improvements in quality of life. Opioid dosage reduced significantly (p < 0.001) at 3 (30%), 12 (93%), 18 (98%), 24 (99%), and 36 months (99%), and 20 of 21 patients were completely opioid-free after 36 months. There were five lead migrations and two electrode fractures (corrected by surgical intervention) and one wound infection (conservatively managed).ConclusionsDRG neuromodulation appears to be a safe, effective, and durable option for treating neuropathic pain caused by PNI. The treatment allows cessation of often ineffective pharmacotherapy (including opioid misuse) and significantly improves quality of life.     

Peripheral Nerve Axon Involvement in Myotonic Dystrophy Type 1, Measured Using the Automated Nerve Excitability Test

Background and Purpose

Primary involvement of the peripheral nerves in myotonic dystrophy type I (MyD1) is controversial. We investigated whether the involvement of peripheral nerves is a primary event of MyD1 or secondary to another complication such as diabetes mellitus (DM).

Methods

The subjects comprised 12 patients with MyD1, 12 with DM and no peripheral nerve involvement, and 25 healthy volunteers. We measured multiple excitability indices in the median motor axons. The strength-duration time constant was calculated from the duration-charge curve, the threshold electrotonus and current-threshold relationships were calculated from the sequential subthreshold current, and the recovery cycle was derived from double suprathreshold stimulation.

Results

The depolarizing and hyperpolarizing threshold electrotonus were significantly reduced and exhibited increased refractoriness in the MyD1 group compared with the DM and control groups. The SDTC, superexcitability, and subexcitability were not significantly altered in the MyD1 group.

Conclusions

The MyD1 group exhibited a depolarized axonal membrane potential. The significant differences in peripheral nerve excitability between the MyD1 group and the DM and normal control groups suggest that peripheral neuropathy is a primary event in MyD1 rather than a secondary complication of DM.