Nonquantal transmission at the vestibular hair cell-calyx synapse: KLV currents modulate fast electrical and slow K+ potentials.

Vestibular hair cells transmit information about head position and motion across synapses to primary afferent neurons. At some of these synapses, the afferent neuron envelopes the hair cell, forming an enlarged synaptic terminal called a calyx. The vestibular hair cell-calyx synapse supports a mysterious form of electrical transmission that does not involve gap junctions, termed nonquantal transmission (NQT). The NQT mechanism is thought to involve the flow of ions from the presynaptic hair cell to the postsynaptic calyx through low-voltage-activated channels driven by changes in cleft [K+] as K+ exits the hair cell. However, this hypothesis has not been tested with a quantitative model and the possible role of an electrical potential in the cleft has remained speculative. Here, we present a computational model that captures experimental observations of NQT and identifies features that support the existence of an electrical potential (ϕ) in the synaptic cleft. We show that changes in cleft ϕ reduce transmission latency and illustrate the relative contributions of both cleft [K+] and ϕ to the gain and phase of NQT. We further demonstrate that the magnitude and speed of NQT depend on calyx morphology and that increasing calyx height reduces action potential latency in the calyx afferent. These predictions are consistent with the idea that the calyx evolved to enhance NQT and speed up vestibular signals that drive neural circuits controlling gaze, balance, and orientation.

Magnetic, but not non-magnetic, reduced graphene oxide in spinal cord increases nociceptive neuronal responsiveness.

The interference between external magnetic fields and neurophysiology is not new, however, the role of the neuronal magnetic field remains unclear. This study aimed at investigating a possible role of the neuronal magnetic field in nociception. Highly and poorly magnetic reduced graphene oxide (rGO) was injected intrathecally in rats. Nociceptive responsiveness was greater in rats that received highly magnetic-rGO in von Frey electronic or intraplantar capsaicin tests. Furthermore, in vitro experiments demonstrated that the number of KCl-responsive DRG-neurons was greater when treated with highly magnetic-rGO when compared with non-magnetic-rGO. Our data also suggested that the mechanism underlying the increased nociceptive responsiveness involves increased Ca2+v activity. Complementary experiments excluded the cytotoxic and inflammatory effects of the magnetic-rGO in neuronal responsiveness. These data suggest that the disturbance of the neuronal magnetic field in spinal cord increases nociceptive responsiveness, suggesting an importance of the magnetic component of the electromagnetic field in neuronal transmission.

Painful cramps and giant myotonic discharges in a family with the Nav1.4-G1306A mutation.

INTRODUCTION: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. METHODS: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. RESULTS: A G1306A mutation in the Nav1.4 voltage-gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. CONCLUSIONS: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium-aggravated myotonia than myotonia fluctuans.

Correlation between Delayed Relief after Microvascular Decompression and Morphology of the Lateral Spread Response in Patients with Hemifacial Spasm-Further Examination with Compound Motor Action Potentials.

Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), postoperative delayed relief is one of its main issues. We previously evaluated the morphology of the lateral spread response (LSR) and reported correlation between delayed relief after MVD and polyphasic morphology of the LSR. This study aimed to investigate the morphology of LSR and the course of recovery of the compound motor action potential (CMAP), to better understand the pathophysiology of delayed healing of HFS. Based on the pattern of the initial LSR morphology on temporal and marginal mandibular branches stimulation, patients were divided into two groups: the monophasic and polyphasic groups. The results of MVD surgery and sequential changes in the CMAP were evaluated 1 week, 1 month, 1 year, and final follow-up after the surgery. Significantly higher rates of persistent postoperative HFS were observed in patients with the polyphasic type of initial LSR at 1 week and 1 month after the surgery (P < 0.05, respectively). In the polyphasic group, the amplitude of the CMAP tended to gradually improve with time, while in the monophasic group, the amplitude of the CMAP decreased on the seventh postoperative day, followed by its gradual improvement. There is a significant correlation between delayed relief after MVD and polyphasic morphology of the initial LSR in patients with HFS. In the polyphasic group, CMAP recovered earlier and showed less reduction in amplitude, suggesting segmental demyelination, with less damage to peripheral nerves.

Perineal and foot muscle synkinesis following trauma to the sacrum in an adult male - A case of motor root ephaptic transmission?

Ephaptic transmission has been proven as an alternative to chemical synaptic neural transmission and occurs in pathological situations, such as epilepsy and demyelination. Hereby, we report the case of an adult male that in 2012 was involved in a low-speed motorcycle accident with sacrum impact that from day three onwards reported unwanted penile movement when performing hallux and toe plantar flexion of the right foot. Urologic studies and perineal MRI were unremarkable but sacral MRI showed a significantly stenotic canal at the S1-S2 level while EMG displayed chronic moderate right S2 radiculopathy. Nine years later the patient underwent surgical decompression of the sacral canal with complete resolution of the synkinesis. We hypothesize ephaptic transmission between adjacent motor nerve fibres at the S2 sacral nerve root to be the likely mechanism explaining this phenomenon.

Significant Correlation between Delayed Relief after Microvascular Decompression and Morphology of the Abnormal Muscle Response in Patients with Hemifacial Spasm.

Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), postoperative delayed relief of persistent HFS is one of the main issues. In patients with hemifacial spasm, stimulation of a branch of the affected facial nerve elicits an abnormal response in the muscles innervated by another branch. Several specific types of waves were found in the abnormal muscle response (AMR). This study aimed to confirm the relationship between the initial morphology of the AMR wave and delayed relief of persistent HFS after MVD. We retrospectively analyzed and compared the data from 47 of 155 consecutive patients who underwent MVD for HFS at our hospital between January 2015 and March 2020. Based on the pattern of the initial AMR morphology on orbicularis oculi and mentalis muscle stimulation, patients were divided into two groups, namely, the monophasic and polyphasic groups. The results of MVD surgery for HFS were evaluated 1 week, 1 month, and 1 year postoperatively, by evaluating whether or not the symptoms of HFS persisted at the time of each follow-up. There were significantly higher rates of persistent postoperative HFS in patients with the polyphasic type of initial AMR at 1 week and 1 month after the surgery (p < 0.05, respectively), as assessed using Yates chi-squared test and Fisher's exact test. A significant correlation was observed between delayed relief after MVD and polyphasic morphology of the AMR in electromyographic analysis in patients with hemifacial spasm.

Simultaneous Dual Recordings From Vestibular Hair Cells and Their Calyx Afferents Demonstrate Multiple Modes of Transmission at These Specialized Endings.

In the vestibular periphery, transmission via conventional synaptic boutons is supplemented by post-synaptic calyceal endings surrounding Type I hair cells. This review focusses on the multiple modes of communication between these receptors and their enveloping calyces as revealed by simultaneous dual-electrode recordings. Classic orthodromic transmission is accompanied by two forms of bidirectional communication enabled by the extensive cleft between the Type I hair cell and its calyx. The slowest cellular communication low-pass filters the transduction current with a time constant of 10-100 ms: potassium ions accumulate in the synaptic cleft, depolarizing both the hair cell and afferent to potentials greater than necessary for rapid vesicle fusion in the receptor and potentially triggering action potentials in the afferent. On the millisecond timescale, conventional glutamatergic quantal transmission occurs when hair cells are depolarized to potentials sufficient for calcium influx and vesicle fusion. Depolarization also permits a third form of transmission that occurs over tens of microseconds, resulting from the large voltage- and ion-sensitive cleft-facing conductances in both the hair cell and the calyx that are open at their resting potentials. Current flowing out of either the hair cell or the afferent divides into the fraction flowing across the cleft into its cellular partner, and the remainder flowing out of the cleft and into the surrounding fluid compartment. These findings suggest multiple biophysical bases for the extensive repertoire of response dynamics seen in the population of primary vestibular afferent fibers. The results further suggest that evolutionary pressures drive selection for the calyx afferent.

Acquired Synergistic Divergence: Contrary to Current Literature.

Current literature reports synergistic divergence as a rare, congenital ocular motility pattern associated with adduction palsy. Its mechanism has been likened to Duane's syndrome, and some suggest it be referred to as Duane's Type 4 (Gupta et al. 2010; Schliesser et al. 2016; Wilcox et al. 1981; Khan et al. 2016). There are no published reports of synergistic divergence as an acquired condition, making this case report seemingly the first of its kind. This case report describes an 18-year-old female who presented to clinic in 2013 with symptoms of diplopia and left eye turning outwards. Orthoptic assessment and MRI confirmed a third nerve palsy secondary to cavernous sinus schwannoma. Further monitoring showed progression of the cranial nerve palsy but a stable schwannoma and no aberrant regeneration noted in five years of follow up. The patient was treated with multiple botulinum toxin injections and had squint correction surgery in 2017. Seven months later, synergistic divergence was first noted and remained stable in all following assessments. While the aetiology of acquired synergistic divergence in this case is unclear, we can be confident it is unlikely to be of congenital origin as it was not noted until adulthood and after five years of investigations. This report will discuss possible aetiologies of acquired synergistic divergence and, contrary to current literature, suggest clinicians should consider the possibility that synergistic divergence can be acquired, though is likely to be even rarer than its congenital form.

[Hemifacial spasm]. / Gemifatsial'nyi spazm.

Hemifacial spasm (HFS), or facial hemispasm, is a paroxysmal hyperkinetic disorder involving muscles innervated by the facial nerve, mainly on the one hand. The development of HFS is based on neurovascular conflict. However, it is impossible to explain the clinical manifestations of HFS only by nerve compression. Both peripheral and central mechanisms are involved in the generation of HFS, with the formation of ephaptic transmission, antidromic excitation, primary or secondary hyper-excitability of the nuclear and supranuclear level of innervation. Two treatment methods are pathogenetically justified: microvascular decompression (MVD) and botulinum toxin (BTX) injections. The effectiveness of MVD is 95.37% with full or partial recovery. The recurrence rate does not exceed 2.4%. Facial nerve paralysis (2.7-22.5%) and hearing loss (1.9-20%) are the most common complications of treatment with the use of the MVD for HFS with partial or complete cure in most cases. Botulinum toxin injection chemo-denervation is a first-line treatment of primary and secondary HFS. HFS is an officially registered indication for the drug dysport (abobotulotoxin) (ABO) in the Russian Federation. Total doses of ABO ranged from 25 to 150 units for one side depending on the severity of the clinical manifestations. Studies demonstrate the statistically significant benefits of HFC treatment with ABO. ABO is generally well-tolerated. Adverse events (up to 3.6%) are transient and include ptosis, lacrimation, blurred vision, double vision, dry eyes and weak facial muscles.

Ephaptic transmission is the origin of the abnormal muscle response seen in hemifacial spasm.

OBJECTIVE: In patients with hemifacial spasm, stimulation of a branch of the affected facial nerve elicits an abnormal response in the muscles innervated by another branch. We tested the hypothesis that this anomaly results from lateral spread of impulses from one motor axon to another at the site of the nerve compression by the offending artery. METHODS: In a preoperative study of 21 patients, we delivered a series of stimuli, in short increments, successively distally along the temporal branch of the facial nerve to record abnormal muscle responses from the orbicularis oculi and mentalis muscles. In intraoperative monitoring of 10 patients during microvascular decompression, we monitored propagating nerve action potentials with a handheld electrode placed on the facial nerve 3mm distal to the vascular compression site. RESULTS: With incremental shifts of stimulating points distally, the latency of abnormal muscle responses increased by 0.3±0.1ms/cm. This finding implicates the antidromic motor impulse as the trigger for lateral spread. The nerve action potentials recorded during surgery comprised the initial antidromic signal followed by one or more additional peaks. The latter immediately abated, together with abnormal muscle responses, after microvascular decompression. Thus, the secondary peaks must represent the orthodromic impulses generated by ephaptic transmission. An average inter-peak interval of 1.1ms between the first and secondary peaks is consistent with the estimated conduction time from the stimulation point to the site of vascular compression but not to the facial nucleus and return. CONCLUSION: An abnormal muscle response results from lateral spread of impulses between motor axons at the site of vascular compression rather than at the facial nucleus. SIGNIFICANCE: This study establishes the mechanism of lateral spread responsible for abnormal muscle responses and contributes to the understanding of pathophysiology underlying hemifacial spasm.

Successful treatment of paroxysmal tonic spasms with topiramate in a patient with neuromyelitis optica.

A 49-year-old woman with neuromyelitis optica (NMO) developed severe quadriplegia and frequent paroxysmal tonic spasms (PTS). Carbamazepine, although initially effective against PTS, caused drug eruption and she was unable to continue. PTS re-emerged after discontinuation of carbamazepine and hindered rehabilitation. Then topiramate was started, and PTS promptly disappeared. The patient became able to resume rehabilitation and her activity of daily life improved significantly. Carbamazepine and topiramate have a common pharmacological action to block voltage-gated sodium channels. The action may have contributed to inhibition of ephaptic transmission in the demyelinating lesions by NMO and eventually improved PTS.

An ephaptic transmission model of CA3 pyramidal cells: an investigation into electric field effects.

Extracellular electric fields existing throughout the living brain affect the neural coding and information processing via ephaptic transmission, independent of synapses. A two-compartment whole field effect model (WFEM) of pyramidal neurons embedded within a resistive array which simulates the extracellular medium i.e. ephapse is developed to study the effects of electric field on neuronal behaviors. We derive the two linearized filed effect models (LFEM-1 and LFEM-2) from WFEM at the stable resting state. Through matching these simplified models to the subthreshold membrane response in experiments of the resting pyramidal cells exposed to applied electric fields, we not only verify our proposed model's validity but also found the key parameters which dominate subthreshold frequency response characteristic. Moreover, we find and give its underlying biophysical mechanism that the unsymmetrical properties of active ion channels results in the very different low-frequency response of somatic and dendritic compartments. Following, WFEM is used to investigate both direct-current (DC) and alternating-current field effect on the neural firing patterns by bifurcation analyses. We present that DC electric field could modulate neuronal excitability, with the positive field improving the excitability, the modest negative field suppressing the excitability, but interestingly, the larger negative field re-exciting the neuron back into spiking behavior. The neuron exposed to the sinusoidal electric field exhibits abundant firing patterns sensitive to the input frequency and intensity. In addition, the electrical properties of ephapse can modulate the efficacy of field effect. Our simulated results are qualitatively in line with the relevant experimental results and can explain some experimental phenomena. Furthermore, they are helpful to provide the predictions which can be tested in future experiments.