Neuropeptides and the Nodes of Ranvier in Cranial Headaches

The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.

Comparative anatomical studies on the cranial nerves of the fully formed embryos of the Nile tilapia Oreochromis niloticus (Ostiechthyes-Cichlidae). I. Nervus glossopharyngeus

The organization of the roots, ganglia and the peripheral distribution of the cranial nerves of the fully formed embryos of Oreochromis niloticus are examined in the transverse serial sections. These nerves carry fibers, which were also analyzed. The results of this study demonstrated that the glossopharyngeal nerve originates by means of only one root, which leaves the cranium through the glossopharyngeal foramen. This nerve gives fibers (visceromotor) to the first internal and external levator arcus branchialis muscles. There is a single epibranchial (petrosal) ganglion located extracranially. Nervus glossopharyngeus has three rami; pharyngeus, pretramticus and posttrematicus. The ramus pharyngeus carries only viscerosensory fibers; general for the pharyngeal epithelium and special ones for the pseudobranch. General viscerosensory fibers are also carried by rami pretrematicus and posttrematicus for the pharyngeal epithelial lining. The special sensory fibers are carried by the ramus pretrematicus for the taste buds and by ramus posttrematicus for the gill filaments. The ramus pretrematicus also carries visceromotor fibers for the first adductor arcus branchialis and to the first obliquus ventralis muscles.

Use of probabilistic tractography to provide reliable distinction of the motor and sensory thalamus for prospective targeting during asleep deep brain stimulation

OBJECTIVE Accurate electrode placement is key to effective deep brain stimulation (DBS). The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for the treatment of essential tremor (ET). Retrospective tractography-based analysis of electrode placement has associated successful outcomes with modulation of motor input to VIM, but no study has yet evaluated the feasibility and efficacy of prospective presurgical tractography-based targeting alone. Therefore, the authors sought to demonstrate the safety and efficacy of probabilistic tractography–based VIM targeting in ET patients and to perform a systematic comparison of probabilistic and deterministic tractography. METHODS Fourteen patients with ET underwent preoperative diffusion imaging. Probabilistic tractography was applied for preoperative targeting, and deterministic tractography was performed as a comparison between methods. Tractography was performed using the motor and sensory areas as initiation seeds, the ipsilateral thalamus as an inclusion mask, and the contralateral dentate nucleus as a termination mask. Tract-density maps consisted of voxels with 10% or less of the maximum intensity and were superimposed onto anatomical images for presurgical planning. Target planning was based on probabilistic tract-density images and indirect target coordinates. Patients underwent robotic image-guided, image-verified implantation of directional DBS systems. Postoperative tremor scores with and without DBS were recorded. The center of gravity and Dice similarity coefficients were calculated and compared between tracking methods. RESULTS Prospective probabilistic targeting of VIM was successful in all 14 patients. All patients experienced significant tremor reduction. Formal postoperative tremor scores were available for 9 patients, who demonstrated a mean 68.0% tremor reduction. Large differences between tracking methods were observed across patients. Probabilistic tractography–identified VIM fibers were more anterior, lateral, and superior than deterministic tractography–identified fibers, whereas probabilistic tractography–identified ventralis caudalis fibers were more posterior, lateral, and superior than deterministic tractography–identified fibers. Deterministic methods were unable to clearly distinguish between motor and sensory fibers in the majority of patients, but probabilistic methods produced distinct separation. CONCLUSIONS Probabilistic tractography–based VIM targeting is safe and effective for the treatment of ET. Probabilistic tractography is more precise than deterministic tractography for the delineation of VIM and the ventralis caudalis nucleus of the thalamus. Deterministic algorithms tended to underestimate separation between motor and sensory fibers, which may have been due to its limitations with crossing fibers. Larger studies across multiple centers are necessary to further validate this method.

Intralaryngeal application of ATP evokes apneic response mainly via acting on P2X3 (P2X2/3) receptors of the superior laryngeal nerve in postnatal rats

Aerosolized adenosine 5'-triphosphate (ATP) induces cough and bronchoconstriction by activating vagal sensory fibers' P2X3 and P2X2/3 receptors (P2X3R and P2X2/3R). The goal of this study is to determine the effect of these receptors on the superior laryngeal nerve (SLN)-mediated cardiorespiratory responses to ATP challenge. We compared the cardiorespiratory responses to intralaryngeal perfusion of either ATP or α,β-methylene ATP in rat pups before and after 1) intralaryngeal perfusion of A-317491 (a P2X3R and P2X2/3R antagonist); 2) bilateral section of the SLN; and 3) peri-SLN treatment with capsaicin (to block conduction in superior laryngeal C-fibers, SLCFs) or A-317491. The immunoreactivity (IR) of P2X3R and P2X2R was determined in laryngeal sensory neurons of the nodose/jugular ganglia. Lastly, a whole-cell patch clamp recording was used to determine ATP- or α,β-mATP-induced currents without and with A-317491 treatment. It was found that intralaryngeal perfusion of both ATP and α,β-mATP induced immediate apnea, hypertension, and bradycardia. The apnea was eliminated and the hypertension and bradycardia were blunted by intralaryngeal perfusion of A-317491 and peri-SLN treatment with either A-317491 or capsaicin, while all of the cardiorespiratory responses were abolished by bilateral section of the SLN. P2X3R- and P2X2R-IR were observed in nodose and jugular ganglionic neurons labeled by fluoro-gold (FG). ATP- and α,β-mATP-induced currents recorded in laryngeal C-neurons were reduced by 75% and 95% respectively by application of A-317491. It is concluded that in anesthetized rat pups, the cardiorespiratory responses to intralaryngeal perfusion of either ATP or α,β-mATP are largely mediated by activation of SLCFs' P2X3R-P2X2/3R.

Restless legs-like syndrome as an emergent adverse event of CGRP monoclonal antibodies: A report of two cases

Background One of the advantages of CGRP monoclonal antibodies is their excellent safety and tolerability. However, postmarketing surveillance, is essential to detect potential rare emergent adverse events. Objectives To report two patients who developed restless legs syndrome symptoms after treatment with CGRP antibodies. Methods and results Two women with chronic refractory migraine, with no significant medical antecedents, developed typical restless legs syndrome symptoms 1.5 and 4 months after starting erenumab 140 mg, respectively. In case 1 symptoms resolved when erenumab was stopped for two months but reappeared on galcanezumab. In both patients migraine attacks had dramatically decreased and no iron deficiency was found. Conclusions Even though caution is needed before establishing a causal relationship, these cases suggest that restless legs-like symptoms might be an emergent adverse event of CGRP antibodies, regardless of the mechanism of action. We propose that plastic changes in CGRP sensory fibers, which are very abundant in legs, induced by CGRP monoclonal antibodies could be the reason for restless legs syndrome development.

Results of the use of low-intensity laser radiation in the treatment of occupational polyneuropathies of the upper extremities

Introduction. Effective therapy of occupational polyneuropathy of the upper extremities is a difficult task, because the characteristic clinical and neurophysiological manifestations of this disease persist for many years even after the termination of contact with the etiological harmful production factor - physical overload. Taking into account the low efficiency of existing treatment methods, as well as the peculiarities of the effect of low-intensity laser therapy (LILT), the task of developing a technique for using LILT for the treatment of patients with professional polyneuropathy and assessing its effectiveness during follow-up is very urgent. The aim of the study was to evaluate the effectiveness of LILT for the treatment of occupational polyneuropathy of the upper extremities. Materials and methods. The results of treatment of 236 patients with an established diagnosis of occupational polyneuropathy of the upper extremities are presented. All patients received usual drug therapy, the treatment of patients of the main group differed from the comparison group in that they were additionally treated with LILT according to the developed method. Results. The effectiveness of the therapy was assessed by studying the dynamics of pain in the hands using a visual pain rating scale, pulse velocity along the sensory fibers of the median and ulnar nerves. Changes in each of these parameters in subgroups were assessed at different stages of follow-up (before and immediately after treatment, after 3 and after 6 months). The division of patients into subgroups was carried out by determining type of the nerve fibers' damage. Conclusion: The developed method of LILT of professional polyneuropathy is simple and convenient for use in clinical practice: it is applicable both in a hospital and on an outpatient basis. After treatment, in patients from the main group, in contrast to the comparison group, there was a statistically significant increase in the parameters of pulse velocity along the sensory fibers of the median and ulnar nerves with a simultaneous decrease in the severity of pain. The effect of LILT in patients from the main group decreased after 6 months, which allows us to recommend such courses of LILT 2 times a year. LILT has a limited list of contraindications and is generally well tolerated by patients with minimal local side effects.

Identification of sensory and motor nerve fascicles by immunofluorescence staining after peripheral nerve injury

Background Inappropriate matching of motor and sensory fibers after nerve repair or nerve grafting can lead to failure of nerve recovery. Identification of motor and sensory fibers is important for the development of new approaches that facilitate neural regeneration and the next generation of nerve signal-controlled neuro-prosthetic limbs with sensory feedback technology. Only a few methods have been reported to differentiate sensory and motor nerve fascicles, and the reliability of these techniques is unknown. Immunofluorescence staining is one of the most commonly used methods to distinguish sensory and motor nerve fibers, however, its accuracy remains unknown. Methods In this study, we aim to determine the efficacy of popular immunofluorescence markers for motor and sensory nerve fibers. We harvested the facial (primarily motor fascicles) and sural (primarily sensory fascicles) nerves in rats, and examined the immunofluorescent staining expressions of motor markers (choline acetyltransferase (ChAT), tyrosine kinase (TrkA)), and sensory markers [neurofilament protein 200 kDa (NF-200), calcitonin gene-related peptide (CGRP) and Transient receptor potential vanillic acid subtype 1 (TRPV1)]. Three methods, including the average area percentage, the mean gray value, and the axon count, were used to quantify the positive expression of nerve markers in the immunofluorescence images. Results Our results suggest the mean gray value method is the most reliable method. The mean gray value of immunofluorescence in ChAT (63.0 ± 0.76%) and TRKA (47.6 ± 0.43%) on the motor fascicles was significantly higher than that on the sensory fascicles (ChAT: 49.2 ± 0.72%, P < 0.001; and TRKA: 29.1 ± 0.85%, P < 0.001). Additionally, the mean gray values of TRPV1 (51.5 ± 0.83%), NF-200 (61.5 ± 0.62%) and CGRP (37.7 ± 1.22%) on the motor fascicles were significantly lower than that on the sensory fascicles respectively (71.9 ± 2.32%, 69.3 ± 0.46%, and 54.3 ± 1.04%) (P < 0.001). The most accurate cutpoint occurred using CHAT/CRCP ratio, where a value of 0.855 had 100% sensitivity and 100% specificity to identify motor and sensory nerve with an area under the ROC curve of 1.000 (P < 0.001). Conclusions A combination of ChAT and CGRP is suggested to distinguish motor and sensory nerve fibers.

Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in hereditary motor sensory neuropathy with agenesis of the corpus callosum

Hereditary motor sensory neuropathy (HMSN/ACC) with agenesis of the corpus callosum (ACC) has been documented in the French-derived populations of Charlevoix and Saguenay/Lac St. Jean in Quebec, Canada, as well as a few sporadic families throughout the world. HMSN/ACC occurs because of loss-of-function mutations in the potassium-chloride cotransporter 3 (KCC3). In HMSN/ACC, motor deficits occur early in infancy with rapid and continual deterioration of motor and sensory fibers into juvenile and adulthood. Genetic work in mice has demonstrated that the disease is caused by loss of KCC3 function in neurons and particularly parvalbumin (PV)-expressing neurons. Currently, there are no treatments or cures for HMSN/ACC other than pain management. As genetic counseling in Quebec has increased as a preventative strategy, most individuals with HSMN/ACC are now adults. The onset of the disease is unknown. In particular, it is unknown if the disease starts early during development and whether it can be reversed by restoring KCC3 function. In this study, we used two separate mouse models that when combined to the PV-CreERT2 tamoxifen-inducible system allowed us to 1) disrupt KCC3 expression in adulthood or juvenile periods; and 2) reintroduce KCC3 expression in mice that first develop with a nonfunctional cotransporter. We show that disrupting or reintroducing KCC3 in the adult mouse has no effect on locomotor behavior, indicating that expression of KCC3 is critical during embryonic development and/or the perinatal period and that once the disease has started, reexpressing a functional cotransporter fails to change the course of HMSN/ACC.

Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways

The vagus nerve supports diverse autonomic functions and behaviors important for health and survival. To understand how specific components of the vagus contribute to behaviors and long-term physiological effects, it is critical to modulate their activity with anatomical specificity in awake, freely behaving conditions using reliable methods. Here, we introduce an organ-specific scalable, multimodal, wireless optoelectronic device for precise and chronic optogenetic manipulations in vivo. When combined with an advanced, coil-antenna system and a multiplexing strategy for powering 8 individual homecages using a single RF transmitter, the proposed wireless telemetry enables low cost, high-throughput, and precise functional mapping of peripheral neural circuits, including long-term behavioral and physiological measurements. Deployment of these technologies reveals an unexpected role for stomach, non-stretch vagal sensory fibers in suppressing appetite and demonstrates the durability of the miniature wireless device inside harsh gastric conditions.