Human Cranial Nerves Research Articles

454 Utilization of Adipose-Derived Stem Cells in Cranial Nerve Regeneration: A Systematic Review

INTRODUCTION: Large peripheral nerve injuries may require surgical reconnection. Cell-based therapies have also been investigated for nerve regeneration. METHODS: PubMed and Embase databases were used to search for primary studies reporting the use ADSCs in the regeneration of cranial nerves. A total of 12 studies were included which all presented data on specific neural injury, therapy, and functional outcomes. RESULTS: Eight studies focused on the facial nerve (66.7%), two on the optic nerve (16.7%), one on the olfactory nerve (8.3%), and one on the hypoglossal nerve (8.3%). One study applied ADSCs to human cranial nerve injuries, while the remainder studied animal models. In these studies, ADSC groups had higher numbers of myelinated fibers, increased myelin thickness and diameter of muscle fibers as well as greater magnitude of compound muscle action potentials (CMAP) when compared to controls. In studies focused on optic nerve regeneration, significant improvements across visual tests were observed. CONCLUSIONS: ADSCs demonstrate potential utility in regard to their ability to facilitate functional recovery of cranial nerves in humans as well as animal models. Further investigation into the use of ADSC should be pursued in both animal and early human studies to validate the findingsof previous literature.

FERM domain\u2013containing protein 6 identifies a subpopulation of varicose nerve fibers in different vertebrate species

FERM domain–containing protein 6 (FRMD6) is a member of the FERM protein superfamily, which is evolutionary highly conserved and has recently been identified as an upstream regulator of the conserved growth-promoting Hippo signaling pathway. In clinical studies, the FRMD6 gene is correlated with high significance to Alzheimer’s disease and cognitive impairment implicating a wider role of this protein in the nervous system. Scare data are available on the localization of endogenous FRMD6 in neural tissues. Using a FRMD6-directed antiserum, we detected specific immunoreactivity in varicose nerve fibers in the rat central and peripheral nervous system. FRMD6-immunoreactive (-ir) neurons were found in the sensory ganglia of cranial nerves, which were marked by a pool of labeled cytoplasmic granules. Cross-species comparative studies detected a morphologically identical fiber population and a comparable fiber distribution in tissues from xenopus and human cranial nerves and ganglia. In the spinal cord, FRMD6-ir was detectable in the terminal endings of primary afferent neurons containing substance P (SP). In the rat diencephalon, FRMD6-ir was co-localized with either SP- or arginine vasopressin–positive fibers in Broca’s diagonal band and the lateral septum. Dense fiber terminals containing both FRMD6-ir and growth hormone-releasing hormone were found in the median eminence. The intimate association of FRMD6 with secretory vesicles was investigated in vitro. Induction of exocytotic vesicles in cultured cells by ectopic expression of the SP precursor molecule preprotachykinin A led to a redistribution and co-localization of endogenous FRMD6 with secretory granules closely mimicking the observations in tissues.

Rapid and Precise Semi-Automatic Axon Quantification in Human Peripheral Nerves

We developed a time-efficient semi-automated axon quantification method using freeware in human cranial nerve sections stained with paraphenylenediamine (PPD). It was used to analyze a total of 1238 facial and masseteric nerve biopsies. The technique was validated by comparing manual and semi-automated quantification of 129 (10.4%) randomly selected biopsies. The software-based method demonstrated a sensitivity of 94% and a specificity of 87%. Semi-automatic axon counting was significantly faster (p < 0.001) than manual counting. It took 1 hour and 47 minutes for all 129 biopsies (averaging 50 sec per biopsy, 0.04 seconds per axon). The counting process is automatic and does not need to be supervised. Manual counting took 21 hours and 6 minutes in total (average 9 minutes and 49 seconds per biopsy, 0.52 seconds per axon). Our method showed a linear correlation to the manual counts (R = 0.944 Spearman rho). Attempts have been made by several research groups to automate axonal load quantification. These methods often require specific hard- and software and are therefore only accessible to a few specialized laboratories. Our semi-automated axon quantification is precise, reliable and time-sparing using publicly available software and should be useful for an effective axon quantification in various human peripheral nerves.

The Cranial Nerve Map App: Easy‐to‐Access for Students to Study on the Go

Learning the names, pathways, distribution pattern and specific individual features for the twelve human cranial nerves can be challenging to the novice. Our project uses illustrations and charts to create an easy to navigate map of cranial nerves. This map is presented in the form of a phone app, accessible for Android phones (and iPhone in future) through the app store. By providing this map as a phone app, students will be able to study the cranial nerves wherever they are. This encourages students to form good study habits, and will help them to more effectively understand a complicated topic in anatomy courses.Through illustrations and charts, all twelve cranial nerves are organized in a way to help students to better visualize and understand the cranial nerves. Illustrations present the following information for each nerve: pathway through the skull exit foramen, type of nerve fiber (modality), and detailed/specific functions. Intuitive charts and diagrams organize the following information: correlating cranial nerve name and number, modality (sensory/motor/both and GSA/SSA/GVA/GSE/GVE/SVE), and clickable links on each modality to a Wikipedia page that describes the modality. In addition, the charts and illustrations are consistently color coded and simple shapes are used in the illustration to help represent different structures (ganglion, sympathetic / parasympathetic fibers, etc.) in an easy to understand way.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Autoantibodies in Guillain-Barré Syndrome

Serum antibodies against glycolipids, mainly gangliosides, are detected in about 60% of patients with Guillain-Barré syndrome (GBS) and its variants. Anti-glycolipid antibodies play a crucial role in the pathogenic mechanisms of GBS. The antibody titer is the highest in the acute phase and decreases gradually. Molecular mimicries occur between the glycolipids and surface molecules on the infectious agents. Clinical subtypes of GBS are related to the antigenic specificities of the antibodies. The distribution of gangliosides in peripheral nervous tissues could explain the different clinical manifestations. The anti-GQ1b antibody is detected in 80-90% of patients with Fisher syndrome characterized by ophthalmoplegia. GQ1b is localized in the paranodes of the human cranial nerves innervating the extraocular muscles. This is consistent with the clinical association between the anti-GQ1b antibody and ophthalmoplegia. The anti-GM1 antibody is associated with acute motor axonal neuropathy, whereas the anti-GD1b antibody is detected in acute sensory ataxic neuropathy. GBS animal models sensitized by gangliosides, such as GM1 or GD1b, develop monophasic peripheral neuropathies. In the animal models, disruption of molecule clusters and deposition of complement products were observed in the nodal and paranodal regions. Clinical and experimental data suggest complement-mediated pathogenic mechanisms triggered by anti-glycolipid antibodies in GBS.

The naming of the cranial nerves: A historical review

The giants of medicine and anatomy have each left their mark on the history of the cranial nerves, and much of the history of anatomic study can be viewed through the lens of how the cranial nerves were identified and named. A comprehensive literature review on the classification of the cranial names was performed. The identification of the cranial nerves began with Galen in the 2nd century AD and evolved up through the mid-20th century. In 1778, Samuel Sömmerring, a German anatomist, classified the 12 cranial nerves as we recognize them today. This review expands on the excellent investigations of Flamm, Shaw, and Simon et al., with discussion of the historical identification as well as the process of naming the human cranial nerves.

Evidence of ancillary trigeminal innervation of levator palpebrae in the general population

The cranial synkineses are a group of disorders encompassing a variety of involuntary co-contractions of the facial, masticatory, or extraocular muscles that occur during a particular volitional movement. The neuroanatomical pathways for synkineses largely remain undefined. Our studies explored a normal synkinesis long observed in the general population – that of jaw opening during efforts to open the eyelids widely. To document this phenomenon, we observed 186 consecutive participants inserting or removing contact lenses to identify jaw opening. Seeking electrophysiological evidence, in a second study we enrolled individuals undergoing vascular decompression for trigeminal neuralgia or hemifacial spasm, without a history of jaw-winking, ptosis, or strabismus, to record any motor responses in levator palpebrae superioris (LPS) upon stimulation of the trigeminal motor root. Stimulus was applied to the trigeminal motor root while an electrode in levator recorded the response. We found that 37 participants (20%) opened their mouth partially or fully during contact lens manipulation. In the second study, contraction of LPS with trigeminal motor stimulation was documented in two of six patients, both undergoing surgery for trigeminal neuralgia. We speculate these results might provide evidence of an endogenous synkinesis, indicating that trigeminal-derived innervation of levator could exist in a significant minority of the general population. Our observations demonstrate plasticity in the human cranial nerve innervation pattern and may have implications for treating Marcus Gunn jaw-winking.

Understanding Human Cranial Nerves through a Patterned Based Comparative Approach

Learning the cranial nerves is a rigorous challenge encountered by first year medical students. Not only must they learn and remember the names, numbers, modalities, pathways, and nuclei of the twelve cranial nerves, in addition they must understand the clinical significance and clinical implications of these complex cranial structures. Educational studies have demonstrated that incorporating patterns as a basis to learning enhances the learning process and improves retention of the learned material. Understanding simple patterns, especially if the patterns are anatomically based, can greatly reduce the learning curve associated with learning complex anatomical topics — like the cranial nerves. Using comparative and developmental anatomy, clear, simple patterns are established to illustrate that cranial nerves are similar to their simpler spinal nerve counterparts. Understanding these patterns takes the random memorization out of the learning process and introduces a logic that brings a deeper meaning to the organization and structure of the cranial nerves. With this logic the learning process becomes easier and more memorable. With improved learning comes improved application in a clinical setting, which should be the ultimate goal.Grant Funding Source: Department of Neurobiology and Anatomy

A Model of Lytic, Latent, and Reactivating Varicella‐Zoster Virus Infections in Isolated Enteric Neurons

Because human primary afferent neurons are not readily obtained, we sought to develop a model in which the lytic, latent, and reactivating phases of varicella-zoster virus (VZV) infection were recapitulated in neurons from an animal source. Enteric neurons were obtained from the small intestine of adult guinea pigs and from the bowel of fetal mice. Latency was established when these neurons were infected by cell-free VZV in the absence of fibroblasts or other cells of mesodermal origin. In contrast, lytic infection ensued when fibroblasts were present or when the enteric neurons were infected by cell-associated VZV. Latency was associated with the expression of a limited subset of viral genes, the products of which were restricted to the cytoplasm. Lysis was associated with the expression of viral glycoproteins, nuclear translocation of latency-associated gene products, and rapid cell death. Reactivation was accomplished by expressing VZV open reading frame (ORF) 61p or herpes simplex virus ICP0 in latently infected neurons. Isolated enteric neurons from guinea pigs and mice recapitulate latent gene expression in human cranial nerve and dorsal root ganglia. Expression of latency-associated VZV gene products was detected in 88% of samples of adult human intestine, suggesting that VZV not only infects enteric neurons but also is latent in the human enteric nervous system. This in vitro model should facilitate further understanding of latency and reactivation of VZV.

Prevalence and distribution of HSV-1, VZV, and HHV-6 in human cranial nerve nuclei III, IV, VI, VII, and XII.

The etiology of idiopathic cranial nerve palsies often remains unresolved. It has been hypothesised that viral reactivation of herpesviruses in the corresponding nuclei in the brainstem is the cause. We investigated the distribution of herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) in nuclei that are associated with peripheral sensory ganglia [oculomotor (nIII), facial (nVII) nuclei] and in nuclei that are not associated with peripheral sensory ganglia [trochlear (nIV), abducens (nVI), and hypoglossal (nXII) nuclei] of five human brainstems. Samples of the cranial nerve nuclei and adjacent control tissue were taken from histological sections after precise identification of every single nucleus and control tissue. DNA and RNA amplification methods were used to determine the prevalence and distribution of HSV-1 and VZV. The distribution of human herpes virus type 6 (HHV-6) was also determined and served as a control, since HHV-6 infection has never been associated with idiopathic cranial nerve palsies. HSV-1 was distributed at random in all cranial nerve nuclei and control tissue, whereas VZV DNA was not detected in any of the samples examined. Surprisingly, HHV-6 was present in almost all samples where HSV-1 was also present, however, the latency associated transcript (LAT) of HSV-1 was not found in any of the samples positive for HSV-1 DNA. The absence of LAT in the samples positive for HSV-1 and the distribution of HSV-1 and HHV-6 do not support the hypothesis that idiopathic cranial nerve palsies result from viral reactivation in the brainstem nuclei.

Acute oropharyngeal palsy associated with anti-GM1b IgG antibody

Sirs: Although patients with Guillain-Barre syndrome (GBS) typically show generalized muscle weakness with areflexia, a few patients have only regional weakness throughout the disease course. O’Leary et al. [4] described three patients who had rapid progression of localized oropharyngeal weakness with or without ataxia. Unlike typical GBS or Fisher syndrome, these patients never developed limb weakness, ophthalmoplegia, or ptosis; they were regarded as having a regional variant of GBS based on detection of anti-GQ1 b and anti-GT1 a IgG antibodies in serum. Another patient with acute oropharyngeal palsy also was reported to have these antibodies [5]. We treated a patient with acute oropharyngeal palsy associated with an isolated anti-GM1 b IgG antibody. This autoantibody has yet to be reported in patients with regional GBS variants, although in more generalized cases it is regarded as a diagnostic marker of GBS [3]. A 47-year-old woman’s voice developed an increasingly nasal quality over a few days. She had no history of a preceding cough, fever, sore throat or diarrhea. Neurological examination on day 5 of her course showed mild dysarthria and mild weakness of neck flexion (Medical Research Council grade, 4). Palatal elevation was diminished and the gag reflex was absent. Pupil size and reactions were normal. No signs of ophthalmoplegia, ptosis, or facial muscle weakness were found. Limb muscle power and tendon reflexes were normal. The patient could not perform tandem gait, but finger-to-nose and heel-to-knee tests were normal. The Romberg test was negative. No sensory or autonomic disturbances were present. The complete blood count and blood chemistry results were normal. Results of serological tests for Campylobacter jejuni, cytomegalovirus, Mycoplasma pneumoniae, varicella-zoster virus, and herpes simplex virus infections were negative. On day 7, serum IgG antibody titer against GM1 b was found to be elevated (1:2,000; normal, less than 1:500). No IgG antibodies against GM2, GM1, GD1 a, GalNAc-GD1 a, GD1b, GT1 a, GT1 b, or GQ1 b were detected. IgM antiganglioside antibodies were absent. Cerebrospinal fluid obtained on day 7 showed normal protein and cell content. Motor nerve conduction studies on day 7 were normal. A sensory nerve action potential was not evoked in the sural nerve, but sensory nerve action potentials and sensory conduction velocities were normal in the median nerve. Cranial MRI with enhancement was normal. From day 10, the patient was given intravenous immunoglobulin (400 mg/kg/day) for 5 consecutive days. She noted some difficulty in swallowing on day 11, but did not require tube feeding. Dysphagia and dysarthria respectively disappeared by days 14 and 28, and all other neurologic abnormalities had resolved completely 2 months after onset. The anti-GM1 b IgG antibody titer had returned to the normal range (less than 500) 8 months following onset of illness. Our patient experienced acute progression of oropharyngeal palsy as well as mild truncal ataxia and neck weakness. She never showed notable limb weakness, ophthalmoplegia, ptosis, or areflexia. These clinical features are simitar to those of O’Leary’s patients with acute oropharyngeal palsy [4]. However, these patients had antiGQ1 b and anti-GT1 a IgG antibodies, while our patient had an antiGM1 b IgG antibody. Anti-GM1 b antibody is closely related to severe limb weakness and slow recovery in generalized GBS [7]. On the whole, GBS patients with anti-GM1 b antibodies are somewhat less likely to have cranial nerve involvement, although this antibody can be detected in half of GBS patients who show oropharyngeal palsy as an initial symptom [2, 6]. Several case reports suggest that anti-GT1 a IgG antibody, with or without cross-reactivity with GQ1 b, is involved in the pathogenesis of oropharyngeal palsy in GBS [1]. Our case supports an association of oropharyngeal palsy with antiGM1 b antibodies. GQ1 b ganglioside in human cranial nerves is believed to be a target of the humoral autoimmune response in patients with Fisher syndrome or GBS with ophthalmoplegia and anti-GT1 a IgG antibody coexists in these conditions. AntiGQ1 b and anti-GT1 a IgG antibodies have also appeared together in acute ophthalmoparesis, Bickerstaff ’s brain stem encephalitis, and the pharyngeal-cervical-brachial variant of GBS [2]. In addition to anti-GT1 a and anti-GQ1 b antibodies, we feel that anti-GM1 b IgG antibody may be a helpful diagnostic marker for acute oropharyngeal palsy in some patients. Since in GBS anti-GT1 a, anti-GQ1 b, and anti-GM1 b IgG antibodies frequently coexist, acute oropharyngeal palsy may represent an early clinical stage of GBS, pharyngeal-cervical-brachial variant of LETTER TO THE EDITORS

Vascular permeability to fluorescent substance in human cranial nerves.

It has recently been reported that in the facial canal, the facial nerve shows enhancement on gadolinium-enhanced magnetic resonance imaging in patients with clinically normal facial nerves. However, the mechanism of this enhancement has not yet been sufficiently clarified. The present study investigated the permeability of blood vessels in human cranial nerves that were obtained from surgically treated patients. The patients received an intravenous injection of sodium fluorescein 45 minutes before nerve resection. For histologic observation, the nerves were removed and frozen at -70 degrees C, and the sections were then cut at 4-microm thickness with a freezing microtome. The localization of the tracers was examined with a fluorescence microscope. Fluorescence was observed in the external nerve sheath and slightly in the endoneurium of these nerves, but was not observed within nerve fibers. These findings indicate that the vascular barrier in human peripheral nerves is incomplete.

Anti-GT1a IgG in Guillain-Barré syndrome

Objective: To investigate the presence of serum anti-GT1a IgG in Guillain-Barré syndrome (GBS) and its relation to clinical manifestations. Background: Several patients with GBS and bulbar palsy have been reported...

Cranial nerve modulation of human cortical swallowing motor pathways.

Animal data indicate that cortical swallowing pathways can be modulated by cranial nerve afferent stimulation. We therefore studied the effects of human trigeminal and vagal nerve excitation on the corticofugal pathways to the oropharynx and esophagus, using electromagnetic stimulation. Unilateral stimulation of either the trigeminal or vagus nerve evoked two distinct reflex electromyographic responses in the pharynx and esophagus, an early response (latency range 19-30 ms) and a late response (latency range 42-72 ms). In the mylohyoid muscles, however, only a single response was seen (latency range 36-64 ms). Cortical stimulation also evoked electromyographic responses in the mylohyoid muscles, pharynx, and esophagus, with latencies of 8.5 +/- 0.3, 9.3 +/- 0.3, and 10.1 +/- 0.4 ms, respectively. When either trigeminal or vagus nerve stimulation preceded cortical stimulation, the cortically evoked responses were facilitated, with maximal effects at interstimulation intervals of 30-200 ms for pharynx and esophagus (P < 0.02) and at interstimulation intervals of 50-100 ms for mylohyoid muscles (P < 0.05). Our results demonstrate that stimulation of human cranial nerve afferent fibers facilitates cortical swallowing motor pathways.

Ganglioside composition of the human cranial nerves, with special reference to pathophysiology of Miller Fisher syndrome

Total ganglioside fractions from the human cranial nerves purified on a Phenyl Sepharose column, were given mild alkaline treatment, after which their composition and amounts of lipid-bound sialic acid were determined by HPTLC-densitometry with resorcinol as the coloring reagent. The total amounts of lipid-bound sialic acid were 156.5 ng/mg of wet tissue in the Ist cranial nerve (olfactory tract) and 131.9 ng/mg in the IInd nerve, greater than the amounts in the other nerves (99.1–120.0 ng/mg). The Ist, IInd, and VIIIth nerves had GM4, but not LM1. It may reflect their histological feature of the central nervous system. The IIIrd, IVth, and VIth nerves, as well as the IInd, had significantly higher percentages of GQ1b (11.6–13.2%) than the other nerves (5.2–8.4%). The high proportion of GQ1b specific to these three cranial nerves involved in the ocular movement lends support to the role of serum anti-GQ1b antibody in the pathogenetic mechanisms of ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome.

Vascular permeability to sodium fluorescein in the rabbit cranial nerve root: possible correlation with normal cranial nerve enhancement on gadolinium-enhanced magnetic resonance imaging.

Vascular permeability in cranial nerve roots was examined after intravenous injection of sodium fluorescein in the adult rabbit. Fluorescence was observed in the distal nerves through the following portions: intracavernous portion of the oculomotor nerve, distal internal auditory canal segment of the facial nerve, and ganglionic portions of the trigeminal, glossopharyngeal and vagus nerves. In the acoustic nerve, the vestibular ganglion showed fluorescence. No fluorescence was observed in the olfactory or optic nerves. During in vivo gadolinium-enhanced magnetic resonance imaging (Gd-MRI) of two separate animals, trigeminal nerve enhancement was observed in the region showing fluorescence. Histologically, intense fluorescence was observed in ganglia and external nerve sheaths of the cranial nerves showing macroscopic fluorescence. A slight fluorescence was also seen in endoneurial connective tissue but not observed within the nerve fibers. The results of this study suggest that the physiological enhancement of human cranial nerves seen on Gd-MRI may correlate with vascular permeability.