Extracranial transport of brain lymphatics via cranial nerve in human.

Extracranial waste transport from the brain interstitial fluid to the deep cervical lymph node (dCLN) is not extensively understood. The present study aims to show the cranial nerves that have a role in the transport of brain lymphatics vessels (LVs), their localization, diameter, and number using podoplanin (PDPN) and CD31 immunohistochemistry (IHC) and Western blotting. Cranial nerve samples from 6 human cases (3 cadavers, and 3 autopsies) were evaluated for IHC and 3 autopsies for Western blotting. The IHC staining showed LVs along the optic, olfactory, oculomotor, trigeminal, facial, glossopharyngeal, accessory, and vagus nerves. However, no LVs present along the trochlear, abducens, vestibulocochlear, and hypoglossal nerves. The LVs were predominantly localized at the endoneurium of the cranial nerve that has motor components, and LVs in the cranial nerves that had sensory components were present in all 3 layers. The number of LVs accompanying the olfactory, optic, and trigeminal nerves was classified as numerous; oculomotor, glossopharyngeal, vagus, and accessory was moderate; and facial nerves was few. The largest diameter of LVs was in the epineurium and the smallest one was in the endoneurium. The majority of Western blotting results correlated with the IHC. The present findings suggest that specific cranial nerves with variable quantities provide a pathway for the transport of wastes from the brain to dCLN. Thus, the knowledge of the transport of brain lymphatics along cranial nerves may help understand the pathophysiology of various neurological diseases.

Monitoring surgery around the cranial nerves.

Intraoperative neurophysiologic monitoring (IONM) of cranial nerve (CN) function is an essential component in multimodality monitoring of surgical procedures where CNs are at risk for injury. In most cases, IONM consists of localizing and mapping CNs and their pathways, and monitoring of CN motor function during surgery. However, CN VIII, which has no motor function, and is at risk for injury in many surgical procedures, can be easily and accurately monitored using brainstem auditory evoked potentials. For motor CNs, the literature is clear that function can be safely and adequately performed using basic electromyographic (EMG) techniques, such as recording of continuous EMG activity and electrically evoked compound muscle actions potentials. Newer techniques, such as corticobulbar motor evoked potentials and reflex studies, show good potential for a greater degree of functional assessment but require further study to determine their clinical utility. EMG remains the basic clinical neurophysiologic technique with the greatest clinical research supporting its utility in IONM of motor CN function and should be used as part of a comprehensive multimodality IONM protocol. Understanding the physiologic basis of EMG and the changes associated with altered motor function will allow the practitioner to alter surgical course to prevent injury and improve patient safety.

Critical Review and Consensus Statement for Neural Monitoring in Otolaryngologic Head, Neck, and Endocrine Surgery.

BACKGROUND: Enhancing patient outcomes in an array of surgical procedures in the head and neck requires the maintenance of complex regional functions through the protection of cranial nerve integrity. This review and consensus statement cover the scope of cranial nerve monitoring of all cranial nerves that are of practical importance in head, neck, and endocrine surgery except for cranial nerves VII and VIII within the temporal bone. Complete and applied understanding of neurophysiologic principles facilitates the surgeon's ability to monitor the at-risk nerve. METHODS: The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) identified the need for a consensus statement on cranial nerve monitoring. An AAO-HNS task force was created through soliciting experts on the subject. Relevant domains were identified, including residency education, neurophysiology, application, and various techniques for monitoring pertinent cranial nerves. A document was generated to incorporate and consolidate these domains. The panel used a modified Delphi method for consensus generation. RESULTS: Consensus was achieved in the domains of education needs and anesthesia considerations, as well as setup, troubleshooting, and documentation. Specific cranial nerve monitoring was evaluated and reached consensus for all cranial nerves in statement 4 with the exception of the spinal accessory nerve. Although the spinal accessory nerve's value can never be marginalized, the task force did not feel that the existing literature was as robust to support a recommendation of routine monitoring of this nerve. In contrast, there is robust supporting literature cited and consensus for routine monitoring in certain procedures, such as thyroid surgery, to optimize patient outcomes. CONCLUSIONS: The AAO-HNS Cranial Nerve Monitoring Task Force has provided a state-of-the-art review in neural monitoring in otolaryngologic head, neck, and endocrine surgery. The evidence-based review was complemented by consensus statements utilizing a modified Delphi method to prioritize key statements to enhance patient outcomes in an array of surgical procedures in the head and neck. A precise definition of what actually constitutes intraoperative nerve monitoring and its benefits have been provided.

Gadolinium enhancement of cranial nerves: Implications for interstitial fluid drainage from brainstem into cranial nerves in humans.

Drainage of interstitial fluid and solutes from the brainstem has not been well studied. To map one drainage pathway in the human brainstem, we took advantage of the focal blood-brain barrier disruption occurring in a multiple sclerosis brainstem lesion, coupled with intravenous injection of gadolinium, which simulates an intraparenchymal injection of gadolinium tracer within the restricted confines of this small brain region. Using high-resolution MRI, we show how it is possible for interstitial fluid to drain into the adjacent trigeminal and oculomotor nerves, in keeping with a pathway of communication between the extracellular spaces of the brainstem and cranial nerve parenchyma.

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.

Cerebrospinal fluid (CSF) is produced by the choroid plexuses within the ventricles of the brain and circulates through the subarachnoid space of the skull and spinal column to provide buoyancy to and maintain fluid homeostasis of the brain and spinal cord. The question of how CSF drains from the subarachnoid space has long puzzled scientists and clinicians. For many decades, it was believed that arachnoid villi or granulations, outcroppings of arachnoid tissue that project into the dural venous sinuses, served as the major outflow route. However, this concept has been increasingly challenged in recent years, as physiological and imaging evidence from several species has accumulated showing that tracers injected into the CSF can instead be found within lymphatic vessels draining from the cranium and spine. With the recent high-profile rediscovery of meningeal lymphatic vessels located in the dura mater, another debate has emerged regarding the exact anatomical pathway(s) for CSF to reach the lymphatic system, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves. In this review, a summary of the historical and contemporary evidence for the different outflow pathways will be presented, allowing the reader to gain further perspective on the recent advances in the field. An improved understanding of this fundamental physiological process may lead to novel therapeutic approaches for a wide range of neurological conditions, including hydrocephalus, neurodegeneration and multiple sclerosis.

Lower cranial nerve syndromes: a review.

The purpose of this paper is to provide a comprehensive review encompassing the syndromes associated with the lower cranial nerves (LCNs). We will discuss the anatomy of some of these syndromes and the historical contributors after whom they were named. The LCNs can be affected individually or in combination, since the cranial nerves at this level share their courses through the jugular foramen and hypoglossal canal and the extracranial spaces. Numerous alterations affecting them have been described in the literature, but much remains to be discovered on this topic. This paper will highlight some of the subtle differences among these syndromes. Symptoms and signs that have localization value for LCN lesions include impaired speech, deglutition, sensory functions, alterations in taste, autonomic dysfunction, neuralgic pain, dysphagia, head or neck pain, cardiac or gastrointestinal compromise, and weakness of the tongue, trapezius, or sternocleidomastoid muscles. To assess the manifestations of LCN lesions correctly, precise knowledge of the anatomy and physiology of the area is required. Treatments currently used for these conditions will also be addressed here. Effective treatments are available in several such cases, but a precondition for complete recovery is a correct and swift diagnosis.

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

SnapShot: Orofacial Sensation.

Ophthalmic, maxillary, and mandibular branches of the trigeminal nerve provide sensory innervation to orofacial tissues. Trigeminal sensory neurons respond to a diverse array of sensory stimuli to generate distinct sensations, including thermosensation, mechanosensation, itching, and pain. These sensory neurons also detect the distinct sharpness or pungency of many foods and beverages. This SnapShot highlights the transduction ion channels critical to orofacial sensation.

Optogenetic Stimulation of Type I GAD65+ Cells in Taste Buds Activates Gustatory Neurons and Drives Appetitive Licking Behavior in Sodium-Depleted Mice.

Mammalian taste buds are comprised of specialized neuroepithelial cells that act as sensors for molecules that provide nutrition (e.g., carbohydrates, amino acids, and salts) and those that are potentially harmful (e.g., certain plant compounds and strong acids). Type II and III taste bud cells (TBCs) detect molecules described by humans as "sweet," "bitter," "umami," and "sour." TBCs that detect metallic ions, described by humans as "salty," are undefined. Historically, type I glial-like TBCs have been thought to play a supportive role in the taste bud, but little research has been done to explore their role in taste transduction. Some evidence implies that type I cells may detect sodium (Na+) via an amiloride-sensitive mechanism, suggesting they play a role in Na+ taste transduction. We used an optogenetic approach to study type I TBCs by driving the expression of the light-sensitive channelrhodopsin-2 (ChR2) in type I GAD65+ TBCs of male and female mice. Optogenetic stimulation of GAD65+ TBCs increased chorda tympani nerve activity and activated gustatory neurons in the rostral nucleus tractus solitarius. "N neurons," whose NaCl responses were blocked by the amiloride analog benzamil, responded robustly to light stimulation of GAD65+ TBCs on the anterior tongue. Two-bottle preference tests were conducted under Na+-replete and Na+-deplete conditions to assess the behavioral impact of optogenetic stimulation of GAD65+ TBCs. Under Na+-deplete conditions GAD65-ChR2-EYFP mice displayed a robust preference for H2O illuminated with 470 nm light versus nonilluminated H2O, suggesting that type I glial-like TBCs are sufficient for driving a behavior that resembles Na+ appetite.SIGNIFICANCE STATEMENT This is the first investigation on the role of type I GAD65+ taste bud cells (TBCs) in taste-mediated physiology and behavior via optogenetics. It details the first definitive evidence that selective optogenetic stimulation of glial-like GAD65+ TBCs evokes neural activity and modulates behavior. Optogenetic stimulation of GAD65+ TBCs on the anterior tongue had the strongest effect on gustatory neurons that responded best to NaCl stimulation through a benzamil-sensitive mechanism. Na+-depleted mice showed robust preferences to "light taste" (H2O illuminated with 470 nm light vs nonilluminated H2O), suggesting that the activation of GAD65+ cells may generate a salt-taste sensation in the brain. Together, our results shed new light on the role of GAD65+ TBCs in gustatory transduction and taste-mediated behavior.

Electrical stimulation of cranial nerves in cognition and disease.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

Cranial Nerve Stimulation for Olfaction (Cranial Nerve 1).

Like sensory maps in other systems, the sense of smell has an organizational structure based on converging projections of olfactory receptor neurons containing unique odorant receptors onto the olfactory bulb in synaptic aggregations termed glomeruli. This organizational structure provides the potential for electrical stimulation and restoration of smell. Prior animal and human studies support the feasibility of an olfactory stimulation device, encouraging ongoing work in development of olfactory implants.

Light-Based Neuronal Activation: The Future of Cranial Nerve Stimulation.

Despite advances in implant hardware, neuroprosthetic devices in otolaryngology have sustained evolutionary rather than revolutionary changes over the past half century. Although electrical stimulation has the capacity for facile activation of neurons and high temporal resolution, it has limited spatial selectivity. Alternative strategies for neuronal stimulation are being investigated to improve spatial resolution. In particular, light-based neuronal stimulation is a viable alternative and complement to electrical stimulation. This article provides a broad overview of light-based neuronal stimulation technologies. Specific examples of active research on light-based prostheses, including cochlear implants, auditory brainstem implants, retinal implants, and facial nerve implants, are reviewed.

Central Effects of Cranial Nerve Stimulation.

The current literature on peripheral cranial nerve stimulation for the purpose of achieving therapeutic effects via altering brain activity is reviewed. Vagus nerve stimulation, which is approved for use in refractory epilepsy, is the most extensively studied cranial nerve stimulator that has direct impact on the central nervous system. Despite the recognized central effects of peripheral cranial nerve stimulation, the mechanism of action for all indications remains incompletely understood. Further research on both mechanisms and indications of central effects of cranial nerve stimulation has the potential to alleviate burden of disease in a large array of conditions.

History of Cranial Nerve-Implanted Stimulators in Otolaryngology.

This article aims to clearly understand the historical development of cranial nerve-implanted stimulators in otolaryngology. The authors also discuss cranial nerve history; initial theory of the functional concept of animal spirit; electrical nerve impulse theory; first electrical otolaryngology cranial nerve stimulation devices; and the development of implanted stimulators.

Cranial nerve 13.

Contrary to popular belief, there are 13 cranial nerves. The thirteenth cranial nerve, commonly referred to as the nervus terminalis or terminal nerve, is a highly conserved multifaceted nerve found just above the olfactory bulbs in humans and most vertebrate species. In most forms its fibers course from the rostral portion of the brain to the olfactory and nasal epithelia. Although there are differing perspectives as to what constitutes this nerve, in most species GnRH-immunoreactive neurons appear to be its defining feature. The involvement of this trophic peptide, as well as the nerve's association with the development of the hypothalamic-pituitary-gonadal axis, suggest a primary role in reproductive development and, in humans, disorders such as Kallmann syndrome. In some species, this enigmatic nerve appears to influence sensory processing, sexual behavior, autonomic and vasomotor control, and pathogenic defense (via secretion of nitric oxide). In this review, we provide a general overview of what is known about this neglected cranial nerve, with the goal of informing neurologists and neuroscientists of its presence and the need for its further study.

Braincase simplification and the origin of lissamphibians.

Dissorophoidea, a group of temnospondyl tetrapods that first appear in the Late Carboniferous, is made up of two clades ⎼ Olsoniformes and Amphibamiformes (Branchiosauridae and Amphibamidae) ⎼ the latter of which is widely thought to have given rise to living amphibians (i.e., Lissamphibia). The lissamphibian braincase has a highly derived morphology with several secondarily lost elements; however, these losses have never been incorporated into phylogenetic analyses and thus the timing and nature of these evolutionary events remain unknown. Hindering research into this problem has been the lack of phylogenetic analyses of Dissorophoidea that includes both taxonomically dense sampling and specific characters to document changes in the braincase in the lineage leading to Lissamphibia. Here we build on a recent, broadly sampled dissorophoid phylogenetic analysis to visualize key events in the evolution of the lissamphibian braincase. Our ancestral character state reconstructions show a clear, step-wise trend towards reduction of braincase ossification leading to lissamphibians, including reduction of the sphenethmoid, loss of the basioccipital at the Amphibamiformes node, and further loss of both the basisphenoid and the hypoglossal nerve foramina at the Lissamphibia node. Our analysis confirms that the highly derived condition of the lissamphibian braincase is characterized by overall simplification in terms of the number and extent of chondrocranial ossifications.

Cranial Nerves: Phylogeny and Ontogeny.

This Special Issue, entitled "Cranial Nerves: phylogeny, ontogeny, morphology and clinical significance," has been divided into two consecutive volumes. We present here the first volume, devoted to phylogeny and ontogeny. Articles in this volume examine these two topics from a microscopic point of view. This volume includes an historical review that serves as an introduction. It also includes a review of the organization of cranial nerves from a neuromeric perspective which, together with two articles in amphioxi and lampreys, give emphasis to a comparative approach. Finally, several articles examine cranial nerves zero (nervus terminalis), I (olfactory), II (optic), III, IV and VI (oculomotor), VIII (cochlear and vestibular), and XI (accessory or spinal). Together, they provide a general overview of the neuroanatomical organization of cranial nerves, while offering insights into an evo-devo paradigm. Anat Rec, 302:378-380, 2019. © 2019 Wiley Periodicals, Inc.