Mapping the rest of the human connectome: Atlasing the spinal cord and peripheral nervous system.

The emergence of diffusion, structural, and functional neuroimaging methods has enabled major multi-site efforts to map the human connectome, which has heretofore been defined as containing all neural connections in the central nervous system (CNS). However, these efforts are not structured to examine the richness and complexity of the peripheral nervous system (PNS), which arguably forms the (neglected) rest of the connectome. Despite increasing interest in an atlas of the spinal cord (SC) and PNS which is simultaneously stereotactic, interactive, electronically dissectible, scalable, population-based and deformable, little attention has thus far been devoted to this task of critical importance. Nevertheless, the atlasing of these complete neural structures is essential for neurosurgical planning, neurological localization, and for mapping those components of the human connectome located outside of the CNS. Here we recommend a modification to the definition of the human connectome to include the SC and PNS, and argue for the creation of an inclusive atlas to complement current efforts to map the brain's human connectome, to enhance clinical education, and to assist progress in neuroscience research. In addition to providing a critical overview of existing neuroimaging techniques, image processing methodologies and algorithmic advances which can be combined for the creation of a full connectome atlas, we outline a blueprint for ultimately mapping the entire human nervous system and, thereby, for filling a critical gap in our scientific knowledge of neural connectivity.

Stereology of the Peripheral Nervous System.

Qualitative histopathology has been the gold standard for evaluation of morphological tissue changes in all organ systems, including the peripheral nervous system. However, the human eye is not sensitive enough to detect small changes in quantity or size. Peripheral nervous system toxicity can manifest as subtle changes in neuron size, neuron number, axon size, number of myelinated or unmyelinated axons, or number of nerve fibers. Detection of these changes may be beyond the sensitivity of the human eye alone, necessitating quantitative approaches in some cases. Although 2-dimensional (2D) histomorphometry can provide additional information and is more sensitive than qualitative evaluation alone, the results are not always representative of the entire tissue and assumptions about the tissue can lead to bias, or inaccuracies, in the data. Design-based stereology provides 3D estimates of number, volume, surface area, or length, and stereological principles can be applied to peripheral nervous system tissues to obtain accurate and precise estimates, such as neuron number and size, axon number, and total intraepidermal nerve fiber length. This review describes practical stereological approaches to 3 compartments of the peripheral nervous system: ganglia, peripheral nerves, and intraepidermal nerve fibers.

Sensory innervation of the human shoulder joint: the three bridges to break.

BACKGROUND: Painful shoulders create a substantial socioeconomic burden and significant diagnostic challenge for shoulder surgeons. Consensus with respect to the anatomic location of sensory nerve branches is lacking. The aim of this literature review was to establish consensus with respect to the anatomic features of the articular branches (ABs) (1) innervating the shoulder joint and (2) the distribution of sensory receptors about its capsule and bursae. MATERIALS AND METHODS: Four electronic databases were queried, between January 1945 and June 2019. Thirty original articles providing a detailed description of the distribution of sensory receptors about the shoulder joint capsule (13) and its ABs (22) were reviewed. RESULTS: The suprascapular, lateral pectoral, axillary, and lower subscapular nerves were found to provide ABs to the shoulder joint. The highest density of nociceptors was found in the subacromial bursa. The highest density of mechanoreceptors was identified within the insertion of the glenohumeral ligaments. The most frequently identified innervation pattern comprised 3 nerve bridges (consisting of ABs from suprascapular, axillary, and lateral pectoral nerves) connecting the trigger and the identified pain generator areas rich in nociceptors. CONCLUSION: Current literature supports the presence of a common sensory innervation pattern for the human shoulder joint. Anatomic studies have demonstrated that the most common parent nerves supplying ABs to the shoulder joint are the suprascapular, lateral pectoral, and axillary nerves. Further studies are needed to assess both the safety and efficacy of selective denervation of the painful shoulders, while limiting the loss of proprioceptive function.

Clinical anatomy of fecal incontinence in women.

Fecal incontinence is a devastating condition that has a severe impact on quality of life. This condition disproportionately affects women and its incidence is increasing with the aging United States population. Fecal continence is maintained by coordination of a functioning anal sphincter complex, intact sensation of the anorectum, rectal compliance, and the ability to consciously control defecation. Particularly important are the puborectalis sling of the levator ani muscle complex and intact innervation of the central and peripheral nervous systems. An understanding of the intricate anatomy required to maintain continence and regulate defecation will help clinicians to provide appropriate medical and surgical management and diminish the negative impact of fecal incontinence. In this article, we describe the anatomic and neural basis of fecal continence and normal defecation as well as changes that occur with fecal incontinence in women. Clin. Anat. 30:901-911, 2017. © 2017 Wiley Periodicals, Inc.

Malignant involvement of the peripheral nervous system in patients with cancer: multimodality imaging and pathologic correlation.

The clinical and imaging evaluation of peripheral neuropathies in patients with cancer is challenging. It is critically important to differentiate malignant invasion of the peripheral nervous system from nonmalignant causes, such as radiation-induced neuritis, neuropathy associated with chemotherapy, and inflammatory neuropathies. Contrast material-enhanced magnetic resonance (MR) imaging is the initial noninvasive test of choice; however, interpretation can be challenging when the anatomic features are distorted by prior surgery, radiation, or both. Fluorine 18 ((18)F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is an imaging adjunct to MR imaging that is particularly helpful for evaluating peripheral nerves because the metabolic activity depicted with (18)F-FDG PET/CT helps differentiate malignant from benign disease and assists in making certain management decisions. For example, sites of high (18)F-FDG activity in a peripheral nerve can be targeted to increase the diagnostic yield of a biopsy because malignant involvement of peripheral nerves can be patchy. Of note, (18)F-FDG PET/CT can show clinically unsuspected metastases elsewhere in the body. If cancer is found, (18)F-FDG PET/CT allows excellent assessment of treatment response. (18)F-FDG PET/CT is also useful in evaluating primary nerve sheath tumors in that such tumors with low metabolic activity on FDG PET/CT images are unlikely to be malignant, although the specificity is limited. It is essential to have a good understanding of the imaging characteristics of benign and malignant causes of peripheral neuropathy if (18)F-FDG PET/CT is to be used effectively for accurate diagnosis.

[New insights on the organization of the nodes of Ranvier]. / Nouveautés sur les mécanismes de formation des nœuds de Ranvier.

Myelin plays a crucial role in the rapid and saltatory conduction of the nerve impulse along myelinated axons. In addition, myelin closely regulates the organization of the axonal compartments. This organization involves several complex mechanisms including axo-glial contact, diffusion barriers, the cytoskeletal network, and the extracellular matrix. In peripheral nerves, the axo-glial contact dictates the formation of the nodes and the clustering of the voltage-gated sodium channels (Nav). The axo-glial contact at nodes implicates adhesion molecules expressed by the Schwann cell (gliomedin and NrCAM), which binds a partner, neurofascin-186, on the axonal side. This complex is essential for the recruitment of ankyrin-G, a cytoskeletal scaffolding protein, which binds and concentrates Nav channels at nodes. The paranodal junctions flanking the nodes also play a complementary function in node formation. These junctions are formed by the association of contactin-1/caspr-1/neurofascin-155 and create a diffusion barrier, which traps proteins at the nodes and dampens their diffusion along the internode. In the central nervous system, the mechanisms of node formation are different and the formation of the paranodal junctions precedes the aggregation of Nav channels at nodes. However, node formation can still happen in absence of paranodal junctions in the CNS. One explanation is that NF186 interacts with components of the extracellular matrix around the node and thereby stabilizes the aggregation of nodal proteins. It is likely that many other proteins are also implicated in the signaling pathways that regulate the differentiation of the axonal compartments. The nature and function of these proteins are yet to be identified.

Innervation and histology of the clitoral-urethal complex: a cross-sectional cadaver study.

INTRODUCTION: Despite its central role in sexual function, we lack a description of the nerve distribution and histology for the central components of the clitoris. AIM: This study aims to characterize microscopic anatomy of the clitoral-urethral complex (CUC) and aid our understanding of sexual sensation METHODS: The CUC was excised from three female fresh-frozen cadavers en bloc and prepared in 5-µm longitudinal sections with hematoxylin and eosin and S100 immunohistochemistry for neural elements. Approximately 20 sections were obtained from each specimen. On low power microscopy, the 30 most innervated fields on each section were identified. On high power, the total number of nerves per field was quantified, then was averaged. The histologic characteristics of each clitoral component were described. Two investigators evaluated all specimens. MAIN OUTCOME MEASURES: Descriptives of large (≥3 fibers) and small nerves based on location in the CUC. RESULTS: Nerve quantification revealed the glans to be the most populated by small nerves (52.1, standard deviation [SD] 26.2). As slices through each specimen moved caudad toward the urethra, the number of small nerves dramatically decreased from 40.4 (SD 10.8) in the body and 29.8 (SD 8.8) (superior CUC) near the bulb to 23.7 (SD 9.8) in the middle CUC and 20.5 (SD 10.4) (inferior CUC) near the urethra. Although the variation in small nerves was striking, large nerves were somewhat uniform and comprised a minority of the overall quantity. Neuroanatomy was consistent for all cadaver specimens. CONCLUSIONS: Our study provided a description of the nerve distribution throughout the central CUC. Increased density of small nerves in the glans suggests this is the location of heightened sensation. Decreasing quantity of nerves in segments closer to the urethra may indicate these zones are less important for sexual sensation. Knowledge of human clitoral innervation is important for understanding the complexities of the female sexual response cycle.

The surgical anatomy of the small saphenous vein and adjacent nerves in relation to endovenous thermal ablation.

BACKGROUND: Thermal damage to peripheral nerves is a known complication of endovenous thermal ablation (EVA) of the small saphenous vein (SSV). Therefore, the main objective of this anatomic study was to define a safe zone in the lower leg where EVA of the SSV can be performed safely. METHODS: The anatomy of the SSV and adjacent nerves was studied in 20 embalmed human specimens. The absolute distances between the SSV and the sural nerve (SN) (closest/nearest branch) were measured over the complete length of the leg (>120 data points per leg), and the presence of the interlaying deep fascia was mapped. The distance between the SSV and the tibial nerve (TN) and the common peroneal nerve was assessed. A new analysis method, computer-assisted surgical anatomy mapping, was used to visualize the gathered data. RESULTS: The distance between the SSV and the SN was highly variable. In the proximal one-third of the lower leg, the distance between the vein and the nerve was <5 mm in 70% of the legs. In 95%, the deep fascia was present between the SSV and the SN. In the distal two-thirds of the lower leg, the distance between the vein and the nerve was <5 mm in 90% of the legs. The deep fascia was present between both structures in 15%. In 19 legs, the SN partially ran beneath the deep fascia. In the saphenopopliteal region, the average shortest distance between the SSV and the TN was 4.4 mm. In 20%, the distance was <1 mm. The average, shortest distance between the SSV and the common peroneal nerve was 14.2 mm. The distance was <1 mm in one leg. CONCLUSIONS: At the saphenopopliteal region, the TN is at risk during EVA. In the distal two-thirds of the lower leg, the SN is at risk for (thermal) damage due to the small distance to the SSV and the absence of the deep fascia between both structures. The proximal one-third of the lower leg is the optimal region for EVA of the SSV to avoid nerve damage; the fascia between the SSV and the SN is a natural barrier in this region that could preclude (thermal) damage to the nerve.

Development of the spinal cord and peripheral nervous system in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus).

The modern monotremes (platypus and echidnas) are characterized by development of their young in a leathery egg that is laid into a nest or abdominal pouch. At hatching, the young are externally immature, with forelimbs capable of digitopalmar prehension, but hindlimbs little advanced beyond limb buds. The embryological collections at the Museum für Naturkunde in Berlin were used to examine the development of the spinal cord and early peripheral nervous system in developing monotremes and to correlate this with known behavioural development. Ventral root outgrowth to the bases of both the fore- and hindlimbs occurs at 6.0 mm crown-rump length (CRL), but invasion of both limbs does not happen until about 8.0-8.5 mm CRL. Differentiation of the ventral horn precedes the dorsal horn during incubation and separate medial and lateral motor columns can be distinguished before hatching. Rexed's laminae begin to appear in the dorsal horn in the first week after hatching, and gracile and cuneate fasciculi emerge during the first two post-hatching months. Qualitative and quantitative comparisons of the structure of the cervicothoracic junction spinal cord in the two monotremes with that in a diprotodont marsupial (the brush-tailed possum, Trichosurus vulpecula) of similar size at birth, did not reveal any significant structural differences between the monotremes and the marsupial. The precocious development of motor systems in the monotreme spinal cord is consistent with the behavioural requirements of the peri-hatching period, that is, rupture of embryonic membranes and egg, and digitopalmar prehension to grasp maternal hair or nest material.

Preparation and analysis of the peripheral nervous system.

This article is from a presentation at the 2010 STP/IFSTP Symposium on Neuropathology. The organization and basic structure of the peripheral nervous system is reviewed. Examples of toxicant-induced peripheral nerve injury such as neuronopathy, axonopathy, and myelinapathy are discussed, as are contemporary methods for examination of these tissues.

[The scientific revolutions in medicine in XVII-XIX centuries: disclaimer of Galenism and initiation of natural-scientific foundations of medicine. Report 5. The development of new conceptions about the structure and mechanisms of functioning of nervous system].

The article deals with the history of study of anatomy and physiology of central and peripheral nervous system in the course of scientific revolution in medicine.

[The scientific revolutions in medicine in XVII-XIX centuries: disclaimer of Galenism and initiation of natural-scientific foundations of medicine. Report 4. The disclaimer of Galen concepts on principles of structure and mechanisms of functioning of nervous system].

The article deals with the history of study of anatomy and physiology of central and peripheral nervous system in the course of scientific revolution in medicine.

Nogo-Nogo receptor signalling in PNS axon outgrowth and pathfinding.

The Nogo/Nogo66 receptor signaling pathway has been characterized as inhibitory for axon growth, regeneration, and structural plasticity in the adult mammalian central nervous system. Nogo and its receptor are highly expressed when axon growth is abundant, however, the function of this pathway in neural development is unclear. We have characterized zebrafish Nogo pathway members and examined their role in the developing nervous system using anti-sense morpholinos that inhibit protein synthesis. Depletion of the Nogo66 receptor or a Nogo isoform causes truncated outgrowth of peripheral nervous system (PNS) axons of the head and lateral line. PNS nerves also show increased defasciculation and numerous guidance defects, including axons invading regions along the body flank that are normally avoided. We propose that localized Nogo expression defines inhibitory territories that through repulsion restrict axon growth to permissive regions.

From basic concepts to emerging technologies in regional anesthesia.

PURPOSE OF REVIEW: The present article details how our understanding of the basic concepts of regional anesthesia has recently evolved. We will appraise current technological advances and question the commensurate nature of the relationship between tradition and innovation. RECENT FINDINGS: Ultrasound localization has enhanced our understanding of the needle-nerve relationship. Intraneural injection of local anesthetic may occur with greater frequency than previously thought without inevitably leading to neurological complications. The ratio of neural to non-neural tissue varies both between and within nerves and may be an important determinant of neural injury. Ultrasonographic evidence of intraneural injection is subject to observer expertise and the resolution of the ultrasound image. Current ultrasound resolution capability does not reliably permit differentiation between intrafascicular and extrafascicular drug injection. Perineural electrical impedance may be a determinant of current threshold and conceivably distinguish between intraneural and extraneural tissue. Technology that enhances the sonographic image of both procedure needle and target nerve is the focus of current endeavors in ultrasound innovation.There is inconclusive evidence that the use of ultrasound technology has reduced the incidence of local anesthetic toxicity. Lipid emulsion therapy is now an accepted treatment for systemic local anesthetic toxicity. There are new reports on the development of an ultra long-acting local anesthetic agent that would permit lower doses and superannuate catheter-based continuous regional anesthesia techniques. SUMMARY: Over the past decade, our understanding of the fundamental concepts of regional anesthesia continues to be challenged by emerging experimental and clinical evidence.

When botany inspired pathology of the peripheral nervous system.

Medicine and botany are 2 distinct disciplines of "natural science," one focusing on humans, the other on plants. However, among the life sciences, both were quite close in earlier times. Moreover, the history of neuropathology, especially in the field of the peripheral nervous system, has been marked by many examples of "botanical images" used to describe certain histopathologic structures. We propose to better understand the reasons why neuropathologists used these botanical terms from a number of interesting anecdotes.

Development of the central and peripheral nervous systems in the lamprey.

Vertebrate brains are highly organized structures that show remarkable diversity throughout the animal groups. Among the vertebrates, the agnathan animals, which diverged from the gnathostomes early in the evolution of the vertebrates, occupy a key phylogenetic position in order to clarify the origin and evolution of the brain. We found that the lamprey brain has the basic molecular mechanisms necessary to form brain compartments. Conversely, the telencephalon and cerebellum display gnathostome-specific developmental mechanisms. We also propose that, in contrast to those of gnathostomes, the maxillary ramus of the trigeminal nerve and buccal ramus of the nerve on the anterior lateral line are not fused in the developing lamprey. Thus, the development of the central nervous system and the framework of the peripheral nerve around the oral region are thought to have improved in the course of the agnathan-gnathostome transition.

The organizational hypothesis and final common pathways: Sexual differentiation of the spinal cord and peripheral nervous system.

In honor of the 50th anniversary of the "organizational hypothesis," this paper reviews work on sexual differentiation of the spinal cord and peripheral nervous system. Topics considered include the spinal nucleus of the bulbocavernosus, the ejaculation center, the cremaster nucleus, sensory and autonomic neurons, and pain. These relatively simple neural systems offer ample confirmation that early exposure to testicular hormones masculinizes the nervous system, including final common pathways. However, I also discuss findings that challenge, or at least stretch, the organizational hypothesis, with important implications for understanding sex differences throughout the nervous system.

The immunohistochemical expression profile of osteopontin in normal human tissues using two site-specific antibodies reveals a wide distribution of positive cells and extensive expression in the central and peripheral nervous systems.

To elucidate the cellular distribution of osteopontin (OPN) in normal human tissues, we undertook immunohistochemistry using two site-specific OPN antibodies. The 10A16 monoclonal antibody was raised against the amino acid sequence just downstream of the thrombin cleavage site, while the O-17 polyclonal antibody was raised against the N-terminal peptide. Each antibody has been confirmed previously to react with both whole OPN and its relevant fragments. The expression pattern for these two antibodies was similar in distribution. In addition, we also identified expression in Ebner's gland, type II pneumocytes, Kupffer cells, cells of the endocrine organs, anterior lens capsule and ciliary body, synovial type A cells, mesothelia, adipocytes, and mast cells. Neurons and glia in the central nervous system and spinal cord, cranial and peripheral nerve sheaths, ganglion cells in the sympathetic ganglion, intestinal plexuses, retina, and choroid plexus also regularly exhibited OPN positivity. Testicular germ cells, pancreatic exocrine cells, and follicular dendritic cells reacted with 10A16 only, whereas lutein cells and taste bud cells exhibited O-17 reactivity alone. These minor differences were hypothesized to reflect the state of OPN in the cells; that is, whether OPN was in its whole molecule or fragmented form. In conclusion, we demonstrate that OPN is widely distributed in normal human cells, particularly those comprising the central and peripheral nervous systems.

[Anatomy and physiology of the peripheral nerve]. / Organisation anatomique et physiologique du nerf périphérique.

The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology.