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The normal sural nerve in man. I. Ultrastructure and numbers of fibres and cells
Abstract
A combined light and electron microscope study of the normal sural nerve in 7 people aged 15-59 years is reported. Qualitative and quantitative studies of the Schwann cells and fibroblasts, myelinated and unmyelinated fibres are made in isolated fascicles. Schwann cells predominate over fibroblasts in the ratio of about 9-1. Most Schwann cells, almost 80%, are attached to unmyelinated fibres. Factors influencing the densities of these cells per cross sectional area are discussed. Some ultrastructural features of the myelinated fibres are described and their numbers per sq.mm and frequency distribution of their sizes are produced. An indirect method is proposed for assessing the mean internodal length for earch of the myelinated fibre size populations in cross sections of fascicles of normal nerves by estimating the proportion of myelinated segments cut through their nucleus. The ultrastructure of unmyelinated fibres is described and the identification of axons of extreme diameter is discussed. Their densities and size frequency histograms are the first to be reported in man by systematic electron microscope studies. The average ratio of unmyelinated to myelinated fibre density is about 3.7:1 though it varies in the fascicles of the different individuals. The implications of axonal diameter in the presence of myelin are commented on.
... The anatomy of the saphenous and sural nerves has been examined in a wide range of species as these nerves innervate hindlimb hairy skin and contain almost exclusively cutaneous axons (Lewin and McMahon 1991b). Many groups have quanti ed the numbers of myelinated (A-bers) and unmyelinated (C-bers) and consistently observed that there are always 3-4 times as many C-bers as A-bers in these nerves (Ochoa and Mair 1969;Alpson and Lal 1980;Scadding 1980;Schwab et al. 1984;Illanes et al. 1990;Stucky et al. 2002;Wetzel et al. 2007;Milenkovic et al. 2007;Stürzebecher et al. 2010). However, in naked mole-rat this ratio is just ~1.5:1 and the low ratio is due to an absolute paucity of unmyelinated nociceptors and not due to increased numbers of A-ber axons (Park et al. 2008;St John Smith et al. 2012;Omerbaši et al. 2016). ...
... A potentially parsimonious explanation for the cutaneous C-ber de cit in naked mole-rats is that they largely lack fur, although specialized sensory hairs are present (Crish et al. 2003). Compared to most other mammals, humans are relatively naked and lack dense body hair, however, human cutaneous nerves also show a ~ 4:1 C to A-ber ratio (Ochoa and Mair 1969). To our knowledge no such investigation has yet been conducted in other "naked" mammals, such as the manatee (Trichechus manatus) or hairless bat (Cheiromeles torquatus). ...
The naked mole-rat (Heterocephalus glaber) is famous for its longevity and unusual physiology. This eusocial species that lives in highly ordered and hierarchical colonies with a single breeding queen, also discovered secrets enabling somewhat pain-free living around 20 million years ago. Unlike most mammals, naked mole-rats do not feel the burn of chili pepper’s active ingredient, capsaicin, nor the sting of acid. Indeed, by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved. Recently, we have identified pain-insensitivity as a trait shared by several closely related African mole-rat species. In this chapter we will show how African mole-rats have evolved pain insensitivity as well as discussing what the proximate factors may have been that led to the evolution of pain-free traits.
... The anatomy of the saphenous and sural nerves have been examined in a wide range of species as these nerves innervate hindlimb hairy skin and contain almost exclusively cutaneous axons (Lewin and McMahon 1991). Many groups have quantified the numbers of myelinated (A-fibers) and unmyelinated (C-fibers) and consistently observed that there are always 3-4 times as many C-fibers as A-fibers in these nerves (Ochoa and Mair 1969;Alpson and Lal 1980;Scadding 1980;Schwab et al. 1984;Illanes et al. 1990;Stucky et al. 2002;Wetzel et al. 2007;Milenkovic et al. 2007;Stürzebecher et al. 2010). However, in naked mole-rat, this ratio is just ~ 1.5:1 and the low ratio is due to absolute paucity of unmyelinated nociceptors and not due to increased numbers of A-fiber axons (Park et al. 2008;Smith et al. 2012;Omerbašić et al. 2016). ...
... A potentially parsimonious explanation for the cutaneous C-fiber deficit in naked mole-rats is that they largely lack fur, although specialized sensory hairs are present (Crish et al. 2003). Compared to most other mammals, humans are relatively naked and lack dense body hair; however, human cutaneous nerves also show a ~ 4:1 C to A-fiber ratio (Ochoa and Mair 1969). To our knowledge no such investigation has yet been conducted in other "naked" mammals, such as the manatee (Trichechus manatus) or hairless bat (Cheiromeles torquatus). ...
The naked mole-rat (Heterocephalus glaber) is famous for its longevity and unusual physiology. This eusocial species that lives in highly ordered and hierarchical colonies with a single breeding queen, also discovered secrets enabling somewhat pain-free living around 20 million years ago. Unlike most mammals, naked mole-rats do not feel the burn of chili pepper’s active ingredient, capsaicin, nor the sting of acid. Indeed, by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved. Recently, we have identified pain insensitivity as a trait shared by several closely related African mole-rat species. One of these African mole-rats, the Highveld mole-rat (Cryptomys hottentotus pretoriae), is uniquely completely impervious and pain free when confronted with electrophilic compounds that activate the TRPA1 ion channel. The Highveld mole-rat has evolved a biophysical mechanism to shut down the activation of sensory neurons that drive pain. In this review, we will show how mole-rats have evolved pain insensitivity as well as discussing what the proximate factors may have been that led to the evolution of pain-free traits.
... The anatomy of the saphenous and sural nerves have been examined in a wide range of species as these nerves innervate hindlimb hairy skin and contain almost exclusively cutaneous axons (Lewin and McMahon 1991). Many groups have quantified the numbers of myelinated (A-fibers) and unmyelinated (C-fibers) and consistently observed that there are always 3-4 times as many C-fibers as A-fibers in these nerves (Ochoa and Mair 1969;Alpson and Lal 1980;Scadding 1980;Schwab et al. 1984;Illanes et al. 1990;Stucky et al. 2002;Wetzel et al. 2007;Milenkovic et al. 2007;Stürzebecher et al. 2010). However, in naked mole-rat, this ratio is just ~ 1.5:1 and the low ratio is due to absolute paucity of unmyelinated nociceptors and not due to increased numbers of A-fiber axons (Park et al. 2008;Smith et al. 2012;Omerbašić et al. 2016). ...
... A potentially parsimonious explanation for the cutaneous C-fiber deficit in naked mole-rats is that they largely lack fur, although specialized sensory hairs are present (Crish et al. 2003). Compared to most other mammals, humans are relatively naked and lack dense body hair; however, human cutaneous nerves also show a ~ 4:1 C to A-fiber ratio (Ochoa and Mair 1969). To our knowledge no such investigation has yet been conducted in other "naked" mammals, such as the manatee (Trichechus manatus) or hairless bat (Cheiromeles torquatus). ...
How the mole-rat lost its pain
Pain alerts our bodies that something is amiss and typically we stop the pain-causing activity. Numerous species of plants and prey animals take advantage of this response by producing pain-causing substances that are released during predation attempts. In turn, species that encounter these substances often evolve ways of turning off the pain-producing mechanism. Eigenbrod et al. searched RNA transcripts in eight species of subterranean rodents related to pain-resistant naked mole-rats. They found multiple changes to ion channels involved in pain across the different species. Understanding such adaptations could elucidate pain mechanisms and help us develop approaches for pain relief.
Science , this issue p. 852
... Unmyelinated fibers predominate in human cutaneous spinal nerves, where the average ratio of unmyelinated to myelinated fiber density is 3.7:1. 23 In unmyelinated fibers, conduction velocity is proportional to the square root of fiber diameter and is much slower compared to saltatory conduction in myelinated fibers ( Hadzic -Lancea/ NYSORA FIGURE 4-7. Saltatory conduction in myelinated nerve fiber. ...
... 5,69 In the elderly, myelinated fiber density decreases. 23,41,[70][71][72] A regular relation between internodal length and fiber diameter becomes less precise with aging. 41,73 This is associated with segmental demyelination and remyelination and the axonal degeneration and regeneration clinically evident as mild peripheral neuropathy. ...
... It has been documented that there is a decrease in the density of myelinated fibres with aging [43 -45]. In contrast, some studies have found a decrease in the density of unmyelinated fibres [43,46], whereas others did not report these changes [47,48]. It has been recognized that myelinated fibres tend to show more decline in density [43] and function [49] than unmyelinated fibres, as well as decreased nerve conduction velocity and structural modifications in the elderly [38,44]. ...
... In contrast, some studies have found a decrease in the density of unmyelinated fibres [43,46], whereas others did not report these changes [47,48]. It has been recognized that myelinated fibres tend to show more decline in density [43] and function [49] than unmyelinated fibres, as well as decreased nerve conduction velocity and structural modifications in the elderly [38,44]. Furthermore, it has been suggested that aging processes affect myelinated A delta fibre, but unmyelinated C-fibre appear to be less affected or unaltered [39]. ...
Introduction
An increasing body of literature on sex and gender differences in pain sensitivity has been accumulated in recent years. There is also evidence from epidemiological research that painful conditions are more prevalent in older people. The aim of this narrative review is to critically appraise the relevant literature investigating the presence of age and sex differences in clinical and experimental pain conditions.
Methods
A scoping search of the literature identifying relevant peer reviewed articles was conducted on May 2016. Information and evidence from the key articles were narratively described and data was quantitatively synthesised to identify gaps of knowledge in the research literature concerning age and sex differences in pain responses.
Results
This critical appraisal of the literature suggests that the results of the experimental and clinical studies regarding age and sex differences in pain contain some contradictions as far as age differences in pain are concerned. While data from the clinical studies are more consistent and seem to point towards the fact that chronic pain prevalence increases in the elderly findings from the experimental studies on the other hand were inconsistent, with pain threshold increasing with age in some studies and decreasing with age in others.
Conclusion
There is a need for further research using the latest advanced quantitative sensory testing protocols to measure the function of small nerve fibres that are involved in nociception and pain sensitivity across the human life span.
Implications
Findings from these studies should feed into and inform evidence emerging from other types of studies ( e.g. brain imaging technique and psychometrics) suggesting that pain in the older humans may have unique characteristics that affect how old patients respond to intervention.
... Thus, the influence of specific peripheral nerves is nevertheless conceivable. At approximately 80%, the majority of peripheral nociceptors in cutaneous skin are unmyelina ted C-fibers [34][35][36][37] and consequently the remaining myelinated A-delta afferents are in the minority 34,35 . More interestingly, animal studies in rats have shown that mucosal nociceptors differ from skin nociceptors with respect to the distribution of their types and certain physiologica l properties 38,39 . ...
Background:
Offset analgesia (OA) is commonly used to quantify endogenous pain inhibition. However, the potential role of afferent inputs and the subsequent peripheral factors from different body areas on the underlying mechanisms are still unclear.
Objectives:
The aim of this cross-sectional study was to compare the magnitude of OA in four different body areas representing a) glabrous and non-glabrous skin, b) trigeminal and extra-trigeminal areas, and c) intra- and extra-oral tissue.
Methods:
OA was assessed at the oral mucosa of the lower lip, at the skin of the cheek, the forearm and the palm of the hand in 32 healthy and pain-free participants. OA testing included two trials: (1) a constant trial (30 seconds of constant heat stimulation at an individualized temperature of Pain50 (pain intensity of 50 out of 100)), and (2) an offset trial (10 seconds of individualized Pain50 , followed by 5 seconds at Pain50 +1°C and 15 seconds at Pain50 ). Participants continuously rated their pain during each trial with a computerized visual analog scale.
Results:
A significant OA response was recorded at the oral mucosa (p<0.001, d=1.24), the cheek (p<0.001, d=0.84) and the forearm (p<0.001, d=1.04), but not at the palm (p=0.19, d=0.24). Significant differences were shown for OA recorded at the cheek versus the mucosa (p=0.02), and between palm and mucosa (p=0.007), but not between the remaining areas (p>0.05).
Conclusion:
This study suggests that intra-oral endogenous pain inhibition assessed with OA is enhanced and supports the role of peripheral mechanisms contributing to the OA response.
... In this study, specimens included not only adult cadavers but also fetal specimens because the simple fascial configuration of the latter would facilitate the understanding of adult morphology. Most knowledge of the nerve sheath structure seems to be based on electron microscopic observations (e.g., Ochoa, 1971;Ochoa & Mair, 1969a, 1969b. However, we believe that even routine histology, including new findings, will provide a better understanding. ...
Unlike the usual peripheral nerve, the optic nerve accompanies a thick “dural sheath,” a thin “sheath of pia mater” (SPM), and multiple “septa,” which divides the nerve fibers into fascicles. We collected specimens from 25 adult cadavers and 15 fetuses and revisited the histological architecture of the optic and oculomotor nerves. In the optic chiasma, the meningeal layer of the dura joins the pia to form a thick SPM, and the periosteum of the sphenoid is continuous with the dural sheath at the orbital exit of the bony optic canal. The septa appeared as a cluster of irregularly arrayed fibrous plates in the intracranial course near the chiasma. Thus, the septa were not derived from either the SPM or the dural sheath. In the orbit, the central artery of the retina accompanies collagenous fibers from the dural sheath and the SPM to provide the vascular sheath in the optic nerve. These connective tissue configurations were the same between adult and fetal specimens. At the optic disk, the dural sheath and SPM merged with the sclera, whereas the septa appeared to end at the lamina cribrosa. However, in fetuses without lamina cribrosa, the septa extend into the nerve fiber layer of the retina. The SPM and septa showed strong elastin immunoreactivity, in contrast to the absence of reactivity in the sheaths of the oculomotor nerve. Each S100 protein‐positive Schwann sheath of the oculomotor nerve was surrounded by collagenous endoneurium. Glial fibrillary acidic protein‐positive astrocytes showed a linear arrangement along the septa.
... In complex nervous systems, specialized glial cells ensheathe long axons, and this 31 wrapping can take many forms. Myelination is the most studied type of ensheathment, but 32 unmyelinated axons make up the majority (~70%) of axons in human peripheral nerves (Ochoa 33 and Mair, 1969;Schmalbruch, 1986). Vertebrate Remak Schwann cells ensheathe and separate 34 unmyelinated axons from one another. ...
Invertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. How this type of ensheathment is controlled and its roles in supporting neuronal function remain unclear. We performed an in vivo RNAi screen in Drosophila to identify glial genes required for axon ensheathment and identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in incomplete ensheathment of axons. We found a strong dominant genetic interaction between Ddr and the fly type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions a collagen receptor to drive wrapping of axons during development. Surprisingly, while ablation of glia that wrap axons severely impaired larval motor behavior, incomplete wrapping in Ddr mutants was sufficient to support basic circuit function. In adult nerves, loss of Ddr from glia decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish a crucial role for non-myelinating glia in peripheral nerve development and function across the lifespan, and identify Ddr as a key regulator of axon-glia interactions during ensheathment.
... Despite being lesser studied than their myelinating counterpart, Remak Schwann cells, in fact, occupy a far greater percentage of the Schwann cells found within the normal human sural nerve (Ochoa & Mair, 1969). Following completion of radial sorting (around postnatal day 15 in rodents), immature Schwann cells will extend processes to encompass the remaining axons, those which are typically smaller than 1 μm in diameter (Webster et al., 1973, and see review by Monk et al., 2015). ...
Recent years have seen an evolving appreciation for the role of glial cells in the nervous system. As we move away from the typical neurocentric view of neuroscience, the complexity and variability of central nervous system glia is emerging, far beyond the three main subtypes: astrocytes, oligodendrocytes, and microglia. Yet the diversity of the glia found in the peripheral nervous system remains rarely discussed. In this review, we discuss the developmental origin, morphology, and function of the different populations of glia found in the peripheral nervous system, including: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap‐derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body. Further, it highlights a complexity that should be appreciated and considered when it comes to a complete understanding of the peripheral nervous system in health and disease. Glia found in the peripheral nervous system are anatomically, morphologically, and functionally diverse. They include: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap‐derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body.
... 22 Compared to most other mammals, humans are relatively naked and lack dense body hair; however, human cutaneous nerves also show a ;4:1 C-fiber to A-fiber ratio. 87 In normal mice, it has been observed that there is ongoing naturally occurring cell death of sensory neurons with C-fiber axons in the early postnatal period. This loss of axons is reflected in a drop in the C-fiber to Afiber ratio from ;6:1 in neonates to ;4:1 in adults. ...
... In eight cases sural nerve biopsy was reviewed to quantify fibre loss. Myelinated fibre nerve density was severely reduced (median 290 myelinated fibres per mm 2 cross-sectional area, ranging from 52 to 2067) compared to age-matched controls [normal range 4000-9000 myelinated fibres/mm 2 (Ochoa and Mair, 1969;Jacobs and Love, 1985)]. There was no significant variation of fibre density across the fascicles (median 28 myelinated fibres per fascicle, ranging from 4 to 81). ...
Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.
... & V i is the volume of the ith voxel (in m 3 ), based on the distances between its eight corners, & ρ noc is the density (in m −3 ) of heat-sensitive pain receptors at different depths below the surface of the target's skin, & T i t ð Þ is the average temperature (in K) of the ith voxel at time step t, averaged over the temperature values T(r, y, t) calculated for each of its eight corners, and & T act is the temperature threshold (in K) at which heatsensitive pain receptors become activated, represented by the horizontal, dashed red line in Fig. 5 ADT CHEETEH then calculates x(t), the total number of heat-sensitive pain receptors activated in the assessed skin at each time step t: This simple approach is based on an approximation of ρ noc , the density of heat-sensitive pain receptors in the skin. We formulated default values for ρ noc that vary with skin depth y, taken from a careful analysis of the medical literature for heat-sensitive C-fibers (a type of pain receptor) [16,[18][19][20][21]. This approach disregards the timing information contained in the action potentials of the activated pain receptors. ...
We developed the Active Denial Technology Computational Human Effects End-To-End Hypermodel (ADT CHEETEH), a computational model to simulate the response of a human target to Active Denial Technology (ADT), including estimates of ADT’s physical, physiological, cognitive, and behavioral effects. The ADT system is a counter-personnel non-lethal weapon for crowd control, convoy protection, and perimeter security. The target is subjected to pulses of focused 95 GHz electromagnetic energy. The energy diffuses approximately 400 μm into the target’s skin, producing no skin damage. However, the target may still perceive a burning sensation strong enough to repel (i.e., compel the target to immediately move away). We use one model component to estimate the physical output of the ADT system, coupled with three additional components to estimate the ADT’s effect on the target’s physiology, cognition, and behavior. All components passed verification tests. Validation data was available for only the physical component, which passed its validation test. Each run of ADT CHEETEH completes in only a few minutes on a standard laptop computer, beginning with a simulation of the ADT beam formation and concluding with the estimated time at which the target is repelled. This end-to-end approach quantifies the ADT system’s main measure of effectiveness (the probability of repel) as well as its intermediate measures of performance (dose on target, temperature and damage in skin, perceived pain level, etc.) Once fully validated, ADT CHEETEH’s comprehensive results may be able to feed into force-on-force simulations to provide educated estimates of ADT effectiveness in military scenarios.
... Der überwiegende Teil der peripheren Nervenfasern sind unmyelinisierte C-Fasern (72-81%; Ochoa und Mair (1969); Schmalbruch (1986) ;Heppelmann, Heuss, und Schmidt (1988); Hines, Birn, Teglbjaerg, und Sinkjaer (1996)). Unter den verbleibenden myelinisierten Afferenzen sind ~70-~80% dünn myelinisierte Aδ-Fasern (Heppelmann et al., 1988;Ochoa & Mair, 1969). Somit kann in Hautnerven prozentual von einem Verhältnis der Axone von Hautnerven zwischen C-, Aδ-und Aβ-Fasern von ca. ...
Die Langzeitpotenzierung im Hinterhorn des Rückenmarks erfordert eine peptiderge C-Faseraktivierung bei Tieren. Zu den wahrnehmbaren Korrelaten der Langzeitpotenzierung nach hochfrequenter elektrischer Stimulation beim Menschen gehören eine erhöhte Empfindlichkeit gegenüber elektrischen Reizen am Ort der hochfrequenten Stromstimulation (homotope Schmerz-Langzeitpotenzierung) und eine erhöhte Empfindlichkeit gegenüber Pinprick in der Umgebung der Hochfrequenz-Stimulationsstelle (heterotope Schmerz-Langzeitpotenzierung bzw. sekundären Hyperalgesie). Zur Charakterisierung der peripheren Faserpopulationen, die an der Induktion der Schmerz-Langzeitpotenzierung beteiligt sind, wurden zwei selektive Nervenblockadexperimente an 30 gesunden männlichen Probanden durchgeführt. Eine funktionelle Blockade von TRPV1-positiven Nozizeptoren durch hochkonzentriertes Capsaicin (verifiziert durch den Verlust von Hitzeschmerzen) reduzierte die Schmerzratings signifikant um 47% (p < 0,001), homotope Schmerz-Langzeitpotenzierung um 71% (p < 0,01), heterotope Schmerz-Langzeitpotenzierung um 92% (p < 0,001) und den Bereich der sekundären Hyperalgesie um 76% (p < 0,001). Die selektive Blockade der A-Faserleitung durch Nervenkompression (verifiziert durch den Verlust des ersten Schmerzes nach Pinprickprickapplikation) reduzierte die Schmerzratings zur Hochfrequenz-Stimulation signifikant um 37% (p < 0,01), nicht aber die homotope Schmerz-Langzeit-Potenzierung (-5%). Es hatte einen marginalen Einfluss auf die heterotope Schmerz-Langzeitpotenzierung (-35%, p = 0,059), während der Bereich der sekundären Hyperalgesie unverändert blieb (-2%, p = 0,88). Zusammenfassend kann gesagt werden, dass alle Nozizeptorunterklassen zu hochfrequenten, stimulierenden Schmerzen beitragen (mit einem relativen Anteil von C > Aδ Fasern und einem gleichen Anteil von TRPV1-positiven und TRPV1-negativen Fasern). TRPV1-positive C-Fasern sind die Hauptinduktoren der homotopen und heterotopen Schmerz-Langzeitpotenzierung. TRPV1-positive A-Fasern tragen wesentlich zur Induktion der heterotopen Schmerz-Langzeitpotenzierung bei. TRPV1-negative C-Fasern induzieren eine Komponente der homotopen Autofazilitation, aber keine heterotope Schmerz-Langzeitpotenzierung. TRPV1-negative A-Fasern vermitteln Pinprickschmerzen und Hyperalgesie, aber sie scheinen nicht zur Induktion der Schmerz-Langzeitpotenzierung beizutragen. Diese Ergebnisse zeigen, dass verschiedene periphere Faserklassen die Induktion einer Schmerzsensitivierung, die der Langzeitpotentierung ähnlich ist, deren räumliche Ausbreitung auf die benachbarte Haut (z.B. sekundäre Hyperalgesie) und die daraus resultierende erhöhte Empfindlichkeit gegenüber Pinprick beim Menschen vermitteln. Nozizeptive Afferenzen, die eine Schmerzsensitivierung induzieren, können leicht von denjenigen, die Schmerzen vermitteln, getrennt werden. Diese Erkenntnisse tragen wesentlich zum Verständnis der Mechanismen der Schmerzsensitivierung bei, die die Grundlage für das Verständnis der Mechanismen der Hyperalgesie bei Patienten bilden.
... At the cellular level a number of baseline differences have been identified in the aged nociceptive system. For example, myelinated and unmyelinated fibers are reduced in peripheral nerves MPX Express Accepted on 20 December 2018 This article can be cited as 10.1177/1744806919839860 10,11 as is the expression of key pain transducer and signaling receptors such as TRPV1 and Nav1.8 12,13 . ...
A well-recognized relationship exists between ageing and increased susceptibility to chronic pain conditions, underpinning the view that pain signaling pathways differ in aged individuals. Yet despite the higher prevalence of altered pain states among the elderly, the majority of preclinical work studying mechanisms of aberrant sensory processing are conducted in juvenile or young adult animals. This mismatch is especially true for electrophysiological studies where patch clamp recordings from aged tissue are generally viewed as particularly challenging. In this study we have undertaken an electrophysiological characterization of spinal dorsal horn neurons in young adult (3-4 months) and aged (28-32 months) mice. We show that patch clamp data can be routinely acquired in spinal cord slices prepared from aged animals and that the excitability properties of aged dorsal horn neurons differ from recordings in tissue prepared from young animals. Specifically, aged dorsal horn neurons more readily exhibit repetitive action potential discharge, indicative of a more excitable phenotype. This observation was accompanied by a decrease in the amplitude and charge of spontaneous excitatory synaptic input to dorsal horn neurons and an increase in the contribution of GABAergic signalling to spontaneous inhibitory synaptic input in aged recordings. While the functional significance of these altered circuit properties remains to be determined, future work should seek to assess if such features may render the aged dorsal horn more susceptible to aberrant injury or disease induced signaling and contribute to increased pain in the elderly.
... They outnumber the myelin forming cells and are spaced closer together along axons compared to their myelin counterparts (Ochoa & Mair, 1969;Aguayo et al., 1973). ...
Following peripheral nerve injury, myelin and Remak Schwann cells up-regulate a repair phenotype, controlled by c-Jun, to facilitate axon regeneration. Despite activation of this phenotype, nerve regeneration in humans is poor. An important factor is the deterioration of the distal nerve stump, a process involving a decrease in trophic factors initially up-regulated following injury and a decline in Schwann cell numbers, resulting in poor long-term regeneration. Regeneration deficits also develop with age - injured nerves in old mice regenerate slowly. I hypothesized that in old mice, and during chronic denervation, c-Jun levels are not maintained. This predicts that in young mice, c-Jun levels fall during chronic denervation, and that by maintaining Schwann cell c-Jun, the deterioration of the distal stump can be prevented. Similarly, by enhancing c-Jun levels in old mice, the regeneration deficit should be reversed. In young mice, Schwann cell c-Jun significantly decreased during chronic denervation. Markers of the repair phenotype also declined. A mouse that over-expressed Schwann cell c-Jun (OE/+) was generated. Following chronic denervation, Schwann cells in denervated nerves maintained c-Jun levels. Regeneration was assessed by suturing a chronically denervated tibial nerve to a freshly cut common peroneal nerve, followed by neuronal backfilling. Improved motor and sensory neuron regeneration was observed in OE/+ mice following chronic denervation. In old OE/+ mice, the reduced c-Jun levels seen in old wild type mice were corrected. Regeneration was assessed by backfilling and old OE/+ nerves maintained the regenerative capacity of young animals. These results highlighted c-Jun as a pharmaceutical target. Sonic hedgehog is elevated after nerve injury and agonists significantly increased c-Jun and trophic factor expression in cultured Schwann cells. This work implicates the c-Jun pathway in the regeneration deficit that occurs following chronic denervation and with advancing age, and highlights hedgehog signalling as an activator of c-Jun.
... This shows that the classification of the smallest myelinated fibers and the largest C fibers is difficult using only diameter as a criterion. Nevertheless, the unmyelinated fibers are usually in a unimodal distribution, as in somatic nerves [23]. ...
Background:
The number and calibre of myelinated and unmyelinated fibres of the sacrococcygeal dorsal roots innervating the tail of rats were studied by means of light and electron microscopy.
Materials and methods:
There were an estimated total of 12,500 myelinated and 25,500 unmyelinated dorsal root fibres innervating the tail of a rat.
Results:
The results showed that from the second sacral (S2) to the fourth sacral (S4) segment, the fibre diameter spectrum of myelinated fibres within each dorsal root was bimodal with two peaks at 5 microns and 10 microns, respectively. The first sacral (S1) segment was composed of numerous smaller-size myelinated fibres, thus forming a right-skewed distribution. The coccygeal (Co) segments showed a unimodal distribution peaking at 10 microns for the first (Co1) segment and gradually shifting to 7 microns for the third (Co3) segment. Overall, there was a continuous relative increase of the larger vs. the smaller myelinated fibres from the sacral to coccygeal segments. The fibre diameter of unmyelinated fibres of all these roots was unimodal with a single peak at 0.5 microns. The ratio of unmy- elinated to myelinated fibre numbers was on average 2.83 for the S1-S2 roots, 1.66 for the S3-S4 roots, and 1.24 for the coccygeal roots.
Conclusions:
The comparison of the left- and right-side nerve fibres show that there was no significant difference, thus implying a symmetrical sensory innervation of the rat's tail.
... The generation of artificial cutaneous signals is not a simple task; as outlined above, there are numerous different types of thermoreceptive and mechanoreceptive channels (Fig. 1). To put this in perspective, there are~17,000 myelinated mechanoreceptors in the glabrous skin of the human hand (Johansson and Vallbo 1979b), and unmyelinated C-fibers compose~80% of the axons in peripheral nerves (including sympathetic innervations; Ochoa and Mair 1969;St John Smith et al. 2012). This represents a vast input, a lot of which is spontaneously active, and it is currently impossible to register and reproduce this level of afference. ...
Our perception of skin wetness is generated readily, yet humans have no known receptor (hygroreceptor) to signal this directly. It is easy to imagine the sensation of water running over our hands, or the feel of rain on our skin. The synthetic sensation of wetness is thought to be produced from a combination of specific skin thermal and tactile inputs, registered through thermoreceptors and mechanoreceptors, respectively. The present review explores how thermal and tactile afference from the periphery can generate the percept of wetness centrally. We propose that the main signals include information about skin cooling, signaled primarily by thinly-myelinated thermoreceptors, and rapid changes in touch, through fast-conducting, myelinated mechanoreceptors. Potential central sites for integration of these signals, and thus the perception of skin wetness, include the primary and secondary somatosensory cortices and the insula cortex. The interactions underlying these processes can also be modeled to aid in understanding and engineering the mechanisms. Further, we discuss the role that sensing wetness could play in precision grip and the dexterous manipulation of objects. We expand on these lines of inquiry to the application of the knowledge in designing and creating skin sensory feedback in prosthetics. The addition of real-time, complex sensory signals would mark a significant advance in the use and incorporation of prosthetic body parts for amputees in everyday life.
... Tactile afference can be divided into discriminative touch, signalled mainly by the fast-conducting (30-75 m/s), myelinated mechanoreceptive afferents, and affective touch, signalled predominantly by the slowly conducting (~1 m/s), C lowthreshold mechanoreceptors (CLTMs in animals), or so-called C-tactile (CT) afferents in humans. Unmyelinated C-fi bres make up ~80 % of the axons in peripheral nerves, accounting for tactile, thermal, nociceptive and sympathetic innervations ( Ochoa and Mair 1969 ;St John Smith et al. 2012 ). Recent work using unbiased sampling and modelling of transcriptional states in single dorsal root ganglion cells ( Usoskin et al. 2014 ) has identifi ed a distinct population of CLTM neurons, whereas the cell bodies of fast-conducting myelinated mechanoreceptors are encoded by the integration of neurons with different transcriptional states. ...
Somatic sensation comprises four main modalities relaying tactile, thermal, painful, or pruritic (itch) information to the central nervous system. These input channels can be further classified as sub-serving sensory functions, such as spatial and temporal discrimination, and the provision of essential information for controlling and guiding exploratory manual behaviours, or affective functions that include the provision of the subjective experience of affective or emotional pleasurable touch. Signalling in fast-conducting myelinated peripheral nerve fibres (Aβ afferents) is important for the discriminative properties of tactile sensations, whereas signalling in unmyelinated peripheral nerve fibres, C-tactile (CT) afferents seems to be important for the rewarding, emotional properties of touch. CT afferents have specific biophysical, electrophysiological, neurobiological and anatomical properties to drive the temporally delayed affective somatic system. This chapter explores step by step the differences between the discriminative and affective touch systems, from the first stage of encoding touch in the skin to the neural pathways in the brain. The below quote from Bentley (Am J Psychol 11:405–425, 1900) reiterates the complexity of the skin and the wonder in the phenomenon of somatosensation:
‘The skin is burdened with offices. One of the surprises of physiology is the revelation of the multitude of functions performed by this apparently simple organ. As a rind it is not only the container, but the warder-off, and also the go-between for the organism and its world; tegument, buckler, interagent. It is small wonder that its work is represented in mental process; that many of our most worn and useful perceptions are made up of cutaneous sensations.’
Most invertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. Here we use Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNAi screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and we found a strong dominant genetic interaction between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish essential roles for non-myelinating glia in nerve development, maintenance, and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber.
Background:
In clinical practice, small myelinated sensory fibers conveying pain and other sensations, Aδ-fibers, cannot be examined with available nerve conduction study techniques.
New method:
Equipment available in clinical neurophysiology laboratories is used to record from human sensory nerves multiple averaged responses to non-painful stimulation of intraepidermal nerves. Ten averaged responses are analyzed in all possible pair combinations with an algorithm applied to a 0.45 ms period of amplitude and frequency (power spectrum). The median of the algorithms is compared to control data to identify potentials generated as response to intraepidermal stimulation.
Results:
Median analysis of the algorithm applied to amplitude and frequency of multiple record pairs identifies potentials with conduction velocities of Aδ-fibers. The analysis of frequency (power spectrum) adds data to the analysis of amplitude. Median analysis of multiple record pairs yields more data than analysis of one pair of alternate averages with the same algorithm.
Comparison with existing method(s):
At present, analysis of one pair of alternate average records with an algorithm is the only method to identify Aδ-fiber generated potentials. Median analysis of the same algorithm applied to the amplitude of multiple record pairs increases the number of Aδ-fiber generated potentials identified. Neither median analysis of amplitude nor frequency of multiple records pairs has ever been used for conduction studies of nerve fibers, including Aδ-fibers.
Conclusions:
Stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify the conduction velocities of Aδ-fibers in human sensory nerves.
Biophysically-based computational models of nerve fibers are important tools for designing electrical stimulation therapies, investigating drugs that affect ion channels, and studying diseases that affect neurons. Although peripheral nerves are primarily composed of unmyelinated axons (i.e., C-fibers), most modeling efforts focused on myelinated axons. We implemented the single-compartment model of vagal afferents from Schild et al. 1994 and extended the model into a multi-compartment axon, presenting the first cable model of a C-fiber vagal afferent. We also implemented the updated parameters from Schild and Kunze 1997. We compared the responses of these novel models to three published models of unmyelinated axons (Rattay and Aberham 1993; Sundt et al. 2015; Tigerholm et al. 2014) and to experimental data from single fiber recordings. Comparing Schild et al. 1994 and 1997 revealed that differences in rest potential and action potential shape were driven by changes in maximum conductances rather than changes in sodium channel dynamics. Comparing the five model axons, the conduction speeds and strength-duration responses were largely within expected ranges, but none of the models captured the experimental threshold recovery cycle-including a complete absence of late subnormality in the models-and their action potential shapes varied dramatically. The Tigerholm et al. 2014 model best reproduced the experimental data, but these modeling efforts make clear that additional data are needed to parameterize and validate future models of autonomic C-fibers.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
The human organs of perception are constantly bombarded with chemicals from the environment. Our bodies have in turn developed complex processing systems, which manifest themselves in our emotions, memory, and language. Yet the available data on the high order cognitive implications of taste and smell are scattered among journals in many fields, with no single source synthesizing the large body of knowledge, much of which has appeared in the last decade. This book presents the first multidisciplinary synthesis of the literature in olfactory and gustatory cognition. Leading experts have written chapters on many facets of taste and smell, including odor memory, cortical representations, psychophysics and functional imaging studies, genetic variation in taste, and the hedonistic dimensions of odors. The approach is integrative, combining perspectives from neuroscience, psychology, anthropology, philosophy, and linguistics, and is appropriate for students and researchers in all of these areas who seek an authoritative reference on olfaction, taste, and cognition.
Peripheral nerves convey signals between the spinal cord and the rest of the body. Peripheral nerve injury (PNI) is a challenging problem with a variety of aetiologies and symptoms. Injuries can be classified into three categories: neurapraxia, axonotmesis and neurotmesis. Axonotmesis and neurotmesis result in Wallerian degeneration of the axons distal to the site of injury. After this process is complete, damaged neurons attempt to regenerate the damaged fibre with axonal budding. Successful axonal growth relies on an intact connective tissue tunnel and the requisite signalling molecules to allow the axon to re-grow in the correct direction and re-innervate the target tissue. Without this, the axons may form a painful neuroma. To differentiate between the different grades of nerve injury special tests can be utilized including neurophysiological investigation–nerve conduction studies and electromyography (EMG). Imaging the damaged nerve with ultrasound or MRI may be useful for diagnosis and surgical planning, however investigations should not delay referral to a nerve surgeon. The aim of surgical repair in nerve injury is to re-establish continuity between the connective tissue structures of the nerve; this allows axons to elongate across the site of injury to reach the target tissue. The simplest technique is tensionless end-to-end epineural repair. In injuries where this is impossible other surgical options include nerve grafting, nerve conduits or nerve transfer.
Schwann cells play a critical role in the development of the peripheral nervous system, establishing important relationships both with the extracellular milieu and other cell types, particularly neurons. In this review, we discuss various Schwann cell interactions integral to the proper establishment, spatial arrangement and function of the peripheral nervous system. We include signals that cascade onto Schwann cells from axons and from the extracellular matrix, bidirectional signals that help to establish the axo‐glial relationship and how Schwann cells in turn support the axon. Further, we speculate on how Schwann cell interactions with other components of the developing peripheral nervous system ultimately promote the complete construction of the peripheral nerve.
A highly regulated endoneurial microenvironment is required for normal axonal function in peripheral nerves and nerve roots, which structurally consist of an outer collagenous epineurium, inner perineurium consisting of multiple concentric layers of specialized epithelioid myofibroblasts that surround the innermost endoneurium, which consists of myelinated and unmyelinated axons embedded in a looser mesh of collagen fibers. Endoneurial homeostasis is achieved by tight junction-forming endoneurial microvessels that control ion, solute, water, nutrient, macromolecule and leukocyte influx and efflux between the bloodstream and endoneurium, and the innermost layers of the perineurium that control interstitial fluid component flux between the freely permeable epineurium and endoneurium. Strictly speaking, endoneurial microvascular endothelium should be considered the blood-nerve barrier (BNB) due to direct communication with circulating blood. The mammalian BNB is considered the second most restrictive vascular system after the blood-brain barrier (BBB) based on classic in situ permeability studies. Structural alterations in endoneurial microvessels or interactions with hematogenous leukocytes have been described in several human peripheral neuropathies; however major advances in BNB biology in health and disease have been limited over the past 50 years. Guided by transcriptome and proteome studies of normal and pathologic human peripheral nerves, purified primary and immortalized human endoneurial endothelial cells that form the BNB and leukocytes from patients with well-characterized peripheral neuropathies, validated by in situ or ex vivo protein expression studies, data are emerging on the molecular and functional characteristics of the human BNB in health and in specific peripheral neuropathies, as well as chronic neuropathic pain. These early advancements have the potential to not only increase our understanding of how the BNB works and adapts or fails to adapt to varying insult, but provide insights relevant to pathogenic leukocyte trafficking, with translational potential and specific therapeutic application for chronic peripheral neuropathies and neuropathic pain.
Peripheral nerves and nerve roots comprise of three structural compartments: the outer epineurium consisting of longitudinal arrays of collagen fibers responsible for structural integrity and the inner perineurium consisting of multiple concentric layers of specialized epithelioid myofibroblasts that surround the innermost endoneurium which consists of myelinated and unmyelinated axons embedded in a looser mesh of collagen fibers. Axons are responsible for signal transduction to and from the central nervous system required for normal physiological processes and are targeted by the immune system in autoimmune disorders. A highly regulated endoneurial microenvironment is required for normal axonal function. This is achieved by tight junction-forming endoneurial microvessels that control ion, solute, water, nutrient, macromolecule and leukocyte influx and efflux between the bloodstream and endoneurium, and the innermost layers of the perineurium that control interstitial fluid component flux between the epineurium and endoneurium. Endoneurial microvascular endothelium is considered the blood-nerve barrier (BNB) due to direct communication with circulating blood. The mammalian BNB is considered the second most restrictive vascular system after the blood-brain barrier (BBB). Guided by human in vitro studies using primary and immortalized endoneurial endothelial cells that form the BNB, in situ studies in normal and pathologic human peripheral nerves, and representative animal models of peripheral nerve autoimmune disorders, knowledge is emerging on human BNB molecular and functional characteristics, including its array of cytokines/cytokine receptors, selectins, and cellular adhesion and junctional complex molecules that may be employed during normal immune surveillance and altered in autoimmune diseases, providing potential targets of efficacious immunotherapy.
The aim of this study was to describe the results of a Brazilian Consensus on Small Fiber Neuropathy (SFN). Fifteen neurologists (members of the Brazilian Academy of Neurology) reviewed a preliminary draft. Eleven panelists got together in the city of Fortaleza to discuss and finish the text for the manuscript submission. Small fiber neuropathy can be defined as a subtype of neuropathy characterized by selective involvement of unmyelinated or thinly myelinated sensory fibers. Its clinical picture includes both negative and positive manifestations: sensory (pain/dysesthesias/pruritus) or combined sensory and autonomic complaints, associated with an almost entirely normal neurological examination. Standard electromyography is normal. A growing list of medical conditions is associated with SFN. The classification of SFN may also serve as a useful terminology to uncover minor discrepancies in the normal values from different neurophysiology laboratories. Several techniques may disclose sensory and/or autonomic impairment. Further studies are necessary to refine these techniques and develop specific therapies.
Introduction
Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS).
Aim
To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS.
Methods and materials
A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or ≥150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1–5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test.
Results
The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index.
Conclusions
Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (≥26) and pulse/heart rate (≥8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.
The biopsy of peripheral nerve has become an integral part of the diagnostic study of patients with disease of the peripheral nervous system (PNS). Nerve biopsy is a more sensitive indicator of peripheral neuropathy than electrodiagnostic studies, especially if the histologic assessment includes nerve-fiber teasing and morphometric analysis as well as light and electron microscopy.15
The histological study of muscle and peripheral nerve forms a major part of paediatric pathology because neuromuscular disorders are common problems. Modern histopathological techniques have led to greater understanding of these disorders and thus to a more rational approach to diagnosis and treatment. Naturally, new problems and controversies have also arisen.
Die Darstellung normal-anatomischer wie pathologisch-anatomischer Verhältnisse soll die für den Neurochirurgen relevanten Ergebnisse enthalten, soweit sie noch nicht in Lehr- oder Handbüchern wiedergegeben oder für das Verständnis der Dokumentation von Nerven Verletzungen und Nerventumoren, den beiden Hauptkapiteln dieses Beitrags, notwendig sind.
Clinical review of 33 patients with acquired predominantly sensory neuropathy defined by electrodiagnostic and clinical findings showed a igh female predominance (76%). Characteristically the neuropathy was asymmetric at onset (73%), evolved in a subacute (45%) or chronic fashion (40%), and started with upper extremity pain (67%). Ataxia (52%) and Adie’s pupils (18%) also seemed characteristic of this neuropathy. In 16 patients (48%) underlying causes such as cancer (12%), connective tissue disorders (9%), drug-induced (9%), and others (18%) were identified, but no etiology was determined in the rest of the patients (52%). Nonspecific serum and CSF immunological abnormalities were common (55%), suggesting underlying immune-mediated disorders in some patients. Electrodiagnostic studies suggested that sensory neuropathy was mainly an axon-loss disorder. The upper extremity preponderance and the asymmetric involvement were confirmed electrodiagnostically in some patients. Nerve biopsies showed scattered acute axonal degeneration and severe loss of myelinated fibers but well-preserved unmyelinated fibers. Corticosteroid or other immunotherapy was not beneficial in most patients treated. In all but two patients, the neuropathy was either progressive or unimproved over an average of 6.2 years of follow-up.
This is an update on aspects of structure, function and pathology of the primary sensory unit in man, emphasizing concepts which form the basis for understanding a) rationales of new physiological clinical tests and b) the nature of neuropathic sensory syndromes of recent recognition.
Cutaneous pinprick testing is a routine medical procedure with applications in family practice, diabetes, neurology, oncology, anesthesiology and ER. In particular it has ramifications for the prognosis of conditions associated with gross morbidity whose pathophysiology is dominated by small nerve fiber destruction. The pinprick deficit produced by such small fiber population loss is commonly reported to precede that of light touch and it is hypothesized, where appropriately discernible, may reflect the development of clinically critical thresholds of neuropathy not revealed by testing with other modalities. However, demonstration of so critical a development is problematic in it’s early stages and this presentation represents part of a larger peer reviewed effort to address issues of clinical efficacy and infection control.
Anesthesiology has followed the general specialty of geriatrics in developing a wealth of information that can be brought to bear on the care of elderly surgical patients. This chapter provides an overview of some of the issues associated with anesthetic care of the elderly. Interested readers are referred to a number of recent publications that expand greatly on the knowledge presented here.
The histological study of muscle and peripheral nerve forms a major part of paediatric pathology since neuromuscular disorders are common problems. Modern histopathological techniques have led to greater understanding of these disorders and thus to a more rational and hopeful approach to diagnosis and treatment. Naturally, new problems and controversies have also arisen.
The development of new techniques for the histological study of muscle and peripheral nerve has led to fresh concepts of the pathogenesis and classification of these disorders, and to a more rational and hopeful approach to both diagnosis and treatment. Naturally, new problems and controversies have also arisen.
This chapter reviews the current concepts regarding the connective tissue matrix of the vertebrate peripheral nervous system. The highly vulnerable neural parenchyma is isolated from adjacent tissues by membranous coverings that surround the nervous system. The meninges in the central nervous system and the peripheral sheaths function as biological barriers that maintain the physiological environment and prevent the invasion of the nervous parenchyma by pathogenic agents. Peripheral nerves contain small amounts of glycosaminoglycans, the only two detected in human femoral nerves being dermatan sulfate and heparitin sulfate. Although mature elastic fibers are not present in nerves, elastic-related fibers are frequently observed. The oxytalan fibers are mainly found in the endo- and perineurium whereas the elaunin fibers predominate in the epineurium. Structurally distinct collagen types are also segregated into different compartments of the nerve: Collagen type III is found mainly in the endo- and perineurium whereas collagen type I predominates in the epineurium. The structure of the epi-, peri-, and endoneurium is consistent with the different roles that the supporting connective tissue plays in each of these nerve compartments.
Skin plays a variety of important roles including sensory, thermoregulatory and host defense, etc, which are essential in protecting the inside human body. However, in extreme environment, uncomfortable feeling or pain sensation is evocated due to extreme hot or cold. Obviously, skin fails in protecting the human body when the temperature is out of normal physiological range. Furthermore, in medicine, with advances in electromagnetic technologies such as laser and microwave, various thermal therapeutic methods have been widely used to cure disease/injury involving skin tissue. The associated problem of pain relief has nonetheless limited the further application and development of these thermal treatments.
As an aid in the interpretation of the physiological properties of unmedullated nerve fibers, particularly those having their cells of origin in the dorsal root ganglia, more precise information about their morphology has been acquired through employment of the electron microscope.
The appearance of the fibers in the skin nerves is described, with special reference to the structure of their sheaths; and a notation is made about the bearing of the axon-sheath relationship on the biophysical mechanism of conduction (p. 714).
There is no basic difference between the sheath systems of the d.r.C and the s.C fibers.
Attention is called to a point of similarity between the sheaths of unmyelinated and myelinated axons (p. 715).
An assessment was made of the likelihood of interaction between the fibers. In action potentials showing temporal dispersion at several distances, the elevations appeared in their calculated positions. A model of a group of Schwann sheaths was constructed from successive electron microscope sections, showing that the lengths of the sheath branches are short in comparison with the wave lengths of the action potentials. Supported by these and other considerations, the argument is strongly in favor of the conclusion that among d.r.C fibers, as in other fibers, there is no cross-excitation between the axons.
A new analysis of the size distribution of the fibers in a sural nerve was made from electron microscope pictures; and from the measurements the action potential was constructed. The result confirmed the view, previously expressed, that the velocities of conduction in the fibers can be precisely accounted for by multiplying the diameters by a constant.
In the dorsal roots, the striking change that takes place in the appearance of the fibers and their disposition in the Schwann sheaths can be seen in Fig. 11. The axons partake of the special properties of the peripheral branches, which necessitated the creation of the subdivision of d.r.C fibers. But, their diameters are much smaller. At a set of reduced conduction velocities the configuration of the compound action potential in the nerves is repeated in the roots, with the root velocities still conforming to the size-velocity rule derived from nerve axons.
Nerve fiber populations of the vagus and sciatic nerves of mice were classified according to the number of myelin lamellae present in the sheaths. This method for classifying fiber populations was superior to others used previously since it provided a more sensitive procedure for the analysis of individual fibers and better control over the technical factors involved in tissue processing.
The relationship of the number of myelin lamellae in the sheath to axon circumference was found to be linear. In fresh tissue there was one myelin lamella for every 0.24 μ increase in axon circumference above da value of 2.32 μ (the mean circumference of an average-sized nonmyelinated fiber). A formula was proposed which may be useful for understanding how axons control myelin development and interpreting developmental stages, as well as for evaluating pathologic conditions affecting the peripheral nervous system.
The critical diameter above which fibers were found to be myelinated was about 0.8 μ for fixed nerve and 1.1 μ for fresh nerve. The ratio of axon diameter to fiber diameter ranged between 0.5 and 0.9 and was not related to fiber size.
A technique for staining sections of osmium-fixed, epoxy-embedded tissues for light microscopy is presented. The method employs aqueous toluidine blue at pH 11.1 and does not require prior removal of embedding medium.When stained with this technique and viewed with an oil immersion objective, the images are striking because of their great definition and resemblance to the images are striking because of their great definition and resemblance to of areas seen in the electron microscope; it also permits better utilization of the full resolving power of the light microscope.
The Schwann cells of the sciatic nerve and brachial plexuses of four human fetuses aged 12, 14, 16, and 22 weeks of intrauterine life, were studied with the electron microscope. Four stages were recognized in the development of these cells: (a) pseudosyncytial, (b) migration, (c) division of cells and separation of axons, and (d) myelination.During all stages of development of human peripheral nerves, Schwann cells seem to have, as a morphological and perhaps physiological function, the isolation of axons from the surrounding connective tissue elements. During the intermediate stages of development, the main function of Schwann cells appears to be the separation of the axon bundles into smaller and smaller bundles, until one single axon has been finally separated from a bundle. This is accomplished by the continued division of the Schwann cells. After axon isolation has been accomplished, the function of the Schwann cells is myelination (14–16 weeks). All axons, either isolated or in bundles, had a complete or almost complete envelope of Schwann cell cytoplasm. At all stages of development a basement membrane separated the Schwann cell axon complexes from the surrounding mesenchymal tissues.It was suggested that the continual formation of cytoplasmic processes and division of the Schwann cells may be determined, at least in part, by the intimate contact of these cells with progressively enlarging axons.
The fine structure and morphological organization of non-myelinated nerve fibres were studied by ultra-thin sectioning and electron microscopy in peripheral nerves, autonomic nerves and dorsal roots. Several non-myelinated fibres share the cytoplasm of a Schwann cell. The Schwann cells of non-myelinated fibres form a syncytium. The fibres are incompletely surrounded by Schwann cell cytoplasm and are suspended in the cytoplasm by mesaxons formed by the plasma membranes of the Schwann cell. The various relationships of mesaxon and nerve fibre are described. Non-myelinated fibres which do not share a Schwann cell are seen very frequently in the sciatic nerve of a new-born mouse but become less common as myelination proceeds and are rare in adults. It is therefore suggested that in developing peripheral nerves, the non-myelinated fibres that are destined to myelinate are not organized into groups within a single Schwann cell, even before their myelin sheath has appeared; they are, at least for the ages examined here, individuals in relation to a surrounding individual Schwann cell. It is also suggested that the non-myelinated fibres that will never acquire a myelin sheath are organized in a developing peripheral nerve in the same manner as in the adult nerve--several fibres sharing a single Schwann cell that is part of a syncytial system of Schwann cells. Thus, in a developing peripheral nerve, it appears that two types of non-myelinated fibres are present--one destined to myelinate and lying alone in its own Schwann cell and the other, destined to remain unmyelinated and sharing, along with other non-myelinated fibres of the same type, a Schwann cell. The significance of these observations is discussed in relation to the development of nerve fibres and possible physiological importance.
1. Filaments were dissected from the aortic nerve of cats and impulses recorded monophasically in vivo .
2. The temporal characteristics of impulses of non‐medullated fibres were compared with those of medullated fibres with conduction velocities between 4·5 and 12 m/sec. There were no obvious qualitative differences between the two types of fibres and they appeared to belong to a homogeneous sample.
3. In non‐medullated fibres the rise time, fall time and absolute refractory period varied inversely with conduction velocity, the relation being similar to that in the medullated fibres. There was practically no difference between the temporal characteristics of the fastest non‐medullated fibres and those of the slowest medullated fibres, a result which might throw light on the question why fibres below 1 μ in diameter are not medullated.
4. The mean blocking temperature of sixteen non‐medullated fibres was 4·3° C, a value that was significantly different from the mean blocking temperature of sixteen medullated fibres (6·5° C).
Fisher: Number, size and myelination of the sensory fibres in the cerebrospinal nerves. In Sensation, its mechanisms and disturbances
- S W Ranson
- W H Droegenmueller
- H K Davenport
Vial: Behaviour of the peripheral nerve structures in chronic neuropathies with special reference to the Schwann cell
- J Ochoa
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