Role of Mechanoinsensitive Nociceptors in Painful Diabetic Peripheral Neuropathy

: The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity and the patients exhibit significantly increased pain thresholds to acute pain, when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because in these patients CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH and CMi fibers allow to identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.

A Loop System along Skin with Transmitted Pilomotor Line for Vibrating Regulation of whole Body Function

In Chinese traditional medicine (CTM), meridians are described as a set of linear and longitudinal pathways along body skin. Acupuncture at acupoints provoke signals that transmit along the pathway and arrive to focal organs, which can treat more than one hundred of diseases. The pathway has been proved by modern anatomical and physiological researches. Linear structure and activity: There exist a loop system along body skin, consisted of a complex of sympathetic-arrector pili muscles (AP muscles) and concentrated mast cells in the rats. Along certain skin pathway, abundant sympathetic endings distribute within the AP muscles, which are appeared as sympathetic-substance lines (SSL) by macro-autoradiography. Under the line, mast cells are densely distributed. After shaving rat’s hairs, the new hairs firstly grow along some lines and loops, called hair-loop-lines (HLL). Acupuncture or injection of α receptor agonist at an acupoint produce a pilomotor line and simulate strong acupuncture effect, accompanying with neurogenic inflammation along the line in the rats. These three lines are coincident each other. The pilomotor line can be blocked by local injecting of α receptor antagonist, by crosscutting off skin or by applying procaine along the line, or by peritoneal injecting of cromoglicate. All these suggest that the pilomotor line along the SSL is the pathway for transmitting acupuncture signals independently and then producing acupuncture effect. Mechanism of linear transmission: The local piloerection stimulates the nerve nets of sympathetic endings and low threshold mechanical sensitive C-fibers around the hair follicles, whose excitation transmit to adjacent hair follicles by cross innervation and provoke new piloerection and neurosecretion respectively by axon reflex. Excited peripherical endings of C-fibers release neuropeptides (SP and CGRP) that stimulate mast cell degranulation. The released histamine stimulates C-fibers to produce gentle itch and further release of neuropeptides from C-fibers. Moreover, histamine stimulates AP muscle contraction. Thus, a positive feedback loop along hair follicles—C-fibers—mast cells is initiated and the pilomotor is enhanced and transmitted, accompanying histamine-mediated inflammation and sensation. The diffusion of released NA and histamine to adjacent skin also play important role in the transmission. Both axon reflex and diffusing action are united to cooperation for chain transmission of acupuncture signals. Mechanism of acupuncture effect: The acupuncture effect does not unidirectionally increase or decrease, but oscillate periodically, with about 28 min per circle. It is assumed that acupuncture leads the whole-body function change undulately and every organ in the body finds their own balance point through vibration. Therefore, acupuncture is auto-regulation, bi-regulation and vibrating regulation. The vibration is assumed by periodically excited and inhibited afferent signals from pilomotor line that lead periodical oscillation of whole CNS and the following oscillation of whole-body function.As a sum, under the guidance of CTM, a novel and unknown linear system hidden along skin have been discovered, which play an important role in the horizontal and integrative regulation on whole-body function, as expected in the integrative physiology. Importantly, there is a new type of mechanical transmission of signal.

Evaluation of sweating responses in patients with collagen disease using the quantitative sudomotor axon reflex test (QSART): a study protocol for an investigator-initiated, prospective, observational clinical study

IntroductionSweat secretion is controlled by the sympathetic nervous system and is less active during winter than in the summer. Raynaud’s phenomenon is affected by an excessive strain of the sympathetic nerves after exposure to a cold environment, thus reducing the quality of life of patients with collagen disease. Herein, we focus on the eccrine sweat glands that receive both adrenergic and cholinergic innervation. Our hypothesis is that excessive activation of sympathetic nerve in Raynaud’s phenomenon can affect sweating, especially in winter. This study is designed to evaluate the neuroactive sweating responses in patients with collagen disease and to assess its association with skin findings in peripheral circulatory disorders.Methods and analysisThe study will be conducted at a single centre in Japan. Patients with systemic sclerosis, Sjogren’s syndrome, systemic lupus erythematosus, mixed connective tissue disease, and dermatomyositis will be assessed using the quantitative sudomotor axon reflex test. The primary outcomes will be sweat volume and reaction time due to axon reflex and the Raynaud’s condition score. The secondary outcomes will include patient background, skin symptoms (digital ulcers, pernio-like eruptions, subcutaneous calcifications, telangiectasia, nailfold capillary dilatation/bleeding and degree of skin sclerosis) and skin surface temperature. Evaluation will be done two times, during the summer and winter, allowing for the assessment of seasonal differences in sweating responses.Ethics and disseminationEthical approval of this study was certified by the clinical research review board of Nagasaki University Hospital (Reference number: CRB19-001). We will disseminate the findings of this study through peer-reviewed publications and conference presentations.Trial registration numberjRCTs072190009; pre-results.

Influence of Migraine on Axon Reflex-Mediated and Endothelial-Dependent Vasodilatation in the Skin

The aim of the study was to evaluate the changes in skin blood flow as a result of local heating tests in migraine patients during the interictal period, measured by laser Doppler perfusion imaging (LDI). The aim of the study was also to estimate the correlations between the results of these tests and interleukin (IL)-8 levels. Twelve migraine patients during their interictal period were compared with twelve healthy control subjects. Only women were included in the study. Both groups were matched with regard of their age, body mass index and blood pressure. For the purpose of measuring cutaneous microvascular blood flow, heating (+44 °C) of the dorsal side of the palm as a response to the local LDI was used. IL-8 was measured in serum by ELISA method. The findings suggested that migraine patients have a cutaneous vasomotor dysfunction during the interictal period. The results showed a significant decrease in the initial peak of vasodilation and the second peak of vasodilation (plateau phase). Also there were significant changes observed in the length of the time interval required to reach the first and second vasodilation peak. It is known that migraine patients have a shorter time interval to reach the first perfusion peak (axonal reflex-mediated) and longer time interval to reach the second peak (endothelium-dependent). The results confirmed the correlation between proinflammatory chemokine IL-8 levels, and the time interval till the second peak of blood flow in all study subjects.

Postganglionic Sudomotor Dysfunction and Brain Glucose Hypometabolism in Patients with Multiple System Atrophy

Background: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. Objective: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. Methods: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. Results: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (β= 1.185, p = 0.013) and Part II (β= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. Conclusion: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study

Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.

Sudomotor Dysfunction

Disorders of sudomotor function are common and diverse in their presentations. Hyperhidrosis or hypohidrosis in generalized or regional neuroanatomical patterns can provide clues to neurologic localization and inform neurologic diagnosis. Conditions that impair sudomotor function include small fiber peripheral neuropathy, sudomotor neuropathy, myelopathy, α-synucleinopathies, autoimmune autonomic ganglionopathy, antibody-mediated hyperexcitability syndromes, and a host of medications. Particularly relevant to neurologic practice is the detection of postganglionic sudomotor deficits as a diagnostic marker of small fiber neuropathies. Extensive anhidrosis is important to recognize, as it not only correlates with symptoms of heat intolerance but may also place the patient at risk for heat stroke when under conditions of heat stress. Methods for assessing sudomotor dysfunction include the thermoregulatory sweat test, the quantitative sudomotor axon reflex test, silicone impressions, and the sympathetic skin response.

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson’s disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.