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

Abstract

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.

Remote Photoplethysmography for Evaluation of Cutaneous Sensory Nerve Fiber Function

“…Laser Doppler studies suggest that during topical skin heating cutaneous hyperemia occurs [ 45 ], characterized by an initial peak within the first 5–6 min and a subsequent nadir followed by a sustained plateau [ 43 ]. Laser Doppler Imaging studies suggest that the peak is caused by an axon reflex, mediated by TRPV1 channel dependent activation of C-fiber afferent neurons that release substance P and calcitonin gene-related peptide (GCRP), with a modest contribution of NO [ 46 ] and may reflect both endothelial and small nerve fiber function [ 47 , 48 ]. That can explain the observation that EMLA treated skin exhibited a diminished initial peak, nadir and duration of initial peak, but not plato phase during the heat-induced vasomotor response.…”

“…Another marker of cutaneous nerve fiber functions assessed in our study is the so-called vasomotor flare response, which manifests as the reddening of the skin outside the directly heated skin region. The evaluation of flare response as a parameter of vasomotor reactivity is widely used in different studies on cutaneous vasculature, using different provocation factors [ 48 ], such as Ach iontophoresis, electrical stimulation and topical skin heating; however, these studies mostly use Laser Doppler techniques (flowmetry or imaging) and cannot be directly attributed to photoplethysmographic data, as these techniques have different principles. The principle LDI is well defined, representing frequency change that light undergoes when reflected by red blood cells, thus output value is determined by flux-product of red blood cell linear velocity and concentration [ 52 ].…”

“…Alongside provocation tests, which through selective stimulus can trigger blood perfusion response attributed to the particular physiological mechanism, another approach is the assessment of circulatory function in the baseline using so-called flowmotions [ 61 ]. Flowmotions are rhythmic oscillations in blood flow, to date widely assessed by Laser Doppler flowmetry, hence there are few studies reporting the use of contact manner reflection photoplethysmography [ 18 , 48 , 62 ]. The current exact genesis of these oscillations is unknown, but existing studies suggest the local origin as the dynamic interaction of sympathetic vasoconstriction, pressure-dependent vasoconstriction, flow-dependent endothelium-mediated vasodilation, metabolic vasodilation, and spontaneous myogenic activity [ 63 ].…”

Clinical diagnosis and management of small fiber neuropathy: an update on best practice

“…The axon-reflex generated in cutaneous nerve fibers induces the release of vasoactive substances mediating a vasodilatory response into a skin area adjacent to the area of stimulation [114]. Vasogenic and neurogenic responses can be differentiated temporally and topographically [115]. Patients with SFN showed reduced or absence of skin flare areas [38,111].…”

The physiological study of emotional piloerection: A literature review and guide for future research

“…There is also some evidence of parasympathetic fibres (Donadio et al, 2019). Only a few experimental studies have been published showing deliberate induction of piloerection via direct sympathetic nerve activation (e.g., Hijazi et al, 2020). Muscarinic receptors are responsible for controlling many parasympathetic functionsthe "rest and digest" bodily functions-and many of these functions oppose the sympathetic nervous system.…”