Small and large cutaneous fibers display different excitability properties to slowly increasing ramp pulses

Abstract

The excitability of large nerve fibers is reduced when their membrane potential is slowly depolarizing, i.e. the fibers display accommodation. The aim of this study was to assess accommodation in small (mainly Aδ) and large (Aβ) cutaneous sensory nerve fibers using the perception threshold tracking (PTT) technique. Linearly increasing ramp currents (1 ms -200 ms) were used to assess the excitability of the nerve fibers by cutaneous electrical stimulation. To investigate the PPT technique's ability to preferentially activate different fiber types, topical application of lidocaine/prilocaine (EMLA) or a placebo cream was applied. By means of computational modelling, the underlying mechanisms governing the perception threshold in the two fiber types was studied. The axon models included the voltage-gated ion channels: NaTTXs, NaTTXr, NaP, KDr, KM, and HCN. Large fibers displayed accommodation, whereas small fibers did not display accommodation (p<0.05). For the pin electrode, a significant interaction was observed between cream (EMLA or placebo) and pulse duration (p<0.05) whereas for the patch electrode, there was no significant interaction between cream and duration which supports the pin electrode's preferential activation of small fibers. The results from the computational model suggested that differences in accommodation between the two fiber types may originate from selective expression of voltage-gated ion channels, particularly the transient NaTTXr and/or KDr. e PTT technique could assess the excitability changes during accommodation in different nerve fibers. Therefore, the PTT technique may be a useful tool for studying excitability in nerve fibers both in healthy as well as in pathological conditions.

Measuring pain and nociception: Through the glasses of a computational scientist. Transdisciplinary overview of methods

“…So far, the only electrical stimulation paradigm that correlates with ongoing pain in patients with neuropathic pain is a lack of adaptation to sine wave stimulation of 1 min duration with 4 Hz (Jonas et al, 2018). The optimal stimulus to activate so called mechanosensitive C-fibers, which are thought to transmit the discriminative aspects of acute nociceptive and painful stimuli, is a slowly depolarizing ramp such as a 500 ms long half sine wave (Rukwied et al, 2020;Tigerholm et al, 2020). Electrical stimulation has also been used to induce hyperalgesia (increased pain sensation to a slightly painful stimulus), allodynia (painful sensation upon nonpainful stimulation), and central sensitization (sensitization in central nervous system) as human surrogate models of hyperalgesia (Koppert et al, 2001;Vo and Drummond 2013;Klein et al, 2004).…”

Perception threshold tracking: validating a novel method for assessing function of large and small sensory nerve fibers in diabetic peripheral neuropathy with and without pain

“…To test whether the method indeed did activate the small and large nerve fibers individually, we also measured accommodation (the ability to adapt to a slowly rising pulse by increasing the excitation threshold for increasing pulse widths). 10,39 This was done because previous studies have shown that probable differences in ion-channel composition of large and small nerve fibers result in different accommodation properties, where large fibers accommodate while small fibers do not. 39,40 This was done by applying a 100-millisecond ramp-shaped electrical impulse, that would cause accommodation in the large sensory nerve fibers.…”

“…10,39 This was done because previous studies have shown that probable differences in ion-channel composition of large and small nerve fibers result in different accommodation properties, where large fibers accommodate while small fibers do not. 39,40 This was done by applying a 100-millisecond ramp-shaped electrical impulse, that would cause accommodation in the large sensory nerve fibers. 17 Accommodation is caused by the transient voltagegated sodium channels becoming refractory and thus increased the excitation threshold of these fibers.…”

“…25,40 The method has been validated in several studies in healthy individuals but is yet to be validated in a large clinical setting of people with painful and nonpainful neuropathy. 11,23,39 The aims of this study were (1) to validate if perception threshold tracking can distinguish between different groups with and without DPN and (2) to distinguish between people with and without painful diabetic neuropathy (PDPN).…”

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET)

“…IMI2-PainCare-BioPain-RCT1 will thus focus on biomarkers derived from peripheral nerve excitability testing (NET) [ 3 – 6 ]. The objective is to assess the effect of lacosamide, pregabalin, and tapentadol on large and small sensory and motor fibers using threshold tracking [ 3 – 7 ]. The assessment of small sensory afferents will be done using perception threshold tracking and will be done on both normal skin and in an area of sensitization using high-frequency electrical stimulation (HFS) on the skin, which causes sustained and reversible hyperalgesia due to sensitization [ 8 , 9 ].…”