Current methods to treat pain have several limitations (e.g., addiction, limited efficacy, etc.) and new options are sorely needed. Photobiomodulation (PBM) at 808 nm has been shown to reduce small fiber axon sensitivities in both human and animal models when applied for the purposes of action potential block. A study using a pulsed light dosing scheme was conducted to determine the viability of using commercially available IPGs for a potential implanted system. Results showed a reduction in pain lasting about 8 days, indicating that this method of delivery has promise for an implanted system.
Previous meta-analyses of photobiomodulation (PBM) parameters have reported correlations between effect size and emitter parameters, but the trends are not robust enough to prospectively predict doses that will yield a significant effect. A meta-analysis of PBM dosing protocols on peripheral nerves with 800 – 840 nm wavelength light was performed using Monte Carlo photon propagation models to elucidate clearer trends between dose and effect. We then tested various doses of PBM applied directly at exposed hindlimb nerve in a rodent pain model. A single application of PBM at the nerve reduced pain associated with heat-sensitive fibers for approximately 7 days.
Infrared (IR) inhibition can induce selective heat block on small-diameter axons. We hypothesize that the selective IR inhibition effect can be reproduced by resistance heating via a heating cuff. We tested the hypothesis in vitro on the pleural-abdominal connective of Aplysia californica. The IR optical fiber, heating cuff, and a thermocouple were co-located to ensure both heating modalities induced a similar temperature increase on the nerve. Electrically stimulated compound action potentials were recorded and segmented to characterize the inhibition effect on different axonal subgroups. The dose-response curve showed that resistance heating can reproduce the selective IR inhibition effect.
Significance: Infrared (IR) inhibition can selectively block peripheral sensory nerve fibers, a potential treatment for autonomic-dysfunction-related diseases (e.g., neuropathic pain and interstitial cystitis). Lowering the IR inhibition threshold can increase its translational potentials.
Aim: Infrared induces inhibition by enhancing potassium channel activation. We hypothesized that the IR dose threshold could be reduced by combining it with isotonic ion replacement.
Approach: We tested the IR inhibition threshold on the pleural-abdominal connective of Aplysia californica. Using a customized chamber system, the IR inhibition was applied either in normal saline or in isotonic ion-replaced saline, which could be high glucose saline, high choline saline, or high glucose/high choline saline. Each modified saline was at a subthreshold concentration for inhibiting neural conduction.
Results: We showed that isotonically replacing ions in saline with glucose and/or choline can reduce the IR threshold and temperature threshold of neural inhibition. Furthermore, the size selectivity of IR inhibition was preserved when combined with high glucose/high choline saline.
Conclusions: The present work of IR inhibition combined with isotonic ion replacement will guide further development of a more effective size-selective IR inhibition modality for future research and translational applications.
Infrared neural inhibition (INI) is a relatively new modality of neural control which has potential as a novel pain therapy due to its high spatial specificity and selective inhibition of small diameter neurons at lower temperatures. Computational modeling using a modified Hodgkin-Huxley model in the squid giant axon has shown that temperature sensitive potassium currents mediate INI’s thermal block. This model was modified to reflect Aplysia parameters which have smaller unmyelinated axons on the order of mammalian C fibers, and simulated results were validated in vitro. Results support he hypothesis that potassium currents are needed to create a thermal block.
Thermal block of unmyelinated axons may serve as a modality for control, suggesting a means for providing therapies for pain. Computational modeling predicted that potassium channels are necessary for mediating thermal block of propagating compound action potentials (CAPs) with infrared (IR) light. Our study tests that hypothesis. Results suggest that potassium channel blockers disrupt the ability of IR to block propagating CAPs in Aplysia californica nerves, whereas sodium channel blockers appear to have no significant effect. These observations validate the modeling results and suggest potential applications of thermal block to many other unmyelinated axons.
Neuromodulation has the potential to treat various diseases (i.e., heart failure, obesity). Several clinical trials have recently failed because of the inability to modulate small-diameter fibers. Previously, we demonstrated preferential inhibition of small-diameter fibers using infrared neuromodulation (IRN). To understand the mechanism of action, we did a mathematical analysis which suggested that any modality acting primarily on the axonal surface would preferentially affect small-diameter axons. To test our hypothesis, we examined whether isotonic glucose solution would give results similar to IRN.
We stimulated the left and right pleural-abdominal connective nerves of Aplysia californica and recorded the resulting compound action potentials (CAPs). We designed a chamber with three isolated compartments through which the nerve passes sequentially. Aplysia saline is perfused in the two outer chambers while the middle chamber can be perfused with either Aplysia saline or an isotonic glucose solution (10.21 w/v %). The width of the middle chamber is adjustable to vary the length of nerve perfused by the isotonic glucose solution. As the length of the middle chamber increases, recorded CAPs are initially unaffected, then show a loss of peaks representing small-diameter axons, then show no activity. We can restore full, unchanged CAPs by washing out the glucose solution and replacing it with Aplysia saline. These results support the hypothesis that any modality (e.g., both IRN and isotonic glucose solution) acting primarily on the axonal surface would preferentially affect small-diameter axons. Future studies will compare IRN with isotonic glucose block.
Many techniques may modulate peripheral nerve activity. Infrared light (IR) can excite or inhibit nerves. Compound action potentials (CAPs) are often measured as an endpoint, focusing on complete block, or overall amplitude reduction. To our knowledge, no standard techniques determine whether CAP sub-components have been modulated. Treatments may alter timing of CAP components as well as blocking them. How can these be distinguished?
We developed a numerical simulation in which extracellularly recorded action potentials were summed, assuming a Gaussian distribution for their onset time. Onset time for sub-populations was delayed (shifting), or amplitudes were reduced to zero (blocking). We demonstrated that area under the rectified curve, divided by the entire duration of the CAP, provided a more stable measure of change than other options (e.g., power). Regions must be selected such that the CAP’s individual components do not shift out of the analysis window. The largest reductions in area under the curve due to shifts were ~55% due to destructive interference, which is likely to be much larger than typically observed experimentally. In contrast, blocking components could reduce the area under the curve to zero.
The analysis was applied to sequential nerve stimulations. At every point, variance of the normalized area was computed. Choosing regions of lowest variance across stimulations defined an objective criterion for boundaries between CAP subcomponents. Analysis was applied to IR effects on CAPs recorded in the pleural-abdominal connective of Aplysia californica and musk shrew vagus. Slower conducting CAP subcomponents were selectively blocked before faster subcomponents.
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