Novel clinical treatments to target peripheral nerves are being developed which primarily use electrical current. Recently, infrared (IR) light was shown to inhibit peripheral nerves with high spatial and temporal specificity. Here, for the first time, we demonstrate that IR can selectively and reversibly inhibit small-diameter axons at lower radiant exposures than large-diameter axons. We provide a mathematical rationale, and then demonstrate it experimentally in individual axons of identified neurons in the marine mollusk Aplysia californica, and in axons within the vagus nerve of a mammal, the musk shrew Suncus murinus. The ability to selectively, rapidly, and reversibly control small-diameter sensory fibers may have many applications, both for the analysis of physiology, and for treating diseases of the peripheral nervous system, such as chronic nausea, vomiting, pain, and hypertension. Moreover, the mathematical analysis of how IR affects the nerve could apply to other techniques for controlling peripheral nerve signaling.

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. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

. 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.

Objective. Infrared neural inhibition (INI) is a method of blocking the generation or propagation of neural action potentials through laser heating with wavelengths strongly absorbed by water. Recent work has identified that the distance heated along axons, the block length (BL), modulates the temperature needed for inhibition; however, this relationship has not been characterized. This study explores how BL during INI can be optimized towards minimizing its temperature threshold. Approach. To understand the relationship between BL and the temperature required for INI, excised nerves from Aplysia californica were laser-heated over different lengths of axon during electrical stimulation of compound action potentials. INI was provided by irradiation (λ = 1470 nm) from a custom probe (n = 6 nerves), and subsequent validation was performed by providing heat block using perfused hot media over nerves (n = 5 nerves). Main Results. Two BL regimes were identified. Short BLs (thermal full width at half maximum (tFWHM) = 0.81–1.13 mm) demonstrated that increasing the tFWHM resulted in lower temperature thresholds for INI (p < 0.0125), while longer BLs (tFWHM = 1.13–3.03 mm) showed no significant change between the temperature threshold and tFWHM (p > 0.0125). Validation of this longer regime was performed using perfused hot media over different lengths of nerves. This secondary heating method similarly showed no significant change (p > 0.025) in the temperature threshold (tFWHM = 1.25–4.42 mm). Significance. This work characterized how the temperature threshold for neural heat block varies with BL and identified an optimal BL around tFWHM = 1.13 mm which minimizes both the maximum temperature applied to tissue and the volume of tissue heated during INI. Understanding how to optimally target lengths of nerve to minimize temperature during INI can help inform the design of devices for longitudinal animal studies and human implementation.

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New tools for monitoring and manipulating neural activity have been developed with steadily improving functionality, specificity, and reliability, which are critical both for mapping neural circuits and treating neurological diseases. This review focuses on the use of an invertebrate animal, the marine mollusk Aplysia californica, in the development of novel neurotechniques. We review the basic physiological properties of Aplysia neurons and discuss the specific aspects that make it advantageous for developing novel neural interfaces: First, Aplysia nerves consist only of unmyelinated axons with various diameters, providing a particularly useful model of the unmyelinated C fibers in vertebrates that are known to carry important sensory information, including those that signal pain. Second, Aplysia’s neural tissues can last for a long period in an ex vivo experimental setup. This allows comprehensive tests such as the exploration of parameter space on the same nerve to avoid variability between animals and minimize animal use. Third, nerves in large Aplysia can be many centimeters in length, making it possible to easily discriminate axons with different diameters based on their conduction velocities. Aplysia nerves are a particularly good approximation of the unmyelinated C fibers, which are hard to stimulate, record, and differentiate from other nerve fibers in vertebrate animal models using epineural electrodes. Fourth, neurons in Aplysia are large, uniquely identifiable, and electrically compact. For decades, researchers have used Aplysia for the development of many novel neurotechnologies. Examples include high-frequency alternating current (HFAC), focused ultrasound (FUS), optical neural stimulation, recording, and inhibition, microelectrode arrays, diamond electrodes, carbon fiber microelectrodes, microscopic magnetic stimulation and magnetic resonance electrical impedance tomography (MREIT). We also review a specific example that illustrates the power of Aplysia for accelerating technology development: selective infrared neural inhibition of small-diameter unmyelinated axons, which may lead to a translationally useful treatment in the future. Generally, Aplysia is suitable for testing modalities whose mechanism involves basic biophysics that is likely to be similar across species. As a tractable experimental system, Aplysia californica can help the rapid development of novel neuromodulation technologies.

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