Identifying the Role of Block Length in Neural Heat Block to Reduce Temperatures During Infrared Neural Inhibition

Abstract

Background and Objectives The objective of this study is to assess the hypothesis that the length of axon heated, defined here as block length (BL), affects the temperature required for thermal inhibition of action potential propagation applied using laser heating. The presence of such a phenomenon has implications for how this technique, called infrared neural inhibition (INI), may be applied in a clinically safe manner since it suggests that temperatures required for therapy may be reduced through the proper spatial application of light. Here, we validate the presence of this phenomenon by assessing how the peak temperatures during INI are reduced when two different BLs are applied using irradiation from either one or two adjacent optical fibers. Study Design/Materials and Methods Assessment of the role of BL was carried out over two phases. First, a computational proof of concept was performed in the neural conduction simulation environment, NEURON, simulating the response of action potentials to increased temperatures applied at different full‐width at half‐maxima (FWHM) along axons. Second, ex vivo validation of these predictions was performed by measuring the radiant exposure, peak temperature rise, and FWHM of heat distributions associated with INI from one or two adjacent optical fibers. Electrophysiological assessment of radiant exposures at inhibition threshold were carried out in ex vivo Aplysia californica (sea slug) pleural abdominal nerves ( n = 6), an invertebrate with unmyelinated axons. Measurement of the maximum temperature rise required for induced heat block was performed in a water bath using a fine wire thermocouple. Finally, magnetic resonance thermometry (MRT) was performed on a nerve immersed in saline to assess the elevated temperature distribution at these radiant exposures. Results Computational modeling in NEURON provided a theoretical proof of concept that the BL is an important factor contributing to the peak temperature required during neural heat block, predicting a 11.7% reduction in temperature rise when the FWHM along an axon is increased by 42.9%. Experimental validation showed that, when using two adjacent fibers instead of one, a 38.5 ± 2.2% (mean ± standard error of the mean) reduction in radiant exposure per pulse per fiber threshold at the fiber output (P = 7.3E−6) is measured, resulting in a reduction in peak temperature rise under each fiber of 23.5 ± 2.1% ( P = 9.3E−5) and 15.0 ± 2.4% ( P = 1.4E−3) and an increase in the FWHM of heating by 37.7 ± 6.4% ( P = 1E−3), 68.4 ± 5.2% ( P = 2.4E−5), and 51.9 ± 9.9% ( P = 1.7E−3) in three MRT slices. Conclusions This study provides the first experimental evidence for a phenomenon during the heat block in which the temperature for inhibition is dependent on the BL. While more work is needed to further reduce the temperature during INI, the results highlight that spatial application of the temperature rise during INI must be considered. Optimized implementation of INI may leverage this cellular response to provide optical modul...

Infrared inhibition impacts on locally initiated and propagating action potentials and the downstream synaptic transmission

“…The inhibition of excitable tissues, 19 – 21 , 32 – 36 including both neural and cardiac preparations, by IR light pulses has been studied extensively and is commonly referred to as IR nerve inhibition (INI). The consensus is that the INI results from temperature-dependent changes of passive membrane properties as well as sodium and potassium ion channel kinetics.…”

Isotonic ion replacement can lower the threshold for selective infrared neural inhibition

“…We have explored ways to apply IR inhibition effectively and safely for translational applications. 21 We showed that IR inhibition is safe and reversible in previous acute studies. 4 , 5 In addition to optimizing the IR inhibition protocol (e.g., changing the block length 21 ), we are exploring whether other inhibition modalities could be combined to reduce the IR threshold.…”

Multi-modal Nonlinear Optical and Thermal Imaging Platform for Label-Free Characterization of Biological Tissue

“…The key advancement allowed by the MANTIS platform is the ability to multiplex optically incompatible imaging techniques such as thermal imaging with nonlinear optical microscopy. Thermal imaging can be used to evaluate fast photothermal processes, such as infrared neural stimulation (48,55,67), with coregistered contrast from nonlinear imaging modalities to study real time biophysical dynamics. To assess the multimodal capabilities of MANTIS, readout of multimodal nonlinear contrast was directly correlated with high-speed temperature changes during infrared neural stimulation in a fresh ex vivo sciatic nerve preparation (Fig.…”

“…Moreover, optical components that suffice for use between 0.4 and 14 µm wavelengths to encompass visible optical and thermal infrared imaging are not readily available. Finite element heat transfer modeling and Monte Carlo simulations of photon transport in scattering media is often regarded as the benchmark approach for temperature estimation of dynamic photothermal processes in biological samples with high water concentrations (48)(49)(50)(51). Several indirect approaches have been demonstrated including temperature-dependent changes in fluorophore emission, and probe beam deflection microscopy (43,(52)(53)(54).…”

“…Several indirect approaches have been demonstrated including temperature-dependent changes in fluorophore emission, and probe beam deflection microscopy (43,(52)(53)(54). While point-based methods (utilizing thermocouples, customized miniature sensors, or intrinsic fluorescence of rare-earth doped glass waveguides) are more direct, they sacrifice spatial information obtained with temperature mapping (29,43,48,55). Translationally, thermal imaging has been applied in vivo towards cancer detection, circulatory diseases, and chronic pain identification (56,57).…”