Biophysical mechanisms of transient optical stimulation of peripheral nerve

Abstract

A new method for in vivo neural activation using low-intensity, pulsed infrared light exhibits advantages over standard electrical means by providing contact-free, spatially selective, artifact-free stimulation. Here we investigate the biophysical mechanism underlying this phenomenon by careful examination of possible photobiological effects after absorption-driven light-tissue interaction. The rat sciatic nerve preparation was stimulated in vivo with a Holmium:yttrium aluminum garnet laser (2.12 microm), free electron laser (2.1 microm), alexandrite laser (750 nm), and prototype solid-state laser nerve stimulator (1.87 microm). We systematically determined relative contributions from a list of plausible interaction types resulting in optical stimulation, including thermal, pressure, electric field, and photochemical effects. Collectively, the results support our hypothesis that direct neural activation with pulsed laser light is induced by a thermal transient. We then present data that characterize and quantify the spatial and temporal nature of this required temperature rise, including a measured surface temperature change required for stimulation of the peripheral nerve (6 degrees C-10 degrees C). This interaction is a photothermal effect from moderate, transient tissue heating, a temporally and spatially mediated temperature gradient at the axon level (3.8 degrees C-6.4 degrees C), resulting in direct or indirect activation of transmembrane ion channels causing action potential generation.

Figures

FIGURE 1

Experimental setup for nerve surface temperature measurements with the thermal camera from UTA.

FIGURE 2

Effect of laser pulse duration on stimulation threshold radiant exposure. Three lasers with comparable tissue absorption coefficients were used: the FEL (5 μs), Ho:YAG (350 μs), and tunable solid-state pulsed diode laser (1, 3, 5 ms). All lie well outside stress confinement but are still thermally confined.

FIGURE 3

Confinement zones based on penetration depth and pulse length for soft tissue. Notice that the three lasers used are all thermally confined but are not stress confined. (Reprinted, modified version of Fig. 13 from Jacques, S. L. 1992. Laser-tissue interactions. Photochemical, photothermal, and photomechanical. Surg. Clin. North Am. 72:531–558, with permission from Elsevier.)

FIGURE 4

DP-OCT measurements of nerve surface displacement resulting from Ho:YAG laser irradiation. (Right) Typical recording of the optical path length change of the nerve surface relative to a stationary coverslip from near threshold radiant exposure (0.4 J/cm2) indicating volumetric tissue expansion on the order of 300 nm. (Left) A total of 18 measured surface displacements over the normal range of use for optical stimulation radiant exposures (R2 = 0.8951).

FIGURE 5

CNAP signal onset time for two different laser pulse durations. Assume the time for conduction over 6 mm from stimulation site to recording electrodes is constant (2.6 ms, arrows) after the pulse energy deposition. (a) CNAP recorded from stimulation at t = 0 using a 2.5 ms pulse duration with the pulsed diode optical nerve stimulator. (b) CNAP recorded from stimulation at t = 0 using a 8.0 ms pulse duration with the pulsed diode optical nerve stimulator. These recordings prove that all laser energy is required before the onset of the CNAP can occur (Gain = 5000).

FIGURE 6

Temperature spatial profile measurement of the nerve surface in vivo using the thermal camera at the end of the laser pulse. Threshold (0.4 J/cm2) radiant exposure with a 600 μm fiber yields a peak tissue temperature = 35.86°C, peak temperature rise = 8.95°C, and average temperature rise = 3.66°C. The calculated Gaussian spot = 0.37 mm2. The position of the maximum pixel for 0.4 J/cm2 stimulation (stars) and Gaussian fit (solid line) of temperature profile for maximum line scan in x and y are shown.

FIGURE 7

(a) Maximum temperature in hydrated tissue as a function of radiant exposure immediately after laser stimulation. Stimulation threshold occurs between 0.3 and 0.4 J/cm2; onset of minimal thermal changes in tissue occurs at 43°C, which corresponds to the onset of thermal damage seen in previously published histological analysis (0.8–1.0 J/cm2). (b) Average temperature rise from multiple trials (n = 18).

FIGURE 8

Temperature profile of peripheral nerve in time, laser stimulation near threshold (0.4 J/cm2), and at over 2 times threshold (0.8 J/cm2). The experimental thermal relaxation time, τth, of peripheral nerve tissue based on the equation shown in the figure is 90 ms.

FIGURE 9

Steady-state maximum temperature increase in nerve tissue from Ho:YAG laser stimulation. (a) Temperature rise from 0.45 J/cm2 radiant exposure pulses at 2 Hz stimulation frequency. (b) Temperature rise from 0.65 J/cm2 radiant exposures at 2 Hz stimulation frequency. (c) Temperature rise from 0.41 J/cm2 threshold radiant exposures at 5 Hz stimulation frequency. (d) Temperature rise from 0.63 J/cm2 threshold radiant exposures at 5 Hz stimulation frequency.