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.
Sensory information is conveyed to the central nervous system via small diameter unmyelinated fibers. In general, smaller diameter axons have slower conduction velocities. Selective control of such fibers could create new clinical treatments for chronic pain, nausea in response to chemo-therapeutic agents, or hypertension. Electrical stimulation can control axonal activity, but induced axonal current is proportional to cross-sectional area, so that large diameter fibers are affected first. Physiologically, however, synaptic inputs generally affect small diameter fibers before large diameter fibers (the size principle). A more physiological modality that first affected small diameter fibers could have fewer side effects (e.g., not recruiting motor axons). A novel mathematical analysis of the cable equation demonstrates that the minimum length along the axon for inducing block scales with the square root of axon diameter. This implies that the minimum length along an axon for inhibition will scale as the square root of axon diameter, so that lower radiant exposures of infrared light will selectively affect small diameter, slower conducting fibers before those of large diameter. This prediction was tested in identified neurons from the marine mollusk Aplysia californica. Radiant exposure to block a neuron with a slower conduction velocity (B43) was consistently lower than that needed to block a faster conduction velocity neuron (B3). Furthermore, in the vagus nerve of the musk shrew, lower radiant exposure blocked slow conducting fibers before blocking faster conducting fibers. Infrared light can selectively control smaller diameter fibers, suggesting many novel clinical treatments.
Nerve block can eliminate spasms and chronic pain. Kilohertz frequency alternating current (KHFAC) produces a safe and reversible nerve block. However, KHFAC-induced nerve block is associated with an undesirable onset response. Optical inhibition using infrared (IR) laser light can produce nerve block without an onset response, but heats nerves. Combining KHFAC with IR inhibition [alternating current and infrared (ACIR)] produces a rapidly reversible nerve block without an onset response. ACIR can be used to rapidly and reversibly provide onset-free nerve block in the unmyelinated nerves of the marine mollusk Aplysia californica and may have significant advantages over either modality alone. ACIR may be of great clinical utility in the future.