ENHANCED PERIPHERAL NERVE REGENERATION BY DC STIMULATION

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The broad objective of this proposal is to test whether regenerating axons in vivo respond to minute electric fields as has been demonstrated in vitro and whether there is any clinical relevance of applied electric currents as a therapeutic tool for peripheral nerve injuries. This project will establish: the degree to which electric fields can enhance mammalian peripheral nerve regeneration, the steps of the repair process that are affected, the anatomical and electrophysiological consequences of electrically enhanced regeneration, and the parameters and modes of application necessary for successful clinical applications. The basic protocol is to produce identical bilateral lesions of the peroneal nerves in guinea pigs and to implant an active electrode in one leg and a sham in the other. The surgery, subsequent evaluations, and all data analysis will be done double-blind. Assessment of regeneration in each leg will be by: functional recovery of specific reflexes, electrophysiological recordings, the pinch test for advancing nerve fronts, and both light and transmission electron microscopy. Preliminary evidence indicates that the rate of functional recovery from a peripheral nerve injury can be enhanced by small (20 microamp) steady electric currents. The implications for clinical medicine are profound. Any technique capable of enhancing the rate of either axonal elongation, growth through the scar, or maturation of fibers will provide a valuable tool of neurologists faced with proximal peripheral nerve injuries. As an adjunct to the mammalian studies, observations will be made of regenerating sensory fibers in the fins of the glass catfish. The optical clarity of these fish allows for direct observation with Nomarski optics of regenerating axons and the consequences of applied electric fields in vivo. Much of what is known about the effects of electric fields on nerves has been learned from in vitro studies of developing amphibian neurites. The glass catfish provides the unique opportunity to test some of these notions on adult regenerating fibers in vivo. Microelectrodes will be used to apply focused electric currents to the growth cone of regenerating fibers to test whether electrical directional cues can overcome the natural contact guidance cues the regenerating fibers normally follow. The fine structure of an individual growth cone will be studied with electron microscopy and correlated with its behavioral response to an applied electric field. These studies will provide powerful insights into the response of vertebrate nerves to electric fields.