The possibility of neural injury during prolonged electrical stimulation of the brain imposes some constraints on the use of this technique for therapeutic and experimental applications. Stimulating electrodes of various sizes were used to investigate the interactions of two stimulus parameters, charge density and charge per phase, in determining the threshold of neural injury induced by electrical stimulation. Platinum electrodes ranging in size from 0.002 to 0.5 cm2 were implanted over the parietal cortex of adult cats. Penetrating microelectrodes fabricated from iridium, with surface areas of 65 +/- 3 x 10(-6) cm2 were inserted into the parietal cortex. Ten days after implantation, the electrodes were pulsed continuously for 7h using charge balanced, current regulated, symmetric pulse pairs, 400 microseconds per phase in duration, at a repetition rate of 50 Hz. The animals were perfused immediately after the stimulation for histologic evaluation of the brain tissue subjacent to the electrode sites. The results show that charge density (as measured at the surface of the stimulating electrode), and charge per phase, interact in a synergistic manner to determine the threshold of stimulation-induced neural injury. This interaction occurs over a wide range of both parameters; for charge density from at least 10 to 800 microC/cm2 and, for charge per phase, from at least 0.05 to 5.0 microC per phase. The significance of these findings in elucidating the mechanisms underlying stimulation-induced injury is discussed.

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Helical electrodes were implanted around the left and right common peroneal nerves of cats. Three weeks after implantation one nerve was stimulated for 4-16 hours using charge-balanced, biphasic, constant current pulses. Compound action potentials (CAP) evoked by the stimulus were recorded from over the cauda equina before, during and after the stimulation. Light and electron microscopy evaluations were conducted at various times following the stimulation. The mere presence of the electrode invariably resulted in thickened epineurium and in some cases increased peripheral endoneurial connective tissue beneath the electrodes. Physiologic changes during stimulation included elevation of the electrical threshold of the large axons in the nerve. This was reversed within one week after stimulation at a frequency of 20 Hz, but often was not reversed following stimulation at 50-100 Hz. Continuous stimulation at 50 Hz for 8-16 hours at 400 microA or more resulted in neural damage characterized by endoneurial edema beginning within 48 hours after stimulation, and early axonal degeneration (EAD) of the large myelinated fibers, beginning by 1 week after stimulation. Neural damage due to electrical stimulation was decreased or abolished by reduction of the duration of stimulation, by stimulating at 20 Hz (vs. 50 Hz) or by use of an intermittent duty cycle. These results demonstrate that axons in peripheral nerves can be irreversely damaged by 8-16 hours of continuous stimulation at 50 Hz. However, the extent to which these axons may subsequently regenerate is uncertain. Therefore, protocols for functional electrical stimulation in human patients probably should be evaluated individually in animal studies.

Arrays of platinum (faradaic) and anodized, sintered tantalum pentoxide (capacitor) electrodes were implanted bilaterally in the subdural space of the parietal cortex of the cat. Two weeks after implantation both types of electrodes were pulsed for seven hours with identical waveforms consisting of controlled-current, charge-balanced, symmetric, anodic-first pulse pairs, 400 microseconds/phase and a charge density of 80-100 microC/cm2 (microcoulombs per square cm) at 50 pps (pulses per second). One group of animals was sacrificed immediately following stimulation and a second smaller group one week after stimulation. Tissues beneath both types of pulsed electrodes were damaged, but the difference in damage for the two electrode types was not statistically significant. Tissue beneath unpulsed electrodes was normal. At the ultrastructural level, in animals killed immediately after stimulation, shrunken and hyperchromic neurons were intermixed with neurons showing early intracellular edema. Glial cells appeared essentially normal. In animals killed one week after stimulation most of the damaged neurons had recovered, but the presence of shrunken, vacuolated and degenerating neurons showed that some of the cells were damaged irreversibly. It is concluded that most of the neural damage from stimulations of the brain surface at the level used in this study derives from processes associated with passage of the stimulus current through tissue, such as neuronal hyperactivity rather than electrochemical reactions associated with current injection across the electrode-tissue interface, since such reactions occur only with the faradaic electrodes.

Localized, long-lasting stimulation-induced depression of neuronal excitability (SIDNE) is a consequence of prolonged, high-frequency microstimulation in the central nervous system (CNS). It represents a persisting refractory state in the neurons and axons near the stimulating microelectrode, that occurs in the absence of histologically detectable tissue injury. It does not involve a change in synaptic efficacy and, in this respect, it differs from the more familiar phenomenon of long-term depression (LTD). Although SIDNE is ultimately reversible (after several days), it must be taken into account in the design of neural prostheses based on microstimulation in the central nervous system and in animal studies that require prolonged microstimulation in the CNS. In this study, we have characterized the phenomenon, using as the paradigm, iridium microelectrodes implanted chronically in the cat's posteroventral cochlear nucleus. Although the SIDNE may persist for several days after the end of the stimulation protocol, it does not become more severe from day to day when the stimulation protocol is repeated on successive days. The severity of the SIDNE is strongly dependent upon both the instantaneous frequency and the duty cycle of the electrical stimulation. The character of the SIDNE, including its localization to the immediate vicinity of the stimulating microelectrodes, suggests that the phenomenon is a direct consequence of the prolonged electrical excitation of the neurons close to the microelectrode. The problem of designing microstimulation systems that allow high-frequency stimulation of a neural substrate, while minimizing SIDNE are discussed.