Abstracts

Rationale: Closed-loop responsive electrical brain stimulation is an emerging new therapy for the treatment of epilepsy. Seizure-prone states may be characterized by changes in tissue oxygenation (OXY), and changes in tissue OXY have been observed in response to spontaneous seizures and epileptiform discharges. If tissue OXY changes contribute to seizure generation, then interventions that alter tissue OXY may have therapeutic value. In this study, we characterized tissue OXY changes in response to a range of electrical stimulation that is used in epilepsy research and therapy in control and tetanus toxin (TX) treated rats. Methods: Focal seizures were induced by injecting TX (50ng/0.5?l) into the neocortex or dorsal hippocampus of adult male Sprague-Dawley rats (275-325g) anesthetized with isoflurane. Each rat was allowed to recover a minimum of two weeks. For tissue OXY experiments, control and TX rats were anesthetized with ketamine (80mg/kg) and xylazine (12mg/kg, IP) and placed in a stereotaxic. An oxygen-sensitive optical probe (Presens) was attached to a platinum-iridium electrode and lowered to the same coordinates used for the TX injection. OXY measurements were acquired continuously at 4 samples/sec from either the hippocampus or neocortex. High-frequency (HFS: 20, 60, 200Hz), and low-frequency (LFS: 1Hz) stimulations were tested. Symmetrical biphasic square wave pulses were used, and were 160?sec/phase for HFS and 500msec/phase for LFS. Pulse amplitudes ranged from 0.1-0.6mA. Burst durations were 2sec for HFS and 10sec for LFS. Because voltage tended to increase with the duration of the LFS, additional voltage-controlled experiments were performed with LFS using long bursts (30-600sec) of low-voltage controlled ( 1V) stimulation. Results: Tissue OXY changes were observed for all stimulation frequencies, and response amplitude tended to increase with current amplitude. The typical response, especially at high amplitudes, was a transient oxygenation decrease lasting several seconds, followed by a prolonged increase lasting for tens of seconds. In some cases, the OXY baseline changed after stimulation. For HFS, 20 and 200Hz evoked a small initial decrease, followed by a much larger OXY increase, while 60Hz stimulation evoked a large initial decrease followed by an even larger increase. The response to LFS was qualitatively different. The late OXY increase was much larger than that of the HFSs and often resulted in a persistent increase in the oxygenation baseline. Further experiments with LFS in the TX rat revealed a transient decrease in EEG spiking after LFS, and a mitigating effect on the OXY decreases associated with spontaneous seizures. Conclusions: The observation that changes in tissue OXY varied by stimulation frequency and intensity suggest that stimulation-induced changes in tissue OXY could contribute to the therapeutic effect of responsive stimulation. These observations also suggest that measurement of tissue OXY can be a useful tool for assessing neural responses to electrical stimulation. Funded by: NIST Advanced Technology Program Cooperative Grant No. 70NANB7H7001