Abstracts

Rationale: With recent advances in the development of microelectromechanical systems, e.g., implantable drug pumps, the possibility of controlling seizures with implantable closed loop devices employing miniaturized drug delivery systems can now be explored. In order to develop a successful adaptive seizure control system with antiepileptic drug (AED) interventions, it is necessary to determine how the AED affects electrophysiological properties of the brain. The benzodiazepine midazolam was tested because of its water solubility, fast action, and ability to terminate refractory status epilepticus. The main goal of this study was to determine whether programmable ICV injections of midazolam could effect demonstrable changes in surface recordings of the EEG in the rat.Methods: Young adult male Fischer 344 rats had partial burr holes made in the skull for 6 recording and 2 anchoring screws. Following placement of the EEG recording screws, The ICV cannula was stereotactically placed into the right ventricle. Video-EEG recordings were obtained at a sampling rate of 200 Hz and displayed with a frequency range of 1-70 Hz using the 32-channel Stellate Systems data acquisition system. A syringe pump (PHD 22/2000 Push/Pull pump, Harvard Apparatus) was programmed to deliver 5 μl of midazolam (0, 10, 30, and 100 nM) over 60 seconds. The ICV cannula was kept patent by use of a dummy probe that was inserted into the cannula when the animal was not being recorded. After obtaining multichannel EEG recordings, EEG power spectra (SenSa, Stellate Systems) were generated to assess the midazolam's effect on the EEG. Residence of the cannula within the right lateral ventricular space was confirmed by the injection of Evans blue (5 μl/min) into the cannula prior to animal sacrifice.Results: Visual inspection of the EEG revealed a generalized suppression of amplitude within ~2 min of midazolam injection at 100 nM. No discernible effects were observed following injections at 0, 10, and 30 nM. The voltage suppression was maintained for several minutes before resumption of baseline activities. Spectral analysis revealed a downward shift in low-frequency (1-15 Hz) power following midazolam (100 nM) injection. Right ventricular positioning of the cannula was confirmed in all animals 2 months following its placement.Conclusions: These results demonstrate the technical feasibility to simultaneously record and deliver effective ICV injections of an AED in a freely moving animal. These findings are being applied to the development of an adaptive closed loop control system in the chronic limbic epilepsy rat model. Supported by Pennsylvania Department of Health Research Formula Fund RFA 04-07-09 to KMK.