Abstracts

Rationale: Cortical dysplasia (CD) is one of the leading causes of drug resistant focal epilepsy. Despite significant advances in various diagnostic and therapeutic methods, the basic mechanisms of higher susceptibility for seizures in patients with CD remain unknown. The purpose of this study is to develop a mathematical framework using principles from second order system dynamics to further characterize the effect of a "second hit" [acute single pentylenetetrazole (PTZ)-induced seizure] in animal model of in utero radiation-induced CD as compared to a PTZ induced seizure in normal control rat. Methods: CD was induced through in utero irradiation of 4 pregnant Sprague Dawley rats at E17 with 145 cGy. Fourteen litters (XRT) were implanted with intracortical depth electrodes targeting the right and left frontal and parietal cortex. A set of 27 aged matched normal rats served as controls. All rats were injected with PTZ at 40 mg/kg. Post PTZ injection, all 14 XRT rats developed seizures (Group 1), 17 out of 27 normal rats developed seizures (Group 2) and in 10 normal rats, PTZ injection failed to induce seizures (Group 3). The flow diagram of experimental steps involved is provided in Fig. 1A. To characterize the response of the abnormal/normal brain to PTZ, the average gamma coherence (C_r) across all pairs of electrode and across all rats within a group was computed for the entire duration of recording (24 hours). The C_r profile can be viewed as the impulse response of an over-damped 2^nd order system (See Fig.1C), the impulse function being the PTZ injection. The system parameters can then be estimated by fitting Eq.1 to C_r. Results: Fig. 1B shows C_r profile and the fitted data for the 3 groups of rats. Table 1, shows the location of poles s₁, s₂, the under-damped natural frequency (ω_n) and the damping ratio of the system (ξ). The slow pole s₁ represents the long-term effects of the PTZ injection whereas the fast pole s₂ dictates the immediate reaction of the system to external perturbation. Note that the slow pole is similar across the 3 groups (Fig. 1D). The location of the pole represents the stability of the system. The location of fast pole is closest to the imaginary axes for XRT rats and hence is suggestive of a less stable system. The lowest damping ratio is for the XRT rat, followed by rats in Group 2 and Group 3. A high damping ratio indicates that the system is resistive to oscillations caused by external perturbations. Conclusions: Our study shows that there exists an internal feedback mechanism within the brain of normal rats which reduces its susceptibility to epileptogenesis. We hypothesize that this feedback control mechanism is dysfunctional within the dysplastic (CD) rat brain. Support for this claim is provided by the relatively lower damping ratio and location of the fast pole of the CD rats (p<0.01). Translation of this concept to human studies using neurostimulation paradigms may provide a novel methodology to characterize and measure epileptogenicity in abnormal/normal tissues. Our future work will be targeted along these lines.