Abstracts

Rationale: Post-traumatic epilepsy (PTE) usually follows traumatic brain injury (TBI) by weeks or months during which time the process of posttraumatic epileptogenesis takes place. To track epileptogenic changes in a rat epilepsy models over time, we recently developed a novel method for paired-pulse transcranial magnetic stimulation (ppTMS) coupled with the mechanomyogram (MMG) to measure cortical inhibition in awake rats. The MMG is a well-tolerated method where muscle activation may be detected by surface accelerometry, rather than by electromyography (EMG) which typically requires needle electrode recording and anesthesia in rats. With ppTMS-MMG, we demonstrated that long-interval ppTMS-MMG inhibition is dependent on activation of the GABA-A receptor. Here, we test whether progressive loss of GABA-A-mediated cortical inhibition may be detected by ppTMS-MMG in the rat fluid percussion injury (FPI) PTE model.Methods: Two groups of rats underwent FPI (2.2 0.03 atm; n=6) or a sham surgical procedure (n=5). Following surgery, rats were tested weekly for 6 weeks by long interval (100-200 ms) ppTMS to measure cortical inhibition of the hindlimb MMG. To control for the confounding effects of repeated TMS, cortical inhibition was measured in a second pair of sham and active FPI groups (n=6/group) 6-7 weeks after injury. Finally, to confirm the epileptogenic nature of the FPI, two separate groups of rats underwent FPI or sham FPI (n=6/group), followed by 24 hours of EEG recorded 6 weeks after injury.Results: The epileptogenic nature of FPI was confirmed with 6 of 6 rats in the FPI group experiencing seizures and 0 of 6 rats experiencing seizures in the sham control group. Over the 6-week post-FPI epileptogenic period, ppTMS-MMG revealed a progressive loss of cortical inhibition in the TBI group. With a 100 ms interstimulus interval (ISI), a significant (p < 0.05) distinction between active and sham TBI groups was evident 3 weeks after injury, and with 200 ms ISI, a significant distinction between groups was evident 1 week after injury (p < 0.01). Rats tested by ppTMS-MMG 6-7 weeks after injury also uniformly showed lost corticomotor inhibition (p < 0.05).Conclusions: Progressive loss of cortical inhibition following epileptogenic TBI was detected by TMS-MMG in rats. These data suggest that ppTMS-derived measures of cortical inhibition may have practical applications in identifying patients at risk for epilepsy after TBI. Further, as LI-ppTMS inhibition is reliant on the GABA-A receptor, our data suggest that progressive loss of GABA-A inhibition may contribute to PTE.