Abstracts

Rationale: Interictal spikes are abnormal discharges that occur frequently between seizures in epileptic patients. While they are often most frequent at a seizure focus, spikes have been associated with behavioral abnormalities in patients with and without seizures. In order to better understand the relationship between interictal and ictal activity as well as behavioral comorbidities, we optimized a rat model that slowly develops interictal spiking after focal tetanus toxin administration into the neocortex.Methods: A neocortical spiking focus was induced in rats using a single tetanus toxin injection into the motor or somatosensory cortex. Following injection, six epidural electrodes (3 on each hemisphere) were implanted to monitor epileptic activities through long term (24h) EEG and video recordings together with activity chamber measurements. Results: Focal spikes were produced with increasing frequency and amplitude over time after injection in both somatosensory and motor cortex, but seizures occurred only with motor cortex injection. While both groups produced increasing frequency and field size of interictal spikes that start to cluster after 2-3 weeks, motor cortex injected rats showed a higher spike frequency over time and earlier spike clustering, that often developed at the time of electrographic and clinical seizures (by 1-2 weeks). The majority of the clinical seizures observed were characterized by interrupted behavioral activity, rhythmic facial twitching, and abrupt motor arrest, although much less tonic-clonic seizures were also observed Although the injection sites were only a few mm away, a marked difference in the spread of the interictal spike field was seen with a predominantly frontal and contralateral spread in somatosensory cortex animals while motor cortex animals spikes spread in a posterior and contralateral pattern. Interictal spike frequency had a similar circadian pattern in both groups with higher spike frequency consistently seen during the light phase, which corresponds to the inactive phase. Interictal spiking also led to significant behavior changes. Spontaneous locomotor activity was significantly increased in somatosensory cortex injected rats showed when compared to both, sham and na ve animals, whereas, motor cortex injected animals showed a much lower level of activity when compared to all groups. Conclusions: Together, these results show that interictal spikes have unique patterns of development, spread, and association with seizures depending on their anatomical location. The markedly different behavioral comorbidities from spikes (and seizures) in different brain areas that range from hyperactivity with spiking alone (somatosensory cortex) to depressed activity with spikes and seizures (motor cortex) suggestan important relationship between these activities and behavior. Having new anima models such as this will be important in investigating the relationship between interictal spikes and seizures and should enable the testing of novel therapeutics for both epilepsy and its behavioral comorbidities.