Abstracts

Rationale: Seizure spread from a cortical focus to the contralateral cortex has not been previously traced. Previous studies indicate that the thalamus is essential for seizure maintenance and generalization, and famous models show two thalamic nuclei active simultaneously. Corpus callosum is an alternate commissural pathway. We propose that seizures spread from the ipsilateral thalamus to the contralateral thalamus by engaging the cortex and corpus callosum.

Methods: To initiate the frontal lobe focal to bilateral seizures, we implanted 1.7 mg of cobalt wire in the right (ipsilateral) premotor cortex. We recorded local field potentials from the bilateral premotor cortex and bilateral ventrolateral thalamic nucleus (VL) simultaneously to determine seizure onset latencies. We injected Cre-driven AAV9 GFP at the seizure focus or in the ipsilateral thalamus in activity reporter TRAP2 mice two weeks before Co insertion to label anatomical projections and seizure-activated cells simultaneously. We also performed callosotomy and used chemogenetic silencing of motor thalamic nuclei to investigate the role of the corpus callosum and thalamus in the spread of frontal lobe focal to bilateral seizures.

Results: Surprisingly, we found that seizures spread faster to the left (contralateral) cortex than to the left thalamus. 53% of all seizures required less than 200 ms to arrive at the left (contralateral) thalamic nucleus VL (59.36 ± 5.61 ms); remaining seizures required several seconds to arrive there (4.47 ± 0.65 s) (30 seizures, 11 mice). However, all seizures required less than 200 ms to arrive at the left cortex (25.49 ± 3.00 ms, 64 seizures, 16 mice), supporting the role of the corpus callosum in seizure generalization. We injected AAV9 Cre-driven GFP at the seizure focus in TRAP2 mice. We found extensive GFP and tdTomato expression in the corpus callosum, indicating that the corpus callosum was active during seizures because the seizure focus sends direct anatomical projections contralaterally across it. We injected AAV9 GFP in the right thalamus and found a lack of anatomical projections to the left thalamus explaining the onset delay in the contralateral thalamus. TRAP2 mice also did not express tdTomato in the left (contralateral) thalamus. Anterior callosotomy stopped the contralateral seizure spread initially. With time and repeated seizures, they spread to the contralateral cortex. We also inhibited ipsilateral (right) VL using chemogenetics, which surprisingly did not stop spread to the contralateral cortex. Chemogenetic studies are ongoing.

Conclusions: Frontal lobe seizures use the corpus callosum for focal to bilateral spread rather than commissural connections between two thalami.

Funding: Please list any funding that was received in support of this abstract.: This work was supported by the National Institute of Health (RO1 NS120945 to J.K.) and the UVA Brain Institute.