Neuronal circuits sustaining neocortical-injury-induced status epilepticus

Abstract

Objectives: Acute injuries or insults to the cortex, such as trauma, subarachnoid hemorrhage, lobar hemorrhage, can cause seizures or status epilepticus(SE). Neocortical SE is associated with coma, worse prognosis, delayed recovery, and the development of epilepsy. The anatomical structures progressively recruited during neocortical-onset status epilepticus (SE) is unknown. Therefore, we constructed large-scale maps of brain regions active during neocortical SE.

Methods: We used a neocortical injury-induced SE mouse model. We implanted cobalt (Co) in the right supplementary motor cortex (M2). We 16 h later administered a homocysteine injection (845 mg/kg, intraperitoneal) to C57Bl/6 J mice to induce SE and monitored it by video and EEG. We harvested animals for 1 h (early-stage) and 2 h (late-stage) following homocysteine injections. To construct activation maps, we immunolabeled whole-brain sections for cFos and NeuN, imaged them using a confocal microscope and quantified cFos immunoreactivity (IR).

Results: SE in the early phase consisted of discrete, focal intermittent seizures, which became continuous and bilateral in the late stage. In this early stage, cFos IR was primarily observed in the right hemisphere, ipsilateral to the Co lesion, specifically in the motor cortex, retrosplenial cortex, somatosensory cortex, anterior cingulate cortex, lateral and medial septal nuclei, and amygdala. We observed bilateral cFos IR in brain regions during the late stage, indicating the bilateral spread of focal seizures. We found increased cFOS IR in the bilateral somatosensory cortex and the motor cortex and subcortical regions, including the amygdala, thalamus, and hypothalamus. There was noticeably different, intense cFos IR in the bilateral hippocampus compared to the early stage. In addition, there was higher activity in the cortex ipsilateral to the seizure focus during the late stage compared with the early one.

Conclusion: We present a large-scale, high-resolution map of seizure spread during neocortical injury-induced SE. Cortico-cortical and cortico subcortical re-entrant circuits sustain neocortical SE. Neuronal loss following neocortical SE, distant from the neocortical focus, may result from seizures.

Keywords: Neocortical status epilepticus; Neuronal activation maps; Neuronal injury; Supplementary motor cortex; cFos immunostaining.