Heterogeneity of ictal firing during generalized seizures in the awake cortex

ABSTRACT Cortico-thalamo-cortical oscillations are central to both normal and pathological brain activities and emerge from complex cortical and thalamic interactions. However, the specific activity of identified cortical neurons during the paroxysmal oscillations associated with absence seizures (ASs) in awake animals remains underexplored. The dominant narrative suggests that seizures indiscriminately disrupt cortical activity through generalized hyperexcitability, but direct evidence supporting this view is lacking. Here, we recorded single units from pyramidal neurons and different interneuron subtypes in the neocortex of two validated rodent models of absence epilepsy under awake, behaving conditions. We find that neurons maintain their firing rank order across interictal and ictal states, regardless of whether their ictal firing rate increases, decreases, or remains stable compared to the interictal phase. Rather than a random cortical takeover, ictal activity represents a scalable modulation of pre-existing network states. These results challenge the generalized hyperexcitability model and highlight the structured, heterogeneous nature of cortical activity during ASs, with implications for mechanistic understanding and targeted therapies.