Two distinct excitability types delineate the partition between normal brain function, engram encoding, and the two phases of hyperexcitability/epileptic susceptibility

Abstract The conventional conceptualization of neuronal excitability as a unitary phenomenon obscures critical distinctions between synaptic and ephaptic mechanisms of neural activation. In the present investigation, we separate excitability into two independent parameters synaptic ( p ) and ephaptic ( b ) within a cellular automata framework. This separation facilitates the precise demarcation of operational regimes across the (p, b) parameter space, encompassing normal brain function (with and without engram encoding), and hyperexcitability/epileptic susceptibility phases (HEPS), including tonic and clonic manifestations. Note that hyperexcitability (HEPS) as defined here does not distinguish between cases of non-epileptic episodes and actual epileptic seizures. Simulations reveal possible contiguous HEPS domains intrinsically linked to memory (normal / encoding) processes, situated (p < 0.90) beneath the elevated synaptic excitabilities traditionally associated with epileptogenesis. Notably, this low-p HEPS region(s) could emerge within the hippocampus during engram formation, suggesting a mechanistic overlap between physiological memory encoding and possible pathological hyperexcitability. Implications for pharmacotherapy are explored, emphasizing targeted modulation of p and b to mitigate epileptic risk in individuals with varying baseline excitabilities, while preserving cognitive faculties. These findings underscore the necessity of disentangling excitability subtypes to refine diagnostic and therapeutic paradigms in neurology and cognitive science.