Occurrence of cerebral infarction, a threshold-sensitive nonlinear process: Lessons from a new stroke model, NAIM

The lifetime accumulation of vascular risk factors shapes susceptibility to ischemic stroke but does not account for the striking divergence in tissue outcome following large artery occlusion, as some individuals experience infarction of variable severity while others remain neurologically intact. Although the classical core–penumbra framework captures general relationships between perfusion severity and tissue viability, it fails to explain this marked inter-individual heterogeneity under comparable ischemic stress. We recently established the nitric oxide synthase inhibitor-mediated large artery ischemic stroke model (NAIM), which converts unilateral carotid occlusion from a typically benign oligemic state into a high-incidence yet non-deterministic infarction paradigm. In this review, we present NAIM as a mechanistically defined platform for investigating infarction occurrence as a threshold-driven process spanning vascular, metabolic, and microcirculatory scales. Using a large-scale NAIM dataset ( n = 900 mice) from our recent study, we reappraise the original findings and extend the analysis to post-hoc observations not addressed in the initial report. Finally, integrating these experimental insights with clinical and basic investigations from our group and the broader literature, we outline how ischemic outcome (tissue survival vs infarction) emerges from a threshold-sensitive nonlinear system defined by collateral anatomy; macro-/micro-vascular integrity; and systemic, metabolic, and genetic modifiers.