Interplay between olfactory inputs and seizure regulation: Mechanisms and evidence

Olfactory stimuli represent a long-standing paradox in epilepsy: identical odors can provoke seizures in some individuals yet suppress them in others. Despite extensive anecdotal and experimental evidence, the mechanisms underlying this duality remain poorly defined. Here we synthesize anatomical, physiological, and clinical data linking olfaction to epileptogenic networks, highlighting the piriform cortex (PC) as a low-threshold hub coupling olfactory bulb (OB) inputs to limbic circuits. We propose an integrative framework in which olfactory influences arise through four interacting levels: (i) circuit competition via defensive and brainstem reflexes, (ii) respiration-locked gating of olfactory-limbic coupling, (iii) state-dependent bias from stress and neuromodulatory tone, and (iv) molecular actions on receptors and ion channels. This framework reconciles the apparent paradox by demonstrating how context and network state determine whether olfactory inputs suppress or facilitate seizures. We argue that the olfactory system offers a unique experimental window into ictogenesis and a tractable platform for probing, and potentially harnessing, state-dependent seizure modulation.