Synergistic Positive Feedback Loops Underlying a Critical Brain State Transition

Brain state transitions have been modeled as tipping points within the phase space1,2, separating two states that are stabilized either by recurrent network activity 3,4 or cellular mechanisms5-9. The critical forces underlying brain state transitions, however, remain unknown. Seizure onset is an extreme, although thankfully rare, type of brain state transition. We show here that this ictal transition is associated with an all-or-nothing change in the response to an optogenetic stimulation indicative of a latent change in dendritic excitability. Our data show how the precipitous nature of the transition can be understood in terms of multiple, synergistic positive feedback mechanisms: raised intracellular Cl- and extracellular K+, coupled to a reduced threshold for dendritic plateau potentials, and which in turn leads to a switch to pyramidal burst firing. These interlinked feedback loops draw together several major lines of epilepsy research and provide a framework for understanding other brain state transitions.