title: Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.
abstract: Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention.
  
  
  CONCLUSIONS
  Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.
authors.affiliation: Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, and.
authors.forename: Laura A
authors.identifier: http://orcid.org/0000-0002-1638-426X
authors.initials: LA
authors.lastname: Ewell
authors.affiliation: Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, and.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, and.
authors.forename: Caren
authors.identifier: http://orcid.org/0000-0001-8010-0850
authors.initials: C
authors.lastname: Armstrong
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, and Neurosurgery and Neurology and Neurological Sciences, Stanford University, Stanford, California 94305.
authors.forename: Ivan
authors.initials: I
authors.lastname: Soltész
authors.affiliation: Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, and Kavli Institute for Brain and Mind, University of California, San Diego, California 92093.
authors.forename: Stefan
authors.initials: S
authors.lastname: Leutgeb
authors.affiliation: Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, and jleutgeb@ucsd.edu.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Leutgeb
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004569:Electroencephalography / Q000379:methods; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology*; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D009415:Nerve Net / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000503:physiopathology*
keywords: REM sleep; brain state; hippocampus; interneuron; seizure prediction; temporal lobe epilepsy