The paper describes the results from a unique experimental and analytical study in a well-controlled animal model of Sudden Unexpected Death in Epilepsy (SUDEP). As the name implies, SUDEP is difficult to impossible to study in humans due to the uncertainty in the timing of death occurrence over years. It is much easier to do this with animals as they also have much shorter life span. The animal model we employed is one of two most prominent animal models of SUDEP. Our aim was to elucidate potential impairments in the functional connectivity between the brain, heart and lungs that could contribute to our better understanding of the underlying causes of SUDEP. This is the first study of its kind in SUDEP and, as far as we know, the first multivariate study between the heart, brain and lungs, part of the emerging field of organomics. In this contribution, we report for the first time results from tri-organ analysis of concurrent electroencephalographic, electrocardiographic and plethysmographic recordings in a control group (wild-type healthy mice) and a group of mice genetically predisposed to SUDEP and epileptic seizures. We were able to produce strong statistical evidence (p<0.001) that SUDEP-prone animals exhibit statistically significant inter-organ (brain, heart and lungs) abnormalities in specific functional afferent and efferent interactions. The graphic abstract is a schematic representation of the statistically significant (a) decreased and (b) increased neuro-cardio-respiratory network interactions of the KO compared to WT mice averaged over frequencies of 1-200 Hz. The thickness of arrows corresponds to the magnitude, and the (+) or (-) sign above the arrows to the signs of the difference of the ssGPDC values of KO from the ones of WT animals for each interaction. We also show the impact of epileptic seizures on the dynamics of these functional connectivities. These results suggest that the novel measures of neuro-cardio-respiratory connectivity we developed from network analysis in the frequency domain do shed light on potential pathophysiological mechanisms of SUDEP and ictogenesis, could be utilized as biomarkers of susceptibility to SUDEP and seizures, as well as in the assessment and improvement of the efficacy of current and future intervention strategies for treatment of seizures and risk to SUDEP. Technology Abstract-Goal: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality and its pathophysiological mechanisms remain unknown. We set to record and analyze for the first time concurrent electroencephalographic (EEG), electrocardiographic (ECG), and unrestrained whole-body plethysmographic (Pleth) signals from control (WT-wild type) and SUDEP-prone mice (KO-knockout Kcna1 animal model). Employing multivariate autoregressive models (MVAR) we measured all tri-organ effective directional interactions by the generalized partial directed coherence (GPDC) in the frequency domain over time (hours). When compared to the control (WT) animals, the SUDEP-prone (KO) animals exhibited (p < 0.001) reduced afferent and efferent interactions between the heart and the brain over the full frequency spectrum (0-200Hz), enhanced efferent interactions from the brain to the lungs and from the heart to the lungs at high (>90 Hz) frequencies (especially during periods with seizure activity), and decreased feedback from the lungs to the brain at low (<40 Hz) frequencies. These results show that impairment in the afferent and efferent pathways in the holistic neuro-cardio-respiratory network could lead to SUDEP, and effective connectivity measures and their dynamics could serve as novel biomarkers of susceptibility to SUDEP and seizures respectively.
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