Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) accounts for 7-17% mortality in epilepsy patients [1]. Although the underlying pathophysiological mechanisms of SUDEP are still unknown, many studies suggest impaired cardiorespiratory performance during seizures [2]. We employed for the first time in an animal model of SUDEP, the Kcna1 knockout mouse [3], concurrent long-term electroencephalographic (EEG), electrocardiographic (ECG) and unrestrained whole-body plethysmographic (Pleth) recordings to study the directional brain-heart-lung interactions during mostly during seizure-free periods, and investigate their possible impairment. Methods: Kcna1-knockout mice have neuronal hyper-excitability and are SUDEP-prone. Kcna1-knockout (n=8) and wild-type (n=7) mice of both sexes were anesthetized and surgically implanted with 6 bilateral EEG electrodes overlying left and right temporal and parietal cortex and two frontal cortex (reference and ground) electrodes. Two thoracic electrodes were tunneled subcutaneously on either side to record the ECG. Mice were allowed to recover for 1 day before recording 8 h of continuous EEG-ECG-Pleth in an unrestrained whole-body plethysmography chamber. EEG, ECG and Pleth were sampled at 1 kHz, 2 kHz and 500 Hz respectively. EEG and ECG were subsequently down-sampled to 500 Hz. The first 4 h (mostly seizure-free) of the recordings were analyzed. Directional interactions with respect to information flow between brain, heart and lungs were estimated by a 3-dimensional multivariate autoregressive (MVAR) model of order 7 that was fit to 10-s consecutive and non-overlapping EEG, ECG and Pleth data segments, and the Generalized Partial Directed Coherence (GPDC) connectivity measure values were estimated [4]. The GPDC values were estimated over 13 frequency bands, from 1 to 200 Hz, per mouse and were then aggregated per interaction and frequency band for each genotype. Results: The mean and standard error of the mean of GPDC values per frequency band for heart<->brain and lung<->brain interactions are shown for the two genotypes in Fig. 1. Three statistically significant observations (p<0.001) were made: 1) SUDEP-prone mice exhibit a reduced functional connection in heart-brain interactions across frequencies (Fig. 1 (a) and (b); 2) In both healthy and SUDEP-prone mice, the connectivity of lung<->brain interactions is reduced in high frequencies (Fig. 1 (c) and (d); 3) Relative to wild-type, SUDEP-prone mice exhibit both an increased lung->brain feedback in lower frequencies and an increased brain->lung connectivity in higher frequencies Fig. 1 (b). The values of each pair interaction, averaged across all frequencies, are plotted in Fig. 2. Conclusions: Heart <-> brain interactions may be impaired in both directions in SUDEP subjects when interactions with the lungs are also taken in consideration. This impairment may lead to abnormally high lungs <->brain interactions in SUDEP prone subjects, possibly as a compensatory mechanism. The above findings suggest that inclusion of the heart and lungs in a network with the brain provides important novel information that could assist with development of frequency dependent biomarkers for risk to and advanced warning of impending SUDEP.References: [1] M. Sperling, Epilepsy Currents, 21-23, 2001; [2] S. D. Shorvon, Epilepsy, 1st ed., Oxford U. Press, 2009; [3] V. Mishra et al., Human Molecular Genetics, 26:2091-2103, 2017. [4] I. Vlachos et al., IEEE TBME, 64:2241-2252, 2017.  Funding: This work was supported by NSF EPSCoR 1632891, CURE 354389 and NIH R21NS089397 and R00HL107641 grants