Directed Connectivity Analysis of the Neuro-Cardio- and Respiratory Systems Reveals Novel Biomarkers of Susceptibility to SUDEP

Abstract

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.

Identifying Refractory Epilepsy Without Structural Abnormalities by Fusing the Common Spatial Patterns of Functional and Effective EEG Networks

“…Finally, there are some alternative ways to estimate the brain networks including the multivariate autoregressive models (MVAR) for functional networks and Granger Causality (GC) for effective networks [14], [15], [17], [61]- [63]. Besides, the generalized partial directed coherence (PDC) would also be an excellent attempt for constructing the functional networks versus effective networks as both networks would have been created via a similar methodology [15], [64], [65]. Further studies could consider to construct functional and effective connectivity using these alternative measurements.…”

“…In addition to MRI, electroencephalograms (EEGs) have been also widely used in studies of epilepsy, including the identification of epilepsy patients [12]- [15], the detection of epileptogenic foci [16], [17] and the prediction of seizures [18]- [24]. Functional or effective network constructed from EEG signals could be used to characterize the internal interaction within brain regions and allow us to distinguish resting-state signals by differentiating specific network patterns [25]- [28].…”

The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

“…Accordingly, results from animal models suggest that altered neuro-cardiac connections could represent a risk factor for SUDEP. 10 The autonomic system and the heart The regulation of cardiac electrical and mechanical activity from sympathetic and parasympathetic innervation depends on the influence of different ion channels expressed on the cardiomyocyte surface, regulating the cellular fluxes of calcium, sodium, and potassium. 11 Through their modulation, the sympathetic system enhances cardiac conduction, HR, repolarization, contractility, and relaxation, while the parasympathetic system mediates the opposite actions.…”

Linear and Nonlinear Directed Connectivity Analysis of the Cardio-Respiratory System in Type 1 Diabetes

“…DTF and other MVAR-based measures of directional connectivity may also be applied to the evaluation of the directional coupling between the cardiac, respiratory, and peripheral blood flow systems. The utility of these measures in neuro-cardiorespiratory network interactions has been shown lately in animal studies of sudden unexpected death in epilepsy (SUDEP), a condition that involves potential failure of central control units of cardiac and respiratory behavior (Hutson et al, 2020).…”