State-dependent connectivity of impaired autonomic brain networks underlying cardiorespiratory dysfunction in epilepsy

PROJECT SUMMARY/ABSTRACT Sudden unexpected death in epilepsy (SUDEP) accounts for up to 18% of all deaths in epilepsy and up to 50% of all deaths in drug-resistant epilepsy. The strongest clinical risk factor for SUDEP is ongoing tonic-clonic seizures (TCS), and failure of cardiorespiratory function during TCS has been implicated as a major cause of SUDEP. Patients with temporal lobe epilepsy (TLE) experience cardiorespiratory and autonomic abnormalities both interictally (between seizures) and ictally (during seizures). These abnormalities have been related to elevated risk for SUDEP and include central apnea during the peri-ictal period and increased cardiac sympathetic modulation during the interictal and peri-ictal periods. However, the neural mechanisms underlying cardiorespiratory deficits in epilepsy and their relationship to SUDEP are largely unknown. Preliminary evidence from animal and human studies suggests that cardiorespiratory dysfunction in epilepsy may be linked to seizure-related disruptions of neural circuits involved in cardiorespiratory and autonomic regulation. In this proposal, we aim to integrate multimodal neuroimaging and electrophysiological data with measurements of cardiorespiratory activity to investigate impaired autonomic brain networks in TLE during the interictal state (Aim 1) and peri-ictal state (Aim 2). Currently, it is unknown how brain network disturbances directly impact cardiorespiratory and autonomic function. Cardiorespiratory activity is not commonly recorded in epilepsy monitoring units or neuroimaging research. We hypothesize that studying dynamic interactions between the central autonomic network and cardiorespiratory activity will reveal neural circuit impairments associated with interictal and ictal cardiorespiratory deficits. In Aim 1, we will analyze simultaneous functional MRI (fMRI), cardiac, and respiratory data to identify cardiorespiratory coupled brain connectivity abnormalities of the central autonomic network in TLE that are related to SUDEP risk factors such as recurrent TCS. This aim will uncover chronic alterations of autonomic circuits that may predispose TLE patients to severe cardiorespiratory dysfunction and SUDEP. We will also leverage advanced preprocessing methods to investigate subcortical autonomic centers that have been under-examined in prior fMRI studies of SUDEP. In Aim 2, we will analyze concurrent stereo-electroencephalography (SEEG) and respiratory data to identify abnormal neural-respiratory coupling and brain connectivity in cortical autonomic regions during temporal lobe seizures with ictal central apnea. This aim will elucidate seizure-induced impairments in respiratory-related neural communication that may serve as a biomarker of ictal apnea. Previous studies have associated ictal apnea occurrence with seizure spread to the amygdala. Here, we hypothesize that that ictal apnea results from transient disruptions of a wider network of brain regions involved in voluntary and autonomic control of respiration. If successful, the proposed aims can guide discovery of novel neural biomarkers of SUDEP risk and cardiorespiratory dysfunction, improving risk stratification and identifying neuromodulation targets for preventive treatment.