Seizures have both local and remote effects on nervous system function. Focal seizures can propagate from the site of onset to engage a larger network and induce severe consequences including impaired arousal, cardiorespiratory changes and in some cases death. Impaired cardiorespiratory function during and following seizures may contribute to chronic hypoxic brain damage and to long-term deficits in epilepsy. In addition, sudden unexpected death in epilepsy (SUDEP) is thought to arise from a state in the post-ictal period in which cardiovascular, breathing and arousal functions are impaired. Although cardiac, autonomic, breathing and arousal effects of seizures have long been recognized, the specific mechanisms by which seizures cause these changes have been relatively neglected. Our prior work investigating impaired consciousness in epilepsy suggests that seizures can depress subcortical arousal circuits including the upper brainstem. Human and animal model studies led to the network inhibition hypothesis, in which seizures inhibit brainstem arousal during and following seizures. Our preliminary data extend this work, showing that decreased ictal and post- ictal cardiorespiratory function in a rodent model is associated with markedly suppressed firing of medullary serotonergic neurons in the lower brainstem. Based on these findings, our central hypothesis is that seizures propagate to inhibitory circuits which depress lower brainstem neuromodulatory and control systems; this in turn impairs cardiorespiratory functions significant for seizure morbidity and mortality. We plan to investigate this hypothesis in detail through a combination of neuroimaging, electrophysiology, and neurotransmitter studies in a rodent model.
Our aims are to first define the network of cortical and subcortical structures which cause impaired cardiorespiratory function during and following seizures using fMRI, local field and multiunit recordings, local electrical and optogenetic stimulation and inactivation experiments. Next, we will investigate the neurotransmitters producing impaired cardiorespiratory function using in vivo biosensor probe measurements. Finally, we will determine the changes in firing patterns of identified brainstem serotonergic and other modulatory neurons as well as cardiorespiratory control neurons using juxtacellular recordings during and following seizures. The integration of information across these levels will increase our understanding of abnormal long-range network changes underlying impaired ictal and post-ictal breathing and cardiac function, potentially leading to new treatment options to prevent seizure-related morbidity and mortality.
Impaired cardiorespiratory function and arousal following seizures are important causes of both chronic deficits and sudden unexpected death in epilepsy. Understanding the fundamental network mechanisms of impaired breathing and cardiac function in seizures may lead to improved surgical, neurostimulation or pharmacotherapies designed to improve outcome and save lives of people with epilepsy.
| Feng, Li; Motelow, Joshua E; Ma, Chanthia et al. (2017) Seizures and Sleep in the Thalamus: Focal Limbic Seizures Show Divergent Activity Patterns in Different Thalamic Nuclei. J Neurosci 37:11441-11454 |
| Zhan, Qiong; Buchanan, Gordon F; Motelow, Joshua E et al. (2016) Impaired Serotonergic Brainstem Function during and after Seizures. J Neurosci 36:2711-22 |
