Sleep Disturbances as a Potential Mechanism of Post-Traumatic Epileptogenesis
Abstract
Disrupted sleep is common and persistent symptom after traumatic brain injury (TBI), which can significantly complicate recovery for civilian population and for military personnel with deployment TBI history. In epilepsy, some types of seizure occur primarily during sleep and can be exacerbated by sleep deprivation. However, the relationship between sleep disturbances following brain trauma and development of post-traumatic epilepsy (PTE) remains poorly understood. To improve quality of life in Service Members and Veterans with PTE, an understanding of the varied mechanisms triggered by TBI is required to prevent or optimally manage development of epileptogenesis. Therefore, our long-term goal in this proposal is to uncover fundamental principles of sleep disturbances during development of post-traumatic epileptogenesis. Rationale: (1) Characterization of the circuits involved in PTE: While sleep disturbances such as difficulty falling and staying asleep are often caused by a disruption of the circadian rhythm, they can be misdiagnosed due to symptomatic overlap with insomnia. Interestingly, the circadian rhythm center, the suprachiasmatic nucleus of the hypothalamus (SCN), is composed exclusively of the inhibitory GABA-ergic interneurons, a type of neurons preferentially affected by trauma. However, the mechanisms underlying the extent of circadian-related sleep disruption following TBI remain poorly understood, as are the potential effects of brain trauma on the circadian rhythms circuitry. (2) Development of new models or better characterization of existing etiologically relevant models for PTE: While the majority of work using animal models of PTE have utilized rats and mice, rodent models of TBI are not capable to accurately represent the biomechanics of brain injury in a gyrencephalic brain, or the effects of white matter injury observed in human TBI. Therefore, brains of large animals such as pigs, with their gyrencephalic structure and appropriate white-to-grey matter ratios, are more closely resemble human architecture and, hence, are important for an accurate biomechanical modeling of all aspects of human TBI. (3) Innovative Research: Currently, there is a lack of studies utilizing continuous electrophysiological monitoring to detect disrupted sleep and circadian rhythms in subcortical regions and deep brain structures starting at time zero and chronically over time post-TBI. The use of continuous electroencephalogram (EEG) instead of sporadic EEG recordings immediately and over time post-TBI will significantly advance our understanding of TBI-induced sleep disturbances. Using continuous EEG monitoring in a large animal model (swine) of controlled-cortical impact (CCI) injury, we demonstrated sleep disturbances starting at the time zero and up to 5 months post-injury. Moreover, using behavioral video monitoring, we demonstrated that marked alterations in sleep states are potentially caused by a disruption of the circadian rhythms. Over time, CCI-injured but not control animals developed seizures predominantly during sleep and detected in the injured cortex. These preliminary results together with histopathological changes observed in the SCN have led to our central hypothesis that network changes in the circadian rhythm center lead to disrupted sleep states over time post-injury and potentially contribute to the development of PTE. Our objectives in this proposal are to identify the extent of interneuron-related pathologies in the SCN that lead to the development of sleep disturbances observed over time post-CCI injury. Our proposal Sleep disturbances as a potential mechanism of post-traumatic epileptogenesis directly addresses several the Focus Areas requested in the Fiscal Year 2021 Epilepsy Research Program ERP Idea Development Award program announcement. The objectives of this proposal will address the Innovative Research Focus Area, specifically falling under the following areas: Devel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210287
Entities
People
- Alexandra V Ulyanova
Organizations
- United States Army
- University of Pennsylvania