Sleep-wake Characteristics in a Mouse Model of Severe Traumatic Brain Injury: Relation to Post-Traumatic Epilepsy.

Abstract

Study objectivesTraumatic brain injury (TBI) results in sequelae that include post-traumatic epilepsy (PTE) and sleep-wake disturbances. Here we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. MethodsFollowing controlled cortical impact (CCI), sham injury (craniotomy only) or no craniotomy (NC), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2 and 3 after injury) 1-week long video-EEG/EMG recordings were examined for epileptiform activity. We analyzed sleep-wake patterns manually and extracted high amplitude interictal events from EEG using an automated method. Sleep spindles and EEG delta power were derived from non-rapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed to quantify the extent of brain lesions in cohorts of sham and CCI. ResultsPosttraumatic seizures were seen with CCI, whereas interictal epileptiform activity as well as sleep-wake disruptions (shorter wake or NREM bout lengths, shorter duration or lower power for spindles, and increased NREM EEG delta power) were seen in CCI and sham groups. No sleep feature predicted PTE. Follow up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. ConclusionsIn our model, interictal epileptiform activity and sleep disruptions resulted from CCI and sham and thus, sham injury was not an optimal negative control. Further work is necessary to determine the relationship between sleep-wake disturbances and PTE. Statement of significanceTraumatic brain injury (TBI) results in sequelae such as post-traumatic seizures and sleep-wake disturbances but it is difficult to predict which individuals will develop these symptoms. Our study is novel in that we characterized epileptiform activity and multiple sleep characteristics in a mouse model of severe TBI (Controlled cortical impact-CCI) and explored whether any specific sleep disturbance can predict post-traumatic epilepsy. Specifically, post-traumatic seizures were seen after CCI only whereas epileptiform activity other than seizures as well as sleep-wake disruptions in mice that received a TBI and their sham injury controls. CT imaging showed that the sham injury group also had small brain lesions suggesting that a more optimal control in TBI research is to perform no craniotomy. No single sleep characteristic was predictive of post-traumatic epilepsy although NREM delta power was different in chronic recordings between TBI mice that developed seizures and those that did not. These studies are relevant to further research in TBI models, to develop a sleep biomarker for PTE. The work is also relevant to humans with TBI as monitoring sleep phenotypes may predict risk, but may also help develop therapies to prevent post-traumatic epilepsy.