• Derek J Doss, Abhijeet Gummadavelli, Graham W Johnson, Ghassan S Makhoul, Jared S Shless, Camden E Bibro, Monica L Jacobs, Hakmook Kang, Kevin F Haas, Sarah K Bick, Douglas P Terry, Benoit M Dawant, Catie Chang, Victoria L Morgan, and Dario J Englot.
• Departments of1Biomedical Engineering.
• J. Neurosurg. 2025 Jan 24: 1101-10.

ObjectiveEpilepsy is a common neurological disease affecting nearly 1% of the global population, and temporal lobe epilepsy (TLE) is the most common type. Patients experience recurrent seizures and chronic cognitive deficits that can impact their quality of life, ability to work, and independence. These cognitive deficits often extend beyond the temporal lobe and are not well understood. It has been proposed in the extended network inhibition hypothesis that repeated spread of seizure activity to the ascending reticular activating system (ARAS) may contribute to these deficits. Disease duration has been associated with other network changes in patients with TLE, but few studies have investigated the relationship between disease duration, ARAS connectivity, and cognitive deficits in TLE. Furthermore, epilepsy surgery can result in seizure freedom and cognitive improvement in some patients, but it is unclear how the surgery affects ARAS connectivity.MethodsResting-state functional MRI data were collected for patients with TLE (preoperatively in 40 and postoperatively in 25), and for 40 age-matched healthy controls. Functional connectivity was computed between all regions. Functional connectivity and segregation, a graph-theory measure of network isolation, were compared across the age spectrum in patients and controls. These same measures were evaluated as a function of epilepsy duration by controlling for age using a linear model built on healthy control data.ResultsThe authors found that increases in epilepsy duration were associated with greater segregation of the ARAS and decreased functional connectivity between the pedunculopontine tegmental nucleus and the frontoparietal association cortex. Furthermore, patients with impaired neurocognitive function were noted to have longer epilepsy duration and higher ARAS segregation compared to patients with spared neurocognition. After surgery, completely seizure-free patients demonstrated ARAS connectivity patterns that resembled those found in controls, whereas patients with residual seizures had persistent abnormal connectivity.ConclusionsThese findings suggest that recurrent seizures may contribute to isolation of critical subcortical activating structures, possibly impacting cognitive function. Furthermore, some ARAS functional connectivity abnormalities can be reversed if seizure freedom is achieved after epilepsy surgery. These results provide support for the extended network inhibition hypothesis, may lend insight into the progressive effect of recurrent seizures on arousal networks, and may lead to improved interventions to halt or reverse network impairments in patients with TLE.

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