A series of studies exploring the patterns of neuronal activity that promote excitability in the brain have identified a new link with potentially important implications to the understanding of epilepsy and other neurologic disorders, and may lead to the development of more effective treatments.
The initiation of seizure activity has been shown to result from specific changes in the patterns of excitability in cortical tissue. Antiepileptic drugs (AEDs) are designed to temper excitability to reduce the incidence and severity of seizures; however, adequate measures to quantify their effectiveness do not exist.
A group of researchers from the U.S., Germany, Australia, and Switzerland, led by National Institute of Mental Health (NIMH) researchers Christian Meisel, MD, and Dietmar Plenz, PhD, sought to quantify the mechanisms of excitability to develop markers that can guide treatment for epilepsy.
The group collaborated on a paper published in the Proceedings of the National Academy of Sciences in the United States of America which examined sleep/wake patterns.1 Substantial increases in patterns of excitability had been shown in previous studies in individuals kept awake for sustained periods (using perturbation methods), which were then resolved with sleep.2,3 This suggested that the amount of amplification correlated to the degree of excitability, a theory the investigators tested with a stimulation protocol that also measured phase synchronization of ongoing activity.
Mean synchronization levels (R) significantly corresponded to amplification across all frequencies tested, from 50 to 400 Hz in 2 patients, suggesting that phase synchronization levels could provide valid markers of excitability in an environment of continuing cortical activity.
The investigators then compared these results to electroencephalographs (EEGs) taken from 10 presurgical patients given various types and doses of AEDs. Over multiday recordings, R levels fluctuated significantly, with the lowest levels recorded at times of peak AED load. Conversely, R values increased at the trough points on AEDs, thereby demonstrating an inverse correlation between R and AED load.
Levels of R continued to vary throughout the day in these patients, independent of AED load, with increased R levels from morning to night followed by a pattern of lows from night to morning, most likely when the individuals were sleeping. Extension of the investigation to a group of healthy subjects who were vigilantly monitored over a 40-hour period confirmed that increases in R correlated significantly with wake time, leading to the conclusion that brain excitability is a function of wakefulness.
The implications of this line of investigation are for the use of intrinsic excitability measures (IEMs) to noninvasively monitor normal ongoing activity levels over lengthy periods of time as a marker of the effectiveness of epilepsy drug therapy, and for disease management strategy.
- Meisel C, Schulze-Bonhage A, Freestone D, et al. Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle. Proc Natl Acad Sci USA. 2015;13:7-16.
- Badawy RA, Curatolo JM, Newton M, et al. Sleep deprivation increases cortical excitability in epilepsy: Syndrome-specific effects. Neurology. 2006;67:1018–1022.
- Huber R, Rosanova M, Casarotto S, et al. Human cortical excitability increases with time awake. Cereb Cortex. 2013;23:332–338.