IGE subjects organised based on different circadian ED distribution patterns.

(A) A pairwise cross-correlation matrix (of size 107 × 107) was calculated using ED hourly rate patterns in order to establish similarities within the IGE cohort. (B) Group 1 (blue, N = 66) and Group 2 (red, N = 41) were identified based on the similarities of hourly ED rate.</p

Supplementary materials.

Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy—so-called interictal epileptiform activity—with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.</div

Model results compared with IGE data.

(A) Histogram of EDs from Group 1 with IGE (blue) and histogram of EDs simulated using the model with λext defined to mimic the different brain excitability during sleep stages (green). (B) Histogram of EDs from Group 2 with IGE (red) and histogram of EDs simulated using the model with λext defined to mimic the impact of CORT on the brain excitability (green).</p

Parameters for the mathematical model.

Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy—so-called interictal epileptiform activity—with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.</div

Characteristics of the subjects from the sleep cohort used in the simulations.

Characteristics of the subjects from the sleep cohort used in the simulations.</p

Impact of timing of sleep and its duration on ED distributions.

Epileptiform discharges for Group 1 (top row) and Group 2 (bottom row) with time normalised such that t = 0 corresponds with sleep onset (A and C) and with sleep offset (B and D). The transparent grey box highlights the average habitual sleep period. The black arrows indicate the peaks in the ED distribution in Group 2. The peaks were determined by identifying the local maxima of the density function (solid red line).</p

Best model fit for Group 1 compared with IGE data.

Histogram of EDs from Group 1 with IGE (blue) and histogram of EDs simulated using the model with λext defined to mimic the impact of the combined mechanism (sleep and CORT) on excitability (green). In this simulation, pS = 1 and pC = 1.2.</p

ED occurrence.

Boxplots showing the distribution of ED across 24 hours for Group 1 (A) and Group 2 (B). Within each box plot, the central line represents the median, and the bottom and top edges represent the 0.25 and 0.75 quantiles, respectively. The whiskers extend to the most extreme data points not considered outliers.</p

ED distribution in people with IGE.

(A) Number of EDs from 107 subjects with idiopathic generalized epilepsy (IGE). (B) Boxplot shows basic sample statistics (minimum, lower quartile, median, upper quartile and maximum) of the number of EDs. (C) normalised EDs rate per hour.</p