Fig. 1
Representative subject demonstrating circadian and multidien rhythms in IEA, as well as preferential timing of seizures. a RNS System comprising cranially implanted neurostimulator connected to intracranial leads (image used with permission from NeuroPace, Inc.). b EEG showing a single-epileptiform discharge (spike) in channels corresponding to left (e1) and right (e2) hippocampal leads. c EEG recorded 1 week later at the same time of day showing higher count of epileptiform discharges, i.e., higher IEA. Inset magnifies one typical element to show waveform morphology. Hourly (d, cyan inset) and daily (e) fluctuation in IEA in one subject over 2 and 12 months, respectively. Red dots indicate times of seizure occurrence. f Wavelet decomposition revealing two component multidien rhythms with periodicities of 10 and 26 days. Combining all multidien wavelet coefficients reconstructs the daily IEA time-series (gray curve, 2–45 d, Pearson correlation r = 0.93, p = 0). g Corresponding periodogram showing ultradian (12 h), circadian (24 h), and multidien (10 and 26 d) peaks in periodicity. Period length displayed on the x-axis, and power index (square root of spectrogram power) on the y-axis. Horizontal double-arrows show span of corresponding wavelet coefficients included for (f) (peak period ± 33%). h Average normalized amplitude of the circadian rhythm as a function of time of the day showing phase preference of seizures near the trough at 5 PM (n = 74 seizures, mean ± SD in red, p = 10−4, Omnibus test, see Methods section). Black and white rectangles (d, h) represent night (6PM–6AM) and day (6AM–6PM), respectively. i, j Average normalized amplitude of the 10 d and 26 d IEA rhythms as a function of their underlying phase (x-axis, full 360 degrees phase; y-axes have different scales). Seizures demonstrate phase preference for the up-slope of both rhythms (10 and 26 days, n = 66 seizures, mean ± SD in red, p = 0.0002 and p = 0.002, respectively, Omnibus test)
