Abstracts

Rationale: Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders such as epilepsy. Recent evidence has shown reduced expression of circadian genes in pathological tissue resected during epilepsy surgery, but it is currently unknown whether there is a functional disruption of chronobiological rhythms specific to the pathological tissue in human epilepsy. Here we investigated this using the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian (daily) and ultradian (minute to hourly) rhythms in different brain regions.

Methods: For each subject we took their entire icEEG recording (median duration 4 days 15 hours), segmented this into 30 second segments, and calculated the power of each canonical EEG band during each segment. We then isolated the chronobiological rhythms (circadian, and 5 ultradian) from this signal using a bandpass filter, mapping these to brain regions. Figure 1a shows the an example of the circadian rhythm in delta power for one subject. We then compared the power of each rhythm in regions clinically identified as the SOZ (pathological regions) to the remainder of regions (other regions), figure 1b-c illustrates this. We used the area under the receiver operator characteristics curve (AUC) for initial comparison, and then calculated an effect size for pathology while taking into account expected variations in chronobiological rhythm strength across brain regions.

Results: We found that functional circadian (figure 1d) and ultradian rhythms (figure 2a) are diminished in the pathological tissue (identified as the seizure onset zone). We also found that chronobiological rhythms vary considerably across brain regions. When taking this effect into account, chronbiological rhythms remained dimished in pathological tissue (figure 2b). Further analysis demonstrated that these diminished rhythms are persistent in time, regardless of seizure load.

Conclusions: These findings provide the first evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in humans, independent of regional variations or pathological events. Currently the direction of causation is unclear, but we hope future work can investigate the potential of modulating chronobiological rhythms in the development of novel therapies.

Funding: P.N.T. and Y.W. are both supported by UKRI Future Leaders Fellowships (MR/T04294X/1, MR/V026569/1). JSD, JdT are supported
by the NIHR UCLH/UCL Biomedical Research Centre.