Authors :
Presenting Author: Ehsan Tadayon, MD – University of California, San Francisco
Saboo Krishnakant, PhD – University of California, San Francisco
Benjamin Speidel, MS – University of California, San Francisco
Jonathan Kleen, MD, PhD – University of California, San Francisco
Ankit Khambhati, PhD – University of California, San Francisco
Joline Fan, MD, MS – Uiversity of California, San Francisco
Vikram Rao, MD – Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco
Rationale:
Circadian rhythms are fundamental to human behavior and brain physiology. In epilepsy, over 80% of patients exhibit circadian patterns of seizures and interictal epileptiform activity. Yet, the timing of these events varies widely across individuals, often in relation to seizure localization, raising the question of whether distinct brain regions are governed by local circadian clocks. We hypothesized that regional variation of circadian patterns of brain activity contributes to this heterogeneity . To test this, we mapped the human brain’s circadian organization through a multimodal approach that integrates intracranial electroencephalography (EEG), resting-state functional magnetic resonance imaging, and transcriptomic data and looked for convergent spatiotemporal patterns.
Methods:
We created a whole-brain circadian organization map by examining daily fluctuations in brain activity using resting-state fMRI data from 1137 healthy young adults in the Human Connectome Project . We inferred regional circadian peaks in brain activity by relating time-of-day at scan to spontaneous blood oxygen level-dependent (BOLD) signal variability. The circadian map derived from resting-state fMRI was then compared to estimated circadian peak hour of intracranial EEG recordings from 80 patients implanted with Responsive Neurostimulation (RNS) devices with leads sampling hippocampus and diverse neocortical regions. For each recording site, circadian peak hour of neural activity was determined by daily fluctuations in broadband power (4-40 Hz). Finally, we hypothesized that regions with similar circadian patterns have similar core clock gene expressions. To test this, we analyzed spatial expression patterns of core circadian clock genes (including BMAL, CLOCK, ARNTL, PER1/2/3, CRY1/2) in postmortem human brain tissue from the Allen Human Brain Atlas (3 donors).
Results:
Regional-specific circadian organization was detected across all three modalities. The whole-brain fMRI-derived circadian map demonstrated a distinct spatial organization: posterior cortical regions (e.g., occipital and parietal cortices) exhibited peak activity around midday (12–2 PM), whereas anterior cortical regions (e.g., prefrontal cortex), hippocampus, and subcortical structures peaked in the early morning hours (2–4 AM). Individual-level circadian peak timing derived from long-term intracranial EEG recordings via RNS showed a significant correlation with the fMRI-based circadian map (r = 0.40, p < 0.001). Additionally, whole-brain fMRI-derived circadian map significantly correlated with the expression profile of core circadian clock genes (circular–linear correlation, r = 0.48, p < 0.001).