Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer

Shennan A. Weiss*, Itzhak Fried, Jerome Engel, Anatol Bragin, Shuang Wang, Michael R. Sperling, Robert K.S. Wong, Yuval Nir, Richard J. Staba

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80–200 Hz) and fast ripples (200–600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ). Methods: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1–2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms. Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < <.001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < <.001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d =.11–.83) and fast ripples (d =.36–.90) at the UP-DOWN transition (p <.05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d =.14–.30) and 8.5% (d =.33–.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3). Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation.

Original languageEnglish
Pages (from-to)362-377
Number of pages16
Issue number2
StatePublished - Feb 2024


FundersFunder number
Christina Louise George Trust
Resnick Family Foundation
National Institutes of HealthK23 NS094633
American Epilepsy SocietyR01 NS033310, R01 NS106957
European Research CouncilERC‐2019‐CoG 864353


    • fast ripple
    • high-frequency oscillation
    • ripple
    • sleep
    • slow wave


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