Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones

Shennan A. Weiss*, Iren Orosz, Noriko Salamon, Stephanie Moy, Linqing Wei, Maryse A. Van't Klooster, Robert T. Knight, Ronald M. Harper, Anatol Bragin, Itzhak Fried, Jerome Engel, Richard J. Staba

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: Ripples (80–150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. Methods: We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ). Results: Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). Significance: Generation of low-frequency (80–150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

Original languageEnglish
Pages (from-to)1916-1930
Number of pages15
Issue number11
StatePublished - 1 Nov 2016
Externally publishedYes


FundersFunder number
National Institute of Neurological Disorders and StrokeR01NS065877


    • Epileptiform discharge
    • High-frequency oscillation
    • Intracranial EEG
    • Mesial temporal lobe epilepsy
    • Ripple


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