title: Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones.
abstract: 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.
  
  
  
  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).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Shennan A
authors.initials: SA
authors.lastname: Weiss
authors.affiliation: Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Iren
authors.initials: I
authors.lastname: Orosz
authors.affiliation: Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Noriko
authors.initials: N
authors.lastname: Salamon
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moy
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Linqing
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Van't Klooster
authors.affiliation: Department of Psychology, University of California Berkeley, Berkeley, California, U.S.A.|Department of Neuroscience, University of California Berkeley, Berkeley, California, U.S.A.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Knight
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Harper
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Anatol
authors.initials: A
authors.lastname: Bragin
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Itzhak
authors.initials: I
authors.lastname: Fried
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Jerome
authors.initials: J
authors.lastname: Engel
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Staba
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D058256:Brain Waves / Q000502:physiology*; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015898:Tomography Scanners, X-Ray Computed; D055815:Young Adult
keywords: Epileptiform discharge; High-frequency oscillation; Intracranial EEG; Mesial temporal lobe epilepsy; Ripple