Abstract
Ripple oscillations (80–250 Hz) are a promising biomarker of epileptic activity, but are also involved in memory consolidation, which impairs their value as a diagnostic tool. Distinguishing physiologic from epileptic ripples has been particularly challenging because usually, invasive recordings are only performed in patients with refractory epilepsy. Here, we identified ‘healthy’ brain areas based on electrical stimulation and hypothesized that these regions specifically generate ‘pure’ ripples not coupled to spikes. Intracranial electroencephalography (EEG) recorded with subdural grid electrodes was retrospectively analyzed in 19 patients with drug-resistant focal epilepsy. Interictal spikes and ripples were automatically detected in slow-wave sleep using the publicly available Delphos software. We found that rates of spikes, ripples and ripples coupled to spikes (‘spike–ripples’) were higher inside the seizure-onset zone (p < 0.001). A comparison of receiver operating characteristic curves revealed that spike–ripples slightly delineated the seizure-onset zone channels, but did this significantly better than spikes (p < 0.001). Ripples were more frequent in the eloquent neocortex than in the remaining non-seizure onset zone areas (p < 0.001). This was due to the higher rates of ‘pure’ ripples (p < 0.001; median rates 3.3/min vs. 1.4/min), whereas spike–ripple rates were not significantly different (p = 0.87). ‘Pure’ ripples identified ‘healthy’ channels significantly better than chance (p < 0.001). Our findings suggest that, in contrast to epileptic spike–ripples, ‘pure’ ripples are mainly physiological. They may be considered, in addition to electrical stimulation, to delineate eloquent cortex in pre-surgical patients. Since we applied open source software for detection, our approach may be generally suited to tackle a variety of research questions in epilepsy and cognitive science.
Highlights
High-frequency oscillations (HFOs), traditionally divided into ripples (80–250 Hz) and fast ripples (250–500 Hz), are a promising marker of epileptic activity. They have been directly linked to seizures [1,2,3,4]; there is a an extensive body of evidence on the value of interictal HFOs: resecting HFO-generating tissue has been associated with seizure-free outcome [5,6,7,8], HFO rates correlated with response to electrical stimulation [9], HFOs were suppressed by antiepileptic medication [10,11], and ripples may identify patients at risk of developing epilepsy [12]
In patient 2, the grid did not cover the seizure onset zone (SOZ); this patient had to be excluded from the patient-specific comparisons of SOZ and non-SOZ channels described below
Several lines of evidence suggest that spike–ripples are a distinct pathophysiological phenomenon: ripples riding on spikes are frequently visible even in unfiltered traces, as recent studies have revealed their value in different clinical scenarios [28,31], and we have reported that spikes with HFOs have a distinct single-neuron correlate [46]
Summary
High-frequency oscillations (HFOs), traditionally divided into ripples (80–250 Hz) and fast ripples (250–500 Hz), are a promising marker of epileptic activity. One reason may be that the visual identification is time-consuming, an obstacle that may be overcome by the increasing efficiency of automatic detectors [13,14,15,16] Another key aspect is that ripples are likely involved in memory consolidation [17,18,19], which may open new avenues for cognitive science, but impairs specificity if ripples are analyzed in epilepsy. To develop strategies that reliably distinguish pathologic from physiologic HFOs is of imminent importance for researchers from both fields [20]
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