Refining epileptogenic high-frequency oscillations using deep learning: a reverse engineering approach
Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, visual verification of HFOs is time-consuming and exhibits poor inter-rater reliability. Furthermore, no method is currently available to distinguish HFOs generated from the epileptogenic zone (epileptogenic HFOs: eHFOs) from those generated from other areas (non-epileptogenic HFOs: non-eHFOs). To address these issues, we constructed a deep learning (DL)-based algorithm using HFO events from chronic intracranial electroencephalogram (iEEG) data via subdural grids from 19 children with medication-resistant neocortical epilepsy to: 1) replicate human expert annotation of artifacts and HFOs with or without spikes, and 2) discover eHFOs by designing a novel weakly supervised model (HFOs from the resected brain regions are initially labeled as eHFOs, and those from the preserved brain regions as non-eHFOs). The "purification power" of DL is then used to automatically relabel the HFOs to distill eHFOs. Using 12,958 annotated HFO events from 19 patients, the model achieved 96.3% accuracy on artifact detection (F1 score = 96.8%) and 86.5% accuracy on classifying HFOs with or without spikes (F1 score = 80.8%) using patient-wise cross-validation. Based on the DL-based algorithm trained from 84,602 HFO events from nine patients who achieved seizure-freedom after resection, the majority of such DL-discovered eHFOs were found to be HFOs with spikes (78.6%, p < 0.001). While the resection ratio of detected HFOs (number of resected HFOs/number of detected HFOs) did not correlate significantly with post-operative seizure freedom (the area under the curve [AUC]=0.76, p=0.06), the resection ratio of eHFOs positively correlated with post-operative seizure freedom (AUC=0.87, p=0.01). We discovered that the eHFOs had a higher signal intensity associated with ripple (80-250 Hz) and fast ripple (250-500 Hz) bands at the HFO onset and with a lower frequency band throughout the event time window (the inverted T-shaped), compared to non-eHFOs. We then designed perturbations on the input of the trained model for non-eHFOs to determine the models decision-making logic. The model probability significantly increased towards eHFOs by the artificial introduction of signals in the inverted T-shaped frequency bands (mean probability increase: 0.285, p < 0.001), and by the artificial insertion of spike-like signals into the time domain (mean probability increase: 0.452, p < 0.001). With this DL-based framework, we reliably replicated HFO classification tasks by human experts. Using a reverse engineering technique, we distinguished eHFOs from others and identified salient features of eHFOs that aligned with current knowledge. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/458385v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@39977dorg.highwire.dtl.DTLVardef@108b182org.highwire.dtl.DTLVardef@1bdf864org.highwire.dtl.DTLVardef@fe9e57_HPS_FORMAT_FIGEXP M_FIG C_FIG