Research ArticleEpilepsy

Cognitive refractory state caused by spontaneous epileptic high-frequency oscillations in the human brain

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Science Translational Medicine  16 Oct 2019:
Vol. 11, Issue 514, eaax7830
DOI: 10.1126/scitranslmed.aax7830
  • Fig. 1 Spatial locations of pathological HFOs and functional HFBs.

    (A) Data recorded from a subset of channels in two representative subjects, S1 (grid) and S4 (depth), showing early involvement of the HFO site in seizure onset. Epileptiform discharges are marked by red stars. (B) Electrode coverage in all subjects with the load of HFOs in each electrode. Results are derived after coregistration of individual preoperative magnetic resonance imaging and postoperative computed tomography images. The selected ROIs in each subject are circled in red; the contacts with HFB activation within the ROI are pointed at by white arrows.

  • Fig. 2 Temporal and spectral profiles of HFO and HFB signals.

    (A) Data plots for exemplar HFO and HFB in the same sites in two representative cases for groups 1 and 2 subjects (S1 and S4). For each sample event, raw data (top) and high-pass–filtered data above 80 Hz (bottom) are shown. For an HFO event, time = 0 indicates the time point corresponding to the peak amplitude; for an HFB event, time = 0 indicates the onset of stimulus onset. (B) Time-frequency maps averaged across all HFO and HFB events in S1 and S4. (C) Averaged power time course in the high-frequency band above 80 Hz for HFO and task-induced HFB in S1 and S4. Task-induced low-band deactivation is also presented. (D) Averaged signal spectra for HFO and HFB in S1 and S4. The spectral width is given by its FWHM (dashed vertical lines). (E) Averaged time-frequency maps, signal duration, and spectral width for HFO and HFB activities in all subjects. **P < 0.01.

  • Fig. 3 Characterization of signal PSD.

    (A) Signal PSD for a single HFO event and an HFB event in S1. Compared with its corresponding baseline (black dashed line), the sample HFO shows a change in the shape of PSD, with its peak localized at about 120 Hz; HFB shows an overall shift in the amplitude, but not the shape of PSD. (B) Average PSD for HFOs and HFBs in all subjects. Plots are shown in scaled windows for visualization purposes. (C) Histogram of exponent coefficient x derived from power-law model fitting for HFOs and HFBs. Results show a shift in the distribution of exponent values only for HFOs. Different window scaling was used for visualization purposes. (D) Comparison between the change in exponent coefficient x for HFO and HFB events in all subjects. **P < 0.01.

  • Fig. 4 Feature distribution of HFBs and HFOs.

    (A) Box plots showing the normalized values for three classical features and four optimized features in S1 and S4 (the first two rows) and in all subjects (the third row). (B) Three-dimensional scatterplots showing the distribution of the three most distinctive features (sub-band power ratio, line length, and relative peak amplitude) in all subjects. ****P < 10−4, ***P < 10−3, and **P < 0.01.

  • Fig. 5 Temporal correlations between HFOs and HFBs during cognitive tasks.

    (A) An illustration of a single-trial HFB response in S1. The power increase was evaluated by calculating the area (green) defined by the power time course of HFB and its corresponding local threshold derived from the prestimulus baseline (red dashed line). (B) Concatenated power time series (100 s) showing spontaneous HFOs and stimulus-locked HFBs during cognitive task in S1. Onsets of the visual stimuli are shown in gray vertical lines. (C) Ten-second scaled window showing the same data as in (B). Five behavioral trials are included. Note the absence of HFB activation during the second and the third trials where two incidents of HFOs had been detected. (D) Relationship between the magnitude of HFO versus HFB per unit of time. Each data point represents the sum of HFB or HFO power within each 1-min window bin. The results are normalized between 0 and 1 and ranked according to the HFO power (from low to high). Data points and error bars represent means and SEM, respectively (darker shades: mean values; lighter shades: individual data). *P < 0.05.

  • Fig. 6 Relationship between HFOs and HFBs during cognitive tasks.

    (A) Likelihood of missed physiological responses (or absence of stimulus-locked HFBs) compared with the time of HFO occurrence. Cortical physiological HFB responses are more likely to be missed if there is an ongoing spontaneous HFO activity within −200 to +100 ms around the onset of stimuli (time 0) for the visual task and −200 to +200 ms for the memory task (P < 10−4). Note that HFB responses are expected to occur ~100 to 200 ms after the onset of visual or memory stimuli (yellow arrows). Solid line: averaged results; dashed line: data in each individual subject. (B) Pearson’s correlation between the time of onset of HFB activation and HFO occurrence relative to the stimulus onset. Results are derived from trials with both HFO and HFB responses. (C) HFB responses in three time windows grouped by the relative time of HFO occurrence (−1500 to −1000 ms, −1000 to −500 ms, −500 to 0 ms to stimulus onset) in S1 and S4. HFBs are weakened as HFOs are approaching the stimulus onset. (D) Relationship between HFO synchronization/power and physiological brain activity. Disruptive HFOs have more electrodes with synchronous activity, as well as higher power, compared with nondisruptive HFOs. Data points and error bars represent means and SEM, respectively. ****P < 10−4, **P < 0.01, and *P < 0.05.

  • Fig. 7 Behavioral effects of pathological HFO.

    (A) Normalized group-level results showing the behavioral effects of prestimulus pathological HFOs during task 2. Square and triangle symbols with gray dash lines depict results for conditions I and II in each individual subject, respectively. Consistently, in all subjects, the reaction accuracy and confidence score decreased, whereas the reaction time increased significantly (P < 0.05, nonparametric Friedman test). (B) Subject with the highest HFO load (S2) had the lowest behavioral performance during memory task, whereas subject with a relatively low baseline HFO rate (S1) had the best performance. These results indicate that subjects’ performance during memory task tends to negatively correlate with the load of HFO during the task and the frequency of HFO during resting state.

  • Table 1 Subject demographical information.

    RNS, responsive neurostimulation.

    SubjectAgeSideNumber of electrodesConfirmed seizure onsetTreatment
    S146Right112Occipital lobeNone
    S223Left116Ventral temporal cortexRNS
    S332Left252Ventral temporal cortexNone
    S445Left + right150MTLRNS
    S532Left + right138MTLRNS
    S624Left + right64MTLRNS
  • Table 2 Unique and common effects for each independent variable.

    FeaturesUniqueCommonTotal
    Peak amplitude0.05750.03400.0915
    High-band power0.05190.02170.0369
    Sub-band power ratio0.01750.39570.4132
    Entropy0.00100.22050.2215
    Line length0.00100.30440.3054
    Relative peak amplitude0.19510.21060.4057
  • Table 3 Behavioral effect of pathological HFOs during task 2.

    SubjectHFO load*CategoryIndoor/outdoor recognition
    (condition I)
    Old/new recognition
    (condition II)
    AccuracyReaction time (s)AccuracyReaction time (s)Confidence
    S458%With HFO100%0.3871%0.92Embedded Image
    Without HFO100%0.3581%0.64Embedded Image
    S588%With HFO82%0.9421%1.42Embedded Image
    Without HFO85%0.8834%1.10Embedded Image
    S665%With HFO74%0.3972%1.76Embedded Image
    Without HFO87%0.2077%0.83Embedded Image

    *HFO load=number of trials with prestimulus HFOtotal number of stimulus trials%.

    Embedded Image: Unsure, “1”; Embedded Image: maybe, “2”; Embedded Image: sure, “3.”

    • Table 4 Behavioral effect of slow spikes during task2, condition II (old/new recognition).

      SubjectCategoryAccuracyReaction time (s)
      S4With HFO71%0.92
      Without HFO81%0.64
      With slow spike79%0.58
      S5With HFO21%1.42
      Without HFO34%1.10
      With slow spike39%1.03
      S6With HFO72%1.76
      Without HFO77%0.83
      With slow spike80%1.08

    Supplementary Materials

    • stm.sciencemag.org/cgi/content/full/11/514/eaax7830/DC1

      Materials and Methods

      Fig. S1. Study design.

      Fig. S2. Pathological HFOs present isolated high-frequency component and generate compact subclusters in the time domain.

      Fig. S3. Comparison between HFB activations in epileptic and in nonepileptic sites.

      Fig. S4. Temporal and spectral profiles of HFO and HFB signals in all subjects.

      Fig. S5. Feature distribution of HFBs and HFOs in all subjects.

      Fig. S6. ROC curves for the SVM classifier.

      Fig. S7. Concatenated power time series showing spontaneous HFOs and stimulus-locked HFBs during cognitive task.

      Fig. S8. Signal properties of HFOs during behavioral task.

      Fig. S9. Comparison between disruptive and nondisruptive HFOs in all subjects.

      Fig. S10. Electrophysiological effect of slow spikes during task 2.

      Data file S1. Raw data.

      References (4852)

    • The PDF file includes:

      • Materials and Methods
      • Fig. S1. Study design.
      • Fig. S2. Pathological HFOs present isolated high-frequency component and generate compact subclusters in the time domain.
      • Fig. S3. Comparison between HFB activations in epileptic and in nonepileptic sites.
      • Fig. S4. Temporal and spectral profiles of HFO and HFB signals in all subjects.
      • Fig. S5. Feature distribution of HFBs and HFOs in all subjects.
      • Fig. S6. ROC curves for the SVM classifier.
      • Fig. S7. Concatenated power time series showing spontaneous HFOs and stimulus-locked HFBs during cognitive task.
      • Fig. S8. Signal properties of HFOs during behavioral task.
      • Fig. S9. Comparison between disruptive and nondisruptive HFOs in all subjects.
      • Fig. S10. Electrophysiological effect of slow spikes during task 2.
      • Legend for data file S1
      • References (4852)

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      Other Supplementary Material for this manuscript includes the following:

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