Phase-Amplitude Coupling Is Elevated in Deep Sleep and in the Onset Zone of Focal Epileptic Seizures

Abstract

The interactions between different EEG frequency bands have been widely investigated in normal and pathologic brain activity. Phase-amplitude coupling (PAC) is one of the important forms of this interaction where the amplitude of higher frequency oscillations is modulated by the phase of lower frequency activity. Here, we studied the dynamic variations of PAC of high (gamma and ripple) and low (delta, theta, alpha, and beta) frequency bands in patients with focal epilepsy in different sleep stages during the interictal period, in an attempt to see if coupling is different in more or less epileptogenic regions. Sharp activities were excluded to avoid their effect on the PAC. The results revealed that the coupling intensity was generally the highest in stage N3 of sleep and the lowest in rapid eye movement sleep. We also compared the coupling strength in different regions [seizure onset zone (SOZ), exclusively irritative zone, and normal zone]. PAC between high and low frequency rhythms was found to be significantly stronger in the SOZ compared to normal regions. Also, the coupling was generally more elevated in spiking channels outside the SOZ than in normal regions. We also examined how the power in the delta band correlates to the PAC, and found a mild but statistically significant correlation between slower background activity in epileptic channels and the elevated coupling in these channels. The results suggest that an elevated PAC may reflect some fundamental abnormality, even after exclusion of sharp activities and even in the interictal period. PAC may therefore contribute to understanding the underlying dynamics of epileptogenic brain regions.

Keywords: cross-frequency coupling; epilepsy; interictal EEG; phase- amplitude coupling; seizure onset zone; sleep.

FIGURE 1

(A) The first sleep cycle of the hypnogram (blue line), and data selection in different sleep stages in pt. 12 as an example: N1, N2, N3, and REM: from light to dark red regions. (B) Extracting phase and amplitude of the signal using Hilbert transform. Shading represents intervals of sharp activities that are removed from the analysis. (C) Average amplitude for a given phase for the signal shown in ‘B’. Red line shows the uniform distribution.

FIGURE 2

(Top) The modulation index calculated for different pairs of low and high frequencies. (Below) Average amplitude for a given phase (from left to right: high, moderate, and low couplings). Solid and broken red lines indicate the mean and the standard deviation among the 200 surrogate data.

FIGURE 3

Average phase-amplitude coupling (PAC) quantified by modulation index (MI) (A) gamma band and low frequencies, (B) ripple band and low frequencies. Green: normal zone (NoZ), Yellow: exclusively irritative zone (EIZ), Red: seizure onset zone (SOZ), Gray: all channels. ^∗ Shows significant difference (p < 0.05, corrected). The order: N1, N2, N3, REM, from light to dark color. Results are plotted as the mean ± SE.

FIGURE 4

Average PAC quantified by MI in different regions (A) gamma band and low frequencies, (B) ripple band and low frequencies (top: delta, middle: theta, below: alpha); Green: NoZ, Yellow: EIZ, Red: SOZ. ^∗ Shows significant difference (p < 0.05, corrected). Results are plotted as the mean ± SE.

FIGURE 5

(A) Higher values of PAC in the SOZ compared to the NoZ, and in N3 compared to other stages. The average of PAC in all channels in different sleep stages, (B) Percentage of channels with significant coupling in different frequency pairs. NoZ, normal zone; EIZ, exclusively irritative zone; SOZ, seizure onset zone; MI, modulation index.

FIGURE 6

Average ripple band amplitude as a function of low-frequency phase in normal and SOZ channels. Phases 0 and π correspond to the low-frequency band peak and trough respectively. The difference in preferred coupling phase in theta and alpha bands compared to delta band is shown by black arrows. More high frequency activity is seen at the trough of theta and alpha rhythms (black circles). NoZ, normal zone; SOZ, seizure onset zone.

FIGURE 7

Average of relative delta power in different regions; Green: NoZ, Yellow: EIZ, Red: SOZ. ^∗ Shows significant difference (p < 0.05, corrected). Results are plotted as the mean ± SE.