Abnormal phase entrainment of low- and high-gamma-band auditory steady-state responses in schizophrenia

Abstract

Introduction: Gamma-band oscillatory deficits have attracted considerable attention as promising biomarkers of schizophrenia (SZ). Notably, a reduced auditory steady-state response (ASSR) in the low gamma band (40 Hz) is widely recognized as a robust finding among SZ patients. However, a comprehensive investigation into the potential utility of the high-gamma-band ASSR in detecting altered neural oscillations in SZ has not yet been conducted.

Methods: The present study aimed to assess the ASSR using magnetoencephalography (MEG) data obtained during steady-state stimuli at frequencies of 20, 30, 40, and 80 Hz from 23 SZ patients and 21 healthy controls (HCs). To evaluate the ASSR, we examined the evoked power and phase-locking factor (PLF) in the time-frequency domain for both the primary and secondary auditory cortices. Furthermore, we calculated the phase-locking angle (PLA) to examine oscillatory phase lead or delay in SZ patients. Taking advantage of the high spatial resolution of MEG, we also focused on the hemispheric laterality of low- and high-gamma-band ASSR deficits in SZ.

Results: We found abnormal phase delay in the 40 Hz ASSR within the bilateral auditory cortex of SZ patients. Regarding the 80 Hz ASSR, our investigation identified an aberrant phase lead in the left secondary auditory cortex in SZ, accompanied by reduced evoked power in both auditory cortices.

Discussion: Given that abnormal phase lead on 80 Hz ASSR exhibited the highest discriminative power between HC and SZ, we propose that the examination of PLA in the 80 Hz ASSR holds significant promise as a robust candidate for identifying neurophysiological endophenotypes associated with SZ. Furthermore, the left-hemisphere phase lead observed in the deficits of 80 Hz PLA aligns with numerous prior studies, which have consistently proposed that SZ is characterized by left-lateralized brain dysfunctions.

Keywords: auditory steady-state response (ASSR); evoked power; gamma oscillation; magnetoencephalography (MEG); phase locking angle (PLA); phase locking factor (PLF); schizophrenia.

FIGURE 1

Regions of interest for source analysis of ASSRs. The green and blue areas indicate the primary and secondary auditory cortices, respectively, in both hemispheres. AC, auditory cortex.

FIGURE 2

The grand average time-frequency maps of the evoked power during 80 Hz stimulation in each HC (upper line) or SZ (lower line) group for each region of interest. From left, the columns show the maps derived from the left primary auditory cortex, the left secondary auditory cortex, the right primary auditory cortex, and the right secondary auditory cortex. The color bar shows the values of the evoked power, in which red indicates a higher value and blue indicates a lower value. HC, healthy control; SZ, schizophrenia; AC, auditory cortex.

FIGURE 3

The time-averaged (200–400 ms) PLAs plotted on the polar coordinate of each subject and the grand average time-averaged PLA in each group (SZ or HC) at each stimulation frequency for each stimulus condition and each region of interest. In each plot, each thin red line indicates the time-averaged PLA of each SZ subject, each thin blue line indicates each HC subject, the thick red line indicates the grand average in the SZ group, and the thick blue line indicates the grand average in the HC group. The numbers placed circularly indicate angles (unit: degree). Each of the 4 plots on a horizontal line shows the plots derived at each stimulation frequency. Each column shows the plots in the same way as in Figure 2. In this figure, the thick green lines highlight the time-averaged PLAs at the 40 Hz stimulation, emphasizing that the SZ group had significant phase lags compared to the HC. The thick red lines highlight the time-averaged PLAs under 80 Hz stimulation in the left secondary auditory cortex, emphasizing that the SZ group had a significant phase lead compared to the HC group. HC, healthy control; SZ, schizophrenia; AC, auditory cortex; PLA, phase-locking angle.

FIGURE 4

The grand average time course difference of 40 Hz PLA in the SZ group for each hemisphere and each ROI compared to HC, in which the PLA in SZ was subtracted from the PLA in HC. The thick red line in each time course indicates the time range used for statistical analysis of the PLA (200–400 ms). HC, healthy control; SZ, schizophrenia; AC, auditory cortex; PLA, phase-locking angle; ROI, regions of interest.

FIGURE 5

The grand average time course of 80 Hz PLA in the SZ group on the left secondary auditory cortex. The thick red line in each time course indicates the time range used for statistical analysis of the PLA (200–400 ms). HC, healthy control; SZ, schizophrenia; AC, auditory cortex; PLA, phase-locking angle.

FIGURE 6

Comparison of receiver operating characteristic (ROC) curves between SZ and HC groups for 80 Hz evoked power (left), 80 Hz phase lead (middle), and 40 Hz phase delay (right). HC, healthy control; SZ, schizophrenia; AC, auditory cortex; PLA, phase-locking angle; ROI, regions of interest.