Individualized Closed-Loop Acoustic Stimulation Suggests an Alpha Phase Dependence of Sound Evoked and Induced Brain Activity Measured with EEG Recordings

Estimation of IAF. A, B, Multitaper time-frequency power spectrograms for the example subject (Sub 136) measured at the frontal (A, Fpz) and prefrontal (B, Fz) locations. Ai, Bi, Detrended spectral density plots used to find the frequency with maximum power as an estimate of IAF for an example subject (Sub 136). Red dot indicates the location of the power maximum in each plot. C, D, The population average of multitaper time-frequency power spectrograms (n = 19) for the frontal (C, Fpz) and prefrontal (D, Fz) locations. Ci, Di, Corresponding population average detrended PSD plots for frontal (Ci) and prefrontal (Di) locations. As the power tends to be lower for people with higher frequency IAF, the population average spectrogram yields IAFs of 9.6 and 9.67 Hz at frontal (Fpz) and prefrontal (Fz) locations, whereas the average of individual IAFs is closer to 10 Hz (see text).

Individualized trough and peak sound onset phases align auditory evoked P1 potentials with poststimulus peak and trough phases with minimal phase-locking error. A, As illustrated for trough phase, the target phases vary systematically with the ERP-P1 latency and IAF (lines Hz) across subjects (n = 19). B–H, Radial plots of individual subject phases (thin lines, circles), population means (thick line), and standard deviations (circular arc). B, C, Radial plots show the opposing distributions of target trough and peak phases which have means (standard deviations) of 127° (44°) and 307° (44°), respectively. This corresponds to opposing (180° shifted) alpha phases. In A–C, the orange filled circles denote the individualized phases for Subject 136 who has an IAF of 11.9 Hz (as in Figs. 1 and 2). In A–C, the pink filled circles show a hypothetical subject with an IAF of 10 Hz and an ERP-P1 latency of 50 ms for reference. D, E, Radial plots show the distribution of actual trough and peak phases which have means (standard deviations) of 127 (−64) and 308 (−68.85) angular degrees, respectively. This corresponds to opposing (181° shifted) alpha phases. The target (B, C) and actual (D, E) phase-locked phases are not significantly different at the frontal (Fpz) location (Watson's U2 test: trough U = 0.002 and p = 0.350; peak U = 0.005, p = 0.300). F, G, At frontal (Fpz) locations, with frontal trough and peak phase-locked sounds, the auditory evoked P1 potentials occur at 337° (38°) and 166° (53°), respectively. Thus, the P1 potentials arrive in opposing (171° shifted) phases with trough and peak sound onsets at Fpz. H, I, At prefrontal (Fz) locations, with frontal trough and peak phase-locked sounds, the auditory evoked P1 potentials occur at 318° (39°) and 137° (42°), respectively. Thus, the P1 potentials arrive in opposing (181° shifted) phases with trough and peak sound onsets at Fz. J, K, The mean actual phases achieved with real-time ecHT phase-locking are close to the target phase. J, The PLV is 0.92(0.02) and the phase-locking error relative to target phase is −9° (5) with the ecHT causal filter signal processing. K, The mean PLV is 0.68 (0.12) and the PE is −13.04° (32) with standard Hilbert transform (sHT) causal filter signal processing. The length of the mean vector denotes the mean, with the arc corresponding to the standard deviation in PEs across participants. Radial histogram phase analysis and radial plots are based on a cosine function estimate of the alpha oscillations and using a bin size of 20°. Data include n = 19 subjects and additional pink dot is a reference point.

High prestimulus alpha levels with “trough and peak phase task” assure potential to phase lock to alpha. A–D, EEG data obtained during the “trough and peak phase task” condition, yields high alpha levels at −500 ms (A, C) versus −700 ms (B, D) prior to sound stimulus onset at frontal (Fpz) and prefrontal (Fz) locations. Alpha levels are highest in the −500 ms time window before sound onsets (A, B). Permutation testing with post hoc cluster analyses confirms that prestimulus alpha power does not vary with trough versus peak phase (p > 0.05). Beta is significantly greater for peak versus trough phases at the frontal (Fpz, A, C) location in the −500 and −700 ms prestimulus windows with p = 0.011 and p = 0.008, respectively. Gamma is significantly greater for peak versus trough at frontal (Fpz, C) locations and greater for trough versus peak at prefrontal (Fz, B) locations with p = 0.0101 and p = 0.020, respectively. E, F, Prestimulus alpha levels are also high with a second analysis that optimizes quantification of power spectral frequencies that are time locked and phase locked to sound onsets in the prestimulus time window (−700 ms) at both locations (Fpz, Fz). In addition, this approach finds high delta band power in the prestimulus time window likely due to the slow quasi periodic ISIs used for playing phase-locked sounds. Permutation testing finds no differences in delta or alpha power levels across phase-locked conditions. G–K, Data obtained during the “random phase task” condition, standard non-normalized PSD analysis confirms that alpha power is at low levels at −500 ms (G, J) and −700 ms (H, K) prior to sound stimulus onset at frontal (Fpz) and prefrontal (Fz) locations. I, L, With the “random phase task” condition, alpha power also is low in the prestimulus time window (−700 ms) using the second method of analysis as in E and F panels.

Amplitudes of the average auditory ERP components vary with individualized alpha phase, but prestimulus alpha levels do not. A, B, The pink-noise auditory ERP response acquired during the “random phase eyes open task” and averaged across all subjects (n = 19) for frontal (Fpz, A) and prefrontal (Fz, B) locations. C, D, Phase-dependent differences are observed across five components (Pa, P1, N1, P2, N2) of the subject averaged auditory ERP at frontal (Fpz, C) and prefrontal (Fz, D) locations. Pa and N2 potentials are smaller for the trough (blue) versus peak (red) phase condition. In contrast, P1, N1, and P2 components are all larger for the trough (blue) versus peak (red) condition. C, D, Bottom, Permutation tests followed by cluster analysis (Materials and Methods) confirms significant phase-dependent differences across all five ERP components. For frontal (Fpz, C) location, the maximum p values for Pa, P1, N1, P2, and N2 are 0.0003, 0.0021, 0.0010, 0.0006, and 0.0134 at 16, 60, 102, 160, and 257 ms time points, respectively. For prefrontal (Fz, D) location, the maximum p values for Pa, P1, N1, P2, and N2 are 0.0002, 0.0026, 0.0040, 0.0008, and 0.0101 at 16, 62, 104, 158, and 260 ms time points, respectively. Shaded boxed areas correspond to the temporal windows used to compare ERP components here and for data shown in Figure 6 used to run additional pairwise t tests (Table 1).

Auditory ERP component latencies are consistent across phase conditions but amplitudes vary with peak versus trough. A, B, No significant differences are observed for ERP component latencies (Pa, P1, N1, P2, and N2) for trough (blue), peak (red), and random (gray) phase conditions at frontal (A, Fpz) or prefrontal (B, Fz) locations. Multiway ANOVA of ERP latency finds significant differences across electrodes (F_(1,144) = 10.08; p = 0.002), but no main effect of condition (F_(2,72) = 2.05; p = 0.130). C, D, Multiway ANOVA of ERP amplitude finds significant differences across electrodes [Fpz vs Fz; (F_(1,144) = 22.88; p = 0.0000023) and trough, peak, and random phase conditions (F_(2,72) = 27.86; p = 0.0000000000033). Notably, the early Pa component is smaller amplitude for trough versus peak conditions, whereas the P1 and N1 components are larger for trough versus peak phase condition. See Table 1 for full statistical comparisons of trough versus peak phase condition effects on latency and amplitude. For above figures, means (horizontal lines), individual values (colored dots), and distribution (half-violin) plots are shown for each measure. Light gray lines show within subject measures across phase conditions.

Phase dependence and electrode differences for the alpha auditory ERO. A–D, The alpha band delimited ERO varies across trough (A, B, blue lines) and peak (C, D, red lines) phase conditions at frontal (A, C, Fpz) and prefrontal (B, D, Fz) locations. A, B, For trough phase condition, alpha oscillations remain high magnitude following sound onset (t = 0) at both locations. C, D, For peak phase condition, alpha oscillations are reduced following sound onset at both locations. E, F, The population average alpha ERO envelope is significantly higher for trough versus peak phase conditions at both locations. For Morlet wavelet transformed data shown here, permutation tests find significant differences in the early time window (50–250 ms) at both locations. For frontal (E, Fpz) and prefrontal (F, Fz) locations, the maximum difference is observed at 92 ms (p = 0052) and at 111 ms (p = 0.0087), respectively (bottom, p value distribution). Similar results are observed with a standard Hilbert transform (data not shown) with a p < 0.004, for the 50–250 ms time window at both locations (Methods). G, H, The phase-dependent difference (trough minus peak) is larger for the prefrontal (H, Fz) versus frontal (G, Fpz) locations. I, J, ERO envelopes are larger for the prefrontal location for both trough (I, Fz, dark blue line) and peak (J, Fz, dark red line) phase conditions. Permutation tests find differences by location are significant in the early time window before 250 ms (bottom, p value distribution). All plots here use the Morlet wavelet transform for spectral time-frequency analysis. Dark lines correspond to the means and light shaded areas the standard errors. The same phase-dependent effects were similarly significant (p < 0.001, for 50–250 ms) over the early poststimulation time window when analyzed with a standard Hilbert transform.

Broadband time-frequency plots illustrate phase-dependent differences in evoked and induced responses at the frontal (Fpz) location. A, B, E, F, Alpha ITPC and evoked power in the alpha range (dotted lines, 8–12 Hz) changes poststimulation (time = 0) in a phase-dependent manner with trough (A, B) versus peak (E, F) phase conditions. Independent of alpha phase, there is a time delayed peak in lower gamma frequency (35–60 Hz) range that coincides with the auditory ERP and a drop in alpha power relative to prestimulus baseline (0 to −200 ms). A, B, With trough phase condition, alpha power remains elevated within a narrow frequency band (arrow, alpha) poststimulation (arrow, alpha). E, F, With peak phase condition, alpha power and frequency (arrow, alpha) both decrease more so than with the trough phase condition. C, G, Baseline normalized Total Power also changes in a phase-dependent manner following sound onset. C, For trough phase, total power in the alpha range (dotted lines) increases (red, positive dB) and then decreases (green-blue, negative dB) in the early (0–300 ms) and late (>300 ms) time windows following sound onset, respectively. G, For peak phase, total power in the alpha range decreases (green-blue) and increases (yellow-green) in the early (0–300 ms) and late (>300 ms) time windows, respectively. D, H, Phase-dependent differences in the baseline normalized induced power are evident as a larger alpha desynchronization (aka power decrease, dark blue) in the late (>300 ms) time window for trough (D) versus peak (H) phase conditions.

Broadband time-frequency plots illustrate phase-dependent differences in evoked and induced responses at the prefrontal (Fz) location. A, B, E, F, Alpha ITPC and evoked power in the alpha range (dotted lines, 8–12 Hz) changes poststimulation (time = 0) in a phase-dependent manner with trough (A, B) versus peak (E, F) phase conditions. Independent of alpha phase, there is a time delayed peak in lower gamma frequency (35–60 Hz) range that coincides with the auditory ERP and a drop in alpha power relative to prestimulus baseline (0 to −200 ms). A, B, With trough phase condition, alpha power remains elevated within a narrow frequency band (arrow, alpha) poststimulation (arrow, alpha). E, F, With peak phase condition, alpha power and frequency (arrow, alpha) both decrease more so than with the trough phase condition. C, G, Baseline normalized total power also changes in a phase-dependent manner following sound onset. C, For trough phase, total power in the alpha range (dotted lines) increases (red, positive dB) and then decreases (yellow-green-blue, negative dB) in the early (0 to 300 ms) and late (>300 ms) time windows following sound onset, respectively. G, For peak phase, total power in the alpha range decreases (green-blue) and then increases (yellow) in the early (0–300 ms) and late (>300 ms) time windows, respectively. D, H, Phase-dependent differences in the baseline normalized induced power are evident as a larger alpha desynchronization (aka power decrease, dark blue) in the late (>300 ms) time window for trough (D) versus peak (H) phase conditions.

Alpha band delimited evoked and induced responses vary distinctly across individualized trough and peak alpha phase conditions. A, B, E, F, The evoked alpha phase coherence (ITPC, A, E) and evoked alpha power (B, F) are both markedly higher for the individualized trough (blue lines) versus peak (red lines) phase conditions in the early (0 to 300 ms) time window at both locations (Fpz, Fz). A, Bottom, Permutation testing with post hoc cluster analyses finds evoked alpha phase coherence (ITPC) and power are significantly higher for trough versus peak phase-locked sounds in the early (0–300 ms) and late (>300 ms) poststimulus time windows at both locations. C, G, Trough (blue lines) and peak (red lines) phase conditions generate opposing phase-dependent effects in early and late time windows for the baseline normalized alpha total power. C, G, Bottom, Permutation testing with post hoc cluster analyses finds total power is significantly higher for trough versus peak phase conditions in the early time for both locations. Only the frontal (Fpz, C) location has significant phase-dependent differences in the later time window for total power. D, H, Alpha desynchronization or decrease in induced alpha power is larger for trough versus peak phase conditions in the later time window at frontal locations (D). D, H, Bottom, Permutation testing finds phase-dependent alpha desynchronization in the late time window is significant at frontal locations only.