Sleep homeostasis and cortical synchronization: III. A high-density EEG study of sleep slow waves in humans

Abstract

Study objectives: The mechanisms responsible for the homeostatic decrease of slow-wave activity (SWA, defined in this study as electroencephalogram [EEG] power between 0.5 and 4.0 Hz) during sleep are unknown. In agreement with a recent hypothesis, in the first of 3 companion papers, large-scale computer simulations of the sleeping thalamocortical system showed that a decrease in cortical synaptic strength is sufficient to account for the decline in SWA. In the model, the reduction in SWA was accompanied by decreased incidence of high-amplitude slow waves, decreased wave slopes, and increased number of waves with multiple peaks. In a second companion paper in the rat, local field potential recordings during early and late sleep confirmed the predictions of the model. Here, we investigated the model's predictions in humans by using all-night high-density (hd)-EEG recordings to explore slow-wave parameters over the entire cortical mantle.

Design: 256-channel EEG recordings in humans over the course of an entire night's sleep.

Setting: Sound-attenuated sleep research room

Patients or participants: Seven healthy male subjects

Interventions: N/A.

Measurements and results: During late sleep (non-rapid eye movement [NREM] episodes 3 and 4, toward morning), when compared with early sleep (NREM sleep episodes 1 and 2, at the beginning of the night), the analysis revealed (1) reduced SWA, (2) fewer large-amplitude slow waves, (3) decreased wave slopes, (4) more frequent multipeak waves. The decrease in slope between early and late sleep was present even when waves were directly matched by wave amplitude and slow-wave power in the background EEG. Finally, hd-EEG showed that multipeak waves have multiple cortical origins.

Conclusions: In the human EEG, the decline of SWA during sleep is accompanied by changes in slow-wave parameters that were predicted by a computer model simulating a homeostatic reduction of cortical synaptic strength.

Figure 1

A: Average power spectra in non-rapid eye movement (NREM) sleep during episodes 1 and 2 (early sleep, black) and episodes 3 and 4 (late sleep, gray) for Fp1 channel (mean ± SEM, n = 7). Triangles indicate significant bins based on SnPM (P < 0.05, single threshold corrected). B: Slow-wave activity (SWA; 0.5–4.0 Hz) profile in NREM sleep during the night for an individual subject (average 1-min values, % of the mean of 4 NREM episodes) rapid eye movement (REM) episodes are indicated by hatched areas. Early and late sleep (including REM episodes) are color-coded in black and gray, respectively. EEG refers to electroencephalogram.

Figure 2

A, top traces: representative 16-s electroencephalogram traces from the Fp1 channel during early and late sleep; bottom traces: corresponding band-pass filtered signal (0.5–4.0 Hz) with wave detections highlighted. Right panel: representative slow wave. The first (1) and second (2) segments, the negative peak (**), and consecutive zero crossings (*) are indicated. B: Distribution of the amplitude of slow waves during early and late sleep for Fp1. The number of waves was computed for groups of waves with logarithmically increasing amplitude. Mean values (± SEM, n = 7) are plotted as a percentage of the total number of waves within early (non-rapid eye movement [NREM] episodes 1 and 2, black) and late (NREM episodes 3 and 4, gray) sleep, respectively. Triangles indicate significance and direction of the nonparametric permutation test (P < 0.05, single threshold corrected). The inset shows mean incidence (number of waves/min of NREM sleep, ± SEM n = 7). C: Slow-wave incidence during early and late sleep for the Fp1 derivation. Slow waves were subdivided into 5 percentiles according to the amplitude of the negative peak. Boxplots show incidence values for all subjects. Notch indicates median value, the box represents the interquartile range, and whiskers extend to 1.5 times the interquartile range. Outliers (> 1.5 times the interquartile range) are plotted as circles. Triangles indicate significance and direction of the nonparametric permutation test (P < 0.05, single threshold corrected).

Figure 3

Slope changes between early and late sleep for Fp1. Slow waves were subdivided into 5 equal percentiles according to the amplitude of the negative peak. Boxplots show differences from the mean between early and late sleep expressed as a percentage ([late-early]*200/[late+early]) for each subject (n = 7). Notch indicates median value, the box represents the interquartile range, and whiskers extend to 1.5 times the interquartile range. Outliers (> 1.5 times the interquartile range) are plotted as circles. Triangles indicate significance and direction of the nonparametric permutation test (P < 0.05, single threshold corrected).

Figure 4

Fp1 waves between early and late sleep were equated based on the best match of the corresponding 4-s epoch 0.5- to 2.0-Hz electroencephalogram (EEG) power and wave amplitude. A: Representative 4-s epochs with the direct wave comparison between early and late sleep highlighted on the band-pass filtered signal. B-E: Boxplot data for each parameter show average differences from the mean between early and late sleep expressed as a percentage ([late-early]*200/[late+early]) for each subject (n = 7; see text). Average slope measurements are in white, maximum slope measurements are in black. Note that both EEG power and amplitude are equated for all comparisons except in E, where EEG power was not equated. Triangles indicate significance (P < 0.05) and the direction of change based on individual nonparametric permutation tests for each parameter (uncorrected). NREM refers to non-rapid eye movement; SWS, slow-wave sleep.

Figure 5

Scatter plots of average slow-wave activity (SWA) values from each of the 4 non-rapid eye movement (NREM) episodes for each subject plotted against the average parameter values for each subject and episode. Incidence values are based on waves in the 80^th–100^th percentile. All other parameter values (percentage of multipeaks, first-segment slopes, and second-segment slopes) are computed from all waves. The data are presented as percentage of the mean across the 4 NREM episodes. A linear regression line has been fit to the data and is shown in black. Significant r-values of the Pearson correlation are shown (P values < 0.001).

Figure 6

Topographic distributions of slow-wave parameter changes during early and late sleep. Values were plotted at the corresponding position on the planar projection of the scalp surface and interpolated (biharmonic spline) between electrodes. Maximal and minimal values (± SEM, n = 7) are shown on the upper left corner of each topographic plot (the scale for color coding is on the right of E, row 1; n.s. refers to not significant). The units for each plot are indicated in the lower left corner. A: Average for early sleep (non-rapid eye movement [NREM] episodes 1 and 2). The channel used for single-channel analysis (Fp1) is indicated with a black dot in the top row. B: Average for late sleep (NREM episodes 3 and 4). Channels that are common to all subjects (n = 167) are indicated with black dots. C: Difference between early and late sleep shown as a percentage of the mean ([late-early]*200/[late+early]). The channels used for the regional comparison shown in E are indicated by colored dots. D: T-values for the comparisons between early and late sleep (2-tailed paired t-test). The minimum t-value for each map (indicated in black) is the criterion for significance (based on single threshold SnPM) at each channel. Gray is indicated only for nonsignificant channels. E: Regional comparison boxplots. The average percentage change for 2 representative regional channels (F=Fp1 and Fp2, black boxes; C=C3 and C4, gray boxes; O=O1 and O2, white boxes) are displayed. Asterisks indicate a significant difference based on nonparametric permutation tests between regions (P < 0.05). Black dots are outliers. Top row: EEG power density for slow-wave activity (0.5–4 Hz). Second row: Slow-wave incidence for high-amplitude waves (80^th-100^th percentile). Third and fourth rows: first- and second-segment average slow-wave slopes of all waves. Fifth and sixth rows: first- and second-segment maximum slow-wave slopes of all waves. Seventh row: Average number of peaks for all waves. Note that the higher average number of peaks is located posteriorly (A,B), but the relative change is more pronounced frontally. Note also that the direction of change between early and late sleep is opposite to that of all other parameters. For simplicity, however, the topographic distribution of t-values for the number of peaks comparison is shown as opposite to its actual sign.

Figure 7

Representative examples of traveling waves for single and multipeak waves. A: Butterfly plots showing electroencephalogram (EEG) traces overlapped for all the channels involved (see Methods) in an individual peak. Red dots show the negative peaks for each derivation. The blue line indicates the representative time for source localization depicted in C (70 ms after the maximum negative peak). B: Topographic display of the interpolated (100×100) delay gradient based on the corresponding time from the earliest channel detection for that peak (see corresponding red dots above). Individual channels are indicated as black dots. Streamlines along the gradient were computed for each channel, and the longest is highlighted in blue. The origin is indicated by the large red dot. C: Top, right, and left views of the minimum norm least squares source estimation 70 ms after the maximum negative peak (indicated by the corresponding vertical blue lines in A). Absolute values of the currents are displayed. Note the correspondence between the maximum current activation and the origin of the slow waves in B.

Supplementary Figure 1

Difference between slopes of the .rst and second slow-wave segments for average (top) and maximum (bottom) slope measurements at Fp1. Slow waves were subdivided into 5 equal percentiles according to the amplitude as before. Box-plots show the slope difference from the mean expressed as a percentage ([1^st–^nd]*200/[1^st+2^nd]) for each subject (n = 7). Triangles indicate significance and direction of the nonparametric permutation test (p < 0.05, single threshold corrected).

Supplementary Figure 2

Bar plots of the proportion of slow waves with more than 1 peak (% of the total number of waves) for early and late sleep for channel Fp1. Individual subject values are shown as white circles connected by lines.

Supplementary Figure 3

Time course of slow-wave activity and slopes. Non-rapid eye movement (NREM) episodes were divided into 10 equal percentiles based on the length of each episode. Average values (± SEM, n = 7).