Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting

Abstract

The coupled interaction between slow-wave oscillations and sleep spindles during non-rapid-eye-movement (NREM) sleep has been proposed to support memory consolidation. However, little evidence in humans supports this theory. Moreover, whether such dynamic coupling is impaired as a consequence of brain aging in later life, contributing to cognitive and memory decline, is unknown. Combining electroencephalography (EEG), structural MRI, and sleep-dependent memory assessment, we addressed these questions in cognitively normal young and older adults. Directional cross-frequency coupling analyses demonstrated that the slow wave governs a precise temporal coordination of sleep spindles, the quality of which predicts overnight memory retention. Moreover, selective atrophy within the medial frontal cortex in older adults predicted a temporal dispersion of this slow wave-spindle coupling, impairing overnight memory consolidation and leading to forgetting. Prefrontal-dependent deficits in the spatiotemporal coordination of NREM sleep oscillations therefore represent one pathway explaining age-related memory decline.

Keywords: age-related memory decline; aging; atrophy; directional cross-frequency coupling; hierarchical nesting; hippocampus-dependent memory consolidation; overnight forgetting; prefrontal cortex; sleep spindles; slow oscillation.

Figure 1. Memory task and oscillatory signatures of sleep

(a) Episodic word-pair task. Participants learned 120 word-nonsense word pairs. Nonsense words were 6–14 letters in length, derived from groups of common phonemes. During encoding trials (upper left) word pairs were presented for 5s. Participants completed the criterion training (upper right) directly after encoding and received feedback after every trial. Recognition trials (lower panel) were performed after a short delay (10min, 45 trials) and again after a full night of sleep (10h, 135 trials). (b) EEG power spectra during NREM sleep at electrode Cz for older (blue) and young (red) adults (mean ± SEM). Grey shaded areas indicate significant differences in low and sleep spindle frequency ranges. Insets depict topographical distribution of SO (<1.5 Hz; upper topographies) and sleep spindle (12–16 Hz; topographies on the right) power. Note that older subjects exhibited significantly reduced oscillatory power across the whole head. (c) Upper left: Hypnogram (MT = movement time) from one exemplary of older subject and full night multi-taper spectrogram at Pz (lower left) with superimposed number of detected SO and sleep spindle events (white solid lines; 5min averages). Upper right: Normalized circular histogram of detected spindle events relative to the SO phase. Note the peak in the right lower quadrant. Lower right: Peak-locked sleep spindle average across all detected events in NREM sleep (black). Low-pass filtered events (red) highlight that the sleep spindles preferentially peaked prior to the SO ‘up-state’. See also Figure S1A. (d) Exemplary young subject. Same conventions as in panel c. Note, the sleep spindle amplitude is maximal after the SO peak.

Figure 2. SO-Spindle interactions in old and young adults

(a) Left: Trough-locked SO grand average for old (blue) and young (red) adults. Note the prominent differences in amplitude. Right: We normalized the SO amplitude for every subject prior to all other analyses to alleviate spurious effects, which could be the result of prominent power and signal-to-noise differences (mean ± SEM). (b) Statistical map of SO-locked power differences across time between older and young subjects. Note the interleaved patterning in the sleep spindle range (12–16 Hz; white dashed box). As reference, the mean SO is superimposed (black; rescaled). See also Figure S2A. (c) Left: Peak-locked spindle grand-averages for old adults with superimposed low-pass filtered signal (black). Red: Peak-locked sleep spindle grand-average for young adults. Top: Averaging mean coupling phase and SD on schematic SO (cosine). (d) Upper: Mean SO phase where sleep spindle power peaks. Red dots depict individual subjects. Note sleep spindle power in older adults peaks prior to the SO positive peak (0°), while sleep spindle power in young subjects peaks around 0°. Lower: Grand-average normalized spindle amplitu de binned relative to the SO phase (mean ± SEM). Again, note the non-uniform distribution, which peaks around 0° for young adults, but earlier for older a dults. See also Figure S1D–H. (e) Upper: SO-spindle coupling strength (resultant vector length) topography for old (left) and young (right) adults. Lower: A statistical difference map (center) indicates that the coupling strength was significantly reduced for fronto-central EEG sensors, while parieto-occipital estimates did not differ (* denotes cluster-corrected two-sided p < 0.05). (f) Statistical map of a data-driven comodulogram. The black-circled area highlights the significant difference between older and young adults, which was confined to the SO-spindle range. See also Figure S2B. (g) Cross-frequency directionality analyses. Values above zero indicate that SO drive sleep spindle activity. Upper: We found that frontal SO drive sleep spindle activity in young but not older adults (electrode Fz; mean ± SEM), while parieto-occipital SO predicts sleep spindle activity in both older and young adults (lower panel; Pz; Figure S2C). However, this effect is pronounced for young adults. The topography (center panel) depicts the spatial extent where directional SO-spindle influences are reduced in older relative to young adults. Note that this effect was independent of the chosen window length (Figure S2D).

Figure 3. Timing of SO-spindle interactions predicts memory retention

(a) Upper: Cluster-corrected circular-linear correlation analysis between the individual mean SO-spindle coupling phase and overnight memory retention after correction for power differences (* indicates significant sensors). The strongest effect was observed at electrode F3. Lower: Blue dots indicate older adults; red dots young adults. We binned the mean behavioral performance relative to the coupling phase in 10 overlapping bins to highlight the u-shaped, non-linear relationship. (b) No significant correlation was observed between coupling strength (resultant vector length) and memory retention (same conventions as in panel A). (c) Sleep spindle frequency relative to SO cycle at a frontal (left) and parieto-occipital (Pz; right) electrode (mean ± SEM). Frontal sleep spindles are slower than posterior sleep spindles. Their frequency only varies as a function of the SO phase over frontal regions where it is significantly lower for older adults (top panel). (d) Cluster-corrected circular-linear correlations after correcting for differences in power distributions and sleep spindle frequencies (see also Figure S3; same conventions as in panel A). Importantly, memory retention was coupling phase dependent in older and young adults. Overall the best performance was observed when the sleep spindles peak just after the SO peak. Blue dots depict older adults. Dark grey bars indicate mean binned memory performance; black solid line depicts a quadratic fit to approximate the non-linear u-shaped relationship. Conversely, red dots, light grey bars and the dashed black line reflect young adults.

Figure 4. Directional SO-spindle coupling depends on prefrontal grey matter volume

(a) Upper right: Definition of the mPFC ROI on coronal, sagittal and axial slices. Upper left: Topographic map of cluster-corrected correlation analysis between grey matter (GM) volume and the directional CFC (PSI), which revealed that directional influences were stronger when subjects’ had more GM volume. Lower panel: Scatter plot of significant correlation at electrode Fz. Hence, age-related GM atrophy contributes to a breakdown of SO-mediated spindle coupling. Note that GM volume was corrected for age-related total intracranial volume. (b) This significant relationship was limited to mPFC, and was not observed in other select regions including the hippocampus, thalamus, adjacent regions such as the OFC and DLPFC, nor in any of additional control regions (occipital, precuneus, posterior cingulate and posterior parietal).