Coordinated NREM sleep oscillations among hippocampal subfields modulate synaptic plasticity in humans

Abstract

The integration of hippocampal oscillations during non-rapid eye movement (NREM) sleep is crucial for memory consolidation. However, how cardinal sleep oscillations bind across various subfields of the human hippocampus to promote information transfer and synaptic plasticity remains unclear. Using human intracranial recordings from 25 epilepsy patients, we find that hippocampal subfields, including DG/CA3, CA1, and SUB, all exhibit significant delta and spindle power during NREM sleep. The DG/CA3 displays strong coupling between delta and ripple oscillations with all the other hippocampal subfields. In contrast, the regions of CA1 and SUB exhibit more precise coordination, characterized by event-level triple coupling between delta, spindle, and ripple oscillations. Furthermore, we demonstrate that the synaptic plasticity within the hippocampal circuit, as indexed by delta-wave slope, is linearly modulated by spindle power. In contrast, ripples act as a binary switch that triggers a sudden increase in delta-wave slope. Overall, these results suggest that different subfields of the hippocampus regulate one another through diverse layers of sleep oscillation synchronization, collectively facilitating information processing and synaptic plasticity during NREM sleep.

Fig. 1. Identification of NREM sleep, and spectra in DG/CA3, CA1, and SUB.

a Identification of NREM sleep (stages N2 and N3) using spectral power. The Hilbert analytic amplitudes of sleep LFP in the spindle (9–17 Hz), low delta (0.5–2 Hz), and high gamma (70–190 Hz) bands were calculated to identify NREM (between the two vertical red lines is the NREM state). All error bars indicate the mean ± SEM. b The spectra showed strong power in the delta and spindle band for all hippocampal subfields. Comparisons of the spectra between the three subfields revealed that the DG/CA3 had higher power than CA1 and SUB in specific bands (cluster-based permutation test, p < 0.001; green represents DG/CA3 > CA1: 10–11 Hz; purple represents DG/CA3 > SUB: 27–30 Hz). Inset: Comparisons of the normalized spectra between the three subfields (cluster-based permutation test, p < 0.001; purple represents SUB > DG/CA3: spindle band, 12–15 Hz). c Shown were 4 s z-scored spectrograms for three subfields of artifact-free data from a single patient. Prominent frequencies were delta bands, spindle bands and high frequency bursts (around 100 Hz). All error bars indicate the mean ± SEM.

Fig. 2. Cross-frequency coupling within each hippocampal subfield.

a Phase-amplitude coupling (PAC) for DG/CA3, CA1, and SUB (white solid line circled areas indicate significant clusters: p < 0.05, corrected). b Ripple-locked grand average band-bass filtered signal in DG/CA3, CA1, and SUB (±0.5 s; mean ± SEM). c Ripple-locked grand average raw signal and time-frequency spectrogram in DG/CA3, CA1, and SUB (±0.5 s; mean ± SEM). d Probability of delta phase corresponding to the maximum ripple. The red vertical lines represent significant coupling phases (Rayleigh-test, Bonferroni correction, p < 0.001). All error bars indicate the mean ± SEM.

Fig. 3. Delta-spindle-ripple coupling in hippocampal subfields.

a Spindle-locked grand average band-bass filtered signal in DG/CA3, CA1, and SUB (±1.5 s; mean ± SEM). b Normalized histogram (18 bins, 20° each) of preferred delta-spindle modulation phases across all detected spindle events (yellow bars represent significant coupling phase ranges; V-test, Bonferroni correction, p < 0.05). c Normalized histogram (18 bins, 20° each) of preferred spindle-ripple modulation phases across all detected spindle events (yellow bars represent significant coupling phase ranges; V-test, Bonferroni correction, p < 0.05). d Average delta, spindle, ripple (and ripple’s analytical amplitude), zoomed in from −0.5 s to +0.5 s to illustrate the nesting of delta-spindle-ripple in CA1 and SUB. The ripple and its analytical amplitude were scaled up by a factor of 30 for better visualization. e Ripple activity in CA1 and SUB as a function of the delta-spindle coupling phase. CA1 showed a significant correlation (correlation between one circular and one linear random variable; r = 0.56, p = 0.0037).

Fig. 4. Cross-frequency coupling between hippocampal subfields.

a Phase-amplitude coupling (PAC) between various hippocampal subfields. DG/CA3 exhibited significant coupling with CA1 and SUB, with the frequency range primarily concentrated in the delta-ripple, (p < 0.05, corrected). b and c are spindle-based event couplings. b Normalized histogram (18 bins, 20° each) of preferred delta-spindle (top) and spindle-ripple (bottom) modulation phases between CA1 and SUB based on CA1 spindles (yellow bars represent significant coupling phase ranges; V-test, Bonferroni correction, p < 0.05). c Normalized histogram of preferred phases between CA1 and SUB based on SUB spindles (yellow bars represent significant coupling phase ranges; V-test, Bonferroni correction, p < 0.05). d Average delta, spindle, ripple (and ripple’s analytical amplitude), zoomed in from −0.5 s to +0.5 s to illustrate the nesting of delta-spindle-ripple between CA1 and SUB. The ripple and its analytical amplitude were scaled up by a factor of 30 for better visualization.

Fig. 5. Delta slope in the hippocampus in relation to spindle and ripple.

a Calculation method for the delta slope. Within each cycle, delta-wave slope was defined as the amplitude over time calculated by the straight line connecting the most negative peak of the signal with the following zero crossing. Then, the mean was taken over the groups. We calculated both the ascending and descending slopes, but as they yielded similar results, we only reported the results for the ascending slope. b Relationships between spindle power in each hippocampal subfield and delta slope in all subfields (Spearman’s correlation; all subfields showed a significant positive correlation with delta slope, rs > 0.9; ps < 0.001, Bonferroni corrected). Spindle power was divided into 20 bins based on the magnitude in ascending order, and we calculated the mean delta slope within the corresponding bins. Lines are standard least-squares regression line. c Relationships between ripple power in each hippocampal subfield and delta slope in all subfields (Spearman’s correlation; Bonferroni correction; Only a few lines showed significant associations). Ripple modulation exhibits a “binary” pattern, exclusively affecting the delta slope when the ripple power reaches its maximum. d Time-resolved delta slope relative to the ripple event (±1.5 s, normalized to the baseline −1.5 s to −1 s). We detected significantly increased delta slope around ripple peaks (cluster-based permutation test, p < 0.05). All error bars indicate the mean ± SEM.