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Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep


During systems-level consolidation, mnemonic representations initially reliant on the hippocampus are thought to migrate to neocortical sites for more permanent storage, with an eminent role of sleep for facilitating this information transfer. Mechanistically, consolidation processes have been hypothesized to rely on systematic interactions between the three cardinal neuronal oscillations characterizing non–rapid eye movement (NREM) sleep. Under global control of de- and hyperpolarizing slow oscillations (SOs), sleep spindles may cluster hippocampal ripples for a precisely timed transfer of local information to the neocortex. We used direct intracranial electroencephalogram recordings from human epilepsy patients during natural sleep to test the assumption that SOs, spindles and ripples are functionally coupled in the hippocampus. Employing cross-frequency phase-amplitude coupling analyses, we found that spindles were modulated by the up-state of SOs. Notably, spindles were found to in turn cluster ripples in their troughs, providing fine-tuned temporal frames for the hypothesized transfer of hippocampal memory traces.

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Figure 1: Implantation and sleep recordings.
Figure 2: Event-locked analysis of hippocampal SO-spindle PAC.
Figure 3: Event-locked analysis of hippocampal spindle-ripple PAC.
Figure 4: Hippocampal ripples.
Figure 5: Hippocampal PAC during NREM sleep.


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The research was supported by a Sir Henry Wellcome Fellowship (WT089049AIA) to B.P.S., the BrainGain Smart Mix Programme of the Netherlands Ministry of Economic Affairs (T.O.B.), the VICI grant (453-09-002) from the NWO (O.J.) and the DFG grants AX82/2, AX82/3 (N.A.) and SFB1089 (N.A. and J.F.).

Author information

Authors and Affiliations



B.P.S. and T.O.B. analyzed the data. B.P.S., T.O.B. and J.F. wrote the manuscript. L.D. acquired data. B.P.S., T.O.B., M.B., R.v.d.M., O.J., N.A. and J.F. provided analytical tools. C.E.E. supervised intracranial recordings.

Corresponding author

Correspondence to Bernhard P Staresina.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Hippocampal recordings.

a. (top) Post-operative MRI (left, depicting a depth electrode implanted along the longitudinal hippocampal axis) and co-registered pre-operative MRI (right) of a sample participant. (bottom) Power spectra (NREM/WAKE) for all 10 electrode contacts of the same participant, showing a maximum in the spindle range (12-16 Hz, dashed vertical lines) in a posterior hippocampus contact which was then carried forward to the group analysis (red arrow). (inset) NREM/WAKE power spectrum for scalp electrode Cz. Y axes are identical across panels, where a ratio of 1 demarks the same spectral power during NREM and WAKE. b. Hippocampal contacts included in the analysis for all participants. Each panel shows sagittal and coronal slices of the post-operative (top) and the co-registered pre-operative (bottom) MRI for a participant. Crosshairs highlight the contact showing the largest spindle amplitudes during NREM sleep relative to WAKE of all hippocampal contacts (as shown in a for a sample participant). MRIs were unavailable for 3 of the 12 participants. Note the different implantation scheme in one participant (right bottom).

Supplementary Figure 2 Event-locked analysis of scalp EEG (Cz) PAC.

Left: SO-spindle PAC. (a) Grand average unfiltered EEG trace across participants (mean ± s.e.m.), aligned to the maximum of the SO trough (time 0). (b) Average of spindle-trough-locked TFR (% change from pre-event baseline). Y-axis starts at 5 Hz to circumvent the dominance of power in the SO range. (c) Statistically significant change from pre-event baseline (P <.05, corrected). Inset shows unit circle of preferred phases of the SO-spindle modulation for each participant, which illustrates the preferred clustering of spindle power towards the SO peak (328°, white line). Yellow circles represent participants whose Rayleigh test for non-uniformity was significant at P <.05. Right: Spindle-ripple PAC. While the EEG trace in (a) reveals the typical waxing and waning pattern of sleep spindles, no reliable ripple power modulation was observed in the spindle-peak-locked TFR (b) (see also Supplementary Table 3b; presumably due to attenuated signal-to-noise ratio of scalp EEG recordings for higher frequencies). Note that the spindle’s mean potential is above zero, reflecting the grouping of spindles in the SO peak (−.25 s to +.25 s, t(11) = 3.45, P <.01). This is further illustrated in the inset, which shows the grand average EEG trace bandpass filtered from 0.5–1.25 Hz (SO range) and from 12–16 Hz (spindle range), respectively.

Supplementary Figure 3 Peri-event time histograms (PETH).

(top) PETH of SO occurrences time-locked to SO down-states for Cz (left) and HC (right), highlighting multiple peaks at the distance of one SO cycle (multi-event oscillations). (bottom) PETH of spindle occurrences time-locked to spindle centers, revealing discernable peaks repeating at the SO frequency.

Supplementary Figure 4 Example hippocampal EEG traces illustrating multi-event SOs along with nested spindles.

Top: Unfiltered raw EEG traces, highlighting data segments identified as a SO (green) and spindle (blue) by our automated algorithm. Bottom: Same data segments after applying the event-specific bandpass filters (SO: 0.5–1.25 Hz, spindle: 12–16 Hz).

Supplementary Figure 5 Temporal relation of spindles with respect to ripples.

Bar graphs show the peri-event time histogram (PETH) of spindle center occurrences relative to ripple centers. Spindle centers show the tendency to occur after ripple centers: Within a search interval from −1 s to +1 s around ripple centers, 15.2% (s.d. = 5.0) of all ripples were followed by spindle centers and 12.6% (s.d. = 4.6) of all ripples were preceded by spindle centers. Note however that this difference in occurrence probabilities was not reliable across participants (t(11) = 1.44, P = .177). Importantly, the tendency of spindle centers to occur after ripple centers does not indicate that ripples ‘trigger’ spindles, as the spindle onset occurs at least 250 ms before the spindle center (given our spindle detection duration criterion of ≥ 500 ms). The inset shows the onsets of spindles with respect to the onset of ripples, revealing that 17.1% (s.d. = 5.4) of all ripple onsets were preceded by a spindle onset from −1 to 0 s, whereas only 9.9% (s.d. = 3.2) of all ripple onsets were followed by a spindle onset from 0 to +1 s (t(11) = 4.08, P =.002). This indicates that ripples reliably occur after a spindle has already started. Note that the same statistical result was obtained when reducing the time window to −.5 s to +.5 s around ripple onset.

Supplementary Figure 6 Spindle-ripple coupling as a function of associated SOs.

a. Peri-event time histogram (PETH) showing the probability of SO occurrence (SO down-state) relative to spindle centers (t = 0 s, dashed vertical line). Dark gray area shows time interval used to determine whether a given spindle is located in the up-state of an SO (i.e., a SO down-state is temporally preceding a spindle at −1 to −0.2 s). Note that while there is a clear peak of SO occurrences in the temporal vicinity of spindles (with the asymmetry pointing to a predominant SO -> spindle sequence), many spindles occurred independently of SOs. The subsequent analyses separated spindle-ripple coupling into spindles immediately preceded by SO down-states (left column, average number of events across participants = 124, range = 30–315) and spindles not immediately preceded by SO down-states (right column, average number of events across participants = 697, range = 154–1467). b. Event-locked analysis. (i) (top) Grand average unfiltered iEEG trace across participants (mean ± s.e.m.), aligned to the maximum of the spindle trough. Insets show the bandpass filtered trace from 0.5–1.25 Hz (SO range) and from 12–16 Hz (spindle range) to better illustrate the relation of the spindle to the SO down-state. Note the pronounced SO emerging in spindle-locked raw traces on the left. (middle) Average of spindle-trough-locked TFR (% change from pre-event baseline). (bottom) Statistically significant change from pre-event baseline (P < .05, corrected, with the initial cluster threshold also set to P <.05 to accommodate smaller trial numbers). Inset shows unit circle of preferred phases of the spindle-ripple modulation for each participant. Both V tests (testing for preferred phase at 180°) are significant: spindles immediately preceded by SO down-states: V = 4.36, P =.037, spindles not immediately preceded by SO down-states: V = 5.75, P =.010. (ii) Direct comparison of spindle-trough-locked TFRs (immediately preceded by SO down-states vs. not immediately preceded by SO down-states), revealing only a relative power decrease at SO down-states, but no differential spindle-ripple modulation. (iii) Example data from one participant (same as in main Fig. 2,3,4), showing the nesting of ripples in spindle troughs for both event types. c. Comodulogram analysis. PAC was calculated for data segments around spindles (–2.5 s to +2.5 s relative to the maximum spindle trough). Maps show cluster-corrected comparisons against phase-scrambled surrogate data (all P <.05). Direct comparison of MI averaged from 12–16 Hz phase-providing frequency and 80–100 Hz amplitude-providing frequency revealed no difference between spindles immediately preceded by SO down-states vs. spindles not immediately preceded by SO down-states (using surrogate corrected MI or non-surrogate-corrected MI, both t(11) < 0.71, P >.49).

Supplementary Figure 7 Example hippocampal EEG traces containing a SO-spindle-ripple interaction.

Top: Unfiltered raw EEG traces, highlighting data segments identified as a SO (green), spindle (blue) and ripple (red) by our automated algorithm. Bottom: Same data segments after applying the event-specific bandpass filters (SO: 0.5–1.25 Hz, spindle: 12–16 Hz, ripple: 80–100 Hz). Insets zoom in on the ripple event, highlighting its oscillatory nature and its nesting in spindle troughs.

Supplementary Figure 8 Cross-regional CFC between Cz and hippocampus.

Peri-event time histograms (PETH) depicting the occurrence probability of hippocampal SOs time-locked to Cz SOs (a) and of hippocampal spindles time-locked to Cz spindles (b).

Supplementary Figure 9 Hippocampal phase-amplitude coupling (PAC) during NREM sleep.

Clusters showing a significant Modulation Index (MI) when comparing NREM PAC with WAKE PAC (left) and with trial-shuffled NREM surrogate data (right). Maps are thresholded to show t value clusters whose P < 0.05 and whose size exceeds 25 contiguous frequency pairs.

Supplementary Figure 10 Event-locked analysis of hippocampal PAC after re-referencing hippocampal data against the most anterior (11 participants) or lateral (1 participant) contact on the same depth electrode.

(a) Contact used for re-referencing in a sample participant (red line). (b) Grand average unfiltered EEG trace across participants (mean ± s.e.m.) and (c) average of event-locked TFR (% change from pre-event baseline), locked to SO peak (left) and spindle trough (right). Spindle power (12–16 Hz) shows a significant increase vs. baseline from.25 to.75 s after SO peak (t(11) = 2.69, P = .021) and ripple power (80–100 Hz) shows a significant increase vs. baseline from –.25 to +.25 s around maximal spindle trough (t(11) = 4.00, P = .002). Spindle power (12–16 Hz) also showed a significant increase in the re-referenced data when aligning the TFR to the ripple center (as done in main text Fig. 4a, t(11) = 4.81, P <.001, –.25 to +.25 s around ripple center).

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Staresina, B., Bergmann, T., Bonnefond, M. et al. Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat Neurosci 18, 1679–1686 (2015).

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