Sleep spindles and hippocampal functional connectivity in human NREM sleep

Abstract

We investigated human hippocampal functional connectivity in wakefulness and throughout non-rapid eye movement sleep. Young healthy subjects underwent simultaneous EEG and functional magnetic resonance imaging (fMRI) measurements at 1.5 T under resting conditions in the descent to deep sleep. Continuous 5 min epochs representing a unique sleep stage (i.e., wakefulness, sleep stages 1 and 2, or slow-wave sleep) were extracted. fMRI time series of subregions of the hippocampal formation (HF) (cornu ammonis, dentate gyrus, and subiculum) were extracted based on cytoarchitectonical probability maps. We observed sleep stage-dependent changes in HF functional coupling. The HF was integrated to variable strength in the default mode network (DMN) in wakefulness and light sleep stages but not in slow-wave sleep. The strongest functional connectivity between the HF and neocortex was observed in sleep stage 2 (compared with both slow-wave sleep and wakefulness). We observed a strong interaction of sleep spindle occurrence and HF functional connectivity in sleep stage 2, with increased HF/neocortical connectivity during spindles. Moreover, the cornu ammonis exhibited strongest functional connectivity with the DMN during wakefulness, while the subiculum dominated hippocampal functional connectivity to frontal brain regions during sleep stage 2. Increased connectivity between HF and neocortical regions in sleep stage 2 suggests an increased capacity for possible global information transfer, while connectivity in slow-wave sleep is reflecting a functional system optimal for segregated information reprocessing. Our data may be relevant to differentiating sleep stage-specific contributions to neural plasticity as proposed in sleep-dependent memory consolidation.

Figure 1.

A, Extension of the HF network during wakefulness. Positive functional connectivity of DMN nodes and the HF is shown (p_FWE < 10⁻⁶, extent > 150 voxel). Color coding indicates t values. MNI coordinates of each slice are given. B, Contrast estimates ±SDs extracted at the peak voxel of the indicated cluster, separated for each sleep stage (W, S1, S2, SWS). MNI coordinates (x, y, z) of the cluster peak voxel are provided.

Figure 2.

A–D, Comparison of HF functional connectivity across sleep stages. Data are thresholded at p_uncorr < 0.001, with a variable voxel extent, resulting in p_FWE,cluster < 0.05 (Table 2). Color coding indicates t values. The HF has been masked out to avoid display of autocorrelations. MNI coordinates of each slice are given.

Figure 3.

A, Activity related to fast sleep spindles in S2 (p_FWE,cluster < 0.05, collection threshold p < 0.001) (supplemental Table 2, available at www.jneurosci.org as supplemental material). Note that the HF is not part of the spindle network. MNI coordinates of each slice are given. B, PPI analysis for the interaction fast spindles × SUB (p_FWE,cluster < 0.05, collection threshold p < 0.001) (supplemental Table 3, available at www.jneurosci.org as supplemental material). Color coding indicates t values. MNI coordinates of each slice are given.