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. 2017 Jun 26:8:15930.
doi: 10.1038/ncomms15930.

Characterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource

S M Purcell  1   2   3 , D S Manoach  2   4   5 , C Demanuele  2   4   5 , B E Cade  6   7 , S Mariani  6   7 , R Cox  2   8 , G Panagiotaropoulou  2   4   5 , R Saxena  9   10   11 , J Q Pan  12 , J W Smoller  2   4   13 , S Redline  2   6   7 , R Stickgold  2   8
Affiliations

Characterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource

S M Purcell et al. Nat Commun. .

Abstract

Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Spindle trait distributions at baseline and across time.
(a) Distribution of spindle density (spindles per min), duration (s), amplitude (μV), frequency (Hz), number of oscillations and symmetry index for all 11,630 individuals at baseline. (b) Scatter plots of baseline versus follow-up estimates of spindle density for individuals in the three studies (CHAT, SHHS and MrOS) with repeated polysomnography, showing standardized residuals from a linear regression of spindle density on age, sex and race by linear regression. Spindle density and other spindle traits exhibited high test–retest correlations, with or without adjustment for age, sex and race (Supplementary Table 4 and Supplementary Fig. 9).
Figure 2
Figure 2. Changes in spindle frequency and density with age.
These plots depict average spindle density estimates (spindles per min) from the variable-frequency analysis (setting the wavelet FC=8 to 18 Hz in 0.25 Hz intervals). (a) Darker shades indicate greater spindle density. The predominant trend is for spindles to increase in frequency during childhood until early adulthood and thereafter decline in density (with the modal spindle frequency remaining stable). (b) Based on the same data as (a), each line represents the mean spindle density (y-axis) for individuals grouped by age range (10=5–15 years; 20=16–25 years, and so on), plotted as a function of targeted spindle frequency (FC) on the x-axis, reinforcing the qualitatively different changes in spindle frequency and density during childhood versus adulthood. (c) Age-dependent expectations for spindle densities for a core range of targeted frequencies (11–15 Hz), derived from a linear model describing spindle density as a nonlinear function of age and other covariates, with each curve normalized to have a maximum of 1.0. Slower spindles (for example, FC=11 Hz) peak earlier in development than faster spindles (for example, FC=15 Hz).
Figure 3
Figure 3. Spindle density across the night.
Mean spindle density (spindles per min) during N2 by sleep cycle and position within the cycle, stratified by age (years) and spindle frequency (Hz). (a) For slow (11 Hz, blue, left column) and fast (15 Hz, green, right column) spindles, mean density averaged over epochs (rather than individuals) stratified by sleep cycle, separately for individuals under 40 (mostly children and adolescents, mean age ∼12 years) versus over 40 (mean age ∼68 years). The first 60 min of each cycle was divided into six 10-min intervals of N2 sleep; an additional >60 min point is included for each cycle also. (b) Spindle density in ascending (unfilled bars) versus descending (filled bars) N2 epochs, stratified by sleep cycle number, age and spindle frequency.
Figure 4
Figure 4. Spectral and spindle traits for two MZ twin pairs and two matched unrelated pairs.
Data from two MZ twin pairs in the Cleveland Family Study, and two randomly selected unrelated individuals (matched for age, sex and race to the corresponding MZ pair, see Supplementary Table 23). (a) Spectral power for each pair; in each plot, different coloured lines represent the first and second members of each pair. (b) Similar results for spindle density from the frequency-dependent spindle analysis (FC varied from 8 to 18Hz). In all cases, the MZ pairs showed greater concordance in spectral and spindle traits.
Figure 5
Figure 5. Heritabilities and genetic correlations for spindle density across a range of frequencies.
The plots show the estimated heritability for spindle density at a range of FC (8–18 Hz) from the frequency-dependent spindle analyses. Heritabilities were estimated by applying mixed models to SNP data available in the CFS, restricted to either (a) black or (b) white individuals. In each panel, the upper right plot gives the estimated heritability (h2) and the lower left plot gives the corresponding significance value for the test of H0: h2=0. Shaded points in the lower right quadrant represent genetic correlations (rG) between spindle densities at different FC, only showing significant (p<0.05) correlations. Grey bars highlight FC=11 and 15 Hz, which correspond to ‘slow’ and ‘fast’ spindles. Although both types of spindle showed significant univariate heritability, there was little evidence for shared genetic factors (significant rG).
Figure 6
Figure 6. Topographical analyses of individual differences in spindle density in the CHAT study.
(a) Mean slow (FC=11 Hz) spindle densities for the subset of individuals in the CHAT study with EEG at 18 electrodes. Electrodes with means significantly (P<0.05/17, that is, Bonferroni correction for 17 tests) greater (or less) than C3 (grey circle) are shown as enlarged white (or black) circles. (b) As above, but for fast (FC=15 Hz) spindles. (c) Correlation in individual slow spindle densities at C3 and C4 across other locations, for both fast and slow spindles. For reference, dotted lines represent r=0.0 and .8. (d) As above, but for fast spindles. Supplementary Fig. 25 shows the underlying scatter plots for each correlation point here.
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