Study ObjectivesSlow wave and spindle coupling supports memory consolidation, and loss of coupling is linked with cognitive decline and neurodegeneration. Coupling is proposed to be a possible biomarker of neurological disease, yet little is known about the different subtypes of coupling that normally occur throughout human development and aging. Here we identify distinct subtypes of spindles within slow wave upstates and describe their relationships with sleep stage across the human lifespan.
MethodsCoupling within a cross-sectional cohort of 582 subjects was quantified from stages N2 and N3 sleep across ages 6-88 years old. Results were analyzed across the study population via mixed model regression. Within a subset of subjects, we further utilized coupling to identify discrete subtypes of slow waves by their coupled spindles.
ResultsTwo different subtypes of spindles were identified during the upstates of (distinct) slow waves: an "early-fast" spindle, more common in stage N2 sleep, and a "late-fast" spindle, more common in stage N3. We further found stages N2 and N3 sleep are composed of two discrete subtypes of slow waves, each identified by their unique coupled-spindle timing and frequency. The relative contribution of coupling subtypes shifts across the human lifespan, and a deeper sleep phenotype prevails during old age.
ConclusionsDistinct subtypes of slow waves and coupled spindles form the composite of slow wave sleep.Our findings support a model of sleep-dependent synaptic regulation via discrete slow wave/spindle coupling subtypes and advance a conceptual framework for the development of coupling-based biomarkers in age-associated neurological disease.
Statement of SignificanceSlow waves of nonrapid eye movement sleep couple with sleep spindles in a process hypothesized to support memory functions. This coupling has recently gained interest as a possible biomarker of cognitive aging and onset of Alzheimer's disease. Most studies have been limited by an assumption that all slow waves (and coupled spindles) are fundamentally the same physiological events. Here we demonstrate that distinct subtypes of slow waves and their coupled spindles can be identified in human sleep. A mixture of different slow wave and spindle subtypes shifts in composition during lighter versus deeper sleep, and aging favors the deep sleep subtypes. These data should inform any future attempts to use slow wave sleep as a biomarker or clinical interventional target. Background: Slow waves occur during stages N2 and N3 Non-Rapid Eye Movement (NREM) sleep and are associated with large-scale synchronization of neuronal populations. 1-3 Spindlesare generated and propagated via cortical-thalamic loops, with timing input from the reticular nucleus of the thalamus. 4,5 In the process of aging, loss of slow waves and sleep spindles is highly correlated with cognitive decline, and abnormal slow wave neuronal circuitry is implicated in the pathogenesis of Alzheimer's disease 6 .
