The effectiveness of auditory stimulation in sleep varies with thalamocortical spindle phase

Slow oscillations and sleep spindles are neural events that both occur during non-rapid eye movement sleep and are implicated in sleep-dependent memory consolidation. Their temporal co-occurrence, or 'coupling', is thought to support sleep-dependent memory processes. The roles of these neural events can be explored through non-invasive brain stimulation techniques. Closed-loop auditory stimulation, which precisely times sounds to enhance or disrupt neural events, can induce slow oscillation and spindle activity, improving memory in some individuals. While spindle-targeted stimulation is now feasible, the effect of slow oscillation-spindle coupling and spindle phase on neurophysiological outcomes remains unexplored. This study investigates how spindle phase timing relates to the neurophysiological effects of closed-loop auditory stimulation timed to slow oscillation up-states. A secondary aim is to characterize predictors of inter-individual differences in stimulation effectiveness. Electroencephalography data collected across multiple nights were analysed from 16 healthy adults, with stimulation delivered at the slow oscillation up-state or withheld (sham condition). Results show that while slow wave activity shows enhancement with minimal phase-dependency, temporally-coordinated spindle activity emerges only in the peak and rising phases. In contrast, trough stimulation delays spindle activity, and stimulation during the falling phase produces no enhanced spindle activity. Across subjects, strength of slow wave and spindle activity was correlated at detection in each frequency band separately, but amplitude at detection did not predict response strength. These findings refine our understanding of sleep oscillation dynamics and inform future uses of closed-loop stimulation, with a view to advancing fundamental science and potentially restoring sleep and memory functions in clinical applications.