Pulsed inhibition of corticospinal excitability by the thalamocortical sleep spindle

Thalamocortical sleep spindles, i.e., oscillatory bursts at ∼12-15 Hz of waxing and waning amplitude, are a hallmark feature of non-rapid eye movement (NREM) sleep and believed to play a key role in sleep-dependent memory reactivation and consolidation. Generated in the thalamus and projecting to neocortex and hippocampus, they are phasically modulated by neocortical slow oscillations (<1 Hz) and in turn phasically modulate hippocampal sharp-wave ripples (>80 Hz). This hierarchical cross-frequency nesting may enable phase-dependent plasticity in the neocortex, and spindles have thus been considered windows of plasticity in the sleeping brain. However, the assumed phasic excitability modulation had not yet been demonstrated for spindles. Utilizing a recently developed real-time spindle detection algorithm, we applied spindle phase-triggered transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) hand area and measured motor evoked potentials (MEP) to characterize corticospinal excitability during sleep spindles. We found a net suppression of MEP amplitudes during spindles, driven by selective inhibition during the falling flank of the spindle oscillation, but no inhibition during its peak, rising flank, and trough. Importantly, this phasic inhibition occurred on top of the general sleep-related inhibition observed during spindle-free NREM sleep and did not extend into the immediate refractory post-spindle periods. We conclude that spindles exert asymmetric “pulsed inhibition” of corticospinal excitability, which is assumedly relevant for processes of phase-dependent plasticity. These findings and the developed real-time spindle targeting methods will enable future studies to uncover the causal role of spindles in synaptic plasticity and systems memory consolidation.