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 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, where slower oscillations group faster ones into certain excitability phases, 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 to characterize the corticospinal excitability profile of spindles via motor evoked potentials (MEP). MEPs showed net suppression during spindles, driven by a "pulse of inhibition" during its falling flank with no inhibition or facilitation during its peak, rising flank, or trough. This unidirectional ("asymmetric") modulation occurred on top of the general sleep-related inhibition during spindle-free NREM sleep and did not extend into the refractory post-spindle periods. We conclude that spindles exert "asymmetric pulsed inhibition" on corticospinal excitability. These findings and the developed real-time spindle targeting methods enable future studies to investigate the causal role of spindles in phase-dependent synaptic plasticity and systems memory consolidation during sleep by repetitively targeting relevant spindle phases.