Highlights A single night of TMR benefits procedural memories up to 10 days later. Spindle density and SO-spindle coupling strength increase immediately upon cue onset. Time spent in N2 but not N3 predicts cueing benefit.

Memory reactivation during Non-Rapid Eye Movement (NREM) sleep is important for memory consolidation but it remains unclear exactly how such activity promotes the development of a stable memory representation. We used Targeted Memory Reactivation (TMR) in combination with longitudinal structural and functional MRI to track the evolution of a motor memory trace over 20 days. We show that repeated reactivation of motor memory during sleep leads to increased precuneus activation 24 h post-TMR. Interestingly, a decrease in precuneus activity over the next 10 days predicts longer-term cueing benefit. We also find both functional and structural changes in sensorimotor cortex in association with effects of TMR 20 days post-encoding. These findings demonstrate that TMR can engage precuneus in the short-term while also impacting on task-related structure and function over longer timescales.

Targeted memory reactivation (TMR) is a technique by which sounds paired with learned information can be used to cue neural reactivation of that information during sleep. While TMR in slow-wave sleep (SWS) has been shown to strengthen procedural memories, it is unclear whether TMR in rapid eye movement (REM) sleep, a state strongly associated with motor consolidation, provides equivalent benefit. Furthermore, it is unclear whether this technique influences dominant and non-dominant hands equally. We applied TMR of a two-handed serial reaction time task (SRTT) during either SWS or REM in thirty-two human right handed adults (sixteen female) to examine the impact of stimulation in each sleep stage on right (dominant) and left hands. While TMR in SWS led to strong benefits in reaction times and sequence-specific skill, equivalent cueing in REM led to no benefit at all, suggesting that reactivation in this sleep stage is not important for the SRTT. Event-related potentials elicited by TMR cues for left and right hand movements differed significantly in REM, but not SWS, showing that these cues are at least processed in REM. Interestingly, TMR benefits were apparent only in the non-dominant hand, potentially due to the weaker performance measured in this hand at the outset. Overall, these findings suggest that memory replay in SWS, but not REM, is important for consolidation of the SRTT, and TMR-cued consolidation is stronger in the non-dominant hand.Significance statementTargeted memory reactivation (TMR) in sleep leads to memory consolidation, but many aspects of this process remain to be understood. We used TMR of a bimanual serial reaction time task to show that behavioural benefit is only observed after stimulation in SWS, even though electrophysiology shows that the TMR cues are processed in REM. Importantly, TMR selectively benefitted the non-dominant hand. These findings suggest that TMR in REM does not benefit this serial reaction time task, and that TMR in SWS preferentially consolidates weaker memory traces relating to the non-dominant hand.

Memory traces develop gradually and link to neural plasticity. Memory reactivation during sleep is crucial for consolidation, but its precise impact on plasticity and contribution to long-term memory storage remains unclear. We used multimodal diffusion-weighted imaging to track the location and timescale of microstructural changes following Targeted Memory Reactivation (TMR) of a motor task. This showed continuous microstructure plasticity in precuneus across 10 days post-TMR, paralleling the gradual development of behavioural benefit. Both early (0 - 24 h post-TMR) and late (24 h - 10 days post-TMR) microstructural changes in striatum and sensorimotor cortex were associated with the emergence of behavioural effects of TMR at day 20. Furthermore, the baseline microstructural architecture of sensorimotor cortex predicted TMR susceptibility. These findings demonstrate that repeated reactivation of memory traces during sleep engenders microstructural plasticity which continues days after the stimulation night and is associated with the emergence of memory benefits at the behavioural level.