Beneficial effects and potential future applications of targeted memory reactivation dur- ing sleep are vast and numerous, especially in regard to cognitive enhancement and, in a clinical setting, psychotherapy.
Since it is hypothesized that targeted memory reactivation during sleep depends on hip- pocampal reactivation processes, most studies in the past attempted to reactivate hippo- campus-dependent memory contents. This technique has so far not only demonstrated to benefit declarative memory consolidation but also to accelerate the consolidation process (Diekelmann et al., 2012) and make newly consolidated memories more resistant to in- terference, i.e., less likely to forget (Diekelmann et al., 2011). Creery and colleagues ad- ditionally demonstrated that beneficial effects of cueing grow proportionally to subjects’ initial performance levels as long as the pre-sleep performance is not already near-perfect. (Creery et al., 2015). One study showed that when cued memory reactivation during sleep is conducted, behavioral performance results increase by approximately 20% compared to regular sleep without cueing (Diekelmann et al., 2011). This 20% increase in perfor- mance could especially benefit children and adults with learning deficits (Sigman et al., 2014). Cued memory reactivation might also be able to facilitate learning of foreign lan- guages (Schreiner and Rasch, 2015a), even though the existence of prior knowledge
seems to be essential for a beneficial memory effect to occur (Groch et al., 2016b). Ad-
ditionally, cued memory reactivation studies have shown possibilities to strengthen crea- tive thinking and problem-solving skills (Ritter et al., 2012), and even to reduce gender and racial bias in individuals (Hu et al., 2015). Another direction for possible future ap- plications of this technique lies within a more clinical setting. The average amount of SWS during the night decreases dramatically with increasing age, which seems to lead to a decline in declarative memory consolidation capabilities with growing age (Backhaus et al., 2007). Targeted memory reactivation could therefore potentially represent a new therapeutic approach to memory impairment of the elderly or even diseases such as de- mentia or Alzheimer’s (Schouten et al., 2017). Targeted memory reactivation could prove to be a useful tool to alleviate symptoms of psychiatric disorders that are associated with
72 dysfunctional sleep and memory, e.g., post-traumatic stress disorder (PTSD), depression, and schizophrenia (Diekelmann and Forcato, 2015). One cued memory reactivation study demonstrated enhanced forgetting of unwanted memories and could thus be useful for patients with PTSD (Simon et al., 2018). This technique could also be incorporated into psychotherapy of social anxiety disorder (Groch et al., 2017) by changing the perception and interpretation of specific emotional situations into a more positive direction. (Diekelmann and Forcato, 2015) (Schouten et al., 2017)
Targeted memory reactivation has the potential to become a non-invasive, cost-effective drug-alternative method to enhance cognitive functions and improve efficiency of psy- chotherapy. Nonetheless, real-life applications of targeted memory reactivations are at present mainly theoretical, have been attempted only once so far (Göldi and Rasch, 2019), and have yet to achieve consistent behavioral results across studies. Further research is required before practical applications in the general population can succeed. Furthermore, many questions remain unanswered in regard to, inter alia, specific cueing conditions, underlying neural mechanisms, continuous long-term effects, limitations, and potential side effects of the cued memory reactivation technique.
Nonetheless, all of the above-mentioned reactivation studies demonstrating the potential benefits and future applications of targeted memory reactivation did not specifically pre- sent cues in-phase with a certain SO phase during post-learning non-REM sleep. They presented cues via an open-loop stimulation system, applying cues in a random fashion regardless of slow oscillation phases. Only one study considered the potential relevance of the application of cues at a specific phase of the slow wave and therefore added a random jitter of 0 to 0.4 s to a set interstimulus interval of 6 s for the presentation of auditory cues (Groch et al, 2016b). This ensured that auditory stimuli reached SOs at variable points, effectively eliminating the possible relevance of the temporal interplay between slow waves and auditory cues. Closed-loop auditory stimulation studies so far have reported improved memory retention compared to sham conditions, with cues pre- sented phase-locked to SO up states (Ong et al., 2016; Ngo et al., 2013, 2015), cues phase- locked to the transition period from SO down states to up states (Shimizu et al., 2018), and cues phase-locked to the negative peaks of SOs (Leminen et al., 2017). Apart from the present study, one other closed-loop study directly compared the memory retention
73 effects of cueing during SO up states, down states, and uncued memories (Göldi et al., 2019). The next step in this line of memory research is to directly compare the effects of closed-loop and open-loop auditory stimulation, each combined with targeted memory reactivation. Further research should also examine whether closed-loop auditory stimula- tion combined with targeted memory reactivation results in greater memory retention ef- fects than these techniques by themselves. Previous open-loop targeted memory reactiva- tion studies could, e.g., be replicated using the exact same experimental set-up but with cues being presented in time with specific phases of SOs via a closed-loop detection al- gorithm. Future closed-loop targeted reactivation studies should also apply auditory stim- uli which are standardized equally in regard to stimulus length, intensity, interstimulus interval and content in order to eliminate these differences from previous studies as po- tential confounding factors. This would allow possible replication of consistent results in order to determine the optimal time frame for cue presentation during non-REM sleep. Additionally, this kind of standardized set-up could be used to determine if specific timing of cues plays a role in regard to enhancement of slow oscillatory activity, phase-coupled spindle activity and consequently declarative memory consolidation compared to open- loop targeted memory reactivation.