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Sounding It Out: Auditory Stimulation and Overnight Memory Processing

Sounding It Out: Auditory Stimulation and Overnight Memory Processing Purpose of Review Auditory stimulation is a technique that can enhance neural oscillations linked to overnight memory consol- idation. In this review, we evaluate the impacts of auditory stimulation on the neural oscillations of sleep and associated memory processes in a variety of populations. Recent Findings Cortical EEG recordings of slow-wave sleep (SWS) are characterised by two cardinal oscillations: slow oscillations (SOs) and sleep spindles. Auditory stimulation delivered in SWS enhances SOs and phase-coupled spindle activity in healthy children and adults, children with ADHD, adults with mild cognitive impairment and patients with major depression. Under certain conditions, auditory stimulation bolsters the benefits of SWS for memory consolidation, although further work is required to fully understand the factors affecting stimulation-related memory gains. Recent work has turned to rapid eye movement (REM) sleep, demonstrating that auditory stimulation can be used to manipulate REM sleep theta oscillations. Summary Auditory stimulation enhances oscillations linked to overnight memory processing and shows promise as a technique for enhancing the memory benefits of sleep. . . . . . Keywords Closed-loop stimulation Slow-wave sleep Slow oscillations Sleep spindles Rapid eye movement sleep Memory consolidation Introduction to their depolarising up-states, and, in doing so, drive the repeated reactivation of hippocampal memory representations After a longstanding debate, it is now generally accepted that [1, 2]. memory consolidation is supported by sleep. Contemporary An abundance of studies have linked SWS and SOs to models of sleep-associated consolidation posit that memories memory consolidation in humans [3–10]. Notwithstanding of recent experiences are actively strengthened during the the obvious importance of this work, many early reports relied deepest stage of non-rapid eye movement (NREM) sleep: on correlational findings, and thus lacked causal evidence of slow-wave sleep (SWS) [1, 2]. Cortical EEG recordings of SOs actively contributing to overnight memory processing. SWS are characterised by <1 Hz slow oscillations (SOs), The first efforts to address this gap used electrical stimulation which emerge in neocortical regions and reflect widespread to experimentally induce SOs during SWS, which, relative to synchronous activity alternating between up-states of neuro- a control condition, improved memory retention [11, 12]. nal excitation and down-states of neuronal silence. Crucially, Importantly, however, these electrical stimulation studies arti- SOs are thought to synchronise fast thalamo-cortical spindles ficially imposed SO rhythms on the brain that were not (~12–16 Hz) and hippocampal ripples (80–100 Hz in humans) synchronised to the brain’s endogenous oscillatory activity, potentially limiting the benefits of SO induction on sleep- associated memory processing. This article is part of the Topical Collection on Sleep and Learning In their seminal study, Ngo and colleagues [13]used an innovative auditory stimulation method to enhance the brain’s * Scott A. Cairney own endogenous rhythm and, consequently, bolster the mem- scott.cairney@york.ac.uk ory benefits of SWS (see Box 1). This work paved the way for Department of Psychology, University of York, York, UK more auditory stimulation studies that aimed to elucidate the York Biomedical Research Institute, University of York, York, UK link between NREM sleep oscillations and offline memory Curr Sleep Medicine Rep (2021) 7:112–119 113 processing. In this review, we provide an overview of the rhythm. Specifically, stimulation induced ‘trains’ of three suc- literature in this important and rapidly developing field. We cessive SO cycles (as compared to the individual SOs first describe the variety of ways in which researchers have observed in the sham condition, see example in Fig. 1B), modified the parameters of auditory stimulation, and the im- increased the amplitude of SO cycles and amplified phase- pact that these modifications have had on the neural oscilla- coupled fast spindle activity during SO up-states. Moreover, tions of sleep and associated memory processes. Next, we stimulation (vs. sham) led to a sizeable improvement in over- outline how the effects of stimulation vary according to the night memory retention, supporting the view that SOs play a demographics of the study participants, focusing on different causal role in offline consolidation. Auditory stimulation out age groups and clinical samples. Finally, we discuss the of phase with the ongoing SO rhythm did not enhance SO behaviourally observable effects of stimulation in different activity or improve memory performance compared to sham. memory domains. Stimulation Parameters Box 1 Number of Clicks Ngo and colleagues [13] delivered auditory stimulation during SWS in synchrony with the brain’s own endogenous rhythm. Given the observed effects of auditory stimulation with two Healthy young adults each participated in two conditions: clicks, an obvious question is whether additional clicks lead to stimulation and sham. In the stimulation condition, frontal further enhancement of oscillatory activity and sleep-associated EEG activity was recorded in real time and, following algo- consolidation. rithmic detection of a supra-threshold SO down-state, two Ngo and colleagues [14] addressed this question in a 50 ms pulses of pink noise (clicks) were delivered in phase follow-up study by comparing their original two-click proto- with the two subsequent SO up-states (see example in Fig. col to a ‘driving stimulation’ protocol, which delivered up to 1A). Timing of the clicks varied according to the temporal four consecutive clicks (also during SO up-states). Driving characteristics of each participant’s SOs (i.e. the average time stimulation (vs. sham) prolonged SO trains, amplified phase- between the negative and positive SO peaks), thereby ensur- locked fast spindle activity and improved overnight retention; ing precise, phase-locked stimulation. In the sham condition, but to no greater extent than that afforded by two-click stim- would-be stimulation events were marked but no clicks were ulation. Similar findings have emerged from more recent work delivered. Auditory stimulation was found to enhance the SO using five-click stimulation protocols [15–17]; whereas Fig. 1 Example of the auditory stimulation protocol used by Ngo and night), and the second after a 1.075 s interval corresponding to the colleagues [13], and its effects on the SO rhythm. A. Following detection typical duration of a full SO cycle. In the sham condition, of a supra-threshold SO down-state (−80 μV; grey line), two 50 ms pulses corresponding time points of would-be stimulation events are marked of pink noise (clicks) are delivered in phase with the two subsequent SO but no clicks are delivered. The detection routine is paused for 2.5 s up-states (red lines). The first click occurs during the predicted SO up- after the second click. B. Relative to the sham condition, stimulation state, based on the average delay between the SO negative and positive typically enhances the SO rhythm, evoking a ‘train’ of three SOs peak (~0.5 s; obtained for each participant during a prior adaptation 114 Curr Sleep Medicine Rep (2021) 7:112–119 stimulation enhanced the SO rhythm and improved next-day frequency of 0.8 Hz (corresponding to the approximate recall, the amplitude of the SOs induced by the clicks typically frequency of SOs). As compared to sham, stimulation declined after the third SO cycle. increased SO and fast spindle power during NREM sleep. Hence, the research to date suggests that delivering However, because a memory test was not included in the more than two clicks does not confer any additional en- study protocol, it was not possible to establish whether hancement to SO activity or overnight memory process- these stimulation-induced changes in oscillatory activity ing. Because enhancing the SO rhythm and synchronised led to improvements in overnight consolidation. excitability carries an increased risk of seizure-like activ- ity, it has been suggested that limitations in the sleeping brain’s responsiveness to auditory stimulation might re- Timing of Stimulation flect the presence of a protective mechanism that prevents the development of hypersynchronicity during SO activity Because the cortical response to auditory stimulation varies [14, 18]. according to the timing of stimulus delivery [13, 33], a recent Interestingly, a number of studies using only a single audi- study aimed to determine the SO phase at which clicks max- tory pulse per stimulation event have observed enhancements imally augment oscillatory activity during SWS [26� ]. in NREM oscillatory activity [19 , 20–22] and overnight re- Relative to sham, applying clicks at any point during the SO tention [22]. Whether one-click stimulation is as effective as up-state increased the amplitude of subsequent SOs and in- two-click stimulation, however, has yet to be established. creased the likelihood of detecting a phase-coupled sleep spin- dle. However, the amplitudes of stimulation-induced SOs and Closed-loop Versus Open-loop Methods spindles were maximal when clicks were delivered close to the SO peak, suggesting that optimization of SO stimulation The vast majority of auditory stimulation studies have used depends critically on precise timing of stimulus delivery. the closed-loop method; that is, utilising the ongoing EEG activity to deliver auditory stimuli in synchrony with the brain’s endogenous rhythm [13, 14, 16, 17, 19, 21–31, 32]. Target Oscillation: Sleep Spindles One study, however, used an open-loop protocol in which the ongoing EEG data had no bearing on the timing of stimulus Given their putative function in overnight consolidation, re- delivery [33]. For each stimulation event, an initial click was searchers have utilised auditory stimulation to directly target delivered without regard to SO phase. Two further clicks were sleep spindles. then delivered at times chosen to maximise their probability of In the first study of its kind, oscillating white noise was coinciding with the up-states of the SOs evoked by the first delivered in 2 s bursts at regular intervals throughout stage click. The interval between the first and second clicks was two sleep and SWS [35]. The sounds were delivered at one based on the average duration of a full SO cycle for the re- of three frequencies: a slow spindle-mimicking frequency of spective participant (~0.9 s; obtained in a prior adaptation 12 Hz, a fast spindle-mimicking frequency of 15 Hz, or a night), and the interval between the second and third clicks control frequency of 50 Hz. Whereas 50 Hz stimulation had was fixed at 1.075 s. no effect on spindle activity, 12 Hz and 15 Hz stimulation Open-loop stimulation, relative to sham, evoked a train of increased slow and fast spindle densities, respectively. The SOs and amplified fast spindle activity during the up-state of evoked spindles were comparable to endogenously generated the first SO cycle. Importantly, however, stimulation led to an spindles in both duration and topography, suggesting that overall decrease in fast spindle power across the entire stimu- spindle stimulation might augment offline memory process- lation period, and had no impact on memory retention when ing. However, because the study protocol did not include a compared to the sham condition. Hence, despite clearly memory test, the effects of spindle stimulation on sleep- influencing oscillatory activity in SWS, open-loop stimulation associated consolidation could not be assessed. might be ineffective at enhancing overnight consolidation. In a later study, application of a rapid sequence of clicks Further work is of course required to build on this single (~15 Hz) during SO up-states had no immediate impact on study. spindle activity [25]. Instead, stimulation evoked an additional SO which was accompanied by an increase in phase-coupled Continuous Stimulation spindle power. This rapid click stimulation did not influence memory retention, as compared to sham. In other works, de- Other work has employed an auditory stimulation method livery of single clicks upon algorithmic detection of sleep that we refer to here as continuous stimulation [34]. spindles evoked a single SO, increased both delta (1–4Hz) Throughout the first 90 min of an overnight sleep oppor- and theta (4–8 Hz) power and improved performance in a tunity, single clicks were delivered continuously at a procedural learning task [36� ]. �� Curr Sleep Medicine Rep (2021) 7:112–119 115 Target Oscillation: REM Sleep Theta memory because many of the neurobiological mechanisms that are necessary for overnight consolidation are otherwise Theta oscillations (~3–7 Hz) are a prominent feature of the impaired (e.g. because of neural atrophy that occurs in normal REM sleep EEG, and were directly targeted in a recent study ageing) [42]. Understanding how the changes in brain mor- using a protocol modelled on the principles of auditory closed- phology that accompany normal ageing influence the oscilla- loop stimulation [37�� ]. Upon algorithmic detection of two tory and mnemonic impacts of auditory stimulation will be an supra-threshold theta cycles, oscillating white noise was de- important challenge for future research. livered at 5 Hz, corresponding to the approximate frequency of endogenous theta waves. Relative to sham, stimulation Children evoked a rapid increase in theta power, which was immedi- ately followed by a prolonged period of theta suppression, and By the age of 12 years, children typically achieve almost twice a prolonged increase in 10–30 Hz beta power. Stimulation had the amount of SWS as adults [43], and can thus provide im- no impact on overnight memory retention. portant insights into overnight consolidation processes medi- ated by SOs. A single study to date has applied auditory stim- ulation to typically developing children aged 8–12 years, and Participant Demographics children with attention deficit hyperactivity disorder (ADHD) of the same ages [23� ]. In both groups, a two-click closed-loop Older Adults stimulation protocol evoked trains of three SO cycles, mirroring findings in healthy adults. Stimulation also im- Because the vast majority of auditory stimulation studies have proved memory recall relative to the sham condition. tested healthy young adults (typically aged 18–30 years), we Whether the efficacy of auditory stimulation differs between focus here on the effects of stimulation in older adults. children and adults has yet to be established. Mirroring findings in young people, a study that delivered five-click, closed-loop stimulation to adults aged 60 to 84 Patients with Major Depression years found that stimulation prolonged SO trains, amplified phase-coupled spindle activity and improved overnight mem- Sleep disturbances are a common feature of nearly all psychi- ory retention, as compared to sham [29]. More recently, how- atric conditions [44, 45]. Whether and how auditory stimula- ever, a direct comparison of the effects of auditory SO stimu- tion affects slow oscillatory activity and associated cognitive lation in young and older adults (aged 49–63 years) revealed a functions among individuals with psychiatric disorders are marked reduction in SO amplitude and phase-coupled spindle important questions for understanding the mechanisms of dis- activity in older people [30 ]. Correspondingly, the memory ease and potential targets for therapeutic intervention. In a benefits of stimulation observed in young adults were absent recent study [27], auditory stimulation (vs. sham) applied to in the older individuals. Other studies paint a similar picture. adults with major depression increased delta (0.5–2.5 Hz) and In healthy middle-aged men (aged 35–48 years), auditory beta (16–25 Hz) power, but decreased oscillatory activity in stimulation increased 0.5–4 Hz delta power across the entire the slow spindle range (12.5−14.5 Hz). The impacts of stim- night but had no impact on memory retention [31]. Likewise, ulation on memory performance were not assessed. stimulation applied to older adults with mild cognitive impair- ment (aged 62–86 years) amplified SO power, but had no effect on overnight consolidation [16]. Memory Domains In sum, these findings point to an age-related decline in the effectiveness of auditory stimulation. Normal ageing is asso- Since the seminal findings of Ngo and colleagues [13], a large ciated with a reduction in the density and amplitude of SOs, number of studies have assessed the memory effects of audi- and a decoupling of SOs and spindles [38–40]. These changes tory stimulation across a variety of memory domains. These reflect a deterioration of synchronised firing in large neuronal studies are summarised in Table 1, organised by memory do- populations. It has been suggested that diminished main and associated task. responsivity to stimulation in older adults could be the result of decreased cortical capability to group large neural popula- tions into synchronised activity in response to peripheral stim- Declarative Memory uli [26� ]. The failure of some studies to detect a benefit of auditory stimulation on memory processing in older adults, Given that SOs are thought to drive the reactivation of despite augmentation of SOs and spindles, offers support to memory representations in the hippocampus, most audi- the ‘functional weakening’ hypothesis [41]. According to this tory stimulation studies have assessed overnight changes view, bolstering sleep in older adults is unlikely to benefit in hippocampus-dependent declarative memories. �� 116 Curr Sleep Medicine Rep (2021) 7:112–119 Table 1 Studies investigating the Memory domain Task memory effects of auditory stimulation in sleep, organised by Declarative Paired associates learning: related word pairs [13, 14, 16, 17, 19 , 22, 25, 29, 30�� , 33, memory domain and task memory 36� ] Paired associated learning: unrelated word pairs [19�� , 23� , 31, 32] Paired associates learning: face-name associations [22] Picture recognition task (encoding after stimulation) [24, 30�� ] Spatial navigation task [19�� ] Motor skills Finger tapping [22, 30 , 36� ] Serial reaction time task [23� ] Emotional memory Picture recognition [22, 37] Working memory N-back task [23� ] Memory for semantically related word pairs (e.g. pan-hob) such that healthy young adults were faster to type sequences typically benefits from closed-loop stimulation [13, 14, 17, of digits that were learned prior to sleep [36� ]. Similarly, rel- 22, 29] (also see: [16, 19�� , 30]), but not open-loop stimulation ative to sham, auditory SO stimulation improved sequence [33], or stimulation directly targeting sleep spindles [25, 36]. learning in children with ADHD [23� ]. However, other studies By contrast, auditory closed-loop stimulation does not seem to have failed to observe a benefit of SO stimulation on finger improve memory for pairs of stimuli with no intrinsic connec- tapping performance in healthy young adults [22]or middle- tion, such as semantically unrelated word pairs (e.g. pan-car) aged and older adults [30�� ]. or face-name pairs [19�� , 22, 31, 32]. A notable exception was observed in a recent study in children, where stimulation im- Emotional Memory proved retention of unrelated word pairs associated with a monetary reward, but not unrewarded word pairs [23� ]. Theta oscillations during REM sleep have been linked to the Hence, the findings to date suggest that auditory stimulation consolidation of emotional memories [49, 50]. In recent work, benefits the consolidation of paired associates that are consis- however, manipulation of theta activity via auditory stimula- tent with pre-existing knowledge, or of personal value to the tion in REM sleep had no impact on the retention of negative individual. or neutral images [37�� ]. Likewise, auditory stimulation dur- A single study has investigated the effect of auditory stim- ing SWS, which has also been implicated in affective memory ulation on visuospatial declarative memory in healthy young processing [51, 52], had no impact on memory for aversive adults [19 ]. Here, stimulation applied during a daytime nap pictures [22]. had no impact on navigation speed in a virtual spatial naviga- tion task. Working Memory Because sleep plays an important role in new learning [46–48], other works have tested the hypothesis that auditory Just one study to date has examined the effect of auditory stimulation improves encoding capabilities in declarative stimulation on working memory [23� ]. In children with memory. In a recent study in healthy adults, the amplitude ADHD, SO stimulation (vs. sham) improved performance in of stimulation-evoked SOs was correlated with hippocampal a n-back task, such that they were faster to correctly identify activation during picture encoding, and better performance in whether or not patterns that they were shown had appeared in a subsequent recognition test [24]. Relative to the sham con- recently preceding trials. dition, however, there was no overall benefit of stimulation for learning. A subsequent study also failed to observe any benefit of auditory stimulation on picture encoding capacities in Conclusion middle-aged and older adults [30�� ]. Auditory stimulation is a powerful tool for inducing, augment- Motor Skills ing and modifying the neural oscillations of sleep. Delivering auditory stimuli during SO up-states reliably enhances the SO Research examining the effects of auditory stimulation on rhythm and boosts phase-coupled spindle activity. Older procedural motor skills has produced mixed results. In one adults appear to be less receptive to auditory stimulation than study, auditory stimulation directly targeting sleep spindles young adults—possibly because of age-related changes in (vs. sham) improved performance on a finger tapping task, brain morphology. Single studies have found that SO �� �� �� Curr Sleep Medicine Rep (2021) 7:112–119 117 stimulation modulates neural rhythms in typically developing Declarations children, children with ADHD, adults with major depression Human and Animal Rights All reported studies/experiments with hu- and older adults with mild cognitive impairment. Multiple man or animal subjects performed by the authors have been previously experiments have observed a significant benefit of auditory published and complied with all applicable ethical standards (including stimulation on memory retention. However, the effect of stim- the Helsinki declaration and its amendments, institutional/national re- ulation on memory seems to vary according to the type of search committee standards, and international/national/institutional guidelines). learning material and the memory system under investigation. Despite significant advances in our understanding of the Open Access This article is licensed under a Creative Commons effects that auditory stimulation can have on electrophysiolo- Attribution 4.0 International License, which permits use, sharing, adap- tation, distribution and reproduction in any medium or format, as long as gy, little is known about how these effects occur. It has long you give appropriate credit to the original author(s) and the source, pro- been known that delivering auditory stimuli during NREM vide a link to the Creative Commons licence, and indicate if changes were sleep evokes K-complexes, which are comparable to SOs in made. The images or other third party material in this article are included both appearance and generating mechanisms [53]. Evoked K- in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's complexes are believed to preserve sleep continuity in the face Creative Commons licence and your intended use is not permitted by of external stimuli that would otherwise fragment sleep by statutory regulation or exceeds the permitted use, you will need to obtain triggering arousal responses [54]. Although speculative, one permission directly from the copyright holder. To view a copy of this possibility is that auditory stimulation exploits this adaptive licence, visit http://creativecommons.org/licenses/by/4.0/. K-complex response to artificially bolster overnight consoli- dation. Specifically, when stimulation is delivered in-phase with an SO up-state, the evoked K-complex has an additive effect on the subsequent SO cycle, which increases its ampli- References tude. Although endogenous SOs often occur in trains, they can occur as singular events [14]. For these solitary SOs, in- Papers of particular interest, published recently, have been phase stimulation could induce a K-complex after the detected highlighted as: SO cycle, giving the appearance of an SO train. � Of importance Our knowledge of how auditory stimulation benefits over- �� Of major importance night consolidation is also somewhat superficial. Presumably, by enhancing SOs and phase-coupled spindle activity─which 1. Born J, Wilhelm I. System consolidation of memory during sleep. 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Sounding It Out: Auditory Stimulation and Overnight Memory Processing

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Abstract

Purpose of Review Auditory stimulation is a technique that can enhance neural oscillations linked to overnight memory consol- idation. In this review, we evaluate the impacts of auditory stimulation on the neural oscillations of sleep and associated memory processes in a variety of populations. Recent Findings Cortical EEG recordings of slow-wave sleep (SWS) are characterised by two cardinal oscillations: slow oscillations (SOs) and sleep spindles. Auditory stimulation delivered in SWS enhances SOs and phase-coupled spindle activity in healthy children and adults, children with ADHD, adults with mild cognitive impairment and patients with major depression. Under certain conditions, auditory stimulation bolsters the benefits of SWS for memory consolidation, although further work is required to fully understand the factors affecting stimulation-related memory gains. Recent work has turned to rapid eye movement (REM) sleep, demonstrating that auditory stimulation can be used to manipulate REM sleep theta oscillations. Summary Auditory stimulation enhances oscillations linked to overnight memory processing and shows promise as a technique for enhancing the memory benefits of sleep. . . . . . Keywords Closed-loop stimulation Slow-wave sleep Slow oscillations Sleep spindles Rapid eye movement sleep Memory consolidation Introduction to their depolarising up-states, and, in doing so, drive the repeated reactivation of hippocampal memory representations After a longstanding debate, it is now generally accepted that [1, 2]. memory consolidation is supported by sleep. Contemporary An abundance of studies have linked SWS and SOs to models of sleep-associated consolidation posit that memories memory consolidation in humans [3–10]. Notwithstanding of recent experiences are actively strengthened during the the obvious importance of this work, many early reports relied deepest stage of non-rapid eye movement (NREM) sleep: on correlational findings, and thus lacked causal evidence of slow-wave sleep (SWS) [1, 2]. Cortical EEG recordings of SOs actively contributing to overnight memory processing. SWS are characterised by <1 Hz slow oscillations (SOs), The first efforts to address this gap used electrical stimulation which emerge in neocortical regions and reflect widespread to experimentally induce SOs during SWS, which, relative to synchronous activity alternating between up-states of neuro- a control condition, improved memory retention [11, 12]. nal excitation and down-states of neuronal silence. Crucially, Importantly, however, these electrical stimulation studies arti- SOs are thought to synchronise fast thalamo-cortical spindles ficially imposed SO rhythms on the brain that were not (~12–16 Hz) and hippocampal ripples (80–100 Hz in humans) synchronised to the brain’s endogenous oscillatory activity, potentially limiting the benefits of SO induction on sleep- associated memory processing. This article is part of the Topical Collection on Sleep and Learning In their seminal study, Ngo and colleagues [13]used an innovative auditory stimulation method to enhance the brain’s * Scott A. Cairney own endogenous rhythm and, consequently, bolster the mem- scott.cairney@york.ac.uk ory benefits of SWS (see Box 1). This work paved the way for Department of Psychology, University of York, York, UK more auditory stimulation studies that aimed to elucidate the York Biomedical Research Institute, University of York, York, UK link between NREM sleep oscillations and offline memory Curr Sleep Medicine Rep (2021) 7:112–119 113 processing. In this review, we provide an overview of the rhythm. Specifically, stimulation induced ‘trains’ of three suc- literature in this important and rapidly developing field. We cessive SO cycles (as compared to the individual SOs first describe the variety of ways in which researchers have observed in the sham condition, see example in Fig. 1B), modified the parameters of auditory stimulation, and the im- increased the amplitude of SO cycles and amplified phase- pact that these modifications have had on the neural oscilla- coupled fast spindle activity during SO up-states. Moreover, tions of sleep and associated memory processes. Next, we stimulation (vs. sham) led to a sizeable improvement in over- outline how the effects of stimulation vary according to the night memory retention, supporting the view that SOs play a demographics of the study participants, focusing on different causal role in offline consolidation. Auditory stimulation out age groups and clinical samples. Finally, we discuss the of phase with the ongoing SO rhythm did not enhance SO behaviourally observable effects of stimulation in different activity or improve memory performance compared to sham. memory domains. Stimulation Parameters Box 1 Number of Clicks Ngo and colleagues [13] delivered auditory stimulation during SWS in synchrony with the brain’s own endogenous rhythm. Given the observed effects of auditory stimulation with two Healthy young adults each participated in two conditions: clicks, an obvious question is whether additional clicks lead to stimulation and sham. In the stimulation condition, frontal further enhancement of oscillatory activity and sleep-associated EEG activity was recorded in real time and, following algo- consolidation. rithmic detection of a supra-threshold SO down-state, two Ngo and colleagues [14] addressed this question in a 50 ms pulses of pink noise (clicks) were delivered in phase follow-up study by comparing their original two-click proto- with the two subsequent SO up-states (see example in Fig. col to a ‘driving stimulation’ protocol, which delivered up to 1A). Timing of the clicks varied according to the temporal four consecutive clicks (also during SO up-states). Driving characteristics of each participant’s SOs (i.e. the average time stimulation (vs. sham) prolonged SO trains, amplified phase- between the negative and positive SO peaks), thereby ensur- locked fast spindle activity and improved overnight retention; ing precise, phase-locked stimulation. In the sham condition, but to no greater extent than that afforded by two-click stim- would-be stimulation events were marked but no clicks were ulation. Similar findings have emerged from more recent work delivered. Auditory stimulation was found to enhance the SO using five-click stimulation protocols [15–17]; whereas Fig. 1 Example of the auditory stimulation protocol used by Ngo and night), and the second after a 1.075 s interval corresponding to the colleagues [13], and its effects on the SO rhythm. A. Following detection typical duration of a full SO cycle. In the sham condition, of a supra-threshold SO down-state (−80 μV; grey line), two 50 ms pulses corresponding time points of would-be stimulation events are marked of pink noise (clicks) are delivered in phase with the two subsequent SO but no clicks are delivered. The detection routine is paused for 2.5 s up-states (red lines). The first click occurs during the predicted SO up- after the second click. B. Relative to the sham condition, stimulation state, based on the average delay between the SO negative and positive typically enhances the SO rhythm, evoking a ‘train’ of three SOs peak (~0.5 s; obtained for each participant during a prior adaptation 114 Curr Sleep Medicine Rep (2021) 7:112–119 stimulation enhanced the SO rhythm and improved next-day frequency of 0.8 Hz (corresponding to the approximate recall, the amplitude of the SOs induced by the clicks typically frequency of SOs). As compared to sham, stimulation declined after the third SO cycle. increased SO and fast spindle power during NREM sleep. Hence, the research to date suggests that delivering However, because a memory test was not included in the more than two clicks does not confer any additional en- study protocol, it was not possible to establish whether hancement to SO activity or overnight memory process- these stimulation-induced changes in oscillatory activity ing. Because enhancing the SO rhythm and synchronised led to improvements in overnight consolidation. excitability carries an increased risk of seizure-like activ- ity, it has been suggested that limitations in the sleeping brain’s responsiveness to auditory stimulation might re- Timing of Stimulation flect the presence of a protective mechanism that prevents the development of hypersynchronicity during SO activity Because the cortical response to auditory stimulation varies [14, 18]. according to the timing of stimulus delivery [13, 33], a recent Interestingly, a number of studies using only a single audi- study aimed to determine the SO phase at which clicks max- tory pulse per stimulation event have observed enhancements imally augment oscillatory activity during SWS [26� ]. in NREM oscillatory activity [19 , 20–22] and overnight re- Relative to sham, applying clicks at any point during the SO tention [22]. Whether one-click stimulation is as effective as up-state increased the amplitude of subsequent SOs and in- two-click stimulation, however, has yet to be established. creased the likelihood of detecting a phase-coupled sleep spin- dle. However, the amplitudes of stimulation-induced SOs and Closed-loop Versus Open-loop Methods spindles were maximal when clicks were delivered close to the SO peak, suggesting that optimization of SO stimulation The vast majority of auditory stimulation studies have used depends critically on precise timing of stimulus delivery. the closed-loop method; that is, utilising the ongoing EEG activity to deliver auditory stimuli in synchrony with the brain’s endogenous rhythm [13, 14, 16, 17, 19, 21–31, 32]. Target Oscillation: Sleep Spindles One study, however, used an open-loop protocol in which the ongoing EEG data had no bearing on the timing of stimulus Given their putative function in overnight consolidation, re- delivery [33]. For each stimulation event, an initial click was searchers have utilised auditory stimulation to directly target delivered without regard to SO phase. Two further clicks were sleep spindles. then delivered at times chosen to maximise their probability of In the first study of its kind, oscillating white noise was coinciding with the up-states of the SOs evoked by the first delivered in 2 s bursts at regular intervals throughout stage click. The interval between the first and second clicks was two sleep and SWS [35]. The sounds were delivered at one based on the average duration of a full SO cycle for the re- of three frequencies: a slow spindle-mimicking frequency of spective participant (~0.9 s; obtained in a prior adaptation 12 Hz, a fast spindle-mimicking frequency of 15 Hz, or a night), and the interval between the second and third clicks control frequency of 50 Hz. Whereas 50 Hz stimulation had was fixed at 1.075 s. no effect on spindle activity, 12 Hz and 15 Hz stimulation Open-loop stimulation, relative to sham, evoked a train of increased slow and fast spindle densities, respectively. The SOs and amplified fast spindle activity during the up-state of evoked spindles were comparable to endogenously generated the first SO cycle. Importantly, however, stimulation led to an spindles in both duration and topography, suggesting that overall decrease in fast spindle power across the entire stimu- spindle stimulation might augment offline memory process- lation period, and had no impact on memory retention when ing. However, because the study protocol did not include a compared to the sham condition. Hence, despite clearly memory test, the effects of spindle stimulation on sleep- influencing oscillatory activity in SWS, open-loop stimulation associated consolidation could not be assessed. might be ineffective at enhancing overnight consolidation. In a later study, application of a rapid sequence of clicks Further work is of course required to build on this single (~15 Hz) during SO up-states had no immediate impact on study. spindle activity [25]. Instead, stimulation evoked an additional SO which was accompanied by an increase in phase-coupled Continuous Stimulation spindle power. This rapid click stimulation did not influence memory retention, as compared to sham. In other works, de- Other work has employed an auditory stimulation method livery of single clicks upon algorithmic detection of sleep that we refer to here as continuous stimulation [34]. spindles evoked a single SO, increased both delta (1–4Hz) Throughout the first 90 min of an overnight sleep oppor- and theta (4–8 Hz) power and improved performance in a tunity, single clicks were delivered continuously at a procedural learning task [36� ]. �� Curr Sleep Medicine Rep (2021) 7:112–119 115 Target Oscillation: REM Sleep Theta memory because many of the neurobiological mechanisms that are necessary for overnight consolidation are otherwise Theta oscillations (~3–7 Hz) are a prominent feature of the impaired (e.g. because of neural atrophy that occurs in normal REM sleep EEG, and were directly targeted in a recent study ageing) [42]. Understanding how the changes in brain mor- using a protocol modelled on the principles of auditory closed- phology that accompany normal ageing influence the oscilla- loop stimulation [37�� ]. Upon algorithmic detection of two tory and mnemonic impacts of auditory stimulation will be an supra-threshold theta cycles, oscillating white noise was de- important challenge for future research. livered at 5 Hz, corresponding to the approximate frequency of endogenous theta waves. Relative to sham, stimulation Children evoked a rapid increase in theta power, which was immedi- ately followed by a prolonged period of theta suppression, and By the age of 12 years, children typically achieve almost twice a prolonged increase in 10–30 Hz beta power. Stimulation had the amount of SWS as adults [43], and can thus provide im- no impact on overnight memory retention. portant insights into overnight consolidation processes medi- ated by SOs. A single study to date has applied auditory stim- ulation to typically developing children aged 8–12 years, and Participant Demographics children with attention deficit hyperactivity disorder (ADHD) of the same ages [23� ]. In both groups, a two-click closed-loop Older Adults stimulation protocol evoked trains of three SO cycles, mirroring findings in healthy adults. Stimulation also im- Because the vast majority of auditory stimulation studies have proved memory recall relative to the sham condition. tested healthy young adults (typically aged 18–30 years), we Whether the efficacy of auditory stimulation differs between focus here on the effects of stimulation in older adults. children and adults has yet to be established. Mirroring findings in young people, a study that delivered five-click, closed-loop stimulation to adults aged 60 to 84 Patients with Major Depression years found that stimulation prolonged SO trains, amplified phase-coupled spindle activity and improved overnight mem- Sleep disturbances are a common feature of nearly all psychi- ory retention, as compared to sham [29]. More recently, how- atric conditions [44, 45]. Whether and how auditory stimula- ever, a direct comparison of the effects of auditory SO stimu- tion affects slow oscillatory activity and associated cognitive lation in young and older adults (aged 49–63 years) revealed a functions among individuals with psychiatric disorders are marked reduction in SO amplitude and phase-coupled spindle important questions for understanding the mechanisms of dis- activity in older people [30 ]. Correspondingly, the memory ease and potential targets for therapeutic intervention. In a benefits of stimulation observed in young adults were absent recent study [27], auditory stimulation (vs. sham) applied to in the older individuals. Other studies paint a similar picture. adults with major depression increased delta (0.5–2.5 Hz) and In healthy middle-aged men (aged 35–48 years), auditory beta (16–25 Hz) power, but decreased oscillatory activity in stimulation increased 0.5–4 Hz delta power across the entire the slow spindle range (12.5−14.5 Hz). The impacts of stim- night but had no impact on memory retention [31]. Likewise, ulation on memory performance were not assessed. stimulation applied to older adults with mild cognitive impair- ment (aged 62–86 years) amplified SO power, but had no effect on overnight consolidation [16]. Memory Domains In sum, these findings point to an age-related decline in the effectiveness of auditory stimulation. Normal ageing is asso- Since the seminal findings of Ngo and colleagues [13], a large ciated with a reduction in the density and amplitude of SOs, number of studies have assessed the memory effects of audi- and a decoupling of SOs and spindles [38–40]. These changes tory stimulation across a variety of memory domains. These reflect a deterioration of synchronised firing in large neuronal studies are summarised in Table 1, organised by memory do- populations. It has been suggested that diminished main and associated task. responsivity to stimulation in older adults could be the result of decreased cortical capability to group large neural popula- tions into synchronised activity in response to peripheral stim- Declarative Memory uli [26� ]. The failure of some studies to detect a benefit of auditory stimulation on memory processing in older adults, Given that SOs are thought to drive the reactivation of despite augmentation of SOs and spindles, offers support to memory representations in the hippocampus, most audi- the ‘functional weakening’ hypothesis [41]. According to this tory stimulation studies have assessed overnight changes view, bolstering sleep in older adults is unlikely to benefit in hippocampus-dependent declarative memories. �� 116 Curr Sleep Medicine Rep (2021) 7:112–119 Table 1 Studies investigating the Memory domain Task memory effects of auditory stimulation in sleep, organised by Declarative Paired associates learning: related word pairs [13, 14, 16, 17, 19 , 22, 25, 29, 30�� , 33, memory domain and task memory 36� ] Paired associated learning: unrelated word pairs [19�� , 23� , 31, 32] Paired associates learning: face-name associations [22] Picture recognition task (encoding after stimulation) [24, 30�� ] Spatial navigation task [19�� ] Motor skills Finger tapping [22, 30 , 36� ] Serial reaction time task [23� ] Emotional memory Picture recognition [22, 37] Working memory N-back task [23� ] Memory for semantically related word pairs (e.g. pan-hob) such that healthy young adults were faster to type sequences typically benefits from closed-loop stimulation [13, 14, 17, of digits that were learned prior to sleep [36� ]. Similarly, rel- 22, 29] (also see: [16, 19�� , 30]), but not open-loop stimulation ative to sham, auditory SO stimulation improved sequence [33], or stimulation directly targeting sleep spindles [25, 36]. learning in children with ADHD [23� ]. However, other studies By contrast, auditory closed-loop stimulation does not seem to have failed to observe a benefit of SO stimulation on finger improve memory for pairs of stimuli with no intrinsic connec- tapping performance in healthy young adults [22]or middle- tion, such as semantically unrelated word pairs (e.g. pan-car) aged and older adults [30�� ]. or face-name pairs [19�� , 22, 31, 32]. A notable exception was observed in a recent study in children, where stimulation im- Emotional Memory proved retention of unrelated word pairs associated with a monetary reward, but not unrewarded word pairs [23� ]. Theta oscillations during REM sleep have been linked to the Hence, the findings to date suggest that auditory stimulation consolidation of emotional memories [49, 50]. In recent work, benefits the consolidation of paired associates that are consis- however, manipulation of theta activity via auditory stimula- tent with pre-existing knowledge, or of personal value to the tion in REM sleep had no impact on the retention of negative individual. or neutral images [37�� ]. Likewise, auditory stimulation dur- A single study has investigated the effect of auditory stim- ing SWS, which has also been implicated in affective memory ulation on visuospatial declarative memory in healthy young processing [51, 52], had no impact on memory for aversive adults [19 ]. Here, stimulation applied during a daytime nap pictures [22]. had no impact on navigation speed in a virtual spatial naviga- tion task. Working Memory Because sleep plays an important role in new learning [46–48], other works have tested the hypothesis that auditory Just one study to date has examined the effect of auditory stimulation improves encoding capabilities in declarative stimulation on working memory [23� ]. In children with memory. In a recent study in healthy adults, the amplitude ADHD, SO stimulation (vs. sham) improved performance in of stimulation-evoked SOs was correlated with hippocampal a n-back task, such that they were faster to correctly identify activation during picture encoding, and better performance in whether or not patterns that they were shown had appeared in a subsequent recognition test [24]. Relative to the sham con- recently preceding trials. dition, however, there was no overall benefit of stimulation for learning. A subsequent study also failed to observe any benefit of auditory stimulation on picture encoding capacities in Conclusion middle-aged and older adults [30�� ]. Auditory stimulation is a powerful tool for inducing, augment- Motor Skills ing and modifying the neural oscillations of sleep. Delivering auditory stimuli during SO up-states reliably enhances the SO Research examining the effects of auditory stimulation on rhythm and boosts phase-coupled spindle activity. Older procedural motor skills has produced mixed results. In one adults appear to be less receptive to auditory stimulation than study, auditory stimulation directly targeting sleep spindles young adults—possibly because of age-related changes in (vs. sham) improved performance on a finger tapping task, brain morphology. Single studies have found that SO �� �� �� Curr Sleep Medicine Rep (2021) 7:112–119 117 stimulation modulates neural rhythms in typically developing Declarations children, children with ADHD, adults with major depression Human and Animal Rights All reported studies/experiments with hu- and older adults with mild cognitive impairment. Multiple man or animal subjects performed by the authors have been previously experiments have observed a significant benefit of auditory published and complied with all applicable ethical standards (including stimulation on memory retention. However, the effect of stim- the Helsinki declaration and its amendments, institutional/national re- ulation on memory seems to vary according to the type of search committee standards, and international/national/institutional guidelines). learning material and the memory system under investigation. Despite significant advances in our understanding of the Open Access This article is licensed under a Creative Commons effects that auditory stimulation can have on electrophysiolo- Attribution 4.0 International License, which permits use, sharing, adap- tation, distribution and reproduction in any medium or format, as long as gy, little is known about how these effects occur. It has long you give appropriate credit to the original author(s) and the source, pro- been known that delivering auditory stimuli during NREM vide a link to the Creative Commons licence, and indicate if changes were sleep evokes K-complexes, which are comparable to SOs in made. The images or other third party material in this article are included both appearance and generating mechanisms [53]. Evoked K- in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's complexes are believed to preserve sleep continuity in the face Creative Commons licence and your intended use is not permitted by of external stimuli that would otherwise fragment sleep by statutory regulation or exceeds the permitted use, you will need to obtain triggering arousal responses [54]. Although speculative, one permission directly from the copyright holder. To view a copy of this possibility is that auditory stimulation exploits this adaptive licence, visit http://creativecommons.org/licenses/by/4.0/. K-complex response to artificially bolster overnight consoli- dation. Specifically, when stimulation is delivered in-phase with an SO up-state, the evoked K-complex has an additive effect on the subsequent SO cycle, which increases its ampli- References tude. Although endogenous SOs often occur in trains, they can occur as singular events [14]. For these solitary SOs, in- Papers of particular interest, published recently, have been phase stimulation could induce a K-complex after the detected highlighted as: SO cycle, giving the appearance of an SO train. � Of importance Our knowledge of how auditory stimulation benefits over- �� Of major importance night consolidation is also somewhat superficial. Presumably, by enhancing SOs and phase-coupled spindle activity─which 1. Born J, Wilhelm I. System consolidation of memory during sleep. 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Journal

Current Sleep Medicine ReportsSpringer Journals

Published: Sep 1, 2021

Keywords: Closed-loop stimulation; Slow-wave sleep; Slow oscillations; Sleep spindles; Rapid eye movement sleep; Memory consolidation

References