The Hierarchy of Coupled Sleep Oscillations Reverses with Aging in Humans.

A well orchestrated coupling hierarchy of slow waves and spindles during slow-wave sleep supports memory consolidation. In old age, the duration of slow-wave sleep and the number of coupling events decrease. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N = 340; 237 females, 103 males) spanning most of the human life span (age range, 15-83 years). We find that, instead of changing abruptly, spindles gradually shift from being driven by slow waves to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow-wave frequency, and starts around midlife (age range, ∼40-48 years), with an established reversed hierarchy between 56 and 83 years of age. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using the phase slope index (PSI) and the number of coupling events, is associated with blood plasma glial fibrillary acidic protein levels, a marker for astrocyte activation. Data-driven models suggest that decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a backshift of the coupling hierarchy (PSI) toward a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.SIGNIFICANCE STATEMENT Evidence accumulates that sleep disturbances and cognitive decline are bidirectionally and causally linked, forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human life span and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human life span.

The promise of portable remote auditory stimulation tools to enhance slow-wave sleep and prevent cognitive decline.

Dementia is the seventh leading cause of mortality, and a major source of disability and dependency in older individuals globally. Cognitive decline (and, to a lesser extent, normal ageing) are associated with sleep fragmentation and loss of slow-wave sleep. Evidence suggests a bidirectional causal link between these losses. Phase-locked auditory stimulation has emerged as a promising non-invasive tool to enhance slow-wave sleep, potentially ameliorating cognitive decline. In laboratory settings, auditory stimulation is usually supervised by trained experts. Different algorithms (simple amplitude thresholds, topographic correlation, sine-wave fitting, phase-locked loop, and phase vocoder) are used to precisely target auditory stimulation to a desired phase of the slow wave. While all algorithms work well in younger adults, the altered sleep physiology of older adults and particularly those with neurodegenerative disorders requires a tailored approach that can adapt to older adults' fragmented sleep and reduced amplitudes of slow waves. Moreover, older adults might require a continuous intervention that is not feasible in laboratory settings. Recently, several auditory stimulation-capable portable devices ('Dreem®', 'SmartSleep®' and 'SleepLoop®') have been developed. We discuss these three devices regarding their potential as tools for science, and as clinical remote-intervention tools to combat cognitive decline. Currently, SleepLoop® shows the most promise for scientific research in older adults due to high transparency and customizability but is not commercially available. Studies evaluating down-stream effects on cognitive abilities, especially in patient populations, are required before a portable auditory stimulation device can be recommended as a clinical preventative remote-intervention tool.

Feasibility, efficacy, and functional relevance of automated auditory closed-loop suppression of slow-wave sleep in humans.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Acoustic stimulation during sleep predicts long-lasting increases in memory performance and beneficial amyloid response in older adults.

BACKGROUND: Sleep and neurodegeneration are assumed to be locked in a bi-directional vicious cycle. Improving sleep could break this cycle and help to prevent neurodegeneration. We tested multi-night phase-locked acoustic stimulation (PLAS) during slow wave sleep (SWS) as a non-invasive method to improve SWS, memory performance and plasma amyloid levels. METHODS: 32 healthy older adults (agemean: 68.9) completed a between-subject sham-controlled three-night intervention, preceded by a sham-PLAS baseline night. RESULTS: PLAS induced increases in sleep-associated spectral-power bands as well as a 24% increase in slow wave-coupled spindles, known to support memory consolidation. There was no significant group-difference in memory performance or amyloid-beta between the intervention and control group. However, the magnitude of PLAS-induced physiological responses were associated with memory performance up to 3 months post intervention and beneficial changes in plasma amyloid. Results were exclusive to the intervention group. DISCUSSION: Multi-night PLAS is associated with long-lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool to build upon and develop long-term protocols for the prevention of cognitive decline.

Sleep-learning impairs subsequent awake-learning.

Although we can learn new information while asleep, we usually cannot consciously remember the sleep-formed memories - presumably because learning occurred in an unconscious state. Here, we ask whether sleep-learning expedites the subsequent awake-learning of the same information. To answer this question, we reanalyzed data (Züst et al., 2019, Curr Biol) from napping participants, who learned new semantic associations between pseudowords and translation-words (guga-ship) while in slow-wave sleep. They retrieved sleep-formed associations unconsciously on an implicit memory test following awakening. Then, participants took five runs of paired-associative learning to probe carry-over effects of sleep-learning on awake-learning. Surprisingly, sleep-learning diminished awake-learning when participants learned semantic associations that were congruent to sleep-learned associations (guga-boat). Yet, learning associations that conflicted with sleep-learned associations (guga-coin) was unimpaired relative to learning new associations (resun-table; baseline). We speculate that the impeded wake-learning originated in a deficient synaptic downscaling and resulting synaptic saturation in neurons that were activated during both sleep-learning and awake-learning.

Automatized online prediction of slow-wave peaks during non-rapid eye movement sleep in young and old individuals: Why we should not always rely on amplitude thresholds.

Brain-state-dependent stimulation during slow-wave sleep is a promising tool for the treatment of psychiatric and neurodegenerative diseases. A widely used slow-wave prediction algorithm required for brain-state-dependent stimulation is based on a specific amplitude threshold in the electroencephalogram. However, due to decreased slow-wave amplitudes in aging and psychiatric conditions, this approach might miss many slow-waves because they do not fulfill the amplitude criterion. Here, we compared slow-wave peaks predicted via an amplitude-based versus a multidimensional approach using a topographical template of slow-wave peaks in 21 young and 21 older healthy adults. We validate predictions against the gold-standard of offline detected peaks. Multidimensionally predicted peaks resemble the gold-standard regarding spatiotemporal dynamics but exhibit lower peak amplitudes. Amplitude-based prediction, by contrast, is less sensitive, less precise and - especially in the older group - predicts peaks that differ from the gold-standard regarding spatiotemporal dynamics. Our results suggest that amplitude-based slow-wave peak prediction might not always be the ideal choice. This is particularly the case in populations with reduced slow-wave amplitudes, like older adults or psychiatric patients. We recommend the use of multidimensional prediction, especially in studies targeted at populations other than young and healthy individuals.

Can a serious game-based cognitive training attenuate cognitive decline related to Alzheimer's disease? Protocol for a randomized controlled trial.

BACKGROUND: Alzheimer's disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood. METHODS: In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60-85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants' group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits. DISCUSSION: The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings. TRIAL REGISTRATION: This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864).

Targeting Arousal and Sleep through Noninvasive Brain Stimulation to Improve Mental Health.

Arousal and sleep represent fundamental physiological domains, and alterations in the form of insomnia (difficulty falling or staying asleep) or hypersomnia (increased propensity for falling asleep or increased sleep duration) are prevalent clinical problems. Current first-line treatments include psychotherapy and pharmacotherapy. Despite significant success, a number of patients do not benefit sufficiently. Progress is limited by an incomplete understanding of the -neurobiology of insomnia and hypersomnia. This work summarizes current concepts of the regulation of arousal and sleep and its modulation through noninvasive brain stimulation (NIBS), including transcranial magnetic, current, and auditory stimulation. Particularly, we suggest: (1) characterization of patients with sleep problems - across diagnostic entities of mental disorders - based on specific alterations of sleep, including alterations of sleep slow waves, sleep spindles, cross-frequency coupling of brain oscillations, local sleep-wake regulation, and REM sleep and (2) targeting these with specific NIBS techniques. While evidence is accumulating that the modulation of specific alterations of sleep through NIBS is feasible, it remains to be tested whether this translates to clinically relevant effects and new treatment developments.

Dismissing the role of the hippocampus in implicit memory is special pleading.

Steinkrauss and Slotnick (this issue) argue against hippocampal involvement in implicit memory, bringing up some important considerations. Their critique, however, exhibits significant flaws. The argumentation is based on an ill-defined key concept of 'implicit memory,' and important theoretical context is missed. Potential confounds are brought to bear against a rather narrow selection of studies, often without explaining how exactly the studies are biased. Refining the conceptual scope, including a broader range of literature, and arguing more inclusively would provide more nuanced insights into the hippocampus's role in implicit memory.

Interindividual differences in mindfulness are linked to sleep-electroencephalographic characteristics.

STUDY OBJECTIVES: Mindfulness describes the ability to focus on the presence, including one's thoughts and feelings. Trait mindfulness-a person's inherent tendency to be mindful-has been connected to increased subjective sleep quality, but evidence from objective EEG-based sleep measures is lacking. Here, we investigate whether objective EEG-based sleep parameters explain interindividual differences in trait mindfulness. METHODS: Whole-night polysomnographic data were gathered from 52 healthy adults (27 females; agemean = 21.5 [SE = 0.28]) in their homes using a portable high-density EEG device. Trait mindfulness was assessed using the Five Facet Mindfulness Questionnaire short form (FFMQ-SF). RESULTS: Trait mindfulness was positively correlated at trend level with the percentage of rapid eye movement (REM), but not N1, N2, or slow wave sleep. Additionally, those exhibiting less REM beta/gamma power and NREM beta power displayed higher trait mindfulness and vice versa. Lastly, we replicated findings connecting higher trait mindfulness to better subjective sleep quality. CONCLUSIONS: REM sleep is pivotal for emotional processing. Decreased REM high-frequency activity was suggested to reflect adrenergic reduction that defuses affective experiences. Increased NREM high-frequency activity is a marker for cognitive hyperarousal in insomnia. We speculate that differences in trait mindfulness might be explained by differences in REM- and NREM-sleep functions that promote ideal emotional regulation and prevent hyperarousal.