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

Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: A systematic review and meta-analysis.

Almost 70% of patients with mental disorders report sleep difficulties and 30% fulfill the criteria for insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia according to current treatment guidelines. Despite this circumstance, insomnia is frequently treated only pharmacologically especially in patients with mental disorders. The aim of the present meta-analysis was to quantify the effects of CBT-I in patients with mental disorders and comorbid insomnia on two outcome parameters: the severity of insomnia and mental health. The databases PubMed, CINHAL (Ebsco) und PsycINFO (Ovid) were searched for randomized controlled trials on adult patients with comorbid insomnia and any mental disorder comparing CBT-I to placebo, waitlist or treatment as usual using self-rating questionnaires as outcomes for either insomnia or mental health or both. The search resulted in 1994 records after duplicate removal of which 22 fulfilled the inclusion criteria and were included for the meta-analysis. The comorbidities were depression (eight studies, 491 patients), post-traumatic stress disorder (PTSD, four studies, 216 patients), alcohol dependency (three studies, 79 patients), bipolar disorder (one study, 58 patients), psychosis (one study, 50 patients) and mixed comorbidities within one study (five studies, 189 patients). The effect sizes for the reduction of insomnia severity post treatment were 0.5 (confidence interval, CI, 0.3-0.8) for patients with depression, 1.5 (CI 1.0-1.9) for patients with PTSD, 1.4 (CI 0.9-1.9) for patients with alcohol dependency, 1.2 (CI 0.8-1.7) for patients with psychosis/bipolar disorder, and 0.8 (CI 0.1-1.6) for patients with mixed comorbidities. Effect sizes for the reduction of insomnia severity were moderate to large at follow-up. Regarding the effects on comorbid symptom severity, effect sizes directly after treatment were 0.5 (CI 0.1-0.8) for depression, 1.3 (CI 0.6-1.9) for PTSD, 0.9 (CI 0.3-1.4) for alcohol dependency in only one study, 0.3 (CI -0.1 - 0.7, insignificant) for psychosis/bipolar, and 0.8 (CI 0.1-1.5) for mixed comorbidities. There were no significant effects on comorbid symptoms at follow-up. Together, these significant, stable medium to large effects indicate that CBT-I is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, PTSD and alcohol dependency. CBT-I is also an effective add-on treatment with the aim of improving mental health in patients with depression, PTSD, and symptom severity in outpatients with mixed diagnoses. Thus, in patients with mental disorders and comorbid insomnia, given the many side effects of medication, CBT-I should be considered as a first-line treatment

Multi-night acoustic stimulation is associated with better sleep, amyloid dynamics, and memory in older adults with cognitive impairment.

Sleep is a potential early, modifiable risk factor for cognitive decline and dementia. Impaired slow wave sleep (SWS) is pronounced in individuals with cognitive impairment (CI). Cognitive decline and impairments of SWS are bi-directionally linked in a vicious cycle. SWS can be enhanced non-invasively using phase-locked acoustic stimulation (PLAS), potentially breaking this vicious cycle. Eighteen healthy older adults (HC, agemean±sd, 68.3 ± 5.1) and 16 older adults (agemean±sd, 71.9 ± 3.9) with CI (Montreal Cognitive Assessment ≤ 25) underwent one baseline (sham-PLAS) night and three consecutive stimulation nights (real-PLAS). EEG responses and blood-plasma amyloid beta Aβ42/Aβ40 ratio were measured pre- and post-intervention, as was episodic memory. The latter was again evaluated 1 week and 3 months after the intervention. In both groups, PLAS induced a significant electrophysiological response in both voltage- and time-frequency analyses, and memory performance improved in association with the magnitude of this response. In the CI group, both electrophysiological and associated memory effects were delayed compared to the healthy group. After 3 intervention nights, electrophysiological response to PLAS was no longer different between CI and HC groups. Only in the CI sample, stronger electrophysiological responses were significantly associated with improving post-intervention Aβ42/Aβ40 ratios. PLAS seems to improve SWS electrophysiology, memory, and amyloid dynamics in older adults with CI. However, effects on memory require more time to unfold compared to healthy older adults. This indicates that PLAS may become a potential tool to ameliorate cognitive decline, but longer interventions are necessary to compensate for declining brain integrity. This study was pre-registered (clinicaltrials.gov: NCT04277104)

Modulating overnight memory consolidation by acoustic stimulation during slow wave sleep – a systematic review and meta-analysis

Study objectives: The low-frequency high-amplitude oscillations of slow wave sleep are considered to promote the consolidation of episodic memory. Previous research suggests that sleep slow waves can be entrained and enhanced by presenting short acoustic stimuli to the up-states of endogenous waves. Several studies have investigated the effects of these increases in slow wave activity on overnight memory consolidation, with inconsistent results. The aim of this meta-analysis was to evaluate the accumulated evidence connecting acoustic stimulation during sleep to episodic memory consolidation. Methods: A systematic literature search was conducted in October 2020 using Pubmed, Web of Science and PsycInfo. Main study inclusion criteria were the application of acoustic slow wave enhancement in healthy participants and an assessment of pre- and post-sleep episodic memory performance. Effect sizes were pooled using a random effects model. Results: Ten primary studies with 11 experiments and 177 participants were included. Results showed a combined effect size (Hedges' g) of 0.25 (p=0.07). Subgroup models based on young adults (n = 8), phase-locked stimulation approaches (n = 8) and their combination (n = 6) showed combined effect sizes of 0.31 (p=0.051), 0.36 (p=0.047) and 0.44 (p=0.01), respectively. There was no indication of publication bias or bias in individual studies. Conclusions: Acoustic enhancement of slow wave sleep tends to increase the overnight consolidation of episodic memory but effects remain small and - with the exception of subgroup models - at trend levels. Currently, the evidence is not sufficient to recommend the use of commercially available devices

Shaping the slow waves of sleep: A systematic and integrative review of sleep slow wave modulation in humans using non-invasive brain stimulation

The experimental study of electroencephalographic slow wave sleep (SWS) stretches over more than half a century and has corroborated its importance for basic physiological processes, such as brain plasticity, metabolism and immune system functioning. Alterations of SWS in aging or pathological conditions suggest that modulating SWS might constitute a window for clinically relevant interventions. This work provides a systematic and integrative review of SWS modulation through non-invasive brain stimulation in humans. A literature search using PubMed, conducted in May 2020, identified 3220 studies, of which 82 fulfilled inclusion criteria. Three approaches have been adopted to modulate the macro- and microstructure of SWS, namely auditory, transcranial electrical and transcranial magnetic stimulation. Our current knowledge about the modulatory mechanisms, the space of stimulation parameters and the physiological and behavioral effects are reported and evaluated. The integration of findings suggests that sleep slow wave modulation bears the potential to promote our understanding of the functions of SWS and to develop new treatments for conditions of disrupted SWS

Investigating Compensatory Brain Activity in Older Adults with Subjective Cognitive Decline

BACKGROUND: Preclinical Alzheimer's disease (AD) is one possible cause of subjective cognitive decline (SCD). Normal task performance despite ongoing neurodegeneration is typically considered as neuronal compensation, which is reflected by greater neuronal activity. Compensatory brain activity has been observed in frontal as well as parietal regions in SCD, but data are scarce, especially outside the memory domain. OBJECTIVE: To investigate potential compensatory activity in SCD. Such compensatory activity is particularly expected in participants where blood-based biomarkers indicated amyloid positivity as this implies preclinical AD. METHODS: 52 participants with SCD (mean age: 71.00±5.70) underwent structural and functional neuroimaging (fMRI), targeting episodic memory and spatial abilities, and a neuropsychological assessment. The estimation of amyloid positivity was based on plasma amyloid-β and phosphorylated tau (pTau181) measures. RESULTS: Our fMRI analyses of the spatial abilities task did not indicate compensation, with only three voxels exceeding an uncorrected threshold at p < 0.001. This finding was not replicated in a subset of 23 biomarker positive individuals. CONCLUSION: Our results do not provide conclusive evidence for compensatory brain activity in SCD. It is possible that neuronal compensation does not manifest at such an early stage as SCD. Alternatively, it is possible that our sample size was too small or that compensatory activity may be too heterogeneous to be detected by group-level statistics. Interventions based on the individual fMRI signal should therefore be explored

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