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

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

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, duration of slow wave sleep and number of coupling events decreases. 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 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, 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 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards 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 StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally 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 lifespan 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 lifespan

The role of slow wave sleep in the development of dementia and its potential for preventative interventions

The increasing incidence rate of dementia underlines the necessity to identify early biomarkers of imminent cognitive decline. Recent findings suggest that cognitive decline and the pathophysiology of Alzheimer's disease are closely linked to disruptions in slow wave sleep (SWS) – the deepest sleep stage. SWS is essential for memory functions and displays a potentially causal and bidirectional link to the accumulation of amyloid beta deposition. Accordingly, improving SWS in older adults – especially when at risk for dementia – might slow down the rate of cognitive decline. Recent work suggests that SWS can be improved by specifically targeting the electrophysiological peaks of the slow waves with acoustic stimulation. In older adults, this approach is still fairly new and accompanied by challenges posed by the specific complexity of their sleep physiology, like lower amplitude slow waves and fragmented sleep architecture. We suggest an approach that tackles these issues and attempts to re-instate a sleep physiology that resembles a younger, healthier brain. With enough SWS of high quality, metabolic clearance and memory functions could benefit and help slowing the process of cognitive aging. Ultimately, acoustic stimulation to enhance SWS could serve as a cost-effective, non-invasive tool to combat cognitive decline

Targeting hippocampal hyperactivity with real-time fMRI neurofeedback: protocol of a single-blind randomized controlled trial in mild cognitive impairment

BACKGROUND Several fMRI studies found hyperactivity in the hippocampus during pattern separation tasks in patients with Mild Cognitive Impairment (MCI; a prodromal stage of Alzheimer's disease). This was associated with memory deficits, subsequent cognitive decline, and faster clinical progression. A reduction of hippocampal hyperactivity with an antiepileptic drug improved memory performance. Pharmacological interventions, however, entail the risk of side effects. An alternative approach may be real-time fMRI neurofeedback, during which individuals learn to control region-specific brain activity. In the current project we aim to test the potential of neurofeedback to reduce hippocampal hyperactivity and thereby improve memory performance. METHODS In a single-blind parallel-group study, we will randomize n = 84 individuals (n = 42 patients with MCI, n = 42 healthy elderly volunteers) to one of two groups receiving feedback from either the hippocampus or a functionally independent region. Percent signal change of the hemodynamic response within the respective target region will be displayed to the participant with a thermometer icon. We hypothesize that only feedback from the hippocampus will decrease hippocampal hyperactivity during pattern separation and thereby improve memory performance. DISCUSSION Results of this study will reveal whether real-time fMRI neurofeedback is able to reduce hippocampal hyperactivity and thereby improve memory performance. In addition, the results of this study may identify predictors of successful neurofeedback as well as the most successful regulation strategies. TRIAL REGISTRATION The study has been registered with clinicaltrials.gov on the 16th of July 2019 (trial identifier: NCT04020744 )

Augmentation of psychotherapy with neurobiological methods: current state and future directions

Background: Psychotherapy and pharmacotherapy are first-line treatments for mental disorders. Despite recent improvements, only approximately 50% of the patients reach sustained remission, indicating a need for novel developments. The main concept put forward in this systematic review and hypothesis article is the targeted co-administration of defined neurobiological interventions and specific psychotherapeutic techniques. Methods: We conducted a systematic literature search for randomized controlled trials comparing the efficacy of augmented psychotherapy to psychotherapy alone. Results: Thirty-five trials fulfilled the inclusion criteria. The majority (29 trials) used augmentation strategies such as D-cycloserine, yohimbine, or sleep to enhance the effects of exposure therapy for anxiety disorders. Fewer studies investigated noninvasive brain stimulation with the aim of improving cognitive control, psychedelic compounds with the aim of enhancing existentially oriented psychotherapy, and oxytocin to improve social communication during psychotherapy. Results demonstrate small augmentation effects for the enhancement of exposure therapy - however, some of the studies found negative results. Other methods are less thoroughly researched, and results are mixed. Conclusions: This approach provides an open matrix for further research and has the potential to systematically guide future studies

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