Divergent Associations of Slow-Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid-Beta.

OBJECTIVE: Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood. METHODS: We acquired simultaneous polysomnography and all-night blood sampling in 60 healthy volunteers aged 20-68 years. Nocturnal plasma concentrations of amyloid-beta-40, amyloid-beta-42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid-beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant-specific random effects. RESULTS: Amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid-beta-40 levels. INTERPRETATION: Slow-wave oscillations are associated with higher plasma amyloid-beta levels, whereas REM sleep is related to decreased amyloid-beta plasma levels, possibly representing changes in central amyloid-beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46-60.

Citizen neuroscience: Wearable technology and open software to study the human brain in its natural habitat.

Citizen science allows the public to participate in various stages of scientific research, including study design, data acquisition, and data analysis. Citizen science has a long history in several fields of the natural sciences, and with recent developments in wearable technology, neuroscience has also become more accessible to citizen scientists. This development was largely driven by the influx of minimal sensing systems in the consumer market, allowing more do-it-yourself (DIY) and quantified-self (QS) investigations of the human brain. While most subfields of neuroscience require sophisticated monitoring devices and laboratories, the study of sleep characteristics can be performed at home with relevant noninvasive consumer devices. The strong influence of sleep quality on waking life and the accessibility of devices to measure sleep are two primary reasons citizen scientists have widely embraced sleep research. Their involvement has evolved from solely contributing to data collection to engaging in more collaborative or autonomous approaches, such as instigating ideas, formulating research inquiries, designing research protocols and methodology, acting upon their findings, and disseminating results. In this article, we introduce the emerging field of citizen neuroscience, illustrating examples of such projects in sleep research. We then provide overviews of the wearable technologies for tracking human neurophysiology and various open-source software used to analyse them. Finally, we discuss the opportunities and challenges in citizen neuroscience projects and suggest how to improve the study of the human brain outside the laboratory.

Can brain stimulation boost memory performance?

Memory performance is crucial across the human life, from early education to age-related decline. A new study in PLOS Biology found that verbal learning can be enhanced by applying repetitive transcranial magnetic stimulation (rTMS) over the left prefrontal cortex.

Functional lateralization of the medial temporal lobe in novel associative processing during creativity evaluation.

Although hemispheric lateralization of creativity has been a longstanding topic of debate, the underlying neurocognitive mechanism remains poorly understood. Here we designed 2 types of novel stimuli-"novel useful and novel useless," adapted from "familiar useful" designs taken from daily life-to demonstrate how the left and right medial temporal lobe (MTL) respond to novel designs of different usefulness. Taking the "familiar useful" design as a baseline, we found that the right MTL showed increased activation in response to "novel useful" designs, followed by "novel useless" ones, while the left MTL only showed increased activation in response to "novel useful" designs. Calculating an asymmetry index suggests that usefulness processing is predominant in the left MTL, whereas the right MTL is predominantly involved in novelty processing. Moreover, the left parahippocampal gyrus (PHG) showed stronger functional connectivity with the anterior cingulate cortex when responding to "novel useless" designs. In contrast, the right PHG showed stronger connectivity with the amygdala, midbrain, and hippocampus. Critically, multivoxel representational similarity analyses revealed that the left MTL was more effective than the right MTL at distinguishing the usefulness differences in novel stimuli, while representational patterns in the left PHG positively predicted the post-behavior evaluation of "truly creative" products. These findings suggest an apparent dissociation of the left and right MTL in integrating the novelty and usefulness information and novel associative processing during creativity evaluation, respectively. Our results provide novel insights into a longstanding and controversial question in creativity research by demonstrating functional lateralization of the MTL in processing novel associations.

Acetylcholine and metacognition during sleep.

Acetylcholine is a neurotransmitter and neuromodulator involved in a variety of cognitive functions. Additionally, acetylcholine is involved in the regulation of REM sleep: cholinergic neurons in the brainstem and basal forebrain project to and innervate wide areas of the cerebral cortex, and reciprocally interact with other neuromodulatory systems, to produce the sleep-wake cycle and different sleep stages. Consciousness and cognition vary considerably across and within sleep stages, with metacognitive capacity being strikingly reduced even during aesthetically and emotionally rich dream experiences. A notable exception is the phenomenon of lucid dreaming-a rare state whereby waking levels of metacognitive awareness are restored during sleep-resulting in individuals becoming aware of the fact that they are dreaming. The role of neurotransmitters in these fluctuations of consciousness and cognition during sleep is still poorly understood. While recent studies using acetylcholinesterase inhibitors suggest a potential role of acetylcholine in the occurrence of lucid dreaming, the underlying mechanisms by which this effect is produced remains un-modelled and unknown; with the causal link between cholinergic mechanisms and upstream psychological states being complex and elusive. Several theories and approaches targeting the association between acetylcholine and metacognition during wakefulness and sleep are highlighted in this review, moving through microscopic, mesoscopic and macroscopic levels of analysis to detail this phenomenon at several organisational scales. Several exploratory hypotheses will be developed to guide future research towards fully articulating how metacognition is affected by activity at the acetylcholine receptor.

Multivariate prediction of cognitive performance from the sleep electroencephalogram.

Human cognitive performance is a key function whose biological foundations have been partially revealed by genetic and brain imaging studies. The sleep electroencephalogram (EEG) is tightly linked to structural and functional features of the central nervous system and serves as another promising biomarker. We used data from MrOS, a large cohort of older men and cross-validated regularized regression to link sleep EEG features to cognitive performance in cross-sectional analyses. In independent validation samples 2.5-10% of variance in cognitive performance can be accounted for by sleep EEG features, depending on the covariates used. Demographic characteristics account for more covariance between sleep EEG and cognition than health variables, and consequently reduce this association by a greater degree, but even with the strictest covariate sets a statistically significant association is present. Sigma power in NREM and beta power in REM sleep were associated with better cognitive performance, while theta power in REM sleep was associated with worse performance, with no substantial effect of coherence and other sleep EEG metrics. Our findings show that cognitive performance is associated with the sleep EEG (r = 0.283), with the strongest effect ascribed to spindle-frequency activity. This association becomes weaker after adjusting for demographic (r = 0.186) and health variables (r = 0.155), but its resilience to covariate inclusion suggest that it also partially reflects trait-like differences in cognitive ability.

Effective or predatory funding? Evaluating the hidden costs of grant applications.

Researchers are spending an increasing fraction of their time on applying for funding; however, the current funding system has considerable deficiencies in reliably evaluating the merit of research proposals, despite extensive efforts on the sides of applicants, grant reviewers and decision committees. For some funding schemes, the systemic costs of the application process as a whole can even outweigh the granted resources-a phenomenon that could be considered as predatory funding. We present five recommendations to remedy this unsatisfactory situation.

FENS-Kavli Network of Excellence: Postponed, non-competitive peer review for research funding.

Receiving research grants is among the highlights of an academic career, affirming previous accomplishments and enabling new research endeavours. Much of the process of acquiring research funding, however, belongs to the less favourite duties of many researchers: It is time consuming, often stressful and, in the majority of cases, unsuccessful. This resentment towards funding acquisition is backed up by empirical research: The current system to distribute research funding, via competitive calls for extensive research applications that undergo peer review, has repeatedly been shown to fail in its task to reliably rank proposals according to their merit, while at the same time being highly inefficient. The simplest, fairest and broadly supported alternative would be to distribute funding more equally across researchers, for example, by an increase of universities' base funding, thereby saving considerable time that can be spent on research instead. Here, I propose how to combine such a 'funding flat rate' model-or other efficient distribution strategies-with quality control through postponed, non-competitive peer review using open science practices.

Cognitive enhancement: Effects of methylphenidate, modafinil, and caffeine on latent memory and resting state functional connectivity in healthy adults.

Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.

Spindle-slow oscillation coupling correlates with memory performance and connectivity changes in a hippocampal network after sleep.

After experiences are encoded, post-encoding reactivations during sleep have been proposed to mediate long-term memory consolidation. Spindle-slow oscillation coupling during NREM sleep is a candidate mechanism through which a hippocampal-cortical dialogue may strengthen a newly formed memory engram. Here, we investigated the role of fast spindle- and slow spindle-slow oscillation coupling in the consolidation of spatial memory in humans with a virtual watermaze task involving allocentric and egocentric learning strategies. Furthermore, we analyzed how resting-state functional connectivity evolved across learning, consolidation, and retrieval of this task using a data-driven approach. Our results show task-related connectivity changes in the executive control network, the default mode network, and the hippocampal network at post-task rest. The hippocampal network could further be divided into two subnetworks of which only one showed modulation by sleep. Decreased functional connectivity in this subnetwork was associated with higher spindle-slow oscillation coupling power, which was also related to better memory performance at test. Overall, this study contributes to a more holistic understanding of the functional resting-state networks and the mechanisms during sleep associated to spatial memory consolidation.

Sleep-spindle frequency: Overnight dynamics, afternoon nap effects, and possible circadian modulation.

Homeostatic and circadian processes play a pivotal role in determining sleep structure, timing, and quality. In sharp contrast with the wide accessibility of the electroencephalogram (EEG) index of sleep homeostasis, an electrophysiological measure of the circadian modulation of sleep is still unavailable. Evidence suggests that sleep-spindle frequencies decelerate during biological night. In order to test the feasibility of measuring this marker in common polysomnographic protocols, the Budapest-Munich database of sleep records (N = 251 healthy subjects, 122 females, age range: 4-69 years), as well as an afternoon nap sleep record database (N = 112 healthy subjects, 30 females, age range: 18-30 years) were analysed by the individual adjustment method of sleep-spindle analysis. Slow and fast sleep-spindle frequencies were characterised by U-shaped overnight dynamics, with highest values in the first and the fourth-to-fifth sleep cycle and the lowest values in the middle of the sleeping period (cycles two to three). Age-related attenuation of sleep-spindle deceleration was evident. Estimated phases of the nadirs in sleep-spindle frequencies were advanced in children as compared to other age groups. Additionally, nap sleep spindles were faster than night sleep spindles (0.57 and 0.39 Hz difference for slow and fast types, respectively). The fine frequency resolution analysis of sleep spindles is a feasible method of measuring the assumed circadian modulation of sleep. Moreover, age-related attenuation of circadian sleep modulation might be measurable by assessing the overnight dynamics in sleep-spindle frequency. Phase of the minimal sleep-spindle frequency is a putative biomarker of chronotype.

Differences in executive abilities rather than associative processes contribute to memory development.

Children's learning capabilities change while growing up. One framework that describes the cognitive and neural development of children's growing learning abilities is the two-component model. It distinguishes processes that integrate separate features into a coherent memory representation (associative component) and executive abilities, such as elaboration, evaluation, and monitoring, that support memory processing (strategic component). In an fMRI study using an object-location association paradigm, we investigated how the two components influence memory performance across development. We tested children (10-12 years, n = 31), late adolescents (18 years, n = 29), and adults (25+ years, n = 30). For studying the associative component, we also probed how the utilisation of prior knowledge (schemas) facilitates memory across age groups. Children had overall lower retrieval performance, while adolescents and adults did not differ from each other. All groups benefitted from schemas, but this effect did not differ between groups. Performance differences between groups were associated with deactivation of the dorsal medial prefrontal cortex (dmPFC), which in turn was linked to executive functioning. These patterns were stronger in adolescents and adults and seemed absent in children. Thus, the children's executive system, the strategic component, is not as mature and thus cannot facilitate memory performance in the same way as in adolescents/adults. In contrast, we did not find age-related differences in the associative component; with activity in the angular gyrus predicting memory performance systematically across groups. Overall, our results suggest that differences of executive rather than associative abilities explain memory differences between children, adolescents, and adults.

Shift-work-related sleep disruption and the risk of decline in cognitive function: The CRUISE Study.

Acute total sleep deprivation and partial sleep deprivation have negative impacts on cognitive performance. Studies in subjects who regularly experience sleep loss, however, are rare and often restricted to examination of internal sleeping disorders. To address this issue, we set up a pilot study to explore the effects of a week characterized by sleep disruption on cognitive functioning, using a case-control setting in a maritime pilot group with chronic exposure to intermittent extrinsic, work-related sleep disruption. Twenty maritime pilots (aged 30-50 years) were compared to sex- and education-matched controls with normal sleep behaviour, from the same age range. We assessed subjective and objective cognitive function, including attention, psychomotor speed, memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Although we were able to confirm poorer sleep in maritime pilots and subjective complaints in some cognitive domains, we did not find objective cognitive deficits in the maritime pilot group compared to controls without sleep disruption. This could suggest that in this group of healthy, young maritime pilots, exposure to sleep disruption resulted in some subjective cognitive complaints, but objective deficits of cognitive function were not detected in comparison with a non-pilot control group. However, given the small sample size, the absence of an effect does not exclude the possibility that sleep disruption could result in cognitive deficits in general. Therefore, our findings have to be confirmed in future prospective studies with a larger sample size and matched controls, regarding age, education and work history.

Impact of menstrual cycle phase and oral contraceptives on sleep and overnight memory consolidation.

Sleep spindles benefit declarative memory consolidation and are considered to be a biological marker for general cognitive abilities. However, the impact of sexual hormones and hormonal oral contraceptives (OCs) on these relationships are less clear. Thus, we here investigated the influence of endogenous progesterone levels of naturally cycling women and women using OCs on nocturnal sleep and overnight memory consolidation. Nineteen healthy women using OCs (MAge  = 21.4, SD = 2.1 years) were compared to 43 healthy women with a natural menstrual cycle (follicular phase: n = 16, MAge  = 21.4, SD = 3.1 years; luteal phase: n = 27, MAge  = 22.5, SD = 3.6 years). Sleep spindle density and salivary progesterone were measured during an adaptation and an experimental night. A word pair association task preceding the experimental night followed by two recalls (pre-sleep and post-sleep) was performed to test declarative memory performance. We found that memory performance improved overnight in all women. Interestingly, women using OCs (characterized by a low endogenous progesterone level but with very potent synthetic progestins) and naturally cycling women during the luteal phase (characterized by a high endogenous progesterone level) had a higher fast sleep spindle density compared to naturally cycling women during the follicular phase (characterized by a low endogenous progesterone level). Furthermore, we observed a positive correlation between endogenous progesterone level and fast spindle density in women during the luteal phase. Results suggest that the use of OCs and the menstrual cycle phase affects sleep spindles and therefore should be considered in further studies investigating sleep spindles and cognitive performance.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study.

Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults. In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (N = 13) or 200 mg modafinil (N = 12) or 200 mg caffeine (N = 14) were administrated to in total 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition compared to task-related activation under placebo. While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show any BOLD signal alterations at all. These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group. However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.

Transcranial Magnetic Stimulation of the Medial Prefrontal Cortex Decreases Emotional Memory Schemas.

Mood-congruent memory bias is a critical characteristic of depression, but the underlying neural mechanism is largely unknown. Negative memory schemas might enhance encoding and consolidation of negative experiences, thereby contributing to the genesis and perpetuation of depressive pathology. To investigate this relationship, we aimed to perturb medial prefrontal cortex (mPFC) processing, using neuronavigated transcranial magnetic stimulation (TMS) targeting the mPFC. Forty healthy volunteers first underwent a negative mood induction to activate negative schema processing after which they received either active inhibitory (N = 20) or control (N = 20) stimulation to the mPFC. Then, all participants performed the encoding of an emotional false memory task. Recall and recognition performance was tested the following morning. Polysomnographic data were recorded continuously during the night before and after encoding. We observed a significantly lower false recognition of negative critical lures following mPFC inhibition, but no differences in veridical memory. These findings were supported by reaction time data, showing a relative slower response to negative compared with positive critical lures. The current findings support previous causal evidence for a role of the mPFC in schema memory processing and further suggest a role of the mPFC in memory bias.

Sound sleep: Lullabies as a test case for the neurobiological effects of music.

Music is part of the cultural practice and, at the same time, is interwoven with biology through its effects on the brain and its likely evolutionary origin. Studies on music, however, are traditionally based on the humanities and often carried out in a purely historical context, without much input from neuroscience and biology. Here, we argue that lullabies are a particularly suited test case to study the biological versus cultural aspects of music.

Sleep fragmentation and lucid dreaming.

Lucid dreaming-the phenomenon of experiencing waking levels of self-reflection within one's dreams-is associated with more wake-like levels of neural activation in prefrontal brain regions. In addition, alternating periods of wakefulness and sleep might increase the likelihood of experiencing a lucid dream. Here we investigate the association between sleep fragmentation and lucid dreaming, with a multi-centre study encompassing four different investigations into subjective and objective measures of sleep fragmentation, nocturnal awakenings, sleep quality and polyphasic sleep schedules. Results across these four studies provide a more nuanced picture into the purported connection between sleep fragmentation and lucid dreaming: While self-assessed numbers of awakenings, polyphasic sleep and physiologically validated wake-REM sleep transitions were associated with lucid dreaming, neither self-assessed sleep quality, nor physiologically validated numbers of awakenings were. We discuss these results, and their underlying neural mechanisms, within the general question of whether sleep fragmentation and lucid dreaming share a causal link.