Bedtime to the brain: how infants' sleep behaviours intertwine with non-rapid eye movement sleep electroencephalography features.

Adequate sleep is critical for development and facilitates the maturation of the neurophysiological circuitries at the basis of cognitive and behavioural function. Observational research has associated early life sleep problems with worse later cognitive, psychosocial, and somatic health outcomes. Yet, the extent to which day-to-day sleep behaviours (e.g., duration, regularity) in early life relate to non-rapid eye movement (NREM) neurophysiology-acutely and the long-term-remains to be studied. We measured sleep behaviours in 32 healthy 6-month-olds assessed with actimetry and neurophysiology with high-density electroencephalography (EEG) to investigate the association between NREM sleep and habitual sleep behaviours. Our study revealed four findings: first, daytime sleep behaviours are related to EEG slow-wave activity (SWA). Second, night-time movement and awakenings from sleep are connected with spindle density. Third, habitual sleep timing is linked to neurophysiological connectivity quantified as delta coherence. And lastly, delta coherence at 6 months predicts night-time sleep duration at 12 months. These novel findings widen our understanding that infants' sleep behaviours are closely intertwined with three particular levels of neurophysiology: sleep pressure (determined by SWA), the maturation of the thalamocortical system (spindles), and the maturation of cortical connectivity (coherence). The crucial next step is to extend this concept to clinical groups to objectively characterise infants' sleep behaviours 'at risk' that foster later neurodevelopmental problems.

An infant sleep electroencephalographic marker of thalamocortical connectivity predicts behavioral outcome in late infancy.

Infancy represents a critical period during which thalamocortical brain connections develop and mature. Deviations in the maturation of thalamocortical connectivity are linked to neurodevelopmental disorders. There is a lack of early biomarkers to detect and localize neuromaturational deviations, which can be overcome with mapping through high-density electroencephalography (hdEEG) assessed in sleep. Specifically, slow waves and spindles in non-rapid eye movement (NREM) sleep are generated by the thalamocortical system, and their characteristics, slow wave slope and spindle density, are closely related to neuroplasticity and learning. Spindles are often subdivided into slow (11.0-13.0 Hz) and fast (13.5-16.0 Hz) frequencies, for which not only different functions have been proposed, but for which also distinctive developmental trajectories have been reported across the first years of life. Recent studies further suggest that information processing during sleep underlying sleep-dependent learning is promoted by the temporal coupling of slow waves and spindles, yet slow wave-spindle coupling remains unexplored in infancy. Thus, we evaluated three potential biomarkers: 1) slow wave slope, 2) spindle density, and 3) the temporal coupling of slow waves with spindles. We use hdEEG to first examine the occurrence and spatial distribution of these three EEG features in healthy infants and second to evaluate a predictive relationship with later behavioral outcomes. We report four key findings: First, infants' EEG features appear locally: slow wave slope is maximal in occipital and frontal areas, whereas slow and fast spindle density is most pronounced frontocentrally. Second, slow waves and spindles are temporally coupled in infancy, with maximal coupling strength in the occipital areas of the brain. Third, slow wave slope, fast spindle density, and slow wave-spindle coupling are not associated with concurrent behavioral status (6 months). Fourth, fast spindle density in central and frontocentral regions at age 6 months predicts overall developmental status at age 12 months, and motor skills at age 12 and 24 months. Neither slow wave slope nor slow wave-spindle coupling predict later behavioral development. We further identified spindle frequency as a determinant of slow and fast spindle density, which accordingly, also predicts motor skills at 24 months. Our results propose fast spindle density, or alternatively spindle frequency, as early EEG biomarker for identifying thalamocortical maturation, which can potentially be used for early diagnosis of neurodevelopmental disorders in infants. These findings are in support of a role of sleep spindles in sensorimotor microcircuitry development. A crucial next step will be to evaluate whether early therapeutic interventions may be effective to reverse deviations in identified individuals at risk.

Effects of auditory sleep modulation approaches on brain oscillatory and cardiovascular dynamics.

Slow waves, the hallmark feature of deep nonrapid eye movement sleep, do potentially drive restorative effects of sleep on brain and body functions. Sleep modulation techniques to elucidate the functional role of slow waves thus have gained large interest. Auditory slow wave stimulation is a promising tool; however, directly comparing auditory stimulation approaches within a night and analyzing induced dynamic brain and cardiovascular effects are yet missing. Here, we tested various auditory stimulation approaches in a windowed, 10 s ON (stimulations) followed by 10 s OFF (no stimulations), within-night stimulation design and compared them to a SHAM control condition. We report the results of three studies and a total of 51 included nights and found a large and global increase in slow-wave activity (SWA) in the stimulation window compared to SHAM. Furthermore, slow-wave dynamics were most pronouncedly increased at the start of the stimulation and declined across the stimulation window. Beyond the changes in brain oscillations, we observed, for some conditions, a significant increase in the mean interval between two heartbeats within a stimulation window, indicating a slowing of the heart rate, and increased heart rate variability derived parasympathetic activity. Those cardiovascular changes were positively correlated with the change in SWA, and thus, our findings provide insight into the potential of auditory slow wave enhancement to modulate cardiovascular restorative conditions during sleep. However, future studies need to investigate whether the potentially increased restorative capacity through slow-wave enhancements translates into a more rested cardiovascular system on a subsequent day.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Auditory deep sleep stimulation in older adults at home: a randomized crossover trial.

Background: Auditory stimulation has emerged as a promising tool to enhance non-invasively sleep slow waves, deep sleep brain oscillations that are tightly linked to sleep restoration and are diminished with age. While auditory stimulation showed a beneficial effect in lab-based studies, it remains unclear whether this stimulation approach could translate to real-life settings. Methods: We present a fully remote, randomized, cross-over trial in healthy adults aged 62-78 years (clinicaltrials.gov: NCT03420677). We assessed slow wave activity as the primary outcome and sleep architecture and daily functions, e.g., vigilance and mood as secondary outcomes, after a two-week mobile auditory slow wave stimulation period and a two-week Sham period, interleaved with a two-week washout period. Participants were randomized in terms of which intervention condition will take place first using a blocked design to guarantee balance. Participants and experimenters performing the assessments were blinded to the condition. Results: Out of 33 enrolled and screened participants, we report data of 16 participants that received identical intervention. We demonstrate a robust and significant enhancement of slow wave activity on the group-level based on two different auditory stimulation approaches with minor effects on sleep architecture and daily functions. We further highlight the existence of pronounced inter- and intra-individual differences in the slow wave response to auditory stimulation and establish predictions thereof. Conclusions: While slow wave enhancement in healthy older adults is possible in fully remote settings, pronounced inter-individual differences in the response to auditory stimulation exist. Novel personalization solutions are needed to address these differences and our findings will guide future designs to effectively deliver auditory sleep stimulations using wearable technology.

Benchmarking Real-Time Algorithms for In-Phase Auditory Stimulation of Low Amplitude Slow Waves With Wearable EEG Devices During Sleep.

OBJECTIVE: In-phase stimulation of EEG slow waves (SW) during deep sleep has shown to improve cognitive function. SW enhancement is particularly desirable in subjects with low-amplitude SW such as older adults or patients suffering from neurodegeneration. However, existing algorithms to estimate the up-phase of EEG suffer from a poor phase accuracy at low amplitudes and when SW frequencies are not constant. METHODS: We introduce two novel algorithms for real-time EEG phase estimation on autonomous wearable devices, a phase-locked loop (PLL) and, for the first time, a phase vocoder (PV). We compared these phase tracking algorithms with a simple amplitude threshold approach. The optimized algorithms were benchmarked for phase accuracy, the capacity to estimate phase at SW amplitudes between 20 and 60 µV, and SW frequencies above 1 Hz on 324 home-based recordings from healthy older adults and Parkinson disease (PD) patients. Furthermore, the algorithms were implemented on a wearable device and the computational efficiency and the performance was evaluated in simulation and with a PD patient. RESULTS: All three algorithms delivered more than 70% of the stimulation triggers during the SW up-phase. The PV showed the highest capacity on targeting low-amplitude SW and SW with frequencies above 1 Hz. The hardware testing revealed that both PV and PLL have marginal impact on microcontroller load, while the efficiency of the PV was 4% lower. Active stimulation did not influence the phase tracking. CONCLUSION: This work demonstrated that phase-accurate auditory stimulation can also be delivered during fully remote sleep interventions in populations with low-amplitude SW.

The Potential Role of Sleep in Promoting a Healthy Body Composition: Underlying Mechanisms Determining Muscle, Fat, and Bone Mass and Their Association with Sleep.

Sleep plays an essential role in human life. While sleep is a state elicited by the brain, its vital role reaches beyond maintaining brain health. Unhealthy sleeping habits have been associated with increased risk for inflammation, obesity, or diabetes. Evidence is emerging that sleep guides processes playing an important role in promoting the regulation of endocrine function involved in tissue regeneration and tissue remodelling. Thereby, sleep presumably is a critical factor contributing to the balance of core body tissues: bone, fat, and muscle mass. Given the increasing prevalence of various chronic diseases and comorbidities due to unhealthy lifestyle choices, sleep could be a key target to promote a healthy body composition up until old age. Here, we review the potential role of sleep and its underlying brain oscillations in body core tissues turnover. Specifically, we discuss potential underlying mechanisms linking sleep to body composition, both during rest and under challenging conditions. Among other described pathways, we highlight the possible role of the growth hormone that was found to be involved in the homeostasis of all core body tissues and has been strongly linked to brain activity dominating deep sleep, the so-called slow waves. Finally, we formulate important questions to be addressed in future research on the effect of sleep on body composition and specifically emphasize the importance of intervention studies to move from correlative to causal evidence.

Neuromodulation of sleep rhythms in schizophrenia: Towards the rational design of non-invasive brain stimulation.

Brain function critically depends on oscillatory synchronization of neuronal populations both during wake and sleep. Originally, neural oscillations have been discounted as an epiphenomenon. More recently, specific deficits in the structure of brain oscillations have been linked to psychiatric diseases. For example, schizophrenia is hallmarked by abnormalities in different brain oscillations. Key sleep rhythms during NEM sleep such as sleep spindles, which are implicated in memory consolidation and are related to cognitive functions, are strongly diminished in these patients compared to healthy controls. To date, it remains unclear whether these reductions in sleep oscillations are causal for the functional impairments observed in schizophrenia. The application of non-invasive brain stimulation permits the causal examination of brain network dynamics and will help to establish the causal association of sleep oscillations and symptoms of schizophrenia. To accomplish this, stimulation paradigms that selectively engage specific network targets such as sleep spindles or slow waves are needed. We propose that the successful development and application of these non-invasive brain stimulation approaches will require rational design that takes network dynamics and neuroanatomical information into account. The purpose of this article is to prepare the grounds for the next steps towards such rational design of non-invasive stimulation, with a special focus on electrical and auditory stimulation. First, we briefly summarize the deficits in network dynamics during sleep in schizophrenia. Then, we discuss today's and tomorrow's non-invasive brain stimulation modalities to engage these network targets.

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r â€‹= â€‹.53 â€‹± .10; range â€‹= â€‹0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 â€‹± .06; 0.35 to 0.51 and 0.43 â€‹± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r â€‹= â€‹.43 â€‹± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r â€‹= â€‹-.53 â€‹± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.

Save Muscle Information-Unfiltered EEG Signal Helps Distinguish Sleep Stages.

Based on the well-established biopotential theory, we hypothesize that the high frequency spectral information, like that higher than 100Hz, of the EEG signal recorded in the off-the-shelf EEG sensor contains muscle tone information. We show that an existing automatic sleep stage annotation algorithm can be improved by taking this information into account. This result suggests that if possible, we should sample the EEG signal with a high sampling rate, and preserve as much spectral information as possible.

Characterization of overnight slow-wave slope changes across development in an age-, amplitude-, and region-dependent manner.

STUDY OBJECTIVES: The restorative function of sleep has been linked to a net reduction in synaptic strength. The slope of slow-waves, a major characteristic of non-rapid eye movement (NREM) sleep, has been shown to directly reflect synaptic strength, when accounting for amplitude changes across the night. In this study, we aimed to investigate overnight slope changes in the course of development in an age-, amplitude-, and region-dependent manner. METHODS: All-night high-density electroencephalography data were analyzed in a cross-sectional population of 60 healthy participants in the age range of 8-29 years. To control for amplitude changes across the night, we matched slow-waves from the first and the last hour of NREM sleep according to their amplitude. RESULTS: We found a reduction of slow-wave slopes from the first to the last hour of NREM sleep across all investigated ages, amplitudes, and most brain regions. The overnight slope change was largest in children and decreased toward early adulthood. A topographical analysis revealed regional differences in slope change. Specifically, for small amplitude waves the decrease was smallest in an occipital area, whereas for large amplitude waves, the decrease was smallest in a central area. CONCLUSIONS: The larger slope decrease in children might be indicative of a boosted renormalization of synapses during sleep in childhood, which, in turn, might be related to increased plasticity during brain maturation. Regional differences in the extent of slow-wave slope reduction may reflect a "smart" down-selection process or, alternatively, indicate amplitude-dependent differences in the generation of slow-waves.

Nonrapid eye movement sleep and risk for autism spectrum disorder in early development: A topographical electroencephalogram pilot study.

OBJECTIVE: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that emerges in the beginning years of life (12-48 months). Yet, an early diagnosis of ASD is challenging as it relies on the consistent presence of behavioral symptomatology, and thus, many children are diagnosed later in development, which prevents early interventions that could benefit cognitive and social outcomes. As a result, there is growing interest in detecting early brain markers of ASD, such as in the electroencephalogram (EEG) to elucidate divergence in early development. Here, we examine the EEG of nonrapid eye movement (NREM) sleep in the transition from infancy to toddlerhood, a period of rapid development and pronounced changes in early brain function. NREM features exhibit clear developmental trajectories, are related to social and cognitive development, and may be altered in neurodevelopmental disorders. Yet, spectral features of NREM sleep are poorly understood in infants/toddlers with or at high risk for ASD. METHODS: The present pilot study is the first to examine NREM sleep in 13- to 30-month-olds with ASD in comparison with age-matched healthy controls (TD). EEG was recorded during a daytime nap with high-density array EEG. RESULTS: We found topographically distinct decreased fast theta oscillations (5-7.25 Hz), decreased fast sigma (15-16 Hz), and increased beta oscillations (20-25 Hz) in ASD compared to TD. CONCLUSION: These findings suggest a possible functional role of NREM sleep during this important developmental period and provide support for NREM sleep to be a potential early marker for ASD.

Neurophysiological substrates of configural face perception in schizotypy.

Face perception is a highly developed function of the human visual system. Previous studies of event-related potentials (ERPs) have identified a face-selective ERP component (negative peak at about 170 ms after stimulus onset, N170) in healthy participants. In contrast, patients with schizophrenia exhibit reduced amplitude of the N170, which may represent a pathological deficit in the neurophysiology of face perception. Interestingly, healthy humans with schizophrenia-like experiences (schizotypy) also exhibit abnormal processing of face perception. Yet, it has remained unknown how schizotypy in healthy humans is associated with the neurophysiological substrates of face perception. Here, we recruited 35 healthy participants and assessed their schizotypy by the magical ideation rating scale. We used high-density electroencephalography to obtain ERPs elicited by a set of Mooney faces (face and non-face visual stimuli). We investigated median and mean reaction times and visual ERP components in response to the stimuli. We observed a significant difference in N170 amplitude between the two face-stimulus conditions and found that the measured schizotypy scores were significantly correlated with both reaction times and N170 amplitude in response to the face stimuli across all participants. Our results thus support the model of schizotypy as a manifestation of a continuum between healthy individuals and patients with schizophrenia, where the N170 impairment serves as a biomarker for the degree of pathology along this continuum.

Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD).

Major depressive disorder (MDD) is one of the most common psychiatric disorders, but pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Here we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) at 10 Hz, which we hypothesized would improve clinical symptoms by renormalizing alpha oscillations in the left dorsolateral prefrontal cortex (dlPFC). To this end, 32 participants with MDD were randomized to 1 of 3 arms and received daily 40 min sessions of either 10 Hz-tACS, 40 Hz-tACS, or active sham stimulation for 5 consecutive days. Symptom improvement was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome. High-density electroencephalograms (hdEEGs) were recorded to measure changes in alpha oscillations as the secondary outcome. For the primary outcome, we did not observe a significant interaction between treatment condition (10 Hz-tACS, 40 Hz-tACS, sham) and session (baseline to 4 weeks after completion of treatment); however, exploratory analyses show that 2 weeks after completion of the intervention, the 10 Hz-tACS group had more responders (MADRS and HDRS) compared with 40 Hz-tACS and sham groups (n = 30, p = 0.026). Concurrently, we found a significant reduction in alpha power over the left frontal regions in EEG after completion of the intervention for the group that received per-protocol 10 Hz-tACS (n = 26, p < 0.05). Our data suggest that targeting oscillations with tACS has potential as a therapeutic intervention for treatment of MDD.

Low-frequency direct cortical stimulation of left superior frontal gyrus enhances working memory performance.

The neural substrates of working memory are spread across prefrontal, parietal and cingulate cortices and are thought to be coordinated through low frequency cortical oscillations in the theta (3-8 Hz) and alpha (8-12 Hz) frequency bands. While the functional role of many subregions have been elucidated using neuroimaging studies, the role of superior frontal gyrus (SFG) is not yet clear. Here, we combined electrocorticography and direct cortical stimulation in three patients implanted with subdural electrodes to assess if superior frontal gyrus is indeed involved in working memory. We found left SFG exhibited task-related modulation of oscillations in the theta and alpha frequency bands specifically during the encoding epoch. Stimulation at the frequency matched to the endogenous oscillations resulted in reduced reaction times in all three participants. Our results provide evidence for SFG playing a functional role in working memory and suggest that SFG may coordinate working memory through low-frequency oscillations thus bolstering the feasibility of using intracranial electric stimulation for restoring cognitive function.

Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia.

BACKGROUND: Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere. METHOD: 22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes. RESULTS: Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions. CONCLUSIONS: To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations.

Social, motor, and cognitive development through the lens of sleep network dynamics in infants and toddlers between 12 and 30 months of age.

Widespread change in behavior and the underlying brain network substrate is a hallmark of early development. Sleep plays a fundamental role in this process. Both slow waves and spindles are key features of nonrapid eye movement sleep (NREM) that exhibit pronounced developmental trajectories from infancy to adulthood. Yet, these prominent features of NREM sleep are poorly understood in infants and toddlers in the age range of 12 to 30 months. Moreover, it is unknown how network dynamics of NREM sleep are associated with outcomes of early development. Addressing this gap in our understanding of sleep during development will enable the subsequent study of pathological changes in neurodevelopmental disorders. The aim of the current study was to characterize the sleep topography with high-density electroencephalography in this age group. We found that δ, θ, and ß oscillations and sleep spindles exhibited clear developmental changes. Low δ and high θ oscillations correlated with motor, language, and social skills, independent of age. These findings suggest an important role of network dynamics of NREM sleep in cortical maturation and the associated development of skills during this important developmental period.

High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.

Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles.