Single closed-loop acoustic stimulation targeting memory consolidation suppressed hippocampal ripple and thalamo-cortical spindle activity in mice.

Brain rhythms of sleep reflect neuronal activity underlying sleep-associated memory consolidation. The modulation of brain rhythms, such as the sleep slow oscillation (SO), is used both to investigate neurophysiological mechanisms as well as to measure the impact of sleep on presumed functional correlates. Previously, closed-loop acoustic stimulation in humans targeted to the SO Up-state successfully enhanced the slow oscillation rhythm and phase-dependent spindle activity, although effects on memory retention have varied. Here, we aim to disclose relations between stimulation-induced hippocampo-thalamo-cortical activity and retention performance on a hippocampus-dependent object-place recognition task in mice by applying acoustic stimulation at four estimated SO phases compared to sham condition. Across the 3-h retention interval at the beginning of the light phase closed-loop stimulation failed to improve retention significantly over sham. However, retention during SO Up-state stimulation was significantly higher than for another SO phase. At all SO phases, acoustic stimulation was accompanied by a sharp increase in ripple activity followed by about a second-long suppression of hippocampal sharp wave ripple and longer maintained suppression of thalamo-cortical spindle activity. Importantly, dynamics of SO-coupled hippocampal ripple activity distinguished SOUp-state stimulation. Non-rapid eye movement (NREM) sleep was not impacted by stimulation, yet preREM sleep duration was effected. Results reveal the complex effect of stimulation on the brain dynamics and support the use of closed-loop acoustic stimulation in mice to investigate the inter-regional mechanisms underlying memory consolidation.

Differential thalamocortical interactions in slow and fast spindle generation: A computational model.

Cortical slow oscillations (SOs) and thalamocortical sleep spindles are two prominent EEG rhythms of slow wave sleep. These EEG rhythms play an essential role in memory consolidation. In humans, sleep spindles are categorized into slow spindles (8-12 Hz) and fast spindles (12-16 Hz), with different properties. Slow spindles that couple with the up-to-down phase of the SO require more experimental and computational investigation to disclose their origin, functional relevance and most importantly their relation with SOs regarding memory consolidation. To examine slow spindles, we propose a biophysical thalamocortical model with two independent thalamic networks (one for slow and the other for fast spindles). Our modeling results show that fast spindles lead to faster cortical cell firing, and subsequently increase the amplitude of the cortical local field potential (LFP) during the SO down-to-up phase. Slow spindles also facilitate cortical cell firing, but the response is slower, thereby increasing the cortical LFP amplitude later, at the SO up-to-down phase of the SO cycle. Neither the SO rhythm nor the duration of the SO down state is affected by slow spindle activity. Furthermore, at a more hyperpolarized membrane potential level of fast thalamic subnetwork cells, the activity of fast spindles decreases, while the slow spindles activity increases. Together, our model results suggest that slow spindles may facilitate the initiation of the following SO cycle, without however affecting expression of the SO Up and Down states.

Memory for nonadjacent dependencies in the first year of life and its relation to sleep.

Grammar learning requires memory for dependencies between nonadjacent elements in speech. Immediate learning of nonadjacent dependencies has been observed in very young infants, but their memory of such dependencies has remained unexplored. Here we used event-related potentials to investigate whether 6- to 8-month-olds retain nonadjacent dependencies and if sleep after learning affects this memory. Infants were familiarised with two rule-based morphosyntactic dependencies, presented in sentences of an unknown language. Brain responses after a retention period reveal memory of the nonadjacent dependencies, independent of whether infants napped or stayed awake. Napping, however, altered a specific processing stage, suggesting that memory evolves during sleep. Infants with high left frontal spindle activity show an additional brain response indicating memory of individual speech phrases. Results imply that infants as young as 6 months are equipped with memory mechanisms relevant to grammar learning. They also suggest that during sleep, consolidation of highly specific information can co-occur with changes in the nature of generalised memory.

Closed-loop acoustic stimulation during an afternoon nap to modulate subsequent encoding.

Sleep is able to contribute not only to memory consolidation, but also to post-sleep learning. The notion exists that either synaptic downscaling or another process during sleep increase post-sleep learning capacity. A correlation between augmentation of the sleep slow oscillation and hippocampal activation at encoding support the contribution of sleep to encoding of declarative memories. In the present study, the effect of closed-loop acoustic stimulation during an afternoon nap on post-sleep encoding of two verbal (word pairs, verbal learning and memory test) and non-verbal (figural pairs) tasks and on electroencephalogram during sleep and learning were investigated in young healthy adults (N = 16). Closed-loop acoustic stimulation enhanced slow oscillatory and spindle activity, but did not affect encoding at the group level. Subgroup analyses and comparisons with similar studies lead us to the tentative conclusion that further parameters such as time of day and subjects' cognitive ability influenced responses to closed-loop acoustic stimulation.

Acute mild dim light at night slightly modifies sleep but does not affect glucose homeostasis in healthy men.

OBJECTIVE: We evaluated the effect of acute mild light exposure at night on sleep architecture and glucose homeostasis. PATIENTS/METHODS: Twenty healthy normal-weight men took part in two conditions of a randomized, controlled, balanced cross-over experimental study: i) two-consecutive nights with 8-h of sleep under dLAN (<5 lux) or ii) total darkness (CON). Sleep was evaluated by polysomnography. In the morning following 'night2', glucose homeostasis was assessed by an intravenous glucose tolerance test (ivGTT) with consecutive measures of glucose, insulin, and c-peptide. Plasma cortisol was measured at night before sleep, after morning awakening, and during mid-afternoon hours. RESULTS: There was no significant difference in total sleep time, sleep efficiency, and sleep latency between conditions (all p > 0.66). However, NREM sleep stage N3 latency was prolonged after dLAN (p = 0.02) and NREM sleep stage 2 was decreased after two nights with dLAN (p = 0.04). During the first sleep hour, power in slow-oscillations, slow-waves, and delta bands diminished after dLAN (all p < 0.04). Glucose, insulin, and c-peptide were not altered by dLAN (all p > 0.14). Cortisol was reduced in the afternoon after 'night1' and in the morning after 'night2' (both p < 0.03). CONCLUSIONS: dLAN slightly disturbed sleep architecture and quality without impairment of glucose homeostasis. Longer exposure to chronic dLAN might be needed to unmask its hypothesized metabolic consequences.

Coupling of gamma band activity to sleep spindle oscillations - a combined EEG/MEG study.

Sleep spindles are crucial to memory consolidation. Cortical gamma oscillations (30-100 Hz) are considered to reflect processing of memory in local cortical networks. The temporal and regulatory relationship between spindles and gamma activity might therefore provide clues into how sleep strengthens cortical memory representations. Here, combining EEG with MEG recordings during sleep in healthy humans (n = 12), we investigated the temporal relationships of cortical gamma band activity, always measured by MEG, during fast (12-16 Hz) and slow (8-12 Hz) sleep spindles detected in the EEG or MEG. Time-frequency distributions did not show a consistent coupling of gamma to the spindle oscillation, although activity in the low gamma (30-40 Hz) and neighboring beta range (<30 Hz) was generally increased during spindles. However, more fine-grained analyses of cross-frequency interactions revealed that both low and high gamma power (30-100 Hz) was coupled to the phase of slow and fast EEG spindles, importantly, with this coupling at a fixed phase only for the oscillations within an individual spindle, but with variable phase across spindles. We did not observe any coupling of gamma activity for spindles detected solely in the MEG and not in parallel EEG recordings, raising the possibility that these are more local spindles of different quality. Similar to fast spindle activity, low gamma band power followed a ~0.025 Hz infraslow rhythm during sleep whose frequency, however, was significantly faster than that of spindle activity. Our findings suggest a general function of fast and slow spindles that by spanning larger cortical networks might serve to synchronize gamma band activity occurring in more local but distributed networks. Thereby, spindles might help linking local memory processing between distributed networks.

Sleep-dependent memory consolidation in infants protects new episodic memories from existing semantic memories.

Any experienced event may be encoded and retained in detail as part of our episodic memory, and may also refer and contribute to our generalized knowledge stored in semantic memory. The beginnings of this declarative memory formation are only poorly understood. Even less is known about the interrelation between episodic and semantic memory during the earliest developmental stages. Here, we show that the formation of episodic memories in 14- to 17-month-old infants depends on sleep, subsequent to exposure to novel events. Infant brain responses reveal that, after sleep-dependent consolidation, the newly stored events are not processed semantically, although appropriate lexical-semantic memories are present and accessible by similar events that were not experienced before the nap. We propose that temporarily disabled semantic processing protects precise episodic memories from interference with generalized semantic memories. Selectively restricted semantic access could also trigger semantic refinement, and thus, might even improve semantic memory.

Acoustic closed-loop stimulation during sleep improves consolidation of reward-related memory information in healthy children but not in children with attention-deficit hyperactivity disorder.

STUDY OBJECTIVES: Slow oscillations (SO) during slow-wave sleep foster the consolidation of declarative memory. Children with attention-deficit hyperactivity disorder (ADHD) display deficits in the sleep-associated consolidation of declarative memory, possibly due to an altered function of SO. The present study aimed at enhancing SO activity using closed-looped acoustic stimulation during slow-wave sleep in children with ADHD. METHODS: A total of 29 male children (14 with ADHD; aged 8-12 years) participated in a double-blind, placebo-controlled study trial. Children spent two experimental nights in a sleep lab, one stimulation night and one sham night. A declarative learning task (word-pair learning) with a reward condition was used as a primary outcome. Secondary outcome variables were a procedural memory (serial reaction time) and working memory (WM; n-back) task. Encoding of declarative and procedural memory took place in the evening before sleep. After sleep, the retrieval took place followed by the n-back task. RESULTS: The stimulation successfully induced SO activity during sleep in children with and without ADHD. After stimulation, only healthy children performed better on high-rewarded memory items (primary outcome). In contrast, there were indications that only children with ADHD benefitted from the stimulation with respect to procedural as well as WM performance (secondary outcome). CONCLUSIONS: We were able to show that the acoustic closed-loop stimulation can be applied to enhance SO activity in children with and without ADHD. Our data indicate that SO activity during sleep interacts with subsequent memory performance (primary outcome: rewarded declarative memory; secondary outcome: procedural and WM) in children with and without ADHD.

Chronobiological aspects of sleep restriction modulate subsequent spontaneous physical activity.

PURPOSE: First evidence suggests that chronobiological aspects of sleep restriction affect metabolic conditions. Our aim was to investigate whether spontaneous free-living physical activity likewise is affected by chronobiological timing of short sleep. METHODS: In an experimental randomized, balanced cross-over design, eleven healthy, normal-weight (BMI: 23.9 ± 0.4 kg/m2) men were evaluated. Physical activity was assessed by tri-axial wrist actigraphy after (i) four-hour sleep during the first night-half of the night ('late night sleep loss'), (ii) four-hour sleep during the second night-half ('early night sleep loss'), and (iii) eight-hour regular sleep ('regular sleep'), from 7:00 to 24:00 (17 h). Feelings of tiredness and activity were measured by semi-quantitative questionnaires. RESULTS: Physical activity differed between sleep conditions (P < 0.05) with the lowest physical activity after 'late night sleep loss'. Accordingly, less time was spent in high-intensity physical activity after 'late night sleep loss' as compared to the 'early night sleep loss' and 'regular sleep' conditions (both P < 0.05). Perceived feelings of tiredness were higher after both short sleep conditions as compared to 'regular sleep' (both P < 0.05). CONCLUSIONS: Sleep restriction during the second half of the night elicits stronger effects on spontaneous physical activity than sleep restriction during the first half of the night despite identical sleep duration, but the impact of longer period awake needs to be evaluated in further research. In sum, these data indicate that not only short sleep per se but also chronobiological aspects modulate physical activity pattern.

Monosynaptic Hippocampal-Prefrontal Projections Contribute to Spatial Memory Consolidation in Mice.

Time locking between neocortical sleep slow oscillations, thalamo-cortical spindles, and hippocampal sharp-wave ripples has convincingly been shown to be a key element of systems consolidation. Here we investigate the role of monosynaptic projections from ventral/intermediate hippocampus to medial prefrontal cortex (mPFC) in sleep-dependent memory consolidation in male mice. Following acquisition learning in the Barnes maze, we optogenetically silenced the axonal terminals of hippocampal projections within mPFC during slow-wave sleep. This silencing during SWS selectively impaired recent but not remote memory in the absence of effects on error rate and escape latencies. Furthermore, it prevented the development of the most efficient search strategy and sleep spindle time-locking to slow oscillation. An increase in post-learning sleep sharp-wave ripple (SPWR) density and reduced time locking of learning-associated SPWR activity to sleep spindles may be a less specific response. Our results demonstrate that monosynaptic projections from hippocampus to mPFC contribute to sleep-dependent memory consolidation, potentially by affecting the temporal coupling of sleep-associated electrophysiological events.SIGNIFICANCE STATEMENT Convincing evidence supports the role of slow-wave sleep (SWS), and the relevance of close temporal coupling of neuronal activity between brain regions for systems consolidation. Less attention has been paid so far to the specific neuronal pathways underlying these processes. Here, we optogenetically silenced the direct monosynaptic projection from ventral/intermediate hippocampus (HC) to medial prefrontal cortex (mPFC) during SWS in male mice following repeated learning trials in a weakly aversive spatial task. Our results confirm the concept that the monosynaptic projection between HC and mPFC contributes to memory consolidation and support an important functional role of this pathway in shaping the temporal precision among sleep-associated electrophysiological events.

Timing Modulates the Effect of Sleep Loss on Glucose Homeostasis.

CONTEXT: Chronobiological factors may modulate the impact of sleep loss on glucose homeostasis. However, these interactions have not been systematically assessed in humans. OBJECTIVE: To assess the effect of sleep loss during the late vs early night on glucose homeostasis. DESIGN: Fifteen normal-weight men participated in three conditions of a randomized, balanced crossover study comprising two conditions with shortened sleep (i.e., 4 hours of sleep during the first or the second half of the night) and a control condition with 8 hours of sleep. Glucose, insulin, cortisol, and glucagon were measured. Insulin sensitivity and secretion were assessed with a Botnia clamp. RESULTS: Compared with regular sleep duration, sleep loss reduced insulin sensitivity (M-value; P = 0.031) irrespective of early- or late-night timing (P = 0.691). The disposition index (i.e., the ß-cell response adjusted for insulin sensitivity) also tended to be impaired by short sleep (P = 0.056) but not by sleep timing (P = 0.543). In contrast, sleep loss in the second half but not the first half of the night induced reductions in morning glucagon and cortisol levels (P < 0.031) followed by a transient increase in cortisol (P < 0.044). CONCLUSIONS: Although sleep deprivation acutely reduced insulin sensitivity irrespective of its nocturnal timing, sleep loss in the early morning compromised α-cell and hypothalamic-pituitary-adrenal axis activity to a greater extent than sleep loss in the first half of the night. This pattern suggests that the timing of sleep restriction can partly potentiate its deleterious metabolic effects.

The reciprocal relation between sleep and memory in infancy: Memory-dependent adjustment of sleep spindles and spindle-dependent improvement of memories.

Sleep spindle activity in infants supports their formation of generalized memories during sleep, indicating that specific sleep processes affect the consolidation of memories early in life. Characteristics of sleep spindles depend on the infant's developmental state and are known to be associated with trait-like factors such as intelligence. It is, however, largely unknown which state-like factors affect sleep spindles in infancy. By varying infants' wake experience in a within-subject design, here we provide evidence for a learning- and memory-dependent modulation of infant spindle activity. In a lexical-semantic learning session before a nap, 14- to 16-month-old infants were exposed to unknown words as labels for exemplars of unknown object categories. In a memory test on the next day, generalization to novel category exemplars was tested. In a nonlearning control session preceding a nap on another day, the same infants heard known words as labels for exemplars of already known categories. Central-parietal fast sleep spindles increased after the encoding of unknown object-word pairings compared to known pairings, evidencing that an infant's spindle activity varies depending on its prior knowledge for newly encoded information. Correlations suggest that enhanced spindle activity was particularly triggered, when similar unknown pairings were not generalized immediately during encoding. The spindle increase triggered by previously not generalized object-word pairings, moreover, boosted the formation of generalized memories for these pairings. Overall, the results provide first evidence for a fine-tuned regulation of infant sleep quality according to current consolidation requirements, which improves the infant long-term memory for new experiences.

Insights on auditory closed-loop stimulation targeting sleep spindles in slow oscillation up-states.

BACKGROUND: The consolidation of sleep-dependent memories is mediated by an interplay of cortical slow oscillations (SOs) and thalamo-cortical sleep spindles. Whereas an enhancement of SOs with auditory closed-loop stimulation has been proven highly successful, the feasibility to induce and boost sleep spindles with auditory stimulation remains unknown thus far. NEW METHOD: Here we tested the possibility to enhance spindle activity during endogenous SOs and thereby to promote memory consolidation. Performing a sleep study in healthy humans, we applied an auditory Spindle stimulation and compared it with an Arrhythmic stimulation and a control condition comprising no stimulation (Sham). RESULTS: With Spindle stimulation we were not able to directly entrain endogenous spindle activity during SO up-states. Instead, both Spindle and Arrhythmic stimulation evoked a resonant SO response accompanied by an increase in spindle power phase-locked to the SO up-state. Assessment of overnight retention of declarative word-pairs revealed no difference between all conditions. COMPARISON WITH EXISTING METHODS: Our Spindle stimulation produced oscillatory evoked responses (i.e., increases in SOs and spindle activity during SO up-states) quite similar to those observed after the auditory closed-loop stimulation of SOs in previous studies, lacking however the beneficial effects on memory retention. CONCLUSION: Our findings put the endeavour for a selective enhancement of spindle activity via auditory pathways into perspective and reveal central questions with regard to the stimulation efficacy on both an electrophysiological and a neurobehavioral level.

Sleep Loss Disrupts Morning-to-Evening Differences in Human White Adipose Tissue Transcriptome.

CONTEXT: Chronodisruption, as caused by such conditions as perturbations of 24-hour rhythms of physiology and behavior, may promote the development of metabolic diseases. OBJECTIVE: To assess the acute effects of sleep curtailment on circadian regulation (i.e., morning-to-evening differences) of white adipose tissue (WAT) transcriptome in normal-weight men. DESIGN: Fifteen healthy men aged 18 to 30 years (mean ± SEM, 24.0 ± 0.9years) were studied. In randomized, balanced order they underwent three separate nights with regular sleep duration (8 hours of sleep between 11:00 pm and 7:00 am), sleep restriction (4 hours of sleep between 3:00 am and 7:00 am), and sleep deprivation (no sleep at all). Sleep was polysomnographically evaluated. WAT biopsy samples were taken twice at 9:00 pm and 7:00 am to assess morning-to-evening differences. WAT transcriptome profile was assessed by RNA sequencing, and expression of relevant circadian core clock genes were analyzed. Glucose homeostasis, lipid profile, and adipokines were assessed. RESULTS: Sleep restriction dramatically blunted morning-to-evening transcriptome variations with further dampening after sleep deprivation. Although most core clock genes remained stably rhythmic, morning-to-evening regulated pathways of carbohydrate and lipid metabolism were highly sensitive to sleep loss. In particular, genes associated with carbohydrate breakdown lost rhythmicity after sleep deprivation, with an overall trend toward an upregulation in the morning. In line with specific transcriptional changes in WAT, retinol-binding-protein 4 was increased and ß-cell secretory capacity was diminished. CONCLUSIONS: Acute sleep loss induces a profound restructuring of morning-to-evening WAT transcriptome with uncoupling from the local clock machinery, resulting in increased WAT carbohydrate turnover and impaired glucose homeostasis. Our data support an optimization of sleep duration and timing to prevent metabolic disorders such as obesity and type 2 diabetes.

Efficacy of slow oscillatory-transcranial direct current stimulation on EEG and memory - contribution of an inter-individual factor.

Despite many reports on beneficial effects of anodal slow oscillatory-transcranial direct current stimulation (so-tDCS) during non-rapid eye movement (NREM) sleep on memory consolidation, frequent negative outcomes have also been observed. Our working hypothesis is that so-tDCS efficacy is strongly dependent upon the susceptibility of the underlying network. One component determining susceptibility of the network is hypothesized to be reflected in learning or 'task-induced' plastic changes. Another component is hypothesized to represent inter-individual confounds. Twenty-five (15 female) healthy students participated in two learning conditions with and without so-tDCS during early nocturnal NREM sleep and in one control condition without learning tasks. So-tDCS was applied in five 5-min blocks. EEG was assessed during two time windows: an acute period with five 1-min epochs after each stimulation block and a 150-min post-stimulation time period. Inter-individual differences were assessed by a memory quotient (MQ) and subjects classified into high- vs. low-scoring groups. Although so-tDCS was efficient in enhancing fast spindle parameters in the 150-min time period in all subjects, so-tDCS failed to modulate memory consolidation. In contrast, in subjects with a high MQ, memory retention on a figural paired-associate task was significantly increased after so-tDCS. Task-induced slow spindle density was modulated in the opposite direction in subjects with high vs. low MQ being increased in the high-MQ group only. Effects of so-tDCS on EEG were limited to fast spindle modulations in both time windows. These results reveal that inter-individual confound can impact so-tDCS efficacy, suggesting potential use of such factors as biomarkers.

The Sleeping Infant Brain Anticipates Development.

From the age of 3 months, infants learn relations between objects and co-occurring words [1]. These very first representations of object-word pairings in infant memory are considered as non-symbolic proto-words comprising specific visual-auditory associations that can already be formed in the first months of life [2-5]. Genuine words that refer to semantic long-term memory have not been evidenced prior to 9 months of age [6-9]. Sleep is known to facilitate the reorganization of memories [9-14], but its impact on the perceptual-to-semantic trend in early development is unknown. Here we explored the formation of word meanings in 6- to 8-month-old infants and its reorganization during the course of sleep. Infants were exposed to new words as labels for new object categories. In the memory test about an hour later, generalization to novel category exemplars was tested. In infants who took a short nap during the retention period, a brain response of 3-month-olds [1] was observed, indicating generalizations based on early developing perceptual-associative memory. In those infants who napped longer, a semantic priming effect [15, 16] usually found later in development [17-19] revealed the formation of genuine words. The perceptual-to-semantic shift in memory was related to the duration of sleep stage 2 and to locally increased sleep spindle activity. The finding that, after the massed presentation of several labeled category exemplars, sleep enabled even 6-month-olds to create semantic long-term memory clearly challenges the notion that immature brain structures are responsible for the typically slower lexical development.

Blindfolding during wakefulness causes decrease in sleep slow wave activity.

Slow wave activity (SWA, 0.5-4 Hz) represents the predominant EEG oscillatory activity during slow wave sleep (SWS). Its amplitude is considered in part a reflection of synaptic potentiation in cortical networks due to encoding of information during prior waking, with higher amplitude indicating stronger potentiation. Previous studies showed that increasing and diminishing specific motor behaviors produced corresponding changes in SWA in the respective motor cortical areas during subsequent SWS Here, we tested whether this relationship can be generalized to the visual system, that is, whether diminishing encoding of visual information likewise leads to a localized decrease in SWA over the visual cortex. Experiments were performed in healthy men whose eyes on two different days were or were not covered for 10.5 h before bedtime. The subject's EEG was recorded during sleep and, after sleep, visual evoked potentials (VEPs) were recorded. SWA during nonrapid eye movement sleep (NonREM sleep) was lower after blindfolding than after eyes open (P < 0.01). The decrease in SWA that was most consistent during the first 20 min of NonREM sleep, did not remain restricted to visual cortex regions, with changes over frontal and parietal cortical regions being even more pronounced. In the morning after sleep, the N75-P100 peak-to-peak-amplitude of the VEP was significantly diminished in the blindfolded condition. Our findings confirm a link between reduced wake encoding and diminished SWA during ensuing NonREM sleep, although this link appears not to be restricted to sensory cortical areas.

Timing matters: open-loop stimulation does not improve overnight consolidation of word pairs in humans.

The application of auditory clicks during non-rapid eye movement (NREM) sleep phase-locked to the up state of the slow oscillation (closed-loop stimulation) has previously been shown to enhance the consolidation of declarative memories. We designed and applied sequences of three clicks during deep NREM sleep to achieve a quasi-phase-dependent open-loop stimulation. This stimulation was successful in eliciting slow oscillation power in the stimulation period. Although fast and slow spindle power were markedly decreased during the stimulation period, memory consolidation did not differ from control. During putative up states fast spindle power remained, however, at control levels. We conclude that concurrence of slow oscillations and fast spindles suffices to maintain memory consolidation at control levels despite an overall decreased spindle activity.

Spindle activity phase-locked to sleep slow oscillations.

The <1Hz slow oscillation (SO) and spindles are hallmarks of mammalian non-rapid eye movement and slow wave sleep. Spindle activity occurring phase-locked to the SO is considered a candidate mediator of memory consolidation during sleep. We used source localization of magnetoencephalographic (MEG) and electroencephalographic (EEG) recordings from 11 sleeping human subjects for an in-depth analysis of the temporal and spatial properties of sleep spindles co-occurring with SOs. Slow oscillations and spindles were identified in the EEG and related to the MEG signal, providing enhanced spatial resolution. In the temporal domain, we confirmed a phase-locking of classical 12-15Hz fast spindle activity to the depolarizing SO up-state and of 9-12Hz slow spindle activity to the up-to-down-state transition of the SO. In the spatial domain, we show a broad spread of spindle activity, with less distinct anterior-posterior separation of fast and slow spindles than commonly seen in the EEG. We further tested a prediction of current memory consolidation models, namely the existence of a spatial bias of SOs over sleep spindles as a mechanism to promote localized neuronal synchronization and plasticity. In contrast to that prediction, a comparison of SOs dominating over the left vs. right hemisphere did not reveal any signs of a concurrent lateralization of spindle activity co-occurring with these SOs. Our data are consistent with the concept of the neocortical SO exerting top-down control over thalamic spindle generation. However, they call into question the notion that SOs locally coordinate spindles and thereby inform spindle-related memory processing.

Slow oscillating transcranial direct current stimulation during non-rapid eye movement sleep improves behavioral inhibition in attention-deficit/hyperactivity disorder.

BACKGROUND: Behavioral inhibition, which is a later-developing executive function (EF) and anatomically located in prefrontal areas, is impaired in attention-deficit and hyperactivity disorder (ADHD). While optimal EFs have been shown to depend on efficient sleep in healthy subjects, the impact of sleep problems, frequently reported in ADHD, remains elusive. Findings of macroscopic sleep changes in ADHD are inconsistent, but there is emerging evidence for distinct microscopic changes with a focus on prefrontal cortical regions and non-rapid eye movement (non-REM) slow-wave sleep. Recently, slow oscillations (SO) during non-REM sleep were found to be less functional and, as such, may be involved in sleep-dependent memory impairments in ADHD. OBJECTIVE: By augmenting slow-wave power through bilateral, slow oscillating transcranial direct current stimulation (so-tDCS, frequency = 0.75 Hz) during non-REM sleep, we aimed to improve daytime behavioral inhibition in children with ADHD. METHODS: Fourteen boys (10-14 years) diagnosed with ADHD were included. In a randomized, double-blind, cross-over design, patients received so-tDCS either in the first or in the second experimental sleep night. Inhibition control was assessed with a visuomotor go/no-go task. Intrinsic alertness was assessed with a simple stimulus response task. To control for visuomotor performance, motor memory was assessed with a finger sequence tapping task. RESULTS: SO-power was enhanced during early non-REM sleep, accompanied by slowed reaction times and decreased standard deviations of reaction times, in the go/no-go task after so-tDCS. In contrast, intrinsic alertness, and motor memory performance were not improved by so-tDCS. CONCLUSION: Since behavioral inhibition but not intrinsic alertness or motor memory was improved by so-tDCS, our results suggest that lateral prefrontal slow oscillations during sleep might play a specific role for executive functioning in ADHD.