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Sleep spindles are transient oscillatory waveforms that occur during non-rapid eye movement (NREM) sleep across widespread cortical areas. In humans, spindles can be classified as either slow or fast, but large individual differences in spindle frequency as well as methodological difficulties have hindered progress towards understanding their function. Using two nights of high-density electroencephalography recordings from 28 healthy individuals, we first characterize the individual variability of NREM spectra and demonstrate the difficulty of determining subject-specific spindle frequencies. We then introduce a novel spatial filtering approach that can reliably separate subject-specific spindle activity into slow and fast components that are stable across nights and across N2 and N3 sleep. We then proceed to provide detailed analyses of the topographical expression of individualized slow and fast spindle activity. Group-level analyses conform to known spatial properties of spindles, but also uncover novel differences between sleep stages and spindle classes. Moreover, subject-specific examinations reveal that individual topographies show considerable variability that is stable across nights. Finally, we demonstrate that topographical maps depend nontrivially on the spindle metric employed. In sum, our findings indicate that group-level approaches mask substantial individual variability of spindle dynamics, in both the spectral and spatial domains. We suggest that leveraging, rather than ignoring, such differences may prove useful to further our understanding of the physiology and functional role of sleep spindles.

Abstract Study Objectives Converging evidence from neuroimaging, sleep, and genetic studies suggest that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD. Methods Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9–17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep. Results ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but their relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite. Conclusions The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.

Abstract Transient oscillatory events in the sleep electroencephalogram represent short-term coordinated network activity. Of particular importance, sleep spindles are transient oscillatory events associated with memory consolidation, which are altered in aging and in several psychiatric and neurodegenerative disorders. Spindle identification, however, currently contains implicit assumptions derived from what waveforms were historically easiest to discern by eye, and has recently been shown to select only a high-amplitude subset of transient events. Moreover, spindle activity is typically averaged across a sleep stage, collapsing continuous dynamics into discrete states. What information can be gained by expanding our view of transient oscillatory events and their dynamics? In this paper, we develop a novel approach to electroencephalographic phenotyping, characterizing a generalized class of transient time-frequency events across a wide frequency range using continuous dynamics. We demonstrate that the complex temporal evolution of transient events during sleep is highly stereotyped when viewed as a function of slow oscillation power (an objective, continuous metric of depth-of-sleep) and phase (a correlate of cortical up/down states). This two-fold power-phase representation has large intersubject variability—even within healthy controls—yet strong night-to-night stability for individuals, suggesting a robust basis for phenotyping. As a clinical application, we then analyze patients with schizophrenia, confirming established spindle (12–15 Hz) deficits as well as identifying novel differences in transient non-rapid eye movement events in low-alpha (7–10 Hz) and theta (4–6 Hz) ranges. Overall, these results offer an expanded view of transient activity, describing a broad class of events with properties varying continuously across spatial, temporal, and phase-coupling dimensions. Graphical Abstract Graphical Abstract

Response inhibition, or the suppression of prepotent, but contextually inappropriate behaviors, is essential to adaptive, flexible responding. In autism spectrum disorders (ASD), difficulty inhibiting prepotent behaviors may contribute to restricted, repetitive behavior (RRB). Individuals with ASD consistently show deficient response inhibition while performing antisaccades, which require one to inhibit the prepotent response of looking towards a suddenly appearing stimulus (i.e., a prosaccade), and to substitute a gaze in the opposite direction. Here, we used fMRI to identify the neural correlates of this deficit. We focused on two regions that are critical for saccadic inhibition: the frontal eye field (FEF), the key cortical region for generating volitional saccades, and the dorsal anterior cingulate cortex (dACC), which is thought to exert top–down control on the FEF. We also compared ASD and control groups on the functional connectivity of the dACC and FEF during saccadic performance. In the context of an increased antisaccade error rate, ASD participants showed decreased functional connectivity of the FEF and dACC and decreased inhibition-related activation (based on the contrast of antisaccades and prosaccades) in both regions. Decreased dACC activation correlated with a higher error rate in both groups, consistent with a role in top–down control. Within the ASD group, increased FEF activation and dACC/FEF functional connectivity were associated with more severe RRB. These findings demonstrate functional abnormalities in a circuit critical for volitional ocular motor control in ASD that may contribute to deficient response inhibition and to RRB. More generally, our findings suggest reduced cognitive control over behavior by the dACC in ASD.

Critical aspects of motor learning and memory happen offline, during both wake and sleep. When healthy young people learn a motor sequence task, most of their performance improvement happens not while typing, but offline, during interleaved rest breaks. In contrast, the performance of patients with dense amnesia due to hippocampal damage actually gets worse over the rest breaks and improves while typing. These findings indicate that an intact hippocampus is necessary for offline motor learning during wake, but do not specify its mechanism. Here, we studied epilepsy patients ( n  = 17) undergoing direct intracranial electroencephalographic monitoring of the hippocampus as they learned the same motor sequence task. Like healthy young people, they show greater speed gains across rest breaks than while typing. They also show higher hippocampal ripple rates during these rest breaks that predict offline gains in speed. This suggests that motor learning during brief rest breaks during wake is mediated by hippocampal ripples. These results expand our understanding of the role of hippocampal ripples beyond declarative memory to include enhancing motor procedural memory. While learning a typing task, epilepsy patients show higher hippocampal ripple rates during brief rest breaks than while typing. These ‘offline’ ripples predict gains in speed, suggesting that ripples contribute to motor learning during wakeful rest.

Sleep spindles, defining oscillations of stage 2 non-rapid eye movement sleep (N2), mediate memory consolidation. Schizophrenia is characterized by reduced spindle activity that correlates with impaired sleep-dependent memory consolidation. In a small, randomized, placebo-controlled pilot study of schizophrenia, eszopiclone (Lunesta®), a nonbenzodiazepine sedative hypnotic, increased N2 spindle density (number/minute) but did not significantly improve memory. This larger double-blind crossover study that included healthy controls investigated whether eszopiclone could both increase N2 spindle density and improve memory. Twenty-six medicated schizophrenia outpatients and 29 healthy controls were randomly assigned to have a placebo or eszopiclone (3 mg) sleep visit first. Each visit involved two consecutive nights of high density polysomnography with training on the Motor Sequence Task (MST) on the second night and testing the following morning. Patients showed a widespread reduction of spindle density and, in both groups, eszopiclone increased spindle density but failed to enhance sleep-dependent procedural memory consolidation. Follow-up analyses revealed that eszopiclone also affected cortical slow oscillations: it decreased their amplitude, increased their duration, and rendered their phase locking with spindles more variable. Regardless of group or visit, the density of coupled spindle-slow oscillation events predicted memory consolidation significantly better than spindle density alone, suggesting that they are a better biomarker of memory consolidation. In conclusion, sleep oscillations are promising targets for improving memory consolidation in schizophrenia, but enhancing spindles is not enough. Effective therapies also need to preserve or enhance cortical slow oscillations and their coordination with thalamic spindles, an interregional dialog that is necessary for sleep-dependent memory consolidation.

Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally-unaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

Chronic medicated patients with schizophrenia have marked reductions in sleep spindle activity and a correlated deficit in sleep-dependent memory consolidation. Using archival data, we investigated whether antipsychotic-naïve early course patients with schizophrenia and young non-psychotic first-degree relatives of patients with schizophrenia also show reduced sleep spindle activity and whether spindle activity correlates with cognitive function and symptoms. Sleep spindles during Stage 2 sleep were compared in antipsychotic-naïve adults newly diagnosed with psychosis, young non-psychotic first-degree relatives of schizophrenia patients and two samples of healthy controls matched to the patients and relatives. The relations of spindle parameters with cognitive measures and symptom ratings were examined. Early course schizophrenia patients showed significantly reduced spindle activity relative to healthy controls and to early course patients with other psychotic disorders. Relatives of schizophrenia patients also showed reduced spindle activity compared with controls. Reduced spindle activity correlated with measures of executive function in early course patients, positive symptoms in schizophrenia and IQ estimates across groups. Like chronic medicated schizophrenia patients, antipsychotic-naïve early course schizophrenia patients and young non-psychotic relatives of individuals with schizophrenia have reduced sleep spindle activity. These findings indicate that the spindle deficit is not an antipsychotic side-effect or a general feature of psychosis. Instead, the spindle deficit may predate the onset of schizophrenia, persist throughout its course and be an endophenotype that contributes to cognitive dysfunction.

Sleep entails significant changes in cerebral hemodynamics and metabolism. Yet, the way these processes evolve throughout wakefulness and sleep and their spatiotemporal dependence remain largely unknown. Here, by integrating a functional PET technique with simultaneous EEG-fMRI, we reveal a tightly coupled temporal progression of global hemodynamics and metabolism during the descent into NREM sleep, with large hemodynamic fluctuations emerging as global glucose metabolism declines, both of which track EEG arousal dynamics. Furthermore, we identify two distinct network patterns that emerge during NREM sleep: a ~0.02-Hz oscillating, high-metabolism sensorimotor network remains active and dynamic, whereas hemodynamic and metabolic activity in the default-mode network is suppressed. These results elucidate how sleep diminishes awareness while preserving sensory responses, and uncover a complex, alternating balance of neuronal, hemodynamic, and metabolic dynamics in the sleeping brain. This work also demonstrates the potential of EEG-PET-MRI to explore neuro-metabolic-hemodynamic mechanisms underlying cognition and arousal in humans. Using simultaneous EEG-PET-MRI, this study reveals tightly coupled physiological dynamics during the descent from wakefulness into NREM sleep and identifies network-specific activity underlying sensory arousal in NREM sleep.

ADHD has been associated with cortico-striatal dysfunction that may lead to procedural memory abnormalities. Sleep plays a critical role in consolidating procedural memories, and sleep problems are an integral part of the psychopathology of ADHD. This raises the possibility that altered sleep processes characterizing those with ADHD could contribute to their skill-learning impairments. On this basis, the present study tested the hypothesis that young adults with ADHD have altered sleep-dependent procedural memory consolidation. Participants with ADHD and neurotypicals were trained on a visual discrimination task that has been shown to benefit from sleep. Half of the participants were tested after a 12-h break that included nocturnal sleep (sleep condition), whereas the other half were tested after a 12-h daytime break that did not include sleep (wakefulness condition) to assess the specific contribution of sleep to improvement in task performance. Despite having a similar degree of initial learning, participants with ADHD did not improve in the visual discrimination task following a sleep interval compared to neurotypicals, while they were on par with neurotypicals during the wakefulness condition. These findings represent the first demonstration of a failure in sleep-dependent consolidation of procedural learning in young adults with ADHD. Such a failure is likely to disrupt automatic control routines that are normally provided by the non-declarative memory system, thereby increasing the load on attentional resources of individuals with ADHD.