Ramping dynamics and theta oscillations reflect dissociable signatures during rule-guided human behavior.

Contextual cues and prior evidence guide human goal-directed behavior. The neurophysiological mechanisms that implement contextual priors to guide subsequent actions in the human brain remain unclear. Using intracranial electroencephalography (iEEG), we demonstrate that increasing uncertainty introduces a shift from a purely oscillatory to a mixed processing regime with an additional ramping component. Oscillatory and ramping dynamics reflect dissociable signatures, which likely differentially contribute to the encoding and transfer of different cognitive variables in a cue-guided motor task. The results support the idea that prefrontal activity encodes rules and ensuing actions in distinct coding subspaces, while theta oscillations synchronize the prefrontal-motor network, possibly to guide action execution. Collectively, our results reveal how two key features of large-scale neural population activity, namely continuous ramping dynamics and oscillatory synchrony, jointly support rule-guided human behavior.

Periodic attention deficits after frontoparietal lesions provide causal evidence for rhythmic attentional sampling.

Contemporary models conceptualize spatial attention as a blinking spotlight that sequentially samples visual space. Hence, behavior fluctuates over time, even in states of presumed "sustained" attention. Recent evidence has suggested that rhythmic neural activity in the frontoparietal network constitutes the functional basis of rhythmic attentional sampling. However, causal evidence to support this notion remains absent. Using a lateralized spatial attention task, we addressed this issue in patients with focal lesions in the frontoparietal attention network. Our results revealed that frontoparietal lesions introduce periodic attention deficits, i.e., temporally specific behavioral deficits that are aligned with the underlying neural oscillations. Attention-guided perceptual sensitivity was on par with that of healthy controls during optimal phases but was attenuated during the less excitable sub-cycles. Theta-dependent sampling (3-8 Hz) was causally dependent on the prefrontal cortex, while high-alpha/low-beta sampling (8-14 Hz) emerged from parietal areas. Collectively, our findings reveal that lesion-induced high-amplitude, low-frequency brain activity is not epiphenomenal but has immediate behavioral consequences. More generally, these results provide causal evidence for the hypothesis that the functional architecture of attention is inherently rhythmic.

Human REM sleep recalibrates neural activity in support of memory formation.

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.

An evolutionary conserved division-of-labor between archicortical and neocortical ripples organizes information transfer during sleep.

Systems-level memory consolidation during sleep depends on the temporally precise interplay between cardinal sleep oscillations. Specifically, hippocampal ripples constitute a key substrate of the hippocampal-neocortical dialog underlying memory formation. Recently, it became evident that ripples are not unique to archicortex, but constitute a wide-spread neocortical phenomenon. To date, little is known about the morphological similarities between archi- and neocortical ripples. Moreover, it remains undetermined if neocortical ripples fulfill distinct functional roles. Leveraging intracranial recordings from the human medial temporal lobe (MTL) and neocortex during sleep, our results reveal region-specific functional specializations, albeit a near-uniform morphology. While MTL ripples synchronize the memory network to trigger directional MTL-to-neocortical information flow, neocortical ripples reduce information flow to minimize interference. At the population level, MTL ripples confined population dynamics to a low-dimensional subspace, while neocortical ripples diversified the population response; thus, constituting an effective mechanism to functionally uncouple the MTL-neocortical network. Critically, we replicated the key findings in rodents, where the same division-of-labor between archi- and neocortical ripples was evident. In sum, these results uncover an evolutionary preserved mechanism where the precisely coordinated interplay between MTL and neocortical ripples temporally segregates MTL information transfer from subsequent neocortical processing during sleep.

Slow oscillation-spindle coupling strength predicts real-life gross-motor learning in adolescents and adults.

Previously, we demonstrated that precise temporal coordination between slow oscillations (SOs) and sleep spindles indexes declarative memory network development (Hahn et al., 2020). However, it is unclear whether these findings in the declarative memory domain also apply in the motor memory domain. Here, we compared adolescents and adults learning juggling, a real-life gross-motor task. Juggling performance was impacted by sleep and time of day effects. Critically, we found that improved task proficiency after sleep lead to an attenuation of the learning curve, suggesting a dynamic juggling learning process. We employed individualized cross-frequency coupling analyses to reduce inter- and intragroup variability of oscillatory features. Advancing our previous findings, we identified a more precise SO-spindle coupling in adults compared to adolescents. Importantly, coupling precision over motor areas predicted overnight changes in task proficiency and learning curve, indicating that SO-spindle coupling relates to the dynamic motor learning process. Our results provide first evidence that regionally specific, precisely coupled sleep oscillations support gross-motor learning.

Aperiodic sleep networks promote memory consolidation.

Hierarchical synchronization of sleep oscillations establishes communication pathways to support memory reactivation, transfer, and consolidation. From an information-theoretical perspective, oscillations constitute highly structured network states that provide limited information-coding capacity. Recent findings indicate that sleep oscillations occur in transient bursts that are interleaved with aperiodic network states, which were previously considered to be random noise. We argue that aperiodic activity exhibits unique and variable spatiotemporal patterns, providing an ideal information-rich neurophysiological substrate for imprinting new mnemonic patterns onto existing circuits. We discuss novel avenues in conceptualizing and quantifying aperiodic network states during sleep to further understand their relevance and interplay with sleep oscillations in support of memory consolidation.

Top-Down Attentional Modulation in Human Frontal Cortex: Differential Engagement during External and Internal Attention.

Decades of electrophysiological research on top-down control converge on the role of the lateral frontal cortex in facilitating attention to behaviorally relevant external inputs. However, the involvement of frontal cortex in the top-down control of attention directed to the external versus internal environment remains poorly understood. To address this, we recorded intracranial electrocorticography while subjects directed their attention externally to tones and responded to infrequent target tones, or internally to their own thoughts while ignoring the tones. Our analyses focused on frontal and temporal cortices. We first computed the target effect, as indexed by the difference in high frequency activity (70-150 Hz) between target and standard tones. Importantly, we then compared the target effect between external and internal attention, reflecting a top-down attentional effect elicited by task demands, in each region of interest. Both frontal and temporal cortices showed target effects during external and internal attention, suggesting this effect is present irrespective of attention states. However, only the frontal cortex showed an enhanced target effect during external relative to internal attention. These findings provide electrophysiological evidence for top-down attentional modulation in the lateral frontal cortex, revealing preferential engagement with external attention.

An electrophysiological marker of arousal level in humans.

Deep non-rapid eye movement sleep (NREM) and general anesthesia with propofol are prominent states of reduced arousal linked to the occurrence of synchronized oscillations in the electroencephalogram (EEG). Although rapid eye movement (REM) sleep is also associated with diminished arousal levels, it is characterized by a desynchronized, 'wake-like' EEG. This observation implies that reduced arousal states are not necessarily only defined by synchronous oscillatory activity. Using intracranial and surface EEG recordings in four independent data sets, we demonstrate that the 1/f spectral slope of the electrophysiological power spectrum, which reflects the non-oscillatory, scale-free component of neural activity, delineates wakefulness from propofol anesthesia, NREM and REM sleep. Critically, the spectral slope discriminates wakefulness from REM sleep solely based on the neurophysiological brain state. Taken together, our findings describe a common electrophysiological marker that tracks states of reduced arousal, including different sleep stages as well as anesthesia in humans.

Electroencephalogram (EEG for short) is a widespread technique that helps to monitor the electrical activity of the brain. In particular, it can be used to examine, recognize and compare different states of brain consciousness such as sleep, wakefulness or general anesthesia. Yet, during rapid eye movement sleep (the sleep phase in which dreaming occurs), the electrical activity of the brain is similar to the one recorded during wakefulness, making it difficult to distinguish these states based on EEG alone. EEG records brain activity in the shape of rhythmic waves whose frequency, shape and amplitude vary depending on the state of consciousness. In the EEG signal from the human brain, the higher frequency waves are weaker than the low-frequency waves: a measure known as spectral slope reflects the degree of this difference in the signal strength. Previous research suggests that spectral slope can be used to distinguish wakefulness from anesthesia and non-REM sleep. Here, Lendner et al. explored whether certain elements of the spectral slope could also discern wakefulness from all states of reduced arousal. EEG readings were taken from patients and volunteers who were awake, asleep or under anesthesia, using electrodes placed either on the scalp or into the brain. Lendner et al. found that the spectral slope could distinguish wakefulness from anesthesia, deep non-REM and REM sleep. The changes in the spectral slope during sleep could accurately track the degree of arousal with great temporal precision and across a wide range of time scales. This method means that states of consciousness can be spotted just from a scalp EEG. In the future, this approach could be embedded into the techniques used for monitoring sleep or anesthesia during operations; it could also be harnessed to monitor other low-response states, such as comas.

Slow oscillation-spindle coupling predicts enhanced memory formation from childhood to adolescence.

Precise temporal coordination of slow oscillations (SO) and sleep spindles is a fundamental mechanism of sleep-dependent memory consolidation. SO and spindle morphology changes considerably throughout development. Critically, it remains unknown how the precise temporal coordination of these two sleep oscillations develops during brain maturation and whether their synchronization indexes the development of memory networks. Here, we use a longitudinal study design spanning from childhood to adolescence, where participants underwent polysomnography and performed a declarative word-pair learning task. Performance on the memory task was better during adolescence. After disentangling oscillatory components from 1/f activity, we found frequency shifts within SO and spindle frequency bands. Consequently, we devised an individualized cross-frequency coupling approach, which demonstrates that SO-spindle coupling strength increases during maturation. Critically, this increase indicated enhanced memory formation from childhood to adolescence. Our results provide evidence that improved coordination between SOs and spindles indexes the development of sleep-dependent memory networks.

Sleep is essential for consolidating the memories that we made during the day. As we lie asleep, unconscious, our brain is busy processing the day's memories, which travel through three parts of the brain before they are filed away. First, the hippocampus, the part of the brain that stores memories temporarily, replays the memories of the day. Then the reactivated memories pass through the thalamus, a central crossroads in the brain, so they can be embedded in the neocortex for long-term storage. Neuroscientists can eavesdrop on the brain at work, day or night, using a technique called EEG. Short for electroencephalogram, an EEG detects brain waves like the bursts of electrical activity known as sleep spindles and slower sleep waves called slow oscillations. These two brain wave patterns represent how the brain processes memories as people sleep ­ and it is all about timing. If the two patterns are running in sync, then the brain's memory systems are thought to be communicating well and memories are more likely to be stored. But patterns of sleep spindles and slow oscillations change dramatically between childhood and adolescence. Memory consolidation also improves in those formative years. Still, it is not yet known if better synchronization between sleep spindles and slow oscillations explains how memory formation improves during this period; that is the going theory. To test it out, Hahn et al. completed a unique study examining how well a group of 33 children could store memories, and then again when the same group were teenagers. Both times, the group was asked to memorise and then recall a set of words before and after a full night's sleep. Hahn et al. measured how much their memory recall improved and whether their brain wave patterns were in sync, looking for any changes between childhood and adolescence. This showed that children whose sleep spindles stacked better with their slow oscillations had improved memory formation once they became teenagers. This work highlights how communication between memory systems in the brain improves as children age, and so does memory. Moreover, it suggests that if disturbances were to be detected in patterns of sleep spindles and slow oscillations, there might be some problem with memory storage. It also points to brain stimulation as a possible treatment option for such problems in the future.

Cognitive neurophysiology of the prefrontal cortex.

The prefrontal cortex (PFC) provides the structural basis for complex rule-guided goal-directed behavior. However, the functional mechanisms that underlie cognitive control and flexibility are not as well understood. Over the last decade, novel electrophysiological methods and analysis techniques have begun to elucidate the neural mechanisms underlying higher cognitive functions. Here we review how electrophysiology and, in particular, intracranial recordings in humans and primates enable imaging of cognitive processing with an unprecedented spatiotemporal resolution. Convergent evidence from multiple species and across several spatial scales suggests that cell assemblies and transient synchronized network activity constitute the functional units of PFC implementation of organized behavior. These observations indicate that the functional architecture of cognition is inherently rhythmic and not static. We highlight that prefrontal neurons exhibit a mixed selectivity to various task-relevant aspects and code information in a time-varying dynamic population code and not at the level of individual neurons or in stable coding schemes. We argue that network neuroscience and network neurology are emergent paradigms to understand complex behavior and mental diseases.

Bidirectional prefrontal-hippocampal dynamics organize information transfer during sleep in humans.

How are memories transferred from short-term to long-term storage? Systems-level memory consolidation is thought to be dependent on the coordinated interplay of cortical slow waves, thalamo-cortical sleep spindles and hippocampal ripple oscillations. However, it is currently unclear how the selective interaction of these cardinal sleep oscillations is organized to support information reactivation and transfer. Here, using human intracranial recordings, we demonstrate that the prefrontal cortex plays a key role in organizing the ripple-mediated information transfer during non-rapid eye movement (NREM) sleep. We reveal a temporally precise form of coupling between prefrontal slow-wave and spindle oscillations, which actively dictates the hippocampal-neocortical dialogue and information transfer. Our results suggest a model of the human sleeping brain in which rapid bidirectional interactions, triggered by the prefrontal cortex, mediate hippocampal activation to optimally time subsequent information transfer to the neocortex during NREM sleep.

Cognitive neurophysiology: Event-related potentials.

Event-related potentials (ERPs) are one of the most commonly used tools to assess cognitive processing with a high temporal resolution. We provide an updated view of the cortical origins of evoked responses and discuss potential mechanisms contributing to ERP generation. In particular, we focus on the relationship between evoked and ongoing oscillatory activity and discuss the differences between ERPs and cortical activation as indexed by high-frequency activity in human intracranial electroencephalography (EEG). We highlight several possibilities for how ERPs can precisely index human perception and behavior in nontraditional approaches, such as neuronal entrainment through steady-state evoked potentials, multivariate decoding, and cross-frequency correlations. We argue that analyses of time-locked responses are beneficial to assess nonlinear and nonsinusoidal neuronal activity on a fine-grained temporal scale, since analyses in the time domain are less susceptible to artifacts than spectral decomposition techniques. Taken together, the current review provides a state-of-the-art overview of ERPs and their application in cognitive and clinical neurophysiology.

Sleep as a Potential Biomarker of Tau and ß-Amyloid Burden in the Human Brain.

Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer's disease (AD): tau and ß-amyloid (Aß). Here we combined PET measures of Aß and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aß burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aß and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and future forecasting) of AD pathology, and carry both therapeutic and public health implications.SIGNIFICANCE STATEMENT Several studies have linked sleep disruption to the progression of Alzheimer's disease (AD). Tau and ß-amyloid (Aß), the primary pathological features of AD, are associated with both objective and subjective changes in sleep. However, it remains unknown whether late life tau and Aß burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aß-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aß in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aß burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.

Neural entrainment and network resonance in support of top-down guided attention.

Which neural mechanisms provide the functional basis of top-down guided cognitive control? Here, we review recent evidence that suggest that the neural basis of attention is inherently rhythmic. In particular, we discuss two physical properties of self-sustained networks, namely entrainment and resonance, and how these shape the timescale of attentional control. Several recent findings revealed theta-band (3-8 Hz) dynamics in top-down guided behavior. These reports were paralleled by intracranial recordings, which implicated theta oscillations in the organization of functional attention networks. We discuss how the intrinsic network architecture shapes covert attentional sampling as well as overt behavior. Taken together, we posit that theta rhythmicity is an inherent feature of the attention network in support of top-down guided goal-directed behavior.

Neural Mechanisms of Sustained Attention Are Rhythmic.

Classic models of attention suggest that sustained neural firing constitutes a neural correlate of sustained attention. However, recent evidence indicates that behavioral performance fluctuates over time, exhibiting temporal dynamics that closely resemble the spectral features of ongoing, oscillatory brain activity. Therefore, it has been proposed that periodic neuronal excitability fluctuations might shape attentional allocation and overt behavior. However, empirical evidence to support this notion is sparse. Here, we address this issue by examining data from large-scale subdural recordings, using two different attention tasks that track perceptual ability at high temporal resolution. Our results reveal that perceptual outcome varies as a function of the theta phase even in states of sustained spatial attention. These effects were robust at the single-subject level, suggesting that rhythmic perceptual sampling is an inherent property of the frontoparietal attention network. Collectively, these findings support the notion that the functional architecture of top-down attention is intrinsically rhythmic.

The rhythmic nature of visual perception.

Our continuous perception of the world could be the result of discrete sampling, where individual snapshots are seamlessly fused into a coherent stream. It has been argued that endogenous oscillatory brain activity could provide the functional substrate of cortical rhythmic sampling. A new study demonstrates that cortical rhythmic sampling is tightly linked to the oculomotor system, thus providing a novel perspective on the neural network underlying top-down guided visual perception.

Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting.

The coupled interaction between slow-wave oscillations and sleep spindles during non-rapid-eye-movement (NREM) sleep has been proposed to support memory consolidation. However, little evidence in humans supports this theory. Moreover, whether such dynamic coupling is impaired as a consequence of brain aging in later life, contributing to cognitive and memory decline, is unknown. Combining electroencephalography (EEG), structural MRI, and sleep-dependent memory assessment, we addressed these questions in cognitively normal young and older adults. Directional cross-frequency coupling analyses demonstrated that the slow wave governs a precise temporal coordination of sleep spindles, the quality of which predicts overnight memory retention. Moreover, selective atrophy within the medial frontal cortex in older adults predicted a temporal dispersion of this slow wave-spindle coupling, impairing overnight memory consolidation and leading to forgetting. Prefrontal-dependent deficits in the spatiotemporal coordination of NREM sleep oscillations therefore represent one pathway explaining age-related memory decline.

Prefrontal cortex modulates posterior alpha oscillations during top-down guided visual perception.

Conscious visual perception is proposed to arise from the selective synchronization of functionally specialized but widely distributed cortical areas. It has been suggested that different frequency bands index distinct canonical computations. Here, we probed visual perception on a fine-grained temporal scale to study the oscillatory dynamics supporting prefrontal-dependent sensory processing. We tested whether a predictive context that was embedded in a rapid visual stream modulated the perception of a subsequent near-threshold target. The rapid stream was presented either rhythmically at 10 Hz, to entrain parietooccipital alpha oscillations, or arrhythmically. We identified a 2- to 4-Hz delta signature that modulated posterior alpha activity and behavior during predictive trials. Importantly, delta-mediated top-down control diminished the behavioral effects of bottom-up alpha entrainment. Simultaneous source-reconstructed EEG and cross-frequency directionality analyses revealed that this delta activity originated from prefrontal areas and modulated posterior alpha power. Taken together, this study presents converging behavioral and electrophysiological evidence for frontal delta-mediated top-down control of posterior alpha activity, selectively facilitating visual perception.

Oscillatory Dynamics of Prefrontal Cognitive Control.

The prefrontal cortex (PFC) provides the structural basis for numerous higher cognitive functions. However, it is still largely unknown which mechanisms provide the functional basis for flexible cognitive control of goal-directed behavior. Here, we review recent findings that suggest that the functional architecture of cognition is profoundly rhythmic and propose that the PFC serves as a conductor to orchestrate task-relevant large-scale networks. We highlight several studies that demonstrated that oscillatory dynamics, such as phase resetting, cross-frequency coupling (CFC), and entrainment, support PFC-dependent recruitment of task-relevant regions into coherent functional networks. Importantly, these findings support the notion that distinct spectral signatures reflect different cortical computations supporting effective multiplexing on different temporal channels along the same anatomical pathways.