Subspace partitioning in the human prefrontal cortex resolves cognitive interference.

The human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between coexisting representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.

Multiple intrinsic timescales govern distinct brain states in human sleep.

Human sleep exhibits multiple, recurrent temporal regularities, ranging from circadian rhythms to sleep stage cycles and neuronal oscillations during non-rapid eye movement (non-REM) sleep. Moreover, recent evidence revealed a functional role of aperiodic activity, which reliably discriminates different sleep stages. Aperiodic activity is commonly defined as the spectral slope χ of the 1/frequency (1/fχ) decay function of the electrophysiological power spectrum. However, several lines of inquiry now indicate that the aperiodic component of the power spectrum might be better characterized by a superposition of several decay processes with associated timescales. Here, we determined multiple timescales, which jointly shape aperiodic activity using human intracranial encephalography (iEEG). Across three independent studies (47 participants, 23 female), our results reveal that aperiodic activity reliably dissociated sleep stage-dependent dynamics in a regionally-specific manner. A principled approach to parametrize aperiodic activity delineated several, spatially- and state-specific timescales. Lastly, we employed pharmacological modulation by means of propofol anesthesia to disentangle state-invariant timescales that may reflect physical properties of the underlying neural population from state-specific timescales that likely constitute functional interactions. Collectively, these results establish the presence of multiple intrinsic timescales that define the electrophysiological power spectrum during distinct brain states.Significance Statement Sleep is characterized by prominent temporal regularities. In this study, we unveil a previously unrecognized principle that governs neural activity during human sleep. Our results shed light on the existence of a set of intrinsic timescales that fundamentally define the current state of the sleeping brain. These timescales serve as indicators of both physiological and functional interactions within the underlying neural population. Through pharmacological modulation, we differentiated state-specific functional interactions from state-invariant timescales, suggesting that the latter may reflect the inherent physical properties of the neural population at play.

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.

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.

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.

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.

Selective modulation of interhemispheric functional connectivity by HD-tACS shapes perception.

Oscillatory neuronal synchronization between cortical areas has been suggested to constitute a flexible mechanism to coordinate information flow in the human cerebral cortex. However, it remains unclear whether synchronized neuronal activity merely represents an epiphenomenon or whether it is causally involved in the selective gating of information. Here, we combined bilateral high-density transcranial alternating current stimulation (HD-tACS) at 40 Hz with simultaneous electroencephalographic (EEG) recordings to study immediate electrophysiological effects during the selective entrainment of oscillatory gamma-band signatures. We found that interhemispheric functional connectivity was modulated in a predictable, phase-specific way: In-phase stimulation enhanced synchronization, anti-phase stimulation impaired functional coupling. Perceptual correlates of these connectivity changes were found in an ambiguous motion task, which strongly support the functional relevance of long-range neuronal coupling. Additionally, our results revealed a decrease in oscillatory alpha power in response to the entrainment of gamma band signatures. This finding provides causal evidence for the antagonistic role of alpha and gamma oscillations in the parieto-occipital cortex and confirms that the observed gamma band modulations were physiological in nature. Our results demonstrate that synchronized cortical network activity across several spatiotemporal scales is essential for conscious perception and cognition.

Different coupling modes mediate cortical cross-frequency interactions.

Cross-frequency coupling (CFC) has been suggested to constitute a highly flexible mechanism for cortical information gating and processing, giving rise to conscious perception and various higher cognitive functions in humans. In particular, it might provide an elegant tool for information integration across several spatiotemporal scales within nested or coupled neuronal networks. However, it is currently unknown whether low-frequency (theta/alpha) or high-frequency gamma oscillations orchestrate cross-frequency interactions, raising the question of who is master and who is slave. While correlative evidence suggested that at least two distinct CFC modes exist, namely, phase-amplitude-coupling (PAC) and amplitude-envelope correlations (AEC), it is currently unknown whether they subserve distinct cortical functions. Novel non-invasive brain stimulation tools, such as transcranial alternating current stimulation (tACS), now provide the unique opportunity to selectively entrain the low- or high-frequency component and study subsequent effects on CFC. Here, we demonstrate the differential modulation of CFC during selective entrainment of alpha or gamma oscillations. Our results reveal that entrainment of the low-frequency component increased PAC, where gamma power became preferentially locked to the trough of the alpha oscillation, while gamma-band entrainment enhanced AECs and reduced alpha power. These results provide causal evidence for the functional role of coupled alpha and gamma oscillations for visual processing.

Spectral fingerprints of large-scale cortical dynamics during ambiguous motion perception.

Ambiguous stimuli have been widely used to study the neuronal correlates of consciousness. Recently, it has been suggested that conscious perception might arise from the dynamic interplay of functionally specialized but widely distributed cortical areas. While previous research mainly focused on phase coupling as a correlate of cortical communication, more recent findings indicated that additional coupling modes might coexist and possibly subserve distinct cortical functions. Here, we studied two coupling modes, namely phase and envelope coupling, which might differ in their origins, putative functions and dynamics. Therefore, we recorded 128-channel EEG while participants performed a bistable motion task and utilized state-of-the-art source-space connectivity analysis techniques to study the functional relevance of different coupling modes for cortical communication. Our results indicate that gamma-band phase coupling in extrastriate visual cortex might mediate the integration of visual tokens into a moving stimulus during ambiguous visual stimulation. Furthermore, our results suggest that long-range fronto-occipital gamma-band envelope coupling sustains the horizontal percept during ambiguous motion perception. Additionally, our results support the idea that local parieto-occipital alpha-band phase coupling controls the inter-hemispheric information transfer. These findings provide correlative evidence for the notion that synchronized oscillatory brain activity reflects the processing of sensory input as well as the information integration across several spatiotemporal scales. The results indicate that distinct coupling modes are involved in different cortical computations and that the rich spatiotemporal correlation structure of the brain might constitute the functional architecture for cortical processing and specific multi-site communication. Hum Brain Mapp 37:4099-4111, 2016. © 2016 Wiley Periodicals, Inc.

Aperiodic Activity Indexes Neural Hyperexcitability in Generalized Epilepsy.

Generalized epilepsy (GE) encompasses a heterogeneous group of hyperexcitability disorders that clinically manifest as seizures. At the whole-brain level, distinct seizure patterns as well as interictal epileptic discharges (IEDs) reflect key signatures of hyperexcitability in magneto- and electroencephalographic (M/EEG) recordings. Moreover, it had been suggested that aperiodic activity, specifically the slope of the 1/ƒx decay function of the power spectrum, might index neural excitability. However, it remained unclear if hyperexcitability as encountered at the cellular level directly translates to putative large-scale excitability signatures, amenable to M/EEG. In order to test whether the power spectrum is altered in hyperexcitable states, we recorded resting-state MEG from male and female GE patients (n = 51; 29 females; 28.82 ± 12.18 years; mean ± SD) and age-matched healthy controls (n = 49; 22 females; 32.10 ± 12.09 years). We parametrized the power spectra using FOOOF ("fitting oscillations and one over f") to separate oscillatory from aperiodic activity to directly test whether aperiodic activity is systematically altered in GE patients. We further identified IEDs to quantify the temporal dynamics of aperiodic activity around overt epileptic activity. The results demonstrate that aperiodic activity indexes hyperexcitability in GE at the whole-brain level, especially during epochs when no IEDs were present (p = 0.0130; d = 0.52). Upon IEDs, large-scale circuits transiently shifted to a less excitable network state (p = 0.001; d = 0.68). In sum, these results uncover that MEG background activity might index hyperexcitability based on the current brain state and does not rely on the presence of epileptic waveforms.

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.

Processing of coherent visual motion in topographically organized visual areas in human cerebral cortex.

Recent imaging studies in human subjects have demonstrated representations of global visual motion in medial parieto-occipital cortex (area V6) and posterior parietal cortex, the latter containing at least seven topographically organized areas along the intraparietal sulcus (IPS0-IPS5, SPL1). In this fMRI study we used topographic mapping procedures to delineate a total of 18 visual areas in human cerebral cortex and tested their responsiveness to coherent visual motion under conditions of controlled attention and fixation. Preferences for coherent visual motion as compared to motion noise as well as hemispheric asymmetries were assessed for contralateral, ipsilateral, and bilateral visual motion presentations. Except for areas V1-V4 and IPS3-5, all other areas showed stronger responses to coherent motion with the most significant activations found in V6, followed by MT/MST, V3A, IPS0-2 and SPL1. Hemispheric differences were negligible altogether suggesting that asymmetries in parietal cortex observed in cognitive tasks do not reflect differences in basic visual response properties. Interestingly, areas V6, MST, V3A, and areas along the intraparietal sulcus showed specific representations of coherent visual motion not only when presented in the hemifield primarily covered by the given visual representation but also when presented in the ipsilateral visual field. This finding suggests that coherent motion induces a switch in spatial representation in specialized motion areas from contralateral to full-field coding.

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.

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.

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.

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.

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.

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.