Emergent effects of synaptic connectivity on the dynamics of global and local slow waves in a large-scale thalamocortical network model of the human brain.

Slow-wave sleep (SWS), characterized by slow oscillations (SO, <1Hz) of alternating active and silent states in the thalamocortical network, is a primary brain state during Non-Rapid Eye Movement (NREM) sleep. In the last two decades, the traditional view of SWS as a global and uniform whole-brain state has been challenged by a growing body of evidence indicating that SO can be local and can coexist with wake-like activity. However, the understanding of how global and local SO emerges from micro-scale neuron dynamics and network connectivity remains unclear. We developed a multi-scale, biophysically realistic human whole-brain thalamocortical network model capable of transitioning between the awake state and slow-wave sleep, and we investigated the role of connectivity in the spatio-temporal dynamics of sleep SO. We found that the overall strength and a relative balance between long and short-range synaptic connections determined the network state. Importantly, for a range of synaptic strengths, the model demonstrated complex mixed SO states, where periods of synchronized global slow-wave activity were intermittent with the periods of asynchronous local slow-waves. Increase of the overall synaptic strength led to synchronized global SO, while decrease of synaptic connectivity produced only local slow-waves that would not propagate beyond local area. These results were compared to human data to validate probable models of biophysically realistic SO. The model producing mixed states provided the best match to the spatial coherence profile and the functional connectivity estimated from human subjects. These findings shed light on how the spatio-temporal properties of SO emerge from local and global cortical connectivity and provide a framework for further exploring the mechanisms and functions of SWS in health and disease.

Modular Phoneme Processing in Human Superior Temporal Gyrus.

Modular organization is fundamental to cortical processing, but its presence is human association cortex is unknown. We characterized phoneme processing with 128-1024 channel micro-arrays at 50-200µm pitch on superior temporal gyrus of 7 patients. High gamma responses were highly correlated within ~1.7mm diameter modules, sharply delineated from adjacent modules with distinct time-courses and phoneme-selectivity. We suggest that receptive language cortex may be organized in discrete processing modules.

Mapping access to meaning in adolescents with autism: Atypical lateralization and spatiotemporal patterns as a function of language ability.

Individuals with autism spectrum disorders (ASD) vary in their language abilities, associated with atypical patterns of brain activity. However, few studies have examined the spatiotemporal profiles of lexico-semantic processing in ASD, particularly as a function of language heterogeneity. Thirty-nine high-functioning adolescents with ASD and 21 typically developing (TD) peers took part in a lexical decision task that combined semantic access with demands on cognitive control. Spatiotemporal characteristics of the processing stages were examined with a multimodal anatomically-constrained magnetoencephalography (aMEG) approach, which integrates MEG with structural MRI. Additional EEG data were acquired from a limited montage simultaneously with MEG. TD adolescents showed the canonical left-dominant activity in frontotemporal regions during both early (N250m) and late (N400m) stages of lexical access and semantic integration. In contrast, the ASD participants showed bilateral engagement of the frontotemporal language network, indicative of compensatory recruitment of the right hemisphere. The left temporal N400m was prominent in both groups, confirming preserved attempts to access meaning. In contrast, the left prefrontal N400m was reduced in ASD participants, consistent with impaired semantic/contextual integration and inhibitory control. To further investigate the impact of language proficiency, the ASD sample was stratified into high- and low-performing (H-ASD and L-ASD) subgroups based on their task accuracy. The H-ASD subgroup performed on par with the TD group and showed greater activity in the right prefrontal and bilateral temporal cortices relative to the L-ASD subgroup, suggesting compensatory engagement. The L-ASD subgroup additionally showed reduced and delayed left prefrontal N400m, consistent with more profound semantic and executive impairments in this subgroup. These distinct spatiotemporal activity profiles reveal the neural underpinnings of the ASD-specific access to meaning and provide insight into the phenotypic heterogeneity of language in ASD, which may be a result of different neurodevelopmental trajectories and adoption of compensatory strategies.

Aperiodic Neural Activity is a Better Predictor of Schizophrenia than Neural Oscillations.

Diagnosis and symptom severity in schizophrenia are associated with irregularities across neural oscillatory frequency bands, including theta, alpha, beta, and gamma. However, electroencephalographic signals consist of both periodic and aperiodic activity characterized by the (1/fX) shape in the power spectrum. In this paper, we investigated oscillatory and aperiodic activity differences between patients with schizophrenia and healthy controls during a target detection task. Separation into periodic and aperiodic components revealed that the steepness of the power spectrum better-predicted group status than traditional band-limited oscillatory power in classification analysis. Aperiodic activity also outperformed the predictions made using participants' behavioral responses. Additionally, the differences in aperiodic activity were highly consistent across all electrodes. In sum, compared to oscillations the aperiodic activity appears to be a more accurate and more robust way to differentiate patients with schizophrenia from healthy controls.

Cortical Ripples during NREM Sleep and Waking in Humans.

Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal-interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just before the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped cofiring between units within the window of spike timing-dependent plasticity. Thus, human NREM cortical ripples are as follows: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit cofiring. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans.SIGNIFICANCE STATEMENT In rodents, hippocampal ripples organize replay during sleep to promote memory consolidation in the cortex, where ripples also occur. However, evidence for cortical ripples in human sleep is limited, and their anatomic distribution and physiological properties are unexplored. Here, using human intracranial recordings, we demonstrate that ripples occur throughout the cortex during waking and sleep with highly stereotyped characteristics. During sleep, cortical ripples tend to occur during spindles on the down-to-upstate transition, and thus participate in a sequence of sleep waves that is important for consolidation. Furthermore, cortical ripples organize single-unit spiking with timing optimal to facilitate plasticity. Therefore, cortical ripples in humans possess essential physiological properties to support memory and other cognitive functions.

Widespread ripples synchronize human cortical activity during sleep, waking, and memory recall.

Declarative memory encoding, consolidation, and retrieval require the integration of elements encoded in widespread cortical locations. The mechanism whereby such "binding" of different components of mental events into unified representations occurs is unknown. The "binding-by-synchrony" theory proposes that distributed encoding areas are bound by synchronous oscillations enabling enhanced communication. However, evidence for such oscillations is sparse. Brief high-frequency oscillations ("ripples") occur in the hippocampus and cortex and help organize memory recall and consolidation. Here, using intracranial recordings in humans, we report that these ∼70-ms-duration, 90-Hz ripples often couple (within ±500 ms), co-occur (≥ 25-ms overlap), and, crucially, phase-lock (have consistent phase lags) between widely distributed focal cortical locations during both sleep and waking, even between hemispheres. Cortical ripple co-occurrence is facilitated through activation across multiple sites, and phase locking increases with more cortical sites corippling. Ripples in all cortical areas co-occur with hippocampal ripples but do not phase-lock with them, further suggesting that cortico-cortical synchrony is mediated by cortico-cortical connections. Ripple phase lags vary across sleep nights, consistent with participation in different networks. During waking, we show that hippocampo-cortical and cortico-cortical coripples increase preceding successful delayed memory recall, when binding between the cue and response is essential. Ripples increase and phase-modulate unit firing, and coripples increase high-frequency correlations between areas, suggesting synchronized unit spiking facilitating information exchange. co-occurrence, phase synchrony, and high-frequency correlation are maintained with little decrement over very long distances (25 cm). Hippocampo-cortico-cortical coripples appear to possess the essential properties necessary to support binding by synchrony during memory retrieval and perhaps generally in cognition.

Dynamical differential covariance recovers directional network structure in multiscale neural systems.

Investigating neural interactions is essential to understanding the neural basis of behavior. Many statistical methods have been used for analyzing neural activity, but estimating the direction of network interactions correctly and efficiently remains a difficult problem. Here, we derive dynamical differential covariance (DDC), a method based on dynamical network models that detects directional interactions with low bias and high noise tolerance under nonstationarity conditions. Moreover, DDC scales well with the number of recording sites and the computation required is comparable to that needed for covariance. DDC was validated and compared favorably with other methods on networks with false positive motifs and multiscale neural simulations where the ground-truth connectivity was known. When applied to recordings of resting-state functional magnetic resonance imaging (rs-fMRI), DDC consistently detected regional interactions with strong structural connectivity in over 1,000 individual subjects obtained by diffusion MRI (dMRI). DDC is a promising family of methods for estimating connectivity that can be generalized to a wide range of dynamical models and recording techniques and to other applications where system identification is needed.

Theta oscillatory dynamics of inhibitory control, error processing, and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation in social drinkers.

BACKGROUND: Alcohol intoxication impairs inhibitory control, resulting in disinhibited, impulsive behavior. The anterior cingulate cortex (ACC) plays an essential role in a range of executive functions and is sensitive to the effects of alcohol, which contributes to the top-down cognitive dysregulation. This study used a multimodal approach to examine the acute effects of alcohol on the neural underpinnings of inhibitory control, inhibition failures, and neurobehavioral optimization as reflected in trial-to-trial dynamics of post-error adjustments. METHODS: Adult social drinkers served as their own controls by participating in the Go/NoGo task during acute alcohol and placebo conditions in a multi-session, counterbalanced design. Distributed source modeling of the magnetoencephalographic signal was combined with structural magnetic resonance imaging to characterize the spatio-temporal dynamics of inhibitory control in the time-frequency domain. RESULTS: Successful response inhibition (NoGo) elicited right-lateralized event-related theta power (4 to 7 Hz). Errors elicited a short-latency increase in theta power in the dorsal (dACC), followed by activity in the rostral (rACC), which may underlie an affective "oh, no!" orienting response to errors. Error-related theta in the dACC was associated with subsequent activity of the motor areas on the first post-error trial, suggesting the occurrence of post-error output adjustments. Importantly, a gradual increase of the dACC theta across post-error trials closely tracked improvements in accuracy under placebo, which may reflect cognitive control engagement to optimize response accuracy. In contrast, alcohol increased NoGo commission errors, dysregulated theta during correct NoGo withholding, and abolished the post-error theta enhancement of cognitive control. CONCLUSIONS: Confirming the sensitivity of frontal theta to inhibitory control and error monitoring, the results support functional and temporal dissociation along the dorso-rostral axis of the ACC and the deleterious effects of alcohol on the frontal circuitry subserving top-down regulation. Over time, alcohol-induced disinhibition may give rise to compulsive drinking and contribute to alcohol misuse.

An estimation of the absolute number of axons indicates that human cortical areas are sparsely connected.

The tracts between cortical areas are conceived as playing a central role in cortical information processing, but their actual numbers have never been determined in humans. Here, we estimate the absolute number of axons linking cortical areas from a whole-cortex diffusion MRI (dMRI) connectome, calibrated using the histologically measured callosal fiber density. Median connectivity is estimated as approximately 6,200 axons between cortical areas within hemisphere and approximately 1,300 axons interhemispherically, with axons connecting functionally related areas surprisingly sparse. For example, we estimate that <5% of the axons in the trunk of the arcuate and superior longitudinal fasciculi connect Wernicke's and Broca's areas. These results suggest that detailed information is transmitted between cortical areas either via linkage of the dense local connections or via rare, extraordinarily privileged long-range connections.

The "when" and "where" of the interplay between attentional capture and response inhibition during a Go/NoGo variant.

Inhibitory control relies on attention, inhibition, and other functions that are integrated across neural networks in an interactive manner. Functional MRI studies have provided excellent spatial mapping of the involved regions. However, finer temporal resolution is needed to capture the underlying neural dynamics and the pattern of their functional contributions. Here, we used anatomically-constrained magnetoencephalography (aMEG) which combines MEG with structural MRI to examine how the spatial ("where") and temporal ("when") processing stages and interregional co-oscillations unfold in real time to contribute to inhibitory control. Healthy participants completed a modified Go/NoGo paradigm in which a subset of stimuli was modified to be visually salient (SAL). Compared to the non-modified condition, the SAL manipulation facilitated response withholding on NoGo trials and hindered responding to Go stimuli, reflecting attentional capture effectuated by an orienting response to SAL stimuli. aMEG source estimates indicate SAL stimuli elicited the attentional "circuit breaker" effect through early activity within a right-lateralized network centered around the lateral temporal cortex with additional activity in the pre-supplementary motor area (preSMA) and anterior insula (aINS/FO). Activity of the bilateral inferior frontal cortex responded specifically to inhibitory demands and was generally unaffected by the attentional manipulation. In contrast, early aINS/FO activity was sensitive to stimulus salience while subsequent activity was specific to inhibitory control. Activity estimated to the medial prefrontal cortex including the dorsal anterior cingulate cortex and preSMA reflected an integrative role that was sensitive to both inhibitory and attentional stimulus properties. At the level of neurofunctional networks, neural synchrony in the theta band (4-7 Hz) revealed interactions between principal cortical regions subserving attentional and inhibitory processes. Together, these results underscore the dynamic, integrative processing stages underlying inhibitory control.

A Whole-Cortex Probabilistic Diffusion Tractography Connectome.

The WU-Minn Human Connectome Project (HCP) is a publicly-available dataset containing state-of-the-art structural magnetic resonance imaging (MRI), functional MRI (fMRI), and diffusion MRI (dMRI) for over a thousand healthy subjects. While the planned scope of the HCP included an anatomic connectome, resting-state fMRI (rs-fMRI) forms the bulk of the HCP's current connectomic output. We address this by presenting a full-cortex connectome derived from probabilistic diffusion tractography and organized into the HCP-MMP1.0 atlas. Probabilistic methods and large sample sizes are preferable for whole-connectome mapping as they increase the fidelity of traced low-probability connections. We find that overall, connection strengths are lognormally distributed and decay exponentially with tract length, that connectivity reasonably matches macaque histologic tracing in homologous areas, that contralateral homologs and left-lateralized language areas are hyperconnected, and that hierarchical similarity influences connectivity. We compare the dMRI connectome to existing rs-fMRI and cortico-cortico-evoked potential connectivity matrices and find that it is more similar to the latter. This work helps fulfill the promise of the HCP and will make possible comparisons between the underlying structural connectome and functional connectomes of various modalities, brain states, and clinical conditions.

MEG Theta during Lexico-Semantic and Executive Processing Is Altered in High-Functioning Adolescents with Autism.

Neuroimaging studies have revealed atypical activation during language and executive tasks in individuals with autism spectrum disorders (ASD). However, the spatiotemporal stages of processing associated with these dysfunctions remain poorly understood. Using an anatomically constrained magnetoencephalography approach, we examined event-related theta oscillations during a double-duty lexical decision task that combined demands on lexico-semantic processing and executive functions. Relative to typically developing peers, high-functioning adolescents with ASD had lower performance accuracy on trials engaging selective semantic retrieval and cognitive control. They showed an early overall theta increase in the left fusiform cortex followed by greater activity in the left-lateralized temporal (starting at ~250 ms) and frontal cortical areas (after ~450 ms) known to contribute to language processing. During response preparation and execution, the ASD group exhibited elevated theta in the anterior cingulate cortex, indicative of greater engagement of cognitive control. Simultaneously increased activity in the ipsilateral motor cortex may reflect a less lateralized and suboptimally organized motor circuitry. Spanning early sensory-specific and late response selection stages, the higher event-related theta responsivity in ASD may indicate compensatory recruitment to offset inefficient lexico-semantic retrieval under cognitively demanding conditions. Together, these findings provide further support for atypical language and executive functions in high-functioning ASD.

Compensatory neuroadaptation to binge drinking: Human evidence for allostasis.

Animal studies have established that acute alcohol increases neural inhibition and that frequent intoxication episodes elicit neuroadaptive changes in the excitatory/inhibitory neurotransmission balance. To compensate for the depressant effects of alcohol, neural hyperexcitability develops in alcohol use disorder and is manifested through withdrawal symptoms. It is unclear, however, whether neuroadaptive changes can be observed in young, emerging adults at lower levels of consumption in the absence of withdrawal symptoms. Here, we used an anatomically constrained magnetoencephalography method to assess cortical excitability in two independent sets of experiments. We measured early visual activity (1) in social drinkers during alcohol intoxication versus placebo conditions and (2) in parallel cohorts of sober binge drinkers (BDs) and light drinkers (LDs). Acute alcohol intoxication attenuated early sensory activity in the visual cortex in social drinkers, confirming its inhibitory effects on neurotransmission. In contrast, sober BDs showed greater neural responsivity compared with a matched group of LDs. A positive correlation between alcohol consumption and neural activity in BDs is indicative of cortical hyperexcitability associated with hazardous drinking. Furthermore, neural responsivity was positively correlated with alcohol intake in social drinkers whose drinking did not reach binge levels. This study provides novel evidence of compensatory imbalance reflected in the downregulation of inhibitory and upregulation of excitatory signaling associated with binge drinking in young, emerging adults. By contrasting acute effects and a history of BD, these results support the mechanistic model of allostasis. Direct neural measures are sensitive to synaptic currents and could serve as biomarkers of neuroadaptation.

Disruption of Frontal Lobe Neural Synchrony During Cognitive Control by Alcohol Intoxication.

Decision making relies on dynamic interactions of distributed, primarily frontal brain regions. Extensive evidence from functional magnetic resonance imaging (fMRI) studies indicates that the anterior cingulate (ACC) and the lateral prefrontal cortices (latPFC) are essential nodes subserving cognitive control. However, because of its limited temporal resolution, fMRI cannot accurately reflect the timing and nature of their presumed interplay. The present study combines distributed source modeling of the temporally precise magnetoencephalography (MEG) signal with structural MRI in the form of "brain movies" to: (1) estimate the cortical areas involved in cognitive control ("where"), (2) characterize their temporal sequence ("when"), and (3) quantify the oscillatory dynamics of their neural interactions in real time. Stroop interference was associated with greater event-related theta (4 - 7 Hz) power in the ACC during conflict detection followed by sustained sensitivity to cognitive demands in the ACC and latPFC during integration and response preparation. A phase-locking analysis revealed co-oscillatory interactions between these areas indicating their increased neural synchrony in theta band during conflict-inducing incongruous trials. These results confirm that theta oscillations are fundamental to long-range synchronization needed for integrating top-down influences during cognitive control. MEG reflects neural activity directly, which makes it suitable for pharmacological manipulations in contrast to fMRI that is sensitive to vasoactive confounds. In the present study, healthy social drinkers were given a moderate alcohol dose and placebo in a within-subject design. Acute intoxication attenuated theta power to Stroop conflict and dysregulated co-oscillations between the ACC and latPFC, confirming that alcohol is detrimental to neural synchrony subserving cognitive control. It interferes with goal-directed behavior that may result in deficient self-control, contributing to compulsive drinking. In sum, this method can provide insight into real-time interactions during cognitive processing and can characterize the selective sensitivity to pharmacological challenge across relevant neural networks.

Theta Bursts Precede, and Spindles Follow, Cortical and Thalamic Downstates in Human NREM Sleep.

Since their discovery, slow oscillations have been observed to group spindles during non-REM sleep. Previous studies assert that the slow-oscillation downstate (DS) is preceded by slow spindles (10-12 Hz) and followed by fast spindles (12-16 Hz). Here, using both direct transcortical recordings in patients with intractable epilepsy (n = 10, 8 female), as well as scalp EEG recordings from a healthy cohort (n = 3, 1 female), we find in multiple cortical areas that both slow and fast spindles follow the DS. Although discrete oscillations do precede DSs, they are theta bursts (TBs) centered at 5-8 Hz. TBs were more pronounced for DSs in NREM stage 2 (N2) sleep compared with N3. TB with similar properties occur in the thalamus, but unlike spindles they have no clear temporal relationship with cortical TB. These differences in corticothalamic dynamics, as well as differences between spindles and theta in coupling high-frequency content, are consistent with NREM theta having separate generative mechanisms from spindles. The final inhibitory cycle of the TB coincides with the DS peak, suggesting that in N2, TB may help trigger the DS. Since the transition to N1 is marked by the appearance of theta, and the transition to N2 by the appearance of DS and thus spindles, a role of TB in triggering DS could help explain the sequence of electrophysiological events characterizing sleep. Finally, the coordinated appearance of spindles and DSs are implicated in memory consolidation processes, and the current findings redefine their temporal coupling with theta during NREM sleep.SIGNIFICANCE STATEMENT Sleep is characterized by large slow waves which modulate brain activity. Prominent among these are downstates (DSs), periods of a few tenths of a second when most cells stop firing, and spindles, oscillations at ∼12 times a second lasting for ∼a second. In this study, we provide the first detailed description of another kind of sleep wave: theta bursts (TBs), a brief oscillation at ∼six cycles per second. We show, recording during natural sleep directly from the human cortex and thalamus, as well as on the scalp, that TBs precede, and spindles follow DSs. TBs may help trigger DSs in some circumstances, and could organize cortical and thalamic activity so that memories can be consolidated during sleep.

Thalamocortical and intracortical laminar connectivity determines sleep spindle properties.

Sleep spindles are brief oscillatory events during non-rapid eye movement (NREM) sleep. Spindle density and synchronization properties are different in MEG versus EEG recordings in humans and also vary with learning performance, suggesting spindle involvement in memory consolidation. Here, using computational models, we identified network mechanisms that may explain differences in spindle properties across cortical structures. First, we report that differences in spindle occurrence between MEG and EEG data may arise from the contrasting properties of the core and matrix thalamocortical systems. The matrix system, projecting superficially, has wider thalamocortical fanout compared to the core system, which projects to middle layers, and requires the recruitment of a larger population of neurons to initiate a spindle. This property was sufficient to explain lower spindle density and higher spatial synchrony of spindles in the superficial cortical layers, as observed in the EEG signal. In contrast, spindles in the core system occurred more frequently but less synchronously, as observed in the MEG recordings. Furthermore, consistent with human recordings, in the model, spindles occurred independently in the core system but the matrix system spindles commonly co-occurred with core spindles. We also found that the intracortical excitatory connections from layer III/IV to layer V promote spindle propagation from the core to the matrix system, leading to widespread spindle activity. Our study predicts that plasticity of intra- and inter-cortical connectivity can potentially be a mechanism for increased spindle density as has been observed during learning.

Alcohol Hits You When It Is Hard: Intoxication, Task Difficulty, and Theta Brain Oscillations.

BACKGROUND: Alcohol intoxication is known to impair decision making in a variety of situations. Previous neuroimaging evidence suggests that the neurofunctional system subserving controlled processing is especially vulnerable to alcohol in conflict-evoking tasks. The present study investigated the effects of moderate alcohol intoxication on the spatiotemporal neural dynamics of event-related total theta (4 to 7 Hz) power as a function of task difficulty. METHODS: Two variants of the Simon task manipulated incongruity via simple spatial stimulus-response mismatch and, in a more difficult version, by combining spatial and semantic interference. Healthy social drinkers participated in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. Whole-head magnetoencephalography (MEG) signals were acquired and event-related total theta power was calculated on each trial with Morlet wavelets. MEG sources were estimated using anatomically constrained, noise-normalized, spectral dynamic statistical parametric mapping. RESULTS: Longer reaction times and lower accuracy confirmed the difficulty manipulation. Response conflict (incongruity) increased and alcohol intoxication decreased event-related theta power overall during both tasks bilaterally in the medial and ventrolateral prefrontal cortices. However, alcohol-induced theta suppression was selective for conflict only in the more difficult task which engaged the dorsal anterior cingulate (dAC) and anterior inferolateral prefrontal cortices. Theta power correlated negatively with drinking levels and disinhibition, suggesting that cognitive control is susceptible in more impulsive individuals with higher alcohol intake. CONCLUSIONS: The spatiotemporal theta profile across the 2 tasks supports the concept of a rostrocaudal activity gradient in the medial prefrontal cortex that is modulated by task difficulty, with the dAC as the key node in the network subserving cognitive control. Conflict-related theta power was selectively reduced by alcohol only under the more difficult task which is indicative of the alcohol-induced impairment of conflict monitoring and top-down regulation. Compromised executive control under alcohol may underlie a range of adverse effects including reduced competency in conflict-inducing or complex situations.

Distribution, Amplitude, Incidence, Co-Occurrence, and Propagation of Human K-Complexes in Focal Transcortical Recordings

K-complexes (KCs) are thought to play a key role in sleep homeostasis and memory consolidation; however, their generation and propagation remain unclear. The commonly held view from scalp EEG findings is that KCs are primarily generated in medial frontal cortex and propagate parietally, whereas an electrocorticography (ECOG) study suggested dorsolateral prefrontal generators and an absence of KCs in many areas. In order to resolve these differing views, we used unambiguously focal bipolar depth electrode recordings in patients with intractable epilepsy to investigate spatiotemporal relationships of human KCs. KCs were marked manually on each channel, and local generation was confirmed with decreased gamma power. In most cases (76%), KCs occurred in a single location, and rarely (1%) in all locations. However, if automatically detected KC-like phenomena were included, only 15% occurred in a single location, and 27% occurred in all recorded locations. Locally generated KCs were found in all sampled areas, including cingulate, ventral temporal, and occipital cortices. Surprisingly, KCs were smallest and occurred least frequently in anterior prefrontal channels. When KCs occur on two channels, their peak order is consistent in only 13% of cases, usually from prefrontal to lateral temporal. Overall, the anterior-posterior separation of electrode pairs explained only 2% of the variance in their latencies. KCs in stages 2 and 3 had similar characteristics. These results open a novel view where KCs overall are universal cortical phenomena, but each KC may variably involve small or large cortical regions and spread in variable directions, allowing flexible and heterogeneous contributions to sleep homeostasis and memory consolidation.

Synchronization of isolated downstates (K-complexes) may be caused by cortically-induced disruption of thalamic spindling.

Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise.

Spatio-temporal processing of words and nonwords: hemispheric laterality and acute alcohol intoxication.

This study examined neurofunctional correlates of reading by modulating semantic, lexical, and orthographic attributes of letter strings. It compared the spatio-temporal activity patterns elicited by real words (RW), pseudowords, orthographically regular, pronounceable nonwords (PN) that carry no meaning, and orthographically illegal, nonpronounceable nonwords (NN). A double-duty lexical decision paradigm instructed participants to detect RW while ignoring nonwords and to additionally respond to words that refer to animals (AW). Healthy social drinkers (N=22) participated in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. Whole-head MEG signals were analyzed with an anatomically-constrained MEG method. Simultaneously acquired ERPs confirm previous evidence. Spatio-temporal MEG estimates to RW and PN are consistent with the highly replicable left-lateralized ventral visual processing stream. However, the PN elicit weaker activity than other stimuli starting at ~230 ms and extending to the M400 (magnetic equivalent of N400) in the left lateral temporal area, indicating their reduced access to lexicosemantic stores. In contrast, the NN uniquely engage the right hemisphere during the M400. Increased demands on lexicosemantic access imposed by AW result in greater activity in the left temporal cortex starting at ~230 ms and persisting through the M400 and response preparation stages. Alcohol intoxication strongly attenuates early visual responses occipito-temporally overall. Subsequently, alcohol selectively affects the left prefrontal cortex as a function of orthographic and semantic dimensions, suggesting that it modulates the dynamics of the lexicosemantic processing in a top-down manner, by increasing difficulty of semantic retrieval.