Parallel and distributed encoding of speech across human auditory cortex.

Speech perception is thought to rely on a cortical feedforward serial transformation of acoustic into linguistic representations. Using intracranial recordings across the entire human auditory cortex, electrocortical stimulation, and surgical ablation, we show that cortical processing across areas is not consistent with a serial hierarchical organization. Instead, response latency and receptive field analyses demonstrate parallel and distinct information processing in the primary and nonprimary auditory cortices. This functional dissociation was also observed where stimulation of the primary auditory cortex evokes auditory hallucination but does not distort or interfere with speech perception. Opposite effects were observed during stimulation of nonprimary cortex in superior temporal gyrus. Ablation of the primary auditory cortex does not affect speech perception. These results establish a distributed functional organization of parallel information processing throughout the human auditory cortex and demonstrate an essential independent role for nonprimary auditory cortex in speech processing.

An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood.

Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by ß-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood.

Neuroscientific Evidence for Processing Without Awareness.

The extent to which we are affected by perceptual input of which we are unaware is widely debated. By measuring neural responses to sensory stimulation, neuroscientific data could complement behavioral results with valuable evidence. Here we review neuroscientific findings of processing of high-level information, as well as interactions with attention and memory. Although the results are mixed, we find initial support for processing object categories and words, possibly to the semantic level, as well as emotional expressions. Robust neural evidence for face individuation and integration of sentences or scenes is lacking. Attention affects the processing of stimuli that are not consciously perceived, and such stimuli may exogenously but not endogenously capture attention when relevant, and be maintained in memory over time. Sources of inconsistency in the literature include variability in control for awareness as well as individual differences, calling for future studies that adopt stricter measures of awareness and probe multiple processes within subjects.

Cross-regional coordination of activity in the human brain during autobiographical self-referential processing.

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANT→HPC/PMC→OFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past.

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

Propofol disrupts alpha dynamics in functionally distinct thalamocortical networks during loss of consciousness.

During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.

Spatiotemporally distributed frontotemporal networks for sentence reading.

Reading a sentence entails integrating the meanings of individual words to infer more complex, higher-order meaning. This highly rapid and complex human behavior is known to engage the inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) in the language-dominant hemisphere, yet whether there are distinct contributions of these regions to sentence reading is still unclear. To probe these neural spatiotemporal dynamics, we used direct intracranial recordings to measure neural activity while reading sentences, meaning-deficient Jabberwocky sentences, and lists of words or pseudowords. We isolated two functionally and spatiotemporally distinct frontotemporal networks, each sensitive to distinct aspects of word and sentence composition. The first distributed network engages the IFG and MTG, with IFG activity preceding MTG. Activity in this network ramps up over the duration of a sentence and is reduced or absent during Jabberwocky and word lists, implying its role in the derivation of sentence-level meaning. The second network engages the superior temporal gyrus and the IFG, with temporal responses leading those in frontal lobe, and shows greater activation for each word in a list than those in sentences, suggesting that sentential context enables greater efficiency in the lexical and/or phonological processing of individual words. These adjacent, yet spatiotemporally dissociable neural mechanisms for word- and sentence-level processes shed light on the richly layered semantic networks that enable us to fluently read. These results imply distributed, dynamic computation across the frontotemporal language network rather than a clear dichotomy between the contributions of frontal and temporal structures.

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.

Regional variability in intracerebral properties of NREM to REM sleep transitions in humans.

Transitions between wake and sleep states show a progressive pattern underpinned by local sleep regulation. In contrast, little evidence is available on non-rapid eye movement (NREM) to rapid eye movement (REM) sleep boundaries, considered as mainly reflecting subcortical regulation. Using polysomnography (PSG) combined with stereoelectroencephalography (SEEG) in humans undergoing epilepsy presurgical evaluation, we explored the dynamics of NREM-to-REM transitions. PSG was used to visually score transitions and identify REM sleep features. SEEG-based local transitions were determined automatically with a machine learning algorithm using features validated for automatic intra-cranial sleep scoring (10.5281/zenodo.7410501). We analyzed 2988 channel-transitions from 29 patients. The average transition time from all intracerebral channels to the first visually marked REM sleep epoch was 8 s ± 1 min 58 s, with a great heterogeneity between brain areas. Transitions were observed first in the lateral occipital cortex, preceding scalp transition by 1 min 57 s ± 2 min 14 s (d = -0.83), and close to the first sawtooth wave marker. Regions with late transitions were the inferior frontal and orbital gyri (1 min 1 s ± 2 min 1 s, d = 0.43, and 1 min 1 s ± 2 min 5 s, d = 0.43, after scalp transition). Intracranial transitions were earlier than scalp transitions as the night advanced (last sleep cycle, d = -0.81). We show a reproducible gradual pattern of REM sleep initiation, suggesting the involvement of cortical mechanisms of regulation. This provides clues for understanding oneiric experiences occurring at the NREM/REM boundary.

Intracerebral Dynamics of Sleep Arousals: A Combined Scalp-Intracranial EEG Study.

As an intrinsic component of sleep architecture, sleep arousals represent an intermediate state between sleep and wakefulness and are important for sleep-wake regulation. They are defined in an all-or-none manner, whereas they actually present a wide range of scalp-electroencephalography (EEG) activity patterns. It is poorly understood how these arousals differ in their mechanisms. Stereo-EEG (SEEG) provides the unique opportunity to record intracranial activities in superficial and deep structures in humans. Using combined polysomnography and SEEG, we quantitatively categorized arousals during nonrapid eye movement sleep into slow wave (SW) and non-SW arousals based on whether they co-occurred with a scalp-EEG SW event. We then investigated their intracranial correlates in up to 26 brain regions from 26 patients (12 females). Across both arousal types, intracranial theta, alpha, sigma, and beta activities increased in up to 25 regions (p < 0.05; d = 0.06-0.63), while gamma and high-frequency (HF) activities decreased in up to 18 regions across the five brain lobes (p < 0.05; d = 0.06-0.44). Intracranial delta power widely increased across five lobes during SW arousals (p < 0.05 in 22 regions; d = 0.10-0.39), while it widely decreased during non-SW arousals (p < 0.05 in 19 regions; d = 0.10-0.30). Despite these main patterns, unique activities were observed locally in some regions such as the hippocampus and middle cingulate cortex, indicating spatial heterogeneity of arousal responses. Our results suggest that non-SW arousals correspond to a higher level of brain activation than SW arousals. The decrease in HF activities could potentially explain the absence of awareness and recollection during arousals.

Theta-Alpha Connectivity in the Hippocampal-Entorhinal Circuit Predicts Working Memory Load.

Working memory (WM) maintenance relies on multiple brain regions and inter-regional communications. The hippocampus and entorhinal cortex (EC) are thought to support this operation. Besides, EC is the main gateway for information between the hippocampus and neocortex. However, the circuit-level mechanism of this interaction during WM maintenance remains unclear in humans. To address these questions, we recorded the intracranial electroencephalography from the hippocampus and EC while patients (N = 13, six females) performed WM tasks. We found that WM maintenance was accompanied by enhanced theta/alpha band (2-12 Hz) phase synchronization between the hippocampus to the EC. The Granger causality and phase slope index analyses consistently showed that WM maintenance was associated with theta/alpha band-coordinated unidirectional influence from the hippocampus to the EC. Besides, this unidirectional inter-regional communication increased with WM load and predicted WM load during memory maintenance. These findings demonstrate that WM maintenance in humans engages the hippocampal-entorhinal circuit, with the hippocampus influencing the EC in a load-dependent manner.

Spatiotemporal Dynamics of Successive Activations across the Human Brain during Simple Arithmetic Processing.

Previous neuroimaging studies have offered unique insights about the spatial organization of activations and deactivations across the brain; however, these were not powered to explore the exact timing of events at the subsecond scale combined with a precise anatomical source of information at the level of individual brains. As a result, we know little about the order of engagement across different brain regions during a given cognitive task. Using experimental arithmetic tasks as a prototype for human-unique symbolic processing, we recorded directly across 10,076 brain sites in 85 human subjects (52% female) using the intracranial electroencephalography. Our data revealed a remarkably distributed change of activity in almost half of the sampled sites. In each activated brain region, we found juxtaposed neuronal populations preferentially responsive to either the target or control conditions, arranged in an anatomically orderly manner. Notably, an orderly successive activation of a set of brain regions-anatomically consistent across subjects-was observed in individual brains. The temporal order of activations across these sites was replicable across subjects and trials. Moreover, the degree of functional connectivity between the sites decreased as a function of temporal distance between regions, suggesting that the information is partially leaked or transformed along the processing chain. Our study complements prior imaging studies by providing hitherto unknown information about the timing of events in the brain during arithmetic processing. Such findings can be a basis for developing mechanistic computational models of human-specific cognitive symbolic systems.

Intracranial Recordings of the Human Orbitofrontal Cortical Activity during Self-Referential Episodic and Valenced Self-Judgments.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.

Encoding of Predictive Associations in Human Prefrontal and Medial Temporal Neurons During Pavlovian Appetitive Conditioning.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities).

BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance imaging image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype, and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Integrating direct electrical brain stimulation with the human connectome.

Neurological and neurodevelopmental conditions are a major public health concern for which new therapies are urgently needed. The development of effective therapies relies on the precise mapping of the neural substrates causally involved in behaviour generation. Direct electrical stimulation (DES) performed during cognitive and neurological monitoring in awake surgery is currently considered the gold standard for the causal mapping of brain functions. However, DES is limited by the focal nature of the stimulation sites, hampering a real holistic exploration of human brain functions at the network level. We used 4137 DES points derived from 612 glioma patients in combination with human connectome data-resting-state functional MRI, n = 1000 and diffusion weighted imaging, n = 284-to provide a multimodal description of the causal macroscale functional networks subtending 12 distinct behavioural domains. To probe the validity of our procedure, we (i) compared the network topographies of healthy and clinical populations; (ii) tested the predictive capacity of DES-derived networks; (iii) quantified the coupling between structural and functional connectivity; and (iv) built a multivariate model able to quantify single subject deviations from a normative population. Lastly, we probed the translational potential of DES-derived functional networks by testing their specificity and sensitivity in identifying critical neuromodulation targets and neural substrates associated with postoperative language deficits. The combination of DES and human connectome data resulted in an average 29.4-fold increase in whole brain coverage compared to DES alone. DES-derived functional networks are predictive of future stimulation points (97.8% accuracy) and strongly supported by the anatomical connectivity of subcortical stimulations. We did not observe any significant topographical differences between the patients and the healthy population at both group and single subject level. Showcasing concrete clinical applications, we found that DES-derived functional networks overlap with effective neuromodulation targets across several functional domains, show a high degree of specificity when tested with the intracranial stimulation points of a different stimulation technique and can be used effectively to characterize postoperative behavioural deficits. The integration of DES with the human connectome fundamentally advances the quality of the functional mapping provided by DES or functional imaging alone. DES-derived functional networks can reliably predict future stimulation points, have a strong correspondence with the underlying white matter and can be used for patient specific functional mapping. Possible applications range from psychiatry and neurology to neuropsychology, neurosurgery and neurorehabilitation.

Default mode network electrophysiological dynamics and causal role in creative thinking.

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. The present study employs stereo-electroencephalography in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?

Despite advances in understanding the cellular and molecular processes underlying memory and cognition, and recent successful modulation of cognitive performance in brain disorders, the neurophysiological mechanisms remain underexplored. High frequency oscillations beyond the classic electroencephalogram spectrum have emerged as a potential neural correlate of fundamental cognitive processes. High frequency oscillations are detected in the human mesial temporal lobe and neocortical intracranial recordings spanning gamma/epsilon (60-150 Hz), ripple (80-250 Hz) and higher frequency ranges. Separate from other non-oscillatory activities, these brief electrophysiological oscillations of distinct duration, frequency and amplitude are thought to be generated by coordinated spiking of neuronal ensembles within volumes as small as a single cortical column. Although the exact origins, mechanisms, and physiological roles in health and disease remain elusive, they have been associated with human memory consolidation and cognitive processing. Recent studies suggest their involvement in encoding and recall of episodic memory with a possible role in the formation and reactivation of memory traces. High frequency oscillations are detected during encoding, throughout maintenance, and right before recall of remembered items, meeting a basic definition for an engram activity. The temporal coordination of high frequency oscillations reactivated across cortical and subcortical neural networks is ideally suited for integrating multimodal memory representations, which can be replayed and consolidated during states of wakefulness and sleep. High frequency oscillations have been shown to reflect coordinated bursts of neuronal assembly firing and offer a promising substrate for tracking and modulation of the hypothetical electrophysiological engram.

Epileptic activity on foramen ovale electrodes is associated with sleep and tau pathology in Alzheimer's disease.

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-ß and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease (AD). However, a bidirectional intertwining relation between sleep and neuronal hyperexcitability might modulate the effects of AD pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography (PSG) recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of AD and in two patients with mild and moderate dementia due to AD, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori defined volumes of interest (VOIs). Linear mixed effects models were used to study associations between interictal epileptiform discharges (IEDs), PSG parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥ 95% of IEDs were not visible on scalp EEG. In one patient two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different VOIs, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and N2 (81/h), followed by N1 (33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent (REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)), and not associated with the arousal index (P = 0.317), apnea-hypopnea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in AD.