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.

Neurophysiology of Human Perceptual Decision-Making.

The discovery of neural signals that reflect the dynamics of perceptual decision formation has had a considerable impact. Not only do such signals enable detailed investigations of the neural implementation of the decision-making process but they also can expose key elements of the brain's decision algorithms. For a long time, such signals were only accessible through direct animal brain recordings, and progress in human neuroscience was hampered by the limitations of noninvasive recording techniques. However, recent methodological advances are increasingly enabling the study of human brain signals that finely trace the dynamics of the unfolding decision process. In this review, we highlight how human neurophysiological data are now being leveraged to furnish new insights into the multiple processing levels involved in forming decisions, to inform the construction and evaluation of mathematical models that can explain intra- and interindividual differences, and to examine how key ancillary processes interact with core decision circuits.

Information structure in Makhuwa: Electrophysiological evidence for a universal processing account.

There is evidence from both behavior and brain activity that the way information is structured, through the use of focus, can up-regulate processing of focused constituents, likely to give prominence to the relevant aspects of the input. This is hypothesized to be universal, regardless of the different ways in which languages encode focus. In order to test this universalist hypothesis, we need to go beyond the more familiar linguistic strategies for marking focus, such as by means of intonation or specific syntactic structures (e.g., it-clefts). Therefore, in this study, we examine Makhuwa-Enahara, a Bantu language spoken in northern Mozambique, which uniquely marks focus through verbal conjugation. The participants were presented with sentences that consisted of either a semantically anomalous constituent or a semantically nonanomalous constituent. Moreover, focus on this particular constituent could be either present or absent. We observed a consistent pattern: Focused information generated a more negative N400 response than the same information in nonfocus position. This demonstrates that regardless of how focus is marked, its consequence seems to result in an upregulation of processing of information that is in focus.

The time course of person perception from voices in the brain.

When listeners hear a voice, they rapidly form a complex first impression of who the person behind that voice might be. We characterize how these multivariate first impressions from voices emerge over time across different levels of abstraction using electroencephalography and representational similarity analysis. We find that for eight perceived physical (gender, age, and health), trait (attractiveness, dominance, and trustworthiness), and social characteristics (educatedness and professionalism), representations emerge early (~80 ms after stimulus onset), with voice acoustics contributing to those representations between ~100 ms and 400 ms. While impressions of person characteristics are highly correlated, we can find evidence for highly abstracted, independent representations of individual person characteristics. These abstracted representationse merge gradually over time. That is, representations of physical characteristics (age, gender) arise early (from ~120 ms), while representations of some trait and social characteristics emerge later (~360 ms onward). The findings align with recent theoretical models and shed light on the computations underpinning person perception from voices.

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.

Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner.

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye-movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling.

Hormonal basis of sex differences in anesthetic sensitivity.

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

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.

Confidence of probabilistic predictions modulates the cortical response to pain.

Pain typically evolves over time, and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the vertex potential: the more confident were participants about their predictions, the smaller the vertex potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning.

Distinct early and late neural mechanisms regulate feature-specific sensory adaptation in the human visual system.

A canonical feature of sensory systems is that they adapt to prolonged or repeated inputs, suggesting the brain encodes the temporal context in which stimuli are embedded. Sensory adaptation has been observed in the central nervous systems of many animal species, using techniques sensitive to a broad range of spatiotemporal scales of neural activity. Two competing models have been proposed to account for the phenomenon. One assumes that adaptation reflects reduced neuronal sensitivity to sensory inputs over time (the "fatigue" account); the other posits that adaptation arises due to increased neuronal selectivity (the "sharpening" account). To adjudicate between these accounts, we exploited the well-known "tilt aftereffect", which reflects adaptation to orientation information in visual stimuli. We recorded whole-brain activity with millisecond precision from human observers as they viewed oriented gratings before and after adaptation, and used inverted encoding modeling to characterize feature-specific neural responses. We found that both fatigue and sharpening mechanisms contribute to the tilt aftereffect, but that they operate at different points in the sensory processing cascade to produce qualitatively distinct outcomes. Specifically, fatigue operates during the initial stages of processing, consistent with tonic inhibition of feedforward responses, whereas sharpening occurs ~200 ms later, consistent with feedback or local recurrent activity. Our findings reconcile two major accounts of sensory adaptation, and reveal how this canonical process optimizes the detection of change in sensory inputs through efficient neural coding.

Activation of the nociceptin/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity.

Sleep/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake control and potential promise as a therapeutic target for the treatment of insomnia.

Causal evidence for a coordinated temporal interplay within the language network.

Recent neurobiological models on language suggest that auditory sentence comprehension is supported by a coordinated temporal interplay within a left-dominant brain network, including the posterior inferior frontal gyrus (pIFG), posterior superior temporal gyrus and sulcus (pSTG/STS), and angular gyrus (AG). Here, we probed the timing and causal relevance of the interplay between these regions by means of concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG). Our TMS-EEG experiments reveal region- and time-specific causal evidence for a bidirectional information flow from left pSTG/STS to left pIFG and back during auditory sentence processing. Adapting a condition-and-perturb approach, our findings further suggest that the left pSTG/STS can be supported by the left AG in a state-dependent manner.

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.

Architectural experience influences the processing of others' body expressions.

The interplay between space and cognition is a crucial issue in Neuroscience leading to the development of multiple research fields. However, the relationship between architectural space and the movement of the inhabitants and their interactions has been too often neglected, failing to provide a unifying view of architecture's capacity to modulate social cognition broadly. We bridge this gap by requesting participants to judge avatars' emotional expression (high vs. low arousal) at the end of their promenade inside high- or low-arousing architectures. Stimuli were presented in virtual reality to ensure a dynamic, naturalistic experience. High-density electroencephalography (EEG) was recorded to assess the neural responses to the avatar's presentation. Observing highly aroused avatars increased Late Positive Potentials (LPP), in line with previous evidence. Strikingly, 250 ms before the occurrence of the LPP, P200 amplitude increased due to the experience of low-arousing architectures, reflecting an early greater attention during the processing of body expressions. In addition, participants stared longer at the avatar's head and judged the observed posture as more arousing. Source localization highlighted a contribution of the dorsal premotor cortex to both P200 and LPP. In conclusion, the immersive and dynamic architectural experience modulates human social cognition. In addition, the motor system plays a role in processing architecture and body expressions suggesting that the space and social cognition interplay is rooted in overlapping neural substrates. This study demonstrates that the manipulation of mere architectural space is sufficient to influence human social cognition.

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.

Top-Down Task Goals Induce the Retrieval State.

Engaging the retrieval state (Tulving, 1983) impacts processing and behavior (Long and Kuhl, 2019, 2021; Smith et al., 2022), but the extent to which top-down factors-explicit instructions and goals-versus bottom-up factors-stimulus properties such as repetition and similarity-jointly or independently induce the retrieval state is unclear. Identifying the impact of bottom-up and top-down factors on retrieval state engagement is critical for understanding how control of task-relevant versus task-irrelevant brain states influence cognition. We conducted between-subjects recognition memory tasks on male and female human participants in which we varied test phase goals. We recorded scalp electroencephalography and used an independently validated mnemonic state classifier (Long, 2023) to measure retrieval state engagement as a function of top-down task goals (recognize old vs detect new items) and bottom-up stimulus repetition (hits vs correct rejections (CRs)). We find that whereas the retrieval state is engaged for hits regardless of top-down goals, the retrieval state is only engaged during CRs when the top-down goal is to recognize old items. Furthermore, retrieval state engagement is greater for low compared to high confidence hits when the task goal is to recognize old items. Together, these results suggest that top-down demands to recognize old items induce the retrieval state independent from bottom-up factors, potentially reflecting the recruitment of internal attention to enable access of a stored representation.

Isolating Neural Signatures of Conscious Speech Perception with a No-Report Sine-Wave Speech Paradigm.

Identifying neural correlates of conscious perception is a fundamental endeavor of cognitive neuroscience. Most studies so far have focused on visual awareness along with trial-by-trial reports of task-relevant stimuli, which can confound neural measures of perceptual awareness with postperceptual processing. Here, we used a three-phase sine-wave speech paradigm that dissociated between conscious speech perception and task relevance while recording EEG in humans of both sexes. Compared with tokens perceived as noise, physically identical sine-wave speech tokens that were perceived as speech elicited a left-lateralized, near-vertex negativity, which we interpret as a phonological version of a perceptual awareness negativity. This response appeared between 200 and 300 ms after token onset and was not present for frequency-flipped control tokens that were never perceived as speech. In contrast, the P3b elicited by task-irrelevant tokens did not significantly differ when the tokens were perceived as speech versus noise and was only enhanced for tokens that were both perceived as speech and relevant to the task. Our results extend the findings from previous studies on visual awareness and speech perception and suggest that correlates of conscious perception, across types of conscious content, are most likely to be found in midlatency negative-going brain responses in content-specific sensory areas.

Development of the Alpha Rhythm Is Linked to Visual White Matter Pathways and Visual Detection Performance.

Alpha is the strongest electrophysiological rhythm in awake humans at rest. Despite its predominance in the EEG signal, large variations can be observed in alpha properties during development, with an increase in alpha frequency over childhood and adulthood. Here, we tested the hypothesis that these changes in alpha rhythm are related to the maturation of visual white matter pathways. We capitalized on a large diffusion MRI (dMRI)-EEG dataset (dMRI n = 2,747, EEG n = 2,561) of children and adolescents of either sex (age range, 5-21 years old) and showed that maturation of the optic radiation specifically accounts for developmental changes of alpha frequency. Behavioral analyses also confirmed that variations of alpha frequency are related to maturational changes in visual perception. The present findings demonstrate the close link between developmental variations in white matter tissue properties, electrophysiological responses, and behavior.

Decoding Remapped Spatial Information in the Peri-Saccadic Period.

It has been suggested that, prior to a saccade, visual neurons predictively respond to stimuli that will fall in their receptive fields after completion of the saccade. This saccadic remapping process is thought to compensate for the shift of the visual world across the retina caused by eye movements. To map the timing of this predictive process in the brain, we recorded neural activity using electroencephalography during a saccade task. Human participants (male and female) made saccades between two fixation points while covertly attending to oriented gratings briefly presented at various locations on the screen. Data recorded during trials in which participants maintained fixation were used to train classifiers on stimuli in different positions. Subsequently, data collected during saccade trials were used to test for the presence of remapped stimulus information at the post-saccadic retinotopic location in the peri-saccadic period, providing unique insight into when remapped information becomes available. We found that the stimulus could be decoded at the remapped location ∼180 ms post-stimulus onset, but only when the stimulus was presented 100-200 ms before saccade onset. Within this range, we found that the timing of remapping was dictated by stimulus onset rather than saccade onset. We conclude that presenting the stimulus immediately before the saccade allows for optimal integration of the corollary discharge signal with the incoming peripheral visual information, resulting in a remapping of activation to the relevant post-saccadic retinotopic neurons.

Computation on Demand: Action-Specific Representations of Visual Task Features Arise during Distinct Movement Phases.

The intention to act influences the computations of various task-relevant features. However, little is known about the time course of these computations. Furthermore, it is commonly held that these computations are governed by conjunctive neural representations of the features. But, support for this view comes from paradigms arbitrarily combining task features and affordances, thus requiring representations in working memory. Therefore, the present study used electroencephalography and a well-rehearsed task with features that afford minimal working memory representations to investigate the temporal evolution of feature representations and their potential integration in the brain. Female and male human participants grasped objects or touched them with a knuckle. Objects had different shapes and were made of heavy or light materials with shape and weight being relevant for grasping, not for "knuckling." Using multivariate analysis showed that representations of object shape were similar for grasping and knuckling. However, only for grasping did early shape representations reactivate at later phases of grasp planning, suggesting that sensorimotor control signals feed back to the early visual cortex. Grasp-specific representations of material/weight only arose during grasp execution after object contact during the load phase. A trend for integrated representations of shape and material also became grasp-specific but only briefly during the movement onset. These results suggest that the brain generates action-specific representations of relevant features as required for the different subcomponents of its action computations. Our results argue against the view that goal-directed actions inevitably join all features of a task into a sustained and unified neural representation.