General Anesthesia Decouples Cortical Pyramidal Neurons.

The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.

Propofol-mediated loss of consciousness disrupts predictive routing and local field phase modulation of neural activity.

Predictive coding is a fundamental function of the cortex. The predictive routing model proposes a neurophysiological implementation for predictive coding. Predictions are fed back from the deep-layer cortex via alpha/beta (8 to 30 Hz) oscillations. They inhibit the gamma (40 to 100 Hz) and spiking that feed sensory inputs forward. Unpredicted inputs arrive in circuits unprepared by alpha/beta, resulting in enhanced gamma and spiking. To test the predictive routing model and its role in consciousness, we collected data from intracranial recordings of macaque monkeys during passive presentation of auditory oddballs before and after propofol-mediated loss of consciousness (LOC). In line with the predictive routing model, alpha/beta oscillations in the awake state served to inhibit the processing of predictable stimuli. Propofol-mediated LOC eliminated alpha/beta modulation by a predictable stimulus in the sensory cortex and alpha/beta coherence between sensory and frontal areas. As a result, oddball stimuli evoked enhanced gamma power, late period (>200 ms from stimulus onset) spiking, and superficial layer sinks in the sensory cortex. LOC also resulted in diminished decodability of pattern-level prediction error signals in the higher-order cortex. Therefore, the auditory cortex was in a disinhibited state during propofol-mediated LOC. However, despite these enhanced feedforward responses in the auditory cortex, there was a loss of differential spiking to oddballs in the higher-order cortex. This may be a consequence of a loss of within-area and interareal spike-field coupling in the alpha/beta and gamma frequency bands. These results provide strong constraints for current theories of consciousness.

Functional near-infrared spectroscopy: A novel tool for detecting consciousness after acute severe brain injury.

Recent advancements in functional neuroimaging have demonstrated that some unresponsive patients in the intensive care unit retain a level of consciousness that is inconsistent with their behavioral diagnosis of awareness. Functional near-infrared spectroscopy (fNIRS) is a portable optical neuroimaging method that can be used to measure neural activity with good temporal and spatial resolution. However, the reliability of fNIRS for detecting the neural correlates of consciousness remains to be established. In a series of studies, we evaluated whether fNIRS can record sensory, perceptual, and command-driven neural processing in healthy participants and in behaviorally nonresponsive patients. At the individual healthy subject level, we demonstrate that fNIRS can detect commonly studied resting state networks, sensorimotor processing, speech-specific auditory processing, and volitional command-driven brain activity to a motor imagery task. We then tested fNIRS with three acutely brain injured patients and found that one could willfully modulate their brain activity when instructed to imagine playing a game of tennis-providing evidence of preserved consciousness despite no observable behavioral signs of awareness. The successful application of fNIRS for detecting preserved awareness among behaviorally nonresponsive patients highlights its potential as a valuable tool for uncovering hidden cognitive states in critical care settings.

The reach of reactivation: Effects of consciously triggered versus unconsciously triggered reactivation of associative memory.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

Interoceptive signals shape the earliest markers and neural pathway to awareness at the visual threshold.

Variations in interoceptive signals from the baroreceptors (BRs) across the cardiac and respiratory cycle can modulate cortical excitability and so affect awareness. It remains debated at what stages of processing they affect awareness-related event-related potentials (ERPs) in different sensory modalities. We investigated the influence of the cardiac (systole/diastole) and the respiratory (inhalation/exhalation) phase on awareness-related ERPs. Subjects discriminated visual threshold stimuli while their electroencephalogram, electrocardiogram, and respiration were simultaneously recorded. We compared ERPs and their intracranial generators for stimuli classified correctly with and without awareness as a function of the cardiac and respiratory phase. Cyclic variations of interoceptive signals from the BRs modulated both the earliest electrophysiological markers and the trajectory of brain activity when subjects became aware of the stimuli: an early sensory component (P1) was the earliest marker of awareness for low (diastole/inhalation) and a perceptual component (visual awareness negativity) for high (systole/exhalation) BR activity, indicating that BR signals interfere with the sensory processing of the visual input. Likewise, activity spread from the primary visceral cortex (posterior insula) to posterior parietal cortices during high and from associative interoceptive centers (anterior insula) to the prefrontal cortex during low BR activity. Consciousness is thereby resolved in cognitive/associative regions when BR is low and in perceptual centers when it is high. Our results suggest that cyclic fluctuations of BR signaling affect both the earliest markers of awareness and the brain processes underlying conscious awareness.

Changes in spatial self-consciousness elicit grid cell-like representation in the entorhinal cortex.

Grid cells in the entorhinal cortex (EC) encode an individual's location in space, integrating both environmental and multisensory bodily cues. Notably, body-derived signals are also primary signals for the sense of self. While studies have demonstrated that continuous application of visuo-tactile bodily stimuli can induce perceptual shifts in self-location, it remains unexplored whether these illusory changes suffice to trigger grid cell-like representation (GCLR) within the EC, and how this compares to GCLR during conventional virtual navigation. To address this, we systematically induced illusory drifts in self-location toward controlled directions using visuo-tactile bodily stimulation, while maintaining the subjects' visual viewpoint fixed (absent conventional virtual navigation). Subsequently, we evaluated the corresponding GCLR in the EC through functional MRI analysis. Our results reveal that illusory changes in perceived self-location (independent of changes in environmental navigation cues) can indeed evoke entorhinal GCLR, correlating in strength with the magnitude of perceived self-location, and characterized by similar grid orientation as during conventional virtual navigation in the same virtual room. These data demonstrate that the same grid-like representation is recruited when navigating based on environmental, mainly visual cues, or when experiencing illusory forward drifts in self-location, driven by perceptual multisensory bodily cues.

Human brain effects of DMT assessed via EEG-fMRI.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

Predictions and rewards affect decision-making but not subjective experience.

To survive, organisms constantly make decisions to avoid danger and maximize rewards in information-rich environments. As a result, decisions about sensory input are not only driven by sensory information but also by other factors, such as the expected rewards of a decision (known as the payoff matrix) or by information about temporal regularities in the environment (known as cognitive priors or predictions). However, it is unknown to what extent these different types of information affect subjective experience or whether they merely result in nonperceptual response criterion shifts. To investigate this question, we used three carefully matched manipulations that typically result in behavioral shifts in decision criteria: a visual illusion (Müller-Lyer condition), a punishment scheme (payoff condition), and a change in the ratio of relevant stimuli (base rate condition). To gauge shifts in subjective experience, we introduce a task in which participants not only make decisions about what they have just seen but are also asked to reproduce their experience of a target stimulus. Using Bayesian ordinal modeling, we show that each of these three manipulations affects the decision criterion as intended but that the visual illusion uniquely affects sensory experience as measured by reproduction. In a series of follow-up experiments, we use computational modeling to show that although the visual illusion results in a distinct drift-diffusion (DDM) parameter profile relative to nonsensory manipulations, reliance on DDM parameter estimates alone is not sufficient to ascertain whether a given manipulation is perceptual or nonperceptual.

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.

Unconscious Manipulation of Conceptual Representations with Decoded Neurofeedback Impacts Search Behavior.

The necessity of conscious awareness in human learning has been a long-standing topic in psychology and neuroscience. Previous research on non-conscious associative learning is limited by the low signal-to-noise ratio of the subliminal stimulus, and the evidence remains controversial, including failures to replicate. Using functional MRI decoded neurofeedback, we guided participants from both sexes to generate neural patterns akin to those observed when visually perceiving real-world entities (e.g., dogs). Importantly, participants remained unaware of the actual content represented by these patterns. We utilized an associative DecNef approach to imbue perceptual meaning (e.g., dogs) into Japanese hiragana characters that held no inherent meaning for our participants, bypassing a conscious link between the characters and the dogs concept. Despite their lack of awareness regarding the neurofeedback objective, participants successfully learned to activate the target perceptual representations in the bilateral fusiform. The behavioral significance of our training was evaluated in a visual search task. DecNef and control participants searched for dogs or scissors targets that were pre-cued by the hiragana used during DecNef training or by a control hiragana. The DecNef hiragana did not prime search for its associated target but, strikingly, participants were impaired at searching for the targeted perceptual category. Hence, conscious awareness may function to support higher-order associative learning. Meanwhile, lower-level forms of re-learning, modification, or plasticity in existing neural representations can occur unconsciously, with behavioral consequences outside the original training context. The work also provides an account of DecNef effects in terms of neural representational drift.

Astrocytes Modulate a Specific Paraventricular Thalamus→Prefrontal Cortex Projection to Enhance Consciousness Recovery from Anesthesia.

Current anesthetic theory is mostly based on neurons and/or neuronal circuits. A role for astrocytes also has been shown in promoting recovery from volatile anesthesia, while the exact modulatory mechanism and/or the molecular target in astrocytes is still unknown. In this study by animal models in male mice and electrophysiological recordings in vivo and in vitro, we found that activating astrocytes of the paraventricular thalamus (PVT) and/or knocking down PVT astrocytic Kir4.1 promoted the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of the PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVT GRM and PVT ChAT neurons. Patch-clamp recording results proved astrocytic Kir4.1-mediated modulation of sevoflurane on the PVT mainly worked on PVT ChAT neurons, which projected mainly to the mPFC. In summary, our findings support the novel conception that there is a specific PVT→prefrontal cortex projection involved in consciousness recovery from sevoflurane anesthesia, which is mediated by the inhibition of sevoflurane on PVT astrocytic Kir4.1 conductance.

Transient Attention Gates Access Consciousness: Coupling N2pc and P3 Latencies Using Dynamic Time Warping.

The N2pc and P3 event-related potentials (ERPs), used to index selective attention and access to working memory and conscious awareness, respectively, have been important tools in cognitive sciences. Although it is likely that these two components and the underlying cognitive processes are temporally and functionally linked, such links have not yet been convincingly demonstrated. Adopting a novel methodological approach based on dynamic time warping (DTW), we provide evidence that the N2pc and P3 ERP components are temporally linked. We analyzed data from an experiment where 23 participants (16 women) monitored bilateral rapid serial streams of letters and digits in order to report a target digit indicated by a shape cue, separately for trials with correct responses and trials where a temporally proximal distractor was reported instead (distractor intrusion). DTW analyses revealed that N2pc and P3 latencies were correlated in time, both when the target or a distractor was reported. Notably, this link was weaker on distractor intrusion trials. This N2pc-P3 association is discussed with respect to the relationship between attention and access consciousness. Our results demonstrate that our novel method provides a valuable approach for assessing temporal links between two cognitive processes and their underlying modulating factors. This method allows to establish links and their modulator for any two time-series across all domains of the field (general-purpose MATLAB functions and a Python module are provided alongside this paper).

Brain organoids, consciousness, ethics and moral status.

Advances in the field of human stem cells are often a source of public and ethical controversy. Researchers must frequently balance diverse societal perspectives on questions of morality with the pursuit of medical therapeutics and innovation. Recent developments in brain organoids make this challenge even more acute. Brain organoids are a new class of brain surrogate generated from human pluripotent stem cells (hPSCs). They have gained traction as a model for studying the intricacies of the human brain by using advancements in stem cell biology to recapitulate aspects of the developing human brain in vitro. However, recent observation of neural oscillations spontaneously emerging from these organoids raises the question of whether brain organoids are or could become conscious. At the same time, brain organoids offer a potentially unique opportunity to scientifically understand consciousness. To address these issues, experimental biologists, philosophers, and ethicists united to discuss the possibility of consciousness in human brain organoids and the consequent ethical and moral implications.

Limitation of life sustaining therapy in disorders of consciousness: ethics and practice.

Clinical conversations surrounding the continuation or limitation of life-sustaining therapies (LLST) are both challenging and tragically necessary for patients with disorders of consciousness (DoC) following severe brain injury. Divergent cultural, philosophical and religious perspectives contribute to vast heterogeneity in clinical approaches to LLST-as reflected in regional differences and inter-clinician variability. Here we provide an ethical analysis of factors that inform LLST decisions among patients with DoC. We begin by introducing the clinical and ethical challenge and clarifying the distinction between withdrawing and withholding life-sustaining therapy. We then describe relevant factors that influence LLST decision-making including diagnostic and prognostic uncertainty, perception of pain, defining a 'good' outcome, and the role of clinicians. In concluding sections, we explore global variation in LLST practices as they pertain to patients with DoC and examine the impact of cultural and religious perspectives on approaches to LLST. Understanding and respecting the cultural and religious perspectives of patients and surrogates is essential to protecting patient autonomy and advancing goal-concordant care during critical moments of medical decision-making involving patients with DoC.

Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Globus pallidus externus drives increase in network-wide alpha power with propofol-induced loss-of-consciousness in humans.

States of consciousness are likely mediated by multiple parallel yet interacting cortico-subcortical recurrent networks. Although the mesocircuit model has implicated the pallidocortical circuit as one such network, this circuit has not been extensively evaluated to identify network-level electrophysiological changes related to loss of consciousness (LOC). We characterize changes in the mesocircuit in awake versus propofol-induced LOC in humans by directly simultaneously recording from sensorimotor cortices (S1/M1) and globus pallidus interna and externa (GPi/GPe) in 12 patients with Parkinson disease undergoing deep brain stimulator implantation. Propofol-induced LOC is associated with increases in local power up to 20 Hz in GPi, 35 Hz in GPe, and 100 Hz in S1/M1. LOC is likewise marked by increased pallidocortical alpha synchrony across all nodes, with increased alpha/low beta Granger causal (GC) flow from GPe to all other nodes. In contrast, LOC is associated with decreased network-wide beta coupling and beta GC from M1 to the rest of the network. Results implicate an important and possibly central role of GPe in mediating LOC-related increases in alpha power, supporting a significant role of the GPe in modulating cortico-subcortical circuits for consciousness. Simultaneous LOC-related suppression of beta synchrony highlights that distinct oscillatory frequencies act independently, conveying unique network activity.

The influence of spatial and temporal attention on visual awareness-a behavioral and ERP study.

Whether attention is a prerequisite of perceptual awareness or an independent and dissociable process remains a matter of debate. Importantly, understanding the relation between attention and awareness is probably not possible without taking into account the fact that both are heterogeneous and multifaceted mechanisms. Therefore, the present study tested the impact on visual awareness of two attentional mechanisms proposed by the Posner model: temporal alerting and spatio-temporal orienting. Specifically, we evaluated the effects of attention on the perceptual level, by measuring objective and subjective awareness of a threshold-level stimulus; and on the neural level, by investigating how attention affects two postulated event-related potential correlates of awareness. We found that alerting and orienting mechanisms additively facilitate perceptual consciousness, with activation of the latter resulting in the most vivid awareness. Furthermore, we found that late positivity is unlikely to constitute a neural correlate of consciousness as its amplitude was modulated by both attentional mechanisms, but early visual awareness negativity was independent of the alerting and orienting mechanisms. In conclusion, our study reveals a nuanced relationship between attention and awareness; moreover, by investigating the effect of the alerting mechanism, this study provides insights into the role of temporal attention in perceptual consciousness.

Breathwork-induced psychedelic experiences modulate neural dynamics.

Breathwork is an understudied school of practices involving intentional respiratory modulation to induce an altered state of consciousness (ASC). We simultaneously investigate the phenomenological and neural dynamics of breathwork by combining Temporal Experience Tracing, a quantitative methodology that preserves the temporal dynamics of subjective experience, with low-density portable EEG devices. Fourteen novice participants completed a course of up to 28 breathwork sessions-of 20, 40, or 60 min-in 28 days, yielding a neurophenomenological dataset of 301 breathwork sessions. Using hypothesis-driven and data-driven approaches, we found that "psychedelic-like" subjective experiences were associated with increased neural Lempel-Ziv complexity during breathwork. Exploratory analyses showed that the aperiodic exponent of the power spectral density-but not oscillatory alpha power-yielded similar neurophenomenological associations. Non-linear neural features, like complexity and the aperiodic exponent, neurally map both a multidimensional data-driven composite of positive experiences, and hypothesis-driven aspects of psychedelic-like experience states such as high bliss.

Neural correlates of an illusionary sense of agency caused by virtual reality.

Sense of agency (SoA) is the sensation that self-actions lead to ensuing perceptual consequences. The prospective mechanism emphasizes that SoA arises from motor prediction and its comparison with actual action outcomes, while the reconstructive mechanism stresses that SoA emerges from retrospective causal processing about the action outcomes. Consistent with the prospective mechanism, motor planning regions were identified by neuroimaging studies using the temporal binding (TB) effect, a behavioral measure often linked to implicit SoA. Yet, TB also occurs during passive observation of another's action, lending support to the reconstructive mechanism, but its neural correlates remain unexplored. Here, we employed virtual reality (VR) to modulate such observation-based SoA and examined it with functional magnetic resonance imaging (fMRI). After manipulating an avatar hand in VR, participants passively observed an avatar's "action" and showed a significant increase in TB. The binding effect was associated with the right angular gyrus and inferior parietal lobule, which are critical nodes for inferential and agency processing. These results suggest that the experience of controlling an avatar may potentiate inferential processing within the right inferior parietal cortex and give rise to the illusionary SoA without voluntary action.

Intensive whole-brain 7T MRI case study of volitional control of brain activity in deep absorptive meditation states.

Jhanas are profound states of mind achieved through advanced meditation, offering valuable insights into the nature of consciousness and tools to enhance well-being. Yet, its neurophenomenology remains limited due to methodological difficulties and the rarity of advanced meditation practitioners. We conducted a highly exploratory study to investigate the neurophenomenology of jhanas in an intensively sampled adept meditator case study (4 hr 7T fMRI collected in 27 sessions) who performed jhana meditation and rated specific aspects of experience immediately thereafter. Linear mixed models and correlations were used to examine relations among brain activity and jhana phenomenology. We identified distinctive patterns of brain activity in specific cortical, subcortical, brainstem, and cerebellar regions associated with jhana. Furthermore, we observed correlations between brain activity and phenomenological qualities of attention, jhanic qualities, and narrative processing, highlighting the distinct nature of jhanas compared to non-meditative states. Our study presents the most rigorous evidence yet that jhana practice deconstructs consciousness, offering unique insights into consciousness and significant implications for mental health and well-being.