Thalamic Roles in Conscious Perception Revealed by Low-Intensity Focused Ultrasound Neuromodulation.

The neural basis of conscious perception remains incompletely understood. While cortical mechanisms of conscious content have been extensively investigated, the role of subcortical structures, including the thalamus, remains less explored. We aim to elucidate the causal contributions of different thalamic regions to conscious perception using transcranial low-intensity focused ultrasound (LIFU) neuromodulation. We hypothesize that modulating different thalamic regions would result in distinct perceptual outcomes. We apply LIFU in human volunteers to investigate region-specific and sonication parameter-dependent effects. We target anterior (transmodal-dominant) and posterior (unimodal-dominant) thalamic regions, further divided into ventral and dorsal regions, while participants perform a near-threshold visual perception task. Task performance is evaluated using Signal Detection Theory metrics. We find that the high duty cycle stimulation of the ventral anterior thalamus enhanced object recognition sensitivity. We also observe a general (i.e., region-independent) effect of LIFU on decision bias (i.e., a tendency toward a particular response) and object categorization accuracy. Specifically, high duty cycle stimulation decreases categorization accuracy, whereas low duty cycle shifts decision bias towards a more conservative stance. In conclusion, our results provide causal insight into the functional organization of the thalamus in shaping human visual experience and highlight the unique role of the transmodal-dominant ventral anterior thalamus.

Measuring the dynamic balance of integration and segregation underlying consciousness, anesthesia, and sleep in humans.

Consciousness requires a dynamic balance of integration and segregation in brain networks. We report an fMRI-based metric, the integration-segregation difference (ISD), which captures two key network properties: network efficiency (integration) and clustering (segregation). With this metric, we quantify brain state transitions from conscious wakefulness to unresponsiveness induced by the anesthetic propofol. The observed changes in ISD suggest a profound shift towards the segregation of brain networks during anesthesia. A common unimodal-transmodal sequence of disintegration and reintegration occurs in brain networks during, respectively, loss and return of responsiveness. Machine learning models using integration and segregation data accurately identify awake vs. unresponsive states and their transitions. Metastability (dynamic recurrence of non-equilibrium transient states) is more effectively explained by integration, while complexity (diversity of neural activity) is more closely linked with segregation. A parallel analysis of sleep states produces similar findings. Our results demonstrate that the ISD reliably indexes states of consciousness.

Propofol disrupts the functional core-matrix architecture of the thalamus in humans.

Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. Here we show a significant shift in this geometry during deep sedation, marked by a transmodal-deficient geometry. This alteration is closely linked to the spatial variations in the matrix cell composition within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core-matrix functional architecture in understanding the neural mechanisms of states of consciousness.

Classifying Unconscious, Psychedelic, and Neuropsychiatric Brain States with Functional Connectivity, Graph Theory, and Cortical Gradient Analysis.

Accurate and generalizable classification of brain states is essential for understanding their neural underpinnings and improving clinical diagnostics. Traditionally, functional connectivity patterns and graph-theoretic metrics have been utilized. However, cortical gradient features, which reflect global brain organization, offer a complementary approach. We hypothesized that a machine learning model integrating these three feature sets would effectively discriminate between baseline and atypical brain states across a wide spectrum of conditions, even though the underlying neural mechanisms vary. To test this, we extracted features from brain states associated with three meta-conditions including unconsciousness (NREM2 sleep, propofol deep sedation, and propofol general anesthesia), psychedelic states induced by hallucinogens (subanesthetic ketamine, lysergic acid diethylamide, and nitrous oxide), and neuropsychiatric disorders (attention-deficit hyperactivity disorder, bipolar disorder, and schizophrenia). We used support vector machine with nested cross-validation to construct our models. The soft voting ensemble model marked the average balanced accuracy (average of specificity and sensitivity) of 79% (62-98% across all conditions), outperforming individual base models (70-76%). Notably, our models exhibited varying degrees of transferability across different datasets, with performance being dependent on the specific brain states and feature sets used. Feature importance analysis across meta-conditions suggests that the underlying neural mechanisms vary significantly, necessitating tailored approaches for accurate classification of specific brain states. This finding underscores the value of our feature-integrated ensemble models, which leverage the strengths of multiple feature types to achieve robust performance across a broader range of brain states. While our approach offers valuable insights into the neural signatures of different brain states, future work is needed to develop and validate even more generalizable models that can accurately classify brain states across a wider array of conditions.

Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex.

Introduction: Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate anesthetic state-dependent effective connectivity of neurons in rat visual cortex in vivo. Methods: Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. Results: Microstimulation caused early (<10 ms) increase followed by prolonged (11-100 ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1 mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. The number of network motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. Conclusion: The results illuminate the impact of anesthesia on functional integrity of local cortical circuits affecting the state of consciousness.

Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex.

Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate the state-dependent effective connectivity of neurons in rat visual cortex in vivo. Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Microstimulation caused early (<10ms) increase followed by prolonged (11-100ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. The number of motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. The results illuminate the impact of anesthesia on functional integrity of local circuits affecting the state of consciousness.

Measuring the dynamic balance of integration and segregation underlying consciousness, anesthesia, and sleep.

Consciousness requires a dynamic balance of integration and segregation in functional brain networks. An optimal integration-segregation balance depends on two key aspects of functional connectivity: global efficiency (i.e., integration) and clustering (i.e., segregation). We developed a new fMRI-based measure, termed the integration-segregation difference (ISD), which captures both aspects. We used this metric to quantify changes in brain state from conscious wakefulness to loss of responsiveness induced by the anesthetic propofol. The observed changes in ISD suggest a profound shift to segregation in both whole brain and all brain subnetworks during anesthesia. Moreover, brain networks displayed similar sequences of disintegration and subsequent reintegration during, respectively, loss and return of responsiveness. Random forest machine learning models, trained with the integration and segregation of brain networks, identified the awake vs. unresponsive states and their transitions with accuracy up to 93%. We found that metastability (i.e., the dynamic recurrence of non-equilibrium transient states) is more effectively explained by integration, while complexity (i.e., diversity and intricacy of neural activity) is more closely linked with segregation. The analysis of a sleep dataset revealed similar findings. Our results demonstrate that the integration-segregation balance is a useful index that can differentiate among various conscious and unconscious states.

Propofol Disrupts the Functional Core-Matrix Architecture of the Thalamus in Humans.

Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. We observed a significant shift in this geometry during unconsciousness, marked by the dominance of unimodal over transmodal geometry. This alteration was closely linked to the spatial variations in the density of matrix cells within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core-matrix functional architecture in understanding the neural mechanisms of states of consciousness.

The neural correlates of arousal: Ventral posterolateral nucleus-global transient co-activation.

Arousal and awareness are two components of consciousness whose neural mechanisms remain unclear. Spontaneous peaks of global (brain-wide) blood-oxygenation-level-dependent (BOLD) signal have been found to be sensitive to changes in arousal. By contrasting BOLD signals at different arousal levels, we find decreased activation of the ventral posterolateral nucleus (VPL) during transient peaks in the global signal in low arousal and awareness states (non-rapid eye movement sleep and anesthesia) compared to wakefulness and in eyes-closed compared to eyes-open conditions in healthy awake individuals. Intriguingly, VPL-global co-activation remains high in patients with unresponsive wakefulness syndrome (UWS), who exhibit high arousal without awareness, while it reduces in rapid eye movement sleep, a state characterized by low arousal but high awareness. Furthermore, lower co-activation is found in individuals during N3 sleep compared to patients with UWS. These results demonstrate that co-activation of VPL and global activity is critical to arousal but not to awareness.

Psychedelic concentrations of nitrous oxide reduce functional differentiation in frontoparietal and somatomotor cortical networks.

Despite the longstanding use of nitrous oxide and descriptions of its psychological effects more than a century ago, there is a paucity of neurobiological investigation of associated psychedelic experiences. We measure the brain's functional geometry (through analysis of cortical gradients) and temporal dynamics (through analysis of co-activation patterns) using human resting-state functional magnetic resonance imaging data acquired before and during administration of 35% nitrous oxide. Both analyses demonstrate that nitrous oxide reduces functional differentiation in frontoparietal and somatomotor networks. Importantly, the subjective psychedelic experience induced by nitrous oxide is inversely correlated with the degree of functional differentiation. Thus, like classical psychedelics acting on serotonin receptors, nitrous oxide flattens the functional geometry of the cortex and disrupts temporal dynamics in association with psychoactive effects.

Theoretical Neurobiology of Consciousness Applied to Human Cerebral Organoids.

Organoids and specifically human cerebral organoids (HCOs) are one of the most relevant novelties in the field of biomedical research. Grown either from embryonic or induced pluripotent stem cells, HCOs can be used as in vitro three-dimensional models, mimicking the developmental process and organization of the developing human brain. Based on that, and despite their current limitations, it cannot be assumed that they will never at any stage of development manifest some rudimentary form of consciousness. In the absence of behavioral indicators of consciousness, the theoretical neurobiology of consciousness being applied to unresponsive brain-injured patients can be considered with respect to HCOs. In clinical neurology, it is difficult to discern a capacity for consciousness in unresponsive brain-injured patients who provide no behavioral indicators of consciousness. In such scenarios, a validated neurobiological theory of consciousness, which tells us what the neural mechanisms of consciousness are, could be used to identify a capacity for consciousness. Like the unresponsive patients that provide a diagnostic difficulty for neurologists, HCOs provide no behavioral indicators of consciousness. Therefore, this article discusses how three prominent neurobiological theories of consciousness apply to human cerebral organoids. From the perspective of the Temporal Circuit Hypothesis, the Global Neuronal Workspace Theory, and the Integrated Information Theory, we discuss what neuronal structures and functions might indicate that cerebral organoids have a neurobiological capacity to be conscious.

Spontaneous and Visual Stimulation Evoked Firing Sequences Are Distinct Under Desflurane Anesthesia.

Recurring spike sequences are thought to underlie cortical computations and may be essential for information processing in the conscious state. How anesthesia at graded levels may influence spontaneous and stimulus-related spike sequences in visual cortex has not been fully elucidated. We recorded extracellular single-unit activity in the rat primary visual cortex in vivo during wakefulness and three levels of anesthesia produced by desflurane. The latencies of spike sequences within 0-200 ms from the onset of spontaneous UP states and visual flash-evoked responses were compared. During wakefulness, spike latency patterns linked to the local field potential theta cycle were similar to stimulus-evoked patterns. Under desflurane anesthesia, spontaneous UP state sequences differed from flash-evoked sequences due to the recruitment of low-firing excitatory neurons to the UP state. Flash-evoked spike sequences showed higher reliability and longer latency when stimuli were applied during DOWN states compared to UP states. At deeper levels, desflurane altered both UP state and flash-evoked spike sequences by selectively suppressing inhibitory neuron firing. The results reveal desflurane-induced complex changes in cortical firing sequences that may influence visual information processing.

Arousal system stimulation and anesthetic state alter visuoparietal connectivity.

Cortical information processing is under the precise control of the ascending arousal system (AAS). Anesthesia suppresses cortical arousal that can be mitigated by exogenous stimulation of the AAS. The question remains to what extent cortical information processing is regained by AAS stimulation. We investigate the effect of electrical stimulation of the nucleus Pontis Oralis (PnO), a distinct source of ascending AAS projections, on cortical functional connectivity (FC) and information storage at mild, moderate, and deep anesthesia. Local field potentials (LFPs) recorded previously in the secondary visual cortex (V2) and the adjacent parietal association cortex (PtA) in chronically instrumented unrestrained rats. We hypothesized that PnO stimulation would induce electrocortical arousal accompanied by enhanced FC and active information storage (AIS) implying improved information processing. In fact, stimulation reduced FC in slow oscillations (0.3-2.5 Hz) at low anesthetic level and increased FC at high anesthetic level. These effects were augmented following stimulation suggesting stimulus-induced plasticity. The observed opposite stimulation-anesthetic impact was less clear in the γ-band activity (30-70 Hz). In addition, FC in slow oscillations was more sensitive to stimulation and anesthetic level than FC in γ-band activity which exhibited a rather constant spatial FC structure that was symmetric between specific, topographically related sites in V2 and PtA. Invariant networks were defined as a set of strongly connected electrode channels, which were invariant to experimental conditions. In invariant networks, stimulation decreased AIS and increasing anesthetic level increased AIS. Conversely, in non-invariant (complement) networks, stimulation did not affect AIS at low anesthetic level but increased it at high anesthetic level. The results suggest that arousal stimulation alters cortical FC and information storage as a function of anesthetic level with a prolonged effect beyond the duration of stimulation. The findings help better understand how the arousal system may influence information processing in cortical networks at different levels of anesthesia.

Classical and non-classical psychedelic drugs induce common network changes in human cortex.

The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical "hot zone," posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.

Microstate analyses as an indicator of anesthesia-induced unconsciousness.

OBJECTIVE: The objective of this study was to identify differences in electroencephalographic microstate topographies across three perioperative phases: anesthetic pre-induction, surgical anesthesia, and post-anesthesia care unit (PACU) admission. METHODS: Whole-scalp 16-channel electroencephalographic recordings were taken throughout the perioperative period on n = 22 adult, non-cardiac surgical patients. RESULTS: Several differences between perioperative periods were identified. Most notably, during surgical anesthesia, patients demonstrated increased mean duration and, consequently, a reduction in the occurrence of microstates when compared to both preoperative baseline and PACU admission. We also observed the presence of microstate F with propofol anesthesia during surgery, which had been previously identified with propofol infusion in laboratory settings using human volunteers. Finally, we observed inverse age effects with mean occurrence and duration of microstates, particularly during PACU recovery. CONCLUSIONS: Microstate duration is significantly increased during surgery compared to both pre-induction and PACU recovery. These data suggest that microstate topographies may be useful in monitoring anesthetic depth. SIGNIFICANCE: This work highlights the potential for microstate analysis in the perioperative setting. We identified distinct topographical signatures across perioperative periods and with increasing age, which is predictive of post-operative delirium.

Functional geometry of the cortex encodes dimensions of consciousness.

Consciousness is a multidimensional phenomenon, but key dimensions such as awareness and wakefulness have been described conceptually rather than neurobiologically. We hypothesize that dimensions of consciousness are encoded in multiple neurofunctional dimensions of the brain. We analyze cortical gradients, which are continua of the brain's overarching functional geometry, to characterize these neurofunctional dimensions. We demonstrate that disruptions of human consciousness - due to pharmacological, neuropathological, or psychiatric causes - are associated with a degradation of one or more of the major cortical gradients depending on the state. Network-specific reconfigurations within the multidimensional cortical gradient space are associated with behavioral unresponsiveness of various etiologies, and these spatial reconfigurations correlate with a temporal disruption of structured transitions of dynamic brain states. In this work, we therefore provide a unifying neurofunctional framework for multiple dimensions of human consciousness in both health and disease.

Modeling cortical synaptic effects of anesthesia and their cholinergic reversal.

General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common anesthetics induces reduction in synaptic excitation while promoting synaptic inhibition. Exogenous modulation of the anesthetics' synaptic effects can help determine the neuronal pathways involved in anesthesia. For example, both animal and human studies have shown that exogenously induced increases in acetylcholine in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. However, the underlying mechanisms of anesthesia reversal at the cellular level have not been investigated. Here we apply a computational model of a network of excitatory and inhibitory neurons to simulate the network-wide effects of anesthesia, due to changes in synaptic inhibition and excitation, and their reversal by cholinergic activation through muscarinic receptors. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts the reversal of anesthetic suppression of neurons' spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model predicts a specific neuronal mechanism for the cholinergic reversal of anesthesia consistent with experimental behavioral observations.

Anterior precuneus related to the recovery of consciousness.

The neural mechanism that enables the recovery of consciousness in patients with unresponsive wakefulness syndrome (UWS) remains unclear. The aim of the current study is to characterize the cortical hub regions related to the recovery of consciousness. In the current fMRI study, voxel-wise degree centrality analysis was adopted to identify the cortical hubs related to the recovery of consciousness, for which a total of 27 UWS patients were recruited, including 13 patients who emerged from UWS (UWS-E), and 14 patients who remained in UWS (UWS-R) at least three months after the experiment performance. Furthermore, other recoverable unconscious states were adopted as validation groups, including three independent N3 sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively). Spatial similarity of the hub characteristic with the validation groups between the UWS-E and UWS-R was compared using the dice coefficient. Finally, with the cortical regions persistently shown as hubs across UWS-E and validation states, functional connectivity analysis was further performed to explore the connectivity patterns underlying the recovery of consciousness. The results identified four cortical hubs in the UWS-E, which showed significantly higher degree centrality for UWS-E than UWS-R, including the anterior precuneus, left inferior parietal lobule, left inferior frontal gyrus, and left middle frontal gyrus, of which the degree centrality value also positively correlated with the patients' Glasgow Outcome Scale (GOS) score that assessed global brain functioning outcome after a brain injury. Furthermore, the anterior precuneus was found with significantly higher similarity of hub characteristics as well as functional connectivity patterns between UWS-E and the validation groups. The results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs in the recoverable unconscious states, especially the anterior precuneus. The identified cortical hub regions could serve as potential treatment targets for patients with UWS.

Network Model With Reduced Metabolic Rate Predicts Spatial Synchrony of Neuronal Activity.

In a cerebral hypometabolic state, cortical neurons exhibit slow synchronous oscillatory activity with sparse firing. How such a synchronization spatially organizes as the cerebral metabolic rate decreases have not been systemically investigated. We developed a network model of leaky integrate-and-fire neurons with an additional dependency on ATP dynamics. Neurons were scattered in a 2D space, and their population activity patterns at varying ATP levels were simulated. The model predicted a decrease in firing activity as the ATP production rate was lowered. Under hypometabolic conditions, an oscillatory firing pattern, that is, an ON-OFF cycle arose through a failure of sustainable firing due to reduced excitatory positive feedback and rebound firing after the slow recovery of ATP concentration. The firing rate oscillation of distant neurons developed at first asynchronously that changed into burst suppression and global synchronization as ATP production further decreased. These changes resembled the experimental data obtained from anesthetized rats, as an example of a metabolically suppressed brain. Together, this study substantiates a novel biophysical mechanism of neuronal network synchronization under limited energy supply conditions.