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IntroductionFiring rate (FR) and population coupling (PC) are intrinsic properties of cortical neurons. Neurons with different FR and PC have diverse excitability to stimulation, tuning curve, and synaptic plasticity. Therefore, investigation of the effect of anesthesia on neurons with different FR and PC would be important to understand state-dependent information processing in neuronal circuits.MethodsTo test how anesthesia affects neurons with diverse PC and FR, we measured single-unit activities in deep layers of primary visual cortex at three levels of anesthesia with desflurane and in wakefulness. Based on PC and FR in wakefulness, neurons were classified into three distinct groups: high PC-high FR (HPHF), low PC-high FR (LPHF), and low PC-low FR (LPLF) neurons.ResultsApplying repeated light flashes as visual stimuli, HPHF neurons showed the strongest early response (FR at 20-150ms post-stimulus) among the three groups, whereas the response of LPHF neurons persisted longest (up to 440ms). Anesthesia profoundly altered PC and FR, and differently affected the three neuron groups: (i) PC and FR became strongly correlated suppressing population-independent spike activity; (ii) Pairwise correlation of spikes between neurons could be predicted by a PC-based raster model suggesting uniform neuron-to-neuron coupling; (iii) Contrary to evoked-potential studies under anesthesia, the flash-induced early response of HPHF neurons was attenuated, and their spike timing was split and delayed; (iv) Late response (FR at 200-400ms post-stimulus) was suppressed both in HPHF and LPHF neurons.ConclusionsAnesthetic-induced association between PC and FR suggests reduced information content in the neural circuit. Altered response of HPHF neurons to visual stimuli suggests that anesthesia interferes with conscious sensory processing in primary sensory cortex.

Background Neurocognitive investigations suggest that conscious sensory perception depends on recurrent neuronal interactions among sensory, parietal, and frontal cortical regions, which are suppressed by general anesthetics. The purpose of this work was to investigate if local interactions in sensory cortex are also altered by anesthetics. The authors hypothesized that desflurane would reduce recurrent neuronal interactions in cortical layer–specific manner consistent with the anatomical disposition of feedforward and feedback pathways. Methods Single-unit neuronal activity was measured in freely moving adult male rats (268 units; 10 animals) using microelectrode arrays chronically implanted in primary and secondary visual cortex. Layer-specific directional interactions were estimated by mutual information and transfer entropy of multineuron spike patterns within and between cortical layers three and five. The effect of incrementally increasing and decreasing steady-state concentrations of desflurane (0 to 8% to 0%) was tested for statistically significant quadratic trend across the successive anesthetic states. Results Desflurane produced robust, state-dependent reduction (P = 0.001) of neuronal interactions between primary and secondary visual areas and between layers three and five, as indicated by mutual information (37 and 41% decrease at 8% desflurane from wakeful baseline at [mean ± SD] 0.52 ± 0.51 and 0.53 ± 0.51 a.u., respectively) and transfer entropy (77 and 78% decrease at 8% desflurane from wakeful baseline at 1.86 ± 1.56 a.u. and 1.87 ± 1.67 a.u., respectively). In addition, a preferential suppression of feedback between secondary and primary visual cortex was suggested by the reduction of directional index of transfer entropy overall (P = 0.001; 89% decrease at 8% desflurane from 0.11 ± 0.18 a.u. at baseline) and specifically, in layer five (P = 0.001; 108% decrease at 8% desflurane from 0.12 ± 0.19 a.u. at baseline). Conclusions Desflurane anesthesia reduces neuronal interactions in visual cortex with a preferential effect on feedback. The findings suggest that neuronal disconnection occurs locally, among hierarchical sensory regions, which may contribute to global functional disconnection underlying anesthetic-induced unconsciousness. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.

Leading neuroscientific theories posit a central role for the functional integration of cortical areas in conscious states. Considerable evidence supporting this hypothesis is based on network changes during anesthesia, but it is unclear whether these changes represent state-related (conscious vs unconscious) or drug-related (anesthetic vs no anesthetic) effects. We recently demonstrated that carbachol delivery to prefrontal cortex (PFC) restored wakefulness despite continuous administration of the general anesthetic sevoflurane. By contrast, carbachol delivery to parietal cortex, or noradrenaline delivery to either prefrontal or parietal cortices, failed to restore wakefulness. Thus, carbachol-induced reversal of sevoflurane anesthesia represents a unique state that combines wakefulness with clinically relevant anesthetic concentrations in the brain. To differentiate the state-related and drug-related associations of cortical connectivity and dynamics, we analyzed the electroencephalographic data gathered from adult male Sprague Dawley rats during the aforementioned experiments for changes in functional cortical gamma connectivity (25–155 Hz), slow oscillations (0.5–1 Hz), and complexity (p≤ 0.02) during sevoflurane anesthesia, an expected finding, but was not restored during wakefulness induced by carbachol delivery to PFC. Conversely, for rats in which wakefulness was not restored, the functional gamma connectivity remained reduced, but there was a significant decrease (p< 0.001) in the power of slow oscillations and increase (p< 0.001) in cortical complexity, which was similar to that observed during wakefulness induced after carbachol delivery to PFC. We conclude that the level of consciousness can be dissociated from cortical connectivity, oscillations, and dynamics.SIGNIFICANCE STATEMENTNumerous theories of consciousness suggest that functional connectivity across the cortex is characteristic of the conscious state and is reduced during anesthesia. However, it is unknown whether the observed changes are state-related (conscious vs unconscious) or drug-related (drug vs no drug). We used a novel rat model in which cholinergic stimulation of PFC produced wakefulness despite continuous exposure to a general anesthetic. We demonstrate that, as expected, general anesthesia reduces connectivity. Surprisingly, the connectivity remains suppressed despite pharmacologically induced wakefulness in the presence of anesthetic, with restoration occurring only after the anesthetic is discontinued. Thus, whether an animal exhibits wakefulness or not can be dissociated from cortical connectivity, prompting a reevaluation of the role of connectivity in level of consciousness.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Elucidating networks underlying conscious perception is important to understanding the mechanisms of anesthesia and consciousness. Previous studies have observed changes associated with loss of consciousness primarily using resting paradigms. The authors focused on the effects of sedation on specific cognitive systems using task-based functional magnetic resonance imaging. The authors hypothesized deepening sedation would degrade semantic more than perceptual discrimination. Methods Discrimination of pure tones and familiar names were studied in 13 volunteers during wakefulness and propofol sedation targeted to light and deep sedation. Contrasts highlighted specific cognitive systems: auditory/motor (tones vs. fixation), phonology (unfamiliar names vs. tones), and semantics (familiar vs. unfamiliar names), and were performed across sedation conditions, followed by region of interest analysis on representative regions. Results During light sedation, the spatial extent of auditory/motor activation was similar, becoming restricted to the superior temporal gyrus during deep sedation. Region of interest analysis revealed significant activation in the superior temporal gyrus during light (t [17] = 9.71, P < 0.001) and deep sedation (t [19] = 3.73, P = 0.001). Spatial extent of the phonologic contrast decreased progressively with sedation, with significant activation in the inferior frontal gyrus maintained during light sedation (t [35] = 5.17, P < 0.001), which didn’t meet criteria for significance in deep sedation (t [38] = 2.57, P = 0.014). The semantic contrast showed a similar pattern, with activation in the angular gyrus during light sedation (t [16] = 4.76, P = 0.002), which disappeared in deep sedation (t [18] = 0.35, P = 0.731). Conclusions Results illustrate broad impairment in cognitive cortex during sedation, with activation in primary sensory cortex beyond loss of consciousness. These results agree with clinical experience: a dose-dependent reduction of higher cognitive functions during light sedation, despite partial preservation of sensory processes through deep sedation.

Background and ObjectivesThe 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 patients with UWS.MethodsVoxel-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 used, 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 including three independent deep sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively) were adopted as validation groups. 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.ResultsFour cortical hubs were identified with 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. Furthermore, the anterior precuneus was found to show significantly higher similarity of hub characteristics as well as functional connectivity pattern between UWS-E and validation groups, compared with UWS-R.DiscussionThe results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs, especially the anterior precuneus. The identified cortical hub regions could serve as potential targets for noninvasive stimulation aimed at promoting the patients’ consciousness recovery.

How anesthesia affects cortical neuronal spiking and information transfer could help understand the neuronal basis of conscious state. Recent investigations suggest that global state of the anesthetized brain is not stationary but changes spontaneously at a fixed level of anesthetic concentration. How cortical unit activity changes with dynamically transitioning brain states under anesthesia is unclear. We hypothesized that distinct cortical states are characterized by distinct neuronal spike patterns. Extracellular unit activity was measured with sixty-four-channel silicon microelectrode arrays in cortical layers 5/6 of primary visual cortex of chronically instrumented, freely moving male rats (N = 7) during stepwise reduction of the anesthetic desflurane (6, 4, 2, and 0%). Unsupervised machine learning applied to multi-unit spike patterns revealed five distinct brain states of which four occurred at various anesthetic concentrations and shifted spontaneously. In deeper anesthesia states, the number of active units and overall spike rate decreased while the remaining active units showed increased bursting (excitatory neurons), spike timing variability, unit-to-population correlation and unit-to-unit transfer entropy, especially among putative excitatory units, despite the overall decrease in transfer entropy. A novel desynchronized brain state with increased spike timing variability, entropy and electromyographic activity that occurred mostly in deep anesthesia was discovered. These results provide evidence for distinct unit activity patterns associated with spontaneous changes in local cortical brain states at stationary anesthetic conditions. The appearance of a paradoxical, desynchronized brain state in deep anesthesia contends the prevailing view of monotonic dose-dependent anesthetic effects on the brain.SIGNIFICANCE STATEMENTRecent studies suggest that spontaneous changes in brain state occur under anesthesia. However, the spiking behavior of cortical neurons associated with such state changes has not been investigated. We found that local brain states defined by multi-unit activity had non-unitary relationship with the current anesthetic level. A paradoxical brain state displaying asynchronous firing pattern and high electromyographic activity was found unexpectedly at high-dose anesthesia. In contrast, the synchronous fragmentation of neuronal spiking appeared to be a robust signature of the state of anesthesia. The findings challenge the assumption of monotonic, anesthetic dose-dependent behavior of cortical neuron populations. They enhance the interpretation of neuroscientific data obtained under anesthesia and understanding of the neuronal basis of anesthetic-induced state of unconsciousness.

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brain’s global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brain’s global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

Accumulating evidence suggest that general anesthetics with diverse chemical structure reduce cerebral metabolism with consequent reduction of intracellular adenosine triphosphate (ATP) levels. How cerebral hypometabolism is associated with the typical electroencephalographic (EEG) changes under general anesthesia remains largely unknown.,. We hypothesized that the deficit in ATP production would reduce high-frequency activity, increase low-frequency activity, and cause burst suppression, which are common dose-dependent anesthetic effects on the EEG. To test the hypothesis, we developed a novel neural network model consisting of leaky integrate-and-fire neurons with additional dependency on ATP dynamics. The effect of varying rate of ATP production on neuronal and population activity patterns was simulated under various excitatory/inhibitory balance conditions. A decrease of ATP production suppressed neuronal spiking and enhanced synchronization of neurons over a range of excitatory/inhibitory synaptic strength ratios. As anticipated, the initially asynchronous fast activity was replaced by globally desynchronized slow oscillation and, on further decrease of ATP production, changed into burst suppression with enhanced global synchronization. This study substantiates a novel biophysical mechanism for anesthetic-induced EEG changes through a relationship between energy production and synchronization of neural network.

Background Consciousness is supported by integrated brain activity across widespread functionally segregated networks. The functional magnetic resonance imaging–derived global brain signal is a candidate marker for a conscious state, and thus the authors hypothesized that unconsciousness would be accompanied by a loss of global temporal coordination, with specific patterns of decoupling between local regions and global activity differentiating among various unconscious states. Methods Functional magnetic resonance imaging global signals were studied in physiologic, pharmacologic, and pathologic states of unconsciousness in human natural sleep (n = 9), propofol anesthesia (humans, n = 14; male rats, n = 12), and neuropathological patients (n = 21). The global signal amplitude as well as the correlation between global signal and signals of local voxels were quantified. The former reflects the net strength of global temporal coordination, and the latter yields global signal topography. Results A profound reduction of global signal amplitude was seen consistently across the various unconscious states: wakefulness (median [1st, 3rd quartile], 0.46 [0.21, 0.50]) versus non-rapid eye movement stage 3 of sleep (0.30 [0.24, 0.32]; P = 0.035), wakefulness (0.36 [0.31, 0.42]) versus general anesthesia (0.25 [0.21, 0.28]; P = 0.001), healthy controls (0.30 [0.27, 0.37]) versus unresponsive wakefulness syndrome (0.22 [0.15, 0.24]; P < 0.001), and low dose (0.07 [0.06, 0.08]) versus high dose of propofol (0.04 [0.03, 0.05]; P = 0.028) in rats. Furthermore, non-rapid eye movement stage 3 of sleep was characterized by a decoupling of sensory and attention networks from the global network. General anesthesia and unresponsive wakefulness syndrome were characterized by a dissociation of the majority of functional networks from the global network. This decoupling, however, was dominated by distinct neuroanatomic foci (e.g., precuneus and anterior cingulate cortices). Conclusions The global temporal coordination of various modules across the brain may distinguish the coarse-grained state of consciousness versus unconsciousness, while the relationship between the global and local signals may define the particular qualities of a particular unconscious state. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The level and richness of consciousness depend on information integration in the brain. Altered interregional functional interactions may indicate disrupted information integration during anesthetic-induced unconsciousness. How anesthetics modulate the amount of information in various brain regions has received less attention. Here, we propose a novel approach to quantify regional information content in the brain by the entropy of the principal components of regional blood oxygen-dependent imaging signals during graded propofol sedation. Fifteen healthy individuals underwent resting-state scans in wakeful baseline, light sedation (conscious), deep sedation (unconscious), and recovery (conscious). Light sedation characterized by lethargic behavioral responses was associated with global reduction of entropy in the brain. Deep sedation with completely suppressed overt responsiveness was associated with further reductions of entropy in sensory (primary and higher sensory plus orbital prefrontal cortices) but not high-order cognitive (dorsal and medial prefrontal, cingulate, parietotemporal cortices and hippocampal areas) systems. Upon recovery of responsiveness, entropy was restored in the sensory but not in high-order cognitive systems. These findings provide novel evidence for a reduction of information content of the brain as a potential systems-level mechanism of reduced consciousness during propofol anesthesia. The differential changes of entropy in the sensory and high-order cognitive systems associated with losing and regaining overt responsiveness are consistent with the notion of "disconnected consciousness", in which a complete sensory-motor disconnection from the environment occurs with preserved internal mentation.

The biological basis of consciousness is one of the most challenging and fundamental questions in 21st century science. A related pursuit aims to identify the neural correlates and causes of unconsciousness. We review current trends in the investigation of physiological, pharmacological, and pathological states of unconsciousness at the level of large-scale functional brain networks. We focus on the roles of brain connectivity, repertoire, graph-theoretical techniques, and neural dynamics in understanding the functional brain disconnections and reduced complexity that appear to characterize these states. Persistent questions in the field, such as distinguishing true correlates, linking neural scales, and understanding differential recovery patterns, are also addressed.

Environmental events are processed on multiple timescales via hierarchical organization of temporal receptive windows (TRWs) in the brain. The dependence of neural timescales and TRWs on altered states of consciousness is unclear. States of reduced consciousness are marked by a shift toward slowing of neural dynamics (n= 23; male/female 14/9) during graded sedation with propofol. We further examined the relationship between the intrinsic timescales (local/voxel level) and its regional connectivity (across neighboring voxels; regional homogeneity, ReHo), global (whole-brain level) functional connectivity (GFC), and topographical similarity (Topo). Additional results were obtained from patients undergoing deep general anesthesia (n= 12; male/female: 5/7) and in patients with disorders of consciousness (DOC) (n= 21; male/female: 14/7). We found that MF, AC, and ReHo increased, whereas GFC and Topo decreased, during propofol sedation. The local alterations occur before changes of distant connectivity. Conversely, all of these parameters decreased in deep anesthesia and in patients with DOC. We conclude that propofol synchronizes local neuronal interactions and prolongs the timescales of intrinsic BOLD signals. These effects may impede communication among distant brain regions. Furthermore, the intrinsic timescales exhibit distinct dynamic signatures in sedation, deep anesthesia, and DOC. These results improve our understanding of the neural mechanisms of unconsciousness in pharmacologic and neuropathologic states.SIGNIFICANCE STATEMENTInformation processing in the brain occurs through a hierarchy of temporal receptive windows (TRWs) in multiple timescales. Anesthetic drugs induce a reversible suppression of consciousness and thus offer a unique opportunity to investigate the state dependence of neural timescales. Here, we demonstrate for the first time that sedation with propofol is accompanied by the prolongation of the timescales of intrinsic BOLD signals presumably reflecting enlarged TRWs. We show that this is accomplished by an increase of local and regional signal synchronization, effects that may disrupt information exchange among distant brain regions. Furthermore, we show that the timescales of intrinsic BOLD signals exhibit distinct dynamic signatures in sedation, deep anesthesia, and disorders of consciousness.

Recent studies indicate that spontaneous low-frequency fluctuations (LFFs) of resting-state functional magnetic resonance imaging (rs-fMRI) blood oxygen level-dependent (BOLD) signals are driven by the slow (

Integrated information theory (IIT) postulates that consciousness arises from the cause-effect structure of a system but the optimal network conditions for this structure have not been elucidated. In the study, we test the hypothesis that network criticality, a dynamically balanced state between a large variation of functional network configurations and a large constraint of structural network configurations, is a necessary condition for the emergence of a cause-effect structure that results in a large Φ, a surrogate of integrated information. We also hypothesized that if the brain deviates from criticality, the cause-effect structure is obscured and Φ diminishes. We tested these hypotheses with a large-scale brain network model and high-density electroencephalography (EEG) acquired during various levels of human consciousness during general anesthesia. In the modeling study, maximal criticality coincided with maximal Φ. The constraint of the structural network on the functional network is maximized in the maximal criticality. The EEG study demonstrated an explicit relationship between Φ, criticality, and level of consciousness. Functional brain network significantly correlated with structural brain network only in conscious states. The results support the hypothesis that network criticality maximizes Φ.

Consciousness is a mental characteristic of the human mind, whose exact neural features remain unclear. We aimed to identify the critical nodes within the brain's global functional network that support consciousness. To that end, we collected a large fMRI resting state dataset with subjects in at least one of the following three consciousness states: preserved (including the healthy awake state, and patients with a brain injury history (BI) that is fully conscious), reduced (including the N1-sleep state, and minimally conscious state), and lost (including the N3-sleep state, anesthesia, and unresponsive wakefulness state). We also included a unique dataset of subjects in rapid eye movement sleep state (REM-sleep) to test for the presence of consciousness with minimum movements and sensory input. To identify critical nodes, i.e., hubs, within the brain's global functional network, we used a graph-theoretical measure of degree centrality conjoined with ROI-based functional connectivity. Using these methods, we identified various higher-order sensory and motor regions including the supplementary motor area, bilateral supramarginal gyrus (part of inferior parietal lobule), supragenual/dorsal anterior cingulate cortex, and left middle temporal gyrus, that could be important hubs whose degree centrality was significantly reduced when consciousness was reduced or absent. Additionally, we identified a sensorimotor circuit, in which the functional connectivity among these regions was significantly correlated with levels of consciousness across the different groups, and remained present in the REM-sleep group. Taken together, we demonstrated that regions forming a higher-order sensorimotor integration circuit are involved in supporting consciousness within the brain's global functional network. That offers novel and more mechanism-guided treatment targets for disorders of consciousness.

SUMMARY Conscious access to sensory information is likely gated at an intermediate site between primary sensory and transmodal association cortices, but the structure responsible remains unknown. We perform functional neuroimaging to determine the neural correlates of conscious access using a volitional mental imagery task, a report paradigm not confounded by motor behavior. Titrating propofol to loss of behavioral responsiveness in healthy volunteers creates dysfunction of the anterior insular cortex (AIC) in association with an impairment of dynamic transitions of default-mode and dorsal attention networks. Candidate subcortical regions mediating sensory gating or arousal (thalamus, basal forebrain) fail to show this association. The gating role of the AIC is consistent with findings in awake participants, whose conscious access is predicted by pre-stimulus AIC activity near perceptual threshold. These data support the hypothesis that AIC, situated at an intermediate position of the cortical hierarchy, regulates brain network transitions that gate conscious access., Graphical abstract, In brief In a human neuroimaging study, Huang et al. manipulate the level and content of consciousness using independent experimental protocols to demonstrate that the anterior insula, situated between unimodal and transmodal cortical areas along the brain’s functional hierarchy, serves as a gate for conscious access of sensory information.

A quest for a systems-level neuroscientific basis of anesthetic-induced loss and return of consciousness has been in the forefront of research for the past 2 decades. Recent advances toward the discovery of underlying mechanisms have been achieved using experimental electrophysiology, multichannel electroencephalography, magnetoencephalography, and functional magnetic resonance imaging. By the careful dosing of various volatile and IV anesthetic agents to the level of behavioral unresponsiveness, both specific and common changes in functional and effective connectivity across large-scale brain networks have been discovered and interpreted in the context of how the synthesis of neural information might be affected during anesthesia. The results of most investigations to date converge toward the conclusion that a common neural correlate of anesthetic-induced unresponsiveness is a consistent depression or functional disconnection of lateral frontoparietal networks, which are thought to be critical for consciousness of the environment. A reduction in the repertoire of brain states may contribute to the anesthetic disruption of large-scale information integration leading to unconsciousness. In future investigations, a systematic delineation of connectivity changes with multiple anesthetics using the same experimental design, and the same analytical method will be desirable. The critical neural events that account for the transition between responsive and unresponsive states should be assessed at similar anesthetic doses just below and above the loss or return of responsiveness. There will also be a need to identify a robust, sensitive, and reliable measure of information transfer. Ultimately, finding a behavior-independent measure of subjective experience that can track covert cognition in unresponsive subjects and a delineation of causal factors versus correlated events will be essential to understand the neuronal basis of human consciousness and unconsciousness.

Consciousness is thought to scale with brain complexity, and it may be diminished in anesthesia. Lempel-Ziv complexity (LZC) of field potentials has been shown to be a promising measure of the level of consciousness in anesthetized human subjects, neurological patients, and across the sleep-wake states in rats. Whether this relationship holds for intrinsic networks obtained by functional brain imaging has not been tested. To fill this gap of knowledge, we estimated LZC from large-scale dynamic analysis of functional magnetic resonance images (fMRI) in conscious sedated and unconscious anesthetized rats. Blood oxygen dependent (BOLD) signals were obtained from 30-min whole-brain resting-state scans while the anesthetic propofol was infused intravenously at constant infusion rates of 20 mg/kg/h (conscious sedated) and 40 mg/kg/h (unconscious). Dynamic brain networks were defined at voxel level by sliding window analysis of regional homogeneity (ReHo) of the BOLD signal. From scans performed at low to high propofol dose, the LZC was significantly reduced by 110%. The results suggest that the difference in LZC between conscious sedated and anesthetized unconscious subjects is conserved in rats and this effect is detectable in large-scale brain network obtained from fMRI.

Determining the level of consciousness in patients with disorders of consciousness (DOC) remains challenging. To address this challenge, resting-state fMRI (rs-fMRI) has been widely used for detecting the local, regional, and network activity differences between DOC patients and healthy controls. Although substantial progress has been made towards this endeavor, the identification of robust rs-fMRI-based biomarkers for level of consciousness is still lacking. Recent developments in machine learning show promise as a tool to augment the discrimination between different states of consciousness in clinical practice. Here, we investigated whether machine learning models trained to make a binary distinction between conscious wakefulness and anesthetic-induced unconsciousness would then be capable of reliably identifying pathologically induced unconsciousness. We did so by extracting rs-fMRI-based features associated with local activity, regional homogeneity, and interregional functional activity in 44 subjects during wakefulness, light sedation, and unresponsiveness (deep sedation and general anesthesia), and subsequently using those features to train three distinct candidate machine learning classifiers: support vector machine, Extra Trees, artificial neural network. First, we show that all three classifiers achieve reliable performance within-dataset (via nested cross-validation), with a mean area under the receiver operating characteristic curve (AUC) of 0.95, 0.92, and 0.94, respectively. Additionally, we observed comparable cross-dataset performance (making predictions on the DOC data) as the anesthesia-trained classifiers demonstrated a consistent ability to discriminate between unresponsive wakefulness syndrome (UWS/VS) patients and healthy controls with mean AUC’s of 0.99, 0.94, 0.98, respectively. Lastly, we explored the potential of applying the aforementioned classifiers towards discriminating intermediate states of consciousness, specifically, subjects under light anesthetic sedation and patients diagnosed as having a minimally conscious state (MCS). Our findings demonstrate that machine learning classifiers trained on rs-fMRI features derived from participants under anesthesia have potential to aid the discrimination between degrees of pathological unconsciousness in clinical patients.

Detecting covert consciousness in behaviorally unresponsive patients by brain imaging is of great interest, but a reproducible model and evidence from independent sources is still lacking. Here we demonstrate the possibility of using general anesthetics in a within-subjects study design to test methods or statistical paradigms of assessing covert consciousness. Using noninvasive neuroimaging in healthy volunteers, we identified a healthy study participant who was able to exhibit the specific fMRI signatures of volitional mental imagery while behaviorally unresponsive due to sedation with propofol. Our findings reveal a novel model that may accelerate the development of new approaches to reproducibly detect covert consciousness, which is difficult to achieve in patients with heterogeneous and sometimes clinically unstable neuropathology.

Theoretical consideration predicts that the alteration of local and shared information in the brain is a key element in the mechanism of anesthetic-induced unconsciousness. Ordinal pattern analysis, such as permutation entropy (PE) and symbolic mutual information (SMI), have been successful in quantifying local and shared information in neurophysiological data, however, they have been rarely applied to altered states of consciousness, especially to data obtained with functional magnetic resonance imaging (fMRI). PE and SMI analysis, together with the superb spatial resolution of fMRI recording, enables us to explore the local information of specific brain areas, the shared information between the areas, and the relationship between the two. Given the spatially divergent action of anesthetics on regional brain activity, we hypothesized that anesthesia would differentially influence entropy (PE) and shared information (SMI) across various brain areas, which may represent fundamental, mechanistic indicators of loss of consciousness. FMRI data were collected from 15 healthy participants during four states: wakefulness (W), light (conscious) sedation (L), deep (unconscious) sedation (D), and recovery (R). Sedation was produced by the common, clinically used anesthetic, propofol. Firstly, we found that that global PE decreased from W to D, and increased from D to R. The PE was differentially affected across the brain areas, specifically, the PE in the subcortical network was reduced more than in the cortical networks. Secondly, SMI was also differentially affected in different areas, as revealed by the reconfiguration of its spatial pattern (topographic structure). The topographic structures of SMI in the conscious states W, L, and R were distinctively different from that of the unconscious state D. Thirdly, PE and SMI were positively correlated in W, L, and R, whereas this correlation was disrupted in D. And lastly, PE changes occurred preferentially in highly connected hub regions. These findings advance our understanding of brain dynamics and information exchange, emphasizing the importance of topographic structure and the relationship of local and shared information in anesthetic-induced unconsciousness.

Variability quenching is a widespread neural phenomenon in which trial-to-trial variability (TTV) of neural activity is reduced by repeated presentations of a sensory stimulus. However, its neural mechanism and functional significance remain poorly understood. Recurrent network dynamics are suggested as a candidate mechanism of TTV, and they play a key role in consciousness. We thus asked whether the variability-quenching phenomenon is related to the level of consciousness. We hypothesized that TTV reduction would be compromised during reduced level of consciousness by propofol anesthetics. We recorded functional magnetic resonance imaging signals of resting-state and stimulus-induced activities in three conditions: wakefulness, sedation, and unconsciousness (i.e., deep anesthesia). We measured the average (trial-to-trial mean, TTM) and variability (TTV) of auditory stimulus-induced activity under the three conditions. We also examined another form of neural variability (temporal variability, TV), which quantifies the overall dynamic range of ongoing neural activity across time, during both the resting-state and the task. We found that (a) TTM deceased gradually from wakefulness through sedation to anesthesia, (b) stimulus-induced TTV reduction normally seen during wakefulness was abolished during both sedation and anesthesia, and (c) TV increased in the task state as compared to resting-state during both wakefulness and sedation, but not anesthesia. Together, our results reveal distinct effects of propofol on the two forms of neural variability (TTV and TV). They imply that the anesthetic disrupts recurrent network dynamics, thus prevents the stabilization of cortical activity states. These findings shed new light on the temporal dynamics of neuronal variability and its alteration during anesthetic-induced unconsciousness.

Consciousness is determined both by level (e.g., being awake versus being anesthetized) and content (i.e., the qualitative aspects of experience). Subcortical areas are known to play a causal role in regulating the level of consciousness [1-9], but the role of the cortex is less well understood. Clinical and correlative data have been used both to support and refute a role for prefrontal and posterior cortices in the level of consciousness [10-22]. The prefrontal cortex has extensive reciprocal connections to wake-promoting centers in the brainstem and diencephalon [23, 24], and hence is in a unique position to modulate level of consciousness. Furthermore, a recent study suggested that the prefrontal cortex might be important in regulating level of consciousness [25] but causal evidence, and a comparison with more posterior cortical sites, is lacking. Therefore, to test the hypothesis that prefrontal cortex plays a role in regulating level of consciousness, we attempted to reverse sevoflurane anesthesia by cholinergic or noradrenergic stimulation of the prefrontal prelimbic cortex and two areas of parietal cortex in rat. General anesthesia was defined by loss of the righting reflex, a widely used surrogate measure in rodents. We demonstrate that cholinergic stimulation of prefrontal cortex, but not parietal cortex, restored wake-like behavior, despite continuous exposure to clinically relevant concentrations of sevoflurane anesthesia. Noradrenergic stimulation of the prefrontal and parietal areas resulted in electroencephalographic activation but failed to produce any signs of wake-like behavior. We conclude that cholinergic mechanisms in prefrontal cortex can regulate the level of consciousness.

The integrated information theory (IIT) proposes a quantitative measure, denoted as Φ, of the amount of integrated information in a physical system, which is postulated to have an identity relationship with consciousness. IIT predicts that the value of Φ estimated from brain activities represents the level of consciousness across phylogeny and functional states. Practical limitations, such as the explosive computational demands required to estimate Φ for real systems, have hindered its application to the brain and raised questions about the utility of IIT in general. To achieve practical relevance for studying the human brain, it will be beneficial to establish the reliable estimation of Φ from multichannel electroencephalogram (EEG) and define the relationship of Φ to EEG properties conventionally used to define states of consciousness. In this study, we introduce a practical method to estimate Φ from high-density (128-channel) EEG and determine the contribution of each channel to Φ. We examine the correlation of power, frequency, functional connectivity, and modularity of EEG with regional Φ in various states of consciousness as modulated by diverse anesthetics. We find that our approximation of Φ alone is insufficient to discriminate certain states of anesthesia. However, a multi-dimensional parameter space extended by four parameters related to Φ and EEG connectivity is able to differentiate all states of consciousness. The association of Φ with EEG connectivity during clinically defined anesthetic states represents a new practical approach to the application of IIT, which may be used to characterize various physiological (sleep), pharmacological (anesthesia), and pathological (coma) states of consciousness in the human brain.

There is current controversy regarding the role of prefrontal versus posterior cortices in consciousness. Clinical and correlative data have been used both to support and refute a causal role for prefrontal cortex in the level of consciousness, but a definitive relationship has not been demonstrated. We used anesthetic-induced unconsciousness as a model system to study the effect of cholinergic and noradrenergic stimulation of rat prefrontal and posterior parietal cortices on the level of consciousness. We demonstrate that cholinergic stimulation of prefrontal cortex, but not parietal cortical areas, restored wakefulness in rats despite continuous exposure to sevoflurane anesthesia. Noradrenergic stimulation of the prefrontal or parietal areas did not reverse the anesthetized state. We conclude that cholinergic mechanisms in prefrontal cortex can control the level of consciousness.One Sentence SummaryPrefrontal cholinergic stimulation restores consciousness in rats despite continuous exposure to sevoflurane anesthesia

Background: Neuronal interactions are fundamental for information processing, cognition, and consciousness. Anesthetics reduce spontaneous cortical activity; however, neuronal reactivity to sensory stimuli is often preserved or augmented. How sensory stimulus–related neuronal interactions change under anesthesia has not been elucidated. In this study, the authors investigated the visual stimulus–related cortical neuronal interactions during stepwise emergence from desflurane anesthesia. Methods: Parallel spike trains were recorded with 64-contact extracellular microelectrode arrays from the primary visual cortex of chronically instrumented, unrestrained rats (N = 6) at 8, 6, 4, and 2% desflurane anesthesia and wakefulness. Light flashes were delivered to the retina by transcranial illumination at 5- to 15-s randomized intervals. Information theoretical indices, integration and interaction complexity, were calculated from the probability distribution of coincident spike patterns and used to quantify neuronal interactions before and after flash stimulation. Results: Integration and complexity showed significant negative associations with desflurane concentration (N = 60). Flash stimulation increased integration and complexity at all anesthetic levels (N = 60); the effect on complexity was reduced in wakefulness. During stepwise withdrawal of desflurane, the largest increase in integration (74%) and poststimulus complexity (35%) occurred before reaching 4% desflurane concentration—a level associated with the recovery of consciousness according to the rats’ righting reflex. Conclusions: Neuronal interactions in the cerebral cortex are augmented during emergence from anesthesia. Visual flash stimuli enhance neuronal interactions in both wakefulness and anesthesia; the increase in interaction complexity is attenuated as poststimulus complexity reaches plateau. The critical changes in cortical neuronal interactions occur during transition to consciousness.

The richness of conscious experience is thought to scale with the size of the repertoire of causal brain states, and it may be diminished in anesthesia. We estimated the state repertoire from dynamic analysis of intrinsic functional brain networks in conscious sedated and unconscious anesthetized rats. Functional resonance images were obtained from 30-min whole-brain resting-state blood oxygen level-dependent (BOLD) signals at propofol infusion rates of 20 and 40 mg/kg/h, intravenously. Dynamic brain networks were defined at the voxel level by sliding window analysis of regional homogeneity (ReHo) or coincident threshold crossings (CTC) of the BOLD signal acquired in nine sagittal slices. The state repertoire was characterized by the temporal variance of the number of voxels with significant ReHo or positive CTC. From low to high propofol dose, the temporal variances of ReHo and CTC were reduced by 78% ± 20% and 76%± 20%, respectively. Both baseline and propofol-induced reduction of CTC temporal variance increased from lateral to medial position. Group analysis showed a 20% reduction in the number of unique states at the higher propofol dose. Analysis of temporal variance in 12 anatomically defined regions of interest predicted that the largest changes occurred in visual cortex, parietal cortex, and caudate-putamen. The results suggest that the repertoire of large-scale brain states derived from the spatiotemporal dynamics of intrinsic networks is substantially reduced at an anesthetic dose associated with loss of consciousness.

Conscious perception relies on interactions between spatially and functionally distinct modules of the brain at various spatiotemporal scales. These interactions are altered by anesthesia, an intervention that leads to fading consciousness. Relatively little is known about brain functional connectivity and its anesthetic modulation at a fine spatial scale. Here, we used functional imaging to examine propofol-induced changes in functional connectivity in brain networks defined at a fine-grained parcellation based on a combination of anatomical and functional features. Fifteen healthy volunteers underwent resting-state functional imaging in wakeful baseline, mild sedation, deep sedation, and recovery of consciousness. Compared with wakeful baseline, propofol produced widespread, dose-dependent functional connectivity changes that scaled with the extent to which consciousness was altered. The dominant changes in connectivity were associated with the frontal lobes. By examining node pairs that demonstrated a trend of functional connectivity change between wakefulness and deep sedation, quadratic discriminant analysis differentiated the states of consciousness in individual participants more accurately at a fine-grained parcellation (e.g., 2000 nodes) than at a coarse-grained parcellation (e.g., 116 anatomical nodes). Our study suggests that defining brain networks at a high granularity may provide a superior imaging-based distinction of the graded effect of anesthesia on consciousness.

Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n=6, sevoflurane: n=10, and ketamine: n=8) with distinct molecular mechanisms on changes in phase-amplitude coupling in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. Phase-amplitude coupling was calculated using the modulation index algorithm between delta (1-4 Hz), theta (4-10 Hz), low gamma (25-55 Hz), and high gamma (65-125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma (p

There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the “bottom up” paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the “top-down” paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness.

State-dependent neuronal firing patterns reflect changes in ongoing information processing and cortical function. A disruption of neuronal coordination has been suggested as the neural correlate of anesthesia. Here, we studied the temporal correlation patterns of ongoing spike activity, during a stepwise reduction of the volatile anesthetic desflurane, in the cerebral cortex of freely moving rats. We hypothesized that the recovery of consciousness from general anesthesia is accompanied by specific changes in the spatiotemporal pattern and correlation of neuronal activity. Sixty-four contact microelectrode arrays were chronically implanted in the primary visual cortex (contacts spanning 1.4-mm depth and 1.4-mm width) for recording of extracellular unit activity at four steady-state levels of anesthesia (8-2% desflurane) and wakefulness. Recovery of consciousness was defined as the regaining of the righting reflex (near 4%). High-intensity firing (HI) periods were segmented using a threshold (200-ms) representing the minimum in the neurons' bimodal interspike interval histogram under anesthesia. We found that the HI periods were highly fragmented in deep anesthesia and gradually transformed to a near-continuous firing pattern at wakefulness. As the anesthetic was withdrawn, HI periods became longer and increasingly correlated among the units both locally and across remote recording sites. Paradoxically, in 4 of 8 animals, HI correlation was also high at the deepest level of anesthesia (8%) when local field potentials (LFP) were burst-suppressed. We conclude that recovery from desflurane anesthesia is accompanied by a graded defragmentation of neuronal activity in the cerebral cortex. Hypersynchrony during deep anesthesia is an exception that occurs only with LFP burst suppression.

Using functional magnetic resonance imaging in human participants, we show that sedation by propofol to the point of lost overt responsiveness during the performance of an auditory verbal memory task unexpectedly increases functional connectivity of the precuneus with cortical regions, particularly the dorsal prefrontal and visual cortices. After recovery of consciousness, functional connectivity returns to a pattern similar to that observed during the wakeful baseline. In the context of a recent proposal that highlights the uncoupling of consciousness, connectedness, and responsiveness in general anesthesia, the increased precuneus functional connectivity under propofol sedation may reflect disconnected endogenous mentation or dreaming that continues at a reduced level of metabolic activity.

Introduction: Previously observed increased sensitivity to noxious stimulation in the Dahl salt-sensitive rat strain (SS/JrHsdMcwi, abbreviated as SS) compared to Brown Norway rats (BN/NhsdMcwi abbreviated as BN) is mediated by genes on a single chromosome. The current study used behavioral and electrocortical data to determine if differences also exist between SS and BN rats in loss of consciousness. Methods: Behavioral responses, including loss of righting, (a putative index of consciousness) and concurrent electroencephalogram recordings, in 12 SS and BN rats were measured during isoflurane at inhaled concentrations of 0, 0.3, 0.6, 0.8, 1.0 and 1.2%. Results: In SS compared to BN rats, the mean ± SEM EC50 for righting was significantly less (0.65 ± 0.01% vs. 0.74 ± 0.02% inhaled isoflurane) and delta fraction in parietal electroencephalogram was enhanced 50–100% at all isoflurane levels during emergence. The frequency decay constant of an exponential fit of the parietal electroencephalogram spectrum graphed as a function of isoflurane level was three times less steep (mean ± SEM slope −57 ± 13 vs. −191 ± 38) and lower at each level of isoflurane in SS versus BN rats (i.e., shifted toward low frequency activity). Electroencephalogram differences between strains were larger during emergence than induction. Conclusions: Sensitivity is higher in SS compared to BN rats leading to unconsciousness at lower levels of isoflurane. This supports using additional strains in this animal model to study the genetic basis for differences in anesthetic action on mechanisms of consciousness. Moreover, induction and emergence appear to involve distinct pathways.

Background Current state of knowledge suggests that disruption of neuronal information integration may be a unitary mechanism of anesthetic-induced unconsciousness. A neural system central for information integration is the thalamocortical system whose specific and nonspecific divisions may play the roles for representing and integrating information; respectively. How anesthetics affect the function of these systems individually is not completely understood. We studied the effect of propofol on thalamocortical functional connectivity in the specific and nonspecific systems using functional magnetic resonance imaging.

Consciousness has been linked to the repertoire of brain states at various spatiotemporal scales. Anesthesia is thought to modify consciousness by altering information integration in cortical and thalamocortical circuits. At a mesoscopic scale, neuronal populations in the cortex form synchronized ensembles whose characteristics are presumably state-dependent but this has not been rigorously tested. In this study, spontaneous neuronal activity was recorded with 64-contact microelectrode arrays in primary visual cortex of chronically instrumented, unrestrained rats under stepwise decreasing levels of desflurane anesthesia (8%, 6%, 4%, and 2% inhaled concentrations) and wakefulness (0% concentration). Negative phases of the local field potentials formed compact, spatially contiguous activity patterns (CAPs) that were not due to chance. The number of CAPs was 120% higher in wakefulness and deep anesthesia associated with burst-suppression than at intermediate levels of consciousness. The frequency distribution of CAP sizes followed a power–law with slope −1.5 in relatively deep anesthesia (8–6%) but deviated from that at the lighter levels. Temporal variance and entropy of CAP sizes were lowest in wakefulness (76% and 24% lower at 0% than at 8% desflurane, respectively) but changed little during recovery of consciousness. CAPs categorized by K-means clustering were conserved at all anesthesia levels and wakefulness, although their proportion changed in a state-dependent manner. These observations yield new knowledge about the dynamic landscape of ongoing population activity in sensory cortex at graded levels of anesthesia. The repertoire of population activity and self-organized criticality at the mesoscopic scale do not appear to contribute to anesthetic suppression of consciousness, which may instead depend on large-scale effects, more subtle dynamic properties, or changes outside of primary sensory cortex.

Sleep, anesthesia and coma share a number of neural features but the recovery profiles are radically different. To understand the mechanisms of reversibility of unconsciousness at the network level, we studied the conditions for gradual and abrupt state transitions in conscious and anesthetized states. We hypothesized that the conditions for explosive synchronization (ES) in human brain networks would be present in the anesthetized brain just over the threshold of unconsciousness. To test this hypothesis, functional brain networks were constructed from multi-channel electroencephalogram (EEG) recordings in seven healthy subjects across conscious, unconscious, and recovery states. We analyzed four conditions that were previously reported as conditions for ES in generic, non-biological networks: (1) correlation between node degree and frequency, (2) disassortativity (i.e., the tendency of highly-connected nodes to link with less-connected nodes, or vice versa), (3) frequency difference of coupled nodes, and (4) an inequality relationship for ES between local and global network properties, which is referred to as the suppressive rule. We observed that the four network conditions for ES were satisfied in the unconscious state. Conditions for ES in the human brain suggest a potential mechanism for rapid recovery from the lightly-anesthetized state. This study demonstrates for the first time that the network conditions for ES, formerly shown in generic networks only, are present in empirically-derived functional brain networks. Further investigations with deep anesthesia, sleep, and coma could provide insight into the underlying causes of variability in recovery profiles of these unconscious states.

Levo-tetrahydropalmatine (l-THP) has shown significant promise in preclinical and clinical studies to treat drug addiction. Pharmacological MRI methods can elucidate the regional cerebral effects of l-THP, but there are potential confounds from the use of general anesthesia. To investigate the possible anesthetic-drug interactions for the pharmacological MRI result of acute l-THP, we examined acute blood oxygen level-dependent responses of both 5 and 20 mg/kg l-THP in naive rats during general anesthesia achieved with three agents: isoflurane, medetomidine, and urethane. We found that with acute l-THP administration, isoflurane revealed the smallest blood oxygen level-dependent activation areas. In addition, urethane had the most activation areas; however, they were all negative. Medetomidine showed mixed positive and negative activations. Region-specific interactions were found between the l-THP-induced blood oxygen level-dependent responses and the anesthetic agents.

Recent theoretical advances describing consciousness from information and integration have highlighted the unique role of the thalamocortical system in leading to integrated information and thus, consciousness. Here, we examined the differential distributions of specific and nonspecific thalamocortical functional connections using resting-state fMRI in a group of healthy subjects and vegetative-state patients. We found that both thalamic systems were widely distributed, but they exhibited different patterns. Nonspecific connections were preferentially associated with brain regions involved in higher-order cognitive processing, self-awareness and introspective mentalizing (e.g., the dorsal prefrontal and anterior cingulate cortices). In contrast, specific connections were prevalent in the ventral and posterior part of the prefrontal and precuneus, known involved in representing externally-directed attentions. Significant reductions of functional connectivity in both systems, especially the nonspecific system, were observed in VS. These data suggest that brain networks sustaining information and integration may be differentiated by the nature of their thalamic functional connectivity.

Background Cortical γ oscillations are thought to play a role in conscious cognitive functions. Suppression of 40-Hz γ activity was implicated in the loss of consciousness during general anesthesia. However, several experimental studies found that γ oscillations were preserved in anesthesia. The authors investigated the concentration-dependent effect of isoflurane on spontaneous γ oscillations in two frequency bands and three distinct brain regions in the rat. Methods Adult Sprague-Dawley rats were chronically implanted with epidural and coaxial depth electrodes to record cortical field potentials in frontal cortex, visual cortex, and hippocampus in waking and at steady-state isoflurane concentrations of 0.4, 0.8, and 1.2%. The γ power was calculated for the frequency bands 30-50 and 70-140 Hz. Temporal variation and interregional synchrony of γ activity were analyzed using wavelet transform. Loss of consciousness was indexed by the loss of righting reflex. Results Rats lost their righting reflex at 0.8 ± 0.1% isoflurane. High-frequency γ power was decreased by isoflurane in a concentration-dependent manner (P < 0.001, 50% decrease at 0.8% isoflurane) in all brain regions. Low-frequency γ power was unaffected by isoflurane. The duration and interregional synchrony of high-frequency γ bursts was also reduced (P l < 0.001, 40% decrease at 0.8% isoflurane). Conclusions Distinction between high- and low-frequency γ bands is important when evaluating the effect of general anesthetics on brain electrical activity. Spontaneous 40-Hz γ power does not indicate the state of consciousness. The attenuation and interregional desynchronization of high-frequency γ oscillations appear to correlate with the loss of consciousness.

Functional connectivity magnetic resonance imaging (fcMRI) studies in rat brain show brain reorganization following peripheral nerve injury. Subacute neuroplasticity was observed two weeks following transection of the four major nerves of the brachial plexus. Direct functional magnetic resonance imaging (fMRI) stimulation of the intact radial nerve reveals an activation pattern in the forelimb regions of the sensory and motor cortices that is significantly different from that observed in normal rats. Results of this fMRI experiment were used to determine seed voxel regions for fcMRI analysis. Intrahemispheric connectivities in the sensorimotor forelimb representations in both hemispheres are largely unaffected by deafferentation, whereas substantial disruption of interhemispheric sensorimotor cortical connectivity occurs. In addition, significant intra- and interhemispheric changes in connectivities of thalamic nuclei were found. These are the central findings of the study. They could not have been obtained from fMRI studies alone—both fMRI and fcMRI are needed. The combination provides a general marker for brain plasticity. The rat visual system was studied in the same animals as a control. No neuroplastic changes in connectivities were found in the primary visual cortex upon forelimb deafferentation. Differences were noted in regions responsible for processing multisensory visual-motor information. This incidental discovery is considered to be significant. It may provide insight into phantom limb epiphenomena.

The regions of the body have cortical and subcortical representation in proportion to their degree of innervation. The rat forepaw has been studied extensively in recent years using functional magnetic resonance imaging (fMRI), typically by stimulation using electrodes directly inserted into the skin of the forepaw. Here we stimulate the nerve directly using surgically implanted electrodes. A major distinction is that stimulation of the skin of the forepaw is mostly sensory, whereas direct nerve stimulation reveals not only the sensory system but also deep brain structures associated with motor activity. In this article, we seek to define both the motor and sensory cortical and subcortical representations associated with the four major nerves of the rodent upper extremity. We electrically stimulated each nerve (median, ulnar, radial, and musculocutaneous) during fMRI acquisition using a 9.4-T Bruker scanner (Bruker BioSpin, Billerica, MA). A current level of 0.5 to 1.0 mA and a frequency of 5 Hz were used while keeping the duration constant. A distinct pattern of cortical activation was found for each nerve that can be correlated with known sensorimotor afferent and efferent pathways to the rat forepaw. This direct nerve stimulation rat model can provide insight into peripheral nerve injury.

The response of the rat visual system to flashes of blue light has been studied by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). The BOLD temporal response is dependent on the number of flashes presented and demonstrates a refractory period that depends on flash frequency. Activated brain regions included the primary and secondary visual cortex, superior colliculus (SC), dorsal lateral geniculate (DLG), and lateral posterior nucleus (LP), which were found to exhibit differing temporal responses. To explain these differences, the BOLD neurovascular response function was modeled. A second-order differential equation was developed and solved numerically to arrive at region-specific response functions. Included in the model are the light input from the diode (duty cycle), a refractory period, a transient response following onset and cessation of stimulus, and a slow adjustment to changes in the average level of the signal. Constants in the differential equation were evaluated for each region by fitting the model to the experimental BOLD response from a single flash, and the equation was then solved for multiple flashes. The simulation mimics the major features of the data; however, remaining differences in the frequency dependence of the response between the cortical and subcortical regions were unexplained. We hypothesized that these discrepancies were due to regional-specific differences in neuronal response to flash frequency. To test this hypothesis, cortical visual evoked potentials (VEPs) were recorded using the same stimulation protocol as the fMRI. Cortical VEPs were more suppressed than subcortical VEPs as flash frequency increased, supporting our hypothesis. This is the first report that regional differences in neuronal activation to the same stimulus lead to differential BOLD activation.

Regional-specific average time courses of spontaneous fluctuations in blood oxygen level dependent (BOLD) MRI contrast at 9.4T in lightly anesthetized resting rat brain are formed, and correlation coefficients between time course pairs are interpreted as measures of connectivity. A hierarchy of regional pairwise correlation coefficients (RPCCs) is observed, with the highest values found in the thalamus and cortex, both intra- and interhemisphere, and lower values between the cortex and thalamus. Independent sensory networks are distinguished by two methods: data driven, where task activation defines regions of interest (ROI), and hypothesis driven, where regions are defined by the rat histological atlas. Success in these studies is attributed in part to the use of medetomidine hydrochloride (Domitor) for anesthesia. Consistent results in two different rat-brain systems, the sensorimotor and visual, strongly support the hypothesis that resting-state BOLD fluctuations are conserved across mammalian species and can be used to map brain systems.

Background The degree of suppression of sensory functions during general anesthesia is controversial. Here, the authors investigated whether discrete flash stimuli induced cortical field potential responses at an isoflurane concentration producing burst suppression and compared the spatiotemporal properties and frequency spectra of flash-induced burst responses with those occurring spontaneously. Methods Rats were equipped with multiple epidural and intracortical electrodes to record cortical field potentials in the right hemisphere at several locations along the anterior-posterior axis. At isoflurane concentrations of 1.1, 1.4, and 1.8%, discrete light flashes were delivered to the left eye while cortical field potentials were continuously recorded. Results Isoflurane at 1.4-1.8% produced burst suppression. Each flash produced a visual evoked potential in the primary visual cortex followed by secondary bursting activity in more anterior regions. The average latency and duration of these bursts were 220 and 810 ms, respectively. The spontaneous and flash-induced bursts were similar in frequency, duration, and spatial distribution. They had maximum power in the frontal (primary motor) cortex with a dominant frequency of 10 Hz. Conclusions The results suggest that discrete flash stimuli activate the motor regions of the cerebral cortex during isoflurane anesthesia and that these activations are analogous with those that occur spontaneously during burst suppression. Electrocortical suppression of the cortex during anesthesia does not prevent its response to visual stimuli.

Background Postoperative cognitive dysfunction (POCD) affects a significant number of patients and may have serious consequences for quality of life. Although POCD is most frequent after cardiac surgery, the prevalence of POCD after noncardiac surgery in older patients is also significant. The risk factors for POCD after noncardiac surgery include advanced age and preexisting cognitive impairment. Self-reported alcohol abuse is a risk factor for postoperative delirium, but its significance for long-term POCD has not been investigated. The goal of this study was to determine whether neurocognitive function is impaired after noncardiac surgery during general anesthesia in older patients with a history of alcohol abuse. Methods Subjects aged 55 yr and older with self-reported alcohol abuse (n = 28) and age-, sex-, education-matched nonalcoholic controls (n = 28) were tested using a neurocognitive battery before and 2 weeks after elective surgery (n = 28) or a corresponding time interval without surgery (n = 28). Verbal memory, visuospatial memory, and executive functions were assessed. A neurologic examination was performed to exclude subjects with potential cerebrovascular damage. Results Significant three-way interactions (analysis of variance) for Visual Immediate Recall, Visual Delayed Recall, Semantic Fluency, Phonemic Fluency, and the Color-Word Stroop Test implied that cognitive performance in the alcoholic group decreased after surgery more than it did in the other three groups. Conclusions The results suggest that a history of alcohol abuse in older patients presents a risk for postoperative cognitive impairment in the domains of visuospatial abilities and executive functions that may have important implications for quality of life and health risks.