When we are anesthetized, we expect consciousness to vanish. But does it always? Although anesthesia undoubtedly induces unresponsiveness and amnesia, the extent to which it causes unconsciousness is harder to establish. For instance, certain anesthetics act on areas of the brain’s cortex near the midline and abolish behavioral responsiveness, but not necessarily consciousness. Unconsciousness is likely to ensue when a complex of brain regions in the posterior parietal area is inactivated. Consciousness vanishes when anesthetics produce functional disconnection in this posterior complex, interrupting cortical communication and causing a loss of integration; or when they lead to bistable, stereotypic responses, causing a loss of information capacity. Thus, anesthetics seem to cause unconsciousness when they block the brain’s ability to integrate information.

General anesthesia consists of amnesia, hypnosis, analgesia, and areflexia. Of these, the mechanism of hypnosis, or loss of consciousness, has been the most elusive, yet a fascinating problem. How anesthetic agents suppress human consciousness has been investigated with neuroimaging for two decades. Anesthetics substantially reduce the global cerebral metabolic rate and blood flow with a degree of regional heterogeneity characteristic to the anesthetic agent. The thalamus appears to be a common site of modulation by several anesthetics, but this may be secondary to cortical effects. Stimulus-dependent brain activation is preserved in primary sensory areas, suggesting that unconsciousness cannot be explained by cortical deafferentation or a diminution of cortical sensory reactivity. The effect of general anesthetics in functional and effective connectivity is varied depending on the agent, dose, and network studied. At an anesthetic depth characterized by the subjects' unresponsiveness, a partial, but not complete, reduction in connectivity is generally observed. Functional connectivity of the frontoparietal association cortex is often reduced, but a causal role of this change for the loss of consciousness remains uncertain. Functional connectivity of the nonspecific (intralaminar) thalamic nuclei is preferentially reduced by propofol. Higher-order thalamocortical connectivity is also reduced with certain anesthetics. The changes in functional connectivity during anesthesia induction and emergence do not mirror each other; the recovery from anesthesia may involve increases in functional connectivity above the normal wakeful baseline. Anesthetic loss of consciousness is not a block of corticofugal information transfer, but a disruption of higher-order cortical information integration. The prime candidates for functional networks of the forebrain that play a critical role in maintaining the state of consciousness are those based on the posterior parietal-cingulate-precuneus region and the nonspecific thalamus.

The ongoing stream of human consciousness relies on two distinct cortical systems, the default mode network and the dorsal attention network, which alternate their activity in an anticorrelated manner. We examined how the two systems are regulated in the conscious brain and how they are disrupted when consciousness is diminished. We provide evidence for a “temporal circuit” characterized by a set of trajectories along which dynamic brain activity occurs. We demonstrate that the transitions between default mode and dorsal attention networks are embedded in this temporal circuit, in which a balanced reciprocal accessibility of brain states is characteristic of consciousness. Conversely, isolation of the default mode and dorsal attention networks from the temporal circuit is associated with unresponsiveness of diverse etiologies. These findings advance the foundational understanding of the functional role of anticorrelated systems in consciousness.

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. Functional connectivity in the resting human brain using blood oxygen level dependent (BOLD) contrast is revealed by analysis of a series of MRI echo-planar images acquired over a period of several minutes with the subject at rest (1). In the present work, functional connectivity experiments are extended from human brain to rat brain and our central hypothesis is that the underlying physiology is conserved across all mammalian species.A reference time course obtained from a reference voxel (or, alternatively, an average over a cluster of voxel time courses in a region of interest [ROI]) is formed. Cross correlation of the reference time course with all voxel time courses in the slice provides a functional connectivity map. A strategy is required for selection of the reference time course, and performance of a task is commonly used to define ROIs in resting brain that can be used to form reference time courses.We have discovered that electrical stimulation using an implanted electrode on the radial nerve of the brachial plexus of a rat (2) results in activation of a network of sensorimotor brain regions, each of which is a suitable candidate for formation of a reference time course when analyzing resting-state data. Experiments not only in the sensorimotor system but also in the visual system provide further support for our central hypothesis. Functional connectivity was studied using reference waveforms obtained from areas that were found to be activated by light incident on the retina that was turned on and off in a block-trial functional MRI (fMRI) experiment.Anatomic images acquired in this experiment are of high quality, and it is possible to define anatomic regions purely by reference to the rat histological atlas (3). One can develop a reference waveform from each of these regions and test a specific hypothesis that functional connectivity to a second region is consistent with a known connectivity. We report here success in this hypothesis-driven approach to analysis of resting-state data. A total of 22 sensorimotor regions were identified, and connectivities between each of these regions and the other 21 regions were determined.Most functional connectivity studies have been in the awake human b...

The α2-adrenoreceptor agonist, medetomidine, which exhibits dose-dependent sedative effects and is gaining acceptance in small-animal functional magnetic resonance imaging (fMRI), has been studied. Rats were examined on the bench using the classic tail-pinch method with three infusion sequences: 100 μg/kg/hr, 300 μg/kg/hr, or 100 μg/kg/hr followed by 300 μg/kg/hr. Stepping the infusion rate from 100 to 300 μg/kg/hr after 2.5 hours resulted in a prolonged period of approximately level sedation that cannot be achieved by a constant infusion of either 100 or 300 μg/kg/hr. By stepping the infusion dosage, experiments as long as six hours are possible. Functional MRI experiments were carried out on rats using a frequency dependent electrical stimulation protocol—namely, forepaw stimulation at 3, 5, 7, and 10 Hz. Each rat was studied for a four-hour period, divided into two equal portions. During the first portion, rats were started at a 100 μg/kg/hr constant infusion. During the second portion, four secondary levels of infusion were used: 100, 150, 200, and 300 μg/kg/hr. The fMRI response to stimulation frequency was used as an indirect measure of modulation of neuronal activity through pharmacological manipulation. The frequency response to stimulus was attenuated at the lower secondary infusion dosages 100 or 150 μg/kg/hr but not at the higher secondary infusion dosages 200 or 300 μg/kg/hr. Parallel experiments with the animal at rest were carried out using both electroencephalogram (EEG) and functional connectivity MRI (fcMRI) methods with consistent results. In the secondary infusion period using 300 μg/kg/hr, resting-state functional connectivity is enhanced.

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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.