A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep.
ABSTRACT: How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states. VIDEO ABSTRACT.
Project description:Propagating slow-waves in electroencephalogram (EEG) or local field potential (LFP) recordings occur during non-rapid eye-movement (NREM) sleep in both mammals and birds. Moreover, in both, input from the thalamus is thought to contribute to the genesis of NREM sleep slow-waves. Interestingly, the general features of slow-waves are also found under isoflurane anesthesia. However, it is unclear to what extent these slow-waves reflect the same processes as those giving rise to NREM sleep slow-waves. Similar slow-wave spatio-temporal properties during NREM sleep and isoflurane anesthesia would suggest that both types of slow-waves are based on related processes. We used a 32-channel silicon probe connected to a transmitter to make intra-cortical recordings of the visual hyperpallium in naturally sleeping and isoflurane anesthetized pigeons (<i>Columba livia</i>) using a within-bird design. Under anesthesia, the amplitude of LFP slow-waves was higher when compared to NREM sleep. Spectral power density across all frequencies (1.5-100 Hz) was also elevated. In addition, slow-wave coherence between electrode sites was higher under anesthesia, indicating higher synchrony when compared to NREM sleep. Nonetheless, the spatial distribution of slow-waves under anesthesia was more comparable to NREM sleep than to wake or REM sleep. Similar to NREM sleep, slow-wave propagation under anesthesia mainly occurred in the thalamic input layers of the hyperpallium, regions which also showed the greatest slow-wave power during both recording conditions. This suggests that the thalamus could be involved in the genesis of slow-waves under both conditions. Taken together, although slow-waves under isoflurane anesthesia are stronger, they share spatio-temporal activity characteristics with slow-waves during NREM sleep.
Project description:<h4>Study objective</h4>Slow wave activity (SWA) during NREM sleep is the best characterized marker of sleep homeostasis, and the occurrence of sleep slow waves is necessary to reduce sleep need. Recent evidence suggests that sleep slow waves may mediate several beneficial effects of sleep on performance, from the prevention of cognitive impairments to memory consolidation. However, slow waves are also triggered by low doses of many anesthetics, but very few reports have examined whether anesthesia-mediated slow waves affect the homeostatic regulation of sleep. Moreover, no study has examined how sleep is affected by higher doses of anesthetics, which lead to a predominantly "isoelectric" EEG tracing without slow waves.<h4>Design</h4>We studied in rats whether 1 hour of a dose of isoflurane or desflurane able to induce almost continuous slow waves (ISO-sw, DES-sw), and of a dose of desflurane resulting in a predominantly isoelectric EEG (DES-iso) reduces the sleep pressure caused by 4 h of sleep deprivation. Anesthesia was compared to a mock condition in which rats were only anesthetized for 2-3 min.<h4>Setting</h4>Basic sleep research laboratory.<h4>Patients or participants</h4>Male WKY rats (n=31).<h4>Interventions</h4>Total sleep deprivation by exposure to novel objects starting at light onset, followed by one hour of anesthesia or mock anesthesia.<h4>Measurements and results</h4>One hour of anesthesia (sw or iso) did not affect either sleep duration or the overall sleep pattern. Anesthesia with ISO-sw or DES-sw, both associated with the occurrence of almost continuous slow waves, reduced the SWA rebound expected following 4 h of sleep deprivation. One hour of anesthesia with DES-iso, associated with isoelectric EEG and few slow waves, also reduced the SWA rebound after sleep deprivation, and did so to an extent similar to that observed after DES-sw. However, in contrast to DES-sw, SWA after DES-iso remained chronically lower than in baseline, resulting in reduced slow wave energy (SWE, SWA × time) for at least 2 days.<h4>Conclusion</h4>The blunted SWA rebound after ISO-sw and DES-sw suggests that anesthesia slow waves may substitute for sleep slow waves. The reduced SWA rebound after DES-iso may reflect a pathological condition that results in a chronic decrease in SWA, or may suggest that anesthesia slow waves are not an absolute requirement to discharge sleep pressure.
Project description:The re-establishment of conscious awareness after discontinuing general anesthesia has often been assumed to be the inverse of loss of consciousness. This is despite the obvious asymmetry in the initiation and termination of natural sleep. In order to characterize the restoration of consciousness after surgery, we recorded frontal electroencephalograph (EEG) from 100 patients in the operating room during maintenance and emergence from general anesthesia. We have defined, for the first time, 4 steady-state patterns of anesthetic maintenance based on the relative EEG power in the slow-wave (<14 Hz) frequency bands that dominate sleep and anesthesia. Unlike single-drug experiments performed in healthy volunteers, we found that surgical patients exhibited greater electroencephalographic heterogeneity while re-establishing conscious awareness after drug discontinuation. Moreover, these emergence patterns could be broadly grouped according to the duration and rapidity of transitions amongst these slow-wave dominated brain states that precede awakening. Most patients progressed gradually from a pattern characterized by strong peaks of delta (0.5-4 Hz) and alpha/spindle (8-14 Hz) power ('Slow-Wave Anesthesia') to a state marked by low delta-spindle power ('Non Slow-Wave Anesthesia') before awakening. However, 31% of patients transitioned abruptly from Slow-Wave Anesthesia to waking; they were also more likely to express pain in the post-operative period. Our results, based on sleep-staging classification, provide the first systematized nomenclature for tracking brain states under general anesthesia from maintenance to emergence, and suggest that these transitions may correlate with post-operative outcomes such as pain.
Project description:The "non-specific" ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the "specific" ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to "non-specific" thalamic nuclei.
Project description:It has long been known that electroencephalogram (EEG) signals generate chaotic strange attractors and the shape of these attractors correlate with depth of anesthesia. We applied chaos analysis to frontal cortical and hippocampal micro-EEG signals from implanted microelectrodes (layer 4 and CA1, respectively). Rats were taken to and from loss of righting reflex (LORR) with isoflurane and behavioral measures were compared to attractor shape. Resting EEG signals at LORR differed markedly from awake signals, more similar to slow wave sleep signals, and easily discerned in raw recordings (high amplitude slow waves), and in fast Fourier transform analysis (FFT; increased delta power), in good agreement with previous studies. EEG activation stimulated by turning rats on their side, to test righting, produced signals quite similar to awake resting state EEG signals. That is, the high amplitude slow wave activity changed to low amplitude fast activity that lasted for several seconds, before returning to slow wave activity. This occurred regardless of whether the rat was able to right itself, or not. Testing paw pinch and tail clamp responses produced similar EEG activations, even from deep anesthesia when burst suppression dominated the spontaneous EEG. Chaotic attractor shape was far better at discerning between these awake-like signals, at loss of responses, than was FFT analysis. Comparisons are provided between FFT and chaos analysis of EEG during awake walking, slow wave sleep, and isoflurane-induced effects at several depths of anesthesia. Attractors readily discriminated between natural sleep and isoflurane-induced "delta" activity. Chaotic attractor shapes changed gradually through the transition from awake to LORR, indicating that this was not an on/off like transition, but rather a point along a continuum of brain states.
Project description:A controversy has developed in recent years over the roles of frontal and posterior cortices in mediating consciousness and unconsciousness. Disruption of posterior cortex during sleep appears to suppress the contents of dreaming, yet activation of frontal cortex appears necessary for perception and can reverse unconsciousness under anesthesia. We used anesthesia to study how regional cortical disruption, mediated by slow wave modulation of broadband activity, changes during unconsciousness in humans. We found that broadband slow-wave modulation enveloped posterior cortex when subjects initially became unconscious, but later encompassed both frontal and posterior cortex when subjects were more deeply anesthetized and likely unarousable. Our results suggest that unconsciousness under anesthesia comprises several distinct shifts in brain state that disrupt the contents of consciousness distinct from arousal and awareness of those contents.
Project description:The mechanism by which sleep consolidates memory is unclear. Based on the two-stage model of memory consolidation, different functions for slow wave sleep (SWS) and rapid eye movement (REM) sleep have been proposed; thus, state-dependent changes of neural oscillations in the hippocampus might clarify this fundamental question.We recorded hippocampal local field potentials from freely behaving monkeys via telemetry and analyzed their nonstationary oscillations using Hilbert-Huang transform.By applying a recently developed empirical mode decomposition analysis, we found strong cross-frequency coupling between high-frequency and slow wave oscillations during SWS and a prominent increase of gamma band activity in short bursts during REM sleep in unanesthetized primates' hippocampus.Spatiotemporal integration through coupled oscillations during slow wave sleep might be a physiological basis of system consolidation, whereas gamma bursts during rapid eye movement sleep might be related to synaptic consolidation in the local hippocampal neural circuit.
Project description:Anesthetic drugs are typically administered to induce altered states of arousal that range from sedation to general anesthesia (GA). Systems neuroscience studies are currently being used to investigate the neural circuit mechanisms of anesthesia-induced altered arousal states. These studies suggest that by disrupting the oscillatory dynamics that are associated with arousal states, anesthesia-induced oscillations are a putative mechanism through which anesthetic drugs produce altered states of arousal. However, an empirical clinical observation is that even at relatively stable anesthetic doses, patients are sometimes intermittently responsive to verbal commands during states of light sedation. During these periods, prominent anesthesia-induced neural oscillations such as slow-delta (0.1-4 Hz) oscillations are notably absent. Neural correlates of intermittent responsiveness during light sedation have been insufficiently investigated. A principled understanding of the neural correlates of intermittent responsiveness may fundamentally advance our understanding of neural dynamics that are essential for maintaining arousal states, and how they are disrupted by anesthetics. Therefore, we performed a high-density (128 channels) electroencephalogram (EEG) study (n = 8) of sevoflurane-induced altered arousal in healthy volunteers. We administered temporally precise behavioral stimuli every 5 s to assess responsiveness. Here, we show that decreased eyes-closed, awake-alpha (8-12 Hz) oscillation power is associated with lack of responsiveness during sevoflurane effect-onset and -offset. We also show that anteriorization-the transition from occipitally dominant awake-alpha oscillations to frontally dominant anesthesia induced-alpha oscillations-is not a binary phenomenon. Rather, we suggest that periods, which were defined by lack of responsiveness, represent an intermediate brain state. We conclude that awake-alpha oscillation, previously thought to be an idling rhythm, is associated with responsiveness to behavioral stimuli.
Project description:Slow cortical waves that propagate across the cerebral cortex forming large-scale spatiotemporal propagation patterns are a hallmark of non-REM sleep and anesthesia, but also occur during resting wakefulness. To investigate how the spatial temporal properties of slow waves change with the depth of anesthetic, we optically imaged population voltage transients generated by mouse layer 2/3 pyramidal neurons across one or two cortical hemispheres dorsally with a genetically encoded voltage indicator (GEVI). From deep barbiturate anesthesia to light barbiturate sedation, depolarizing wave events recruiting at least 50% of the imaged cortical area consistently appeared as a conserved repertoire of distinct wave motifs. Toward awakening, the incidence of individual motifs changed systematically (the motif propagating from visual to motor areas increased while that from somatosensory to visual areas decreased) and both local and global cortical dynamics accelerated. These findings highlight that functional endogenous interactions between distant cortical areas are not only constrained by anatomical connectivity, but can also be modulated by the brain state.
Project description:Memory reprocessing following acquisition enhances memory consolidation. Specifically, neural activity during encoding is thought to be 'replayed' during subsequent slow-wave sleep. Such memory replay is thought to contribute to the functional reorganization of neural memory traces. In particular, memory replay may facilitate the exchange of information across brain regions by inducing a reconfiguration of connectivity across the brain. Memory reactivation can be induced by external cues through a procedure known as "targeted memory reactivation". Here, we analysed data from a published study with auditory cues used to reactivate visual object-location memories during slow-wave sleep. We characterized effects of memory reactivation on brain network connectivity using graph-theory. We found that cue presentation during slow-wave sleep increased global network integration of occipital cortex, a visual region that was also active during retrieval of object locations. Although cueing did not have an overall beneficial effect on the retention of cued versus uncued associations, individual differences in overnight memory stabilization were related to enhanced network integration of occipital cortex. Furthermore, occipital cortex displayed enhanced connectivity with mnemonic regions, namely the hippocampus, parahippocampal gyrus, thalamus and medial prefrontal cortex during cue sound presentation. Together, these results suggest a neural mechanism where cue-induced replay during sleep increases integration of task-relevant perceptual regions with mnemonic regions. This cross-regional integration may be instrumental for the consolidation and long-term storage of enduring memories.