Desflurane Selectively Suppresses Long-latency Cortical Neuronal Response to Flash in the Rat

Background—The effect of inhalational anesthetics on sensory-evoked unit activity in the cerebral cortex has been controversial. Desflurane has desirable properties for in vivo neurophysiologic studies but its effect on cortical neuronal activity and neuronal responsiveness is not known. We studied the effect of desflurane on resting and visual evoked unit activity in rat visual cortex in vivo. Methods—Desflurane was administered to adult albino rats at steady-state concentrations at 2%, 4%, 6% and 8%. Flashes from a light emitting diode were delivered to the left eye at 5-second intervals. Extracellular unit activity within the right visual cortex was recorded using a 49-electrode array. Individual units were identified using principal components analysis. Results—At 2% desflurane 578 active units were found. Of these, 75% increased their firing rate in response to flash. Most responses contained early (0–100ms) and late (150–1000ms) components. With increasing desflurane concentration, the number of units active at baseline decreased (−13%), the number of early responding units increased (+31%), and number of late responding units decreased (−15%). Simultaneously, baseline firing rate decreased (−77%), the early response was unchanged, and the late response decreased (−60%). Conclusions—The results indicate that visual cortex neurons remain responsive to flash stimulation under desflurane anesthesia but the long-latency component of their response is attenuated in a concentration-dependent manner. Suppression of the long-latency response may be related to a loss of cortico-cortical feedback and loss of consciousness

Critical Changes in Cortical Neuronal Interactions in Anesthetized and Awake Rats

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. Here we investigated 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%, 2% desflurane anesthesia and wakefulness. Light flashes were delivered to the retina by transcranial illumination at 5-15s 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 post-stimulus complexity (35%) occurred prior to reaching 4% desflurane concentration – a level associated with the recovery of consciousness according to the rats\u27 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 post-stimulus complexity reaches plateau. The critical changes in cortical neuronal interactions occur during transition to consciousness

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

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

Monosynaptic Functional Connectivity in Cerebral Cortex During Wakefulness and Under Graded Levels of Anesthesia

The balance between excitation and inhibition is considered to be of significant importance for neural computation and cognitive function. Excitatory and inhibitory functional connectivity in intact cortical neuronal networks in wakefulness and graded levels of anesthesia has not been systematically investigated. We compared monosynaptic excitatory and inhibitory spike transmission probabilities using pairwise cross-correlogram (CCG) analysis. Spikes were measured at 64 sites in the visual cortex of rats with chronically implanted microelectrode arrays during wakefulness and three levels of anesthesia produced by desflurane. Anesthesia decreased the number of active units, the number of functional connections, and the strength of excitatory connections. Connection probability (number of connections per number of active unit pairs) was unaffected until the deepest anesthesia level, at which a significant increase in the excitatory to inhibitory ratio of connection probabilities was observed. The results suggest that the excitatory–inhibitory balance is altered at an anesthetic depth associated with unconsciousness

Modeling Resting-State Functional Networks When the Cortex Falls Asleep: Local and Global Changes

The transition from wakefulness to sleep represents the most conspicuous change in behavior and the level of consciousness occurring in the healthy brain. It is accompanied by similarly conspicuous changes in neural dynamics, traditionally exemplified by the change from "desynchronized” electroencephalogram activity in wake to globally synchronized slow wave activity of early sleep. However, unit and local field recordings indicate that the transition is more gradual than it might appear: On one hand, local slow waves already appear during wake; on the other hand, slow sleep waves are only rarely global. Studies with functional magnetic resonance imaging also reveal changes in resting-state functional connectivity (FC) between wake and slow wave sleep. However, it remains unclear how resting-state networks may change during this transition period. Here, we employ large-scale modeling of the human cortico-cortical anatomical connectivity to evaluate changes in resting-state FC when the model "falls asleep” due to the progressive decrease in arousal-promoting neuromodulation. When cholinergic neuromodulation is parametrically decreased, local slow waves appear, while the overall organization of resting-state networks does not change. Furthermore, we show that these local slow waves are structured macroscopically in networks that resemble the resting-state networks. In contrast, when the neuromodulator decrease further to very low levels, slow waves become global and resting-state networks merge into a single undifferentiated, broadly synchronized networ

Arousal system stimulation and anesthetic state alter visuoparietal connectivity

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

Retino‐cortical stimulus frequency‐dependent gamma coupling: evidence and functional implications of oscillatory potentials

Long‐range gamma band EEG oscillations mediate information transmission between distant brain regions. Gamma band‐based coupling may not be restricted to cortex‐to‐cortex communication but may include extracortical parts of the visual system. The retinogram and visual event‐related evoked potentials exhibit time‐locked, forward propagating oscillations that are candidates of gamma oscillatory coupling between the retina and the visual cortex. In this study, we tested if this gamma coupling is present as indicated by the coherence of gamma‐range (70–200 Hz) oscillatory potentials (OPs) recorded simultaneously from the retina and the primary visual cortex in freely moving, adult rats. We found significant retino‐cortical OP coherence in a wide range of stimulus duration (0.01–1000 msec), stimulus intensity (800–5000 mcd/mm2), interstimulus interval (10–400 msec), and stimulus frequency (0.25–25 Hz). However, at low stimulus frequencies, the OPs were time‐locked, flickering light at 25 Hz entrained continuous OP coherence (steady‐state response, SSR). Our results suggest that the retina and the visual cortex exhibit oscillatory coupling at high‐gamma frequency with precise time locking and synchronization of information transfer from the retina to the visual cortex, similar to cortico‐cortical gamma coupling. The temporal fusion of retino‐cortical gamma coherence at stimulus rates of theater movies may explain the mechanism of the visual illusion of continuity. How visual perception depends on early transformations of ascending sensory information is incompletely understood. By simultaneous measurement of flash‐evoked potentials in the retina and the visual cortex in awake, freely moving rats, we demonstrate for the first time that time‐locked gamma oscillatory potentials exhibit stable retino‐cortical synchrony across a wide range of stimulus parameters and that the temporal continuity of coherence changes with stimulus frequency according to the expected change in the visual illusion of continuity.The retina and the visual cortex exhibit oscillatory coupling at high‐gamma frequency with precise time locking and synchronization of information transfer from the retina to the visual cortex, similar to cortico‐cortical gamma coupling. The temporal fusion of retino‐cortical gamma coherence at stimulus rates of theater movies may explain the mechanism of the visual illusion of continuity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134072/1/phy212986.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134072/2/phy212986_am.pd

Disrupted neural variability during propofol‐induced sedation and 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.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146388/1/hbm24304_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146388/2/hbm24304.pd