Propofol and Etomidate Depress Cortical, Thalamic, and Reticular Formation Neurons During Anesthetic-Induced Unconsciousness

Andrada, Jason; Livingston, Preetha; Lee, Bong Jae; Antognini, Joseph F.

doi:10.1213/ane.0b013e3182405228

Cited by 35 publications

(21 citation statements)

References 28 publications

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“…Necessary for these functions, layer IV in ferret PFC receives many afferents from the mediodorsal nuclei of the thalamus (Duque and McCormick 2010). Various anesthetics have been shown to decrease thalamic activity (Andrada et al 2012) and thalamocortical connectivity (Hudetz 2012). At first glance, reduced thalamic activity is seemingly at odds with increased MU firing in layer IV of V1.…”

Section: Discussionmentioning

confidence: 99%

“…The specific subunit composition of the GABA A receptor appears to modulate the effect of propofol (Franks 2006). Cats anesthetized with propofol exhibit a spectral peak around 12 Hz and decreased spontaneous single-unit firing of occipital cortical neurons (Andrada et al 2012). Loss of consciousness (LOC) induced by propofol in humans is marked by frontal alpha oscillations as measured by EEG (Purdon et al 2013).…”

Section: Discussionmentioning

confidence: 99%

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Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer

Sellers

Bennett

Hutt

et al. 2013

Journal of Neurophysiology

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Anesthesia is widely used in medicine and research to achieve altered states of consciousness and cognition. Whereas changes to macroscopic cortical activity patterns by anesthesia measured at the spatial resolution of electroencephalography have been widely studied, modulation of mesoscopic and microscopic network dynamics by anesthesia remain poorly understood. To address this gap in knowledge, we recorded spontaneous mesoscopic (local field potential) and microscopic (multiunit activity) network dynamics in primary visual cortex (V1) and prefrontal cortex (PFC) of awake and isoflurane anesthetized ferrets ( Mustela putoris furo). This approach allowed for examination of activity as a function of cortical area, cortical layer, and anesthetic depth with much higher spatial and temporal resolution than in previous studies. We hypothesized that a primary sensory area and an association cortical area would exhibit different patterns of network modulation by anesthesia due to their different functional roles. Indeed, we found effects specific to cortical area and cortical layer. V1 exhibited minimal changes in rhythmic structure with anesthesia but differential modulation of input layer IV. In contrast, anesthesia profoundly altered spectral power in PFC, with more uniform modulation across cortical layers. Our results demonstrate that anesthesia modulates spontaneous cortical activity in an area- and layer-specific manner. These finding provide the basis for 1) refining anesthesia monitoring algorithms, 2) reevaluating the large number of systems neuroscience studies performed in anesthetized animals, and 3) increasing our understanding of differential dynamics across cortical layers and areas.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer

Sellers

Bennett

Hutt

et al. 2013

Journal of Neurophysiology

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“…Then, the detected decrease of transfer time for maximum connectivity during unconsciousness could be due to less information transferred. A reduction of information could be caused by thalamic actions and thalamocortical interactions as propofol also reduces thalamic activity [29], [30]. Although STEn analyses only detect cortico-cortical interactions, the thalamic role for loss of consciousness can not be disregarded.…”

Section: Discussionmentioning

confidence: 99%

Fronto-Parietal Connectivity Is a Non-Static Phenomenon with Characteristic Changes during Unconsciousness

et al. 2014

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BackgroundIt has been previously shown that loss of consciousness is associated with a breakdown of dominating fronto-parietal feedback connectivity as assessed by electroencephalogram (EEG) recordings. Structure and strength of network connectivity may change over time. Aim of the current study is to investigate cortico-cortical connectivity at different time intervals during consciousness and unconsciousness. For this purpose, EEG symbolic transfer entropy (STEn) was calculated to indicate cortico-cortical information transfer at different transfer times.MethodsThe study was performed in 15 male volunteers. 29-channel EEG was recorded during consciousness and propofol-induced unconsciousness. EEG data were analyzed by STEn, which quantifies intensity and directionality of the mutual information flow between two EEG channels. STEn was computed over fronto-parietal channel pair combinations (10 s length, 0.5–45 Hz total bandwidth) to analyze changes of intercortical directional connectivity. Feedback (fronto → parietal) and feedforward (parieto → frontal) connectivity was calculated for transfer times from 25 ms to 250 ms in 5 ms steps. Transfer times leading to maximum directed interaction were identified to detect changes of cortical information transfer (directional connectivity) induced by unconsciousness (p<0.05).ResultsThe current analyses show that fronto-parietal connectivity is a non-static phenomenon. Maximum detected interaction occurs at decreased transfer times during propofol-induced unconsciousness (feedback interaction: 60 ms to 40 ms, p = 0.002; feedforward interaction: 65 ms to 45 ms, p = 0.001). Strength of maximum feedback interaction decreases during unconsciousness (p = 0.026), while no effect of propofol was observed on feedforward interaction. During both consciousness and unconsciousness, intensity of fronto-parietal interaction fluctuates with increasing transfer times.ConclusionNon-stationarity of directional connectivity may play a functional role for cortical network communication as it shows characteristic changes during propofol-induced unconsciousness.

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“…The brainstem arousal pathways and thalamocortical system are considered to be important targets for propofol-induced hypnosis [25, 29]. Although we did not observe down-regulation of pCREB in the thalamus, propofol likely inhibits some parts of the brainstem and thalamus in neonatal rats, leading to inhibition of the righting reflex and sedation [30], because GABA A receptor signaling is inhibitory in these regions even at P7. We speculate that in the presence of bumetanide, propofol-induced LORR was enhanced because bumetanide may suppress the propofol-induced activation of the cortex without affecting inhibition of the caudal CNS in P7 rats.…”

Section: Discussionmentioning

confidence: 85%

Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats

et al. 2016

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Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner. In the present study, we tested the hypothesis that propofol-induced loss of righting reflex (LORR) but not immobilizing actions are modulated by NKCC1-dependent mechanisms and reduced in neonatal rats compared with adolescent rats. We estimated neuronal activity in the cortex, hippocampus and thalamus after propofol administration with or without bumetanide, an NKCC1 inhibitor, by immunostaining of phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB). We studied effects of bumetanide on propofol-induced LORR and immobilizing actions in postnatal day 7 and 28 (P7 and P28) rats. The pCREB expression in the cortex (P = 0.001) and hippocampus (P = 0.01) was significantly greater in the rats receiving propofol only than in the rats receiving propofol plus bumetanide at P 7. Propofol-induced LORR or immobilizing effects did not differ significantly between P7 and P28. Bumetanide significantly enhanced propofol-induced LORR (P = 0.031) but not immobilization in P7 rats. These results are partially consistent with our hypothesis. They suggest that propofol may activate the rostral but not caudal central nervous system dependently on NKCC1, and these differential actions may underlie the different properties of sedative and immobilizing actions observed in neonatal rats.

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Propofol and Etomidate Depress Cortical, Thalamic, and Reticular Formation Neurons During Anesthetic-Induced Unconsciousness

Cited by 35 publications

References 28 publications

Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer

Anesthesia differentially modulates spontaneous network dynamics by cortical area and layer

Fronto-Parietal Connectivity Is a Non-Static Phenomenon with Characteristic Changes during Unconsciousness

Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats

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