The Mouse as a Model Organism for Assessing Anesthetic Sensitivity

Wasilczuk, Andrzej Z.; Maier, Kaitlyn; Kelz, Max B.

doi:10.1016/bs.mie.2018.01.008

Cited by 25 publications

(25 citation statements)

References 57 publications

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“…The concentration of anesthetic at which 50% of patient lose their ability to respond to verbal commands is known at MAC-awake (Franks, 2008). In rodent literature, the righting reflex (RR) is typically used to establish whether a mouse is awake or not (Figure 1A) (Wasilczuk et al, 2018; Franks, 2006). MAC-awake and the EC 50 for loss of RR are closely correlated across mechanistically distinct anesthetics (Franks, 2008).…”

Section: Introductionmentioning

confidence: 99%

Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia

McKinstry-Wu

Wasilczuk

Harrison

et al. 2019

eLife

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Traditionally, drug dosing is based on a concentration-response relationship estimated in a population. Yet, in specific individuals, decisions based on the population-level effects frequently result in over or under-dosing. Here, we interrogate the relationship between population-based and individual-based responses to anesthetics in mice and zebrafish. The anesthetic state was assessed by quantifying responses to simple stimuli. Individual responses dynamically fluctuated at a fixed drug concentration. These fluctuations exhibited resistance to state transitions. Drug sensitivity varied dramatically across individuals in both species. The amount of noise driving transitions between states, in contrast, was highly conserved in vertebrates separated by 400 million years of evolution. Individual differences in anesthetic sensitivity and stochastic fluctuations in responsiveness complicate the ability to appropriately dose anesthetics to each individual. Identifying the biological substrate of noise, however, may spur novel therapies, assure consistent drug responses, and encourage the shift from population-based to personalized medicine.

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Section: Introductionmentioning

confidence: 99%

Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia

McKinstry-Wu

Wasilczuk

Harrison

et al. 2019

eLife

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“…By definition, anesthesia induction in mice occurs at the drug concentration when the righting reflex is lost, whereas emergence from anesthesia occurs at the concentration when the righting reflex returns 2,38 . For instance, the EC50 for the induction of halothane anesthesia is more than 2.5 times the EC50 for emergence.…”

Section: Discussionmentioning

confidence: 99%

“…Recovery to a conscious state in humans usually comprises full cortical desynchronization, initiation of movement and behavioral reactivity to sensory stimuli 1 . However, the combination of these parameters in rodents is rarely used when assessing arousal when emerging from anesthesia 2 or when investigating the neuronal pathways underlying reversing anesthetic states in animal models 3-6 . A clear discrepancy arises when analyzing cortical activity 7 and behavior among anesthetics.…”

Section: Introductionmentioning

confidence: 99%

“…The accepted view states that awakening in rodents correlates with individual events, such as spontaneous movement of a body part 12 , motor response after painful stimuli 8 or righting reflex 4,6,13 and implies that a single event can denote the restoration of motor behavior from a coma-like state. The righting reflex is considered the gold standard test to assess arousal in rodents, because vestibular inputs that sense head movement typically indicate awareness of the surroundings 2,14 . However, the righting reflex is retained in comatose-like rodents 15 , it lacks cortical involvement 16 and persists after precollicular transections in rodents 17 .…”

Section: Introductionmentioning

confidence: 99%

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Continuous regimens of cortico-motor integration calibrate levels of arousal during emergence from anesthesia

Gao

Calderon

2020

Preprint

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31Background: Recovery to a conscious state when emerging from anesthesia requires 32 full cortical desynchronization, initiation of movement and behavioral reactivity to 33 sensory stimuli. However, the variety of cortical electroencephalogram (EEG) patterns 34 associated with specific anesthetics and the paucity of behavioral descriptions during 35 emergence from anesthesia have prevented EEG and behavior as feasible tracking 36 methods to assess emerging from anesthesia. We propose a detailed combined 37 analysis of motor and cortical activity to determine levels of arousal in rodents. 39Methods: Using decreasing anesthetic concentrations, we simultaneously recorded 40 local field potentials (LFPs) and movement in mice. We delineated cortical dynamics 41 and sub-states during emergence from anesthesia by applying a smoothed-Z score to 42 extract dominant frequencies from spectrogram. Then, we implemented KMeans to 43 obtain cortical sub-states. Finally, we used density estimation and an abrupt change 44 detection algorithm to segment cortical activity into periods. We used cortical sub-states 45 obtained during isoflurane traces to supervise sub-states in sevoflurane and a 46 pharmacologically induced-arousal model. This information together with examining 47 videos were used to categorize behavior. 49Results: We identified five cortical periods with restored motor behavior during 50 emergence from isoflurane anesthetic. Periods of structured sub-states denoted when 51 specific motor behaviors occurred. No significant differences were found when 52 comparing the combined cortical features and motor behavior using isoflurane, 53 3 sevoflurane and our arousal-rodent model. We describe graded regimens of cortico-54 motor activity during emergence from anesthesia to assess arousal levels. 55 56 Conclusion: We show cortical patterns denote gradual motor behaviors when emerging 57 from anesthesia. Restoring motor behavior is a dynamic process that begins tens of 58 minutes earlier than the righting reflex. Combining cortical activity and motor behavior 59 unveils novel biomarkers to accurately track emerging from general anesthesia in 60 rodents and likely other species. 61 62 Key words: Emergence from anesthesia, movement, behavioral arousal, cortical 63 biomarkers, cortical periods, spectral analysis, smoothed Z score algorithm, k-means 64 classifier, righting reflex 65 66 67 68 69 70 71 72 4Introduction: 73 Recovery to a conscious state in humans usually comprises full cortical 74 desynchronization, initiation of movement and behavioral reactivity to sensory stimuli 1 . 75 However, the combination of these parameters in rodents is rarely used when assessing 76 arousal when emerging from anesthesia 2 or when investigating the neuronal pathways 77 underlying reversing anesthetic states in animal models 3-6 . A clear discrepancy arises 78 when analyzing cortical activity 7 and behavior among anesthetics. Some data suggests 79 excluding these parameters. For example, the onset of movement during the emergence 8...

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“…RR is the gold standard for assessing arousal/recovery of consciousness (ROC) in rodents and relies on vestibular inputs that sense head movement, indicating awareness of surroundings 1,2 . The RR is assessed by placing the rodent on its back and measuring the time it takes for the animal to right itself (Fig.…”

Section: Robust Alternative To the Righting Reflex To Assess Arousal mentioning

confidence: 99%

Robust alternative to the righting reflex to assess arousal in rodents

Gao

Calderon

2020

Sci Rep

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The righting reflex (RR) is frequently used to assess level of arousal and applied to animal models of a range of neurological disorders. RR produces a binary result that, when positive, is used to infer restoration of consciousness, often without further behavioral corroboration. We find that RR is an unreliable metric for arousal/recovery of consciousness. Instead, cortical activity and motor behavior that accompany RR are a non-binary, superior criterion that accurately calibrates and establishes level of arousal in rodents.

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The Mouse as a Model Organism for Assessing Anesthetic Sensitivity

Cited by 25 publications

References 57 publications

Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia

Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia

Continuous regimens of cortico-motor integration calibrate levels of arousal during emergence from anesthesia

Robust alternative to the righting reflex to assess arousal in rodents

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