Analysis of stochastic fluctuations in responsiveness is a critical step toward personalized anesthesia
- University of Pennsylvania, United States
- The Ohio State University, United States
- Drexel University College of Medicine, United States
Figures
Figure 1
Different individual behaviors can produce identical population effects.
(A) Presence (top) or absence (bottom) of righting reflex is a binary behavioral measure that distinguishes awake from anesthetized mice. Schematic representations of three qualitatively distinct …
Figure 2 with 3 supplements
Individual responsiveness fluctuates over time with unchanging population response.
(A) Twenty mice were exposed to 0.6% isoflurane for 2 hr, then righting reflex was assessed every 3 min for another 2 hr at the same isoflurane concentration. Fluctuations between responsive (green) …
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Figure 2—source data 1
Mean population response probabilities of righting reflex assays in mice at 0.6% isoflurane and startle reflex assays in zebrafish at 3µM propofol.
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig2-data1-v1.xlsx
Figure 2—figure supplement 1
Response probabilities in mice at varying isoflurane concentrations.
Individual response probabilities and population response probabilities (PRP) are shown for 20 mice exposed to (A) 0.3% isoflurane, (B) 0.4% isoflurane, (C) 0.7% isoflurane, and (D) 0.9% isoflurane. …
Figure 2—figure supplement 2
Characterization of zebrafish startle response.
(A) The population response probability averaged across 48 zebrafish exposed to E3 larval medium alone is 0.72 ± 0.07 (mean ± SD, red line in A). SR was assessed every 30 s for 3 hrs after a 1-hr …
Figure 2—figure supplement 3
Chamber equilibration occurs within 5 min.
Target volatile anesthetic concentrations were reached within 5 min of drug exposure onset. Chamber equilibration is shown for a target concentration of 0.9% isoflurane. One volume turnover per …
Figure 3
Response probability is state-dependent.
(A) Twenty simulations of a Bernoulli process where the response probability is 44% for all trials (identical to the average PRP in mice at 0.6% isoflurane) were performed. Each simulation consisted …
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Figure 3—source data 1
Individual simulated and experimental response probabilities and probability of transitions (total, P(U|U), and P(U|R)).
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig3-data1-v1.xlsx
Figure 4 with 1 supplement
Stability of responsiveness and unresponsiveness are linked.
(A) (Left) The transition probability matrix for each individual can be represented as a point on a plane spanned by the diagonal elements P(U|U) and P(R|R) denoting the probability of staying in …
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Figure 4—source data 1
Individual mouse and zebrafish P(U|U) and P(R|R) values.
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig4-data1-v1.xlsx
Figure 4—figure supplement 1
Estimates for dwell time distributions and autocorrelation functions from individual behavioral assays.
(A) Responsive (green) and unresponsive (blue) dwell time distributions for each mouse exposed to 0.6% isoflurane are shown on semi-log scale. (B) Responsive and unresponsive dwell time …
Figure 5
Variability in drug sensitivity is a stable characteristic of an individual at steady state equilibrium.
Transition probability matrices were independently estimated for each mouse across the first two and last two of exposures to isoflurane and projected onto the first principal component. For …
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Figure 5—source data 1
PC1 values in mice for exposures 1/2 and 3/4 and in zebrafish for first and second half of exposure.
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig5-data1-v1.xlsx
Figure 6 with 1 supplement
Individual response probabilities between different drug concentrations overlap at a population level.
(A) Individual empirically-estimated transition probability matrices are plotted in the plane spanned by P(U|U) and P(R|R) for animals exposed to 0.3% isoflurane (n = 18, blue dots) and 0.6% …
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Figure 6—source data 1
PC1 values for mice exposed to 0.6% and for mice exposed to 0.3% isoflurane.
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig6-data1-v1.xlsx
Figure 6—figure supplement 1
Individual response probabilities between different drug concentrations overlap in zebrafish.
(A) Transition probability matrix estimated for each individual is represented by a point in a plane spanned by P(R|R) and P(U|U) for zebrafish exposed to either E3 medium (n=48, blue dots) or 3 μM …
Figure 7 with 1 supplement
Varying degrees of overlap in response probability are present at the individual level between different isoflurane concentrations.
(A) Probability density of the individual across-trial response probabilities were estimated for mice exposed to 0.4% isoflurane (blue) and 0.7% isoflurane (red). In contrast to results in Figure 6B …
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Figure 7—source data 1
PC1 values for mice exposed to both 0.4% and 0.7% isoflurane.
- https://cdn.elifesciences.org/articles/50143/elife-50143-fig7-data1-v1.xlsx
Figure 7—figure supplement 1
Ability to discriminate across two drug concentrations within individuals is highly variable.
Individual response probabilities are shown for 20 mice exposed to 0.7% isoflurane (blue) and 0.4% isoflurane (red). Righting reflex (RR) was assessed every 3 min for the final 2 hrs of a 4-hr …
Figure 8
A simple bistable neuronal network model with noise, reproduces experimental findings.
(A) The network consists of two neuronal populations (β and α) which are operationally defined as ‘sleep active’ and ‘wake active’ respectively. Neuronal populations are mutually inhibitory and …
Additional files
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Source code 1
Estimation of Dwell Time Distributions.
- https://cdn.elifesciences.org/articles/50143/elife-50143-code1-v1.m
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Source code 2
Estimation of Transition Probability Matrix.
- https://cdn.elifesciences.org/articles/50143/elife-50143-code2-v1.m
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Source code 3
Simulation of a Markov Process.
- https://cdn.elifesciences.org/articles/50143/elife-50143-code3-v1.m
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Transparent reporting form
- https://cdn.elifesciences.org/articles/50143/elife-50143-transrepform-v1.docx
