Electroencephalographic Evidence for Individual Neural Inertia in Mice That Decreases With Time

Abstract

Previous studies have demonstrated that the brain has an intrinsic resistance to changes in arousal state. This resistance is most easily measured at the population level in the setting of general anesthesia and has been termed neural inertia. To date, no study has attempted to determine neural inertia in individuals. We hypothesize that individuals with markedly increased or decreased neural inertia might be at increased risk for complications related to state transitions, from awareness under anesthesia, to delayed emergence or confusion/impairment after emergence. Hence, an improved theoretical and practical understanding of neural inertia may have the potential to identify individuals at increased risk for these complications. This study was designed to explicitly measure neural inertia in individuals and empirically test the stochastic model of neural inertia using spectral analysis of the murine EEG. EEG was measured after induction of and emergence from isoflurane administered near the EC50 dose for loss of righting in genetically inbred mice on a timescale that minimizes pharmacokinetic confounds. Neural inertia was assessed by employing classifiers constructed using linear discriminant or supervised machine learning methods to determine if features of EEG spectra reliably demonstrate path dependence at steady-state anesthesia. We also report the existence of neural inertia at the individual level, as well as the population level, and that neural inertia decreases over time, providing direct empirical evidence supporting the predictions of the stochastic model of neural inertia.

Hormonal basis of sex differences in anesthetic sensitivity

“…1 E ). Previous studies using this apparatus established that isoflurane concentration in the brain reaches steady state within 10 min ( 55 ). Consistent with the results in Fig.…”

“…While it is possible that pharmacokinetic differences exist between males and females, here we demonstrate that such differences cannot account for the observed differences in anesthetic sensitivity. To accomplish this, we utilized a behavioral paradigm developed in our lab ( 53 , 54 ), which allows us to study behavioral responses under steady-state anesthetic administration ( 55 ). To further support the conclusion that differences in anesthetic sensitivity cannot be solely due to differences in drug absorption, we directly confirmed that the steady-state concentration of isoflurane in the brain does not depend on sex or hormonal milieu.…”

“…Mice were exposed to each concentration step for 15 min prior to righting reflex assessment. Flow rates of one volume turnover per minute have been shown to equilibrate chambers within 5 min ( 53 ) with resulting brain concentrations equilibrating in approximately 10 min ( 55 ). An animal was considered to have an intact righting reflex if it was able to return to a prone position when rotated on its back, otherwise the righting reflex was considered absent.…”

“…Mice (n = 5 WT M, 5 WT F, 10 Ca.M, 9 Ov.F) were exposed to 1.00% isoflurane for 2 h and then rapidly killed by cervical dislocation to quantify whole brain isoflurane concentrations. Brains were subjected to high-performance liquid chromatography analysis as previously described ( 55 , 87 ).…”

In VivoPhotoadduction of Anesthetic Ligands in Mouse Brain Markedly Extends Sedation and Hypnosis

“…All signals were recorded using the freely available open source open-ephys GUI acquisition software ( www.open-ephys.org ) and analyzed in MATLAB (2022a, The MathWorks) using custom code using the signal processing and statistics toolboxes. EEG preprocessing was conducted as previously described ( Wasilczuk et al, 2021 ), except that bandpass filters with cutoffs of 0.5 and 100 Hz were used. After mean re-referencing, a single EEG lead overlying the left frontal association area (bregma 2.6 mm, 0.7 mm left lateral) was analyzed.…”