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

Abstract

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.

Asymmetric neural dynamics characterize loss and recovery of consciousness

“…Feedback between local neuronal populations or between functional brain regions may initiate state transitions and stabilization of the new state ( Joiner et al, 2013 ). As an example, anesthetics may hijack the sleep-wake circuitry by exciting sleep-promoting and inhibiting wake-promoting neurons ( McKinstry-Wu et al, 2019 ; Moore et al, 2012 ; Proekt and Hudson, 2018 ; Zhang et al, 2015 ). These neuronal populations mutually inhibit each other and thus exhibit self-reinforcing behavior ( McKinstry-Wu et al, 2019 ).…”

“…As an example, anesthetics may hijack the sleep-wake circuitry by exciting sleep-promoting and inhibiting wake-promoting neurons ( McKinstry-Wu et al, 2019 ; Moore et al, 2012 ; Proekt and Hudson, 2018 ; Zhang et al, 2015 ). These neuronal populations mutually inhibit each other and thus exhibit self-reinforcing behavior ( McKinstry-Wu et al, 2019 ). Once sleep-active neurons activate beyond a certain threshold, they shut down the wake-active neurons thereby decreasing their inhibitory effects and further strengthen mutual excitation amongst the sleep-active neurons ( Proekt and Hudson, 2018 ; Saper et al, 2005 ).…”

Molecular Diversity of Anesthetic Actions Is Evident in Electroencephalogram Effects in Humans and Animals

“…Note that individual patients can have varying electrophysiological response dynamics around LOR and ROR given their individual dynamic responses to the anesthetic agents ( Figure 5 ). Differences in response dynamics may occur because of the molecular binding dynamics of diverse agents or between individuals themselves [ 29 , 30 ].…”

Propofol Anesthesia Concentration Rather Than Abrupt Behavioral Unresponsiveness Linearly Degrades Responses in the Rat Primary Auditory Cortex

“…Throughout the experiment and propofol infusion, intermittent behavioral assessment was performed every 12 minutes between blocks of auditory stimulation. This assessment was done to estimate the behavioral responsiveness as a function of the propofol levels of each animal/time (Banks et al, 2018;Church & Shucard, 1987;Devor & Zalkind, 2001;Du et al, 2020;McKinstry-Wu et al, 2019). Assessment included a battery of behavioral tests using standardized procedures (Devor & Zalkind, 2001;Pillay, Vizuete, McCallum, & Hudetz, 2011): turning on back to assess for loss of righting reflex (LORR), tail pinch and hind-foot pinch to assess long spinal reflex, fore-paw pinch to assess short spinal reflex, dropping saline on eye for corneal reflex, touching whiskers for whisking reflex.…”