Abstract

Simple SummaryTo understand brain function in rats and mice functional magnetic resonance imaging of the brain is used. With this type of “brain scan” regional changes in blood flow and oxygen consumption are measured as an indirect surrogate for activity of brain regions. Animals are often anesthetized for the experiments to prevent stress and blurred images due to movement. However, anesthesia may alter the measurements, as blood flow within the brain is differently affected by different anesthetics, and anesthetics also directly affect brain function. Consequently, results obtained under one anesthetic protocol may not be comparable with those obtained under another, and/or not representative for awake animals and humans. We have systematically searched the existing literature for studies analyzing the effects of different anesthesia methods or studies that compared anesthetized and awake animals. Most studies reported that anesthetic agents, doses and timing had an effect on functional magnetic resonance imaging results. To obtain results which promote our understanding of brain function, it is therefore essential that a standard for anesthetic protocols for functional magnetic resonance is defined and their impact is well characterized.In rodent models the use of functional magnetic resonance imaging (fMRI) under anesthesia is common. The anesthetic protocol might influence fMRI readouts either directly or via changes in physiological parameters. As long as those factors cannot be objectively quantified, the scientific validity of fMRI in rodents is impaired. In the present systematic review, literature analyzing in rats and mice the influence of anesthesia regimes and concurrent physiological functions on blood oxygen level dependent (BOLD) fMRI results was investigated. Studies from four databases that were searched were selected following pre-defined criteria. Two separate articles publish the results; the herewith presented article includes the analyses of 83 studies. Most studies found differences in BOLD fMRI readouts with different anesthesia drugs and dose rates, time points of imaging or when awake status was compared to anesthetized animals. To obtain scientifically valid, reproducible results from rodent fMRI studies, stable levels of anesthesia with agents suitable for the model under investigation as well as known and objectively quantifiable effects on readouts are, thus, mandatory. Further studies should establish dose ranges for standardized anesthetic protocols and determine time windows for imaging during which influence of anesthesia on readout is objectively quantifiable.

Highlights

  • Functional magnetic resonance imaging is commonly used in rat and mice models to study mechanisms underlying physiological as well as pathological brain functions [1,2,3].The present review concentrates on blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI).Assuming that neuronal activity is coupled to local blood flow— this may not apply to all brain regions [4], and the direction of correlations may vary [5]—this diagnostic imaging technique assesses neuronal activation based on measured changes in blood oxygen (O2 ) levels [6]: If certain brain regions are neuronally activated, arterioles and eventually capillaries are dilated and more fully oxygenated blood flows in [7]

  • Part a [15] of this review showed that changes in physiological parameters confound results of BOLD fMRI studies when undetected—in particular arterial partial pressure of Animals 2021, 11, 199 carbon dioxide (CO2 ), blood oxygenation and arterial blood pressures

  • Results of the systematic search, including a PRISMA flow chart as well as detailed results of the risk of bias assessment of all included studies, are reported in part a of the review [15]. This part of the review reports synthesized findings of the 83 references which investigated effects of different states of anesthesia on BOLD fMRI readouts in rats (70 references based on 62 datasets) and mice (13 references based on 11 datasets)

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Summary

Introduction

Functional magnetic resonance imaging (fMRI) is commonly used in rat and mice models to study mechanisms underlying physiological as well as pathological brain functions [1,2,3].The present review concentrates on blood oxygen level dependent (BOLD) fMRI.Assuming that neuronal activity is coupled to local blood flow— this may not apply to all brain regions [4], and the direction of correlations may vary [5]—this diagnostic imaging technique assesses neuronal activation based on measured changes in blood oxygen (O2 ) levels [6]: If certain brain regions are neuronally activated, arterioles and eventually capillaries are dilated and more fully oxygenated blood flows in [7]. Functional magnetic resonance imaging (fMRI) is commonly used in rat and mice models to study mechanisms underlying physiological as well as pathological brain functions [1,2,3]. Changes in the ratio of deoxy- to oxyhemoglobin content per unit of brain determine changes in BOLD signal. Cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2 ) and cerebral blood flow (CBF) are determinants of deoxyhemoglobin content [8]. Without an underlying change in neural activity, changes in CMRO2 , CBF or CBV may affect BOLD signal intensity

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