Effects of neonatal isoflurane anesthesia exposure on learning-specific and sensory systems in adults

Abstract

Millions of children undergo general anesthesia each year, and animal and human studies have indicated that exposure to anesthesia at an early age can impact neuronal development, leading to behavioral and learning impairments that manifest later in childhood and adolescence. Here, we examined the effects of isoflurane, a commonly-used general anesthetic, which was delivered to newborn rabbits. Trace eyeblink classical conditioning was used to assess the impact of neonatal anesthesia exposure on behavioral learning in adolescent subjects, and a variety of MRI techniques including fMRI, MR volumetry, spectroscopy and DTI captured functional, metabolic, and structural changes in key regions of the learning and sensory systems associated with anesthesia-induced learning impairment. Our results demonstrated a wide array of changes that were specific to anesthesia-exposed subjects, which supports previous studies that have pointed to a link between early anesthesia exposure and the development of learning and behavioral deficiencies. These findings point to the need for caution in avoiding excessive use of general anesthesia in young children and neonates.

Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia

“…The apoptosis observed by Jiang et al [125], who also administered anesthesia for six cumulative hours, across three sessions on postnatal days 7, 14 and 21, was so severe that there was a significant reduction in the rat hippocampal volume, compared to what was observed in the control group. Similarly, a reduction in hippocampal volume has also been observed in adult rabbits after they were exposed to three instances of neonatal anesthesia [113] (Figure 2e). The same study also conducted diffusion tensor imaging and identified significant changes in the fractional anisotropy of the CA1 region (Figure 2f-h), indicative of a reduction in cells and dendritic branching.…”

“…However, since neonatal anesthesia affects the development of the GABAergic system, it can result in weakened hemodynamic functioning. Neurovascular deficiency in adult animals resulting from neonatal anesthesia has already been shown by changes in both blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), during stimulation [ 113 , 138 ] and regional resting state fMRI signals [ 139 ]. The observed reduction in the magnitude of BOLD fMRI response indicates that the deficiency is at the neuronal level, vascular level or both.…”

The Contribution of Dysfunctional Chloride Channels to Neurovascular Deficiency and Neurodegeneration

“…These neurodegenerative and apoptotic processes can alter the delicate excitatory/inhibitory balance of cortical networks ( Aksenov et al, 2020a ). This imbalance can account for, at least in part, the negative developmental changes ( Johnston et al, 2002 ; Aksenov et al, 2020a ; Aksenov et al, 2020b ) and impeded GABAergic system development ( Young et al, 2012 ; Nisimov et al, 2018 ) following neonatal anesthesia. This disproportionate cell death leading to a shift in the excitatory/inhibitory balance requires further research in terms of occurrence of the local chronic hypoxia in later years, and how this shift caused by anesthesia, adapts throughout development.…”

Behavior and Regional Cortical BOLD Signal Fluctuations Are Altered in Adult Rabbits After Neonatal Volatile Anesthetic Exposure

“…While a number of structural changes have been identified that may link anesthesia and learning disability (Jevtovic-Todorovic et al, 2003), including cell loss in both the cortex and the hippocampus in infant animals (Jevtovic-Todorovic et al, 2003;Fredriksson et al, 2007;Istaphanous et al, 2011), functional changes in the brain associated with the learning and memory impairments remain poorly understood. Only a limited number of functional MRI (fMRI) studies were used to evaluate functional brain changes in response to neonatal anesthesia exposure (Aksenov et al, 2016(Aksenov et al, , 2020bChen et al, 2019).…”

“…As widespread neuronal injury has been reported in the hippocampus, cortex, and thalamus in animal models of neonatal inhaled anesthetic exposure (Patel and Sun, 2009), we hypothesized that rsfMRI would reveal alterations in long-range functional connectivity between the thalamus and the cortex due to the effects of neonatal anesthesia on thalamocortical input, as well as changes in short-range functional connectivity due to disrupted intracortical processing. We utilized a non-sedated rabbit model of neonatal isoflurane exposure (Aksenov et al, 2016(Aksenov et al, , 2020b) that allowed us to avoid the confounding influence of anesthesia during imaging.…”