1 Abstract

In recent studies, significant evidence has emerged that suggests anesthetic exposure during early development can result in neuronal and glial injury and death, as well as behavioral and cognitive impairments, in animal models as well as retrospective human studies. Few studies have though investigated the effect of low-level anesthesia associated with imaging scans or relatively brief surgical interventions on early postnatal brain development. In this study, we show the effects of anesthesia exposure (ketamine and isoflurane) on early brain development in two distinct cohorts of typically developing rhesus macaques. Under two different settings of anesthesia exposure, handling, and image acquisition,  we show that multiple, short exposures to commonly used anesthetics are enough to cause marked changes in the white matter microstructure. Using high-resolution diffusion MRI, we show significant, widespread reductions in fractional anisotropy and corresponding increases in mean, axial and radial diffusivity occur across the brain measured at ages of 12-18 month as a result of exposures in the first year of life. These effects show a dose dependency and are as large as 40%  for large sections of the brain. These effects remain significant after accounting for gender and age via a generalized linear model. It is unknown if or to what degree the brain is able to recover from this white matter pathology fractional anisotropy later on life. This study is among the first to examine short, clinically relevant anesthesia exposures and their effects on the brain. 

2 Introduction

There is increasing scrutiny of the effects of anesthesia exposure on the developing brain. Employing rodent models, various studies showed that exposure to a wide range of anesthetics both before and soon after birth lead to neuroapoptosis \cite{Saito_1993,Jevtovic_Todorovic_2003,Young_2009,Lu_2006,Ma_2007,Cattano_2008,Liang_2010}. Studies using primate models found similar effects with histological studies demonstrating widespread neuroapoptosis after exposure to ketamine and isoflurane (Slikker 2007, Zou 2009, Brambrink 2010, Paule 2011, Brambrink 2012,Brambrink 2012a). It has also been demonstrated that neurodevelopmental outcomes are affected as well, with exposed macaques showing slower response times and poorer performance on a range of learning tasks even 3.5 years after exposure (Paule 2011). Another study examining the effects of repeated anesthetic exposures found that the frequency of anxiety-related behaviors increased in exposed macaques (Raper 2015) although it did not affect main aspects of social behavior, suggesting that the impact of anesthesia may be brain region specific. However, a major limitation of currently published studies is that they have predominantly used exposure times far beyond any clinically relevant exposure duration (as long as 24 hours). No study to date has looked at short, clinically relevant exposures that would correspond to the dosage (both in amount and duration of exposure) a typical human would receive during a minor pediatric surgery or a standard MR imaging session. Additionally, the majority of published studies relied on post-mortem histological analyses to quantify the effects of exposure. The in vivo effects at the neuroanatomical level have not yet been well characterized.