General anaesthesia during infancy reduces white matter micro-organisation in developing rhesus monkeys

Abstract

Background: Non-human primates are commonly used in neuroimaging research for which general anaesthesia or sedation is typically required for data acquisition. In this analysis, the cumulative effects of exposure to ketamine, Telazol® (tiletamine and zolazepam), and the inhaled anaesthetic isoflurane on early brain development were evaluated in two independent cohorts of typically developing rhesus macaques.

Methods: Diffusion MRI scans were analysed from 43 rhesus macaques (20 females and 23 males) at either 12 or 18 months of age from two separate primate colonies.

Results: Significant, widespread reductions in fractional anisotropy with corresponding increased axial, mean, and radial diffusivity were observed across the brain as a result of repeated anaesthesia exposures. These effects were dose dependent and remained after accounting for age and sex at time of exposure in a generalised linear model. Decreases of up to 40% in fractional anisotropy were detected in some brain regions.

Conclusions: Multiple exposures to commonly used anaesthetics were associated with marked changes in white matter microstructure. This study is amongst the first to examine clinically relevant anaesthesia exposures on the developing primate brain. It will be important to examine if, or to what degree, the maturing brain can recover from these white matter changes.

Keywords: diffusion MRI; general anaesthesia isoflurane; ketamine; neurotoxicity; rhesus monkeys; white matter.

Fig 1

Omnibus of DTI properties FDR corrected p-values from the GLM. In both cohorts there is widespread significant effect of TNE across all regions of the brain and all major tracts. HPL, Harlow Primate Laboratory; YNPRC, Yerkes National Primate Research Center.

Fig 2

Plots showing the change in FA as a function of the TNE to general anaesthesia for two selected tracts. In tracts across the brain a steady decrease in FA was seen as the exposure increases. Note that the effect is more extensive in the YNPRC cohort, in part due to the longer exposure to anaesthesia. FA, fractional anisotropy; HPL, Harlow Primate Laboratory; YNPRC, Yerkes National Primate Research Center.

Fig 3

Visualization of the change in FA across the length of the tract averaged over all subjects for two particular tracts (genu and left optic tract) in the YNPRC cohort. Mean FA values are plotted as solid lines and dotted lines indicate standard deviation. There is a clear delination between the groups of a single (green, no prior MRI session) and repeated (red, 4 prior MRI sessions) exposures of anaesthesia. Similar figures for AD, MD, and RD are shown in thr Supplemental Material Figure S5.

Fig 4

Visualization of the expected, average effect of the anaesthesia exposure in the HPL (top) and YNPRC (middle) cohort as a percent change in local FA per MRI session related exposure. For comparison, the mean FA values at 18 months of age in the single exposure group are shown in the bottom row. Note the different color scale used for each cohort. HPL, Harlow Primate Laboratory; YNPRC, Yerkes National Primate Research Center.

Fig 5

Post hoc p values for normalized total exposure effect. Tracts without values indicate exclusion of that tract during the quality control phase. Red indicates p-values ≤0.001, orange ≤0.01, green ≤0.05, and blue >0.05. Tracts are listed in anterior to posterior anatomical order. AD, axial diffusivity; FA, fractional anisotropy; FDR, false discovery rate; HPL, Harlow Primate Laboratory; MD, mean diffusivity; NA, not applicable due to exclusion; RD, radial diffusivity; YNPRC, Yerkes National Primate Research Center.