Effects of anesthesia exposure on postnatal maturation of white matter in rhesus monkeys.

There is increasing concern about the potential effects of anesthesia exposure on the developing brain. The effects of relatively brief anesthesia exposures used repeatedly to acquire serial magnetic resonance imaging scans could be examined prospectively in rhesus macaques. We analyzed magnetic resonance diffusion tensor imaging (DTI) of 32 rhesus macaques (14 females, 18 males) aged 2 weeks to 36 months to assess postnatal white matter (WM) maturation. We investigated the longitudinal relationships between each DTI property and anesthesia exposure, taking age, sex, and weight of the monkeys into consideration. Quantification of anesthesia exposure was normalized to account for variation in exposures. Segmented linear regression with two knots provided the best model for quantifying WM DTI properties across brain development as well as the summative effect of anesthesia exposure. The resulting model revealed statistically significant age and anesthesia effects in most WM tracts. Our analysis indicated there were major effects on WM associated with low levels of anesthesia even when repeated as few as three times. Fractional anisotropy values were reduced across several WM tracts in the brain, indicating that anesthesia exposure may delay WM maturation, and highlight the potential clinical concerns with even a few exposures in young children.

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

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.

Impact of gonadectomy on maturational changes in brain volume in adolescent macaques.

Adolescence is a transitional period between childhood and adulthood characterized by significant changes in global and regional brain tissue volumes. It is also a period of increasing vulnerability to psychiatric illness. The relationship between these patterns and increased levels of circulating sex steroids during adolescence remains unclear. The objective of the current study was to determine whether gonadectomy, prior to puberty, alters adolescent brain development in male rhesus macaques. Ninety-six structural MRI scans were acquired from 12 male rhesus macaques (8 time points per animal over a two-year period). Six animals underwent gonadectomy and 6 animals underwent a sham operation at 29 months of age. Mixed-effects models were used to determine whether gonadectomy altered developmental trajectories of global and regional brain tissue volumes. We observed a significant effect of gonadectomy on the developmental trajectory of prefrontal gray matter (GM), with intact males showing peak volumes around 3.5 years of age with a subsequent decline. In contrast, prefrontal GM volumes continued to increase in gonadectomized males until the end of the study. We did not observe a significant effect of gonadectomy on prefrontal white matter or on any other global or regional brain tissue volumes, though we cannot rule out that effects might be detected in a larger sample. Results suggest that the prefrontal cortex is more vulnerable to gonadectomy than other brain regions.

The UNC-Wisconsin Rhesus Macaque Neurodevelopment Database: A Structural MRI and DTI Database of Early Postnatal Development.

Rhesus macaques are commonly used as a translational animal model in neuroimaging and neurodevelopmental research. In this report, we present longitudinal data from both structural and diffusion MRI images generated on a cohort of 34 typically developing monkeys from 2 weeks to 36 months of age. All images have been manually skull stripped and are being made freely available via an online repository for use by the research community.

UNC-Emory Infant Atlases for Macaque Brain Image Analysis: Postnatal Brain Development through 12 Months.

Computational anatomical atlases have shown to be of immense value in neuroimaging as they provide age appropriate reference spaces alongside ancillary anatomical information for automated analysis such as subcortical structural definitions, cortical parcellations or white fiber tract regions. Standard workflows in neuroimaging necessitate such atlases to be appropriately selected for the subject population of interest. This is especially of importance in early postnatal brain development, where rapid changes in brain shape and appearance render neuroimaging workflows sensitive to the appropriate atlas choice. We present here a set of novel computation atlases for structural MRI and Diffusion Tensor Imaging as crucial resource for the analysis of MRI data from non-human primate rhesus monkey (Macaca mulatta) data in early postnatal brain development. Forty socially-housed infant macaques were scanned longitudinally at ages 2 weeks, 3, 6, and 12 months in order to create cross-sectional structural and DTI atlases via unbiased atlas building at each of these ages. Probabilistic spatial prior definitions for the major tissue classes were trained on each atlas with expert manual segmentations. In this article we present the development and use of these atlases with publicly available tools, as well as the atlases themselves, which are publicly disseminated to the scientific community.