Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

Multi-channel 4D parametrized Atlas of Macro- and Microstructural Neonatal Brain Development

ABSTRACTStructural and diffusion MRI provide complimentary anatomical and microstructural characterization of early brain maturation. The existing models of the developing brain in time include only either structural or diffusion channels. Furthermore, there is a lack of tools for combined analysis of structural and diffusion MRI in the same reference space.In this work we propose methodology to generate multi-channel (MC) continuous spatio-temporal parametrized atlas of brain development based on MC registration driven by both T2-weighted and orientation distribution functions (ODF) channels along with the Gompertz model (GM) fitting of the signals and spatial transformations in time. We construct a 4D MC atlas of neonatal brain development during 38 to 44 week PMA range from 170 normal term subjects from developing Human Connectomme Project. The resulting atlas consists of fourteen spatio-temporal microstructural indices and two parcellation maps delineating white matter tracts and neonatal transient structures. We demonstrate applicability of the atlas for quantitative region-specific comparison of 140 term and 40 preterm subjects scanned at the term-equivalent age. We show multi-parametric microstructural differences in multiple white matter regions, including the transient compartments. The atlas and software will be available after publication of the article.

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (ß-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.