Neurometabolic trajectory of the developing brain

Phenomenal neurochemical changes occur during human brain maturation. These changes are both heterogenous across different brain regions and heterochronous for different metabolites during this period of growth. Investigating the neurometabolic trajectory of the healthy developing brain will help establish biomarkers for dysfunctional development and brain injuries. With high prevalence of cardiometabolic risk factors among women of reproductive age in the U.S., understanding the effects of these risk factors on infant brain oxidative stress and neurotransmission becomes critical. Key neurometabolites of interest include neurotransmitters and neuromodulators such as glutamate (Glu), gamma-aminobutyric acid (GABA), aspartate (Asp), and N- acetylaspartylglutamate (NAAG), antioxidants such as glutathione (GSH) and ascorbate (Asc), indicators of mitochondrial dysfunction lactate (Lac), and neuronal integrity N-acetylaspartate (NAA). Magnetic resonance spectroscopy (MRS) is the only non-invasive tool that can measure these metabolite levels in vivo. MRS techniques incorporating imaging (MRSI) extend spatial coverage and allow the spatial distribution of brain metabolites to be mapped. However, a lack of motion-immune advanced MRS/MRSI techniques for infants and young children to map multiple metabolites simultaneously has resulted in limited knowledge of neurochemistry of early brain development. This knowledge gap directly results from the technology gap, which must be prioritized to determine the neurometabolic trajectory of the developing brain. This project will help address these gaps using two approaches: i) determining the neurometabolic trajectory of the developing brain localized to a single voxel in the bilateral thalamus from 0-15 months of age and determining the effect of maternal cardiometabolic risk factors to the developing neurometabolic trajectory, both of these using the publicly available HEALthy Brain and Child Development (HBCD) study MRS data; and ii) by developing an advanced multi-metabolite edited MRSI technique with robust motion correction for the pediatric population that will enable mapping of the spatial distribution of neurometabolites across the developing brain. This Pathway to Independence Award will be supported by excellent career development resources at Johns Hopkins University, and training from a mentoring team of world experts in the field of pediatric and neurodevelopmental research, advanced edited MRS, and motion-correction methods for MRI. This project will generate novel motion-robust tools to study metabolic processes in pediatric populations and also leverage the HBCD study data to advance the understanding of pediatric neurobiology, potentially indicating biomarkers for deviations from healthy brain development. Project Number: 1K99HD118185-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Saipavitra Venkateshwaran Murali Manohar | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $133,432 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 BP-R (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HD11818501A1