Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy.

Between birth and late adolescence, the human brain undergoes exponential maturational changes. Using in vivo magnetic resonance spectroscopy, we determined the developmental profile for 6 metabolites in 5 distinct brain regions based on spectra from 309 children from 0 to 18 years of age. The concentrations of N-acetyl-aspartate (an indicator for adult-type neurons and axons), creatine (energy metabolite), and glutamate (excitatory neurotransmitter) increased rapidly between birth and 3 months, a period of rapid axonal growth and synapse formation. Myo-inositol, implicated in cell signaling and a precursor of membrane phospholipid, as well as an osmolyte and astrocyte marker, declined rapidly during this period. Choline, a membrane metabolite and indicator for de novo myelin and cell membrane synthesis, peaked from birth until approximately 3 months, and then declined gradually, reaching a plateau at early childhood. Similarly, taurine, involved in neuronal excitability, synaptic potentiation, and osmoregulation, was high until approximately 3 months and thereafter declined. These data indicate that the first 3 months of postnatal life are a critical period of rapid metabolic changes in the development of the human brain. This study of the developmental profiles of the major brain metabolites provides essential baseline information for future analyses of the pediatric health and disease.

[1]  M Noble,et al.  Specific Expression of N‐Acetylaspartate in Neurons, Oligodendrocyte‐Type‐2 Astrocyte Progenitors, and Immature Oligodendrocytes In Vitro , 1992, Journal of neurochemistry.

[2]  R. Hernández-Benítez,et al.  Taurine and Brain Development: Trophic or Cytoprotective Actions? , 2010, Neurochemical Research.

[3]  Jens Frahm,et al.  Regional Age Dependence of Human Brain Metabolites from Infancy to Adulthood as Detected by Quantitative Localized Proton MRS , 1999, Pediatric Research.

[4]  I. Kostović,et al.  Structural and histochemical reorganization of the human prefrontal cortex during perinatal and postnatal life. , 1990, Progress in brain research.

[5]  I. Silver,et al.  Metabolism and role of glutamate in mammalian brain , 1990, Progress in Neurobiology.

[6]  Stephen K Fisher,et al.  Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance , 2002, Journal of neurochemistry.

[7]  F. Gilles Myelination in the neonatal brain. , 1976, Human pathology.

[8]  D. Bergel Geigy Scientific Tables , 1991 .

[9]  R. Huxtable Taurine in the central nervous system and the mammalian actions of taurine , 1989, Progress in Neurobiology.

[10]  S. Schelling,et al.  Pediatric neuroimaging. , 1994, Seminars in veterinary medicine and surgery.

[11]  N. Herschkowitz,et al.  N-acetyl-L-aspartate is a major source of acetyl groups for lipid synthesis during rat brain development. , 1991, Developmental neuroscience.

[12]  B. Trapp,et al.  N‐acetylaspartate is an axon‐specific marker of mature white matter in vivo: A biochemical and immunohistochemical study on the rat optic nerve , 2002, Annals of neurology.

[13]  H. Kinney,et al.  Sequence of Central Nervous System Myelination in Human Infancy. II. Patterns of Myelination in Autopsied Infants , 1988, Journal of neuropathology and experimental neurology.

[14]  Neil L. Harrison,et al.  Taurine Is a Potent Activator of Extrasynaptic GABAA Receptors in the Thalamus , 2008, The Journal of Neuroscience.

[15]  G. Šimić,et al.  Extraordinary neoteny of synaptic spines in the human prefrontal cortex , 2011, Proceedings of the National Academy of Sciences.

[16]  U. Ruotsalainen,et al.  Cerebral metabolic rate for glucose during the first six months of life: an FDG positron emission tomography study. , 1996, Archives of disease in childhood. Fetal and neonatal edition.

[17]  François Lazeyras,et al.  Magnetic Resonance in Preterm and Term Newborns: 1H-Spectroscopy in Developing Human Brain , 1991, Pediatric Research.

[18]  H. Haas,et al.  GABAA‐receptor modification in taurine transporter knockout mice causes striatal disinhibition , 2007, The Journal of physiology.

[19]  L. Willmore,et al.  Collapse of extracellular glutamate regulation during epileptogenesis: down‐regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid , 2001, Journal of neurochemistry.

[20]  A. Toga,et al.  Mapping Continued Brain Growth and Gray Matter Density Reduction in Dorsal Frontal Cortex: Inverse Relationships during Postadolescent Brain Maturation , 2001, The Journal of Neuroscience.

[21]  P. C. Murphy,et al.  Cerebral Cortex , 2017, Cerebral Cortex.

[22]  W. Mcentee,et al.  Glutamate: its role in learning, memory, and the aging brain , 2005, Psychopharmacology.

[23]  N. Lundbom,et al.  Barbiturate anesthesia and brain proton spectroscopy. , 1999, AJNR. American journal of neuroradiology.

[24]  Judith Rumsey,et al.  The NIH MRI study of normal brain development: Performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery , 2007, Journal of the International Neuropsychological Society.

[25]  Milos Judas,et al.  Lifespan alterations of basal dendritic trees of pyramidal neurons in the human prefrontal cortex: a layer-specific pattern. , 2008, Cerebral cortex.

[26]  D. Gadian,et al.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  E. Perry,et al.  Glutamate receptor binding in the human hippocampus and adjacent cortex during development and aging , 1996, Neurobiology of Aging.

[28]  J. Dirgo,et al.  Taurine: a role in osmotic regulation of mammalian brain and possible clinical significance. , 1980, Life sciences.

[29]  H. Kinney,et al.  Myelination in the developing human brain: Biochemical correlates , 1994, Neurochemical Research.

[30]  J. Shapiro,et al.  Effects of hypernatremia on organic brain osmoles. , 1990, The Journal of clinical investigation.

[31]  J. Volpe Neurology of the Newborn , 1959, Major problems in clinical pediatrics.

[32]  B D Ross,et al.  Absolute Quantitation of Water and Metabolites in the Human Brain. I. Compartments and Water , 1993 .

[33]  M. Norenberg,et al.  Osmotic regulation ofmyo-inositol uptake in primary astrocyte cultures , 1994, Neurochemical Research.

[34]  P. Goldman-Rakic,et al.  Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness. , 1994, Progress in brain research.

[35]  Rebecca D Folkerth,et al.  Axonal development in the cerebral white matter of the human fetus and infant , 2005, The Journal of comparative neurology.

[36]  G. V. Van Hoesen,et al.  Neural connections of the posteromedial cortex in the macaque , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Rolf Gruetter,et al.  Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1H NMR spectroscopy , 2003, Magnetic resonance in medicine.

[38]  P. Huttenlocher,et al.  Regional differences in synaptogenesis in human cerebral cortex , 1997, The Journal of comparative neurology.

[39]  B. Brody,et al.  Sequence of Central Nervous System Myelination in Human Infancy. I. An Autopsy Study of Myelination , 1987, Journal of neuropathology and experimental neurology.

[40]  Tian-Le Xu,et al.  Taurine acts as a glycine receptor agonist in slices of rat inferior colliculus , 2006, Hearing Research.

[41]  J. Morris,et al.  Greenfield's Neuropathology Edited by J. Hume-Adams and L. W. Ducken. Fifth edition. Oxford University Press, New York (1992), 1557pp. Price £145, U.S.$195 , 1993, Neuroscience.

[42]  C. Shatz,et al.  The subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex. , 1994, Annual review of neuroscience.

[43]  Joseph T. Coyle,et al.  The Glutamatergic Dysfunction Hypothesis for Schizophrenia , 1996, Harvard review of psychiatry.

[44]  P. Rakić,et al.  Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain , 1990, The Journal of comparative neurology.

[45]  J. Dobbing,et al.  Vulnerability of developing brain: relative effects of growth restriction during the fetal and suckling periods on behavior and brain composition of adult rats. , 1973, The Journal of nutrition.

[46]  J. Mazziotta,et al.  Positron emission tomography study of human brain functional development , 1987, Annals of neurology.

[47]  Alan C. Evans,et al.  Brain development during childhood and adolescence: a longitudinal MRI study , 1999, Nature Neuroscience.

[48]  Der,et al.  Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. , 1990, Radiology.

[49]  Peter M. G. Munro,et al.  Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. , 1996, Neuroreport.

[50]  K. Hayes,et al.  Taurine in metabolism. , 1981, Annual review of nutrition.

[51]  Marvin D Nelson,et al.  MR imaging of newborns by using an MR-compatible incubator with integrated radiofrequency coils: initial experience. , 2004, Radiology.

[52]  A. Minkowski,et al.  Regional Development of the Brain in Early Life , 1968 .

[53]  W. Sherman,et al.  myo-Inositol: A Newly Identified Nonnitrogenous Osmoregulatory Molecule in Mammalian Brain , 1989, Pediatric Research.

[54]  P. Rakić,et al.  Neuronal migration, with special reference to developing human brain: a review. , 1973, Brain research.

[55]  J. Changeux,et al.  Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks , 1976, Nature.

[56]  Hannah C. Kinney,et al.  The Human Brain: Prenatal Development and Structure , 2012 .

[57]  D. Leibfritz,et al.  Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. , 1993, Developmental neuroscience.

[58]  V. Gallo,et al.  Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K+ channel block , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[59]  I. Kostović,et al.  Prenatal development of neurons in the human prefrontal cortex. II. A quantitative Golgi study , 1992, The Journal of comparative neurology.

[60]  A. Guidotti,et al.  Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. , 1989, Molecular pharmacology.

[61]  P. Yancey,et al.  Developmental changes in organic osmolytes in prenatal and postnatal rat tissues. , 2000, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[62]  R. Kikinis,et al.  Quantitative magnetic resonance imaging of brain development in premature and mature newborns , 1998, Annals of neurology.

[63]  D. Davies Child Development: A Practitioner's Guide , 1999 .

[64]  J. Dobbing,et al.  Quantitative growth and development of human brain , 1973, Archives of disease in childhood.

[65]  Pl Lantos,et al.  Greenfield's Neuropathology , 1985 .

[66]  F. Gage,et al.  Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency , 2004, The Journal of Neuroscience.

[67]  M. Phelps,et al.  Metabolic Maturation of the Brain: A Study of Local Cerebral Glucose Utilization in the Developing Cat , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[68]  C Boesch,et al.  Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy , 2002, Magnetic resonance in medicine.

[69]  T. Patel,et al.  Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. , 1979, The Biochemical journal.

[70]  H. Kinney,et al.  Late Development of the GABAergic System in the Human Cerebral Cortex and White Matter , 2011, Journal of neuropathology and experimental neurology.

[71]  F. Franconi,et al.  Lactate, N‐acetylaspartate, choline and creatine concentrations, and spin‐spin relaxation in thalamic and occipito‐parietal regions of developing human brain , 1996, Magnetic resonance in medicine.

[72]  K. Uğurbil,et al.  On the reliability of 13C metabolic modeling with two‐compartment neuronal‐glial models , 2007, Journal of neuroscience research.

[73]  P. Rakić,et al.  Development of the corpus callosum and cavum septi in man , 1968, The Journal of comparative neurology.

[74]  T. Wallimann,et al.  Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1 , 2005, BMC Developmental Biology.

[75]  S. Bluml,et al.  Magnetic resonance spectroscopy of the human brain , 2001, The Anatomical record.

[76]  Rebecca D Folkerth,et al.  Neuron deficit in the white matter and subplate in periventricular leukomalacia , 2012, Annals of neurology.

[77]  P. Huttenlocher Synaptic density in human frontal cortex - developmental changes and effects of aging. , 1979, Brain research.

[78]  Roland Kreis,et al.  Development of the human brain: In vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy , 1993, Magnetic resonance in medicine.

[79]  S. Zeisel,et al.  Choline, phosphatidylcholine and sphingomyelin in human and bovine milk and infant formulas. , 1986, The Journal of nutrition.

[80]  H. Uylings,et al.  Neuronal development in human prefrontal cortex in prenatal and postnatal stages. , 1990, Progress in brain research.

[81]  G. Berry Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia? , 2011, Journal of Inherited Metabolic Disease.

[82]  D. R. Curtis,et al.  Amino acid transmitters in the mammalian central nervous system. , 1974, Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie.

[83]  W. Macklin,et al.  Glutamate Stimulates Oligodendrocyte Progenitor Migration Mediated via an αv Integrin/Myelin Proteolipid Protein Complex , 2006, The Journal of Neuroscience.

[84]  Goran Sedmak,et al.  evelopmental history of the subplate zone , subplate neurons and interstitial hite matter neurons : relevance for schizophrenia , 2011 .

[85]  J. Clark,et al.  N-Acetyl Aspartate: A Marker for Neuronal Loss or Mitochondrial Dysfunction , 1998, Developmental Neuroscience.

[86]  P. Yakovlev,et al.  The myelogenetic cycles of regional maturation of the brain , 1967 .

[87]  O. Pryds,et al.  Metabolite concentrations in the developing brain estimated with proton MR spectroscopy , 1994, Journal of magnetic resonance imaging : JMRI.