Preterm infants are at risk of neurodevelopmental impairments. At present, proton magnetic resonance spectroscopy (1H-MRS) is used to evaluate brain metabolites in asphyxiated term infants. The aim of this review is to assess associations between cerebral 1H-MRS and neurodevelopment after preterm birth.
PubMed and Embase were searched to identify studies using 1H-MRS and preterm birth. Eligible studies for this review included 1H-MRS of the brain, gestational age ≤32 weeks, and neurodevelopment assessed at a corrected age (CA) of at least 12 months up to the age of 18 years.
Twenty papers evaluated 1H-MRS in preterm infants at an age between near-term and 18 years and neurodevelopment. 1H-MRS was performed in both white (WM) and gray matter (GM) in 12 of 20 studies. The main regions were frontal and parietal lobe for WM and basal ganglia for GM. N-acetylaspartate/choline (NAA/Cho) measured in WM and/or GM is the most common metabolite ratio associated with motor, language, and cognitive outcome at 18–24 months CA.
NAA/Cho in WM assessed at term-equivalent age was associated with motor, cognitive, and language outcome, and NAA/Cho in deep GM was associated with language outcome at 18–24 months CA.
In preterm born infants, brain metabolism assessed using 1H-MRS at term-equivalent age is associated with motor, cognitive, and language outcomes at 18–24 months.
1H-MRS at term-equivalent age in preterm born infants may be used as an early indication of brain development.
Specific findings relating to NAA were most predictive of outcome.
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Liu, L. et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet 388, 3027–3035 (2016).
Panigrahy, A. et al. Neuroimaging biomarkers of preterm brain injury: toward developing the preterm connectome. Pediatr. Radiol. 42, 33–61 (2012).
Aarnoudse-Moens, C. S. et al. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics 124, 717–728 (2009).
Saigal, S. & Doyle, L. W. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 371, 261–269 (2008).
Kerr-Wilson, C. O., Mackay, D. F., Smith, G. C. S. & Pell, J. P. Meta-analysis of the association between preterm delivery and intelligence. J. Public Health 34, 209–216 (2011).
de Kieviet, J. F. et al. Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis. Dev. Med. Child Neurol. 54, 313–323 (2012).
van Noort-van der Spek, I. L., Franken, M. C. J. P. & Weisglas-Kuperus, N. Language functions in preterm-born children: a systematic review and meta-analysis. Pediatrics 129, 745–754 (2012).
Johnson, S. et al. Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation. Pediatrics 124, e249–e257 (2009).
Moster, D., Lie, R. T. & Markestad, T. Long-term medical and social consequences of preterm birth. N. Engl. J. Med. 359, 262–273 (2008).
Smith, F. W. The value of NMR imaging in pediatric practice—a preliminary report. Pediatr. Radiol. 13, 141–147 (1983).
Johnson, M. A. et al. Clinical NMR imaging of the brain in children—normal and neurologic disease. Am. J. Neuroradiol. 4, 1013–1026 (1983).
Groenendaal, F. & de Vries, L. S. Fifty years of brain imaging in neonatal encephalopathy following perinatal asphyxia. Pediatr. Res. 81, 150–155 (2017).
Moore, G. J. Proton magnetic resonance spectroscopy in pediatric neuroradiology. Pediatr. Radiol. 28, 805–814 (1998).
Kreis, R. et al. Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn. Reson. Med. 48, 949–958 (2002).
Roelants-van Rijn, A. M., van der Grond, J., Stigter, R. H., de Vries, L. S. & Groenendaal, F. Cerebral structure and metabolism and long-term outcome in small-for-gestational-age preterm neonates. Pediatr. Res. 56, 285–290 (2004).
Heerschap, A., Kok, R. D. & van den Berg, P. P. Antenatal proton MR spectroscopy of the human brain in vivo. Childs Nerv. Syst. 19, 418–421 (2003).
Moher, D., Liberati, A., Tetzlaff, J. & Altman, D. G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int. J. Surg. 8, 336–341 (2010).
Law, M. et al. Guidelines for Critical Review of the Literature: Quantitative Studies, Vol. 14, 1–11 (McMaster University, 1998).
Cheong, J. L. et al. Altered posterior cingulate brain metabolites and cognitive dysfunction in preterm adolescents. Pediatr. Res. 79, 716–722 (2016).
Gasparovic, C. et al. The long-term effect of erythropoiesis stimulating agents given to preterm infants: a proton magnetic resonance spectroscopy study on neurometabolites in early childhood. Pediatr. Radiol. 48, 374–382 (2018).
Bapat, R., Narayana, P., Zhou, Y. & Parikh, N. Magnetic Resonance spectroscopy at term equivalent age in extremely preterm infants: association with cognitive and language development. Pediatr. Neurol. 51, 53–59 (2014).
Hyodo, R. et al. Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes. Arch. Dis. Child Fetal Neonatal Ed. 103, 238–244 (2018).
Phillips, J. P. et al. Anterior cingulate and frontal lobe white matter spectroscopy in early childhood of former very LBW premature infants. Pediatr. Res. 69, 224–229 (2011).
Simões, R. V. et al. Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome. Am. J. Obstet. Gynecol. 216, 1–14 (2017).
Tanifuji, S. et al. Temporal brain metabolite changes in preterm infants with normal development. Brain Dev. 39, 196–202 (2017).
Van Kooij, B. J. et al. Cerebellar volume and proton magnetic resonance spectroscopy at term, and neurodevelopment at 2 years of age in preterm infants. Dev. Med. Child Neurol. 54, 260–266 (2012).
Groenendaal, F. et al. Early cerebral proton MRS and neurodevelopmental outcome in infants with cystic leukomalacia. Dev. Med. Child Neurol. 39, 373–379 (1997).
Hart, A. R. et al. Diffusion-weighted imaging and magnetic resonance proton spectroscopy following preterm birth. Clin. Radiol. 69, 870–879 (2014).
Kendall, G. S. et al. White matter NAA/Cho and Cho/Cr ratios at MR spectroscopy are predictive of motor outcome in preterm infants. Radiology 271, 230–238 (2014).
Podrebarac, S. K. et al. Antenatal exposure to antidepressants is associated with altered brain development in very preterm-born neonates. Neuroscience 7, 252–262 (2017).
Durlak, W. et al. Relationship between proton magnetic resonance spectroscopy of frontoinsular gray matter and neurodevelopmental outcomes in very low birth weight children at the age of 4. PLoS ONE 11, e0156064 (2016).
Chau, V. et al. Abnormal brain maturation in preterm neonates associated with adverse developmental outcomes. Neurology 81, 2082–2089 (2013).
Xu, D. et al. MR spectroscopy of normative premature newborns. J. Magn. Reson. Imaging 33, 306–311 (2011).
Akasaka, M. et al. Assessing temporal brain metabolite changes in preterm infants using multivoxel magnetic resonance spectroscopy. Magn. Reson. Med. Sci. 15, 187–192 (2016).
Rademaker, K. J. et al. Neonatal hydrocortisone treatment related to 1H-MRS of the hippocampus and short-term memory at school age in preterm born children. Pediatr. Res. 59, 309–313 (2006).
Taylor, M. J. et al. Magnetic resonance spectroscopy in very preterm-born children at 4 years of age: developmental course from birth and outcomes. Neuroradiology 60, 1063–1073 (2018).
Inder, T. E. et al. Abnormal cerebral structure is present at term in premature infants. Pediatrics 115, 286–294 (2005).
Augustine, E. M. et al. Can magnetic resonance spectroscopy predict neurodevelopmental outcome in very low birth weight preterm infants? J. Perinatol. 28, 611–618 (2008).
Bjartmar, C., Battistuta, J., Terada, N., Dupree, E. & Trapp, B. D. N-acetylaspartate is an axon-specific marker of mature White matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann. Neurol. 51, 51–58 (2002).
Birken, D. L. & Oldendorf, W. H. N-acetyl-L-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci. Biobehav. Rev. 13, 23–31 (1989).
Braissant, O. et al. Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev. Biol. 5, 9 (2005).
Pouwels, P. J. et al. Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatr. Res. 46, 474–485 (1999).
Zeisel, S. H., Char, D. & Sheard, N. F. Choline, phosphatidylcholine and sphingomyelin in human and bovine milk and infant formulas. J. Nutr. 116, 50–58 (1986).
Brandon, E. P. et al. Choline transporter 1 maintains cholinergic function in choline acetyltransferase haplo insufficiency. J. Neurosci. 24, 5459–5466 (2004).
Stork, C. & Renshaw, P. F. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol. Psychiatry 10, 900–919 (2005).
Howe, F. A. et al. Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn. Reson. Med. 49, 223–232 (2003).
Miller, B. L. A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate,creatine and choline. NMR Biomed. 4, 47–52 (1991).
Licata, S. C. & Renshaw, P. F. Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. Ann. NY Acad. Sci. 1187, 148–171 (2010).
Richards, T. L. Proton MR spectroscopy in multiple sclerosis: value in establishing diagnosis, monitoring progression, and evaluating therapy. Am. J. Roentgenol. 157, 1073–1078 (1991).
Berry, G. T. Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia? J. Inherit. Metab. Dis. 34, 345–355 (2011).
Lien, Y. H., Shapiro, J. I. & Chan, L. Effects of hypernatremia on organic brain osmoles. J. Clin. Invest. 85, 1427–1435 (1990).
Thurston, J. H., Sherman, W. R., Hauhart, R. E. & Kloepper, R. F. Myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatr. Res. 26, 482–485 (1989).
Isaacks, R. E., Bender, A. S., Kim, C. Y., Prieto, N. M. & Norenberg, M. D. Osmotic regulation of myo-inositol uptake in primary astrocyte cultures. Neurochem. Res. 19, 331–338 (1994).
Robertson, N. J. et al. Early increases in brain myo-inositol measured by proton magnetic resonance spectroscopy in term infants with neonatal encephalopathy. Pediatr. Res. 50, 692–700 (2001).
Xu, D. & Vigneron, D. Magnetic resonance spectroscopy imaging of the newborn brain-a technical review. Semin. Perinatol. 34, 20–27 (2010).
Barkovich, A. J. et al. Proton MR spectroscopy for the evaluation of brain injury in asphyxiated, term neonates. Am. J. Neuroradiol. 20, 1399–1405 (1999).
Cheong, J. L. et al. Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: metabolite peak-area ratios, relaxation times, and absolute concentrations. Am. J. Neuroradiol. 27, 1546–1554 (2006).
Barkovich, A. J. et al. MR imaging, MR spectroscopy, and diffusion tensor imaging of sequential studies in neonates with encephalopathy. Am. J. Neuroradiol. 27, 533–547 (2006).
Miller, S. P. et al. Predictors of 30-month outcome after perinatal depression: role of proton MRS and socioeconomic factors. Pediatr. Res. 52, 71–77 (2002).
Shu, S. K., Ashwal, S., Holshouser, B. A., Nystrom, G. & Hinshaw, D. B. Prognostic value of 1H-MRS in perinatal CNS insults. Pediatr. Neurol. 17, 309–318 (1997).
Groenendaal, F. et al. Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated fullterm neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr. Res. 35, 148–151 (1994).
Robertson, N. J. et al. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr. Res. 46, 287–296 (1999).
Thayyil, S. et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics 125, 382–395 (2010).
Coyle, J. T. The glutamatergic dysfunction hypothesis for schizophrenia. Harv. Rev. Psychiatry 3, 241–253 (1996).
Ueda, Y. et al. Collapse of extracellular glutamate regulation during epileptogenesis: downregulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid. J. Neurochem. 76, 892–900 (2001).
Nguyen, L. et al. Neurotransmitters as early signals for central nervous system development. Cell Tissue Res. 305, 187–202 (2001).
Manev, H., Favaron, M., Guidotti, A. & Costa, E. Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol. Pharmacol. 36, 106–112 (1989).
Fein, G. & Meyerhoff, D. J. Ethanol in human brain by magnetic resonance spectroscopy: correlation with blood and breath levels, relaxation, and magnetization transfer. Clin. Exp. Res. 24, 1227–1235 (2000).
Gruetter, R. et al. Resolution improvements in in vivo 1H NMR spectra with increased magnetic field strength. J. Magn. Reson. 135, 260–264 (1998).
Cheong, J. L. Y. et al. Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury:metabolite peak-area ratios, relaxation times, and absolute concentrations. Am. J. Neuroradiol. 27, 1546–1554 (2006).
Provencher, S. W. Automatic quantitation of localized in vivoH 1 spectra with LCModel. NMR Biomed. 14, 260–264 (2001).
Moore, G. J. Proton magnetic resonance spectroscopy in pediatric neuroradiology. Pediatr. Radiol. 28, 805–814 (1998).
Anderson, P. J., Cheong, J. L. & Thompson, D. K. The predictive validity of neonatal MRI for neurodevelopmental outcome in very preterm children. Semin. Perinatol. 39, 147–158 (2015).
Smyser, C. D., Kidokoro, H. & Inder, T. E. Magnetic resonance imaging of the brain at term equivalent age in extremely premature neonates. J. Paediatr. Child Health 48, 794–800 (2012).
Inder, T. E. et al. Defining the nature of the cerebral abnormalities in the premature infant: aqualitative magnetic resonance imaging study. J. Pediatr. 143, 171–179 (2003).
Kidokoro, H., Neil, J. J. & Inder, T. E. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. Am. J. Neuroradiol. 34, 2208–2214 (2013).
Volpe, J. J. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 8, 110–124 (2009).
Bax, M., Tydeman, C. & Flodmark, O. Clinical and MRI correlates of cerebral palsy: the European Cerebral Palsy Study. JAMA 296, 1602–1608 (2006).
Himpens, E. et al. Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: a meta- analytic review. Dev. Med. Child Neurol. 50, 334–340 (2008).
Spittle, A. J. et al. Neonatal white matter abnormality predicts childhood motor impairment in very preterm children. Dev. Med. Child Neurol. 53, 1000–1006 (2011).
Riddle, A. et al. Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury. J. Neurosci. 26, 3045–3055 (2006).
Peterson, B. S. et al. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics 111, 939–948 (2003).
Soria-Pastor, S. et al. Decreased regional brain volume and cognitive impairment in preterm children at low risk. Pediatrics 124, 1161–1170 (2009).
Peterson, B. S. et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 284, 1939–1947 (2000).
Anderson, P. & Doyle, L. W. Neurobehavioral outcomes of school-age children born extremely low birth weight or very preterm in the 1990s. JAMA 289, 3264–3272 (2003).
Woodward, L. J. et al. Object working memory deficits predicted by early brain injury and development in the preterm infant. Brain 128, 2578–2587 (2005).
Beauchamp, M. H. et al. Preterm infant hippocampal volumes correlate with later working memory deficits. Brain 131, 2986–2994 (2008).
Leviton, A. & Gressens, P. Neuronal damage accompanies perinatal white-matter damage. Trends Neurosci. 30, 473–478 (2007).
Carpenter, K. L. H. et al. Magnetic susceptibility of brain iron is associated with childhood spatial IQ. Neuroimage 132, 167–174 (2016).
Srinivasan, L. et al. Quantification of deep gray matter in preterm infants at term-equivalent age using manual volumetry of 3-tesla magnetic resonance images. Pediatrics 119, 759–765 (2007).
Pierson, C. R. et al. Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol. 114, 619–631 (2007).
Baillieux, H., De Smet, H. J., Paquier, P. F., De Deyn, P. P. & Marien, P. Cerebellar neurocognition: insights into the bottom of the brain. Clin. Neurol. Neurosurg. 110, 763–773 (2008).
Tavano, A. et al. Disorders of cognitive and affective development in cerebellar malformations. Brain 130, 2646–2660 (2007).
Limperopoulos, C. et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics 120, 584–593 (2007).
Limperopoulos, C. et al. Cerebellar hemorrhage in the preterm infant: ultrasonographic findings and risk factors. Pediatrics 116, 717–724 (2005).
Bednarek, N. et al. Outcome of cerebellar injury in very low birth-weight infants: 6 case reports. J. Child Neurol. 23, 906–911 (2008).
Tam, E. W. et al. Cerebellar hemorrhage on magnetic resonance imaging in preterm newborns associated with abnormal neurologic outcome. J. Pediatr. 15, 245–250 (2011).
Annink, K. V. et al. Introduction of ultra-high-field MR imaging in infants: preparations and feasibility. Am. J. Neuroradiol. 41, 1532–1537 (2020).
Alderliesten, T. et al. MRI and spectroscopy in (near) term neonates with perinatal asphyxia and therapeutic hypothermia. Arch. Dis. Child Fetal Neonatal Ed. 102, F147–F152 (2017).
Tkáč, I., Öz, G., Adriany, G., Uǧurbil, K. & Gruetter, R. In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn. Reson. Med. 62, 868–879 (2009).
Cudalbu, C., Mlynárik, V. & Gruetter, R. Handling macromolecule signals in the quantification of the neurochemical profile. J. Alzheimer’s Dis. 31, 101–115 (2012).
Wilson, M. et al. Methodological consensus on clinical proton MRS of the brain: review and recommendations. Magn. Reson. Med. 82, 527–550 (2019).
Near, J. et al. Preprocessing, analysis and quantification in single-voxel magnetic resonance spectroscopy: experts’ consensus recommendations. NMR Biomed. https://doi.org/10.1002/nbm.4257 (2020).
Lin, A. et al. Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): experts’ consensus recommendations. NMR Biomed. https://doi.org/10.1002/nbm.4484 (2021).
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Cebeci, B., Alderliesten, T., Wijnen, J.P. et al. Brain proton magnetic resonance spectroscopy and neurodevelopment after preterm birth: a systematic review. Pediatr Res 91, 1322–1333 (2022). https://doi.org/10.1038/s41390-021-01539-x