{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:43:22Z","timestamp":1777434202687,"version":"3.51.4"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T00:00:00Z","timestamp":1549238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T00:00:00Z","timestamp":1549238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy (<jats:sup>1<\/jats:sup>H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality <jats:sup>1<\/jats:sup>H-MRS at median 33.0 (IQR 31.6\u201335.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0\u201329.0) weeks. <jats:sup>1<\/jats:sup>H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value\u2009&lt;\u20090.0001) and negative correlation of Cho\/Cr ratio (R \u22120.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value\u2009&lt;\u20090.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.<\/jats:p>","DOI":"10.1038\/s41598-018-37203-4","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T11:04:09Z","timestamp":1549278249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury"],"prefix":"10.1038","volume":"9","author":[{"given":"Sudeepta K.","family":"Basu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subechhya","family":"Pradhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kushal","family":"Kapse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"McCarter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Murnick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1797-8449","authenticated-orcid":false,"given":"Taeun","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Limperopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,2,4]]},"reference":[{"key":"37203_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s12311-014-0597-9","volume":"14","author":"M Brossard-Racine","year":"2015","unstructured":"Brossard-Racine, M., du Plessis, A. J. & Limperopoulos, C. Developmental cerebellar cognitive affective syndrome in ex-preterm survivors following cerebellar injury. Cerebellum 14, 151\u2013164 (2015).","journal-title":"Cerebellum"},{"key":"37203_CR2","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1093\/cercor\/bhs354","volume":"24","author":"C Limperopoulos","year":"2014","unstructured":"Limperopoulos, C. et al. Injury to the premature cerebellum: outcome is related to remote cortical development. Cereb. Cortex 24, 728\u2013736 (2014).","journal-title":"Cereb. Cortex"},{"key":"37203_CR3","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1007\/s12311-013-0487-6","volume":"12","author":"SJ Steggerda","year":"2013","unstructured":"Steggerda, S. J. et al. Small cerebellar hemorrhage in preterm infants: perinatal and postnatal factors and outcome. Cerebellum 12, 794\u2013801 (2013).","journal-title":"Cerebellum"},{"key":"37203_CR4","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.braindev.2015.01.009","volume":"37","author":"S Kobayashi","year":"2015","unstructured":"Kobayashi, S. et al. The neurological outcomes of cerebellar injury in premature infants. Brain Dev. 37, 858\u2013863 (2015).","journal-title":"Brain Dev."},{"key":"37203_CR5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1111\/j.1469-8749.2011.04168.x","volume":"54","author":"BJ Van Kooij","year":"2012","unstructured":"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\u2013266 (2012).","journal-title":"Dev. Med. Child Neurol."},{"key":"37203_CR6","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1542\/peds.2004-1169","volume":"115","author":"C Limperopoulos","year":"2005","unstructured":"Limperopoulos, C. et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics 115, 688\u2013695 (2005).","journal-title":"Pediatrics"},{"key":"37203_CR7","doi-asserted-by":"publisher","first-page":"2852","DOI":"10.1093\/cercor\/bhq035","volume":"20","author":"CD Smyser","year":"2010","unstructured":"Smyser, C. D. et al. Longitudinal analysis of neural network development in preterm infants. Cereb. Cortex 20, 2852\u20132862 (2010).","journal-title":"Cereb. Cortex"},{"key":"37203_CR8","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1002\/jmri.25098","volume":"43","author":"W Lee","year":"2016","unstructured":"Lee, W. et al. Longitudinal cerebellar growth following very preterm birth. J. Magn. Reson. Imaging 43, 1462\u20131473 (2016).","journal-title":"J. Magn. Reson. Imaging"},{"key":"37203_CR9","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/cne.901390407","volume":"139","author":"P Rakic","year":"1970","unstructured":"Rakic, P. & Sidman, R. L. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J. Comp. Neurol. 139, 473\u2013500 (1970).","journal-title":"J. Comp. Neurol."},{"key":"37203_CR10","doi-asserted-by":"publisher","first-page":"33.e1","DOI":"10.1016\/j.jpeds.2016.10.034","volume":"182","author":"M Brossard-Racine","year":"2017","unstructured":"Brossard-Racine, M. et al. Cerebellar Microstructural Organization is Altered by Complications of Premature Birth: A Case-Control Study. J. Pediatr. 182, 33.e1 (2017).","journal-title":"J. Pediatr."},{"key":"37203_CR11","doi-asserted-by":"publisher","first-page":"92.e2","DOI":"10.1016\/j.jpeds.2016.05.010","volume":"175","author":"HJ Jeong","year":"2016","unstructured":"Jeong, H. J. et al. Cerebellar Development in Preterm Infants at Term-Equivalent Age Is Impaired after Low-Grade Intraventricular Hemorrhage. J. Pediatr. 175, 92.e2 (2016).","journal-title":"J. Pediatr."},{"key":"37203_CR12","doi-asserted-by":"crossref","unstructured":"Herzmann, C. S. et al. Cerebellar Functional Connectivity in Term- and Very Preterm-Born Infants. Cereb. Cortex (2018).","DOI":"10.1093\/cercor\/bhy023"},{"key":"37203_CR13","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s12311-016-0766-0","volume":"16","author":"S Sancak","year":"2017","unstructured":"Sancak, S., Gursoy, T., Karatekin, G. & Ovali, F. Effect of Intraventricular Hemorrhage on Cerebellar Growth in Preterm Neonates. Cerebellum 16, 89\u201394 (2017).","journal-title":"Cerebellum"},{"key":"37203_CR14","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s12098-016-2215-y","volume":"84","author":"U Balakrishnan","year":"2017","unstructured":"Balakrishnan, U., Amboiram, P., Ninan, B., Chandrasekar, A. & Rangasami, R. Correlation among Magnetic Resonance Imaging Parameters of Brain in Preterm Neonates at Term Equivalent Age. Indian J. Pediatr. 84, 13\u201319 (2017).","journal-title":"Indian J. Pediatr."},{"key":"37203_CR15","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1159\/000480695","volume":"113","author":"V Neubauer","year":"2018","unstructured":"Neubauer, V. et al. The Cerebellar-Cerebral Microstructure Is Disrupted at Multiple Sites in Very Preterm Infants with Cerebellar Haemorrhage. Neonatology 113, 93\u201399 (2018).","journal-title":"Neonatology"},{"key":"37203_CR16","doi-asserted-by":"publisher","first-page":"187","DOI":"10.2463\/mrms.mp.2015-0041","volume":"15","author":"M Akasaka","year":"2016","unstructured":"Akasaka, M. et al. Assessing Temporal Brain Metabolite Changes in Preterm Infants Using Multivoxel Magnetic Resonance Spectroscopy. Magn. Reson. Med. Sci. 15, 187\u2013192 (2016).","journal-title":"Magn. Reson. Med. Sci."},{"key":"37203_CR17","doi-asserted-by":"publisher","first-page":"e0160990","DOI":"10.1371\/journal.pone.0160990","volume":"11","author":"M Koob","year":"2016","unstructured":"Koob, M. et al. Creatine, Glutamine plus Glutamate, and Macromolecules Are Decreased in the Central White Matter of Premature Neonates around Term. PLoS One 11, e0160990 (2016).","journal-title":"PLoS One"},{"key":"37203_CR18","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1097\/NEN.0b013e31822f471c","volume":"70","author":"G Xu","year":"2011","unstructured":"Xu, G. et al. Late development of the GABAergic system in the human cerebral cortex and white matter. J. Neuropathol. Exp. Neurol. 70, 841\u2013858 (2011).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"37203_CR19","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.braindev.2016.10.006","volume":"39","author":"S Tanifuji","year":"2017","unstructured":"Tanifuji, S. et al. Temporal brain metabolite changes in preterm infants with normal development. Brain Dev. 39, 196\u2013202 (2017).","journal-title":"Brain Dev."},{"key":"37203_CR20","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1542\/peds.2009-1046","volume":"125","author":"S Thayyil","year":"2010","unstructured":"Thayyil, S. et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics 125, 382 (2010).","journal-title":"Pediatrics"},{"key":"37203_CR21","doi-asserted-by":"crossref","unstructured":"Hyodo, R. et al. Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes. Arch. Dis. Child. Fetal Neonatal Ed (2017).","DOI":"10.1136\/archdischild-2016-311403"},{"key":"37203_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08195-4","volume":"7","author":"M Brossard-Racine","year":"2017","unstructured":"Brossard-Racine, M. et al. Altered Cerebellar Biochemical Profiles in Infants Born Prematurely. Sci. Rep. 7, 4 (2017).","journal-title":"Sci. Rep."},{"key":"37203_CR23","doi-asserted-by":"publisher","first-page":"e82746","DOI":"10.1371\/journal.pone.0082746","volume":"8","author":"M Tomiyasu","year":"2013","unstructured":"Tomiyasu, M. et al. Neonatal brain metabolite concentrations: an in vivo magnetic resonance spectroscopy study with a clinical MR system at 3 Tesla. PLoS One 8, e82746 (2013).","journal-title":"PLoS One"},{"key":"37203_CR24","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.mri.2015.06.003","volume":"33","author":"S Pradhan","year":"2015","unstructured":"Pradhan, S. et al. Comparison of single voxel brain MRS AT 3T and 7T using 32-channel head coils. Magn. Reson. Imaging 33, 1013\u20131018 (2015).","journal-title":"Magn. Reson. Imaging"},{"key":"37203_CR25","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.3174\/ajnr.A3521","volume":"34","author":"H Kidokoro","year":"2013","unstructured":"Kidokoro, H., Neil, J. J. & Inder, T. E. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. AJNR Am. J. Neuroradiol. 34, 2208\u20132214 (2013).","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"37203_CR26","doi-asserted-by":"crossref","unstructured":"Volpe, J. J. In Neurology of the Newborn 517\u2013588 (Saunders Elsevier, Philadelphia, PA, 2008).","DOI":"10.1016\/B978-1-4160-3995-2.10011-1"},{"key":"37203_CR27","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/S0022-3476(78)80282-0","volume":"92","author":"LA Papile","year":"1978","unstructured":"Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J. Pediatr. 92, 529\u2013534 (1978).","journal-title":"J. Pediatr."},{"key":"37203_CR28","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1002\/nbm.698","volume":"14","author":"SW Provencher","year":"2001","unstructured":"Provencher, S. W. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 14, 260\u2013264 (2001).","journal-title":"NMR Biomed."},{"key":"37203_CR29","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/1522-2594(200008)44:2<185::AID-MRM4>3.0.CO;2-V","volume":"44","author":"R Bartha","year":"2000","unstructured":"Bartha, R., Drost, D. J., Menon, R. S. & Williamson, P. C. Comparison of the quantification precision of human short echo time (1)H spectroscopy at 1.5 and 4.0 Tesla. Magn. Reson. Med. 44, 185\u2013192 (2000).","journal-title":"Magn. Reson. Med."},{"key":"37203_CR30","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/nbm.701","volume":"14","author":"S Cavassila","year":"2001","unstructured":"Cavassila, S., Deval, S., Huegen, C., van Ormondt, D. & Graveron-Demilly, D. Cramer-Rao bounds: an evaluation tool for quantitation. NMR Biomed. 14, 278\u2013283 (2001).","journal-title":"NMR Biomed."},{"key":"37203_CR31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/pr.2013.62","volume":"74","author":"D Card","year":"2013","unstructured":"Card, D. et al. Brain metabolite concentrations are associated with illness severity scores and white matter abnormalities in very preterm infants. Pediatr. Res. 74, 75\u201381 (2013).","journal-title":"Pediatr. Res."},{"key":"37203_CR32","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/mrm.25568","volume":"75","author":"R Kreis","year":"2016","unstructured":"Kreis, R. The trouble with quality filtering based on relative Cramer-Rao lower bounds. Magn. Reson. Med. 75, 15\u201318 (2016).","journal-title":"Magn. Reson. Med."},{"key":"37203_CR33","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1046\/j.1471-4159.2001.00285.x","volume":"77","author":"C Demougeot","year":"2001","unstructured":"Demougeot, C. et al. N-Acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury. J. Neurochem. 77, 408\u2013415 (2001).","journal-title":"J. Neurochem."},{"key":"37203_CR34","doi-asserted-by":"publisher","first-page":"2944","DOI":"10.1093\/cercor\/bhs283","volume":"23","author":"S Bluml","year":"2013","unstructured":"Bluml, S. et al. Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy. Cereb. Cortex 23, 2944\u20132955 (2013).","journal-title":"Cereb. Cortex"},{"key":"37203_CR35","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1002\/mrm.10497","volume":"50","author":"I Tkac","year":"2003","unstructured":"Tkac, I., Rao, R., Georgieff, M. K. & Gruetter, R. Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1H NMR spectroscopy. Magn. Reson. Med. 50, 24\u201332 (2003).","journal-title":"Magn. Reson. Med."},{"key":"37203_CR36","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1002\/mrm.1910300405","volume":"30","author":"R Kreis","year":"1993","unstructured":"Kreis, R., Ernst, T. & Ross, B. D. Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn. Reson. Med. 30, 424\u2013437 (1993).","journal-title":"Magn. Reson. Med."},{"key":"37203_CR37","doi-asserted-by":"publisher","first-page":"e0180973","DOI":"10.1371\/journal.pone.0180973","volume":"12","author":"MJ Holmes","year":"2017","unstructured":"Holmes, M. J. et al. Longitudinal increases of brain metabolite levels in 5\u201310 year old children. PLoS One 12, e0180973 (2017).","journal-title":"PLoS One"},{"key":"37203_CR38","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/pr.2011.40","volume":"71","author":"V Chau","year":"2012","unstructured":"Chau, V. et al. Postnatal infection is associated with widespread abnormalities of brain development in premature newborns. Pediatr. Res. 71, 274\u2013279 (2012).","journal-title":"Pediatr. Res."},{"key":"37203_CR39","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.bbi.2017.07.013","volume":"66","author":"S Tremblay","year":"2017","unstructured":"Tremblay, S. et al. Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model. Brain Behav. Immun. 66, 257\u2013276 (2017).","journal-title":"Brain Behav. Immun."},{"key":"37203_CR40","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/pr.2018.2","volume":"83","author":"FJ Drost","year":"2018","unstructured":"Drost, F. J. et al. Severe retinopathy of prematurity is associated with reduced cerebellar and brainstem volumes at term and neurodevelopmental deficits at 2 years. Pediatr. Res. 83, 818\u2013824 (2018).","journal-title":"Pediatr. Res."},{"key":"37203_CR41","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1159\/000487847","volume":"114","author":"K Sveinsdottir","year":"2018","unstructured":"Sveinsdottir, K. et al. Relation of Retinopathy of Prematurity to Brain Volumes at Term Equivalent Age and Developmental Outcome at 2 Years of Corrected Age in Very Preterm Infants. Neonatology 114, 46\u201352 (2018).","journal-title":"Neonatology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37203-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37203-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37203-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T05:20:56Z","timestamp":1671254456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-37203-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,4]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["37203"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-37203-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,4]]},"assertion":[{"value":"21 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1212"}}