{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:01:45Z","timestamp":1791086505787,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Benjamin Walker Hanson Neonatology Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Hypoxic ischemic encephalopathy (HIE) remains a significant cause of disability despite treatment with therapeutic hypothermia (TH). Many survive with more subtle deficits that affect daily functioning and school performance. We have previously shown an early indication of hippocampal changes in infants with HIE despite TH. The aim of this study was to evaluate the hippocampal volume via MRI and memory function at 5 years of age. A cohort of children followed from birth returned for a 5-year follow-up (n = 10 HIE treated with TH, n = 8 healthy controls). The children underwent brain MRI and neurodevelopmental testing to assess their brain volume, general development, and memory function. Children with HIE had smaller hippocampal volumes than the controls despite no differences in the total brain volume (p = 0.02). Children with HIE generally scored within the average range on developmental testing. Though there was no difference in the memory scores between these groups, there was a positive within-group correlation between the hippocampal volume and memory scores in children with HIE (sentence recall r = 0.66, p = 0.038). There was no relationship between newborn memory function and 5-year hippocampal size. Children with HIE treated with TH experienced significant and lasting changes to the hippocampus despite improvements in survival and severe disability. Future studies should target diminishing injury to the hippocampus to improve overall outcomes.<\/jats:p>","DOI":"10.3390\/children10061005","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T08:50:31Z","timestamp":1685695831000},"page":"1005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Reduced Hippocampal Volumes in Children with History of Hypoxic Ischemic Encephalopathy after Therapeutic Hypothermia"],"prefix":"10.3390","volume":"10","author":[{"given":"Katie M.","family":"Pfister","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, 2450 Riverside Ave., AO-401, Minneapolis, MN 55454, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally M.","family":"Stoyell","sequence":"additional","affiliation":[{"name":"Institute of Child Development, University of Minnesota, Campbell Hall, 51 E River Rd., Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4517-2028","authenticated-orcid":false,"given":"Zachary R.","family":"Miller","sequence":"additional","affiliation":[{"name":"Institute of Child Development, University of Minnesota, Campbell Hall, 51 E River Rd., Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruskin H.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Institute of Child Development, University of Minnesota, Campbell Hall, 51 E River Rd., Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth P.","family":"Zorn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, 2450 Riverside Ave., AO-401, Minneapolis, MN 55454, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Institute of Child Development, University of Minnesota, Campbell Hall, 51 E River Rd., Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.earlhumdev.2010.05.010","article-title":"Epidemiology of neonatal encephalopathy and hypoxic\u2013ischaemic encephalopathy","volume":"86","author":"Kurinczuk","year":"2010","journal-title":"Early Hum. Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1056\/NEJMcps050929","article-title":"Whole-body hypothermia for neonates with hypoxic\u2013ischemic encephalopathy","volume":"353","author":"Shankaran","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1056\/NEJMoa1315788","article-title":"Effects of hypothermia for perinatal asphyxia on childhood outcomes","volume":"371","author":"Azzopardi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e624","DOI":"10.1542\/peds.2014-1566","article-title":"Cognitive outcomes after neonatal encephalopathy","volume":"135","author":"Pappas","year":"2015","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1053\/j.semperi.2016.09.007","article-title":"Outcomes in childhood following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE)","volume":"40","author":"Natarajan","year":"2016","journal-title":"Semin. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1001\/jamapediatrics.2019.4011","article-title":"Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia","volume":"174","author":"Finder","year":"2020","journal-title":"JAMA Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/brain\/123.3.499","article-title":"Developmental amnesia associated with early hypoxic-ischaemic injury","volume":"123","author":"Gadian","year":"2000","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41390-018-0115-8","article-title":"The long-term effect of perinatal asphyxia on hippocampal volumes","volume":"85","author":"Annink","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.pediatrneurol.2006.05.003","article-title":"Teenage outcome after being born at term with moderate neonatal encephalopathy","volume":"35","author":"Lagerroos","year":"2006","journal-title":"Pediatr. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.1552-6569.2003.tb00159.x","article-title":"Residual hippocampal atrophy in asphyxiated term neonates","volume":"13","author":"Olondo","year":"2003","journal-title":"J. Neuroimaging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/87565641.2011.581320","article-title":"Specific memory impairment following neonatal encephalopathy in term-born children","volume":"37","author":"Jongmans","year":"2012","journal-title":"Dev. Neuropsychol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1038\/s41598-021-83982-8","article-title":"Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy","volume":"11","author":"Annink","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/pr.2016.169","article-title":"ERP evidence of preserved early memory function in term infants with neonatal encephalopathy following therapeutic hypothermia","volume":"80","author":"Pfister","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10055","DOI":"10.1073\/pnas.1233756100","article-title":"Developmental Amnesia: Effect of age at injury","volume":"100","author":"Salmond","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1126\/science.277.5324.376","article-title":"Differential effects of early hippocampal pathology on episodic and semantic memory","volume":"277","author":"Gadian","year":"1997","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.ejpn.2013.05.005","article-title":"Region-specific reduction in brain volume in young adults with perinatal hypoxic-ischaemic encephalopathy","volume":"17","author":"Bregant","year":"2013","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101857","DOI":"10.1016\/j.nicl.2019.101857","article-title":"Reduced hippocampal subfield volumes and memory function in school-aged children born preterm with very low birthweight (VLBW)","volume":"23","author":"Aanes","year":"2019","journal-title":"Neuroimage Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1038\/s41372-018-0253-1","article-title":"Preserved speed of processing and memory in infants with a history of moderate neonatal encephalopathy treated with therapeutic hypothermia","volume":"38","author":"Zorn","year":"2018","journal-title":"J. Perinatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Committee on Fetus and Newborn (2014). Hypothermia and neonatal encephalopathy. Pediatrics, 133, 1146\u20131150.","DOI":"10.1542\/peds.2014-0899"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.neuroimage.2015.04.042","article-title":"A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI","volume":"115","author":"Iglesias","year":"2015","journal-title":"Neuroimage Clin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.33549\/physiolres.934198","article-title":"Impact of perinatal hypoxia on the developing brain","volume":"69","author":"Piesova","year":"2020","journal-title":"Physiol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1159\/000430862","article-title":"Effects of neonatal hypoxic-ischemic injury and hypothermic neuroprotection on neural progenitor cells in the mouse hippocampus","volume":"37","author":"Kwak","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000346324","article-title":"Short-term effects of hypothermia on axonal injury, preoligodendrocyte accumulation and oligodendrocyte myelination after hypoxia-ischemia in the hippocampus of immature rat brain","volume":"35","author":"Xiong","year":"2013","journal-title":"Dev. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1159\/000497056","article-title":"Calbindin-1 expression in the hippocampus following neonatal hypoxia-ischemia and therapeutic hypothermia and deficits in spatial memory","volume":"40","author":"Sanabria","year":"2018","journal-title":"Dev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/hipo.22965","article-title":"Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model","volume":"28","author":"Emerson","year":"2018","journal-title":"Hippocampus"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.pediatrneurol.2014.03.002","article-title":"Therapeutic hypothermia in neonates and selective hippocampal injury on diffusion-weighted magnetic resonance imaging","volume":"51","author":"Kasdorf","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.neulet.2012.03.092","article-title":"Hippocampal calbindin-1 immunoreactivity correlate of recognition memory performance in aged mice","volume":"10","author":"Soontornniyomkij","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22046","DOI":"10.1038\/s41598-021-01097-6","article-title":"Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia-ischemia in male rat pups","volume":"11","author":"Yazdani","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1177\/0883073819828625","article-title":"Current Practice of Therapeutic Hypothermia for Mild Hypoxic Ischemic Encephalopathy","volume":"34","author":"Saw","year":"2019","journal-title":"J. Child. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1055\/s-0040-1716341","article-title":"Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children\u2019s Hospital Neonatal Consortium","volume":"39","author":"Rao","year":"2022","journal-title":"Am. J. Perinatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.nlm.2016.05.011","article-title":"Global hypoxia induced impairment in learning and spatial memory is associated with precocious hippocampal aging","volume":"133","author":"Biswal","year":"2016","journal-title":"Neurobiol. Learn. Mem."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/6\/1005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:48:02Z","timestamp":1760125682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/6\/1005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,2]]},"references-count":31,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["children10061005"],"URL":"https:\/\/doi.org\/10.3390\/children10061005","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,2]]}}}