{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:16:32Z","timestamp":1787760992610,"version":"build-2784847793"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"publisher","award":["31870981"],"award-info":[{"award-number":["31870981"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Despite verifying proton magnetic resonance spectroscopy (\n                      <jats:sup>1<\/jats:sup>\n                      H-MRS) for focal localization in magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE), it is necessary to illustrate metabolic changes and screen for effective biomarkers for monitoring therapeutic effect. We used\n                      <jats:sup>1<\/jats:sup>\n                      H-MRS to investigate the role of metabolic levels in MRI-negative TLE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      Thirty-seven patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200937, 14 women) and 20 healthy controls (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920, 11 women) were investigated by\n                      <jats:sup>1<\/jats:sup>\n                      H-MRS. We compared the metabolite level changes in the epileptic and contralateral sides on the mesial temporal and dorsolateral prefrontal cortices and analyzed their association with clinical symptoms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      \u03b3-Aminobutyric acid (GABA) levels were significantly lower on the epileptic side (2.292\u2009\u00b1\u20090.890) than in the contralateral side (2.662\u2009\u00b1\u20090.742,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.029*) in patients on the mesial temporal lobe. N-acetylaspartate (NAA) levels were significantly lower on the epileptic side (7.284\u2009\u00b1\u20091.314) than on the contralateral side (7.655\u2009\u00b1\u20091.549,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.034*). NAA\u2009+\u2009N-acetylaspartylglutamate levels were significantly lower on the epileptic side (7.668\u2009\u00b1\u20091.406) than on the contralateral side (8.086\u2009\u00b1\u20091.675,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.032*). Glutamate levels were significantly lower on the epileptic side (7.773\u2009\u00b1\u20091.428) than on the contralateral side (8.245\u2009\u00b1\u20091.616,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.040*). Moreover, a significant negative correlation was found between GABA levels in the epileptic mesial temporal lobe and tonic\u2013clonic seizure frequency (r\u2009=\u2009\u22120.338,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.046*).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\u03b3-Aminobutyric acid (GABA) is a potential biomarker for lateralization and monitoring seizure frequency in MRI-negative TLE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2023.1184440","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:39:40Z","timestamp":1684111180000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["\u03b3-Aminobutyric acid as a biomarker of the lateralizing and monitoring drug effect in patients with magnetic resonance imaging-negative temporal lobe epilepsy"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuohua","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huige","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renhua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1007\/s11064-016-2105-8","article-title":"Mechanisms of excessive extracellular glutamate accumulation in temporal lobe epilepsy","volume":"42","author":"Albrecht","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e4245","DOI":"10.1002\/nbm.4245","article-title":"In vivo Glx and Glu measurements from GABA-edited MRS at 3 T","volume":"34","author":"Bell","year":"2021","journal-title":"NMR Biomed."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1212\/WNL.0b013e3181fc29dd","article-title":"Antiepileptic drug response in temporal lobe epilepsy: a clinical and MRI morphometry study","volume":"75","author":"Bilevicius","year":"2010","journal-title":"Neurology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/glia.23247","article-title":"Epilepsy and astrocyte energy metabolism","volume":"66","author":"Boison","year":"2018","journal-title":"Glia"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1002\/ana.20380","article-title":"Extracellular metabolites in the cortex and hippocampus of epileptic patients","volume":"57","author":"Cavus","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref5","first-page":"3","article-title":"Magnetic resonance spectroscopy studies of GABA in neuropsychiatric disorders","volume":"64","author":"Chang","year":"2003","journal-title":"J. Clin. Psychiatry"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1002\/jmri.24611","article-title":"Investigation of glutamine and GABA levels in patients with idiopathic generalized epilepsy using MEGAPRESS","volume":"41","author":"Chowdhury","year":"2015","journal-title":"J. Magn. Reson. Imag.: JMRI"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1212\/wnl.51.1.61","article-title":"Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy","volume":"51","author":"Connelly","year":"1998","journal-title":"Neurology"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"309ra161","DOI":"10.1126\/scitranslmed.aaa7095","article-title":"Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy","volume":"7","author":"Davis","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.tins.2012.11.008","article-title":"Glia and epilepsy: excitability and inflammation","volume":"36","author":"Devinsky","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.ejrad.2003.08.009","article-title":"High-field proton MRS of human brain","volume":"48","author":"Di Costanzo","year":"2003","journal-title":"Eur. J. Radiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1111\/j.1528-1167.2010.02544.x","article-title":"Alterations of intracerebral \u03b3-aminobutyric acid (GABA) levels by titration with levetiracetam in patients with focal epilepsies","volume":"51","author":"Doelken","year":"2010","journal-title":"Epilepsia"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/s0140-6736(03)15166-5","article-title":"Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy","volume":"363","author":"Eid","year":"2004","journal-title":"Lancet (London, England)"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1002\/ana.25325","article-title":"Low-voltage fast seizures in humans begin with increased interneuron firing","volume":"84","author":"Elahian","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/s0140-6736(74)90956-8","article-title":"Mesial temporal (Ammon's horn) sclerosis as a common cause of epilepsy. Aetiology, treatment, and prevention","volume":"2","author":"Falconer","year":"1974","journal-title":"Lancet (London, England)"},{"key":"ref150","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1111\/epi.13827","article-title":"Postictal hypoperfusion\/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction","volume":"58","author":"Farrell","year":"2017","journal-title":"Epilepsia"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1111\/epi.13670","article-title":"Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE Commission for Classification and Terminology","volume":"58","author":"Fisher","year":"2017","journal-title":"Epilepsia"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1111\/epi.16768","article-title":"In vivo \u03b3-aminobutyric acid increase as a biomarker of the epileptogenic zone: an unbiased metabolomics approach","volume":"62","author":"Hamelin","year":"2021","journal-title":"Epilepsia"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1111\/j.1468-1331.2006.01293.x","article-title":"Identifying the affected hemisphere by (1) H-MR spectroscopy in patients with temporal lobe epilepsy and no pathological findings in high resolution MRI","volume":"13","author":"Hammen","year":"2006","journal-title":"Eur. J. Neurol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1111\/j.1528-1167.2006.00856.x","article-title":"1H-MR spectroscopy indicates severity markers in temporal lobe epilepsy: correlations between metabolic alterations, seizures, and epileptic discharges in EEG","volume":"48","author":"Hammen","year":"2007","journal-title":"Epilepsia"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"107683","DOI":"10.1016\/j.yebeh.2020.107683","article-title":"Gamma-aminobutyric acid (GABA) changes in the hippocampus and anterior cingulate cortex in patients with temporal lobe epilepsy","volume":"115","author":"He","year":"2021","journal-title":"Epilepsy Behav.r: E & B"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1111\/epi.13515","article-title":"Diagnostic utility of invasive EEG for epilepsy surgery: indications, modalities, and techniques","volume":"57","author":"Jayakar","year":"2016","journal-title":"Epilepsia"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1212\/wnl.58.3.368","article-title":"Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults","volume":"58","author":"Kuzniecky","year":"2002","journal-title":"Neurology"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1111\/j.1528-1167.2008.01669.x","article-title":"How do seizures stop?","volume":"49","author":"Lado","year":"2008","journal-title":"Epilepsia"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/j.1528-1167.2012.03610.x","article-title":"Hippocampal sclerosis--origins and imaging","volume":"53","author":"Malmgren","year":"2012","journal-title":"Epilepsia"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1111\/epi.13699","article-title":"MRI-negative temporal lobe epilepsy-what do we know?","volume":"58","author":"Muhlhofer","year":"2017","journal-title":"Epilepsia"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.neuroimage.2012.12.004","article-title":"Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA","volume":"86","author":"Mullins","year":"2014","journal-title":"NeuroImage"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1177\/1073858402238515","article-title":"GABA and glutamate in the human brain","volume":"8","author":"Petroff","year":"2002","journal-title":"Neuroscientist: Rev. 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Neurol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1016\/S1474-4422(14)70156-5","article-title":"Epilepsy surgery in children and adults","volume":"13","author":"Ryvlin","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1111\/j.1528-1167.2012.03642.x","article-title":"Seizure worsening and its predictors after epilepsy surgery","volume":"53","author":"Sarkis","year":"2012","journal-title":"Epilepsia"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.seizure.2021.06.028","article-title":"Brain concentrations of glutamate and GABA in human epilepsy: a review","volume":"91","author":"Sarlo","year":"2021","journal-title":"Seizure"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1111\/epi.13709","article-title":"ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology","volume":"58","author":"Scheffer","year":"2017","journal-title":"Epilepsia"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1038\/ncomms2056","article-title":"Evidence of an inhibitory restraint of seizure activity in humans","volume":"3","author":"Schevon","year":"2012","journal-title":"Nat. Commun."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1177\/1535370221989263","article-title":"Influence of glutamate and GABA transport on brain excitatory\/inhibitory balance","volume":"246","author":"Sears","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.neubiorev.2015.12.014","article-title":"GABA-ergic cell therapy for epilepsy: advances, limitations and challenges","volume":"62","author":"Shetty","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1111\/j.0013-9580.2004.13503.x","article-title":"Areas of interictal spiking are associated with metabolic dysfunction in MRI-negative temporal lobe epilepsy","volume":"45","author":"Shih","year":"2004","journal-title":"Epilepsia"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1212\/01.wnl.0000086903.69738.dc","article-title":"Proton MRS reveals frontal lobe metabolite abnormalities in idiopathic generalized epilepsy","volume":"61","author":"Simister","year":"2003","journal-title":"Neurology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.eplepsyres.2008.11.006","article-title":"Proton MR spectroscopy of metabolite concentrations in temporal lobe epilepsy and effect of temporal lobe resection","volume":"83","author":"Simister","year":"2009","journal-title":"Epilepsy Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1016\/j.neuropharm.2007.08.016","article-title":"Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H]glutamate: comparison with the Na+ channel-mediated release","volume":"53","author":"Sitges","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1212\/wnl.58.5.821","article-title":"1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy","volume":"58","author":"Suhy","year":"2002","journal-title":"Neurology"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1007\/s00330-018-5443-x","article-title":"Quantitative MR spectroscopy reveals metabolic changes in the dorsolateral prefrontal cortex of patients with temporal lobe epilepsy","volume":"28","author":"Tan","year":"2018","journal-title":"Eur. Radiol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S0140-6736(18)32596-0","article-title":"Epilepsy in adults","volume":"393","author":"Thijs","year":"2019","journal-title":"Lancet (London, England)"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1046\/j.1528-1157.2001.042suppl.3008.x","article-title":"GABAergic mechanisms in epilepsy","volume":"42","author":"Treiman","year":"2001","journal-title":"Epilepsia"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.pbb.2007.09.004","article-title":"Microdialysis of GABA and glutamate: analysis, interpretation and comparison with microsensors","volume":"90","author":"Van Der Zeyden","year":"2008","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1002\/1531-8249(199903)45:3<369::aid-ana13>3.0.co;2-q","article-title":"Short echo time single-voxel p magnetic resonance spectroscopy in magnetic resonance imaging-negative temporal lobe epilepsy: different biochemical profile compared with hippocampal sclerosis","volume":"45","author":"Woermann","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1002\/ana.10696","article-title":"GABA, gamma-hydroxybutyric acid, and neurological disease","volume":"54","author":"Wong","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1007\/s00702-014-1180-8","article-title":"(Bernasconi et al. 2003) the healthy brain","volume":"121","author":"Zhou","year":"2014","journal-title":"J. Neural Trans. (Vienna Austria): 1996"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nrneurol.2017.190","article-title":"Epilepsy in 2017: precision medicine drives epilepsy classification and therapy","volume":"14","author":"Zuberi","year":"2018","journal-title":"Nat. Rev. Neurol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1184440\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:39:44Z","timestamp":1684111184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1184440\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,15]]},"references-count":50,"alternative-id":["10.3389\/fnins.2023.1184440"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1184440","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,15]]},"article-number":"1184440"}}