{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T04:41:31Z","timestamp":1766983291027,"version":"3.41.2"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. However, few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We performed DTI scans in 42 treatment-na\u00efve first-episode schizophrenia patients and 38 healthy controls. Voxel-based method of fractional anisotropy (FA) derived from DTI was used to assess WM integrity. Participants' peripheral blood genomic DNAm status, quantified by using Infinium\u00ae Human Methylation 450K BeadChip, was examined in parallel with DTI scanning. Participants completed Digit Span test and Trail Making test, as well as Positive and Negative Syndrome Scale measurement. We acquired genes that are differentially expressed in the brain regions with abnormal FA values according to the Allen anatomically comprehensive atlas, obtained DNAm levels of the corresponding genes, and then performed Z-test to compare the differential epigenetic-imaging associations (DEIAs) between the two groups.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Significant decreases of FA values in the patient group were in the right middle temporal lobe WM, right cuneus WM, right anterior cingulate WM, and right inferior parietal lobe WM, while the significant increases were in the bilateral middle cingulate WM (<jats:italic>P<\/jats:italic>s &amp;lt; 0.01, GRF correction). Abnormal FA values were correlated with patients' clinical symptoms and cognitive impairments. In the DEIAs, patients showed abnormal couple patterns between altered FA and DNAm components, for which the enriched biological processes and pathways could be largely grouped into three biological procedures: the neurocognition, immune, and nervous system.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Schizophrenia may not cause widespread neuropathological changes, but subtle alterations affecting local cingulum WM, which may play a critical role in positive symptoms and cognitive impairments. This imaging-epigenetics study revealed for the first time that DNAm of genes enriched in neuronal, immunologic, and cognitive processes may serve as the basis in the effect of WM deficits on clinical behaviors in schizophrenia.<\/jats:p>","DOI":"10.3389\/fpsyt.2021.777407","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T06:21:56Z","timestamp":1639376516000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["DNA Methylation Basis in the Effect of White Matter Integrity Deficits on Cognitive Impairments and Psychopathological Symptoms in Drug-Naive First-Episode Schizophrenia"],"prefix":"10.3389","volume":"12","author":[{"given":"Xiaofen","family":"Zong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changchun","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyue","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaohua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luxian","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deen","family":"Sang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiufen","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huafu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maolin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.jpsychires.2019.05.008","article-title":"Meta-analysis of the positive and Negative Syndrome Scale (PANSS) factor structure","volume":"115","author":"Shafer","year":"2019","journal-title":"J Psychiatr Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1093\/schbul\/sbn187","article-title":"The neurodevelopmental hypothesis of schizophrenia, revisited","volume":"35","author":"Fatemi","year":"2009","journal-title":"Schizophr Bull."},{"key":"B3","doi-asserted-by":"publisher","first-page":"409","DOI":"10.31887\/DCNS.2010.12.3\/nandreasen","article-title":"The lifetime trajectory of schizophrenia and the concept of neurodevelopment","volume":"12","author":"Andreasen","year":"2010","journal-title":"Dialogues Clin Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/S0006-3223(03)00419-0","article-title":"Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study","volume":"54","author":"Kubicki","year":"2003","journal-title":"Biol Psychiatry."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1038\/mp.2017.170","article-title":"Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group","volume":"23","author":"Kelly","year":"2018","journal-title":"Mol Psychiatry."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e15219","DOI":"10.1371\/journal.pone.0015219","article-title":"Cerebellum abnormalities in idiopathic generalized epilepsy with generalized tonic-clonic seizures revealed by diffusion tensor imaging","volume":"5","author":"Li","year":"2010","journal-title":"PLoS ONE."},{"key":"B7","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/nbm.782","article-title":"The basis of anisotropic water diffusion in the nervous system\u2013a technical review","volume":"15","author":"Beaulieu","year":"2002","journal-title":"NMR Biomed."},{"key":"B8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fnint.2013.00009","article-title":"What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia","volume":"7","author":"Alba-Ferrara","year":"2013","journal-title":"Front Integr Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.pscychresns.2017.09.014","article-title":"White matter and schizophrenia: a meta-analysis of voxel-based morphometry and diffusion tensor imaging studies","volume":"270","author":"Vitolo","year":"2017","journal-title":"Psychiatry Res Neuroimaging."},{"key":"B10","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.pscychresns.2019.09.001","article-title":"Computer-assisted cognitive remediation therapy for patients with schizophrenia induces microstructural changes in cerebellar regions involved in cognitive functions","volume":"292","author":"Matsuoka","year":"2019","journal-title":"Psychiatry Res Neuroimaging."},{"key":"B11","first-page":"4410","article-title":"Reduced white matter integrity associated with cognitive deficits in patients with drug-naive first-episode schizophrenia revealed by diffusion tensor imaging","volume":"12","author":"Peng","year":"2020","journal-title":"Am J Transl Res."},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-97307-4","volume-title":"Neuroimaging of Schizophrenia and Other Primary Psychotic Disorders: Achievements and Perspectives","author":"Galderisi","year":"2019"},{"key":"B13","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s43440-020-00177-0","article-title":"Magnetic resonance diffusion tensor imaging in psychiatry: a narrative review of its potential role in diagnosis","volume":"73","author":"Podwalski","year":"2021","journal-title":"Pharmacol Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/gm397","article-title":"DNA methylation in schizophrenia: progress and challenges of epigenetic studies","volume":"4","author":"Nishioka","year":"2012","journal-title":"Genome Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"401","DOI":"10.2217\/epi-2018-0127","article-title":"GRIN2B promoter methylation deficits in early-onset schizophrenia and its association with cognitive function","volume":"11","author":"Fachim","year":"2019","journal-title":"Epigenomics."},{"key":"B16","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1111\/pcn.12622","article-title":"methylation of membrane-bound catechol-O-methyltransferase in Malaysian schizophrenia patients","volume":"72","author":"Nour El Huda","year":"2018","journal-title":"Psychiatry Clin Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.3389\/fpsyg.2016.01496","article-title":"Epigenetics in schizophrenia: a pilot study of global DNA methylation in different brain regions associated with higher cognitive functions","volume":"7","author":"Alel\u00fa-Paz","year":"2016","journal-title":"Front Psychol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-00968-0","article-title":"Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population","author":"Li","year":"2020","journal-title":"Mol Psychiatry."},{"key":"B19","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.schres.2015.08.035","article-title":"The association of DNA methylation and brain volume in healthy individuals and schizophrenia patients","volume":"169","author":"Liu","year":"2015","journal-title":"Schizophr Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jad.2014.09.042","article-title":"Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression","volume":"172","author":"Choi","year":"2015","journal-title":"J Affect Disord."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e866","DOI":"10.1038\/tp.2016.137","article-title":"Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder","volume":"6","author":"Won","year":"2016","journal-title":"Transl Psychiatry."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1038\/s41380-017-0008-y","article-title":"Meta-analysis of epigenome-wide association studies of cognitive abilities","volume":"23","author":"Marioni","year":"2018","journal-title":"Mol Psychiatry."},{"key":"B23","doi-asserted-by":"publisher","first-page":"367","DOI":"10.2217\/epi.13.36","article-title":"Testing two models describing how methylome-wide studies in blood are informative for psychiatric conditions","volume":"5","author":"Aberg","year":"2013","journal-title":"Epigenomics."},{"key":"B24","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nature11405","article-title":"An anatomically comprehensive atlas of the adult human brain transcriptome","volume":"489","author":"Hawrylycz","year":"2012","journal-title":"Nature."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1093\/schbul\/sby175","article-title":"A dissociation in effects of risperidone monotherapy on functional and anatomical connectivity within the default mode network","volume":"45","author":"Zong","year":"2019","journal-title":"Schizophr Bull."},{"key":"B26","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/schbul\/13.2.261","article-title":"The positive and negative syndrome scale (PANSS) for schizophrenia","volume":"13","author":"Kay","year":"1987","journal-title":"Schizophr Bull."},{"key":"B27","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.brainresbull.2012.03.005","article-title":"Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder","volume":"88","author":"Oral","year":"2012","journal-title":"Brain Res Bull."},{"key":"B28","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.acn.2007.01.022","article-title":"Trail Making Test in traumatic brain injury, schizophrenia, and normal ageing: sample comparisons and normative data","volume":"22","author":"Peri\u00e1\u00f1ez","year":"2007","journal-title":"Arch Clin Neuropsychol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"359","DOI":"10.3389\/fpsyt.2020.00359","article-title":"Metabolic syndrome and cognitive functions in schizophrenia-implementation of dietary intervention","volume":"11","author":"Adamowicz","year":"2020","journal-title":"Front Psychiatry."},{"key":"B30","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1177\/1073191115602552","article-title":"The trail making test","volume":"24","author":"Llin\u00e0s-Regl\u00e0","year":"2017","journal-title":"Assessment."},{"volume-title":"A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary","year":"2006","author":"Strauss","key":"B31"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.31.018283","article-title":"Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype","author":"Hu","year":"2020","journal-title":"bioRxiv [preprint]."},{"key":"B33","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1023\/B:MATG.0000002982.52104.02","article-title":"Estimating Pearson's correlation coefficient with Bootstrap confidence interval from serially dependent time series","volume":"35","author":"Mudelsee","year":"2003","journal-title":"Math Geol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.neubiorev.2018.05.008","article-title":"The cingulum bundle: anatomy, function, and dysfunction","volume":"92","author":"Bubb","year":"2018","journal-title":"Neurosci Biobehav Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1176\/appi.neuropsych.15050120","article-title":"Diffusion tensor imaging study using a voxel-based analysis, region-of-interest method to analyze white matter abnormalities in first-episode, treatment-na\u00efve major depressive disorder","volume":"28","author":"Srivastava","year":"2016","journal-title":"J Neuropsychiatry Clin Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"531993","DOI":"10.3389\/fneur.2020.531993","article-title":"Diffusion tensor imaging in Parkinson's disease and parkinsonian syndrome: a systematic review","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"109955","DOI":"10.1016\/j.pnpbp.2020.109955","article-title":"The relationship between cingulum bundle integrity and different aspects of executive functions in chronic schizophrenia","volume":"102","author":"Tyburski","year":"2020","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry."},{"key":"B39","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.schres.2004.04.009","article-title":"NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI","volume":"72","author":"Northoff","year":"2005","journal-title":"Schizophr Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1093\/brain\/awt162","article-title":"The role of the posterior cingulate cortex in cognition and disease","volume":"137","author":"Leech","year":"2014","journal-title":"Brain."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e575","DOI":"10.1038\/tp.2015.69","article-title":"Altered functional connectivity of the cingulate subregions in schizophrenia","volume":"5","author":"Wang","year":"2015","journal-title":"Transl Psychiatry."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.4161\/epi.29223","article-title":"MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls","volume":"9","author":"Walton","year":"2014","journal-title":"Epigenetics."},{"key":"B43","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.brainresbull.2016.07.013","article-title":"Actin filament-microtubule interactions in axon initiation and branching","volume":"126","author":"Pacheco","year":"2016","journal-title":"Brain Res Bull."},{"key":"B44","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1124\/mi.3.1.27","article-title":"Recent advances in the neurobiology of schizophrenia","volume":"3","author":"Miyamoto","year":"2003","journal-title":"Mol Interv."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1017\/S0033291719001685","article-title":"Peripheral inflammatory and neurotrophic biomarkers of cognitive impairment in schizophrenia: a meta-analysis","volume":"49","author":"Bora","year":"2019","journal-title":"Psychol Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1440-1711.2005.01305.x","article-title":"Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis?","volume":"83","author":"Jones","year":"2005","journal-title":"Immunol Cell Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.pnpbp.2012.12.013","article-title":"Is there an association between peripheral immune markers and structural\/functional neuroimaging findings?","volume":"48","author":"Frodl","year":"2014","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry."},{"key":"B48","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.schres.2014.09.043","article-title":"Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study","volume":"161","author":"Prasad","year":"2015","journal-title":"Schizophr Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuroimage.2010.04.015","article-title":"Voxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy","volume":"52","author":"Li","year":"2010","journal-title":"Neuroimage."},{"key":"B50","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3389\/fnins.2019.00052","article-title":"Increased peripheral interleukin 10 relate to white matter integrity in schizophrenia","volume":"13","author":"Fu","year":"2019","journal-title":"Front Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.jpsychires.2020.03.013","article-title":"Plasticity of DNA methylation, functional brain connectivity and efficiency in cognitive remediation for schizophrenia","volume":"126","author":"Ho","year":"2020","journal-title":"J Psychiatr Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s11434-014-0690-y","article-title":"DNA methylation in schizophrenia: progress and challenges","volume":"60","author":"Zong","year":"2015","journal-title":"Sci Bull."}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2021.777407\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T06:22:00Z","timestamp":1639376520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2021.777407\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":52,"alternative-id":["10.3389\/fpsyt.2021.777407"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2021.777407","relation":{},"ISSN":["1664-0640"],"issn-type":[{"type":"electronic","value":"1664-0640"}],"subject":[],"published":{"date-parts":[[2021,12,13]]},"article-number":"777407"}}