{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:22:23Z","timestamp":1793715743919,"version":"4.6.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"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. Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder with memory loss and cognitive impairment. The white matter (WM) BOLD signal has recently been shown to provide an important role in understanding the intrinsic cerebral activity. Although the altered homotopic functional connectivity within gray matter (GM-HFC) has been examined in AD, the abnormal HFC to WM remains unknown. The present study sought to identify changes in the WM-HFC and anatomic characteristics by combining functional magnetic resonance imaging with diffusion tensor imaging (DTI). Resting-state and DTI magnetic resonance images were collected from the OASIS-3 dataset and consisted of 53 mild cognitive impairment (MCI) patients, 90 very MCI (VMCI), and 100 normal cognitive (NC) subjects. Voxel-mirrored HFC was adopted to examine whether WM-HFC was disrupted in VMCI and MCI participants. Moreover, the DTI technique was used to investigate whether specific alterations of WM-HFC were associated with anatomic characteristics. Support vector machine analyses were used to identify the MCI and VMCI participants using the abnormal WM-HFC as the features. Compared with NC, MCI, and VMCI participants showed significantly decreased GM-HFC in the middle occipital gyrus and inferior parietal gyrus and decreased WM-HFC in the bilateral middle occipital and parietal lobe-WM. In addition, specific WM-functional network alteration for the bilateral sub-lobar-WM was found in MCI subjects. MCI subjects showed abnormal anatomic characteristics for bilateral sub-lobar and parietal lobe-WM. Results of GM-HFC mainly showed common neuroimaging features for VMCI and MCI subjects, whereas analysis of WM-HFC showed specific clinical neuromarkers and effectively compensated for the lack of GM-HFC to distinguish NC, VMCI, and MCI subjects.<\/jats:p>","DOI":"10.3389\/fnins.2021.697493","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T05:13:23Z","timestamp":1632287603000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Altered Homotopic Functional Connectivity Within White Matter in the Early Stages of Alzheimer\u2019s Disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Pan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zedong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharat B.","family":"Biswal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1093\/cercor\/bhq190","article-title":"Decreased interhemispheric functional connectivity in autism.","volume":"21","author":"Anderson","year":"2011","journal-title":"Cereb. Cortex"},{"key":"B2","article-title":"Support vector machines (SVM) as a technique for solvency analysis","author":"Auria","year":"2008","journal-title":"DIW Berlin Discussion Paper No. 811"},{"key":"B3","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1002\/mrm.1910340409","article-title":"Functional connectivity in the motor cortex of resting human brain using echo-planar mri.","volume":"34","author":"Biswal","year":"1995","journal-title":"Magn. Reson. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1038\/nrn2459","article-title":"The parietal cortex and episodic memory: an attentional account.","volume":"9","author":"Cabeza","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1145\/1961189.1961199","article-title":"LIBSVM: a library for support vector machines.","volume":"2","author":"Chang","year":"2011","journal-title":"Acm Trans. Intell. Syst. Technol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1097\/WCO.0b013e3282f4594b","article-title":"Diffusion tensor imaging in mild cognitive impairment and Alzheimer\u2019s disease: a review.","volume":"21","author":"Chua","year":"2008","journal-title":"Curr. Opin. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1126\/science.1090349","article-title":"Looking backward to move forward: early detection of neurodegenerative disorders.","volume":"302","author":"Dekosky","year":"2003","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.neuroimage.2006.01.021","article-title":"An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.","volume":"31","author":"Desikan","year":"2006","journal-title":"Neuroimage"},{"key":"B9","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1007\/bf03206676","article-title":"Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer\u2019s disease.","volume":"2","author":"Dickerson","year":"2005","journal-title":"NeuroRx"},{"key":"B10","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1073\/pnas.1711567115","article-title":"Detection of synchronous brain activity in white matter tracts at rest and under functional loading.","volume":"115","author":"Ding","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B11","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.neuroimage.2010.12.008","article-title":"DTI measures in crossing-fibre areas: increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer\u2019s disease.","volume":"55","author":"Douaud","year":"2011","journal-title":"Neuroimage"},{"key":"B12","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"Mini-mental state. A practical method for grading the cognitive state of patients for the clinician.","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatric Res."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240513","article-title":"Functional connectivity of white matter as a biomarker of cognitive decline in Alzheimer\u2019s disease.","volume":"15","author":"Gao","year":"2020","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.neulet.2005.05.028","article-title":"Visual attention deficits in Alzheimer\u2019s disease: an fMRI study.","volume":"385","author":"Hao","year":"2005","journal-title":"Neurosci. Lett."},{"key":"B15","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1523\/jneurosci.3430-11.2012","article-title":"The energetics of CNS white matter.","volume":"32","author":"Harris","year":"2012","journal-title":"J. Neurosci."},{"key":"B16","first-page":"39","article-title":"Combination of voxel based morphometry and diffusion tensor imaging in patients with Alzheimer\u2019s disease.","volume":"30","author":"Ibrahim","year":"2009","journal-title":"Neuroendocrinol. Lett."},{"key":"B17","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.scib.2017.03.021","article-title":"Low-frequency blood oxygen level-dependent fluctuations in the brain white matter: more than just noise.","volume":"62","author":"Ji","year":"2017","journal-title":"Sci. Bull."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1002\/hbm.24444","article-title":"Regional and network properties of white matter function in Parkinson\u2019s disease.","volume":"40","author":"Ji","year":"2019","journal-title":"Hum. Brain Mapp."},{"key":"B19","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1148\/radiol.13131638","article-title":"Generalized tonic-clonic seizures: aberrant interhemispheric functional and anatomical connectivity.","volume":"271","author":"Ji","year":"2014","journal-title":"Radiology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.neuroimage.2018.04.018","article-title":"White-matter functional networks changes in patients with schizophrenia.","volume":"190","author":"Jiang","year":"2019","journal-title":"Neuroimage"},{"key":"B21","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1148\/radiology.219.1.r01ap14101","article-title":"Mild cognitive impairment and Alzheimer disease: regional diffusivity of water.","volume":"219","author":"Kantarci","year":"2001","journal-title":"Radiology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.biopsych.2010.11.022","article-title":"Reduced interhemispheric resting state functional connectivity in cocaine addiction.","volume":"69","author":"Kelly","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1097\/WAD.0b013e3181a6f101","article-title":"Longitudinal rates of lobar atrophy in frontotemporal dementia, semantic dementia, and Alzheimer\u2019s Disease.","volume":"24","author":"Krueger","year":"2010","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.1002\/hbm.24705","article-title":"Exploring the functional connectome in white matter.","volume":"40","author":"Li","year":"2019","journal-title":"Hum. Brain Mapp."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1007\/s11682-018-0001-3","article-title":"Nicotine in action: cigarette smoking modulated homotopic functional connectivity in schizophrenia.","volume":"13","author":"Liao","year":"2019","journal-title":"Brain Imaging Behav."},{"key":"B26","first-page":"1526","article-title":"Interhemispheric functional and structural alterations and their relationships with alertness in unilateral temporal lobe epilepsy.","volume":"20","author":"Liu","year":"2016","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1146\/annurev.med.57.121304.131442","article-title":"Current pharmacotherapy for Alzheimer\u2019s disease.","volume":"57","author":"Lleo","year":"2006","journal-title":"Annu. Rev. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1006\/nimg.1997.0315","article-title":"Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations.","volume":"7","author":"Lowe","year":"1998","journal-title":"Neuroimage"},{"key":"B29","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1093\/cercor\/bhx319","article-title":"Distinctive neuroanatomical substrates for depression in bipolar disorder versus major depressive disorder.","volume":"29","author":"Matsuo","year":"2019","journal-title":"Cereb. Cortex"},{"key":"B30","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.neurobiolaging.2005.03.026","article-title":"White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study.","volume":"27","author":"Medina","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"B31","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1093\/brain\/awx355","article-title":"Fibre-specific white matter reductions in Alzheimer\u2019s disease and mild cognitive impairment.","volume":"141","author":"Mito","year":"2018","journal-title":"Brain"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.1212\/WNL.43.11.2412-a","article-title":"The clinical dementia rating (Cdr)-current version and scoring rules.","volume":"43","author":"Morris","year":"1993","journal-title":"Neurology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jalz.2018.08.012","article-title":"Altered bile acid profile in mild cognitive impairment and Alzheimer\u2019s disease: relationship to neuroimaging and CSF biomarkers.","volume":"15","author":"Nho","year":"2019","journal-title":"Alzheimers Dementia"},{"key":"B34","doi-asserted-by":"publisher","first-page":"6394","DOI":"10.1523\/jneurosci.3872-16.2017","article-title":"Evidence for functional networks within the human brain\u2019s white matter.","volume":"37","author":"Peer","year":"2017","journal-title":"J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1001\/archneur.56.3.303","article-title":"Mild cognitive impairment-Clinical characterization and outcome.","volume":"56","author":"Petersen","year":"1999","journal-title":"Arch. Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2142","DOI":"10.1016\/j.neuroimage.2011.10.018","article-title":"Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion.","volume":"59","author":"Power","year":"2012","journal-title":"Neuroimage"},{"key":"B37","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.neuroimage.2007.08.018","article-title":"A simple view of the brain through a frequency-specific functional connectivity measure.","volume":"39","author":"Salvador","year":"2008","journal-title":"Neuroimage"},{"key":"B38","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.neuroimage.2012.08.052","article-title":"An improved framework for confound regression and filtering for control of motion artifact in the preprocessing of resting-state functional connectivity data.","volume":"64","author":"Satterthwaite","year":"2013","journal-title":"Neuroimage"},{"key":"B39","doi-asserted-by":"publisher","first-page":"13754","DOI":"10.1523\/jneurosci.4544-08.2008","article-title":"Regional variation in interhemispheric coordination of intrinsic hemodynamic fluctuations.","volume":"28","author":"Stark","year":"2008","journal-title":"J. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1212\/01.wnl.0000228231.26111.6e","article-title":"Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI.","volume":"67","author":"Storandt","year":"2006","journal-title":"Neurology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1109\/42.650881","article-title":"Creating connected representations of cortical gray matter for functional MRI visualization.","volume":"16","author":"Teo","year":"1997","journal-title":"IEEE Trans. Med. Imaging"},{"key":"B42","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1006\/nimg.2001.0978","article-title":"Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.","volume":"15","author":"Tzourio-Mazoyer","year":"2002","journal-title":"Neuroimage"},{"key":"B43","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/jmri.26214","article-title":"Disrupted functional connectivity and activity in the white matter of the sensorimotor system in patients with pontine strokes.","volume":"49","author":"Wang","year":"2019","journal-title":"J. Magn. Reson. Imaging"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3313","DOI":"10.1093\/cercor\/bhz311","article-title":"The organization of the human corpus callosum estimated by intrinsic functional connectivity with white-matter functional networks.","volume":"30","author":"Wang","year":"2020","journal-title":"Cereb. Cortex"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117642","article-title":"Structural and functional connectivity mapping of the human corpus callosum organization with white-matter functional networks.","volume":"227","author":"Wang","year":"2021","journal-title":"Neuroimage"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126310","article-title":"Interhemispheric functional and structural disconnection in Alzheimer\u2019s Disease: a combined resting-state fMRI and DTI study.","volume":"10","author":"Wang","year":"2015","journal-title":"PLoS One"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112411","article-title":"Efficacy of distortion correction on diffusion imaging: comparison of fsl eddy and eddy_correct using 30 and 60 directions diffusion encoding.","volume":"9","author":"Yamada","year":"2014","journal-title":"PLoS One"},{"key":"B48","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.braindev.2012.01.002","article-title":"Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI (vol 29, pg 83, 2007).","volume":"34","author":"Zang","year":"2012","journal-title":"Brain Dev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"5621","DOI":"10.1073\/pnas.090504197","article-title":"A universal scaling law between gray matter and white matter of cerebral cortex.","volume":"97","author":"Zhang","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1407","article-title":"Functional connectivity between white matter and gray matter based on fMRI for Alzheimer\u2019s disease classification.","volume":"9","author":"Zhao","year":"2019","journal-title":"Brain Behav."},{"key":"B51","doi-asserted-by":"publisher","first-page":"15034","DOI":"10.1523\/jneurosci.2612-10.2010","article-title":"Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy.","volume":"30","author":"Zuo","year":"2010","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.697493\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T05:13:29Z","timestamp":1632287609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.697493\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,22]]},"references-count":51,"alternative-id":["10.3389\/fnins.2021.697493"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.697493","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,22]]},"article-number":"697493"}}