{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:03:27Z","timestamp":1789419807192,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"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. Behav. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuronal intranuclear inclusion disease (NIID) is a complex neurodegenerative disorder characterized by progressive cognitive decline. However, the patterns of functional network reorganization, as well as the underlying structural white matter (WM) damage and molecular mechanisms contributing to cognitive impairment, remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Nine patients with genetically-confirmed NIID (following the exclusion of one patient due to excessive head motion) and 10 age- and sex-matched healthy controls underwent multimodal MRI. We integrated voxel-level functional connectivity strength (FCS) with DTI-derived metrics (FA, AD, RD, and MD) across 20 major WM tracts. Cognitive performance was assessed via Montreal Cognitive Assessment (MoCA). We employed a \u201cstructure-function-metabolism\u201d analytical pipeline to examine how WM disintegration relates to cortical dysconnectivity and how these changes align with normative receptor maps (via JuSpace) and cerebral blood flow.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NIID patients demonstrated a distinct pattern of functional reorganization, marked by decreased FCS in the right opercular part of the inferior frontal gyrus (IFGoperc) and increased FCS in the left gyrus rectus; notably, the reduced FCS in the right IFGoperc was positively correlated with MoCA scores. Significant WM degeneration was observed in the bilateral anterior thalamic radiation (ATR) and the forceps minor, with FA values in the latter showing a significant positive correlation with MoCA scores. Crucially, the severity of WM damage (reduced FA; elevated AD, RD, and MD) in the left ATR was significantly correlated with functional disconnection in the IFGoperc, suggesting a structural-functional cascade may underlie cognitive deterioration. Molecular enrichment analysis further demonstrated that these functional deficits were spatially coupled with specific serotonergic (5-HT1b\/2a) and glutamatergic (mGluR5) receptor profiles, as well as regional hyperperfusion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest a potential multi-level pathophysiological framework in NIID, where structural disintegration of thalamo-cortical and interhemispheric tracts may serve as a topographical substrate for downstream functional network reorganization. This structural-functional-molecular axis, characterized by the convergence of network dysfunction, regional hyperperfusion, and specific neurotransmitter profiles, provides preliminary insights into the neurobiological mechanisms potentially underlying cognitive decline in NIID.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnbeh.2026.1854155","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:41:19Z","timestamp":1783057279000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural and molecular substrates underlying functional dysconnectivity and cognitive impairment in neuronal intranuclear inclusion disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Shujun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Radiology, Affiliated Hospital of Jining Medical University, Jining","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guorong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Jining Medical University","place":["Jining, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahui","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Affiliated Hospital of Jining Medical University, Jining","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Medical Imaging and Laboratory, Jining Medical University, Jining","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology, Affiliated Hospital of Jining Medical University, Jining","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiehuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Affiliated Hospital of Jining Medical University, Jining","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1038\/mp.2017.183","article-title":"Quantification of brain cholinergic denervation in Alzheimer\u2019s disease using PET imaging with [18F]-FEOBV.","volume":"22","author":"Aghourian","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1038\/jcbfm.2015.53","article-title":"Long-term test-retest reliability of striatal and extrastriatal dopamine D2\/3 receptor binding: Study with [(11)C]raclopride and high-resolution PET.","volume":"35","author":"Alakurtti","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B3","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.tics.2013.12.003","article-title":"Inhibition and the right inferior frontal cortex: One decade on.","volume":"18","author":"Aron","year":"2014","journal-title":"Trends Cogn. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.neuroimage.2007.07.007","article-title":"A fast diffeomorphic image registration algorithm.","volume":"38","author":"Ashburner","year":"2007","journal-title":"NeuroImage"},{"key":"B5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s12031-007-0029-0","article-title":"Diffusion tensor imaging (DTI)-based white matter mapping in brain research: A review.","volume":"34","author":"Assaf","year":"2007","journal-title":"J. Mol. Neurosci."},{"key":"B6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/1531-8249(199902)45:2<247::AID-ANA16>3.0.CO;2-U","article-title":"Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: Correlation with disease phase and interferon-beta therapy.","volume":"45","author":"Becher","year":"1999","journal-title":"Ann. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1523\/JNEUROSCI.2830-16.2016","article-title":"A high-resolution in vivo atlas of the human brain\u2019s serotonin system.","volume":"37","author":"Beliveau","year":"2017","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1523\/JNEUROSCI.5062-08.2009","article-title":"Cortical hubs revealed by intrinsic functional connectivity: Mapping, assessment of stability, and relation to Alzheimer\u2019s disease.","volume":"29","author":"Buckner","year":"2009","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fnhum.2013.00042","article-title":"PANDA: A pipeline toolbox for analyzing brain diffusion images.","volume":"7","author":"Cui","year":"2013","journal-title":"Front. Hum. Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1136\/jmedgenet-2019-106268","article-title":"Long-read sequencing identified repeat expansions in the 5\u2032UTR of theNOTCH2NLCgene from Chinese patients with neuronal intranuclear inclusion disease.","volume":"56","author":"Deng","year":"2019","journal-title":"J. Med. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/hbm.25244","article-title":"JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps.","volume":"42","author":"Dukart","year":"2020","journal-title":"Hum. Brain Mapp."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.1093\/cercor\/bhw157","article-title":"The human brainnetome atlas: A new brain atlas based on connectional architecture.","volume":"26","author":"Fan","year":"2016","journal-title":"Cereb. Cortex"},{"key":"B13","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/nrn4023","article-title":"A new mechanism of nervous system plasticity: Activity-dependent myelination.","volume":"16","author":"Fields","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"391","DOI":"10.3233\/rnn-2009-0493","article-title":"Neuroplasticity and cognitive aging: The scaffolding theory of aging and cognition.","volume":"27","author":"Goh","year":"2009","journal-title":"Restorative Neurol. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.neuroimage.2007.07.053","article-title":"Tract probability maps in stereotaxic spaces: Analyses of white matter anatomy and tract-specific quantification.","volume":"39","author":"Hua","year":"2008","journal-title":"NeuroImage"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1038\/s41588-019-0458-z","article-title":"Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.","volume":"51","author":"Ishiura","year":"2019","journal-title":"Nat. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1007\/s00259-017-3645-0","article-title":"Test-retest measurements of dopamine D1-type receptors using simultaneous PET\/MRI imaging.","volume":"44","author":"Kaller","year":"2017","journal-title":"Eur. J. Nuclear Med. Mol. Imaging"},{"key":"B18","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1002\/ana.410170419","article-title":"Brain neurotransmitter abnormalities in neuronal intranuclear inclusion body disorder.","volume":"17","author":"Kish","year":"1985","journal-title":"Ann. Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1178307","DOI":"10.3389\/fneur.2023.1178307","article-title":"Longitudinal course of hyperintensity on diffusion weighted imaging in adult-onset neuronal intranuclear inclusion disease patients.","volume":"14","author":"Liu","year":"2023","journal-title":"Front. Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"699010","DOI":"10.3389\/fnins.2021.699010","article-title":"Altered spontaneous neural activity and functional connectivity in Parkinson\u2019s disease with subthalamic microlesion.","volume":"15","author":"Luo","year":"2021","journal-title":"Front. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1007\/s00234-024-03406-y","article-title":"Mapping macrostructural and microstructural brain alterations in patients with neuronal intranuclear inclusion disease.","volume":"66","author":"Lv","year":"2024","journal-title":"Neuroradiology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1097\/WCO.0b013e32832d954b","article-title":"White matter atlases based on diffusion tensor imaging.","volume":"22","author":"Mori","year":"2009","journal-title":"Curr. Opin. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","article-title":"The montreal cognitive assessment, MoCA: A brief screening tool for mild cognitive impairment.","volume":"53","author":"Nasreddine","year":"2005","journal-title":"J. Am. Geriatr. Soc."},{"key":"B24","doi-asserted-by":"publisher","first-page":"117878","DOI":"10.1016\/j.neuroimage.2021.117878","article-title":"A high-resolution in vivo atlas of the human brain\u2019s benzodiazepine binding site of GABAA receptors.","volume":"232","author":"N\u00f8rgaard","year":"2021","journal-title":"NeuroImage"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1038\/jcbfm.2015.46","article-title":"Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test-retest reproducibility, and gender differences.","volume":"35","author":"Normandin","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B26","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.neuroscience.2013.11.007","article-title":"Role of myelin plasticity in oscillations and synchrony of neuronal activity.","volume":"276","author":"Pajevic","year":"2014","journal-title":"Neuroscience"},{"key":"B27","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1146\/annurev.psych.59.103006.093656","article-title":"The adaptive brain: Aging and neurocognitive scaffolding.","volume":"60","author":"Park","year":"2009","journal-title":"Annu. Rev. Psychol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/s11065-014-9270-9","article-title":"How does it STAC Up? Revisiting the scaffolding theory of aging and cognition.","volume":"24","author":"Reuter-Lorenz","year":"2014","journal-title":"Neuropsychol. Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.neuroimage.2012.07.001","article-title":"Normative database of the serotonergic system in healthy subjects using multi-tracer PET.","volume":"63","author":"Savli","year":"2012","journal-title":"NeuroImage"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2473","DOI":"10.2174\/138161206777698909","article-title":"Serotonin and human cognitive performance.","volume":"12","author":"Schmitt","year":"2006","journal-title":"Curr. Pharm. Design"},{"key":"B31","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.neurobiolaging.2006.10.023","article-title":"Neural networks in frontotemporal dementia\u2013a meta-analysis.","volume":"29","author":"Schroeter","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"B32","doi-asserted-by":"publisher","first-page":"5833","DOI":"10.1523\/jneurosci.0053-12.2012","article-title":"Serotonin selectively modulates reward value in human decision-making.","volume":"32","author":"Seymour","year":"2012","journal-title":"J. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"S208","DOI":"10.1016\/j.neuroimage.2004.07.051","article-title":"Advances in functional and structural MR image analysis and implementation as FSL.","volume":"23","author":"Smith","year":"2004","journal-title":"NeuroImage"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1038\/s41588-019-0459-y","article-title":"Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.","volume":"51","author":"Sone","year":"2019","journal-title":"Nat. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3170","DOI":"10.1093\/brain\/aww249","article-title":"Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.","volume":"139","author":"Sone","year":"2016","journal-title":"Brain"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1212\/WNL.0b013e3182166e13","article-title":"Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease.","volume":"76","author":"Sone","year":"2011","journal-title":"Neurology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/j.neuroimage.2003.07.005","article-title":"Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia.","volume":"20","author":"Song","year":"2003","journal-title":"NeuroImage"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1006\/nimg.2002.1267","article-title":"Dysmyelination revealed through MRI as increased radial (but Unchanged Axial) diffusion of water.","volume":"17","author":"Song","year":"2002","journal-title":"NeuroImage"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.3174\/ajnr.A5336","article-title":"MR imaging features of the cerebellum in adult-onset neuronal intranuclear inclusion disease: 8 cases.","volume":"38","author":"Sugiyama","year":"2017","journal-title":"Am. J. Neuroradiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1212\/cpj.0000000000000664","article-title":"MRI diagnosis of neuronal intranuclear inclusion disease leukoencephalopathy.","volume":"9","author":"Suthiphosuwan","year":"2019","journal-title":"Neurol. Clin. Pract."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1081383","DOI":"10.3389\/fnins.2022.1081383","article-title":"Characteristic cerebral perfusion pattern in neuronal intranuclear inclusion disease.","volume":"16","author":"Tai","year":"2022","journal-title":"Front. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e200057","DOI":"10.1212\/nxg.0000000000200057","article-title":"Clinical features and classification of neuronal intranuclear inclusion disease.","volume":"9","author":"Tai","year":"2023","journal-title":"Neurology Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1046\/j.1440-1789.2003.00524.x","article-title":"Neuronal intranuclear hyaline inclusion disease.","volume":"23","author":"Takahashi-Fujigasaki","year":"2003","journal-title":"Neuropathology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1136\/jnnp-2022-329772","article-title":"Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease.","volume":"93","author":"Tian","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B45","doi-asserted-by":"publisher","first-page":"9885","DOI":"10.1073\/pnas.1001414107","article-title":"Functional connectivity density mapping.","volume":"107","author":"Tomasi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B46","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.neuroimage.2007.02.049","article-title":"Reproducibility of quantitative tractography methods applied to cerebral white matter.","volume":"36","author":"Wakana","year":"2007","journal-title":"NeuroImage"},{"key":"B47","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1186\/s12915-024-02039-0","article-title":"Molecular mechanisms underlying the neural correlates of working memory.","volume":"22","author":"Xu","year":"2024","journal-title":"BMC Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s12021-016-9299-4","article-title":"DPABI: Data processing & analysis for (resting-state) brain imaging.","volume":"14","author":"Yan","year":"2016","journal-title":"Neuroinformatics"},{"key":"B49","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12883-023-03217-3","article-title":"Sex-dependent gut microbiota-brain-cognition associations: A multimodal MRI study.","volume":"23","author":"Zhang","year":"","journal-title":"BMC Neurol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e3054","DOI":"10.1002\/brb3.3054","article-title":"Impact of sex and serum lipids interaction on working memory: A large-scale brain networks study.","volume":"13","author":"Zhang","year":"","journal-title":"Brain Behav."},{"key":"B51","doi-asserted-by":"publisher","first-page":"814477","DOI":"10.3389\/fnins.2022.814477","article-title":"Brain network topology and structural\u2013functional connectivity coupling mediate the association between gut microbiota and cognition.","volume":"16","author":"Zhang","year":"2022","journal-title":"Front. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.neurad.2023.09.004","article-title":"MRI features of neuronal intranuclear inclusion disease, combining visual and quantitative imaging investigations.","volume":"51","author":"Zhang","year":"","journal-title":"J. Neuroradiol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.scib.2025.08.021","article-title":"Multimodal, multifaceted, imaging-based human brain white matter atlas.","volume":"71","author":"Zhou","year":"2026","journal-title":"Sci. Bull."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1478065","DOI":"10.3389\/fnagi.2024.1478065","article-title":"Diffusion and functional MRI reveal microstructural and network connectivity impairment in adult-onset neuronal intranuclear inclusion disease.","volume":"16","author":"Zhu","year":"","journal-title":"Front. Aging Neurosci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"5795","DOI":"10.1007\/s10072-024-07699-y","article-title":"Clinical and multimodal imaging features of adult-onset neuronal intranuclear inclusion disease.","volume":"45","author":"Zhu","year":"","journal-title":"Neurol. Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1093\/cercor\/bhr269","article-title":"Network centrality in the human functional connectome.","volume":"22","author":"Zuo","year":"2011","journal-title":"Cereb. Cortex"}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2026.1854155\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:41:20Z","timestamp":1783057280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2026.1854155\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":56,"alternative-id":["10.3389\/fnbeh.2026.1854155"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2026.1854155","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]},"article-number":"1854155"}}