{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:32:50Z","timestamp":1790767970886,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["R01 NS055903"],"award-info":[{"award-number":["R01 NS055903"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["071108"],"award-info":[{"award-number":["071108"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["1S10OD025025-01"],"award-info":[{"award-number":["1S10OD025025-01"]}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["R01 NS055903"],"award-info":[{"award-number":["R01 NS055903"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["071108"],"award-info":[{"award-number":["071108"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["1S10OD025025-01"],"award-info":[{"award-number":["1S10OD025025-01"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health","award":["R01 NS055903"],"award-info":[{"award-number":["R01 NS055903"]}]},{"name":"National Institutes of Health","award":["071108"],"award-info":[{"award-number":["071108"]}]},{"name":"National Institutes of Health","award":["1S10OD025025-01"],"award-info":[{"award-number":["1S10OD025025-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Huntington\u2019s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, with a rare juvenile-onset form (JoHD) marked by early, rigid motor symptoms. This study examined cortical and subcortical resting-state connectivity in JoHD, hypothesizing preserved cortical networks but altered striatal connectivity, in line with early subcortical atrophy despite relatively spared cortical volume. Methods: Participants included children and young adults with clinician-confirmed Juvenile-Onset Huntington\u2019s Disease (JoHD; n = 19) and gene-non-expanded (GNE) controls (n = 64), both drawn from longitudinal studies at the University of Iowa. Resting-state functional MRI scans were analyzed to assess canonical cortical network and striatal connectivity, and linear mixed-effects models tested group differences and associations with motor, cognitive, and clinical outcomes. Results: JoHD participants showed reduced connectivity within the left somatomotor network and striatal circuits, despite largely typical cortical network connectivity. Striatal connectivity was associated with disease burden and cognitive ability, while left somatomotor connectivity was unrelated to clinical outcomes. Conclusions: These findings support the hypothesis of antagonistic pleiotropy in JoHD, where early neural advantages\u2014such as relatively preserved or possibly enhanced cortical function\u2014may contribute to later striatal vulnerability and degeneration. The observed left-lateralized somatomotor hypoconnectivity aligns with prior volumetric and gene expression research, highlighting the role of excitotoxic glutamatergic input and the selective vulnerability of high-functioning circuits in disease progression.<\/jats:p>","DOI":"10.3390\/brainsci15060663","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T03:05:27Z","timestamp":1750388727000},"page":"663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cortical and Striatal Functional Connectivity in Juvenile-Onset Huntington\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Amy","family":"Barry","sequence":"first","affiliation":[{"name":"Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Department of Psychology and Brain Sciences, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-1903","authenticated-orcid":false,"given":"Peg C.","family":"Nopoulos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A Novel Gene Containing a Trinucleotide Repeat That Is Expanded and Unstable on Huntington\u2019s Disease Chromosomes. The Huntington\u2019s Disease Collaborative Research Group","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","article-title":"International Huntington\u2019s Disease Collaborative Group A New Model for Prediction of the Age of Onset and Penetrance for Huntington\u2019s Disease Based on CAG Length","volume":"65","author":"Langbehn","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1750-1172-5-40","article-title":"Huntington\u2019s Disease: A Clinical Review","volume":"5","author":"Roos","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e002085","DOI":"10.1136\/bmjopen-2012-002085","article-title":"Juvenile Huntington\u2019s Disease: A Population-Based Study Using the General Practice Research Database","volume":"3","author":"Douglas","year":"2013","journal-title":"BMJ Open"},{"key":"ref_5","unstructured":"Roos, R. (2025, March 05). Orpha.net: Juvenile Huntington Disease. Available online: https:\/\/www.orpha.net."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Achenbach, J., Thiels, C., L\u00fccke, T., and Saft, C. (2020). Clinical Manifestation of Juvenile and Pediatric HD Patients: A Retrospective Case Series. Brain Sci., 10.","DOI":"10.3390\/brainsci10060340"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1908","DOI":"10.1212\/WNL.0000000000009364","article-title":"Abnormal Development of Cerebellar-Striatal Circuitry in Huntington Disease","volume":"94","author":"Tereshchenko","year":"2020","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/mds.29251","article-title":"Longitudinal Clinical and Biological Characteristics in Juvenile-Onset Huntington\u2019s Disease","volume":"38","author":"Schultz","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/mrm.22176","article-title":"PROMO: Real-Time Prospective Motion Correction in MRI Using Image-Based Tracking","volume":"63","author":"White","year":"2010","journal-title":"Magn. Reson. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tustison, N.J., Cook, P.A., Holbrook, A.J., Johnson, H.J., Muschelli, J., Devenyi, G.A., Duda, J.T., Das, S.R., Cullen, N.C., and Gillen, D.L. (2021). The ANTsX Ecosystem for Quantitative Biological and Medical Imaging. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-87564-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neuroimage.2007.04.042","article-title":"A Component Based Noise Correction Method (CompCor) for BOLD and Perfusion Based FMRI","volume":"37","author":"Behzadi","year":"2007","journal-title":"Neuroimage"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1093\/cercor\/bhx179","article-title":"Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI","volume":"28","author":"Schaefer","year":"2018","journal-title":"Cereb. Cortex"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Young Kim, E., and Johnson, H.J. (2013). Robust Multi-Site MR Data Processing: Iterative Optimization of Bias Correction, Tissue Classification, and Registration. Front. Neuroinform., 7.","DOI":"10.3389\/fninf.2013.00029"},{"key":"ref_14","doi-asserted-by":"crossref","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":"ref_15","doi-asserted-by":"crossref","unstructured":"Huntington Study Group (1996). Unified Huntington\u2019s Disease Rating Scale: Reliability and Consistency. Mov. Disord., 11, 136\u2013142.","DOI":"10.1002\/mds.870110204"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wechsler, D. (2014). Wechsler Intelligence Scale for Children, Pearson. [5th ed.].","DOI":"10.1037\/t79359-000"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wechsler, D. (2008). Wechsler Adult Intelligence Scale, Pearson. [4th ed.].","DOI":"10.1037\/t15169-000"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling False Discovery Rate\u2014Practical Powerful Approach Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1939","DOI":"10.1212\/WNL.0000000000007355","article-title":"Brain Structure in Juvenile-Onset Huntington Disease","volume":"92","author":"Tereshchenko","year":"2019","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1002\/ana.27046","article-title":"Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy","volume":"96","author":"Neema","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_21","first-page":"1524","article-title":"Single Nuclei RNA-Seq Reveals a Medium Spiny Neuron Glutamate Excitotoxicity Signature Prior to the Onset of Neuronal Death in an Ovine Huntington\u2019s Disease Model","volume":"33","author":"Jiang","year":"2024","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1093\/brain\/awad275","article-title":"Genetic Topography and Cortical Cell Loss in Huntington\u2019s Disease Link Development and Neurodegeneration","volume":"146","author":"Altmann","year":"2023","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Stocksdale, J.T., Leventhal, M.J., Lam, S., Xu, Y.-X., Wang, Y.O., Wang, K.Q., Thomas, R., Faghihmonzavi, Z., Raghav, Y., and Smith, C. (2025). Intersecting Impact of CAG Repeat and Huntingtin Knockout in Stem Cell-Derived Cortical Neurons. Neurobiol. Dis., 210.","DOI":"10.1016\/j.nbd.2025.106914"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kuhlmann, N., Wagner Valladolid, M., Quesada-Ram\u00edrez, L., Farrer, M.J., and Milnerwood, A.J. (2021). Chronic and Acute Manipulation of Cortical Glutamate Transmission Induces Structural and Synaptic Changes in Co-Cultured Striatal Neurons. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.569031"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lila, E., Hunt, D., Child, D.D., Latimer, C., Le, B., Davis, M., Jayadev, S., Bird, T.D., Shojaie, A., and Mac Donald, C.L. (2025). Asymmetric Brain Atrophy in Huntington\u2019s Disease: A Postmortem MRI Study. J. Huntingt. Dis., 18796397251333334.","DOI":"10.1177\/18796397251333334"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.14802\/jmd.21006","article-title":"Gene Therapy for Huntington\u2019s Disease: The Final Strategy for a Cure?","volume":"15","author":"Byun","year":"2022","journal-title":"J. Mov. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2310\/7010.2006.00055","article-title":"Clinical Characteristics of Childhood-Onset (Juvenile) Huntington Disease: Report of 12 Patients and Review of the Literature","volume":"21","author":"Afifi","year":"2006","journal-title":"J. Child Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3233\/JHD-231523","article-title":"Clinical Review of Juvenile Huntington\u2019s Disease","volume":"13","author":"Oosterloo","year":"2024","journal-title":"J. Huntingt. Dis."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/6\/663\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:55:17Z","timestamp":1760032517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/6\/663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":28,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["brainsci15060663"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15060663","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]}}}