{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:58:55Z","timestamp":1789988335167,"version":"4.0.1"},"reference-count":73,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T00:00:00Z","timestamp":1392076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Finding a Cure for Epilepsy and Seizures (FACES)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Genetic loss of <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>sc1\/<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>sc2 function in tuberous sclerosis complex (<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>) results in altered mammalian target of rapamycin (m<jats:styled-content style=\"fixed-case\">TOR)<\/jats:styled-content> signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell\u2010specific pattern of m<jats:styled-content style=\"fixed-case\">TORC<\/jats:styled-content>1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the m<jats:styled-content style=\"fixed-case\">TORC<\/jats:styled-content>1 and m<jats:styled-content style=\"fixed-case\">TORC<\/jats:styled-content>2 biomarkers phospho\u2010<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>6 (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>er235\/236), phospho\u2010<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>6 (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>er240\/244), and phospho\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>kt (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>er473), in addition to evaluating the differential expression levels of several neuronal and glial\u2010specific proteins in tubers and peritubers, as compared to non\u2010<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> epilepsy specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Tubers demonstrated mild to severe disruption of cortical lamination, the presence of p<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>6\u2010positive dysplastic neurons and giant cells, an overall increase in m<jats:styled-content style=\"fixed-case\">TORC<\/jats:styled-content>1 and a decrease in m<jats:styled-content style=\"fixed-case\">TORC<\/jats:styled-content>2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> and was negatively correlated with deficient myelination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our results show an extension of cellular dysplasia and dysregulated m<jats:styled-content style=\"fixed-case\">TOR<\/jats:styled-content> signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> and supports the intrinsic epileptogenicity of normal\u2010appearing perituberal cortex.<\/jats:p><jats:p>A PowerPoint slide summarizing this article is available for download in the Supporting Information section <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.12545\/suppinfo\">here<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12545","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T10:36:32Z","timestamp":1392201392000},"page":"539-550","source":"Crossref","is-referenced-by-count":104,"title":["Developmental brain abnormalities in tuberous sclerosis complex: A comparative tissue analysis of cortical tubers and perituberal cortex"],"prefix":"10.1111","volume":"55","author":[{"given":"V\u00e9ronique","family":"Ruppe","sequence":"first","affiliation":[{"name":"Department of Neurology School of Medicine New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pelin","family":"Dilsiz","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol Shoshkes","family":"Reiss","sequence":"additional","affiliation":[{"name":"Department of Biology and Neural Science New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orrin","family":"Devinsky","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine New York University New York New York U.S.A"},{"name":"Department of Neurosurgery School of Medicine New York University New York New York U.S.A"},{"name":"Department of Psychiatry School of Medicine New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Zagzag","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery School of Medicine New York University New York New York U.S.A"},{"name":"Department of Pathology School of Medicine New York University New York New York U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard L.","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery School of Medicine New York University New York New York 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