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However, few studies investigate E\/I imbalance at the macroscale, whole\u2010brain level, and its microcircuit\u2010level mechanisms and clinical significance remain incompletely understood. Here, the Hurst exponent, an index of the E\/I ratio, is computed from resting\u2010state fMRI time series, and microcircuit parameters are simulated\u00a0using biophysical models. A broad decrease in the Hurst exponent is observed in pharmaco\u2010resistant temporal lobe epilepsy (TLE), suggesting more excitable network dynamics. Connectome decoders point to temporolimbic and frontocentral cortices as plausible network epicenters of E\/I imbalance. Furthermore, computational simulations reveal that enhancing cortical excitability in TLE reflects atypical increases in recurrent connection strength of local neuronal ensembles. Mixed cross\u2010sectional and longitudinal analyses show stronger E\/I ratio elevation in patients\u00a0with longer disease duration, more frequent electroclinical seizures as well as interictal epileptic spikes, and worse cognitive functioning. Hurst exponent\u2010informed classifiers discriminate patients from healthy controls with high accuracy (72.4% [57.5%\u201382.5%]). Replicated in an independent dataset, this work provides in vivo evidence of a macroscale shift in E\/I balance in TLE patients and points to progressive functional imbalances that relate to cognitive decline.<\/jats:p>","DOI":"10.1002\/advs.202406835","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:42:14Z","timestamp":1736815334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Temporal Lobe Epilepsy Perturbs the Brain\u2010Wide Excitation\u2010Inhibition Balance: Associations with Microcircuit Organization, Clinical Parameters, and Cognitive Dysfunction"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7101-2493","authenticated-orcid":false,"given":"Ke","family":"Xie","sequence":"first","affiliation":[{"name":"McConnell Brain Imaging Centre Montreal Neurological Institute and Hospital McGill University  Montreal QC H3A 2B4 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