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It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease\u2010modifying drugs, lovastatin (40\u2009mg) and minocycline (100\u2009mg), administered alone for 8\u2009weeks and in combination for 12\u2009weeks, in 19 patients (mean age of 23.58\u2009\u00b1\u20091.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short\u2010interval intracortical inhibition, long\u2010interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8\u2009weeks of monotherapy (visit 2 of the clinical trial) and after 12\u2009weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20\u2009weeks. This was reflected by a significant increase in the resting\u2010motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short\u2010intracortical inhibition, a marker of GABAa\u2010mediated inhibition after 8\u2009weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">clinicaltrials.gov<\/jats:ext-link> (NCT02680379).<\/jats:p>","DOI":"10.1002\/aur.3222","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T09:55:46Z","timestamp":1725875746000},"page":"1944-1956","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the <scp>LOVAMIX<\/scp> randomized clinical trial"],"prefix":"10.1002","volume":"17","author":[{"given":"Florence","family":"Morin\u2010Parent","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine and Health Sciences Sherbrooke University  Sherbrooke Canada"},{"name":"Sherbrooke University Hospital Research Center  Sherbrooke 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