{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T14:49:10Z","timestamp":1776091750288,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"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. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Fragile X syndrome (FXS) is the leading cause of genetic intellectual disability. Among the neurobehavioral dysfunctions in FXS individuals, language development and literacy are compromised. Recent evidence hypothesized that the disruption of excitatory glutamatergic and GABAergic inhibitory neurotransmission balance might be responsible for impairment in cognitive function. In this study, we evaluated for the first time, the safety, tolerability, and efficacy of anodal prefrontal transcranial direct current stimulation (tDCS) combined with standard speech therapy to enhance language function in FXS patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In total, 16 adult FXS patients were enrolled. Participants underwent 45\u2009min of anodic tDCS combined with speech therapy for 5\u2009weeks (3 times per week). Language function was evaluated using the Test for Reception of Grammar\u2013Version 2 (TROG-2) and subtests of the Italian Language Examination (Esame del Linguaggio \u2013 II, EDL-II). Right and left dorsolateral prefrontal cortex transcranial magnetic stimulation and concurrent electroencephalography (TMS-EEG) recordings were collected at baseline and after the treatment to evaluate cortical reactivity and connectivity changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After 5\u2009weeks of combined therapy, we observed a significant improvement in the writing (7.5%), reading (20.3%), repetition (13.3%), and TROG-2 (10.2%) tests. Parallelly with clinical change, TMS-EEG results showed a significant difference in TMS-evoked potential amplitude over the left frontal cortex after treatment (\u22120.73\u2009\u00b1\u20090.87\u2009\u03bcV) compared to baseline (0.18\u2009\u00b1\u20090.84\u2009\u03bcV).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study provides novel evidence that left anodal prefrontal tDCS combined with standard speech therapy could be effective in enhancing language function in FXS patients, mainly by inducing a rebalance of the dysfunctional prefrontal cortical excitability.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1268165","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T11:00:03Z","timestamp":1701774003000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Transcranial direct current stimulation combined with speech therapy in Fragile X syndrome patients: a pilot study"],"prefix":"10.3389","volume":"14","author":[{"given":"Chiara","family":"Picciuca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Assogna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romina","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"D\u2019Acunto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Ferraresi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Picazio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Borghi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Martino Cinnera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Bonn\u00ec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Chiurazzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Koch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1542\/peds.2013-4301","article-title":"Fragile X syndrome: a review of associated medical problems","volume":"134","author":"Kidd","year":"2014","journal-title":"Pediatrics"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"251","DOI":"10.2174\/1573396315666190625110748","article-title":"New targeted treatments for fragile X syndrome","volume":"15","author":"Protic","year":"2019","journal-title":"Curr Pediatr Rev"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1093\/hmg\/9.6.901","article-title":"Understanding the molecular basis of fragile X syndrome","volume":"9","author":"Jin","year":"2000","journal-title":"Hum Mol Genet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.neuron.2008.10.004","article-title":"Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function","volume":"60","author":"Bassell","year":"2008","journal-title":"Neuron"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.3390\/ijms23041935","article-title":"Fragile X syndrome: from molecular aspect to clinical treatment","volume":"23","author":"Protic","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/tld.0b013e3181a72016","article-title":"Language development in individuals with fragile X syndrome","volume":"29","author":"Finestack","year":"2009","journal-title":"Top Lang Disord"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"929379","DOI":"10.3389\/fpsyg.2022.929379","article-title":"Communication in fragile X syndrome: patterns and implications for assessment and intervention","volume":"13","author":"Hoffmann","year":"2022","journal-title":"Front Psychol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"fcz042","DOI":"10.1093\/braincomms\/fcz042","article-title":"A neurophysiological model of speech production deficits in fragile X syndrome","volume":"2","author":"Schmitt","year":"2019","journal-title":"Brain Commun"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"17065","DOI":"10.1038\/nrdp.2017.65","article-title":"Fragile X syndrome","volume":"3","author":"Hagerman","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1146\/annurev-neuro-060909-153138","article-title":"The pathophysiology of fragile X (and what it teaches us about synapses)","volume":"35","author":"Bhakar","year":"2012","journal-title":"Annu Rev Neurosci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.2147\/NDT.S42919","article-title":"Modulation of the GABAergic pathway for the treatment of fragile X syndrome","volume":"10","author":"Lozano","year":"2014","journal-title":"Neuropsychiatr Dis Treat"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e787","DOI":"10.1038\/tp.2016.48","article-title":"Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in fragile X syndrome","volume":"6","author":"Ethridge","year":"2016","journal-title":"Transl Psychiatry"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.conb.2018.07.009","article-title":"Gamma oscillations in cognitive disorders","volume":"52","author":"Mably","year":"2018","journal-title":"Curr Opin Neurobiol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"8423420","DOI":"10.1155\/2018\/8423420","article-title":"Impaired GABA neural circuits are critical for fragile X syndrome","author":"Gao","year":"2018","journal-title":"Neural Plast"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.neuropharm.2016.12.010","article-title":"Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice","volume":"116","author":"Sabanov","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.3390\/jcm11102839","article-title":"Transcranial direct current stimulation as an approach to mitigate neurodevelopmental disorders affecting excitation\/inhibition balance: focus on autism Spectrum disorder, schizophrenia, and attention deficit\/hyperactivity disorder","volume":"11","author":"Sousa","year":"2022","journal-title":"J Clin Med"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1162\/jocn_a_01115","article-title":"Individual differences and long-term consequences of tDCS-augmented cognitive training","volume":"29","author":"Katz","year":"2017","journal-title":"J Cogn Neurosci"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s41465-017-0030-7","article-title":"Transcranial direct current stimulation (tDCS) of the anterior prefrontal cortex (aPFC) modulates reinforcement learning and decision-making under uncertainty: a double-blind crossover study","volume":"1","author":"Casula","year":"2017","journal-title":"J Cogn Enhanc"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"640","DOI":"10.3109\/02699206.2011.570852","article-title":"The use of the bilingual aphasia test for assessment and transcranial direct current stimulation to modulate language acquisition in minimally verbal children with autism","volume":"25","author":"Schneider","year":"2011","journal-title":"Clin Linguist Phon"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.1162\/jocn.2010.21579","article-title":"Transcranial direct current stimulation improves word retrieval in healthy and nonfluent aphasic subjects","volume":"23","author":"Fiori","year":"2011","journal-title":"J Cogn Neurosci"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.bbr.2011.08.008","article-title":"Electrical stimulation over the left inferior frontal gyrus (IFG) determines long-term effects in the recovery of speech apraxia in three chronic aphasics","volume":"225","author":"Marangolo","year":"2011","journal-title":"Behav Brain Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1080\/09602011.2013.804847","article-title":"How conversational therapy influences language recovery in chronic non-fluent aphasia","volume":"23","author":"Marangolo","year":"2013","journal-title":"Neuropsychol Rehabil"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.cortex.2018.08.002","article-title":"Altered topology of the functional speech production network in non-fluent\/agrammatic variant of PPA","volume":"108","author":"Mandelli","year":"2018","journal-title":"Cortex"},{"key":"ref24","year":""},{"key":"ref25","first-page":"1","volume-title":"Test for reception of grammar: TROG-2. Version 2","author":"Bishop","year":"2003"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/0013-4694(94)90029-9","article-title":"Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee","volume":"91","author":"Rossini","year":"1994","journal-title":"Electroencephalogr Clin Neurophysiol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.neuroimage.2016.10.031","article-title":"Analysing concurrent transcranial magnetic stimulation and electroencephalographic data: a review and introduction to the open-source TESA software","volume":"147","author":"Rogasch","year":"2017","journal-title":"NeuroImage"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e156869","DOI":"10.1155\/2011\/156869","article-title":"FieldTrip: open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data","volume":"2011","author":"Oostenveld","year":"2010","journal-title":"Comput Intell Neurosci"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1177\/00222194020350040401","article-title":"Remedial interventions for children with reading disabilities: speech perception--an effective component in phonological training?","volume":"35","author":"del Rosario Ortiz Gonz\u00e1lez","year":"2002","journal-title":"J Learn Disabil"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"19391","DOI":"10.1038\/s41598-022-23040-z","article-title":"Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex","volume":"1","author":"Maiella","year":"2022","journal-title":"Sci Rep"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1088\/0031-9155\/57\/8\/2137","article-title":"Evaluation of local electric fields generated by transcranial direct current stimulation with an extracephalic reference electrode based on realistic 3D body modeling","volume":"57","author":"Im","year":"2012","journal-title":"Phys Med Biol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"641","DOI":"10.3389\/fnins.2017.00641","article-title":"Transcranial direct current stimulation (tDCS): a beginner\u2019s guide for design and implementation","volume":"11","author":"Thair","year":"2017","journal-title":"Front Neurosci"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.neuroimage.2018.10.052","article-title":"The non-transcranial TMS-evoked potential is an inherent source of ambiguity in TMS-EEG studies","volume":"185","author":"Conde","year":"2019","journal-title":"NeuroImage"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/S1388-2457(99)00070-X","article-title":"The role of the coil click in TMS assessed with simultaneous EEG","volume":"110","author":"Nikouline","year":"1999","journal-title":"Clin Neurophysiol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1007\/s10548-013-0312-z","article-title":"Masking the auditory evoked potential in TMS-EEG: a comparison of various methods","volume":"28","author":"ter Braack","year":"2015","journal-title":"Brain Topogr"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.brs.2016.06.004","article-title":"Safety of transcranial direct current stimulation: evidence based update 2016","volume":"9","author":"Bikson","year":"2016","journal-title":"Brain Stimul"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.cnp.2016.12.003","article-title":"Adverse events of tDCS and tACS: a review","volume":"2","author":"Matsumoto","year":"2016","journal-title":"Clin Neurophysiol Pract"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.neuroimage.2018.04.011","article-title":"Dynamic reorganization of TMS-evoked activity in subcortical stroke patients","volume":"175","author":"Pellicciari","year":"2018","journal-title":"NeuroImage"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s00702-023-02599-5","article-title":"Neurobiological correlates and attenuated positive social intention attribution during laughter perception associated with degree of autistic traits","volume":"130","author":"Martinelli","year":"2023","journal-title":"J Neural Transm (Vienna)"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1162\/jocn_a_01725","article-title":"Transcranial direct current stimulation modulates connectivity of left dorsolateral prefrontal cortex with distributed cortical networks","volume":"33","author":"Kim","year":"2021","journal-title":"J Cogn Neurosci"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1136\/jnnp-2012-302825","article-title":"Transcranial direct current stimulation (tDCS) and language","volume":"84","author":"Monti","year":"2013","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.bbr.2009.10.030","article-title":"Naming facilitation induced by transcranial direct current stimulation","volume":"208","author":"Fertonani","year":"2010","journal-title":"Behav Brain Res"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3233\/RNN-2011-0587","article-title":"Improved picture naming in aphasia patients treated with cathodal tDCS to inhibit the right Broca\u2019s homologue area","volume":"29","author":"Kang","year":"2011","journal-title":"Restor Neurol Neurosci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"230","DOI":"10.3389\/fpsyg.2011.00230","article-title":"Non-invasive brain stimulation enhances the effects of melodic intonation therapy","volume":"2","author":"Vines","year":"2011","journal-title":"Front Psychol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"13775","DOI":"10.3390\/ijms232213775","article-title":"Neuroprotection and non-invasive brain stimulation: facts or fiction?","volume":"23","author":"Guidetti","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"103293","DOI":"10.1016\/j.isci.2021.103293","article-title":"Altered inflammatory response in FMRP-deficient microglia","volume":"24","author":"Parrott","year":"2021","journal-title":"iScience"},{"key":"ref47","first-page":"47","article-title":"Responsivity education\/prelinguistic milieu teaching","author":"Warren","year":"2006","journal-title":"Treat Lang Disord Child"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1080\/13682820600623960","article-title":"Phonological awareness intervention for children with childhood apraxia of speech","volume":"41","author":"Moriarty","year":"2006","journal-title":"Int J Lang Commun Disord"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1268165\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T11:00:06Z","timestamp":1701774006000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1268165\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,5]]},"references-count":48,"alternative-id":["10.3389\/fneur.2023.1268165"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1268165","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,5]]},"article-number":"1268165"}}