{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:03:33Z","timestamp":1780401813632,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Background: Functional Neurological Disorder (FND) is a common and disabling condition at the interface of neurology and psychiatry, characterized by motor, sensory, seizure-like, or cognitive symptoms that are incongruent with recognized neurological disease but associated with substantial impairment. Despite its frequency and marked female predominance, FND remains underdiagnosed and often misunderstood. Methods: This narrative review synthesizes evidence from neurobiological, biomarker, and treatment studies, with attention to predictive coding, salience network dysfunction, impaired sense of agency, stress-related mechanisms, and sex- and gender-related vulnerability. Results: Current evidence supports a model of FND as a disorder of distributed brain network dysfunction involving abnormal interactions among salience, limbic, motor, and self-monitoring systems. Predictive coding and impaired agency models provide clinically useful frameworks for understanding symptom generation, although they remain mechanistic hypotheses rather than definitive causal explanations. Candidate biomarkers, including functional connectivity alterations, autonomic dysregulation, and HPA axis measures, offer pathophysiological insight but remain insufficiently validated for routine diagnosis. Female predominance likely reflects interacting biological, psychological, and sociocultural mechanisms rather than a single neuroendocrine pathway. Conclusions: This review contributes an integrated, clinically oriented framework linking neurobiology, biomarkers, sex\/gender vulnerability, and treatment in FND. Current evidence supports multidisciplinary care combining diagnostic communication, specialized physiotherapy, psychotherapy, and coordinated follow-up, while future research should prioritize standardized phenotyping, longitudinal designs, and multimodal biomarker validation.<\/jats:p>","DOI":"10.3390\/neurolint18060109","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:14:57Z","timestamp":1780395297000},"page":"109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Neurological Disorder: Neurobiological Mechanisms, Biomarkers, and Integrated Treatment in a Female-Predominant Neuropsychiatric Condition"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7058-4927","authenticated-orcid":false,"given":"Giuseppe","family":"Marano","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Head-Neck and Chest, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy"},{"name":"Department of Neuroscience, Section of Psychiatry, Universit\u00e0 Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-8162","authenticated-orcid":false,"given":"Marianna","family":"Mazza","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Head-Neck and Chest, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy"},{"name":"Department of Neuroscience, Section of Psychiatry, Universit\u00e0 Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.clineuro.2010.05.011","article-title":"Who is referred to neurology clinics?\u2014The diagnoses made in 3781 new patients","volume":"112","author":"Stone","year":"2010","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1001\/jamaneurol.2018.1264","article-title":"Current concepts in diagnosis and treatment of functional neurological disorders","volume":"75","author":"Espay","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1093\/brain\/aws129","article-title":"A Bayesian account of \u201chysteria\u201d","volume":"135","author":"Edwards","year":"2012","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Kazis, D., Kamal, F.Z., Gurzu, I.L., Ciobica, A., P\u0103durariu, M., Novac, B., and Iordache, A. (2024). Understanding Functional Neurological Disorder: Recent Insights and Diagnostic Challenges. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084470"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102623","DOI":"10.1016\/j.nicl.2021.102623","article-title":"Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda","volume":"30","author":"Perez","year":"2021","journal-title":"Neuroimage Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1176\/appi.neuropsych.14090217","article-title":"Functional neuroanatomy and neurophysiology of functional neurological disorders (conversion disorder)","volume":"28","author":"Voon","year":"2016","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1136\/jnnp-2021-328462","article-title":"Functional movement disorder gender, age and phenotype study: A systematic review and individual patient meta-analysis of 4905 cases","volume":"93","author":"Lidstone","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/B978-0-12-801772-2.00005-9","article-title":"Epidemiology","volume":"Volume 139","author":"Hallett","year":"2016","journal-title":"Functional Neurological Disorders"},{"key":"ref_9","first-page":"52","article-title":"Neural correlates of recall of life events in conversion disorder","volume":"72","author":"Aybek","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1136\/jnnp-2018-319201","article-title":"Emotional processing in functional neurological disorder: A review, biopsychosocial model and research agenda","volume":"90","author":"Pick","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/practneurol-2015-001242","article-title":"Explaining functional disorders in the neurology clinic: A photo story","volume":"16","author":"Carson","year":"2016","journal-title":"Pract. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1136\/jnnp-2014-309255","article-title":"Physiotherapy for functional motor disorders: A consensus recommendation","volume":"86","author":"Nielsen","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1136\/jnnp.73.3.241","article-title":"Functional weakness and sensory disturbance","volume":"73","author":"Stone","year":"2002","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S1525-5050(03)00104-5","article-title":"Psychogenic nonepileptic seizures: Review and update","volume":"4","author":"Reuber","year":"2003","journal-title":"Epilepsy Behav."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1177\/1550059414555905","article-title":"An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: Neural functional unawareness","volume":"46","author":"Perez","year":"2015","journal-title":"Clin. EEG Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Marano, G., D\u2019Abate, C., Traversi, G., Mazza, O., Gaetani, E., Esposito, R., Pavese, F., Paris, I., and Mazza, M. (2026). Neuroinflammation and the Female Brain: Sex-Specific Mechanisms Underlying Mood Disorders and Stress Vulnerability. Life, 16.","DOI":"10.3390\/life16010139"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5945","DOI":"10.3748\/wjg.v29.i45.5945","article-title":"Gut microbiota in women: The secret of psychological and physical well-being","volume":"29","author":"Marano","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1055\/a-2761-1554","article-title":"Women\u2019s Issues and Female-specific Factors in Functional Neurological Disorder","volume":"46","author":"Boylan","year":"2026","journal-title":"Semin. Neurol."},{"key":"ref_19","first-page":"555","article-title":"A framework for understanding the pathophysiology of functional neurological disorder","volume":"4","author":"Drane","year":"2020","journal-title":"CNS Spectr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41398-025-03385-5","article-title":"Altered brain network dynamics in motor functional neurological disorders: The role of the right temporo-parietal junction","volume":"15","author":"Weber","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/7854_2024_473","article-title":"Predictive Processing and the Pathophysiology of Functional Neurological Disorder","volume":"74","author":"Jungilligens","year":"2025","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e001309","DOI":"10.1136\/bmjno-2025-001309","article-title":"Pathophysiology of functional neurological disorder for the general neurologist","volume":"7","author":"Phillips","year":"2025","journal-title":"BMJ Neurol. Open"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103899","DOI":"10.1016\/j.nicl.2025.103899","article-title":"Modulating the sense of agency in functional neurological disorder using real-time fMRI neurofeedback: A proof-of-concept study","volume":"48","author":"Loukas","year":"2025","journal-title":"Neuroimage Clin."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106358","DOI":"10.1016\/j.neubiorev.2025.106358","article-title":"Mechanisms of motor dysfunction in functional neurological disorder: A narrative review","volume":"178","author":"Lo","year":"2025","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.psyneuen.2017.08.023","article-title":"Biological and perceived stress in motor functional neurological disorders","volume":"85","author":"Apazoglou","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mazza, M., Biondi-Zoccai, G., Lisci, F.M., Brisi, C., Sfratta, G., Rossi, S., Traversi, G., Gaetani, E., Pola, R., and Morini, S. (2024). The Brain-Heart Axis: An Umbrella Review on Impact of Psychiatric Disease on Incidence, Management, and Outlook of Cardiovascular Disease. Life, 14.","DOI":"10.3390\/life14080919"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103625","DOI":"10.1016\/j.nicl.2024.103625","article-title":"BOLD signal variability as potential new biomarker of functional neurological disorders","volume":"43","author":"Schneider","year":"2024","journal-title":"Neuroimage Clin."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mark, V.W. (2024). Biomarkers and Rehabilitation for Functional Neurological Disorder. J. Pers. Med., 14.","DOI":"10.20944\/preprints202407.1728.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1474-4422(21)00422-1","article-title":"Functional neurological disorder: New subtypes and shared mechanisms","volume":"21","author":"Hallett","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_30","first-page":"151","article-title":"The outcome of neurology outpatients with medically unexplained symptoms","volume":"60","author":"Carson","year":"2003","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1136\/jnnp-2018-318297","article-title":"Stress and functional neurological disorders: Mechanistic insights","volume":"90","author":"Keynejad","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Perjoc, R.S., Roza, E., Vladacenco, O.A., Teleanu, D.M., Neacsu, R., and Teleanu, R.I. (2023). Functional Neurological Disorder-Old Problem New Perspective. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20021099"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00612","DOI":"10.1016\/j.neurot.2025.e00612","article-title":"Functional neurological disorder: Practical management","volume":"22","author":"Dworetzky","year":"2025","journal-title":"Neurotherapeutics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1007\/s00415-020-09772-w","article-title":"Management of functional neurological disorder","volume":"267","author":"Gilmour","year":"2020","journal-title":"J. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1136\/practneurol-2017-001835","article-title":"You\u2019ve made the diagnosis of functional neurological disorder: Now what?","volume":"18","author":"Adams","year":"2018","journal-title":"Pract. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S2215-0366(20)30128-0","article-title":"Cognitive behavioral therapy for adults with dissociative seizures (CODES): A pragmatic, multicentre, randomized controlled trial","volume":"7","author":"Goldstein","year":"2020","journal-title":"Lancet Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100478","DOI":"10.1016\/j.ebr.2021.100478","article-title":"Using evidence-based psychotherapy to tailor treatment for patients with functional neurological disorders","volume":"16","author":"Myers","year":"2021","journal-title":"Epilepsy Behav. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1093\/brain\/awp060","article-title":"In the psychiatrist\u2019s chair: How neurologists understand conversion disorder","volume":"132","author":"Kanaan","year":"2009","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1037\/0033-2909.130.5.793","article-title":"Psychological mechanisms of medically unexplained symptoms: An integrative conceptual model","volume":"130","author":"Brown","year":"2004","journal-title":"Psychol. Bull."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.eplepsyres.2008.12.008","article-title":"Non-Epileptic Seizures (NES) are predicted by depressive and dissociative symptoms","volume":"84","author":"Mazza","year":"2009","journal-title":"Epilepsy Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S2215-0366(18)30051-8","article-title":"Stressful life events and maltreatment in conversion (functional neurological) disorder: Systematic review and meta-analysis","volume":"5","author":"Ludwig","year":"2018","journal-title":"Lancet Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1136\/jnnp-2016-314408","article-title":"Randomised feasibility study of physiotherapy for patients with functional motor symptoms","volume":"88","author":"Nielsen","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1080\/09593985.2025.2514126","article-title":"Physical therapy evaluation and treatment of functional movement disorders: A case series","volume":"41","author":"Mowry","year":"2025","journal-title":"Physiother. Theory Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1007\/s00415-014-7495-4","article-title":"Multidisciplinary treatment for functional neurological symptoms: A prospective study","volume":"261","author":"Demartini","year":"2014","journal-title":"J. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1136\/jnnp-2012-304181","article-title":"A systematic review of transcranial magnetic stimulation in the treatment of functional (conversion) neurological symptoms","volume":"85","author":"Pollak","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/mds.27727","article-title":"Repetitive transcranial magnetic stimulation for functional tremor: A randomized controlled study","volume":"34","author":"Taib","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fneur.2017.00338","article-title":"Impact of Transcranial Magnetic Stimulation on Functional Movement Disorders: Cortical Modulation or a Behavioral Effect?","volume":"8","author":"Garcin","year":"2017","journal-title":"Front. Neurol."}],"container-title":["Neurology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8377\/18\/6\/109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:13:06Z","timestamp":1780398786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8377\/18\/6\/109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["neurolint18060109"],"URL":"https:\/\/doi.org\/10.3390\/neurolint18060109","relation":{},"ISSN":["2035-8377"],"issn-type":[{"value":"2035-8377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]}}}