{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T14:24:23Z","timestamp":1761402263846,"version":"3.41.2"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Smell and taste disturbances are among the most frequent neurological symptoms in patients with COVID-19. A concomitant impairment of the trigeminal nerve has been suggested in subjects with olfactory dysfunction, although it has not been confirmed with objective measurement techniques. In this study, we explored the trigeminal function and its correlations with clinical features in COVID-19 patients with impaired smell perception using electrophysiological testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We enrolled 16 consecutive patients with mild COVID-19 and smell impairment and 14 healthy controls (HCs). Olfactory and gustatory symptoms were assessed with self-reported questionnaires. Electrophysiological evaluation of the masseter inhibitory reflex (MIR) and blink reflex (BR) was carried out to test the trigeminal function and its connections within the brainstem.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Masseter inhibitory reflex (MIR) analysis revealed higher latency of ipsilateral and contralateral early silent period in patients when compared with HCs. No significant differences between groups were detected as regards the duration of the early and late silent period. However, several patients showed a prolonged duration of the early silent period. BR evaluation disclosed only an increased amplitude of early components in patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Patients with COVID-19 and smell impairment show a subclinical trigeminal nerve impairment. Trigeminal alterations mainly involve the oligosynaptic pathway, as a result of either direct viral damage or secondary neuroinflammation of the peripheral trigeminal fibers, whereas the polysynaptic ponto-medullary circuits seem to be spared. The prolonged duration of the early silent period and the increased amplitude of early BR response might reflect a compensatory upregulation of the trigeminal function as a consequence of the olfactory dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.981888","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T12:13:41Z","timestamp":1665749621000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Electrophysiological evidence of subclinical trigeminal dysfunction in patients with COVID-19 and smell impairment: A pilot study"],"prefix":"10.3389","volume":"13","author":[{"given":"Giuseppe","family":"Cosentino","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenia","family":"Maiorano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Todisco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Prunetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Antoniazzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Tammam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Quartesan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Lettieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"De Icco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo Guido","family":"Corsico","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Benazzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Tassorelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Alfonsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e2112131","DOI":"10.1001\/jamanetworkopen.2021.12131","article-title":"Global incidence of neurological manifestations among patients hospitalized with COVID-19\u2013a report for the GCS-NeuroCOVID consortium and the ENERGY consortium","volume":"4","author":"Chou","year":"2021","journal-title":"JAMA Netw Open."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1007\/s00415-021-10406-y","article-title":"Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19)","volume":"268","author":"Harapan","year":"2021","journal-title":"J Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.neurop.2021.03.002","article-title":"Prevalence of neurological manifestations in COVID-19 and their association with mortality","volume":"1","author":"Carlos","year":"2021","journal-title":"Neurol Perspect."},{"key":"B4","doi-asserted-by":"publisher","first-page":"17504","DOI":"10.1038\/s41598-021-96987-0","article-title":"Assessing the extent and timing of chemosensory impairments during COVID-19 pandemic","volume":"11","author":"Cecchetto","year":"2021","journal-title":"Sci Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.17305\/bjbms.2021.6341","article-title":"COVID-19 associated cranial nerve neuropathy: a systematic review","volume":"22","author":"Finsterer","year":"2022","journal-title":"Bosn J Basic Med Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1002\/jmv.26289","article-title":"Clinical neurophysiology and cerebrospinal liquor analysis to detect Guillain-Barr\u00e9 syndrome and polyneuritis cranialis in COVID-19 patients: a case series","volume":"93","author":"Manganotti","year":"2021","journal-title":"J Med Virol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S1474-4422(21)00025-9","article-title":"Isolated bulbar palsy after SARS-CoV-2 infection","volume":"20","author":"Todisco","year":"2021","journal-title":"Lancet Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1111\/ene.15045","article-title":"Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: a critical systematic review","volume":"28","author":"Cosentino","year":"2021","journal-title":"Eur J Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1056\/NEJMc2008597","article-title":"Neurologic features in severe SARS-CoV-2 infection","volume":"382","author":"Helms","year":"2020","journal-title":"N Engl J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"118568","DOI":"10.1016\/j.lfs.2020.118568","article-title":"Involvement of the nervous system in COVID-19: the bell should toll in the brain","volume":"262","author":"Satarker","year":"2020","journal-title":"Life Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"102999","DOI":"10.1016\/j.amjoto.2021.102999","article-title":"Cranial nerve involvement in COVID-19","volume":"42","author":"Doblan","year":"2021","journal-title":"Am J Otolaryngol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1002\/alr.22796","article-title":"Trigeminal features in COVID-19 patients with smell impairment","volume":"11","author":"Ferreli","year":"2021","journal-title":"Int Forum Allergy Rhinol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.anl.2021.07.012","article-title":"Patients with COVID-19-associated olfactory impairment also show impaired trigeminal function","volume":"49","author":"Otte","year":"2022","journal-title":"Auris Nasus Larynx."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3437","DOI":"10.1007\/s10072-020-04801-y","article-title":"Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions","volume":"41","author":"Favas","year":"2020","journal-title":"Neurol Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s10194-021-01367-8","article-title":"Headache, anosmia, ageusia and other neurological symptoms in COVID-19: a cross-sectional study","volume":"23","author":"Sampaio Rocha-Filho","year":"2022","journal-title":"J Headache Pain."},{"key":"B16","doi-asserted-by":"publisher","first-page":"103170","DOI":"10.1016\/j.amjoto.2021.103170","article-title":"Clinical, virological and immunological evolution of the olfactory and gustatory dysfunction in COVID-19","volume":"43","author":"Maiorano","year":"2022","journal-title":"Am J Otolaryngol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1093\/chemse\/bjh061","article-title":"Usefulness of the odor stick identification test for Japanese patients with olfactory dysfunction","volume":"29","author":"Hashimoto","year":"2004","journal-title":"Chem Senses."},{"key":"B18","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1017\/S002221511200076X","article-title":"Comparison of subjective olfaction ratings in patients with and without olfactory disorders","volume":"126","author":"Haxel","year":"2012","journal-title":"J Laryngol Otol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.3390\/microorganisms8071052","article-title":"SARS-CoV-2 Virologic and immunologic correlates in patients with olfactory and taste disorders","volume":"8","author":"Benazzo","year":"2020","journal-title":"Microorganisms."},{"key":"B20","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.parkreldis.2011.12.001","article-title":"Validation of a new scale to assess olfactory dysfunction in patients with Parkinson's disease","volume":"18","author":"Millar Vernetti","year":"2012","journal-title":"Parkinsonism Relat Disord."},{"key":"B21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1017\/S0022215116000761","article-title":"Olfactory event-related potentials: a new approach for the evaluation of olfaction in nasopharyngeal carcinoma patients treated with chemo-radiotherapy","volume":"130","author":"Galletti","year":"2016","journal-title":"J Laryngol Otol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.14336\/AD.2018.0819","article-title":"Olfactory dysfunction and its relationship with clinical symptoms of Alzheimer disease","volume":"9","author":"Yu","year":"2018","journal-title":"Aging Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1702\/2228.24016","article-title":"Italian validation of the chemotherapy induced taste alteration scale","volume":"35","author":"Campagna","year":"2016","journal-title":"Assist Inferm Ric."},{"key":"B24","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1188\/13.ONF.E79-E85","article-title":"Development and validation of a chemotherapy-induced taste alteration scale","volume":"40","author":"Kano","year":"2013","journal-title":"Oncol Nurs Forum."},{"key":"B25","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/S1388-2457(99)00291-6","article-title":"The clinical use of brainstem reflexes and hand-muscle reflexes","volume":"111","author":"Cruccu","year":"2000","journal-title":"Clin Neurophysiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1002\/(sici)1097-4598(199810)21:10<1256::aid-mus3>3.0.co;2-a","article-title":"Mechanisms underlying spinal motor neuron excitability during the cutaneous silent period in humans","volume":"21","author":"Manconi","year":"1998","journal-title":"Muscle Nerve"},{"key":"B27","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/0168-5597(91)90023-Q","article-title":"Silent period induced by cutaneous stimulation","volume":"81","author":"Uncini","year":"1991","journal-title":"Electroencephalogr Clin Neurophysiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1007\/BF00275005","article-title":"The masseter inhibitory reflex is evoked by innocuous stimuli and mediated by A beta afferent fibres","volume":"77","author":"Cruccu","year":"1989","journal-title":"Exp Brain Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1093\/brain\/awh366","article-title":"Brainstem reflex circuits revisited","volume":"128","author":"Cruccu","year":"2005","journal-title":"Brain"},{"key":"B30","first-page":"61","article-title":"Neurophysiologic examination of the trigeminal, facial, hypoglossal, and spinal accessory nerves in cranial neuropathies and brain stem disorders","volume-title":"Clinical Electromyography","author":"Ongerboer de Visser","year":"1993"},{"key":"B31","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/0013-4694(94)90131-7","article-title":"Human reflexes and late responses report of an IFCN committee","volume":"90","author":"Kimura","year":"1994","journal-title":"Electroencephalogr Clin Neurophysiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3598","DOI":"10.1007\/s00415-021-10474-0","article-title":"Brainstem clinical and neurophysiological involvement in COVID-19","volume":"268","author":"Bocci","year":"2021","journal-title":"J Neurol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"594495","DOI":"10.3389\/fmed.2020.594495","article-title":"Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2","volume":"7","author":"Salamanna","year":"2020","journal-title":"Front Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41368-020-0074-x","article-title":"High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa","volume":"12","author":"Xu","year":"2020","journal-title":"Int J Oral Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/v12010014","article-title":"Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system?","volume":"12","author":"Desforges","year":"2019","journal-title":"Viruses."},{"key":"B36","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/0042-6822(89)90446-7","article-title":"Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves","volume":"170","author":"Perlman","year":"1989","journal-title":"Virology."},{"key":"B37","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1101\/2020.06.04.135012","article-title":"Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19","volume":"24","author":"Meinhardt","year":"2021","journal-title":"Nat Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e109","DOI":"10.1016\/S0140-6736(20)31282-4","article-title":"Early evidence of pronounced brain involvement in fatal COVID-19 outcomes","volume":"395","author":"von Weyhern","year":"2020","journal-title":"Lancet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"154","DOI":"10.3390\/brainsci12020154","article-title":"Olfactory dysfunction, headache, and mental clouding in adults with long-COVID-19: what is the link between cognition and olfaction? A cross-sectional study","volume":"12","author":"Di Stadio","year":"2022","journal-title":"Brain Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1136\/jnnp.55.9.774","article-title":"Gating of trigemino-facial reflex from low-threshold trigeminal and extratrigeminal cutaneous fibres in humans","volume":"55","author":"Rossi","year":"1992","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B41","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/j.clinph.2005.12.004","article-title":"Dissociation between pain and the nociceptive blink reflex during psychological arousal","volume":"117","author":"Koh","year":"2006","journal-title":"Clin Neurophysiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1007\/s00221-019-05668-y","article-title":"Jendrassik maneuver effect on spinal and brainstem reflexes","volume":"237","author":"Ertuglu","year":"2019","journal-title":"Exp Brain Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1093\/cercor\/bhl135","article-title":"Interactions between olfaction and the trigeminal system: what can be learned from olfactory loss","volume":"17","author":"Frasnelli","year":"2007","journal-title":"Cereb Cortex."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.981888\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T12:13:48Z","timestamp":1665749628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.981888\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":43,"alternative-id":["10.3389\/fneur.2022.981888"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.981888","relation":{},"ISSN":["1664-2295"],"issn-type":[{"type":"electronic","value":"1664-2295"}],"subject":[],"published":{"date-parts":[[2022,10,14]]},"article-number":"981888"}}