Complete Regression of Central Sensitization after Bilateral Focused Ultrasound Medial Thalamotomies in Atypical Orofacial Pain – A Case Report

Complete Regression of Central Sensitization after Bilateral Focused Ultrasound Medial Thalamotomies in Atypical Orofacial Pain – A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Complete Regression of Central Sensitization after Bilateral Focused Ultrasound Medial Thalamotomies in Atypical Orofacial Pain – A Case Report Matus Velicky Buecheler, Lukasz Kolakowski, Marie Therese Kleinsorge, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8858517/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Orofacial pain syndromes are a heterogenous group of pain disorders resulting in substantial morbidity. They are often refractory to medical treatment and can have an enormous impact on quality of life. Central sensitization plays a major role in chronic pain disorders and poses a diagnostic and therapeutic challenge. Transcranial magnetic resonance-guided focused ultrasound bilateral medial thalamotomy is an emerging treatment in chronic pain syndromes with central sensitization. We here describe a 76-year-old female patient with a long history of atypical orofacial pain and central sensitization with complete resolution of the latter after medial thalamotomy using bilateral focused ultrasound. orofacial pain central sensitization focused ultrasound central lateral thalamotomy Figures Figure 1 Figure 2 Introduction Orofacial pain – that is pain in the face or mouth – is one of the most common regional pain disorders 1 . Chronic orofacial pain is a broad term describing unremitting pain syndromes 2 with a large impact on quality of life 3 . However, there are diagnostic and therapeutic uncertainties in this field, delaying proper diagnosis and treatment 4 . The need for a comprehensive classification of orofacial pain was recently met with the publication of the International Classification of Orofacial Pain, 1st Edition (ICOP) in 2020. Analogous to the ICHD-3, the ICOP offers a clinical tool in navigating the orofacial pain syndromes 4 . Central sensitization (CS) refers to an increase in the excitability of nociceptive neurons 5 , 6 and plays a major role both in amplification of pain responses as well as spread of pain to other areas in chronic pain disorders 7 . There is not one optimal approach to assess CS 8 . Apart from hyperalgesia and allodynia, expansion of the affected area beyond the initial site of pain is also a characteristic clinical trait of CS 9 . Discriminating between a functional spread of pain due to possible secondary gain and CS can be challenging. Pressure pain thresholds 10 , intradermal/topical capsaicin application, low/high-frequency electrical stimulation 8 or somatosensory evoked potentials 11 have been used in assessing CS. Clinical assessment of CS, however, remains a diagnostic and therapeutic challenge with pharmacologic treatments often resulting in unsatisfactory outcomes 12 . Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has proven its safety and feasibility in refractory neuropathic pain 13 , 14 , 20 , 21 , rendering it a potential treatment for patients with otherwise intractable chronic pain. The following article provides a comprehensive work-up of a case of chronic orofacial pain with CS leading to MRgFUS bilateral thalamotomy, highlighting a novel therapeutic avenue and contributing meaningful evidence to un underexplored field. Case Report History and Clinical Presentation A 76-year-old female patient with a 7-year history of COFP in her left maxilla and upper lip was referred for an evaluation of a neurosurgical procedure after having failed several treatments. She had gradually developed the symptoms after extraction of several teeth in her left maxilla for the purpose of fitting a dental prosthesis. She described her pain as burning, pungent and piercing with worsening in a relaxed state and alleviation with physical or psychical distraction. Sleep was profoundly affected. There was no history of neurological or psychiatric disorders. A thorough diagnostic work-up followed including MRI of the head excluding a neurovascular conflict or other cerebral pathology [Supplemental Fig. 1(a-e)], allergology exam excluding a possible hypersensitivity to metals in the prosthesis and even a tongue biopsy with normal findings. Extensive oral and maxillofacial surgery evaluations failed to identify the exact cause and alleviate the pain. There was no sufficient response to treatment with pregabalin (maximal dose NA), amitriptyline (up to 35mg/d), duloxetine (up to 120mg/d), lamotrigine (up to 150mg/d) or tapentadol (up to 100mg/d) . An oral nerve block failed to afford any improvement, neither did an infraorbital-nerve-block or glycerol gangliolysis of the trigeminal ganglion. Her sleep got better with mirtazapine , and she reported slight improvement with gabapentin , the dose being 3x600mg daily upon referral to our institution. Her neurological examination showed a small area of pins-and-needles sensation in the area supplied by the maxillary division of the left trigeminal nerve; both maxillary and mandibular divisions showed slight hypoesthesia bilaterally with otherwise normal findings. She located the pain maximum to her left upper lip and maxilla, with propagation to the back of her neck, thorax, and both arms and legs. The pain was constant with the aforementioned qualities and visual analog scale (VAS) of 6/10, with acute exacerbations to 10/10. Pain had spread considerably over the years from being initially localized to the left maxilla and upper lip (Fig. 1). History and presentation were not consistent with a classical trigeminal neuralgia. Our diagnosis of the pain syndrome remained descriptive, although we could have formally diagnosed other trigeminal neuropathic pain according to the ICOP 4 . Headache attributed to the disorder of the teeth according to the ICHD-3 remained a differential diagnosis, but this diagnosis was less appropriate considering the extent of the pain syndrome. Interdisciplinary Assessment We evaluated the patient in our interdisciplinary board consisting of experts from oral and maxillofacial surgery, neurology, neurosurgery, neuroradiology, ENT, rheumatology, psychiatry and physical therapy. The clinical impression was that central sensitization was now dominating and stereotactic treatment was proposed. Considering the costs and reimbursement from the health insurance, transcranial magnetic resonance-guided focused ultrasound (MRgFUS) was the most suitable option. A pre-operative CT scan showed that the patient technically qualified for the treatment, with a skull density ratio of 0.7. MRI of the brain with navigation protocol followed. The standardized medical and psychiatric evaluation did not reveal contraindications for the stereotactic treatment. Neurosurgical Procedure The patient eventually consented to and underwent MRgFUS of the posterior part of the central lateral nucleus of the thalamus (CLp) bilaterally, 7 years and 2 months after symptom onset (Insightec Exablate 4000 system in combination with Siemens VidaFit 3T MRI). Based on the experience reported by Gallay et al. 20 , bilateral ablations were planned from the beginning. She received 4 ablations altogether, 2 per side at 6.5mm laterally of the ventricular border, 0mm anterior and 6mm superior of PC, 9.5mm laterally, 1.5mm anterior, 6mm superior and 5.5 laterally, 0.5 anterior and 6mm superior, as suggested previously 20 [Figure 2(a-c)]. Five sonications with ablative intention at 7000J/sonication were applied altogether, leading to tissue ablation between 56 and 57°C average, 56–60°C peak temperature for 11s each. After the first sonication (6.5mm left) the patient showed a short-term nystagmus to the left, which ceased after seconds without sequelae. After the second sonication (9.5mm left) the patient reported a mild right-sided facial hypaesthesia, which was completely regredient after 5 minutes. She reported no immediate effects on the pain until the end of the procedure. The total duration of the procedure was 2:40h (frame-on to frame-off). Post-Interventional Follow-up The patient was re-evaluated on the day following the procedure. The local pain intensity in her upper lip/maxilla on the left went from VAS 10/10 just prior to the procedure to VAS 2/10. Strikingly, the pain radiation ceased completely. On the follow-up 2 months after the procedure, she could still report a 70% alleviation of the local pain, there was no pain radiation anymore. The small area of pins-and-needles in the maxillary division of the trigeminal nerve on the left remained, but this was not bothersome for the patient. At 3 months after the treatment her local pain went slightly up (VAS 3–4/10); however, the radiating pain had not come back. Given the good tolerability, the dose of gabapentin was increased to 4x600mg daily. There was no impairment of the activities of daily living due to pain reported at the 6-month follow-up, the quality of sleep was reported as very good. The standardized neuropsychological assessment at 6 months demonstrated improvement in the verbal memory as well as the executive functions comparing to baseline. The geriatric depression scale failed to disclose any symptoms of depression. At the last available follow-up at 9 months the local pain had remained sufficiently controlled, radiating pain was not reported and gabapentin remained well tolerated. There have been no adverse events of the stereotactic treatment reported during the ongoing follow up. Discussion This patient history demonstrates the frequent diagnostic and therapeutic odyssey in people with chronic pain syndromes. Our patient developed a constant and radiating pain beyond the initial symptom presentation over the course of several years with no response from first- to third-line treatments of neuropathic pain 15 . Central sensitization requires a multimodal and individually tailored treatment 16 . The pharmacologic treatment is analogous to treatment of chronic neuropathic pain consisting of tricyclic antidepressants, α2δ ligands and serotonin norepinephrine reuptake inhibitors 16 , 18 . However, treatment success remains limited 12 . The role of the central lateral nucleus (CL) of the thalamus, mainly its posterior part (CLp), has long been recognized in maintenance and propagation of neurogenic pain and the targeted thalamotomy of CLp has been deemed not only safe, but also effective 20 , 21 . The relatively more abundant connections of the CL to the cortex and the spinal cord than the ventral posterior nucleus render this particular target central to the stereotactic suppression of pain 19 . Emerging evidence suggests that MRgFUS is a safe, feasible and effective treatment in chronic neuropathic pain 13 , 14 , 17 , 20 , 21 . The reported pain syndromes treated with MRgFUS so far consisted mostly of unilateral or localized neuropathic pain or neuralgia of a known cause. The focus of this case report is on the effects of MRgFUS beyond the areas of initial neuropathic pain. In our patient, not only did the MRgFUS significantly alleviate the local neuropathic pain, it abolished the radiating pain to otherwise healthy body parts, thus further supporting the notion that CS had played a major role in this particular pain syndrome. Should future research corroborate our observation, MRgFUS could become a treatment option in chronic pain syndromes with CS. The pain has remained sufficiently controlled for the patient even 9 months after the stereotactic treatment. The major limitation of this case report is the short follow-up. More long-term data is warranted to be able to draw conclusions in regard to MRgFUS in the treatment of chronic pain with CS. Conclusion Transcranial magnetic resonance-guided focused ultrasound can pose an invaluable treatment modality in otherwise intractable neuropathic pain syndromes with central sensitization. Abbreviations CLp – central lateral nucleus of the thalamus, posterior part CS – central sensitization ICHD-3 – international classification of headache disorders, 3 rd edition MRgFUS – transcranial magnetic resonance-guided focused ultrasound Declarations Statement of Ethics The authors confirm that the approval of an institutional review board was not required for this work. This retrospective review of patient data did not require ethical approval in accordance with local guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Disclosures Funding Sources and Conflict of Interest:No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Conflict of Interest Statement The authors have no conflicts of interest to declare. Funding Sources This work was not supported by any sponsor or funder. Data Availability Statement No new data was generated in this work. Patient privacy considerations preclude public sharing of the data supporting this case report. Further enquiries can be directed to the corresponding author. Consent to Publish Declaration The authors as well as the patient presented provide consent for the publication of the manuscript detailed above, including any accompanying images or data contained within the manuscript. The authors as well as the patient understand that this information will be freely available online, and accessible to the general public. The authors and the patient understand that under the terms of publication, this information may be reproduced and used for other purposes, including commercial uses. The authors as well as the patient acknowledge that this will reduce their actual privacy to the extent of the content of the manuscript. The authors as well as the patient confirm that all parties have been given the opportunity to view the manuscript prior to publication, and understand that once published, it cannot be removed from the published record except in exceptional circumstances. References Macfarlane TVa, Blinkhorn ASa, et al. Orofacial pain: just another chronic pain? Results from a population-based survey. Pain. October 2002;99(3):453–8. Benoliel R, Sharav Y. Chronic orofacial pain. Curr Pain Headache Rep. 2010;14(1):33–40. PMID: 20425212. De Vinícius. Magalhães Barros, Paulo Isaias Seraidarian, Maria Ilma De Souza Côrtes, Lylian Vieira De Paula. 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Supplementary Files CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1a.tiff CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1b.tiff CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1c.tif CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1d.tiff CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1e.tiff Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Mar, 2026 Reviewers agreed at journal 10 Mar, 2026 Reviews received at journal 05 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviews received at journal 25 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers invited by journal 19 Feb, 2026 Editor invited by journal 16 Feb, 2026 Editor assigned by journal 13 Feb, 2026 Submission checks completed at journal 13 Feb, 2026 First submitted to journal 12 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8858517","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":595802630,"identity":"cece827e-61d9-4ef9-86ec-02e04e7384fc","order_by":0,"name":"Matus Velicky Buecheler","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":true,"prefix":"","firstName":"Matus","middleName":"Velicky","lastName":"Buecheler","suffix":""},{"id":595802632,"identity":"5f153ddb-f0a1-4c2a-8c09-5502e33333ba","order_by":1,"name":"Lukasz Kolakowski","email":"","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":false,"prefix":"","firstName":"Lukasz","middleName":"","lastName":"Kolakowski","suffix":""},{"id":595802633,"identity":"e5246ce4-697c-4d45-9a0f-2eec31da48b9","order_by":2,"name":"Marie Therese Kleinsorge","email":"","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"Therese","lastName":"Kleinsorge","suffix":""},{"id":595802634,"identity":"79400f57-aeef-4abf-97a4-692a38cd31c5","order_by":3,"name":"Heiko Pohl","email":"","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":false,"prefix":"","firstName":"Heiko","middleName":"","lastName":"Pohl","suffix":""},{"id":595802635,"identity":"69bf4b29-d8e2-49ae-ab14-b2505b9ecc38","order_by":4,"name":"Lennart Stieglitz","email":"","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":false,"prefix":"","firstName":"Lennart","middleName":"","lastName":"Stieglitz","suffix":""},{"id":595802637,"identity":"47537ae5-9694-4ef1-8ffc-00320b90995c","order_by":5,"name":"Susanne Wegener","email":"","orcid":"","institution":"University Hospital of Zurich","correspondingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"","lastName":"Wegener","suffix":""}],"badges":[],"createdAt":"2026-02-12 06:54:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8858517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8858517/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103400338,"identity":"044aa019-b2a5-497a-91ed-596b90c03e90","added_by":"auto","created_at":"2026-02-25 09:18:53","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":623957,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePain localisation and propagation before bilateral MRgFUS ablation of the CLp\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pain maximum in the maxillary division of the trigeminal nerve on the left is represented in red. The thunderbolts represent radiating pain; the solid lines depict radiating pain of higher intensity; the dashed lines represent radiating pain of lower intensity.\u003c/p\u003e","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainFigure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/c47c24cf9e2064aa96c2b4a8.jpeg"},{"id":103400339,"identity":"2f1ef6ff-be4b-4a23-b1ff-83beb9490ece","added_by":"auto","created_at":"2026-02-25 09:18:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2817543,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCranial MRI one day after bilateral MRgFUS ablation of the CLp\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Shows a superposition of preoperative MPRAGE with the accumulated CEM43 dose map (cumulative equivalent minutes at 43°C)\u003csup\u003e22\u003c/sup\u003e. The light and dark blue voxels represent the 17 and 240 minutes isodose, respectively. The blue circle illustrates the maximum accessible range of tissue around the transducer focus during the rights-sided ablations. The ablation target during the last sonication is shown in green. The red outlines represent volume with calcified tissue (as typically the choroid plexus), which is excluded from the sonication. (B and C) The postoperative MRI (native T1, Siemens 3T Magnetom Vida Fit) on day 1 after the treatment shows the four ablations (a) and the surrounding edema (b).\u003c/p\u003e","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/639e882fa02ec9635b1d0841.png"},{"id":103510031,"identity":"644dc875-7026-4944-b923-0e7cc18767e1","added_by":"auto","created_at":"2026-02-26 14:03:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5116811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/4499c339-2d10-4eb9-ba2e-c798cabf09f4.pdf"},{"id":103507460,"identity":"b25abb30-c644-4135-bae5-388362b200a9","added_by":"auto","created_at":"2026-02-26 13:41:22","extension":"tiff","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":363503,"visible":true,"origin":"","legend":"","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1a.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/aa6fcd07f8c596481b6dc3b2.tiff"},{"id":103400342,"identity":"358f7f29-b1bf-403e-ba3c-0e0a0d7c707b","added_by":"auto","created_at":"2026-02-25 09:18:53","extension":"tiff","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":85310,"visible":true,"origin":"","legend":"","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1b.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/e16437bc7a7b96963b02d1e8.tiff"},{"id":103507971,"identity":"78dd219b-2ece-46e8-9e5d-46417c6ae3ad","added_by":"auto","created_at":"2026-02-26 13:46:43","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":398861,"visible":true,"origin":"","legend":"","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1c.tif","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/14429e30589b211e1df89716.tif"},{"id":103507653,"identity":"b5c6a927-e87b-40d6-9563-df2dcc2fc6ae","added_by":"auto","created_at":"2026-02-26 13:42:52","extension":"tiff","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":133169,"visible":true,"origin":"","legend":"","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1d.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/ba98a7e38befef9a687d8a1a.tiff"},{"id":103400343,"identity":"183e321c-992c-417f-aa22-235c941371af","added_by":"auto","created_at":"2026-02-25 09:18:53","extension":"tiff","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":117911,"visible":true,"origin":"","legend":"","description":"","filename":"CompleteRegressionofCentralSensitizationafterBilateralFocusedUltrasoundMedialThalamotomiesinAtypicalOrofacialPainSupplementalFigure1e.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8858517/v1/570371391e9b0a9ccabd5586.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Complete Regression of Central Sensitization after Bilateral Focused Ultrasound Medial Thalamotomies in Atypical Orofacial Pain – A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOrofacial pain \u0026ndash; \u003cem\u003ethat is pain in the face or mouth\u003c/em\u003e \u0026ndash; is one of the most common regional pain disorders\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Chronic orofacial pain is a broad term describing unremitting pain syndromes\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e with a large impact on quality of life\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. However, there are diagnostic and therapeutic uncertainties in this field, delaying proper diagnosis and treatment\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The need for a comprehensive classification of orofacial pain was recently met with the publication of the \u003cem\u003eInternational Classification of Orofacial Pain, 1st Edition (ICOP)\u003c/em\u003e in 2020. Analogous to the ICHD-3, the ICOP offers a clinical tool in navigating the orofacial pain syndromes\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCentral sensitization (CS) refers to an increase in the excitability of nociceptive neurons\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and plays a major role both in amplification of pain responses as well as spread of pain to other areas in chronic pain disorders\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. There is not one \u003cem\u003eoptimal\u003c/em\u003e approach to assess CS\u003csup\u003e8\u003c/sup\u003e. Apart from hyperalgesia and allodynia, expansion of the affected area beyond the initial site of pain is also a characteristic clinical trait of CS\u003csup\u003e9\u003c/sup\u003e. Discriminating between a functional spread of pain due to possible secondary gain and CS can be challenging. Pressure pain thresholds\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, intradermal/topical capsaicin application, low/high-frequency electrical stimulation\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e or somatosensory evoked potentials\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e have been used in assessing CS. Clinical assessment of CS, however, remains a diagnostic and therapeutic challenge with pharmacologic treatments often resulting in unsatisfactory outcomes\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has proven its safety and feasibility in refractory neuropathic pain\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, rendering it a potential treatment for patients with otherwise intractable chronic pain.\u003c/p\u003e \u003cp\u003eThe following article provides a comprehensive work-up of a case of chronic orofacial pain with CS leading to MRgFUS bilateral thalamotomy, highlighting a novel therapeutic avenue and contributing meaningful evidence to un underexplored field.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eHistory and Clinical Presentation\u003c/h2\u003e \u003cp\u003eA 76-year-old female patient with a 7-year history of COFP in her left maxilla and upper lip was referred for an evaluation of a neurosurgical procedure after having failed several treatments. She had gradually developed the symptoms after extraction of several teeth in her left maxilla for the purpose of fitting a dental prosthesis. She described her pain as burning, pungent and piercing with worsening in a relaxed state and alleviation with physical or psychical distraction. Sleep was profoundly affected. There was no history of neurological or psychiatric disorders.\u003c/p\u003e \u003cp\u003eA thorough diagnostic work-up followed including MRI of the head excluding a neurovascular conflict or other cerebral pathology [Supplemental Fig.\u0026nbsp;1(a-e)], allergology exam excluding a possible hypersensitivity to metals in the prosthesis and even a tongue biopsy with normal findings. Extensive oral and maxillofacial surgery evaluations failed to identify the exact cause and alleviate the pain. There was no sufficient response to treatment with \u003cem\u003epregabalin (maximal dose NA), amitriptyline (up to 35mg/d), duloxetine (up to 120mg/d), lamotrigine (up to 150mg/d)\u003c/em\u003e or \u003cem\u003etapentadol (up to 100mg/d)\u003c/em\u003e. An oral nerve block failed to afford any improvement, neither did an infraorbital-nerve-block or glycerol gangliolysis of the trigeminal ganglion. Her sleep got better with \u003cem\u003emirtazapine\u003c/em\u003e, and she reported slight improvement with \u003cem\u003egabapentin\u003c/em\u003e, the dose being 3x600mg daily upon referral to our institution.\u003c/p\u003e \u003cp\u003eHer neurological examination showed a small area of pins-and-needles sensation in the area supplied by the maxillary division of the left trigeminal nerve; both maxillary and mandibular divisions showed slight hypoesthesia \u003cem\u003ebilaterally\u003c/em\u003e with otherwise normal findings. She located the pain maximum to her left upper lip and maxilla, with propagation to the back of her neck, thorax, and both arms and legs. The pain was constant with the aforementioned qualities and visual analog scale (VAS) of 6/10, with acute exacerbations to 10/10. Pain had spread considerably over the years from being initially localized to the left maxilla and upper lip (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eHistory and presentation were not consistent with a classical trigeminal neuralgia. Our diagnosis of the pain syndrome remained descriptive, although we could have formally diagnosed \u003cem\u003eother trigeminal neuropathic pain\u003c/em\u003e according to the ICOP\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eHeadache attributed to the disorder of the teeth\u003c/em\u003e according to the ICHD-3 remained a differential diagnosis, but this diagnosis was less appropriate considering the extent of the pain syndrome.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInterdisciplinary Assessment\u003c/h3\u003e\n\u003cp\u003eWe evaluated the patient in our interdisciplinary board consisting of experts from oral and maxillofacial surgery, neurology, neurosurgery, neuroradiology, ENT, rheumatology, psychiatry and physical therapy. The clinical impression was that central sensitization was now dominating and stereotactic treatment was proposed. Considering the costs and reimbursement from the health insurance, transcranial magnetic resonance-guided focused ultrasound (MRgFUS) was the most suitable option. A pre-operative CT scan showed that the patient technically qualified for the treatment, with a skull density ratio of 0.7. MRI of the brain with navigation protocol followed. The standardized medical and psychiatric evaluation did not reveal contraindications for the stereotactic treatment.\u003c/p\u003e\n\u003ch3\u003eNeurosurgical Procedure\u003c/h3\u003e\n\u003cp\u003eThe patient eventually consented to and underwent MRgFUS of the posterior part of the central lateral nucleus of the thalamus (CLp) bilaterally, 7 years and 2 months after symptom onset (Insightec Exablate 4000 system in combination with Siemens VidaFit 3T MRI). Based on the experience reported by Gallay et al.\u003csup\u003e20\u003c/sup\u003e, bilateral ablations were planned from the beginning. She received 4 ablations altogether, 2 per side at 6.5mm laterally of the ventricular border, 0mm anterior and 6mm superior of PC, 9.5mm laterally, 1.5mm anterior, 6mm superior and 5.5 laterally, 0.5 anterior and 6mm superior, as suggested previously\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e [Figure 2(a-c)].\u003c/p\u003e \u003cp\u003eFive sonications with ablative intention at 7000J/sonication were applied altogether, leading to tissue ablation between 56 and 57\u0026deg;C average, 56\u0026ndash;60\u0026deg;C peak temperature for 11s each. After the first sonication (6.5mm left) the patient showed a short-term nystagmus to the left, which ceased after seconds without sequelae. After the second sonication (9.5mm left) the patient reported a mild right-sided facial hypaesthesia, which was completely regredient after 5 minutes. She reported no immediate effects on the pain until the end of the procedure. The total duration of the procedure was 2:40h (frame-on to frame-off).\u003c/p\u003e\n\u003ch3\u003ePost-Interventional Follow-up\u003c/h3\u003e\n\u003cp\u003eThe patient was re-evaluated on the day following the procedure. The local pain intensity in her upper lip/maxilla on the left went from VAS 10/10 just prior to the procedure to VAS 2/10. Strikingly, the pain radiation ceased completely. On the follow-up 2 months after the procedure, she could still report a 70% alleviation of the local pain, there was no pain radiation anymore. The small area of pins-and-needles in the maxillary division of the trigeminal nerve on the left remained, but this was not bothersome for the patient. At 3 months after the treatment her local pain went slightly up (VAS 3\u0026ndash;4/10); however, the radiating pain had not come back. Given the good tolerability, the dose of \u003cem\u003egabapentin\u003c/em\u003e was increased to 4x600mg daily. There was no impairment of the activities of daily living due to pain reported at the 6-month follow-up, the quality of sleep was reported as very good. The standardized neuropsychological assessment at 6 months demonstrated improvement in the verbal memory as well as the executive functions comparing to baseline. The geriatric depression scale failed to disclose any symptoms of depression. At the last available follow-up at 9 months the local pain had remained sufficiently controlled, radiating pain was not reported and gabapentin remained well tolerated. There have been no adverse events of the stereotactic treatment reported during the ongoing follow up.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis patient history demonstrates the frequent diagnostic and therapeutic odyssey in people with chronic pain syndromes. Our patient developed a constant and radiating pain beyond the initial symptom presentation over the course of several years with no response from first- to third-line treatments of neuropathic pain\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCentral sensitization requires a multimodal and individually tailored treatment\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The pharmacologic treatment is analogous to treatment of chronic neuropathic pain consisting of tricyclic antidepressants, α2δ ligands and serotonin norepinephrine reuptake inhibitors\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. However, treatment success remains limited\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe role of the central lateral nucleus (CL) of the thalamus, mainly its posterior part (CLp), has long been recognized in maintenance and propagation of \u003cem\u003eneurogenic pain\u003c/em\u003e and the targeted thalamotomy of CLp has been deemed not only safe, but also effective\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The relatively more abundant connections of the CL to the cortex and the spinal cord than the ventral posterior nucleus render this particular target central to the stereotactic suppression of pain\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that MRgFUS is a safe, feasible and effective treatment in chronic neuropathic pain\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The reported pain syndromes treated with MRgFUS so far consisted mostly of unilateral or localized neuropathic pain or neuralgia of a known cause. The focus of this case report is on the effects of MRgFUS \u003cem\u003ebeyond the areas\u003c/em\u003e of initial neuropathic pain. In our patient, not only did the MRgFUS significantly alleviate the local neuropathic pain, it abolished the radiating pain to otherwise healthy body parts, thus further supporting the notion that CS had played a major role in this particular pain syndrome. Should future research corroborate our observation, MRgFUS could become a treatment option in chronic pain syndromes with CS. The pain has remained sufficiently controlled for the patient even 9 months after the stereotactic treatment. The major limitation of this case report is the short follow-up. More long-term data is warranted to be able to draw conclusions in regard to MRgFUS in the treatment of chronic pain with CS.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTranscranial magnetic resonance-guided focused ultrasound can pose an invaluable treatment modality in otherwise intractable neuropathic pain syndromes with central sensitization.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eCLp \u0026ndash; central lateral nucleus of the thalamus, posterior part\u003c/p\u003e\n\u003cp\u003eCS \u0026ndash; central sensitization\u003c/p\u003e\n\u003cp\u003eICHD-3 \u0026ndash; international classification of headache disorders, 3\u003csup\u003erd\u003c/sup\u003e edition\u003c/p\u003e\n\u003cp\u003eMRgFUS \u0026ndash; transcranial magnetic resonance-guided focused ultrasound\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the approval of an institutional review board was not required for this work. This retrospective review of patient data did not require ethical approval in accordance with local guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding Sources and Conflict of Interest:No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was not supported by any sponsor or funder.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo new data was generated in this work. Patient privacy considerations preclude public sharing of the data supporting this case report. Further enquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors as well as the patient presented provide consent for the publication of the manuscript detailed above, including any accompanying images or data contained within the manuscript. The authors as well as the patient understand that this information will be freely available online, and accessible to the general public. The authors and the patient understand that under the terms of publication, this information may be reproduced and used for other purposes, including commercial uses. The authors as well as the patient acknowledge that this will reduce their actual privacy to the extent of the content of the manuscript. The authors as well as the patient confirm that all parties have been given the opportunity to view the manuscript prior to publication, and understand that once published, it cannot be removed from the published record except in exceptional circumstances.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMacfarlane TVa, Blinkhorn ASa, et al. Orofacial pain: just another chronic pain? Results from a population-based survey. Pain. October 2002;99(3):453\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenoliel R, Sharav Y. Chronic orofacial pain. Curr Pain Headache Rep. 2010;14(1):33\u0026ndash;40. PMID: 20425212.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Vin\u0026iacute;cius. Magalh\u0026atilde;es Barros, Paulo Isaias Seraidarian, Maria Ilma De Souza C\u0026ocirc;rtes, Lylian Vieira De Paula. The Impact of Orofacial Pain on the Quality of Life of Patients with Temporomandibular Disorder. J Oral Facial Pain Headache. 2009;23(1):28\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Classification of Orofacial Pain. 1st edition (ICOP). Cephalalgia. 2020;40(2):129\u0026ndash;221. PMID: 32103673.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi R-R, Kohno T, Moore KA, Clifford J, Woolf. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends in Neurosciences, 26, Issue 12, 2003. Pages 696\u0026ndash;705. ISSN 0166\u0026ndash;2236.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018;129(2):343\u0026ndash;66. PMID: 29462012; PMCID: PMC6051899.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696\u0026ndash;705.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuesada C, Kostenko A, Ho I, et al. Human surrogate models of central sensitization: A critical review and practical guide. Eur J Pain. 2021;25:1389\u0026ndash;428.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYunus MB. Central Sensitivity Syndromes: A New Paradigm and Group Nosology for Fibromyalgia and Overlapping Conditions, and the Related Issue of Disease versus Illness. Semin Arthritis Rheum. 2008;37(6):339\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmiri M, Alavinia M, Singh M, Kumbhare D. Pressure Pain Threshold in Patients With Chronic Pain: A Systematic Review and Meta-Analysis. Am J Phys Med Rehabil. 2021;100(7):656\u0026ndash;74. PMID: 33002911.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G. 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Eur Radiol. 2013;23(8):2215\u0026ndash;27. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00330-013-2825-y\u003c/span\u003e\u003cspan address=\"10.1007/s00330-013-2825-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2013 Apr 4. PMID: 23553588; PMCID: PMC3799975.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"orofacial pain, central sensitization, focused ultrasound, central lateral thalamotomy","lastPublishedDoi":"10.21203/rs.3.rs-8858517/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8858517/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOrofacial pain syndromes are a heterogenous group of pain disorders resulting in substantial morbidity. They are often refractory to medical treatment and can have an enormous impact on quality of life. Central sensitization plays a major role in chronic pain disorders and poses a diagnostic and therapeutic challenge. Transcranial magnetic resonance-guided focused ultrasound bilateral medial thalamotomy is an emerging treatment in chronic pain syndromes with central sensitization. We here describe a 76-year-old female patient with a long history of atypical orofacial pain and central sensitization with complete resolution of the latter after medial thalamotomy using bilateral focused ultrasound.\u003c/p\u003e","manuscriptTitle":"Complete Regression of Central Sensitization after Bilateral Focused Ultrasound Medial Thalamotomies in Atypical Orofacial Pain – A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-25 09:18:48","doi":"10.21203/rs.3.rs-8858517/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T09:40:13+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"32931735126778485759859515022591452293","date":"2026-03-10T08:45:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-05T08:14:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67595481375040602784025359370919253089","date":"2026-03-05T05:58:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-25T18:43:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300657798741247935618094528083959699859","date":"2026-02-20T23:05:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279094138561024171312832141410264428796","date":"2026-02-20T08:16:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-20T03:49:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-16T15:34:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-14T00:33:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-14T00:30:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-02-12T06:40:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"331ce8f3-b295-440f-a5fe-29217b3fdf56","owner":[],"postedDate":"February 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T04:24:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-25 09:18:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8858517","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8858517","identity":"rs-8858517","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}