{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T01:06:57Z","timestamp":1794445617264,"version":"4.9.1"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"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:p>Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.<\/jats:p>","DOI":"10.3389\/fneur.2023.1098454","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T15:58:07Z","timestamp":1678291087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration"],"prefix":"10.3389","volume":"14","author":[{"given":"Aleksandar","family":"Videnovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle C. V.","family":"Pfeiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tylki-Szyma\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Berry-Kravis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih","family":"Ezg\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitendra","family":"Ganju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Jurecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ymgme.2010.11.164","article-title":"Research challenges in central nervous system manifestations of inborn errors of metabolism","volume":"102","author":"Dickson","year":"2011","journal-title":"Mol Genet Metab."},{"key":"B2","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.ymgme.2022.07.015","article-title":"The transformation of drug development for the 21st century: time for a change","volume":"137","author":"Kakkis","year":"2022","journal-title":"Mol Genet Metab."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1177\/0883073813495959","article-title":"Clinical trials in rare disease: challenges and opportunities","volume":"28","author":"Augustine","year":"2013","journal-title":"J Child Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s13023-018-0925-0","article-title":"Applicability and added value of novel methods to improve drug development in rare diseases","volume":"13","author":"Mitroiu","year":"2018","journal-title":"Orphanet J Rare Dis."},{"key":"B5","volume-title":"Guideline on Clinical Trials in Small Populations","author":"European Medicines","year":"2006"},{"key":"B6","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s13023-014-0170-0","article-title":"A comparison of interventional clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrialsgov","volume":"9","author":"Bell","year":"2014","journal-title":"Orphanet J Rare Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.2174\/1574884713666180604081349","article-title":"Trends of clinical trials for drug development in rare diseases","volume":"13","author":"Sakate","year":"2018","journal-title":"Curr Clin Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/s41436-018-0022-8","article-title":"A proposed nosology of inborn errors of metabolism","volume":"21","author":"Ferreira","year":"2019","journal-title":"Genet Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s13023-014-0177-6","article-title":"Rare inborn errors of metabolism with movement disorders: a case study to evaluate the impact upon quality of life and adaptive functioning","volume":"9","author":"Eggink","year":"2014","journal-title":"Orphanet J Rare Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"582160","DOI":"10.3389\/fneur.2020.582160","article-title":"A proposed diagnostic algorithm for inborn errors of metabolism presenting with movements disorders","volume":"11","author":"Ortigoza-Escobar","year":"2020","journal-title":"Front Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.ejpn.2011.04.013","article-title":"Hypokinetic-rigid syndrome in children and inborn errors of metabolism","volume":"15","author":"Garc\u00eda-Cazorla","year":"2011","journal-title":"Eur J Paediatr Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1007\/s10545-009-1194-9","article-title":"Inborn errors of metabolism and motor disturbances in children","volume":"32","author":"Garc\u00eda-Cazorla","year":"2009","journal-title":"J Inherit Metab Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s10545-014-9723-6","article-title":"Parkinsonism and inborn errors of metabolism","volume":"37","author":"Garcia-Cazorla","year":"2014","journal-title":"J Inherit Metab Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.ymgme.2019.09.002","article-title":"Incidence of PKAN determined by bioinformatic and population-based analysis of ~140,000 humans","volume":"128","author":"Brezavar","year":"2019","journal-title":"Mol Genet Metab."},{"key":"B15","first-page":"293","article-title":"Neurodegeneration with brain iron accumulation","volume-title":"Handbook of Clinical Neurology","author":"Hayflick","year":"2018"},{"key":"B16","doi-asserted-by":"publisher","first-page":"103869","DOI":"10.1016\/j.ebiom.2022.103869","article-title":"Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases","volume":"77","author":"Kolarova","year":"2022","journal-title":"EBioMedicine."},{"key":"B17","article-title":"Pantothenate kinase-associated neurodegeneration","volume-title":"GeneReviews","author":"Gregory","year":"2017"},{"key":"B18","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/S1474-4422(21)00462-2","article-title":"Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study","volume":"21","author":"Iba\u00f1ez","year":"2022","journal-title":"Lancet Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1136\/jnnp-2021-328045","article-title":"Diagnostic approach in adult-onset neurometabolic diseases","volume":"93","author":"Fern\u00e1ndez-Eulate","year":"2022","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B20","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.ymgme.2016.11.004","article-title":"Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN)","volume":"120","author":"Hogarth","year":"2017","journal-title":"Mol Genet Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1056\/NEJMoa020817","article-title":"Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome","volume":"348","author":"Hayflick","year":"2003","journal-title":"N Engl J Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1111\/cns.13294","article-title":"Natural history and genotype-phenotype correlation of pantothenate kinase-associated neurodegeneration","volume":"26","author":"Chang","year":"2020","journal-title":"CNS Neurosci Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1002\/mds.20282","article-title":"Clinical and neuropsychological correlates in two brothers with pantothenate kinase-associated neurodegeneration","volume":"20","author":"Marelli","year":"2005","journal-title":"Mov Disord."},{"key":"B24","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13023-019-1142-1","article-title":"Diagnostic and clinical experience of patients with pantothenate kinase-associated neurodegeneration","volume":"14","author":"Marshall","year":"2019","journal-title":"Orphanet J Rare Dis."},{"key":"B25","volume-title":"Rare Diseases: Common Issues in Drug Development.","year":"2019"},{"key":"B26","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.ymgme.2020.01.003","article-title":"The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII","volume":"129","author":"Wang","year":"2020","journal-title":"Mol Genet Metab."},{"key":"B27","volume-title":"Rare Diseases: Natural History Studies for Drug Development.","year":"2019"},{"key":"B28","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13023-020-1332-x","article-title":"A roadmap to using historical controls in clinical trials - by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG)","volume":"15","author":"Ghadessi","year":"2020","journal-title":"Orphanet J Rare Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1007\/s43441-021-00302-y","article-title":"The use of external controls in FDA regulatory decision making","volume":"55","author":"Jahanshahi","year":"2021","journal-title":"Ther Innov Regul Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s13023-017-0718-x","article-title":"Measuring what matters to rare disease patient\u2014reflections on the work by the IRDiRC taskforce on patient-centered outcome measures","volume":"12","author":"Morel","year":"2017","journal-title":"Orphanet J Rare Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1007\/s12325-019-00920-x","article-title":"The case for the use of patient and caregiver perception of change assessments in rare disease clinical trials: a methodologic overview","volume":"36","author":"Contesse","year":"2019","journal-title":"Adv Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/s12874-019-0866-x","article-title":"Goal attainment scaling as an outcome measure in rare disease trials: a conceptual proposal for validation","volume":"19","author":"Gaasterland","year":"2019","journal-title":"BMC Med Res Methodol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"S801","DOI":"10.1007\/s11606-014-2892-z","article-title":"Patient-reported outcomes in clinical trials of rare diseases","volume":"29","author":"Basch","year":"2014","journal-title":"J Gen Intern Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1016\/j.jval.2017.05.015","article-title":"Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials: an ISPOR COA emerging good practices task force report","volume":"20","author":"Benjamin","year":"2017","journal-title":"Value Health."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1007\/s40265-017-0788-z","article-title":"Gispen-de Wied CC, Stoyanova-Beninska V, Biegstraaten M. Factors contributing to the efficacy-effectiveness gap in the case of orphan drugs for metabolic diseases","volume":"77","author":"Schuller","year":"2017","journal-title":"Drugs."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1042\/BST20140098","article-title":"Defective pantothenate metabolism and neurodegeneration","volume":"42","author":"Hayflick","year":"2014","journal-title":"Biochem Soc Trans."},{"key":"B37","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1002\/mdc3.12716","article-title":"A scale to assess activities of daily living in pantothenate kinase-associated neurodegeneration","volume":"6","author":"Marshall","year":"2019","journal-title":"Mov Disord Clin Pract."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1002\/mds.28392","article-title":"Fosmetpantotenate randomized controlled trial in pantothenate kinase-associated neurodegeneration","volume":"36","author":"Klopstock","year":"2021","journal-title":"Mov Disord."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1002\/mds.27129","article-title":"Clinical rating scale for pantothenate kinase-associated neurodegeneration: a pilot study","volume":"32","author":"Darling","year":"2017","journal-title":"Mov Disord."},{"key":"B40","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1212\/WNL.35.1.73","article-title":"Validity and reliability of a rating scale for the primary torsion dystonias","volume":"35","author":"Burke","year":"1985","journal-title":"Neurology."},{"key":"B41","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1002\/mds.25579","article-title":"Dystonia rating scales: critique and recommendations","volume":"28","author":"Albanese","year":"2013","journal-title":"Mov Disord."},{"key":"B42","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1093\/brain\/awq022","article-title":"Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation","volume":"133","author":"Timmermann","year":"2010","journal-title":"Brain"},{"key":"B43","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1186\/s13023-020-01530-5","article-title":"Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study","volume":"15","author":"Chang","year":"2020","journal-title":"Orphanet J Rare Dis."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1002\/mds.28057","article-title":"Minimal clinically important differences for Burke-Fahn-Marsden Dystonia Rating Scale and 36-Item short-form health survey","volume":"35","author":"Pint\u00e9r","year":"2020","journal-title":"Mov Disord."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1002\/mds.22340","article-title":"Movement disorder society-sponsored revision of the unified parkinson's disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results","volume":"23","author":"Goetz","year":"2008","journal-title":"Mov Disord."},{"key":"B46","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/S1474-4422(19)30142-5","article-title":"Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study","volume":"18","author":"Klopstock","year":"2019","journal-title":"Lancet Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1002\/mdc3.12632","article-title":"Minimal clinically important difference for UPDRS-III in daily practice","volume":"5","author":"S\u00e1nchez-Ferro","year":"2018","journal-title":"Mov Disord Clin Pract."},{"key":"B48","doi-asserted-by":"publisher","first-page":"467131","DOI":"10.1155\/2014\/467131","article-title":"Minimal clinically important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended release","volume":"2014","author":"Hauser","year":"2014","journal-title":"Parkinsons Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3390\/ijms21103664","article-title":"Harmful iron-calcium relationship in pantothenate kinase associated neurodegeneration","volume":"21","author":"Santambrogio","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B50","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s12967-022-03304-y","article-title":"Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency","volume":"20","author":"Li","year":"2022","journal-title":"J Transl Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.parkreldis.2021.02.029","article-title":"How to detect late-onset inborn errors of metabolism in patients with movement disorders\u2014a modern diagnostic approach","volume":"85","author":"Koens","year":"2021","journal-title":"Parkinsonism Relat Disord."},{"key":"B52","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1007\/s10545-008-0854-5","article-title":"Movement disorders and inborn errors of metabolism in adults: a diagnostic approach","volume":"31","author":"Sedel","year":"2008","journal-title":"J Inherit Metab Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1177\/1740774519845673","article-title":"The FOsmetpantotenate Replacement Therapy (FORT) randomized, double-blind, placebo-controlled pivotal trial: study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration","volume":"16","author":"Klopstock","year":"2019","journal-title":"Clin Trials"},{"key":"B54","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1177\/0883073809344222","article-title":"Long-term miglustat therapy in children with Niemann-Pick disease type C","volume":"25","author":"Patterson","year":"2010","journal-title":"J Child Neurol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/S1474-4422(07)70194-1","article-title":"Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study","volume":"6","author":"Patterson","year":"2007","journal-title":"Lancet Neurol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/jimd.12428","article-title":"Efficacy and safety of arimoclomol in Niemann-Pick disease type C: results from a double-blind, randomised, placebo-controlled, multinational phase 2\/3 trial of a novel treatment","volume":"44","author":"Mengel","year":"2021","journal-title":"J Inherit Metab Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of intraventricular cerliponase alfa for CLN2 disease","volume":"378","author":"Schulz","year":"2018","journal-title":"N Engl J Med."},{"key":"B58","unstructured":"2022"},{"key":"B59","year":"2019","journal-title":"Adaptive Designs for Clinical Trials of Drugs and Biologics."},{"key":"B60","year":"2019","journal-title":"Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products."},{"key":"B61","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1186\/s13023-018-0919-y","article-title":"Recent advances in methodology for clinical trials in small populations: the InSPiRe project","volume":"13","author":"Friede","year":"2018","journal-title":"Orphanet J Rare Dis."},{"key":"B62","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1177\/0962280214538016","article-title":"The potential for increased power from combining P-values testing the same hypothesis","volume":"26","author":"Ganju","year":"2017","journal-title":"Stat Methods Med Res."},{"key":"B63","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/pst.1582","article-title":"Robust inference from multiple test statistics via permutations: a better alternative to the single test statistic approach for randomized trials","volume":"12","author":"Ganju","year":"2013","journal-title":"Pharm Stat."},{"key":"B64","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1002\/pst.1735","article-title":"Robust inference from multiple test statistics via permutations: a better alternative to the single test statistics approach for randomized trials","volume":"15","author":"Ganju","year":"2016","journal-title":"Pharm Stat."},{"key":"B65","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1002\/ajmg.a.38413","article-title":"Challenges of developing and conducting clinical trials in rare disorders","volume":"176","author":"Kempf","year":"2018","journal-title":"Am J Med Genet A."},{"key":"B66","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s13023-018-0931-2","article-title":"Recommendations for the design of small population clinical trials","volume":"13","author":"Day","year":"2018","journal-title":"Orphanet J Rare Dis."},{"key":"B67","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13023-018-0926-z","article-title":"Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties","volume":"13","author":"Pontes","year":"2018","journal-title":"Orphanet J Rare Dis."},{"key":"B68","unstructured":"2022"},{"key":"B69","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1186\/s13063-018-2645-0","article-title":"A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial","volume":"19","author":"Crow","year":"2018","journal-title":"Trials."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1016\/S0140-6736(17)31465-4","article-title":"Intrathecal 2-hydroxypropyl-\u03b2-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial","volume":"390","author":"Ory","year":"2017","journal-title":"Lancet."},{"key":"B71","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/mds.27568","article-title":"Movement disorders in treatable inborn errors of metabolism","volume":"34","author":"Ebrahimi-Fakhari","year":"2019","journal-title":"Mov Disord."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1098454\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T15:58:12Z","timestamp":1678291092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1098454\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":71,"alternative-id":["10.3389\/fneur.2023.1098454"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1098454","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]},"article-number":"1098454"}}