{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T14:42:44Z","timestamp":1776868964012,"version":"3.51.2"},"reference-count":137,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Restless legs syndrome (RLS) is traditionally conceptualized as a dopamine-responsive sensorimotor disorder; however, new evidence suggests a more complex and heterogeneous neurobiological basis. Findings from neuroimaging, genetic studies, circadian biology, and clinical research indicate that dopaminergic dysfunction occurs within a broader context of neuromodulatory imbalance involving iron metabolism, adenosinergic signalling, glutamatergic excitability, and, potentially, noradrenergic pathways. In parallel, quantitative susceptibility mapping and related approaches have provided indirect evidence of altered brain iron distribution, although results remain variable across studies. Clinically, RLS extends beyond nocturnal discomfort and is associated with sleep fragmentation, impaired quality of life, and neuropsychiatric comorbidity, as well as treatment-related complications such as augmentation. However, current diagnostic frameworks remain predominantly phenomenological, and available biomarkers lack sufficient validation for routine clinical use. In this narrative review, the available clinical, genetic, and neuroimaging evidence is synthesized to propose an integrative, network-based model in which iron-dependent neuromodulatory processes influence excitability across cortico\u2013striatal\u2013thalamo\u2013limbic circuits. This framework is intended as a hypothesis-generating model rather than a definitive explanation of disease mechanisms. Substantial heterogeneity across studies, together with variability in clinical presentation and limited reproducibility of candidate biomarkers, underscores the need for standardized methodologies and longitudinal, multimodal investigations. Future work should aim to test this model empirically, refine biological stratification, and determine whether network-informed approaches can improve diagnosis and therapeutic targeting in RLS.<\/jats:p>","DOI":"10.3390\/brainsci16050440","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T13:44:33Z","timestamp":1776865473000},"page":"440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restless Legs Syndrome: A Network Model of Iron-Dependent Neuromodulation\u2014A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-7571","authenticated-orcid":false,"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Neurociencias Cl\u00ednica, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico"},{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City 14380, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1303646","article-title":"Comparison of pregabalin with pramipexole for restless legs syndrome","volume":"370","author":"Allen","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41572-021-00311-z","article-title":"Restless legs syndrome","volume":"7","author":"Manconi","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nrneurol.2010.55","article-title":"Restless legs syndrome: Pathophysiology, clinical presentation and management","volume":"6","author":"Trenkwalder","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101461","DOI":"10.1016\/j.smrv.2021.101461","article-title":"We need to do better: A systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments","volume":"58","author":"Fulda","year":"2021","journal-title":"Sleep Med. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/j.mayocp.2020.12.026","article-title":"The Management of Restless Legs Syndrome: An Updated Algorithm","volume":"96","author":"Silber","year":"2021","journal-title":"Mayo Clin. Proc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1002\/mds.10231","article-title":"Long-term course of restless legs syndrome in dialysis patients after kidney transplantation","volume":"17","author":"Winkelmann","year":"2002","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/mds.27260","article-title":"Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017) (section sign)","volume":"33","author":"Winkelmann","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.sleep.2014.05.009","article-title":"Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease)","volume":"15","author":"Earley","year":"2014","journal-title":"Sleep Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/S1474-4422(17)30327-7","article-title":"Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: A meta-analysis","volume":"16","author":"Schormair","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Winkelmann, J., Czamara, D., Schormair, B., Knauf, F., Schulte, E.C., Trenkwalder, C., Dauvilliers, Y., Polo, O., Hogl, B., and Berger, K. (2011). Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet., 7.","DOI":"10.1371\/annotation\/393ad2d3-df4f-4770-87bc-00bfabf79362"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5664\/jcsm.11390","article-title":"Treatment of restless legs syndrome and periodic limb movement disorder: An American Academy of Sleep Medicine clinical practice guideline","volume":"21","author":"Winkelman","year":"2025","journal-title":"J. Clin. Sleep Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1001\/archinte.165.11.1286","article-title":"Restless legs syndrome prevalence and impact: REST general population study","volume":"165","author":"Allen","year":"2005","journal-title":"Arch. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/sleep\/31.2.219","article-title":"Epidemiology of restless legs syndrome in Korean adults","volume":"31","author":"Cho","year":"2008","journal-title":"Sleep"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1212\/WNL.54.5.1064","article-title":"Prevalence and risk factors of RLS in an elderly population: The MEMO study. Memory and Morbidity in Augsburg Elderly","volume":"54","author":"Rothdach","year":"2000","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.sleep.2009.03.007","article-title":"Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: Prevalence and characteristics","volume":"11","author":"Allen","year":"2010","journal-title":"Sleep Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1212\/WNL.0000000000002542","article-title":"Restless legs syndrome associated with major diseases: A systematic review and new concept","volume":"86","author":"Trenkwalder","year":"2016","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.sleep.2019.07.003","article-title":"TOX3 gene variant could be associated with painful restless legs","volume":"65","author":"Karroum","year":"2020","journal-title":"Sleep Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.sleep.2011.11.020","article-title":"Descriptors of restless legs syndrome sensations","volume":"13","author":"Kerr","year":"2012","journal-title":"Sleep Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.sleep.2004.03.006","article-title":"Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: The REST (RLS epidemiology, symptoms, and treatment) primary care study","volume":"5","author":"Hening","year":"2004","journal-title":"Sleep Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.5664\/jcsm.10160","article-title":"Polysomnographic features of idiopathic restless legs syndrome: A systematic review and meta-analysis of 13 sleep parameters and 23 leg movement parameters","volume":"18","author":"Zhang","year":"2022","journal-title":"J. Clin. Sleep Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/1531-8257(199901)14:1<102::AID-MDS1017>3.0.CO;2-E","article-title":"Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome","volume":"14","author":"Trenkwalder","year":"1999","journal-title":"Mov. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101975","DOI":"10.1016\/j.smrv.2024.101975","article-title":"Prevalence of depression or depressive state in patients with restless legs syndrome: A systematic review and meta-analysis","volume":"77","author":"Miyaguchi","year":"2024","journal-title":"Sleep Med. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s00415-005-0604-7","article-title":"\u201cAnxietas tibiarum\u201d. Depression and anxiety disorders in patients with restless legs syndrome","volume":"252","author":"Winkelmann","year":"2005","journal-title":"J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1212\/01.wnl.0000287072.93277.c9","article-title":"Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study","volume":"70","author":"Winkelman","year":"2008","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1161\/HYPERTENSIONAHA.111.174037","article-title":"Restless legs syndrome and hypertension in middle-aged women","volume":"58","author":"Malhotra","year":"2011","journal-title":"Hypertension"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1093\/eurheartj\/ehr007","article-title":"Sleep duration predicts cardiovascular outcomes: A systematic review and meta-analysis of prospective studies","volume":"32","author":"Cappuccio","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1161\/CIRCULATIONAHA.111.038968","article-title":"Association of incident cardiovascular disease with periodic limb movements during sleep in older men: Outcomes of sleep disorders in older men (MrOS) study","volume":"124","author":"Koo","year":"2011","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.sleep.2016.10.010","article-title":"World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG)","volume":"26","author":"Ferri","year":"2016","journal-title":"Sleep Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.sleep.2013.02.005","article-title":"Blood pressure changes associated with periodic leg movements during sleep in healthy subjects","volume":"14","author":"Pennestri","year":"2013","journal-title":"Sleep Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/sleep\/22.5.575","article-title":"The evoked heart rate response to periodic leg movements of sleep","volume":"22","author":"Winkelman","year":"1999","journal-title":"Sleep"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.amjcard.2010.09.037","article-title":"Relation of periodic leg movements during sleep and mortality in patients with systolic heart failure","volume":"107","author":"Yumino","year":"2011","journal-title":"Am. J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"763","DOI":"10.5665\/sleep.3586","article-title":"Motor events during healthy sleep: A quantitative polysomnographic study","volume":"37","author":"Frauscher","year":"2014","journal-title":"Sleep"},{"key":"ref_33","first-page":"1221","article-title":"Periodic limb movements during sleep: Population prevalence, clinical correlates, and racial differences","volume":"31","author":"Scofield","year":"2008","journal-title":"Sleep"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.smrv.2017.06.002","article-title":"The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review","volume":"38","author":"Kolla","year":"2018","journal-title":"Sleep Med. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"929","DOI":"10.2147\/NSS.S513538","article-title":"Exploring the Top 50 Drugs Associated with Restless Legs Syndrome Based on the FDA Data from 2004 to 2024","volume":"17","author":"Wei","year":"2025","journal-title":"Nat. Sci. Sleep"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.sleep.2023.11.1138","article-title":"Prevalence of restless legs syndrome in maintenance hemodialysis patients: A systematic review and meta-analysis","volume":"114","author":"Liu","year":"2024","journal-title":"Sleep Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1520","DOI":"10.1212\/WNL.0000000000206855","article-title":"Long-term Safety, Dose Stability, and Efficacy of Opioids for Patients with Restless Legs Syndrome in the National RLS Opioid Registry","volume":"100","author":"Winkelman","year":"2023","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"641","DOI":"10.5664\/jcsm.10524","article-title":"Opioids and restless legs syndrome: A double-edged sword","volume":"19","author":"Winkelman","year":"2023","journal-title":"J. Clin. Sleep Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1111\/ene.14840","article-title":"Association between restless legs syndrome and peripheral neuropathy: A systematic review and meta-analysis","volume":"28","author":"Agundez","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103275","DOI":"10.1016\/j.msard.2021.103275","article-title":"Restless legs syndrome in people with multiple sclerosis: An updated systematic review and meta-analyses","volume":"56","author":"Ozdogar","year":"2021","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1056\/NEJMoa072743","article-title":"A genetic risk factor for periodic limb movements in sleep","volume":"357","author":"Stefansson","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.sleep.2024.07.015","article-title":"Prevalence and clinical profile of patients with restless legs syndrome in Parkinson\u2019s disease: A meta-analysis","volume":"121","author":"Maggi","year":"2024","journal-title":"Sleep Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.smrv.2011.05.002","article-title":"Epidemiology of restless legs syndrome: A synthesis of the literature","volume":"16","author":"Ohayon","year":"2012","journal-title":"Sleep Med. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1093\/brain\/awad283","article-title":"Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome","volume":"147","author":"Walters","year":"2024","journal-title":"Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111075","DOI":"10.1016\/j.jocn.2025.111075","article-title":"Impact of continuous positive airway pressure therapy on restless legs syndrome in patients with coexistent obstructive sleep apnea: A qualitative systematic review","volume":"133","author":"Srivali","year":"2025","journal-title":"J. Clin. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.amjmed.2012.06.040","article-title":"Vascular risk factors, cardiovascular disease, and restless legs syndrome in women","volume":"126","author":"Winter","year":"2013","journal-title":"Am. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.sleep.2024.03.009","article-title":"Restless legs syndrome in patients with obstructive sleep apnea: Association between apnea severity and symptoms of depression, insomnia, and daytime sleepiness","volume":"117","author":"Kim","year":"2024","journal-title":"Sleep Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhu, X.Y., Wu, T.T., Wang, H.M., Li, X., Ni, L.Y., Chen, T.J., Qiu, M.Y., Shen, J., Liu, T., and Ondo, W.G. (2020). Correlates of Nonanemic Iron Deficiency in Restless Legs Syndrome. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.00298"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1055\/s-2004-835066","article-title":"The restless legs syndrome and periodic limb movement disorder: A review of management","volume":"24","author":"Lesage","year":"2004","journal-title":"Semin. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1177\/1073858418791763","article-title":"New Insights into the Neurobiology of Restless Legs Syndrome","volume":"25","author":"Ferre","year":"2019","journal-title":"Neuroscientist"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1001\/jama.2025.0452","article-title":"Iron Deficiency in Adults: A Review","volume":"333","author":"Auerbach","year":"2025","journal-title":"J. Am. Med. Assoc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/ajh.23397","article-title":"The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia","volume":"88","author":"Allen","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.sleep.2016.07.018","article-title":"Brain imaging and networks in restless legs syndrome","volume":"31","author":"Rizzo","year":"2017","journal-title":"Sleep Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.smrv.2017.10.003","article-title":"Prevalence of restless legs syndrome during pregnancy: A systematic review and meta-analysis","volume":"40","author":"Chen","year":"2018","journal-title":"Sleep Med. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1515\/jpm-2024-0208","article-title":"Prevalence of restless legs syndrome during pregnancy and postpartum period","volume":"52","author":"Lepuzanovic","year":"2024","journal-title":"J. Perinat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jsat.2016.10.001","article-title":"Prevalence of restless legs syndrome during detoxification from alcohol and opioids","volume":"73","author":"Mackie","year":"2017","journal-title":"J. Subst. Abuse Treat."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"110941","DOI":"10.1016\/j.mehy.2022.110941","article-title":"Exploring the role of the endogenous opiate system in the pathogenesis of anemia in an opiate receptor knock-out model of Restless Legs Syndrome","volume":"167","author":"Walters","year":"2022","journal-title":"Med. Hypotheses"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106442","DOI":"10.1016\/j.neubiorev.2025.106442","article-title":"Noradrenergic dysregulation in the locus coeruleus: Implications for neuropsychiatric disease pathophysiology\u2014A systematic review","volume":"179","author":"Mir","year":"2025","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00415-025-13285-9","article-title":"RLS shows increased resting state sympathetic activity and decreased sympathetic response capability","volume":"272","author":"Best","year":"2025","journal-title":"J. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/s41392-025-02415-4","article-title":"Multiple sclerosis: Molecular pathogenesis and therapeutic intervention","volume":"10","author":"Eixarch","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/sleep\/23.5.1b","article-title":"Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients","volume":"23","author":"Winkelmann","year":"2000","journal-title":"Sleep"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1212\/01.wnl.0000261016.90374.fd","article-title":"Canadian restless legs syndrome twin study","volume":"68","author":"Xiong","year":"2007","journal-title":"Neurology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/s41588-024-01763-1","article-title":"Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction","volume":"56","author":"Schormair","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/ng.3749","article-title":"Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits","volume":"49","author":"Lane","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/bs.apha.2019.03.003","article-title":"Role of MEIS1 in restless legs syndrome: From GWAS to functional studies in mice","volume":"84","author":"Salminen","year":"2019","journal-title":"Adv. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Sarayloo, F., Dion, P.A., and Rouleau, G.A. (2019). MEIS1 and Restless Legs Syndrome: A Comprehensive Review. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00935"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1111\/j.1537-2995.2012.03629.x","article-title":"A genetic risk factor for low serum ferritin levels in Danish blood donors","volume":"52","author":"Sorensen","year":"2012","journal-title":"Transfusion"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.sleep.2005.11.009","article-title":"MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome","volume":"7","author":"Earley","year":"2006","journal-title":"Sleep Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/mds.21230","article-title":"Substantia nigra hypoechogenicity: Definition and findings in restless legs syndrome","volume":"22","author":"Godau","year":"2007","journal-title":"Mov. Disord."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1365-2869.2004.00403.x","article-title":"CSF iron, ferritin and transferrin levels in restless legs syndrome","volume":"14","author":"Mizuno","year":"2005","journal-title":"J. Sleep Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1093\/brain\/awr012","article-title":"Profile of altered brain iron acquisition in restless legs syndrome","volume":"134","author":"Connor","year":"2011","journal-title":"Brain"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/14737175.2025.2603544","article-title":"Evaluating the adenosine hypothesis of restless legs syndrome and its implications for current and future treatment strategies","volume":"26","author":"Mogavero","year":"2026","journal-title":"Expert. Rev. Neurother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.sleep.2020.01.024","article-title":"Iron-deficiency and dopaminergic treatment effects on RLS-Like behaviors of an animal model with the brain iron deficiency pattern of the restless legs syndrome","volume":"71","author":"Allen","year":"2020","journal-title":"Sleep Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"51","DOI":"10.5665\/sleep.2300","article-title":"Increased synaptic dopamine in the putamen in restless legs syndrome","volume":"36","author":"Earley","year":"2013","journal-title":"Sleep"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.sleep.2005.09.006","article-title":"Circadian changes in CSF dopaminergic measures in restless legs syndrome","volume":"7","author":"Earley","year":"2006","journal-title":"Sleep Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3988\/jcn.2022.18.3.290","article-title":"Alterations of Functional Connectivity in Patients with Restless Legs Syndrome","volume":"18","author":"Park","year":"2022","journal-title":"J. Clin. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuropharm.2016.09.002","article-title":"Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome","volume":"111","author":"Quiroz","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/ana.26876","article-title":"The Melanocortin and Endorphin Neuropeptides in Patients with Restless Legs Syndrome","volume":"95","author":"Koo","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1212\/WNL.0b013e318294b3f6","article-title":"Thalamic glutamate\/glutamine in restless legs syndrome: Increased and related to disturbed sleep","volume":"80","author":"Allen","year":"2013","journal-title":"Neurology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.sleep.2017.04.014","article-title":"Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: Results from the Danish Blood Donor Study","volume":"36","author":"Didriksen","year":"2017","journal-title":"Sleep Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3122\/jabfm.19.5.487","article-title":"Exercise and restless legs syndrome: A randomized controlled trial","volume":"19","author":"Aukerman","year":"2006","journal-title":"J. Am. Board Fam. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e13980","DOI":"10.1111\/jsr.13980","article-title":"Perceptions of exercise and restless legs syndrome: Results from a nationwide survey","volume":"33","author":"Cederberg","year":"2024","journal-title":"J. Sleep Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tolkien, Z., Stecher, L., Mander, A.P., Pereira, D.I., and Powell, J.J. (2015). Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: A systematic review and meta-analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117383"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.5664\/jcsm.11846","article-title":"Efficacy and safety of intravenous iron in patients with restless legs syndrome with normal serum ferritin levels: A stratified subanalysis","volume":"21","author":"Silber","year":"2025","journal-title":"J. Clin. Sleep Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/mds.27040","article-title":"Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial","volume":"32","author":"Trenkwalder","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/ajh.27290","article-title":"A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia","volume":"99","author":"Short","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1212\/WNL.59.10.1573","article-title":"Treatment of restless legs syndrome with gabapentin: A double-blind, cross-over study","volume":"59","author":"Larrosa","year":"2002","journal-title":"Neurology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Qin, Z., Zhu, Y., Shi, D.D., Chen, R., Li, S., and Wu, J. (2024). The gap between statistical and clinical significance: Time to pay attention to clinical relevance in patient-reported outcome measures of insomnia. BMC Med. Res. Methodol., 24.","DOI":"10.1186\/s12874-024-02297-0"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.sleep.2009.03.009","article-title":"Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized, double-blind, placebo-controlled study","volume":"11","author":"Inoue","year":"2010","journal-title":"Sleep Med."},{"key":"ref_90","first-page":"CD006009","article-title":"Dopamine agonists for restless legs syndrome","volume":"2011","author":"Scholz","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.sleep.2007.03.022","article-title":"Diagnostic standards for dopaminergic augmentation of restless legs syndrome: Report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute","volume":"8","author":"Allen","year":"2007","journal-title":"Sleep Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.sleep.2010.11.002","article-title":"A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome","volume":"12","author":"Silver","year":"2011","journal-title":"Sleep Med."},{"key":"ref_93","first-page":"81","article-title":"Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: A case-control study","volume":"33","author":"Cornelius","year":"2010","journal-title":"Sleep"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1111\/ene.13449","article-title":"Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: A comparative meta-analysis","volume":"24","author":"Iftikhar","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/S1474-4422(13)70239-4","article-title":"Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: A double-blind, randomised, placebo-controlled trial with an open-label extension","volume":"12","author":"Trenkwalder","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_96","first-page":"1","article-title":"Guidelines for the first-line treatment of restless legs syndrome\/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: A combined task force of the IRLSSG, EURLSSG, and the RLS-foundation","volume":"21","author":"Silber","year":"2016","journal-title":"Sleep Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"zsad190","DOI":"10.1093\/sleep\/zsad190","article-title":"Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: A randomized clinical trial","volume":"46","author":"Bogan","year":"2023","journal-title":"Sleep"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.sleep.2019.12.009","article-title":"Contribution of transcranial magnetic stimulation in restless legs syndrome: Pathophysiological insights and therapeutical approaches","volume":"71","author":"Nardone","year":"2020","journal-title":"Sleep Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.chest.2022.05.014","article-title":"Treating Severe Refractory and Augmented Restless Legs Syndrome","volume":"162","author":"Winkelman","year":"2022","journal-title":"Chest"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s40266-013-0090-z","article-title":"Dopamine agonist withdrawal syndrome: Implications for patient care","volume":"30","author":"Nirenberg","year":"2013","journal-title":"Drugs Aging"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1093\/aje\/kws016","article-title":"Prospective study of restless legs syndrome and risk of depression in women","volume":"176","author":"Li","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1001\/jamainternmed.2013.3733","article-title":"Pharmacologic therapy for primary restless legs syndrome: A systematic review and meta-analysis","volume":"173","author":"Wilt","year":"2013","journal-title":"JAMA Intern. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.sleep.2017.12.003","article-title":"Restless Legs Syndrome \u201cPatient Odyssey\u201d survey of disease burden on patient and spouses\/partners","volume":"47","author":"Ondo","year":"2018","journal-title":"Sleep Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.amjmed.2015.12.020","article-title":"Symptom Severity of Restless Legs Syndrome Predicts Its Clinical Course","volume":"129","author":"Lee","year":"2016","journal-title":"Am. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e199966","DOI":"10.1001\/jamanetworkopen.2019.9966","article-title":"Association of Restless Legs Syndrome with Risk of Suicide and Self-harm","volume":"2","author":"Zhuang","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/S0272-6386(96)90494-1","article-title":"Restless legs syndrome in end-stage renal disease","volume":"28","author":"Winkelman","year":"1996","journal-title":"Am. J. Kidney Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e018674","DOI":"10.1161\/JAHA.120.018674","article-title":"Treating Restless Legs Syndrome Was Associated with Low Risk of Cardiovascular Disease: A Cohort Study with 3.4 Years of Follow-Up","volume":"10","author":"Gao","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Muhoberac, B.B., and Vidal, R. (2019). Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01195"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-1-4939-2095-2_10","article-title":"A systems biology approach to iron metabolism","volume":"844","author":"Chifman","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00018-014-1771-4","article-title":"Iron transport across the blood-brain barrier: Development, neurovascular regulation and cerebral amyloid angiopathy","volume":"72","author":"McCarthy","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_111","first-page":"880","article-title":"The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases","volume":"24","author":"Jomova","year":"2025","journal-title":"EXCLI J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s43556-023-00142-2","article-title":"The mechanism of ferroptosis and its related diseases","volume":"4","author":"Feng","year":"2023","journal-title":"Mol. Biomed."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"102164","DOI":"10.1016\/j.redox.2021.102164","article-title":"Mitochondrial iron-sulfur clusters: Structure, function, and an emerging role in vascular biology","volume":"47","author":"Read","year":"2021","journal-title":"Redox Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41392-024-02071-0","article-title":"Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/biof.80","article-title":"Iron in neuronal function and dysfunction","volume":"36","author":"Salvador","year":"2010","journal-title":"Biofactors"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41467-021-27657-y","article-title":"Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation","volume":"13","author":"Cuellar","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Ortega, R., Cloetens, P., Deves, G., Carmona, A., and Bohic, S. (2007). Iron storage within dopamine neurovesicles revealed by chemical nano-imaging. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000925"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Rodrigues, M.S., Ferreira, S.G., Quiroz, C., Earley, C.J., Garcia-Borreguero, D., Cunha, R.A., Ciruela, F., Kofalvi, A., and Ferre, S. (2022). Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome. Molecules, 27.","DOI":"10.3390\/molecules27051489"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"101744","DOI":"10.1016\/j.pneurobio.2019.101744","article-title":"Regional iron distribution and soluble ferroprotein profiles in the healthy human brain","volume":"186","author":"McAllum","year":"2020","journal-title":"Prog. Neurobiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.bbagen.2008.08.005","article-title":"Iron, the substantia nigra and related neurological disorders","volume":"1790","author":"Snyder","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1002\/glia.70043","article-title":"What Does Iron Mean to an Oligodendrocyte?","volume":"73","author":"Wade","year":"2025","journal-title":"Glia"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"7853","DOI":"10.1074\/jbc.RA118.001949","article-title":"Inflammation-induced iron transport and metabolism by brain microglia","volume":"293","author":"McCarthy","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Dong, K., Liu, B., Cheng, G., Li, Y., Xie, F., Zhang, J., and Qian, L. (2025). Stress-Induced Dysregulation of Brain Iron Metabolism and Its Links to Neurological Disorders. Biology, 14.","DOI":"10.3390\/biology14111575"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.neuro.2021.11.003","article-title":"Mitochondrial iron metabolism and neurodegenerative diseases","volume":"88","author":"Cheng","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/s41531-025-01052-6","article-title":"Parkinsonism disrupts cortical function by dysregulating oscillatory, network and synaptic activity of parvalbumin positive interneurons","volume":"11","author":"Minetti","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainresrev.2007.10.013","article-title":"Noradrenergic modulation of arousal","volume":"58","author":"Berridge","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e32324","DOI":"10.1097\/MD.0000000000032324","article-title":"Exploration of restless legs syndrome under the new concept: A review","volume":"101","author":"Liu","year":"2022","journal-title":"Medicine"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S1389-9457(03)00010-8","article-title":"Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology: A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health","volume":"4","author":"Allen","year":"2003","journal-title":"Sleep Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1093\/brain\/awp125","article-title":"Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome","volume":"132","author":"Connor","year":"2009","journal-title":"Brain"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"103024","DOI":"10.1016\/j.nicl.2022.103024","article-title":"Revisiting brain iron deficiency in restless legs syndrome using magnetic resonance imaging","volume":"34","author":"Beliveau","year":"2022","journal-title":"Neuroimage Clin."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1002\/ana.27040","article-title":"Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome","volume":"96","author":"Akcimen","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"12173","DOI":"10.1038\/s41598-018-30665-6","article-title":"A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1","volume":"8","author":"Catoire","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"An, T., Sun, H., Yuan, L., Wu, X., and Lu, B. (2024). Associations of anxiety and depression with restless leg syndrome: A systematic review and meta-analysis. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1366839"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Tang, M., Sun, Q., Zhang, Y., Li, H., Wang, D., Wang, Y., and Wang, Z. (2023). Circadian rhythm in restless legs syndrome. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1105463"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.12688\/f1000research.9180.1","article-title":"Circadian influences on dopamine circuits of the brain: Regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease","volume":"5","author":"Verwey","year":"2016","journal-title":"F1000Research"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Aggarwal, A., Negrean, A., Chen, Y., Iyer, R., Reep, D., Liu, A., Palutla, A., Xie, M.E., MacLennan, B.J., and Hagihara, K.M. (2025). Glutamate indicators with increased sensitivity and tailored deactivation rates. bioRxiv.","DOI":"10.1038\/s41592-025-02965-z"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"e70337","DOI":"10.1111\/ene.70337","article-title":"The Locus Coeruleus-Noradrenergic System in the Healthy and Diseased Brain: A Narrative Review","volume":"32","author":"Caestecker","year":"2025","journal-title":"Eur. J. Neurol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/440\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T13:53:14Z","timestamp":1776865994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":137,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["brainsci16050440"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16050440","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]}}}