{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:43:15Z","timestamp":1787496195982,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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>Objective: Recent research has expanded the understanding of the potential role of sympathetic nervous system activation in the implications of sleep-related movement disorders, particularly in the mechanisms of dopaminergic dysfunction and iron deficiency. This multifactorial perspective aims to provide insights into disease mechanisms and opportunities for targeted interventions that address both neurological and autonomic contributors to sleep-related movements. Methods: To synthesize the current evidence on the role of sympathetic activation in sleep-related movement disorders, we conducted a review of the literature to identify studies exploring the intersection of autonomic nervous system activity and motor phenomena during sleep. Results: Studies indicate that sympathetic activation may contribute directly to the initiation and propagation of motor events during sleep. Evidence from electrophysiological studies and heart rate variability analyses in patients with sleep-related movement disorders shows that sympathetic bursts often precede or coincide with leg movements and arousals, suggesting a causal rather than reactive role. Moreover, iron deficiency appears to exacerbate both dopaminergic and autonomic dysfunction, providing a unifying mechanism that bridges these pathways. Conclusions: These findings support a shift from viewing sympathetic activity as a secondary response to arousal to recognizing it as a possible primary trigger of sleep-related motor events.<\/jats:p>","DOI":"10.3390\/brainsci16050539","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:12:54Z","timestamp":1779286374000},"page":"539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sympathetic Activation and Sleep-Related Movements: Integrating Autonomic, Dopaminergic, and Iron Deficiency Mechanisms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-2840","authenticated-orcid":false,"given":"Gulcin Benbir","family":"Senel","sequence":"first","affiliation":[{"name":"Sleep and Disorders Unit, Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul 34320, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3349-8426","authenticated-orcid":false,"given":"Lourdes M.","family":"DelRosso","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Francisco, Fresno, CA 93701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.5665\/sleep.5528","article-title":"Impact of Restless Legs Syndrome on Cardiovascular Autonomic Control","volume":"39","author":"Bertisch","year":"2016","journal-title":"Sleep"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11940-017-0446-5","article-title":"The Clinical Importance of Periodic Leg Movements in Sleep","volume":"19","author":"Figorilli","year":"2017","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1161\/HYPERTENSIONAHA.119.13456","article-title":"Neurological Sleep Disorders and Blood Pressure: Current Evidence","volume":"74","author":"Mansukhani","year":"2019","journal-title":"Hypertension"},{"key":"ref_4","first-page":"e49703","article-title":"The Impact of Sleep Disorders on Cardiovascular Health: Mechanisms and Interventions","volume":"15","author":"Sarode","year":"2023","journal-title":"Cureus"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Guo, S., Huang, J., Jiang, H., Han, C., Li, J., Xu, X., Zhang, G., Lin, Z., Xiong, N., and Wang, T. (2017). Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00171"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.5664\/jcsm.8718","article-title":"Heart rate variability during sleep in children and adolescents with restless sleep disorder: A comparison with restless legs syndrome and normal controls","volume":"16","author":"DelRosso","year":"2020","journal-title":"J. Clin. Sleep Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.sleep.2004.01.008","article-title":"Changes in cerebral and autonomic activity heralding periodic limb movements in sleep","volume":"5","author":"Ferrillo","year":"2004","journal-title":"Sleep Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00221-008-1337-5","article-title":"Organization of brain somatomotor-sympathetic circuits","volume":"187","author":"Kerman","year":"2008","journal-title":"Exp. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sforza, E., Roche, F., and Pichot, V. (2019). Determinants of Nocturnal Cardiovascular Variability and Heart Rate Arousal Response in Restless Legs Syndrome (RLS)\/Periodic Limb Movements (PLMS). J. Clin. Med., 8.","DOI":"10.3390\/jcm8101619"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1016\/j.cell.2024.04.022","article-title":"Spinal projecting neurons in rostral ventromedial medulla co-regulate motor and sympathetic tone","volume":"187","author":"Zhang","year":"2024","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/B978-0-444-63912-7.00020-5","article-title":"Body temperature and sleep","volume":"156","author":"Szymusiak","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.sleep.2013.12.005","article-title":"Sympathetic and cardiovascular changes during sleep in narcolepsy with cataplexy patients","volume":"15","author":"Donadio","year":"2014","journal-title":"Sleep Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1523\/JNEUROSCI.01-08-00876.1981","article-title":"Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle","volume":"1","author":"Bloom","year":"1981","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102285","DOI":"10.1016\/j.smrv.2026.102285","article-title":"Why do we sleepwalk? A noradrenergic hypothesis of NREM sleep parasomnias","volume":"87","author":"Bellesi","year":"2026","journal-title":"Sleep Med. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"182","DOI":"10.2174\/1574884711308030003","article-title":"How to assess sympathetic nervous system activity in clinical practice","volume":"8","author":"Seravalle","year":"2013","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.sleep.2019.09.005","article-title":"Moderate to severe but not mild RLS is associated with greater sleep-related sympathetic autonomic activation than healthy adults without RLS","volume":"68","author":"Jin","year":"2020","journal-title":"Sleep Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"463","DOI":"10.5664\/jcsm.8234","article-title":"An elevated leg movement index during sleep in atopic dermatitis and periodic leg movement disorder may be an indication of sympathetic activation common to both","volume":"16","author":"Gupta","year":"2020","journal-title":"J. Clin. Sleep Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.sleep.2021.05.044","article-title":"Signs of sympathetic and endothelial cell activation in the skin of patients with restless legs syndrome","volume":"84","author":"Bergmann","year":"2021","journal-title":"Sleep Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/sleep\/30.6.755","article-title":"The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep","volume":"30","author":"Guggisberg","year":"2007","journal-title":"Sleep"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e14394","DOI":"10.1111\/jsr.14394","article-title":"Spectral EEG and heart rate changes associated with leg movements during the suggested immobilization test in patients with restless legs syndrome","volume":"34","author":"Tunali","year":"2025","journal-title":"J. Sleep Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.jsmc.2021.03.003","article-title":"Restless Sleep Disorder","volume":"16","author":"DelRosso","year":"2021","journal-title":"Sleep Med. Clin."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gottesmann, C. (2011). The involvement of noradrenaline in rapid eye movement sleep mentation. Front. Neurol., 2.","DOI":"10.3389\/fneur.2011.00081"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Giri, S., Mehta, R., and Mallick, B.N. (2023). REM Sleep Loss-Induced Elevated Noradrenaline Plays a Significant Role in Neurodegeneration: Synthesis of Findings to Propose a Possible Mechanism of Action from Molecule to Patho-Physiological Changes. Brain Sci., 14.","DOI":"10.3390\/brainsci14010008"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.neuint.2017.03.016","article-title":"Reciprocal changes in noradrenaline and GABA levels in discrete brain regions upon rapid eye movement sleep deprivation in rats","volume":"108","author":"Mehta","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.smrv.2010.11.001","article-title":"REM sleep loss increases brain excitability: Role of noradrenalin and its mechanism of action","volume":"15","author":"Mallick","year":"2011","journal-title":"Sleep Med. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1093\/ijnp\/pyx026","article-title":"Acute and Chronic Noradrenergic Effects on Cortical Excitability in Healthy Humans","volume":"20","author":"Kuo","year":"2017","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Singh, A., Das, G., Kaur, M., and Mallick, B.N. (2019). Noradrenaline Acting on Alpha1 Adrenoceptor as well as by Chelating Iron Reduces Oxidative Burden on the Brain: Implications with Rapid Eye Movement Sleep. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00007"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"654","DOI":"10.12659\/MSM.890252","article-title":"The association of Restless Legs Syndrome with hypertension and cardiovascular disease","volume":"20","author":"Katsi","year":"2014","journal-title":"Med. Sci. Monit."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chiang, J.K., Lin, Y.C., and Kao, Y.H. (2023). Oscillation of Sympathetic Activity in Patients with Obstructive Sleep Apnea during the First Hour of Sleep. Healthcare, 11.","DOI":"10.3390\/healthcare11192701"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1016\/j.hrthm.2020.06.018","article-title":"Skin sympathetic nerve activity in patients with obstructive sleep apnea","volume":"17","author":"He","year":"2020","journal-title":"Heart Rhythm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00004691-199301000-00004","article-title":"New investigations of autonomic nervous system function","volume":"10","author":"Schondorf","year":"1993","journal-title":"J. Clin. Neurophysiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.sleep.2016.06.030","article-title":"Demonstration of sympathetic dysfunction in patients with obstructive sleep apnea syndrome by measuring sympathetic skin responses from the neck","volume":"25","author":"Korkmaz","year":"2016","journal-title":"Sleep Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s11325-019-01939-8","article-title":"Autonomic dysfunction in restless legs syndrome","volume":"24","author":"Erdal","year":"2020","journal-title":"Sleep Breath."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.sleep.2014.01.025","article-title":"What features differentiate unilateral from bilateral restless legs syndrome? A comparative observational study of 195 patients","volume":"15","author":"Shukla","year":"2014","journal-title":"Sleep Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101566","DOI":"10.1016\/j.smrv.2021.101566","article-title":"Peripheral arterial tonometry-PAT technology","volume":"61","author":"Schnall","year":"2022","journal-title":"Sleep Med. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"zsaa155","DOI":"10.1093\/sleep\/zsaa155","article-title":"Comparison between oral ferrous sulfate and intravenous ferric carboxymaltose in children with restless sleep disorder","volume":"44","author":"DelRosso","year":"2021","journal-title":"Sleep"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yu, L., Shu, L., Gao, S., and Li, L. (2025). CPAP improves sleep stability and attenuates acute nocturnal hypertension (NBPF) in OSA, with maximal benefits in severe cases. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1587127"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1097\/MCP.0000000000000319","article-title":"Obstructive sleep apnea during rapid eye movement sleep: Clinical relevance and therapeutic implications","volume":"22","author":"Alzoubaidi","year":"2016","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1080\/19390211.2024.2308262","article-title":"GABA Supplementation, Increased Heart-Rate Variability, Emotional Response, Sleep Efficiency and Reduced Depression in Sedentary Overweight Women Undergoing Physical Exercise: Placebo-Controlled, Randomized Clinical Trial","volume":"21","author":"Seidel","year":"2024","journal-title":"J. Diet. Suppl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.sleep.2010.03.019","article-title":"Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep","volume":"12","author":"Manconi","year":"2011","journal-title":"Sleep Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"294058","DOI":"10.1155\/2012\/294058","article-title":"The Effects of a Gentle Yoga Program on Sleep, Mood, and Blood Pressure in Older Women with Restless Legs Syndrome (RLS): A Preliminary Randomized Controlled Trial","volume":"2012","author":"Innes","year":"2012","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_42","first-page":"e82413","article-title":"Restless Legs and Iron Deficiency: Unraveling the Hidden Link and Unlocking Relief","volume":"17","author":"Alzaabi","year":"2025","journal-title":"Cureus"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.sleep.2004.01.012","article-title":"Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)","volume":"5","author":"Allen","year":"2004","journal-title":"Sleep Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Reid, B.M., and Georgieff, M.K. (2023). The Interaction between Psychological Stress and Iron Status on Early-Life Neurodevelopmental Outcomes. Nutrients, 15.","DOI":"10.3390\/nu15173798"},{"key":"ref_45","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_46","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.neuron.2024.12.009","article-title":"Anything but small: Microarousals stand at the crossroad between noradrenaline signaling and key sleep functions","volume":"113","author":"Nedergaard","year":"2025","journal-title":"Neuron"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1097\/HJH.0000000000002661","article-title":"Sympathetic nerve traffic overactivity in chronic kidney disease: A systematic review and meta-analysis","volume":"39","author":"Grassi","year":"2021","journal-title":"J. Hypertens."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"80","DOI":"10.5935\/1984-0063.20170015","article-title":"Heart rate variability in restless legs syndrome and periodic limb movements of Sleep","volume":"10","author":"Barone","year":"2017","journal-title":"Sleep Sci."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/539\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:33:15Z","timestamp":1779287595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/5\/539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["brainsci16050539"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16050539","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}