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Background: High‐frequency, repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex (DLPFC) is widely used in research to promote neuroplasticity and cognitive enhancement. RTMS is a promising intervention to tackle cognitive decline in people living with age‐related neurodegenerative diseases. However, there is currently no systematic evidence examining the effects of DLPFC‐targeted, high‐frequency rTMS on cognitive function in this population. The aim of this systematic review was to evaluate the efficacy and moderators of this treatment intervention. Method: A comprehensive literature search of five electronic databases was performed to identify articles published before October, 2022. Following PRISMA guidelines, the identified articles were screened, data was extracted, and the methodological quality was assessed using the Cochrane tool, Risk of Bias 2 (ROB2). Meta‐analyses were performed using R Studio (v4.1.2). Result: Sixteen studies involving 474 participants met the inclusion criteria, of which 8 studies measured global cognitive function. The results from the random‐effects meta‐analysis showed rTMS significantly improved global cognitive function relative to control groups shown by a large, significant effect size (g = 1.39, 95% CI, 0.34‐2.43; p =.017). No significant effects were found between subgroups or for individual cognitive domains. Conclusion: High‐frequency rTMS, targeted over the DLPFC, appears to improve global cognitive function in people living with age‐related neurodegenerative diseases. However, these results should be interpreted with caution due to the small number of studies included, and high between‐study heterogeneity. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self‐reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features—in the absence of a face‐to‐face interview—was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS‐like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep‐state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS‐like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

In this study, we aim to automate the sleep stage scoring process of overnight polysomnography (PSG) data while adhering to expert‐based rules. We developed a sleep stage scoring algorithm utilizing the generalized linear modelling (GLM) framework and extracted features from electroencephalogram (EEG), electromyography (EMG) and electrooculogram (EOG) signals based on predefined rules of the American Academy of Sleep Medicine (AASM) Manual for Scoring Sleep. Specifically, features were computed in 30‐s epochs in the time and frequency domains of the signals and were then used to model the probability of an epoch being in each of five sleep stages: N3, N2, N1, REM or Wake. Finally, each epoch was assigned to a sleep stage based on model predictions. The algorithm was trained and tested on PSG data from 38 healthy individuals with no reported sleep disturbances. The overall scoring accuracy reached on the test set was 81.50 ± 1.14% (Cohen's kappa, κ=0.73±0.02). The test set results were highly comparable to the training set, indicating robustness of the algorithm. Furthermore, our algorithm was compared to three well‐known commercialized sleep‐staging tools and achieved higher accuracies than all of them. Our results suggest that automatic classification is highly consistent with visual scoring. We conclude that our algorithm can reproduce the judgement of a scoring expert and is also highly interpretable. This tool can assist visual scorers to speed up their process (from hours to minutes) and provides a method for a more robust, quantitative, reproducible and cost‐effective PSG evaluation, supporting assessment of sleep and sleep disorders. [ABSTRACT FROM AUTHOR]

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2 δ ligands (gabapentin).Methods: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate.Results: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole.Interpretation: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951-960. [ABSTRACT FROM AUTHOR]

Background The exact genetic causes within each of the known restless legs syndrome ( RLS) loci are still unknown. Recently, it was suggested that an intronic protein tyrosine phosphatase, receptor type δ ( PTPRD) single-nucleotide polymorphism ( SNP) (reference SNP no. rs2381970) is associated with its expression, which may lead to RLS and other related phenotypes. Another study identified 3 nonsynonymous PTPRD variants in familial RLS cases: p.Q447E (a residue change from glutamine to glutamic acid at position 447), p.T781A (a residue change from threonine to alanine at position 781), and p.R995C (a residue change from arginine to cysteine at position 995). Methods Two cohorts of sporadic RLS, a French-Canadian cohort and a cohort from the United States, with a total of 577 patients and 455 controls, and an additional familial RLS cohort with a total of 635 individuals (140 families) were genotyped for these 4 variants (rs2381970, p.Q447E, p.T781A, and p.R995C) by using specific TaqMan probes, and the effects of each variant as well as haplotypes were analyzed. Results None of the 4 PTPRD-specific variants or haplotypes that were tested were associated with RLS in the case-control cohorts or in the familial cohort. The frequencies of the rs2381970 variant in the French-Canadian and US cohorts were 0.07 and 0.04, respectively, and their frequencies in the respective control populations were 0.06 and 0.04, respectively ( P > 0.4 for both). Similar results were obtained for the 3 nonsynonymous variants. Conclusions Although the PTPRD gene is well established as an RLS-associated locus, the rs2381970 SNP and the 3 nonsynonymous PTPRD variants are not likely to cause or affect the risk for developing RLS in the study population. More studies in other populations are needed to determine their potential role in RLS. [ABSTRACT FROM AUTHOR]

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score ≥ 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo ( P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were −4.5 (95% CI: −6.9, −2.2) for 2 mg/24 hr rotigotine, −5.2 (95% CI: −7.5, −2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 −0.65 (95% CI: −1.0, −0.3) and −0.9 (95% CI: −1.3, −0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level-I trials were included in the efficacy tables; if no Level-I trials were available then Level-II trials were included or, in the absence of Level-II trials, Level-III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end-stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

While the restless legs syndrome (RLS) may have been known in antiquity, it has only recently come to medical attention. Individuals with RLS fall along a spectrum from mild, infrequent symptoms to those with severe daily life-impairing discomforts and sleep disruption. These problems can cause impaired mood, daytime fatigue, cognitive difficulties, and inability to participate in a variety of quiet activities. This leads to a general reduction in quality of life similar to other significant psychiatric and medical disorders. Recent studies suggest that RLS may be a risk factor for developing both psychiatric disorders (such as major depression and anxiety) and somatic diseases (such as hypertension and cardiovascular disease). In dialysis patients, RLS has been found to be a risk factor for mortality. Therefore, those with RLS who have clinically significant symptoms suffer increased morbidity and are at risk for impaired long-term medical outcomes. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The impressive relief from restless legs syndrome (RLS) symptoms provided by levodopa treatment indicates RLS is caused by a dopaminergic abnormality. But similar and more lasting relief also occurs for iron treatment in some patients. Thus there are two major putative causes for RLS: CNS dopaminergic abnormality and CNS iron insufficiency. This article presents the data documenting that both peripheral and CNS iron insufficiency occur with RLS symptoms. Brain iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without iron deficiency (ID) anemia. Autopsy studies and intravenous iron treatment further link brain iron insufficiency to RLS. The brain iron insufficiency in patients with RLS is now well established. In this article the data are reviewed that support the following postulates combining dopaminergic and iron causes of RLS: (1) All conditions that compromise iron availability will increase the risk of RLS leading to a higher than expected prevalence of RLS in these conditions. (2) Some patients with RLS have marginal CNS iron status that can become insufficient when deprived of normal access to adequate peripheral iron or may be insufficient even with normal access to adequate peripheral iron. (3) The change or reduced CNS iron status produces RLS symptoms largely through its effects on the dopaminergic system and the corollary to 3. (4) Dopaminergic system abnormalities producing RLS symptoms will be included in those produced by brain ID. Study of the iron model of RLS offers hope for developing new treatment approaches and perhaps methods to prevent or cure the disorder. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The Restless Legs Syndrome (RLS) is a sensorimotor disorder that has only recently been extensively investigated by validated methods. Following the first presentation of diagnostic criteria by the International RLS Study Group in 1995, several methods were specifically developed for clinical trials in RLS or adapted from other areas of medicine and health sciences. We present a critical overview on validated methods to assess (1) severity of RLS symptoms [International RLS Rating Scale (IRLS), John Hopkins RLS Severity Scale (JHRLSSS), the RLS-6 scales, and the investigtor-based Clincial Global Impressions (CGI)]; (2) quality of life [RLS Quality of Life Instrument (RLS-QLI), Hopkins RLS Quality of Life Questionnaire (RLSQoL), and the RLS Quality of Life Questionnaire (QoL-RLS)]; (3) sleep disturbances and sudden onset of sleep; (4) sleep laboratory methods (polysomnography, limb activity monitoring by actigraphy) to evaluate sleep and periodic leg movements (including the 'suggested immobilization test'); and (5) severity of augmentation (Augmentation Severity Rating Scale, ASRS). It is concluded that several validated methods are available to investigate the main features of RLS in practice and in clinical trials; however, further developments are needed to address new questions like the consequences of RLS on life functioning in areas such as ability to travel, days missed at work or impaired work performance. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Augmentation constitutes the main complication of long-term dopaminergic treatment in restless legs syndrome (RLS). Although this condition was first described in 1996, and is characterized by an overall increase in severity of RLS symptoms (including earlier onset of symptoms during the day, faster onset of symptoms when at rest, expansion to the upper limbs and trunk, and shorter duration of the treatment effect), precise diagnostic criteria were not established until 2003. These criteria have recently been updated to form a new definition of augmentation based on multicentric studies. The present article reviews our current knowledge on clinical diagnosis, evaluation, pathophysiology, and treatment recommendations for this condition. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a clinical diagnosis based primarily on self-reports of individuals. The International RLS Study Group has published diagnostic criteria that are essential for an operational diagnosis of RLS; further clinical features are considered by the group supportive for or associated with RLS. However, sensitivity and specificity are not perfect and 'mimics' of RLS have been reported, i.e., other conditions like nocturnal cramps sometimes can appear to fulfill the essential diagnostic criteria indicating the need for more thorough understanding of the diagnostic criteria and better differential diagnoses. To contribute to the accuracy of diagnostic processes in RLS, we recapitulate the definition of RLS as an urge to move focused on the legs (and arms in some patients). This urge to move often but not always occurs together with dysesthesia, i.e. unpleasant abnormal sensations appearing without any apparent sensory stimulation. The urge to move and any accompanying dysesthesia must be engendered by rest, relieved by movement and worse in the evening or night. Succinctly, RLS can be summarized in medical terminology as a 'movement-responsive quiescegenic nocturnal focal akathisia usually with dysesthesias.' Empirical approaches to investigate the independence of the essential criteria 'worsening at night' and 'worsening at rest' are reported. Possible differential diagnoses of RLS are discussed under the perspective of the NIH diagnostic criteria of RLS. Standardized methods to assess a RLS diagnosis are presented which might improve differential diagnosis and in general the reliability and validity of RLS diagnosis. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The European Restless Legs Syndrome (RLS) Study Group (EURLSSG) is an association of European RLS experts who are actively involved in RLS research. A major aim of the Study Group is the development and continuous improvement of standards for diagnosis and treatment of RLS. Several members developed study designs and evaluation methods in investigator-initiated trials early in the 1990s, and all members have since contributed to many pivotal and nonpivotal drug trials for the treatment of RLS. The recommendations on clinical investigations of pharmacological treatment of RLS patients summarize the group's expertise and knowledge acquired through clinical trials. The recommendations primarily address how to plan and conduct confirmatory, randomized clinical studies in patients with idiopathic RLS. Advice is presented for the diagnosis of RLS and clinical and polysomnographic inclusion and exclusion criteria. Primary and secondary endpoints for an evaluation of efficacy are based on a critical description of validated methods for both short- and long-term trials, also in special populations (children, pregnant women, elderly patients). The recommendations include the assessment of augmentation. Finally, general issues including the evaluation of safety and tolerability, as well as specific neurological and cardiovascular risks and sleep attacks/daytime somnolence, are discussed. The aim of these recommendations is to support research groups or pharmaceutical companies in the design of optimized study protocols. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

We evaluated rest effects on restless legs syndrome (RLS) sensory and motor symptoms. During two 60-minute Suggested Immobilization Tests (SIT) subject's signals of RLS leg sensations and periodic leg movements while awake (PLMW) were recorded. Sensations, PLMW, sensations preceding or after PLMW, sensations occurring without following PLMW, and PLMW occurring without preceding sensation were determined. The RLS patients were divided into equal-sized high and low PLMW groups for further analysis. Data from 46 subjects (28 RLS and 18 controls) revealed sensations increased linearly with rest in RLS patients and controls. Movement rate increased linearly with rest for controls but increased rapidly for the first 45 minutes for all RLS patients. PLMW/hour increased with further rest for low but not high PLMW patients. Sensations followed by PLMW and PLMW without preceding sensations followed similar patterns. Sensations without subsequent PLMW increased dramatically in the last 15 minutes of the SITs. Whereas both sensory and motor signs of RLS increase with rest, there is minimal increase for controls. Patients with higher but not lower PLMW rates reached a ceiling for PLMW after 35 to 40 minutes. The temporal dissociation between sensory and motor events supports viewing these motor and sensory events as separate but loosely linked manifestations of RLS. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The article presents a study to evaluate the impacts on recovery progress of the people and property involved in recovery plan development and implementation. It examines the jurisdiction over the habitat of endangered species in the U.S. Results of the study recommend that species on federal lands may benefit from less division of labor among jurisdictional agencies in the nation.

Midazolam (15 mg) was compared with temazepam (30 mg) in a randomized, double-blind, parallel group study. An initial screening period was followed by 3 days of placebo baseline, 4 to 12 weeks of nightly oral use of the medication and a 4-day placebo withdrawal period. One hundred seventy-five patients with chronic insomnia participated in this multicenter outpatient study. Because the elimination half-life of midazolam, a new trizolobenzodiazepine hypnotic, is short (1.3-2.2 hr) compared to temazepam's (12-16 hr), more problems with tolerance and rebound insomnia were expected to occur. Hypnotic efficacy (increased total sleep time, decreased wake time, and decreased sleep latency) was demonstrated for both medications over the entire 3-month period without the development of tolerance, In fact, if anything, efficacy increased with time on medication, suggesting possible facilitation or 'inverse tolerance' effect. On withdrawal, sleep was improved compared with baseline, suggesting partial resolution of the insomniac condition rather than rebound insomnia. These effects were both statistically and clinically significant for midazolam, with 16% to 50% improvement in sleep measures. The results of this study suggest that patients with chronic insomnia may benefit from 30 to 90 days of treatment. A three-factor model that separates pharmacologic from behavioral and psychologic effects of hypnotics was proposed to explain these results in part. [ABSTRACT FROM AUTHOR]

The author talks about organ donation rates and transplantation in Australia, discussing the need for improvement in it, an article on this topic in the issue, and the donation after circulatory death (DCD).

The article describes a clinical test for detecting defects of cingulate lesions in man. Bilateral anterior cingulotomies that use stereotaxic techniques have been performed on man for relief of psychic stress and intractable pain. Until recently, there was no indication of any cognitive impairments in man consequent to this operation. The animal 1iterature, however, indicated that for rats cingulate lesions severely disrupted time-dependent sequential behavior. It was possible to develop a clinical test based upon the animal findings and use this test to evaluate the cognitive effects of cingulotomies on a small group of patients at Baltimore City Hospitals.

A single-channel method of recording eye movements, using two active electrodes, is described. Illustrations are presented of its accuracy, efficiency, and degree of common-mode rejection. The method appears to offer advantages in possible computer scoring of eye-movement data, as well as improvements in speed and accuracy of hand-scoring such data. [ABSTRACT FROM AUTHOR]

Restless Legs Syndrome (RLS) is a sensory motor disorder that is thought to affect 5-10% of the population. Symptoms include an urge to move the extremities, usually the legs, often accompanied by uncomfortable dysesthesias or paresthesias, which occur primarily during the evening hours. Recent autopsy evidence suggests that iron homeostasis in the brain is altered in RLS. This dysregulation has been linked to the iron regulatory proteins (IRPs), specifically IRP1. The objective of this study was to examine if a peripheral lymphocytes reflect the iron protein profile abnormalities that were observed in the autopsy brain studies of RLS patients. RLS lymphocytes reflect an iron-depleted protein profile (decreased H-ferritin, and increased transferrin, transferrin receptor, and divalent metal transporter 1) relative to the controls. Ferroportin, which transports iron from the cell, is also increased, a finding which is counterintuitive to intracellular iron insufficiency. Hypoxia was explored as a mechanism to explain these divergent results. RLS primary lymphocytes were found to have increased nuclear hypoxia inducible factor (HIF)-1α activity as well as increased erythropoietin (EPO) immunoreactivity. Based on these findings, we conclude that both iron and HIF-1α may have a role in the molecular mechanism of RLS. [ABSTRACT FROM AUTHOR]