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Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat.

ABSTRACT: In this study we uncovered, through targeted ablation, a potential role for corticospinal, cerebello-rubro-spinal, and hypothalamic A11 dopaminergic systems in the development of restless legs syndrome (RLS)-like movements during sleep. Targeted lesions in select basal ganglia (BG) structures also revealed a major role for nigrostriatal dopamine, the striatum, and the external globus pallidus (GPe) in regulating RLS-like movements, in particular pallidocortical projections from the GPe to the motor cortex. We further showed that pramipexiole, a dopamine agonist used to treat human RLS, reduced RLS-like movements. Taken together, our data show that BG-cortico-spinal, cerebello-rubro-spinal and A11 descending projections all contribute to the suppression of motor activity during sleep and sleep-wake transitions, and that disruption of these circuit nodes produces RLS-like movements. Taken together with findings from recent genomic studies in humans, our findings provide additional support for the concept that the anatomic and genetic etiological bases of RLS are diverse.

SUBMITTER: Guo CN

PROVIDER: S-EPMC5575019 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat.

Guo Chun-Ni CN Yang Wen-Jia WJ Zhan Shi-Qin SQ Yang Xi-Fei XF Chen Michael C MC Fuller Patrick M PM Lu Jun J

Scientific reports 20170829 1

In this study we uncovered, through targeted ablation, a potential role for corticospinal, cerebello-rubro-spinal, and hypothalamic A11 dopaminergic systems in the development of restless legs syndrome (RLS)-like movements during sleep. Targeted lesions in select basal ganglia (BG) structures also revealed a major role for nigrostriatal dopamine, the striatum, and the external globus pallidus (GPe) in regulating RLS-like movements, in particular pallidocortical projections from the GPe to the mo ...[more]

PMID: 28852150

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Project description:Background: Restless legs syndrome (RLS) affects approximately 30% of patients with end-stage kidney disease and is associated with impaired sleep and health-related quality of life. Medications used to treat RLS in patients receiving dialysis may have an increased risk of adverse events with dose titration, and residual RLS symptoms are common despite the use of effective treatments. Randomized controlled trials of monotherapy and combination pharmacologic therapy for RLS in hemodialysis are needed.Objective: To perform a randomized, crossover, placebo-controlled blinded trial of pharmacologic therapy for RLS in hemodialysis.Design/setting: The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) trial is a randomized, crossover, placebo-controlled blinded trial of fixed low-dose pharmacologic therapy in patients receiving hemodialysis in 10 centers across Canada. It uses patient partners in its design, conduct, and reporting.Participants: Adults receiving thrice-weekly hemodialysis for at least 3 months with RLS of at least mild symptoms defined International Restless Legs Syndrome Study Group Rating Scale (IRLS) of 10 or more will enter a double placebo run-in period to exclude nonadherent participants and those unable to tolerate double placebo. Seventy-two participants who completed the run-in period will be randomized to 1 of 8 treatment sequences based on modeling with 4 treatment periods.Methods: Each treatment period lasts 4 weeks and consists of ropinirole 0.5 mg daily and gabapentin 100 mg daily, both together or neither with a double dummy placebo control for each treatment. The primary outcome is the difference in change scores of the IRLS between study treatments. Secondary outcomes are the differences in change scores of the Restless Legs Syndrome-6 Scale, patient global impression, 5-level EQ-5D version, and safety outcomes.Results: This randomized, crossover, placebo-controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination of ropinirole and gabapentin in patients receiving hemodialysis with RLS.Limitations: Patients with chronic kidney disease not on dialysis, kidney transplant recipients and those receiving peritoneal dialysis or home hemodialysis are not included. The intervention's long term safety and efficacy including the risk of augmentation is not captured.Conclusion: This randomized crossover placebo controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination ropinirole and gabapentin in patients receiving hemodialysis with RLS.Trial registration: ClinicalTrials.gov (NCT03806530).

Dataset Information

Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat.

Publications

Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat.

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