Glutamate, Hyperarousal and Restless Legs Syndrome

NCT01675323 | Completed

• 1 other identifier: NA_00073951
• Study Type: observational
• Target: 77
• Locations: 1 country
• Sites: 2

Brief Summary

Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of RLS.This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features.

Conditions

Restless Legs Syndrome

Keywords

Restless Legs Syndrome; RLS

Outcome Measures

Primary Outcomes (2)

• MR Spectroscopy - Glutamate

  Study of thalamic glutamate levels in the brain using MR Spectroscopy

  2nd Day of Phase 2

• MR Spectroscopy - GABA

  Study of thalamic GABA levels in the brain using MR Spectroscopy

  2nd Day of Phase 2

Study Arms (2)

RLS Patients

Participants who have diagnosed RLS with diagnosis confirmed by study investigators.

Healthy Controls

Participants without RLS who are generally healthy and matched for gender, age, educational level, and race to patients in the RLS group.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Subjects with RLS and healthy subjects, 18 years of age or older, matched for age, gender, race, and educational level. Both men and women will be included.

You may qualify if:

• All subjects
• years or older
• Normal mental status and able to give informed consent.
• Regular sleep times start between 21:00 and 01:00 5 out of 7 days a week
• General good health and ambulatory
• RLS patients
• Diagnosis of primary RLS confirmed by the PI or Dr. Earley
• History indicating if RLS symptoms were not treated, thy would for the last 6 months
• Occur at least 5 out of 7 days a week
• Almost always disrupt sleep
• For phase 2 admission to the Clinical Research Unit: Home screening on a clinical log shows RLS symptoms for at least 5 of 7 days, IRLS score at the end of home monitoring ≥ 15 and PAM-RL measures show average PLMS/hr ≥15.
• Control subjects
• No history of any of the 4 essential criteria for diagnosis of RLS (1).
• For phase 2 admission to the Clinical Research Unit: Home screening on the PAM-RL indicates average PLMS/hr ≤ 10 and the sleep-wake log shows regular times in bed between 21:00 and 01:00 bed times with 6.0 to 10.0 hours in bed for 5 out of for 7 nights.

You may not qualify if:

• All subjects
• Major mental history as determined by history
• Clinically significant sleep apnea on prior PSG or on screening first night PSG (apnea/hypopnea rate \>15/hr).
• Any medical or neurological disorder other than RLS likely to compromise normal sleep, interfere with interpretation of results, or would place the subject at risk when participating in the study (e.g. Chronic pain, dementia, ALS, stroke, MS, untreated thyroid).
• Any use of DA antagonists for more than one week in the past 6 months, other than for nausea.
• Women who are pregnant or lactating or at risk for getting pregnant (not using appropriate birth control nor post-menopausal).
• Failure to have clear hand dominance, ambidextrous as assessed by the Edinburgh Handedness Inventory (Could influence outcomes on TMS).
• Musicians and professional typists (Might influence performance on TMS measure)
• A significant neurological disorder (such as stroke, Parkinson's Disorder, Multiple Sclerosis) that could impair fine motor performance.
• Metal in the body (e.g., pacemakers, implantable pumps, stimulators, orthodontics, etc) that would cause problems for the MRI or TMS.
• Medication use that would alter sleep including any GABA active medications and any anti- depressants or other significant psychiatric medications or medications that would affect Glu.
• History of claustrophobia or problems with closed MRI scans not resolved.
• History of vertigo, seizure disorder, middle-ear disorder, or double vision.
• Body size not compatible with using T7 MRI.
• RLS patients

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institutes of Health (NIH): collaborator

Study Sites (2)

Johns Hopkins Baview Medical

Baltimore, Maryland, 21224, United States

Location

Johns Hopkins Bayview Medical Campus

Baltimore, Maryland, 21224, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood and urine (female participants only)

MeSH Terms

Conditions

Restless Legs Syndrome

Condition Hierarchy (Ancestors)

Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Parasomnias; Mental Disorders

Study Officials

• Richard Allen, Ph.D.

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Associate, Department of Neurology

Study Record Dates

• First Submitted: August 27, 2012
• First Posted: August 29, 2012
• Study Start: August 1, 2012
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: March 1, 2017

Record last verified: 2017-02

Locations

US (2)