Thomas C. Wetter

Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome

BACKGROUND There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. METHODS Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. RESULTS The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. CONCLUSIONS This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patients life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.

A randomized controlled study of pergolide in patients with restless legs syndrome

Background: Open clinical trials indicate that low doses of pergolide, a long-acting D1 and D2 dopamine agonist, lead to a reduction in the symptoms of restless legs syndrome (RLS) with subjective improvement in sleep quality. Objective: To assess the therapeutic efficacy of pergolide in improving sleep and subjective measures of well-being in patients with idiopathic RLS using polysomnography and clinical ratings. Methods: In a randomized, double-blind, placebo-controlled crossover design we enrolled 30 patients with idiopathic RLS according to the criteria of the International RLS Study Group. All patients were free of psychoactive drugs for at least 2 weeks before the study. Patients were monitored using polysomnography, clinical ratings, and sleep diaries at baseline and at the end of a 4-week pergolide or placebo treatment period. The initial dosage of 0.05 mg pergolide was increased to the best subjective improvement paralleled by 20 mg domperidone tid. Results: At a mean dosage of 0.51 mg pergolide as a single daily dose 2 hours before bedtime, there were fewer periodic leg movements per hour of time in bed (5.7 versus 54.9, p < 0.0001), and total sleep time was significantly longer (373 versus 261 minutes, p < 0.0001). Ratings of subjective sleep quality, quality of life, and severity of RLS were improved significantly without relevant adverse events. Conclusion: Pergolide given as a single low-to-medium bedtime dose in combination with domperidone provides a well-tolerated and effective treatment of sensorimotor symptoms and sleep disturbances in patients with primary RLS.

Altered Processing of Acoustic Stimuli during Sleep: Reduced Auditory Activation and Visual Deactivation Detected by a Combined fMRI/EEG Study

Although there is evidence that acoustic stimuli are processed differently during sleep and wakefulness, little is known about the underlying neuronal mechanisms. In the present study, the processing of an acoustic stimulus was investigated during different non rapid eye movement (NREM) sleep stages using a combined EEG/fMRI approach in healthy human volunteers: A text stimulus was presented to sleep-deprived subjects prior to and after the onset of sleep, and single-slice silent fMRI were acquired. We found significantly different blood oxygenation level-dependent (BOLD) contrast responses during sleep compared to wakefulness. During NREM sleep stages 1 and 2 and during slow wave sleep (SWS) we observed reduced activation in the auditory cortex and a pronounced negative signal in the visual cortex and precuneus. Acoustic stimulation during sleep was accompanied by an increase in EEG frequency components in the low delta frequency range. Provided that neurovascular coupling is not altered during sleep, the negative transmodal BOLD response which is most pronounced during NREM sleep stages 1 and 2 reflects a deactivation predominantly in the visual cortex suggesting that this decrease in neuronal activity protects the brain from the arousing effects of external stimulation during sleep not only in the primary targeted sensory cortex but also in other brain regions.

Gray Matter-Changes and Correlates of Disease Severity in Schizophrenia: A Statistical Parametric Mapping Study

Voxel-based morphometry has recently been used successfully to detect gray matter volume reductions in schizophrenic patients. The aim of the present study was to confirm the findings on gray-matter changes and to complement these by applying the methodology to CSF-differences. Also, we wanted to determine whether a correlation exists between a clinically defined parameter of disease severity and brain morphology in schizophrenic patients. We investigated 48 schizophrenic patients and compared them with 48 strictly age- and sex-matched controls. High-resolution whole-brain MR-images were segmented and analyzed using SPM99. In a further analysis, the covariate effect of the global assessment of functioning-score (GAF) was calculated. Main findings were (i) left-dominant frontal, temporal, and insular GM-reductions and (ii) GM-increases in schizophrenic patients in the right basal ganglia and bilaterally in the superior cerebellum; (iii) CSF-space increases in patients complementary to some GM-reductions; (iv) a correlation between the GAF-score and local GM-volume in the left inferior frontal and inferior parietal lobe of schizophrenic patients. This study confirms and extends some earlier findings on GM-reduction and detected distinct GM-increases in schizophrenic patients. These changes were corroborated by complementary CSF-increases. Most importantly, a correlation could be established between two particular gray matter-regions and the overall disease severity, with more severely ill patients displaying a local GM-deficit. These findings may be of potentially large importance for both the future interpretation and design of neuroimaging studies in schizophrenia and the further elucidation of possible pathophysiological processes occurring in this disease.

Functional MRI during sleep : BOLD signal decreases and their electrophysiological correlates

Prominent local decreases in blood oxygenation level (BOLD) can be observed by functional magnetic resonance imaging (fMRI) upon acoustic stimulation during sleep. The goal of this study was to further characterize this BOLD signal decrease with respect to corresponding neurophysiological phenomena using a simultaneous electroencephalography (EEG)/fMRI approach in sleeping human subjects. Healthy volunteers were subjected to acoustic stimulation during non‐rapid eye movement (NREM) sleep. On the basis of statistical parametric maps, the correlations between the fMRI response (both amplitude and extent of the BOLD response) and the concomittant changes in the EEG (delta power and K‐complexes) were calculated. Amplitude and extent of the stimulus‐induced negative BOLD effect correlated positively with measures of EEG synchronization, namely an increase in the number of K‐complexes and EEG delta power. Stimulus‐induced BOLD decreases were most prominent during light (stage 2) NREM sleep and disappeared during slow wave sleep, indicating an influence of the baseline degree of hyperpolarization. Our observations provide first evidence that ‘negative’ BOLD signal changes during human sleep are associated with electrophysiological indicators of altered neuronal activity. Increased number of K‐complexes and delta power reflecting hyperpolarization suggests true cortical deactivation upon stimulus presentation. This sleep stage‐dependent deactivation might serve to protect the brain from arousing stimuli, particularly during the light phases of sleep shortly after sleep onset.

Functional microstates within human REM sleep : first evidence from fMRI of a thalamocortical network specific for phasic REM periods

High thalamocortical neuronal activity characterizes both, wakefulness and rapid eye movement (REM) sleep, but apparently this network fulfills other roles than processing external information during REM sleep. To investigate thalamic and cortical reactivity during human REM sleep, we used functional magnetic resonance imaging with simultaneous polysomnographic recordings while applying acoustic stimulation. Our observations indicate two distinct functional substates within general REM sleep. Acoustic stimulation elicited a residual activation of the auditory cortex during tonic REM sleep background without rapid eye movements. By contrast, periods containing bursts of phasic activity such as rapid eye movements appear characterized by a lack of reactivity to sensory stimuli. We report a thalamocortical network including limbic and parahippocampal areas specifically active during phasic REM periods. Thus, REM sleep has to be subdivided into tonic REM sleep with residual alertness, and phasic REM sleep with the brain acting as a functionally isolated and closed intrinsic loop.

The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects

Aging is associated with a dramatic decrease in slow wave sleep (SWS) and sleep consolidation. Previous studies revealed that various GABA(A) agonists and the GABA uptake inhibitor tiagabine augment slow frequency components in the EEG within non-REM sleep, and thus promote deep sleep in young individuals and/or rats. In the present double-blind, placebo-controlled study, we assessed the effect of a single oral dose of 5 mg tiagabine on nocturnal sleep in ten healthy elderly volunteers (6 females). During the placebo night the subjects displayed a low sleep efficiency, due to high amounts of intermittent wakefulness, and little SWS. Tiagabine significantly increased sleep efficiency, tendentially decreased wakefulness and prominently increased both SWS and low-frequency activity in the EEG within non-REM sleep. The present findings demonstrate that tiagabine increases sleep quality in aged subjects. Moreover, the effects of tiagabine closely match those evoked by the GABA(A) agonist gaboxadol in young subjects and indicate that such compounds may have prospects in the treatment of sleep disturbances, particularly of those commonly occurring in the elderly.

Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients.

Background: The restless legs syndrome (RLS) is a common sensomotor disorder associated with severe sleep disturbances. Symptoms clearly improve following treatment with dopaminergic or opioidergic agonists.Objective: To further elucidate the involvement of opioidergic and dopaminergic mechanisms in the pathophysiology of RLS, the effects of specific antagonists on motor (periodic leg movements) and subjective (sensory) RLS-symptoms during daytime were assessed.Methods: A modified suggested immobilization test was performed in eight drug-naive RLS-patients. An infusion of either naloxone, metoclopramide or placebo was administered. In addition, the hormonal levels of adrenocorticotropic hormone, cortisol, prolactin and growth hormone were determined, to elucidate a possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) system in RLS.Results: RLS sensory or motor symptoms could not be provoked. Hormonal responses showed no abnormal profiles.Conclusions: Rather than a general alteration of the opioidergic/dopaminergic tone and an involvement of the HPA system, it is more likely that specific neuronal dopaminergic or opioidergic pathways are altered in the pathophysiology of RLS.

Rapid eye movement-related brain activation in human sleep: a functional magnetic resonance imaging study.

In animal models, ponto-geniculo-occipital waves appear as an early sign of rapid eye movement sleep and may be functionally significant for brain plasticity processes. In this pilot study, we use a combined polysomnographic and functional magnetic resonance imaging approach, and show distinct magnetic resonance imaging signal increases in the posterior thalamus and occipital cortex in close temporal relationship to rapid eye movements during human rapid eye movement sleep. These findings are consistent with cell recordings in animal experiments and demonstrate that functional magnetic resonance imaging can be utilized to detect ponto-geniculo-occipital-like activity in humans. Studying intact neuronal networks underlying sleep regulation is no longer confined to animal models, but has been shown to be feasible in humans by a combined functional magnetic resonance imaging and electroencephalograph approach.

Increased sleep pressure reduces resting state functional connectivity

ObjectIn humans, even a single night of partial sleep deprivation (PSD) can have a negative impact on cognition and affective processing, suggesting that sleep pressure represents a basic physiological constraint of brain function. Among the spontaneously fluctuating resting state networks, the default mode network (DMN) and its anticorrelated network (ACN) hold key functions in segregating internally and externally directed awareness. Task fMRI after sleep deprivation has revealed altered activation patterns in both networks. We hypothesized that effects of PSD in these intrinsically coupled networks can be detected by resting state fMRI.MethodsWe obtained 6-minute echoplanar imaging time series (1.5 Tesla) during eyes-closed, wakeful-resting experiments from 16 healthy volunteers after normal sleep and after PSD. We used independent component and cross-correlation analysis to study functional connectivity (fc), focusing on the DMN and ACN.ResultsAfter PSD, focal reductions of auto-correlation strength were detected in the posterior and anterior midline node of the DMN and in the lateral parietal and insular nodes of the ACN. Cross-correlation analysis confirmed reduced cortico-cortical connectivity within and between the DMN and ACN.ConclusionsIncreased sleep pressure is reflected in reduced fc of main DMN and ACN nodes during rest. Results have implications for understanding perceptual and cognitive changes after sleep deprivation and are relevant to clinical studies on conditions in which increased sleep propensity is present.