Rachel E. Salas

Update in restless legs syndrome

PURPOSE OF REVIEW Although restless legs syndrome (RLS) is a disorder recognized in the medical literature since the 17th century, there have only recently been significant clinical and scientific advances in diagnosis, epidemiology and understanding the disorder, mainly due to the advent of dopaminergic treatment. RECENT FINDINGS Recent discoveries have uncovered the iron-dopamine connection in RLS and the basic dopaminergic pathology related to the RLS symptoms. These have led to new understanding of the morbidity of RLS and the many conditions associated with RLS, which have also supported new approaches to treatment. These developments are each briefly described here. SUMMARY Although there has been progress in understanding, diagnosing and treating RLS, it remains an underdiagnosed and undertreated condition severely impairing functioning of patients with moderate-to-severe disease. Much work is needed to improve on current, as well as other novel therapies.

Motor Learning Interference Is Proportional to Occlusion of LTP-Like Plasticity

Learning interference occurs when learning something new causes forgetting of an older memory (retrograde interference) or when learning a new task disrupts learning of a second subsequent task (anterograde interference). This phenomenon, described in cognitive, sensory, and motor domains, limits our ability to learn multiple tasks in close succession. It has been suggested that the source of interference is competition of neural resources, although the neuronal mechanisms are unknown. Learning induces long-term potentiation (LTP), which can ultimately limit the ability to induce further LTP, a phenomenon known as occlusion. In humans we quantified the magnitude of occlusion of anodal transcranial direct current stimulation-induced increased excitability after learning a skill task as an index of the amount of LTP-like plasticity used. We found that retention of a newly acquired skill, as reflected by performance in the second day of practice, is proportional to the magnitude of occlusion. Moreover, the degree of behavioral interference was correlated with the magnitude of occlusion. Individuals with larger occlusion after learning the first skill were (1) more resilient to retrograde interference and (2) experienced larger anterograde interference when training a second task, as expressed by decreased performance of the learned skill in the second day of practice. This effect was not observed if sufficient time elapsed between training the two skills and LTP-like occlusion was not present. These findings suggest competition of LTP-like plasticity is a factor that limits the ability to remember multiple tasks trained in close succession.

Increased synaptic dopamine in the putamen in restless legs syndrome

STUDY OBJECTIVES Prior studies using positron emission tomography (PET) or single-photon emission computed tomography techniques have reported inconsistent findings regarding differences between patients with restless legs syndrome (RLS) and control patients in the striatal dopamine-2 receptor (D2R) binding potentials (BP). D2R-BP does reflect receptor-ligand interactions such as receptor affinity (K(d)) and density (β(max)) or neurotransmitter synaptic concentrations. Thus, differences in D2R-BP reflect changes in these primary factors. PET techniques are currently available to estimate D2R β(max) and K(d). DESIGN Separate morning and evening PET scans were performed. The D2R-BP were measured in basal ganglia using [(11)C]raclopride. SETTING Academic medical center. PATIENTS OR PARTICIPANTS Thirty-one patients with primary RLS and 36 age- and sex-matched control patients completed the study. MEASURES AND RESULTS Patients with RLS had lower D2R-BP in putamen and caudate but not the ventral striatum. A subgroups analysis of those RLS patients who had not previously taken dopaminergic medications continued to show a significantly lower D2R-BP in the posterior putamen. D2R-BP did not differ between night and day for either group. D2R β(max) and K(d) did not differ significantly between patients with RLS and control patients but did show a strong and significant increase at night in the ventral striatum. Primary and secondary clinical measures of disease status failed to show any relation to D2R in any brain region. CONCLUSIONS Given the lack of any difference in either β(max) or K(d) and the prior studies supporting an increase in presynaptic dopaminergic activity, the current changes found in D2R-BP likely reflect an increase in synaptic dopamine.

Evaluating sleep and cognition in HIV

Objective:To examine the relationship between measures of sleep quality and cognitive performance in HIV-positive individuals stable on combination antiretroviral therapy. Design:Multimethod assessments of sleep quality, patterns, and cognitive performance were assessed in a predominantly black HIV-positive cohort. Methods:Sleep quality and patterns were characterized in 36 subjects by polysomnogram, 2-week actigraphy monitoring, and validated sleep questionnaires. Cognitive performance was assessed with a battery of neuropsychological tests. Results:The majority of participants were cognitively impaired [based on Frascati (75%) criteria]. Self-reported mean scores on the Pittsburgh sleep quality index and the insomnia severity scale suggested poor sleep quality. Better cognitive performance, particularly on tasks of attention, frontal/executive function, and psychomotor/motor speed, was associated with polysomnogram sleep indices (ie, reduced wake after sleep onset, greater sleep efficiency, greater sleep latency, and greater total sleep time). Thirty-seven percent of participants had sleep patterns suggestive of chronic partial sleep deprivation, which was associated with significantly worse performance on the digit symbol test (P = 0.006), nondominant pegboard (P = 0.043), and verbal fluency tests (P = 0.044). Conclusions:Our results suggest that compromised sleep quality and duration may have a significant impact on cognitive performance in HIV-positive individuals. Future studies are warranted to determine the utility of sleep quality and quantity indices as potential predictive biomarkers for development and progression of future HIV-associated neurocognitive disorder.

Sleep Medicine Pharmacotherapeutics Overview: Today, Tomorrow, and the Future (Part 1: Insomnia and Circadian Rhythm Disorders)

Over the past 10 years, significant strides have been made in the understanding, development, and availability of sleep disorder therapeutics. In this review series, we discuss the current evidence surrounding the mechanisms of actions, indications, efficacy, and adverse side effects associated with the available armamentarium of sleep over-the-counter and pharmacotherapeutics. This article is the first of a two-part series that covers the therapeutics for insomnia and circadian rhythm disorders.

All the wrong moves: a clinical review of restless legs syndrome, periodic limb movements of sleep and wake, and periodic limb movement disorder

Restless legs syndrome, periodic limb movements in sleep, and periodic limb movement disorder are a group of conditions that merit awareness from the medical community. These disorders are commonly encountered yet are often confused and misdiagnosed by health care professionals. It is imperative that health care providers are able to recognize these conditions to accurately diagnose, manage, and appropriately refer patients.

Disrupting the ventral premotor cortex interferes with the contribution of action observation to use-dependent plasticity

Action observation (AO), observing another individual perform an action, has been implicated in several higher cognitive processes including forming basic motor memories. Previous work has shown that physical practice (PP) results in cortical motor representational changes, referred to as use-dependent plasticity (UDP), and that AO combined with PP potentiates UDP in both healthy adults and stroke patients. In humans, AO results in activation of the ventral premotor cortex (PMv), however, whether this PMv activation has a functional contribution to UDP is not known. Here, we studied the effects disruption of PMv has on UDP when subjects performed PP combined with AO (PP + AO). Subjects participated in two randomized crossover sessions measuring the amount of UDP resulting from PP + AO while receiving disruptive (1 Hz) TMS over the fMRI-activated PMv or over frontal cortex (Sham). We found that, unlike the sham session, disruptive TMS over PMv reduced the beneficial contribution of AO to UDP. To ensure that disruption of PMv was specifically interfering with the contribution of AO and not PP, subjects completed two more control sessions where they performed only PP while receiving disruptive TMS over PMv or frontal cortex. We found that the magnitude of UDP for both control sessions was similar to PP + AO with TMS over PMv. These findings suggest that the fMRI activation found in PMv during AO studies is functionally relevant to task performance, at least for the beneficial effects that AO exerts over motor training.

Normal Sleep and Circadian Processes

The onset of sleep is associated with a variety of changes in both behavioral and physiologic states. Sleep is not a uniform state either: it has different stages that affect different areas of the brain and body. Nonrapid eye movement sleep stages are as different from rapid eye movement sleep as is wakefulness. Circadian rhythms of physiologic systems also impact wake, sleep, sleepiness, and alertness. There are characteristic changes in both sleep patterns and circadian rhythm that occur with aging. The cardiovascular, respiratory, endocrine and gastrointestinal systems also undergo changes with sleep onset. This article reviews the aspects of normal sleep, physiologic changes that occur in the human body with sleep, and how sleep changes over the lifespan.

A step out of the dark: improving the sleep medicine knowledge of trainees.

OBJECTIVE Over 40-million Americans are undiagnosed, misdiagnosed, or untreated for sleep disorders. Despite the growing need to integrate sleep medicine knowledge into the medical education curriculum, educational leaders have struggled to incorporate contemporary medical topics such as sleep medicine into the already packed curricula. We set out to examine the efficacy of an online, self-paced, sleep medicine learning module as an educational tool for medical students. METHODS We studied 87 Johns Hopkins medical students. Participants were randomly assigned to the sham module (SM, n=40) or learning module (LM, n=47). The efficacy of the tool was assessed based on changes in performance (pre- and post-module completion) on a validated sleep knowledge questionnaire (the Dartmouth Sleep Knowledge and Attitude Survey). RESULTS Improvement in overall sleep knowledge, as measured by the Dartmouth Sleep Knowledge and Attitude Survey, was significantly higher in the LM group compared to the SM group (F(1,84)=9.71, p<.01, η(2)=0.10). Although the SM groups improvement was significantly lower than the LM group, within-subject comparisons did show improvement from their pre- to post-assessment scores as well. CONCLUSION A self-paced learning module is an effective educational tool for delivering sleep medicine knowledge to medical students.

Increased use-dependent plasticity in chronic insomnia.

STUDY OBJECTIVES During normal sleep several neuroplasticity changes occur, some of which are considered to be fundamental to strengthen memories. Given the evidence linking sleep to neuroplasticity, it is conceivable that individuals with chronic sleep disruption, such as patients with chronic insomnia (CI), would experience abnormalities in neuroplastic processes during daytime. Protocols testing use-dependent plasticity (UDP), one of the mechanisms underlying formation of motor memories traces, provide a sensitive measure to assess neuroplasticity in the context of motor training. DESIGN AND PARTICIPANTS A well-established transcranial magnetic stimulation (TMS) paradigm was used to evaluate the ability of patients with CI and age-matched good sleeper controls to undergo UDP. We also investigated the effect of insomnia on intracortical motor excitability measures reflecting GABAergic and glutamatergic mechanisms. SETTING Human Brain Physiology Laboratory, Johns Hopkins Medical Institutions. MEASUREMENTS AND RESULTS We found that patients with CI experienced increased UDP changes relative to controls. This effect was not due to differences in motor training. In addition, patients with CI showed enhanced intracortical facilitation relative to controls, in the absence of changes in intracortical inhibitory measures. CONCLUSION This study provides the first evidence that patients with chronic insomnia have an increased plasticity response to physical exercise, possibly due to larger activation of glutamatergic mechanisms. This suggests a heightened state of neuroplasticity, which may reflect a form of maladaptive plasticity, similar to what has been described in dystonia patients and chronic phantom pain after amputation. These results could lead to development of novel treatments for chronic insomnia.