Deep brain stimulation of the subthalamic nucleus facilitates coordination of hand preshaping in Parkinson's disease.

Several studies have found that Parkinson's disease (PD) disrupts the organization of complex motor sequences regardless of the influence of parkinsonian medications. A clear candidate for the neural bases of such deficits, which we term "coordinative," is the failure to integrate propioceptive and visual information by cortico-striatal circuits in a timed fashion. Recent reports, however, have indicated that deep-brain stimulation of the subthalamic nucleus (STN DBS) may result in an improvement in coordinative deficits beyond the amelioration of "intensive deficits" such as bradykinesia and scaling errors. The present study examined the spatio-temporal organization underlying the shaping of the hand during reaching to grasp objects differing in shape. Six PD patients ON and OFF their STN DBS when OFF their concomitant medications and six age-matched controls participated in this study. STN DBS improved the coordination involved in preshaping the hand while grasping. We discuss these results in light of our earlier work with PD patients on and off dopamine replacement therapy.

Restless Legs Syndrome and the five-factor model of personality: results from a community sample.

OBJECTIVE: To examine personality characteristics as potential mediators of the association between Restless Legs Syndrome (RLS) and psychiatric disorders. METHOD: Revised NEO Personality Inventory traits are compared in respondents with (n=42) versus without (n=982) a diagnosis of RLS in a general population sample. RESULTS: RLS was associated with higher neuroticism after adjusting for potential confounders, including current psychopathology. Further analysis showed that the association between RLS and neuroticism contributes to, but does not fully explain, the relationship between RLS and either panic disorder or major depression. CONCLUSIONS: Neuroticism may mediate part of the relationship between RLS and depression or panic, but the mechanisms of these associations need further exploration.

Medication use in patients with restless legs syndrome compared with a control population.

Primary restless legs syndrome (RLS) is a sensorimotor disorder causing chronic sleep deprivation in those with moderate to severe symptoms. It has been associated with other medical conditions, such as high blood pressure, depression and attention deficit hyperactive disorder (ADHD). If these conditions are more prevalent for RLS patients, then it would be expected RLS patients would use relatively more of the medications treating these conditions. Current medication use was obtained from 110 RLS patients and 54 age, race and gender-matched local-community controls. Each subject was diagnosed as primary RLS or having no indications for RLS by a clinician board-certified in sleep medicine. The RLS group used more medications than the control group even when medications used for treating RLS were excluded. Significantly more of the RLS patients than controls used anti-depressants, gastro-intestinal (GI) medications and asthma/allergy medications. RLS patients compared with those without RLS are more likely to use medications not related to treating RLS. Moreover they use medications for conditions that have not previously been considered related to RLS, i.e. GI and asthma/allergy conditions.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice.

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self-assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI-S), and the Mini-Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI-S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Long-term follow-up on restless legs syndrome patients treated with opioids.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37-88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty-three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1-23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1-15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

The brain decade in debate: VII. Neurobiology of sleep and dreams

This article is a transcription of an electronic symposium held on February 5, 2001 by the Brazilian Society of Neuroscience and Behavior (SBNeC) during which eight specialists involved in clinical and experimental research on sleep and dreaming exposed their personal experience and theoretical points of view concerning these highly polemic subjects. Unlike most other bodily functions, sleep and dreaming cannot, so far, be defined in terms of definitive functions that play an ascribable role in maintaining the organism as a whole. Such difficulties appear quite clearly all along the discussions. In this symposium, concepts on sleep function range from a protective behavior to an essential function for maturation of the nervous system. Kleitman's hypothesis [Journal of Nervous and Mental Disease (1974), 159: 293-294] was discussed, according to which the basal state is not the wakeful state but sleep, from which we awake to eat, to protect ourselves, to procreate, etc. Dreams, on the other hand, were widely discussed, being considered either as an important step in consolidation of learning or simply the conscious identification of functional patterns derived from the configuration of released or revoked memorized information

The brain decade in debate: VII. Neurobiology of sleep and dreams.

This article is a transcription of an electronic symposium held on February 5, 2001 by the Brazilian Society of Neuroscience and Behavior (SBNeC) during which eight specialists involved in clinical and experimental research on sleep and dreaming exposed their personal experience and theoretical points of view concerning these highly polemic subjects. Unlike most other bodily functions, sleep and dreaming cannot, so far, be defined in terms of definitive functions that play an ascribable role in maintaining the organism as a whole. Such difficulties appear quite clearly all along the discussions. In this symposium, concepts on sleep function range from a protective behavior to an essential function for maturation of the nervous system. Kleitman's hypothesis [Journal of Nervous and Mental Disease (1974), 159: 293-294] was discussed, according to which the basal state is not the wakeful state but sleep, from which we awake to eat, to protect ourselves, to procreate, etc. Dreams, on the other hand, were widely discussed, being considered either as an important step in consolidation of learning or simply the conscious identification of functional patterns derived from the configuration of released or revoked memorized information.

Automatic orienting of visuospatial attention in Parkinson's disease.

The basal ganglia are involved in not only motor behavior, but also other more cognitive processes, such as attention. We tested Parkinson's disease (PD) patients in a task that measures reflexive orienting of spatial attention. Seven patients with idiopathic PD and eight control subjects performed a covert orienting task where spatial attention was directed by means of exogenous cues (luminance increments) with no predictive validity for target position. The subjects' task was to make a speeded saccade to a visual target, which appeared a variable time after onset of the cue either in the cued or an uncued spatial position. There was no overall difference between PD patients and control subjects in terms of the initial facilitation following reflexive cues, and later inhibition of return (IOR). However, PD patients differed from control subjects in two important respects. First, they were significantly faster than were control subjects on this reflexive visual-orienting task. Second, disease severity correlated with attentional performance; more advanced patients showed less initial facilitation but greater IOR. Thus PD patients show better performance on a reflexive saccade task and, for more advanced patients, greater IOR than control subjects. These findings are consistent with the possibility that reflexive attentional processes in PD patients may be more active.

The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets in Parkinson's disease.

We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions. The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement.

Procedural motor learning in Parkinson's disease.

We have been investigating motor control and learning in parkinsonian subjects. In the current study, we sought to explore the existence of deficits in procedural motor learning, which is a form of implicit motor learning where skill improves over repetitive blocks of trials. We sought to determine, in particular, whether any such deficit is accentuated during specific types or phases of learning. We would expect that those specific learning tasks would require the greatest participation of the basal ganglia. Numerous studies have found that Parkinson's disease (PD) patients may show deficits in learning. Combined with information about basal ganglia neuronal connections and activity, this led some investigators to suggest that one of the key functions of the basal ganglia is to facilitate learning. To investigate these learning deficits, we used a robotic device to generate conservative force fields that disturbed the subjects' arm movements, thereby generating a "virtual mechanical environment" that subjects learned to manipulate. Movements were successively grouped into blocks comprising five different conditions: motor performance, early learning, late learning, negative transfer, and aftereffect motor performance. Our results with eight right-handed PD subjects and nine age-matched controls showed a relative decrease in the rate of learning for the PD patients in all blocks, but greater differences emerged between groups during novelty phases of learning. In particular, the difference in performance during the negative transfer condition reached statistical significance, suggesting that the basal ganglia might be a key center for "switching" motor patterns. Our results support the hypothesis that deficiencies in procedural motor learning are characteristic of PD. They add to existing evidence which has suggested a key role for the basal ganglia when new sensorimotor mappings are required by novel task environments. Better understanding of these deficits should facilitate the rehabilitation of PD patients.

The timing of arm-trunk coordination is deficient and vision-dependent in Parkinson's patients during reaching movements.

The role of the basal ganglia in the coordination of different body segments and utilization of motor synergies was investigated by analyzing reaching movements to remembered three-dimensional (3D) targets in patients with Parkinson's disease (PD). Arm movements were produced alone or in combination with a forward bending of the trunk, with or without visual feedback. Movements in PD patients were more temporally segmented, as evidenced by irregular changes in tangential velocity profiles. In addition, the relative timing in the onsets and offsets of fingertip and trunk motions were substantially different in PD patients than in control subjects. While the control subjects synchronized both onsets and offsets, the PD patients had large mean intervals between the onsets and offsets of the fingertip and trunk motions. Moreover, PD patients showed substantially larger trial-to-trial variability in these intervals. The degree of synchronization in PD patients gradually increased during the movement under the influence of visual feedback. The mean and variability of the intersegmental intervals decreased as the fingertip approached the target. This improvement in timing occurred even though the separate variability in the timing of arm and trunk motions was not reduced by vision. In combined movements, even without vision, the PD patients were able to achieve normal accuracy, suggesting they were able to use the same movement synergies as normals to control the multiple degrees of freedom involved in the movements and to compensate for the added trunk movement. However, they were unable to recruit these synergies in the stereotyped manner characteristic of healthy subjects. These results suggest that the basal ganglia are involved in the temporal coordination of movement of different body segments and that related timing abnormalities may be partly compensated by vision. Abnormal intersegmental timing may be a highly sensitive indicator of a deficient ability to assemble complex movements in patients with basal-ganglia dysfunction. This abnormality may be apparent even when the overall movement goal of reaching a target is preserved and normal movement synergies appear to be largely intact.

Epidemiology of restless legs symptoms in adults.

BACKGROUND: Restless legs syndrome (RLS) is a disorder characterized by sleep-disrupting unpleasant leg sensations, often accompanied by daytime behavioral problems. Treatment for this condition is available, but it is suspected that most instances of RLS remain undiagnosed. The goal of this investigation was to assess the prevalence and health status correlates of restless legs symptoms (hereinafter referred to as restless legs) in the general population. METHODS: A question reflecting the clinical features of RLS was added to the 1996 Kentucky Behavioral Risk Factor Surveillance Survey. Data on the frequency of experiencing restless legs, self-rated general and mental health status, demographics, and behavioral risk factors were collected by telephone interview from 1803 men and women, 18 years and older. RESULTS: Experiencing restless legs 5 or more nights per month was reported by 3% of participants aged 18 to 29 years, 10% of those aged 30 to 79 years, and 19% of those 80 years and older. The age-adjusted prevalence for Kentucky adults is 10.0%; prevalence did not vary significantly by sex. The adjusted odds ratios (95% confidence intervals) for restless legs and diminished general health and poor mental health status were 2.4 (1.4-4.0) and 3.1 (2.0-4.6), respectively. Restless legs were significantly associated with increased age and body mass index, lower income, smoking, lack of exercise, low alcohol consumption, and diabetes. CONCLUSIONS: The prevalence of restless legs in the general adult population is high. Restless legs may be associated with decreased well-being, emphasizing the need for further research and greater medical recognition of this condition.

A novel quantitative method for 3D measurement of Parkinsonian tremor.

OBJECTIVE: To demonstrate the usefulness of a three dimensional (3D) motion analysis system for the quantitative measurement of tremor in patients with Parkinson's disease (PD). METHODS: Six PD patients with hand tremors were studied using a system that employed 3D electromagnetic position sensors to measure the actual, cumulative displacement of the tremoring finger. Patients were studied in different hand positions and activating conditions before and 30, 60, 90 and 120 min after intake of Pramipexole, a dopamine agonist known to reduce tremor. Tremor amplitude and frequency, before and after drug intake, were compared using Mann-Whitney U test and Wilcoxon rank test, respectively. RESULTS: The motion analysis system allowed discrimination of tremor related events from movement artifact and allowed the calculation of real world movement of the finger tremor despite altered hand positions and orientation. Average 3D tremor frequency ranged from 3.71 to 4.34 Hz. Median tremor amplitude (total distance traveled per 5 s interval) decreased with drug from 4.9 to 1.6 cm for resting tremor, 4.5 to 3.7 cm for postural tremor, 3.4 to 3.3 cm for precision tremor, 10.2 to 3.3 cm for tapping activation and 108.6 to 5.7 cm for counting activation. CONCLUSIONS: Our method of 3D analysis provides a robust, single quantitative measure of tremor amplitude that is intuitive and likely to reflect the functional impact of tremor. This methodology should be useful in comparing tremor across patients and in measuring the efficacy of therapeutic interventions.

Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder.

Fourteen consecutive children who were newly diagnosed with attention-deficit hyperactivity disorder (ADHD) and who had never been exposed to stimulants and 10 control children without ADHD underwent polysomnographic studies to quantify Periodic Limb Movements in Sleep (PLMS) and arousals. Parents commonly gave both false-negative and false-positive reports of PLMS in their children, and a sleep study was necessary to confirm their presence or absence. The prevalence of PLMS on polysomnography was higher in the children with ADHD than in the control subjects. Nine of 14 (64%) children with ADHD had PLMS at a rate of >5 per hour of sleep compared with none of the control children (p <0.0015). Three of 14 children with ADHD (21%) had PLMS at a rate of >20 per hour of sleep. Many of the PLMS in the children with ADHD were associated with arousals. Historical sleep times were less for children with ADHD. The children with ADHD who had PLMS chronically got 43 minutes less sleep at home than the control subjects (p = 0.0091). All nine children with ADHD who had a PLMS index of >5 per hour of sleep had a long-standing clinical history of sleep onset problems (>30 minutes) and/or maintenance problems (more than two full awakenings nightly) thus meeting the criteria for Periodic Limb Movement Disorder (PLMD). None of the control children had a clinical history of sleep onset or maintenance problems. The parents of the children with ADHD were more likely to have restless legs syndrome (RLS) than the parents of the control children. Twenty-five of 28 biologic parents of the children with ADHD and all of the biologic parents of the control children were reached for interview. Eight of twenty-five parents of the children with ADHD (32%) had symptoms of RLS as opposed to none of the control parents (p = 0.011). PLMS may directly lead to symptoms of ADHD through the mechanism of sleep disruption. Alternative explanations for the association between ADHD and RLS/PLMS are that they are genetically linked, they share a common dopaminergic deficit, or both.

Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome.

STUDY OBJECTIVES: To determine if motor restlessness in the Restless Legs Syndrome (RLS) shows a circadian rhythm with maximum at night, as previously found for subjective discomfort and periodic limb movements (PLMs), and to correlate RLS peak intensity with the core temperature cycle. DESIGN: Subjects underwent two days of normally timed wakefulness and sleep followed by a night and subsequent day of sleep deprivation. Activity was standardized through modified suggested immobilization tests (mSITs). SETTING: The study was conducted in a laboratory environment with a bedroom equipped for polysomnography during sleep and the mSITs. PATIENTS: Nine patients (mean age 59.8+/-11.3 years [range: 33-72]; 4 males, 5 females) with clinically severe idiopathic RLS. INTERVENTIONS: Patients were monitored with continuous ambulatory activity and core temperature recording. The mSITs were performed every three hours while subjects were awake. During the mSITs, subjective discomfort was measured every 15 minutes while motor restlessness was assessed through activity monitoring. MEASUREMENTS AND RESULTS: Subjective discomfort and motor restlessness increased from a trough in the morning to a maximum at night in the hours following midnight. Peak intensity was found on the falling phase of the core temperature cycle, whose circadian rhythm appeared to be within the normal range for age. CONCLUSIONS: An independent circadian factor modulates the intensity of RLS, which seems to peak on the falling phase of the core temperature cycle. Therefore, the diagnostic criteria that RLS occurs with rest and during the night have independent bases. Furthermore, RLS may be partially controlled by some process or substance whose level varies with the normal circadian rhythm.