Levodopa-induced dyskinesia in Parkinson disease: Sleep matters.

OBJECTIVE: The spectrum of clinical symptom changes during the course of Parkinson disease (PD). Levodopa therapy, while offering remarkable control of classical motor symptoms, causes abnormal involuntary movements as the disease progresses. This levodopa-induced dyskinesia (LID) has been associated with abnormal cortical plasticity. Because slow wave activity (SWA) of nonrapid eye movement (NREM) sleep underlies adjustment of cortical excitability, we sought to elucidate the relationship between this physiological process and LID. METHODS: Thirty-six patients at different stages of PD underwent whole-night video polysomnography-high-density electroencephalography (vPSG-hdEEG), preceded by 1 week of actigraphy. To represent the broad spectrum of the disease, patients were divided into 3 groups by disease stage-(1) de novo (n = 9), (2) advanced (n = 13), and (3) dyskinetic (DYS; n = 14)-were compared to an age-matched control group (n = 12). The SWA-NREM content of the vPSG-hdEEG was then temporally divided into 10 equal parts, from T1 to T10, and power and source analyses were performed. T2-T3-T4 were considered early sleep and were compared to T7-T8-T9, representing late sleep. RESULTS: We found that all groups, except the DYS group, manifested a clear-cut SWA decrease between early and late sleep. INTERPRETATION: Our data demonstrate a strong pathophysiological association between sleep and PD. Given that SWA may be a surrogate for synaptic strength, our data suggest that DYS patients do not have adequate synaptic downscaling. Further analysis is needed to determine the effect of drugs that can enhance cortical SWA in LID. Ann Neurol 2018;84:905-917.

Slow wave activity across sleep-night could predict levodopa-induced dyskinesia.

A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID's appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.

Impairment of sleep homeostasis in cervical dystonia patients.

Alterations in brain plasticity seem to play a role in the pathophysiology of cervical dystonia (CD). Since evidences indicate that sleep regulates brain plasticity, we hypothesized that an alteration in sleep homeostatic mechanisms may be involved in the pathogenesis of CD. We explored sleep in control subjects (CTL) and CD patients before (Tpre-BoNT) and after (Tpost-BoNT) botulinum toxin (BoNT) treatment. A physiological slow wave activity (SWA) power decrease throughout the night was observed in CTL but not in CD at Tpre-BoNT. BoNT restored the physiological SWA decrease in CD at Tpost-BoNT. Furthermore, in the first part of the night, CD at Tpost-BNT showed a frontal increase and parietal decrease in SWA power compared to CD at Tpre-BoNT, with a SWA distribution comparable to that observed in CTL. Our data highlighted a pathophysiological relationship between SWA during sleep and CD and provided novel insight into the transient central plastic effect of BoNT.

High-density EEG power topography and connectivity during confusional arousal.

Confusional arousal is the milder expression of a family of disorders known as Disorders of Arousal (DOA) from non-REM sleep. These disorders are characterized by recurrent abnormal behaviors that occur in a state of reduced awareness for the external environment. Despite frequent amnesia for the nocturnal events, when actively probed, patients are able to report vivid hallucinatory/dream-like mental imagery. Traditional (low-density) scalp and stereo-electroencephalographic (EEG) recordings previously showed a pathological admixture of slow oscillations typical of NREM sleep and wake-like fast-mixed frequencies during these phenomena. However, our knowledge about the specific neural EEG dynamics over the entire brain is limited. We collected 2 consecutive in-laboratory sleep recordings using high-density (hd)-EEG (256 vertex-referenced geodesic system) coupled with standard video-polysomnography (v-PSG) from a 12-year-old drug-naïve and otherwise healthy child with a long-lasting history of sleepwalking. Source power topography and functional connectivity were computed during 20 selected confusional arousal episodes (from -6 to +18 sec after motor onset), and during baseline slow wave sleep preceding each episode (from - 3 to -2 min before onset). We found a widespread increase in slow wave activity (SWA) theta, alpha, beta, gamma power, associated with a parallel decrease in the sigma range during behavioral episodes compared to baseline sleep. Bilateral Broadman area 7 and right Broadman areas 39 and 40 were relatively spared by the massive increase in SWA power. Functional SWA connectivity analysis revealed a drastic increase in the number and complexity of connections from baseline sleep to full-blown episodes, that mainly involved an increased out-flow from bilateral fronto-medial prefrontal cortex and left temporal lobe to other cortical regions. These effects could be appreciated in the 6 sec window preceding behavioral onset. Overall, our results support the idea that DOA are the expression of peculiar brain states, compatible with a partial re-emergence of consciousness.

Clinical implication of high-density EEG sleep recordings in Parkinson's disease.

The diagnosis of Parkinson's disease (PD) is made relatively late in the pathological process, when already most of the dopaminergic synapses have died. The evidence showed that, at the time of the clinical diagnosis, which can be done only after motor symptoms' appearance, the pathogenetic process is too advanced for a potential neuroprotective agent to be efficacious. Thus, the identification of early markers of neurodegeneration would be essential in the fight again the disease. A growing body of literature reported that non-motor symptoms, including sleep disorders, are commonly the earliest manifestation of the disease (i.e. prodromal stage). Furthermore, evidence claimed that these disturbances may have an impact on the progression of the disease itself, possibly altering its phenotype and leading to the emergence of levodopa-induced dyskinesia (LID), a typical treatment-related complication. The early recognition of subjects at risk of developing PD would offer the opportunity to evaluate the efficacy of possible neuroprotective agents. Additionally, the early identification of sleep alterations, which could possibly be considered an indicator of aberrant brain plasticity and thus be helpful in predicting the emergence of LID, if confirmed, would offer a platform for testing possible sleep targeted therapies able to protect the patients from the development of this treatment-induced condition. In this review, new techniques for the study of sleep will be addressed, in order to investigate their possible role as diagnostic and prognostic tools in the evaluation of patients suffering from PD.

Sleep phenotypes in attention deficit hyperactivity disorder.

OBJECTIVE: A case-control study was performed to test the hypothesis that children with attention deficit hyperactivity disorder (ADHD) have chronic sleep deprivation and may be classified into specific sleep-related phenotypes. METHODS: Thirty outpatients with ADHD (nine females, mean age 10.1 ± 2.1 years) were recruited consecutively, and given a comprehensive sleep assessment, including blood exams, sleep questionnaires, laboratory video-polysomnographic recordings (v-PSG), multiple sleep latency tests, and one-week actigraphy. The PSG parameters were compared to those of 25 age-matched controls (12 females, mean age 10.34 ± 1.54 years) who underwent only the v-PSG. RESULTS: ADHD children were classified as follows: a narcolepsy-like phenotype was found in four; delayed sleep onset insomnia in five; obstructive sleep apnea (OSA) in 15; periodic limb movements in eight, and sleep epileptiform discharges in 10 children. All subjects had a total sleep time shorter than 9 h at actigraphy, ferritin levels lower than 60 mcg/L, and a history of sleep problems (mainly OSA and insomnia). Compared to controls, the ADHD group had a higher apnea-hypopnea index at PSG. CONCLUSIONS: A full sleep assessment in children with ADHD confirmed the validity of the sleep phenotypes hypothesis, and revealed a much higher percentage of sleep problems than that found in the literature. Beyond the sleep phenotypes, all children reported a history of sleep problems and slept less than 9 h per night, indicating chronic sleep deprivation that should be evaluated as a possible unifying marker of ADHD.

Shooting a high-density electroencephalographic picture on sleep in children with attention-deficit/hyperactivity disorder.

STUDY OBJECTIVES: Sleep-related slow-wave activity (SWA) has been recognized as a marker of synaptic plasticity. In children affected by attention deficit hyperactivity disorder (ADHD), SWA is mainly located in the central rather than frontal regions, reflecting a maturational delay. A detailed subjective and objective sleep investigation, including a full night video-polysomnography (PSG-HD-EEG), was performed on 30 consecutive drug naïve outpatients with a diagnosis of ADHD. They received a diagnosis of sleep disorders in 29/30 cases, and most of them had a past history of sleep problems. They had a higher apnea-hypopnea index at PSG, and slept less than 9 hr at actigraphy. We aimed to describe the SWA behavior in the same group of children with ADHD. MATERIALS AND METHODS: The full-night PSG-HD EEG of children with ADHD was compared with the one of the 25 healthy controls. The scalp SWA mapping, the decrease of SWA during the night, and the EEG source of SWA were analyzed. RESULTS: At scalp topography, the focus of SWA was observed over the centro-parietal-occipital regions in participants with ADHD (p < 0.01), which remained significant in the subgroups divided between subgroups according to the sleep diagnosis (p < 0.01). The physiological decrease in SWA was more evident in control participants. The source analysis revealed a greater delta power over the posterior cingulate in participants with ADHD (p < 0.01). CONCLUSIONS: Our results confirm static and dynamic changes in SWA behavior in children with ADHD, which may reflect a maturational delay occurring at a vulnerable age, as a consequence of chronic sleep deprivation.

A New Prospective, Home-Based Monitoring of Motor Symptoms in Parkinson's Disease.

BACKGROUND: Subjective symptoms, which are retrospectively assessed during clinical interviews in the office, may be influenced by patient recall in Parkinson's disease (PD). Prospective collection of subjective data might be an effective tool to overcome this bias. OBJECTIVE: We investigated the correspondence between prospectively and retrospectively assessed motor symptoms in PD. METHODS: Forty-two consecutive patients (9 females, 67±9.8 years old) with mild to moderate PD reported their symptoms four times a day for two weeks, using the "SleepFit" application (app) for tablets. This app incorporates a new Visual Analogue Scale assessing global mobility (m-VAS), and the Scales for Outcome in Parkinson Assessment Diary Card (SCOPA-DC). At day 14, the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and IV questionnaires were completed at the hospital. Agreement (root mean square difference) and the tendency to under- or overestimate their symptoms by patients (relative difference after normalization) were calculated to compare prospectively vs. retrospectively collected information. RESULTS: Although agreement was good for overall scores (m-VAS: 10.0%; SCOPA-DC: 18.3%), and for single motor symptoms (involuntary movements, hand dexterity, walking, changing position; each <20%), some individuals with more advanced disease, higher fatigue or worse sleep quality showed poor symptom recall in retrospect. Moreover, a subgroup of patients (16.7%) either over- or underestimated symptom severity. CONCLUSIONS: Regular, prospective monitoring of motor symptoms is suitable in PD patients. SleepFit might be a useful tool in routine practice to identify patients tending to under- or overestimate their symptoms, and for their follow-up.

Brain plasticity and sleep: Implication for movement disorders.

Brain plasticity is a lifelong process and involves both Hebbian and non-Hebbian synaptic plasticity. The latter, such as intrinsic plasticity and homeostatic synaptic plasticity or synaptic scaling, is thought to counteract Hebbian plasticity, in order to maintain a balanced network. Recent studies support the role of sleep in the regulation of homeostatic synaptic plasticity involved in memory and learning processes. Most evidence focus on the dependence of memory and plasticity in sleep mechanisms. Abnormal brain plasticity during sleep might be implicated in the development of movement disorders, particularly Parkinson's disease (PD) and dystonia. From that, the great interest to understand the underlying process of sleep in relation to movement disorders. The first objective of the review is to summarize the latest knowledge about brain plasticity. The second objective is to analyze the association between sleep, memory and brain plasticity. Finally, the review aims to assess the consequence of abnormal plasticity during PD and dystonia with a viewpoint on the underling pathogenesis of these disorders.

Different Frontal Involvement in ALS and PLS Revealed by Stroop Event-Related Potentials and Reaction Times.

BACKGROUND: A growing body of evidence suggests a link between cognitive and pathological changes in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobar degeneration (FTLD). Cognitive deficits have been investigated much less extensively in primary lateral sclerosis (PLS) than in ALS. OBJECTIVE: To investigate bioelectrical activity to Stroop test, assessing frontal function, in ALS, PLS, and control groups. METHODS: Thirty-two non-demented ALS patients, 10 non-demented PLS patients, and 27 healthy subjects were included. Twenty-nine electroencephalography channels with binaural reference were recorded during covert Stroop task performance, involving mental discrimination of the stimuli and not vocal or motor response. Group effects on event-related potentials (ERPs) latency were analyzed using statistical multivariate analysis. Topographic analysis was performed using low-resolution brain electromagnetic tomography (LORETA). RESULTS: Amyotrophic lateral sclerosis patients committed more errors in the execution of the task but they were not slower, whereas PLS patients did not show reduced accuracy, despite a slowing of reaction times (RTs). The main ERP components were delayed in ALS, but not in PLS, compared with controls. Moreover, RTs speed but not ERP latency correlated with clinical scores. ALS had decreased frontotemporal activity in the P2, P3, and N4 time windows compared to controls. CONCLUSION: These findings suggest a different pattern of psychophysiological involvement in ALS compared with PLS. The former is increasingly recognized to be a multisystems disorder, with a spectrum of executive and behavioral impairments reflecting frontotemporal dysfunction. The latter seems to mainly involve the motor system, with largely spared cognitive functions. Moreover, our results suggest that the covert version of the Stroop task used in the present study, may be useful to assess cognitive state in the very advanced stage of the disease, when other cognitive tasks are not applicable.

Cortical control of unilateral simple movement in healthy aging.

Normal aging is associated with several modifications in the cerebral motor system that reflect into an increased and more bilateral activation in elderly subjects. Twelve young and nine elderly healthy right-handed subjects performed a self-initiated brisk right thumb extension while recorded with 32-channel EEG. The aging effect over cortical generators of bereithshaftspotential, reconstructed using cortical current density (CCD) method and a realistic volume conductor, was evaluated in five different periods and in both mesial and lateral motor-related areas. Over-activation occurred mainly at movement initiation in those areas related to simple movements (caudal mesial areas and both sensorimotor cortices) and in contralateral sensorimotor cortex during the post-movement phase. In those areas, the elderly group recruited a larger neuronal population than the young one in the presence of a significantly longer movement. This more likely suggests their reduced selectivity in activating the motor cortex than a compensatory mechanism to produce an optimum performance. Movement duration resulted negatively correlated with pre-SMA activity, suggesting its involvement in movement termination.

Compensatory movement-related recruitment in amyotrophic lateral sclerosis patients with dominant upper motor neuron signs: an EEG source analysis study.

Cortical reorganization to simple movement in patients with amyotrophic lateral sclerosis (ALS) has been investigated in neuroimaging studies, reporting recruitment of ipsilateral primary sensorimotor (iSMC) and premotor regions (PMd). In order to investigate the spatiotemporal pattern of such overactivation, EEG source analysis to brisk self-paced finger movements was performed in thirty-two ALS patients, able to initiate their movement as fast as controls and clustered according to their most affected motor neuron (upper or lower). Reduced activity within cortical sources in bilateral SMC and caudal mesial areas was found only in patients subgroup with extensive upper motor neuron (UMN) clinical signs and mild motor weakness (U>L). Its absence in patients with opposite clinical features (L>U) suggest that this reduction might represent a possible marker of UMN impairment, and that the lower motor neuron (LMN) degeneration in L>U patients did not exert a retrograde effect over their cortical motor neurons. An ipsilateral premotor recruitment was observed in U>L patients only and since its extent positively correlated with movement initiation speed and right hand Medical Research Council (MRC) score, it might represent a compensatory recruitment. The latter correlation might suggest that the slight motor weakness in those patients may at least partly depend from a UMN dysfunction that can be compensated by cortical recruitment.