Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Actigraphy Enables Home Screening of Rapid Eye Movement Behavior Disorder in Parkinson's Disease.

OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is a potentially harmful, often overlooked sleep disorder affecting up to 70% of Parkinson's disease patients. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome examination requiring specific clinical expertise. Here, we explored the use of wrist actigraphy to enable automatic RBD diagnoses in home settings. METHODS: A total of 26 Parkinson's disease patients underwent 2-week home wrist actigraphy, followed by two in-laboratory evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We comprehensively characterized patients' movement patterns during sleep using actigraphic signals. We then trained machine learning classification algorithms to discriminate patients with or without RBD using the most relevant features. Classification performance was quantified with respect to clinical diagnosis, separately for in-laboratory and at-home recordings. Performance was further validated in a control group of non-Parkinson's disease patients with other sleep conditions. RESULTS: To characterize RBD, actigraphic features extracted from both (1) individual movement episodes and (2) global nocturnal activity were critical. RBD patients were more active overall, and showed movements that were shorter, of higher magnitude, and more scattered in time. Using these features, our classification algorithms reached an accuracy of 92.9 ± 8.16% during in-clinic tests. When validated on home recordings in Parkinson's disease patients, accuracy reached 100% over a 2-week window, and was 94.4% in non-Parkinson's disease control patients. Features showed robustness across tests and conditions. INTERPRETATION: These results open new perspectives for faster, cheaper, and more regular screening of sleep disorders, both for routine clinical practice and clinical trials. ANN NEUROL 2023;93:317-329.

Subjective sleep alterations in healthy subjects worldwide during COVID-19 pandemic: A systematic review, meta-analysis and meta-regression.

OBJECTIVE: We conducted a systematic review and meta-analysis to provide an update on sleep quality in different world areas and better characterize subjective sleep alterations during the COVID-19 pandemic. Considering gender distribution and specific pandemic-related parameters, we also intend to identify significant predictors of sleep problems. METHODS: Six electronic databases were searched from December 2019 to November 2021 for studies investigating sleep during COVID-19 employing the Pittsburgh Sleep Quality Index, the Medical Outcomes Study Sleep, the Insomnia Severity Index or the Epworth Sleepiness Scale. Random-effects models were implemented to estimate the pooled raw means of subjective sleep alterations. Also, we considered the role of several pandemic-related parameters (i.e., days from the first COVID-19 case, government stringency index, new cases for a million people, new deaths for a million people) by means of meta-regression analyses. RESULTS: A total of 139 studies were selected. The pooled mean of the global Pittsburgh Sleep Quality Index score (PSQIgen) was 6.73 (95% CI, 6.61-6.85). The insomnia severity index score was reported from 50 studies with a pooled mean of 8.44 (95% CI, 7.53-9.26). Subgroup analyses confirmed that most subcategories had poor sleep quality and subclinical insomnia. Meta-regressions showed that PSQIgen was predicted by days from the first COVID-19 case and government restrictions with a negative slope and by female gender with a positive slope. The government stringency index was positively correlated with the direct subjective evaluation of sleep quality. CONCLUSIONS: We found an overall impaired sleep and widespread subthreshold insomnia during the COVID-19 pandemic. The female percentage seems to be the best predictor of impaired sleep quality, consistently to the available literature. Noteworthy, sleep alterations were inversely associated with governmental restrictions and decreased during the pandemic. Our results give a contribution to critically orienting further studies on sleep since COVID-19 pandemic.

The SleepFit Tablet Application for Home-Based Clinical Data Collection in Parkinson Disease: User-Centric Development and Usability Study.

BACKGROUND: Parkinson disease (PD) is a common, multifaceted neurodegenerative disorder profoundly impacting patients' autonomy and quality of life. Assessment in real-life conditions of subjective symptoms and objective metrics of mobility and nonmotor symptoms such as sleep disturbance is strongly advocated. This information would critically guide the adaptation of antiparkinsonian medications and nonpharmacological interventions. Moreover, since the spread of the COVID-19 pandemic, health care practices are being reshaped toward a more home-based care. New technologies could play a pivotal role in this new approach to clinical care. Nevertheless, devices and information technology tools might be unhandy for PD patients, thus dramatically limiting their widespread employment. OBJECTIVE: The goals of the research were development and usability evaluation of an application, SleepFit, for ecological momentary assessment of objective and subjective clinical metrics at PD patients' homes, and as a remote tool for researchers to monitor patients and integrate and manage data. METHODS: An iterative and user-centric strategy was employed for the development of SleepFit. The core structure of SleepFit consists of (1) an electronic finger-tapping test; (2) motor, sleepiness, and emotional subjective scales; and (3) a sleep diary. Applicable design, ergonomic, and navigation principles have been applied while tailoring the application to the specific patient population. Three progressively enhanced versions of the application (alpha, v1.0, v2.0) were tested by a total of 56 patients with PD who were asked to perform multiple home assessments 4 times per day for 2 weeks. Patient compliance was calculated as the proportion of completed tasks out of the total number of expected tasks. Satisfaction on the latest version (v2.0) was evaluated as potential willingness to use SleepFit again after the end of the study. RESULTS: From alpha to v1.0, SleepFit was improved in graphics, ergonomics, and navigation, with automated flows guiding the patients in performing tasks throughout the 24 hours, and real-time data collection and consultation were made possible thanks to a remote web portal. In v2.0, the kiosk-mode feature restricts the use of the tablet to the SleepFit application only, thus preventing users from accidentally exiting the application. A total of 52 (4 dropouts) patients were included in the analyses. Overall compliance (all versions) was 88.89% (5707/6420). SleepFit was progressively enhanced and compliance increased from 87.86% (2070/2356) to 89.92% (2899/3224; P=.04). Among the patients who used v2.0, 96% (25/26) declared they would use SleepFit again. CONCLUSIONS: SleepFit can be considered a state-of-the-art home-based system that increases compliance in PD patients, ensures high-quality data collection, and works as a handy tool for remote monitoring and data management in clinical research. Thanks to its user-friendliness and modular structure, it could be employed in other clinical studies with minimum adaptation efforts. TRIAL REGISTRATION: ClinicalTrials.gov NCT02723396; https://clinicaltrials.gov/ct2/show/NCT02723396.

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

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.

Automated sleep scoring: A review of the latest approaches.

Clinical sleep scoring involves a tedious visual review of overnight polysomnograms by a human expert, according to official standards. It could appear then a suitable task for modern artificial intelligence algorithms. Indeed, machine learning algorithms have been applied to sleep scoring for many years. As a result, several software products offer nowadays automated or semi-automated scoring services. However, the vast majority of the sleep physicians do not use them. Very recently, thanks to the increased computational power, deep learning has also been employed with promising results. Machine learning algorithms can undoubtedly reach a high accuracy in specific situations, but there are many difficulties in their introduction in the daily routine. In this review, the latest approaches that are applying deep learning for facilitating and accelerating sleep scoring are thoroughly analyzed and compared with the state of the art methods. Then the obstacles in introducing automated sleep scoring in the clinical practice are examined. Deep learning algorithm capabilities of learning from a highly heterogeneous dataset, in terms both of human data and of scorers, are very promising and should be further investigated.

Subjective sleep dysfunction and insomnia symptoms in Parkinson's disease: Insights from a cross-sectional evaluation of the French CoPark cohort.

INTRODUCTION: Twenty-seven to 80% of patients with Parkinson's Disease (PD) complain of subjective sleep dysfunction and insomnia symptoms. Our aim is to describe the prevalence and features of subjective sleep dysfunction and insomnia symptoms in patients with PD compared to other patients. METHODS: Cross-sectional analysis of 636 adult PD patients compared to 143 age and sex-matched non-PD control patients consulting their general practitioners. Insomnia symptoms and other sleep features were assessed by the Pittsburgh Sleep Quality Index (PSQI), a global score > 5 defining impaired sleep. The Chi-square test or the Student's t-test were used to assess the potential clinical and demographic differences between groups and between PD patients with vs. without sleep dysfunction. Logistic regression analysis was employed to test multivariate effects. RESULTS: Sleep dysfunction and insomnia symptoms were more frequent in PD patients compared to control patients (63 vs. 45%, p = 0.001). Female gender, PD duration, presence of depression and anxiety were associated with the presence of insomnia in PD. Subjective sleep efficiency, habitual sleep quality, sleep disturbance and daytime dysfunction, but not sleep latency, were reduced in PD patients compared to controls. CONCLUSIONS: The prevalence of sleep dysfunction is higher in PD than in other general medical conditions. Insomnia in PD seems to affect sleep maintenance and consolidation, but not sleep onset.

Distinctive features of NREM parasomnia behaviors in parkinson's disease and multiple system atrophy.

OBJECTIVE: To characterize parasomnia behaviors on arousal from NREM sleep in Parkinson's Disease (PD) and Multiple System Atrophy (MSA). METHODS: From 30 patients with PD, Dementia with Lewy Bodies/Dementia associated with PD, or MSA undergoing nocturnal video-polysomnography for presumed dream enactment behavior, we were able to select 2 PD and 2 MSA patients featuring NREM Parasomnia Behviors (NPBs). We identified episodes during which the subjects seemed to enact dreams or presumed dream-like mentation (NPB arousals) versus episodes with physiological movements (no-NPB arousals). A time-frequency analysis (Morlet Wavelet Transform) of the scalp EEG signals around each NPB and no- NPB arousal onset was performed, and the amplitudes of the spectral frequencies were compared between NPB and no-NPB arousals. RESULTS: 19 NPBs were identified, 12 of which consisting of 'elementary' NPBs while 7 resembling confusional arousals. With quantitative EEG analysis, we found an amplitude reduction in the 5-6 Hz band 40 seconds before NPBs arousal as compared to no-NPB arousals at F4 and C4 derivations (p<0.01). CONCLUSIONS: Many PD and MSA patients feature various NREM sleep-related behaviors, with clinical and electrophysiological differences and similarities with arousal parasomnias in the general population. SIGNIFICANCE: This study help bring to attention an overlooked phenomenon in neurodegenerative diseases.

Sepsis-induced morbidity in mice: effects on body temperature, body weight, cage activity, social behavior and cytokines in brain.

Infection negatively impacts mental health, as evidenced by the lethargy, malaise, and cognitive deficits experienced during illness. These changes in central nervous system processes, collectively termed sickness behavior, have been shown in animal models to be mediated primarily by the actions of cytokines in brain. Most studies of sickness behavior to date have used bolus injection of bacterial lipopolysaccharide (LPS) or selective administration of the proinflammatory cytokines interleukin-1ß (IL-1ß) or IL-6 as the immune challenge. Such models, although useful for determining mechanisms responsible for acute changes in physiology and behavior, do not adequately represent the more complex effects on central nervous system (CNS) processes of a true infection with replicating pathogens. In the present study, we used the cecal ligation and puncture (CLP) model to quantify sepsis-induced alterations in several facets of physiology and behavior of mice. We determined the impact of sepsis on cage activity, body temperature, food and water consumption and body weights of mice. Because cytokines are critical mediators of changes in behavior and temperature regulation during immune challenge, we also quantified sepsis-induced alterations in cytokine mRNA and protein in brain during the acute period of sepsis onset. We now report that cage activity and temperature regulation in mice that survive are altered for up to 23 days after sepsis induction. Food and water consumption are transiently reduced, and body weight is lost during sepsis. Furthermore, sepsis decreases social interactions for 24-48 h. Finally, mRNA and protein for IL-1ß, IL-6, and tumor necrosis factor-α (TNFα) are upregulated in the hypothalamus, hippocampus, and brain stem during sepsis onset, from 6h to 72 h post sepsis induction. Collectively, these data indicate that sepsis not only acutely alters physiology, behavior and cytokine profiles in brain, but that some brain functions are impaired for long periods in animals that survive.

REM and NREM sleep enactment behaviors in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies.

BACKGROUND/OBJECTIVE: Nocturnal sleep enactment behaviors (SEBs) are common in patients affected by Parkinson's disease (PD), dementia associated with Parkinson's disease (PDD), and dementia with Lewy bodies (DLB). We investigated the occurrence and neurobiological significance of abnormal SEBs in the context of PD without cognitive decline compared to PDD/DLB patients. METHODS: We evaluated a sample of 139 patients with PD, PDD, or DLB in a cross-sectional survey. One hundred and seventeen patients showing either no cognitive impairment (PD group) or meeting the diagnostic requirements for dementia (PDD/DLB group) underwent video-polysomnography. Seventy subjects (42 males) in whom a clear-cut diagnosis of abnormal sleep-related motor-behavioral episodes was possible were included in the final analysis. RESULTS: SEBs consisting of RBD or occurring on arousal from NREM or REM sleep were globally more frequent in the dementia group (PDD/DLB) than in the PD group (p=0.001), the difference being statistically significant for arousal-related episodes (p=0.002), while a trend emerged for RBD (p=0.07). Male sex, daytime sleepiness, higher motor impairment, and lower mini-mental score were significantly more frequent with the occurrence of abnormal sleep-related motor-behavioral episodes. CONCLUSION: SEBs in PD, PDD, and DLB may consist of RBD episodes or of arousal-related NREM and REM episodes. These latter are more frequent in patients with PDD/DLB and seem to be mainly related to more advanced stages of disease with a higher degree of cognitive decline.

Sleep paralysis in narcolepsy: more than just a motor dissociative phenomenon?

Sleep paralyses are viewed as pure motor phenomena featured by a dissociated state in which REM-related muscle atonia coexists with a wakefulness state of full consciousness. We present a 59-year-old man diagnosed with narcolepsy experiencing sleep paralysis, who failed to establish the boundaries between real experience and dream mentation during the paralysis: the patient's recall was indeed featured by uncertainty between real/unreal and awaken/dreaming. Hereby, we suggest that sleep paralysis may represent a more complex condition encompassing a dissociated state of mind together with the dissociative motor component. Neurophysiological data (spectral EEG analysis corroborated by cross-correlation analysis) reinforce the idea that the patient was in an intermediate state of mind between wake and REM sleep during the paralysis. The persistence of local impaired activity proper of REM sleep in cortical circuits necessary for self-reflective awareness and insight, in conflict with wakefulness-related activation of the remaining brain areas, could account for disrupted processing of afferent inputs in our patient, representing the underlying pathophysiologic substrate for patient's failure to establish the boundaries between real experience and dream mentation.

Secondary ''incidental'' REM sleep behavior disorder: do we ever think of it?

Most secondary forms of REM sleep behavior disorder are associated with neurodegenerative diseases belonging to the α-synucleinopathies or with narcolepsy. However, RBD may also occur in subacute- or acute-onset conditions involving the central nervous system, irrespective of subjects' age and sex, and with or without relapse at follow-up. These conditions include structural brain lesions (vascular, demyelinating, tumoral, iatrogenic, etc.), CNS diseases (encephalitis, Guillain-Barré syndrome, etc.), forms induced by drug consumption or alcohol withdrawal, and possibly post-traumatic stress disorder. This review focuses on these forms of RBD, which are referred to as 'acute' as they occur as incidental phenomena within the context of other subacute- or acute-onset disorders. In these cases, RBD does not appear as a 'classical' clinical feature of the underlying condition, but rather as an intercurrent, somewhat unexpected phenomenon that deserves consideration in routine clinical practice, in order to avoid misdiagnoses and mistreatments.

Hallucinations and REM sleep behaviour disorder in Parkinson's disease: dream imagery intrusions and other hypotheses.

REM sleep behaviour disorder (RBD) is a REM sleep-related parasomnia which may be considered a "dissociated state of wakefulness and sleep", given that conflicting elements of REM sleep (dreaming) and of wakefulness (sustained muscle tone and movements) coexist during the episodes, leading to motor and behavioural manifestations reminiscent of an enacted dream. RBD has been reported in association with α-synucleinopathies: around a third of patients with Parkinson's disease (PD) have full-blown RBD. Recent data indicate that PD patients with RBD are more prone to hallucinations than PD patients without this parasomnia. However it is still not clear why RBD in PD is associated with an increased prevalence of VHs. Data exist which suggest that visual hallucinations in PD may be the result of untimely intrusions of REM visual imagery into wakefulness. RBD, which is characterised by a REM sleep dissociation pattern, might be a condition that particularly favours such intrusions. However, other hypotheses may be advanced. In fact, deficits in attentional, executive, visuoperceptual and visuospatial abilities have been documented in RBD and found to occur far more frequently in PD with RBD than in PD without RBD. Neuropsychological deficits involving visual perception and attentional processes are thought to play an important role in the pathophysiology of VHs. On this basis, RBD in PD could be viewed as a contributory risk factor for VHs.

Excessive muscle activity increases over time in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by excessive electromyographic (EMG) activity due to dysfunction of the brainstem structures modulating REM sleep atonia. Patients with idiopathic RBD often develop a neurodegenerative disease, such as Parkinson disease, over the years, suggesting progression of an underlying pathologic process in the brainstem. It is unknown if the excessive EMG activity in REM sleep changes over time in patients with idiopathic RBD. SETTING: University hospital sleep disorders center. PARTICIPANTS: Eleven patients with idiopathic RBD who were studied at baseline and after a mean follow-up of 5 years. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Eleven patients with idiopathic RBD underwent polysomnography (PSG) at the moment of the diagnosis of RBD (PSG1) and after a mean follow-up of 5 years (PSG2). Tonic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle during REM sleep. Phasic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle, both biceps brachii, and both anterior tibialis during REM sleep. Patients were 9 men and 2 women with a mean age of 73.2 +/- 5.4 years and a mean RBD duration of 10.7 +/- 5.3 years at PSG2. In each of the 5 muscles and combination of muscles evaluated, phasic EMG activity was significantly greater in PSG2 than in PSG1 (P < 0.022 in all muscles studied). Mentalis tonic EMG activity increased from 30% to 54% (P = 0.013). No correlation was found between age of the patients and quantity of EMG activity at PSG1 (tonic; P = 0.69, phasic P = 0.89) and at PSG2 (tonic; P = 0.16, phasic; P = 0.42). CONCLUSION: Excessive tonic and phasic EMG activity during REM sleep increases over time in subjects with idiopathic RBD. This finding suggests that, in subjects with idiopathic RBD, there is an underlying progressive pathologic process damaging the brainstem structures that modulate REM sleep.