Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review.

PURPOSE OF REVIEW: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances". RECENT FINDINGS: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

A New Remote Guided Method for Supervised Web-Based Cognitive Testing to Ensure High-Quality Data: Development and Usability Study.

BACKGROUND: The global COVID-19 pandemic has triggered a fundamental reexamination of how human psychological research can be conducted safely and robustly in a new era of digital working and physical distancing. Online web-based testing has risen to the forefront as a promising solution for the rapid mass collection of cognitive data without requiring human contact. However, a long-standing debate exists over the data quality and validity of web-based studies. This study examines the opportunities and challenges afforded by the societal shift toward web-based testing and highlights an urgent need to establish a standard data quality assurance framework for online studies. OBJECTIVE: This study aims to develop and validate a new supervised online testing methodology, remote guided testing (RGT). METHODS: A total of 85 healthy young adults were tested on 10 cognitive tasks assessing executive functioning (flexibility, memory, and inhibition) and learning. Tasks were administered either face-to-face in the laboratory (n=41) or online using remote guided testing (n=44) and delivered using identical web-based platforms (Cambridge Neuropsychological Test Automated Battery, Inquisit, and i-ABC). Data quality was assessed using detailed trial-level measures (missed trials, outlying and excluded responses, and response times) and overall task performance measures. RESULTS: The results indicated that, across all data quality and performance measures, RGT data was statistically-equivalent to in-person data collected in the lab (P>.40 for all comparisons). Moreover, RGT participants out-performed the lab group on measured verbal intelligence (P<.001), which could reflect test environment differences, including possible effects of mask-wearing on communication. CONCLUSIONS: These data suggest that the RGT methodology could help ameliorate concerns regarding online data quality-particularly for studies involving high-risk or rare cohorts-and offer an alternative for collecting high-quality human cognitive data without requiring in-person physical attendance.

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences.

Background: Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). Methods: A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Results: Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. Conclusion: The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

Sex differences in alpha-synucleinopathies: a systematic review.

Background: Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach. Methods: In this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid. Results: One hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects. Conclusion: Future studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.

Visuo-spatial imagery in dreams of congenitally and early blind: a systematic review.

Background: The presence of visual imagery in dreams of congenitally blind people has long been a matter of substantial controversy. We set to systematically review body of published work on the presence and nature of oneiric visuo-spatial impressions in congenitally and early blind subjects across different areas of research, from experimental psychology, functional neuroimaging, sensory substitution, and sleep research. Methods: Relevant studies were identified using the following databases: EMBASE, MEDLINE and PsychINFO. Results: Studies using diverse imaging techniques and sensory substitution devices broadly suggest that the "blind" occipital cortex may be able to integrate non-visual sensory inputs, and thus possibly also generate visuo-spatial impressions. Visual impressions have also been reported by blind subjects who had near-death or out-of-body experiences. Conclusion: Deciphering the mechanistic nature of these visual impression could open new possibility in utilization of neuroplasticity and its potential role for treatment of neurodisability.

Mental Imagery in Dreams of Congenitally Blind People.

It is unclear to what extent the absence of vision affects the sensory sensitivity for oneiric construction. Similarly, the presence of visual imagery in the mentation of dreams of congenitally blind people has been largely disputed. We investigate the presence and nature of oneiric visuo-spatial impressions by analysing 180 dreams of seven congenitally blind people identified from the online database DreamBank. A higher presence of auditory, haptic, olfactory, and gustatory sensation in dreams of congenitally blind people was demonstrated, when compared to normally sighted individuals. Nonetheless, oneiric visual imagery in reports of congenitally blind subjects was also noted, in opposition to some previous studies, and raising questions about the possible underlying neuro-mechanisms.