Chronobiology of Parkinson's disease: Past, present and future.

Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non-motor symptoms. Sleep complaints are among the most common non-motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24-h cycles that control essential physiological functions, or with side effects from levodopa medication and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such, we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology-based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed important new light on the aetiology and symptomatology of the disease and may allow for improvements in the quality of life for the millions of people with Parkinson's disease.

"Tell Me More About Your Child's Sleep": A Qualitative Investigation Of Sleep Problems In Children With ADHD.

OBJECTIVE: To investigate parental experiences and perceptions of sleep problems in their children with Attention Deficit Hyperactivity Disorder (ADHD), the perceived impacts of sleep problems and coping strategies deployed by parents. METHODS: Semi-structured interviews with twenty-six parents of pre-adolescent children with a diagnosis of ADHD, followed by thematic analysis of the interview transcripts. RESULTS: Three themes were generated from the data: Children's Sleep Difficulties; Impacts of Children's Sleep; and Improving Children's Sleep. Sleep initiation problems in children with ADHD were commonly reported by parents, were perceived to be linked in a bidirectional manner with executive and emotional problems, and were reported as being disruptive to parental sleep. Some parents reported that their children's sleep problems were the initial prompt that lead to a diagnosis of ADHD. Parents reported utilizing a range of coping strategies to mitigate sleep problems, such as controlling the bedroom sensory environment and using emotional "wind down" as part of the bedtime routine. Some parents endorsed a beneficial effect of melatonin on their children's sleep. CONCLUSIONS: Sleep problems in children with ADHD were perceived as important issues by parents. Equipping parents with evidence-based strategies for the management of their children's sleep may lead to benefits for the children, parents and wider household.

Posttraumatic stress disorder, complex PTSD and subtypes of loneliness among older adults.

OBJECTIVES: Research examining the relationship between loneliness and Complex Posttraumatic Stress Disorder (CPTSD) is scarce, particularly among older adults. CPTSD includes the core symptoms of PTSD along with additional symptoms reflecting "disturbances in self-organisation" (DSO). This study examined the cross-sectional relationships between loneliness (emotional and social loneliness) and CPTSD symptoms (i.e., PTSD and DSO symptoms) in older adults. METHODS: Structural equation modelling was used to examine these relationships in a nationally representative sample of US adults aged 60-70 years (n = 456). RESULTS: Controlling for covariates, emotional loneliness was associated with PTSD (ß = 0.31) and DSO (ß = 0.57) symptoms whereas social loneliness was only associated with DSO symptoms (ß = 0.25). The model explained 35.0% of the variance in PTSD symptoms and 71.3% in DSO symptoms. CONCLUSION: These findings have important implications for treating and understanding PTSD/CPTSD and their correlates among older adults.

Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD.

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22) = 3.26, p = 0.004), ZT24 (t(22) = - 2.66, p = 0.015), ZT28 (t(20) = - 2.14, p = 0.045) and Per3 at ZT8 (t(22) = - 4.27, p < 0.001) and ZT12 (t(22) = - 2.61, p = 0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to eveningness; similar as prevalent in ADHD.

The Role of the Circadian System in Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterised by the core symptoms of inattention, impulsivity and hyperactivity. Similar to many other neuropsychiatric conditions, ADHD is associated with very high levels of sleep disturbance. However, it is not clear whether such sleep disturbances are precursors to, or symptoms of, ADHD. Neither is it clear through which mechanisms sleep and ADHD are linked. One possible link is via modulation of circadian rhythms. In this chapter we overview the evidence that ADHD is associated with alterations in circadian processes, manifesting as later chronotype and delayed sleep phase in ADHD, and examine some mechanisms that may lead to such changes. We also interrogate how the circadian clock may be a substrate for therapeutic intervention in ADHD (chronotherapy) and highlight important new questions to be addressed to move the field forward.

The impact of social jetlag and chronotype on attention, inhibition and decision making in healthy adults.

Sleep and circadian clock disruption are associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder, but the impact on neurocognitive performance is unclear. We assessed whether chronotype and everyday circadian misalignment manifested as social jetlag were associated with inter-individual neurocognitive performance across domains of attention, inhibitory control and decision making. One hundred and eighty-eight healthy young adults were assessed for sleep and circadian properties and performed two neurocognitive tasks, the Continuous Performance Test and the Iowa Gambling Task. Social jetlag was associated with significantly faster and less variable reaction times and commission errors on the Continuous Performance Test. Poorer subjective sleep quality was associated with poorer decision making on the Iowa Gambling Task. No effects were present for polymorphisms in the circadian clock genes CLOCK and PER3. We conclude that circadian disruption shaped by everyday environmental factors may impact on attentional/inhibitory performance but not on a measure of risky decision making.

Clocks in the clinic: circadian rhythms in health and disease.

Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a '24/7' lifestyle where activity often occurs during the body's 'biological night', resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility.

Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1.

The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155-binding sites in its 3'-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.

How does healthy aging impact on the circadian clock?

Circadian rhythms are recurring patterns in a host of physiological and other parameters that recur with periods of near 24 h. These rhythms reflect the temporal organization of an organism's homeostatic control systems and as such are key processes in ensuring optimal physiological performance. Dysfunction of circadian processes is linked with adverse health conditions. In this review we highlight the evidence that normal, healthy aging is associated with changes in the circadian system; we examine the molecular mechanisms through which such changes may arise, discuss whether more robust circadian function is a predictor of longevity and highlight the role of circadian rhythms in age-related diseases. Overall, the literature shows that aging is associated with marked changes in circadian processes, both at the behavioral and molecular levels, and the molecular mechanisms through which such changes arise remain to be elucidated, but may involve inflammatory process, redox homeostasis and epigenetic modifications. Understanding the nature of age-related circadian dysfunction will allow for the design of chronotherapeutic intervention strategies to attenuate circadian dysfunction and thus improve health and quality of life.

The time course of systems consolidation of spatial memory from recent to remote retention: A comparison of the Immediate Early Genes Zif268, c-Fos and Arc.

Systems consolidation is a process involving the stabilisation of memory traces in the neocortex over time. The medial prefrontal cortex becomes increasingly important during the retrieval of older memories, however the timescale of its involvement is unclear, and the contribution of other neocortical brain regions to remote memory have received little attention. The Immediate Early Genes (IEGs) Zif268, c-Fos and Arc have been utilised as markers of neural activity during spatial memory retrieval, however the lack of a direct comparison between them hinders the interpretation of results. To address these questions, we examined the expression of Zif268, Arc and c-Fos protein in the medial prefrontal cortex, as well as the hippocampus, and the entorhinal, perirhinal, retrosplenial and parietal cortices of male Wistar rats following a probe trial of the Morris water maze either one day, seven days, 14 days or 30 days after acquisition. Activity of the medial prefrontal cortex during retrieval, as measured by all three IEGs, increased in correspondence with the age of the memory, reaching significance between 14 and 30 days. Similar increases in c-Fos and Arc were observed over the course of consolidation in other neocortical and parahippocampal areas, however this pattern was not observed with Zif268. Activity of the hippocampus remained largely unchanged across retention intervals. These findings suggest that systems consolidation of spatial memory takes at least two weeks, are consistent with an ongoing role for the hippocampus in the retrieval of spatial memory, and suggest that c-Fos and Arc may be a more sensitive measure of neural activity in response to behavioural tasks than Zif268.

Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse.

Post-septic encephalopathy is a poorly understood condition in survivors of sepsis that is characterised by cognitive and affective impairments. In this study we have sought to better understand this condition by undertaking a comprehensive behavioural and cognitive assessment of mice who had previously survived sepsis. Mice were treated with lipopolysaccharide (LPS; 5mg/kg) and one month after this assessed on a battery of tests. Post-septic animals were found to display significantly more immobility in the tail suspension test and show a significantly decreased sucrose preference. Acute fluoxetine treatment reversed the increase in immobility in the tail suspension test in post-septic animals. Post-septic animals also showed less overall exploratory behaviour in the novel object recognition task and also showed increased anxiety-like behaviour in the elevated plus maze. Post-septic mice did not show signs of cognitive impairment, as assessed in the Morris watermaze, the 8-arm radial maze or on preference for the novel object in the novel object recognition task. Immunohistochemical analysis revealed significant upregulation of the microglial marker CD-11b, F4/80 and IBA-1 in the hippocampus of post-septic animals, as well as significant downregulation of the plasticity-related immediate early gene products ARC and EGR1. We also observed a decrease in neural stem cell proliferation in the dentate gyrus of post-septic animals as judged by BrdU incorporation. Co-treatment with the NF-κB pathway inhibitor PDTC attenuated the long-lasting effects of LPS on most of the affected parameters, but not on neural stem cell proliferation. These results show that LPS-induced sepsis in the mouse is followed by long-lasting increases in depressive- and anxiety-like behaviours, as well as by changes in neuroinflammatory- and neural plasticity-associated factors, and that attenuation of the severity of sepsis by PDTC attenuates many of these effects.

Does prior sepsis alter subsequent circadian and sickness behaviour response to lipopolysaccharide treatment in mice?

Previous data has shown that prior history of immune challenge may affect central and behavioural responses to subsequent immune challenge, either leading to exaggerated responses via priming mechanisms or lessened responses via endotoxin tolerance. In this set of experiments we have examined how previously lipopolysaccharide (LPS)-induced sepsis shapes the response to subsequent treatment with lower dose LPS. After treatment with LPS (5 mg/kg) or saline mice were allowed to recover for 3-4 months before being challenged with a lower dose of LPS (100 µg/kg) for assessment of sickness behaviours. Performance on the open field test and the tail suspension test was assessed, and no evidence was found that prior sepsis altered sickness or depressive-like behaviour following LPS treatment. We then examined the responsiveness of the circadian system of mice to LPS. We found that in control animals, LPS induced a significant phase delay of the behavioural rhythm and that this was not the case in post-septic animals (4-6 weeks after sepsis), indicating that prior sepsis alters the responsivity of the circadian system to subsequent immune challenge. We further assessed the induction of the immediate early genes c-Fos and EGR1 in the hippocampus and the suprachiasmatic nucleus (SCN; the master circadian pacemaker) by LPS in control or post-septic animals, and found that post-septic animals show elevated expression in the hippocampus but not the SCN. These data suggest that previous sepsis has some effect on behavioural and molecular responses to subsequent immune challenge in mice.

Stability of social jetlag and sleep timing into the second year of the Covid-19 pandemic: Results from a longitudinal study of a nationally representative adult sample in Ireland.

The early phase of the COVID-19 pandemic has previously been associated with marked changes in sleep/wake timing arising from the imposition of society-wide infection mitigation measures. Such observations are considered of broader significance as they reveal the social pressures that sleep timing normally operates under. In order to assess how persistent such changes were as the COVID-19 pandemic developed, we assessed sleep timing and quality in a longitudinal study of a nationally-representative sample of Irish adults with data collected at two time-points (December 2021 and March 2021). Data on social jetlag and chronotype was derived from the micro Munich Chronotype Questionnaire from 830 and 843 participants who provided data in December 2020 and March 2021 respectively, of which 338 contributed data to both timepoints. Demographics and measures of insomnia symptoms, anxiety, depression and loneliness were also collected, and data was analysed both within-subjects and cross-sectionally within data waves. Social jetlag (the mismatch between sleep timing on "work" and "free" days) and other measures of sleep timing were stable across the two time-points, although insomnia symptoms improved slightly from December 2020 to March 2021. The mean social jetlag at both timepoints was ~ 30 minutes, considerably lesser than reported pre-pandemic levels in similar populations. Multiple regression analysis of cross-sectional data reveals that the timing of midsleep on "free" days was only a weak-to-moderate predictor of social jetlag, whilst hours worked per week was the strongest predictor of social jetlag. Requirement for "face-to-face" contact with the public at work and urban location of residence also emerged as predictors of social jetlag, although insomnia, anxiety and depression symptoms and loneliness rating did not. We conclude that sleep timing changes that occurred during the initial phase of the COVID-19 pandemic persisted into the second year of the pandemic, and these results further illustrate the key roles working practices and other social factors have in shaping social jetlag.

Associations between sleep problems in children with ADHD and parental insomnia and ADHD symptoms.

Sleep problems are common in children with attention deficit hyperactivity disorder (ADHD). Children's sleep problem may influence, and be influenced by, parents' sleep problems as well as parents' ADHD symptoms. In the current study we examined the associations of parent-rated sleep quality and sleep timing of pre-adolescent children with parental insomnia symptoms, parental ADHD symptoms and dysfunctional attitudes and beliefs about sleep in a convenience sample recruited by advertisement (N = 120). Childhood sleep problems were common in the sample, with 82% of children exceeding the threshold for the presence of a paediatric sleep disorder. Children's sleep quality showed minimal association with their sleep timing and chronotype. Parental insomnia symptoms, ADHD symptoms and dysfunctional beliefs and attitudes about sleep all associated with their children's sleep quality, and with the sleep subdomains of sleep anxiety and parasomnias. In multiple regression analysis only parental insomnia score was a significant predictor of children's sleep quality. Children's bedtimes, wake times, sleep duration, chronotype or social jetlag did not associate with parents' ADHD or insomnia symptoms. Sleep quality was significantly poorer in children whose parents scored as both consistent for adult ADHD and probable for insomnia disorder compared to parents who scored as either ADHD consistent or insomnia probable, or those who parents scored as neither. We discuss the putative nature of the relationships between sleep quality of children with ADHD and parental ADHD and insomnia symptoms, and suggest that clinicians consider parental sleep when attending to children with ADHD.

Sleep and daytime functioning in children with tourette syndrome: A two-week case-control study with actigraphy and cognitive assessments.

There is increasing recognition of the high prevalence of sleep issues in children with Tourette syndrome (TS), a condition characterised by motor and vocal tics. Overnight polysomnography (PSG) has been the primary mode of sleep assessment in the TS literature, despite the extensive use of actigraphy in other neurodevelopmental populations. As a result, there are existing research gaps surrounding day-to-day variability of sleep in TS and links to daytime functioning. This study adopts a naturalistic, intensive longitudinal design to examine sleep in children with TS while considering potential links to tic severity and daytime functioning. Participants were 34 children aged between 8 and 12 years (12 with TS, 22 neurotypical controls). Wrist actigraphs tracked sleep-wake cycles across two weeks and a battery of scales and cognitive assessments measured sleep disturbances and daytime functioning. Mixed models using N = 476 nights of actigraphy data found that relative to controls, children with TS had significantly increased time in bed, increased sleep onset latency, reduced sleep efficiency, lower subjective sleep quality, but comparable actual sleep time. Higher self-report tic severity at bedtime did not predict increased sleep onset latency. In the sleep disturbance scale, 83.33 % of children with TS met the clinical cut-off for a sleep disorder. Parent-report emotional, behavioural, and executive difficulties were greater in the TS group relative to controls, but performance on cognitive tasks was comparable between groups. Together, findings highlight sleep disturbances as an important clinical factor to consider in the management of TS, though further research is required to substantiate findings in larger-scale studies. This study demonstrates the feasibility of assessing sleep via actigraphy in children with TS, supporting more widespread use in the future.

Circadian Variation in the Response to Vaccination: A Systematic Review and Evidence Appraisal.

Molecular timing mechanisms known as circadian clocks drive endogenous 24-h rhythmicity in most physiological functions, including innate and adaptive immunity. Consequently, the response to immune challenge such as vaccination might depend on the time of day of exposure. This study assessed whether the time of day of vaccination (TODV) is associated with the subsequent immune and clinical response by conducting a systematic review of previous studies. The Cochrane Library, PubMed, Google, Medline, and Embase were searched for studies that reported TODV and immune and clinical outcomes, yielding 3114 studies, 23 of which met the inclusion criteria. The global severe acute respiratory syndrome coronavirus 2 vaccination program facilitated investigation of TODV and almost half of the studies included reported data collected during the COVID-19 pandemic. There was considerable heterogeneity in the demography of participants and type of vaccine, and most studies were biased by failure to account for immune status prior to vaccination, self-selection of vaccination time, or confounding factors such as sleep, chronotype, and shiftwork. The optimum TODV was concluded to be afternoon (5 studies), morning (5 studies), morning and afternoon (1 study), midday (1 study), and morning or late afternoon (1 study), with the remaining 10 studies reporting no effect. Further research is required to understand the relationship between TODV and subsequent immune outcome and whether any clinical benefit outweighs the potential effect of this intervention on vaccine uptake.

Thematic Daily Sleep Routine Analysis of Adults Not in Employment Living with Type 2 Diabetes Mellitus.

BACKGROUND: Day-to-day variations in sleep timing have been associated with poorer glycemic control in type 2 diabetes mellitus, although the factors that influence this sleep timing variability are poorly understood. METHODS: Daily routines of sleep in a sample of seventeen adults with type 2 diabetes mellitus who were either retired or not currently working were examined qualitatively through the application of semi-structured interviews and a thematic analysis of the resulting transcripts. RESULTS: Four themes were identified: "Consistent Sleeping Patterns", "Fluctuating Sleep Timing", "Night-Time Disruptions" and "Lasting Effort Needed with Type Two Diabetes Mellitus". The subthemes reflected that many participants had consistent sleep schedules across the seven-day week, but that a desire to maintain a sense of normality, household routines, television schedules and socializing were associated with different sleep timing on weekends. Active disease monitoring and timed medication taking were not identified as important factors in shaping sleep timing. Nocturia, stress and rumination were identified as important factors linked to disrupted sleep. Sleep was not reported as an issue discussed during routine clinical care. CONCLUSION: Sleep timing in participants appears to be driven by interacting psychosocial and physiological factors, although active disease management does not emerge as a major influence on sleep schedules.

Association between circadian rhythms, sleep and cognitive impairment in healthy older adults: an actigraphic study.

There is increasing evidence for the relationship between circadian rhythm disturbance and cognitive decline in the older adult. This study measured circadian activity rhythms in a small group of healthy community-dwelling older adults (n = 26). Each participant completed a battery of neuropsychological tests and completed sleep diaries and 6 days of actigraphy. Ten participants were identified as having very early signs of cognitive decline as indicated by their performance on the memory tests. Results showed minimal differences on the sleep/activity and circadian parameters across the two groups (declined vs. intact), although there was a significant difference in the acrophase between the declined and intact groups. These findings, although exploratory, suggest that very subtle changes in circadian rhythm may be detected in older adults showing pre-clinical changes in cognitive performance.

Sleep disturbances and circadian CLOCK genes in borderline personality disorder.

Borderline personality disorder (BPD) is characterised by a deep-reaching pattern of affective instability, incoherent identity, self-injury, suicide attempts, and disturbed interpersonal relations and lifestyle. The daily activities of BPD patients are often chaotic and disorganized, with patients often staying up late while sleeping during the day. These behavioural patterns suggest that altered circadian rhythms may be associated with BPD. Furthermore, BPD patients frequently report suffering from sleep disturbances. In this review, we overview the evidence that circadian rhythms and sleep are disturbed in BPD, and we explore the possibility that personality traits that are pertinent for BPD may be associated with circadian typology, and perhaps to circadian genotypes. With regards to sleep architecture, we review the evidence that BPD patients display altered non-REM and REM sleep. A possible cue to a deeper understanding of this temporal dysregulation might be an analysis of the circadian clock at the molecular and cellular level, as well as behavioural studies using actigraphy and we suggest avenues for further exploration of these factors.