Comparative transcriptome analysis and CRISPR/Cas9 gene editing reveal that E4BP4 mediates lithium upregulation of Per2 expression

Bipolar disorder (BPD) is a psychiatric disorder characterized by alternate episodes of mania and depression. Disruption of normal circadian clock and abnormal sleep cycles are common symptoms of BPD patients. Lithium salt is currently an effective clinical therapeutic drug for BPD. Animal and cellular studies have found that lithium salt can upregulate the expression of the clock gene Per2 , but the mechanism is unknown. We aim to understand the mechanism underlying the Per2 upregulation by lithium treatment. By taking approaches of both comparative transcriptome analysis and comparative qPCR analysis between human and murine cells, Lumicycle assay, luciferase assay and RT-qPCR assay showed that lithium could significantly upregulate the expression of Per2 in both mouse and human cells, and significantly inhibit the expression of E4bp4 , which encodes a transcriptional inhibitor of Per2 . After knocking out the cis-element upstream on the Per2 promoter that responds to E4BP4, the upregulation effect on Per2 by lithium disappeared. When E4bp4 gene was knocked out, the upregulation effect on Per2 by lithium salt disappeared. This study has found that lithium upregulates Per2 expression by reducing the expression of transcription factor E4BP4, but the mechanism of lithium salt downregulation of E4BP4 remains to be further studied. Our study provides a new therapeutic target and approaches for treating BPD.

The association between vision acuity, sleep duration, and physical activity among US adults aged 50 years and older

Studies suggested that people with low vision are more likely to have worse sleep quality and less frequent participation in physical activities compare with people with better vision. Studies also showed that physical activities is a very important factor for one’s sleep. However, there is relatively little research on the association between vision acuity, sleep, and physical activity. This study examines the relationships between vision acuity and sleep duration among middle-aged and older adults in the US, and the role of leisure-time physical activity in this relationship. Using nationally representative data from the National Health and Nutrition Examination Survey 2007-2008, a cross-sectional analysis on adults age 50 years and older was conducted (n=2.247). Visual acuity was assessed by participant’s vision of better-seeing eye (i.e., none, mild, moderate, and server visual impairment), and we measured sleep duration (i.e., short, average, and long duration) and leisure-time Physical Activity (i.e., inactive/insufficiently active and sufficiently active). Descriptive analysis showed that 31.06% of older adults experienced moderate or severe visual impairment, and 46.81% respondents experienced abnormal sleep duration. Multinomial logistic regression analyses showed that compared to people without visual impairment, people with moderate or severe visual impairment were more likely to have longer sleep duration than normal sleep duration (OR, 1.62, p<0.05). Leisure-time physical activity was not found to significantly mediate the relationship between visual acuity and sleep duration. Other variables were controlled in the models. Findings suggest that US adults age 50+ with low vision are at greater risk of experiencing abnormal sleep duration.

Cardiopulmonary Sleep Spectrograms Open a Novel Window Into Sleep Biology—Implications for Health and Disease

The interactions of heart rate variability and respiratory rate and tidal volume fluctuations provide key information about normal and abnormal sleep. A set of metrics can be computed by analysis of coupling and coherence of these signals, cardiopulmonary coupling (CPC). There are several forms of CPC, which may provide information about normal sleep physiology, and pathological sleep states ranging from insomnia to sleep apnea and hypertension. As CPC may be computed from reduced or limited signals such as the electrocardiogram or photoplethysmogram (PPG) vs. full polysomnography, wide application including in wearable and non-contact devices is possible. When computed from PPG, which may be acquired from oximetry alone, an automated apnea hypopnea index derived from CPC-oximetry can be calculated. Sleep profiling using CPC demonstrates the impact of stable and unstable sleep on insomnia (exaggerated variability), hypertension (unstable sleep as risk factor), improved glucose handling (associated with stable sleep), drug effects (benzodiazepines increase sleep stability), sleep apnea phenotypes (obstructive vs. central sleep apnea), sleep fragmentations due to psychiatric disorders (increased unstable sleep in depression).

Measurement of Sleep Behaviors in Chromosome 15q11.2-13.1 Duplication (Dup15q Syndrome)

Duplication of chromosome 15q11.2-q13.1 (dup15q syndrome) results in hypotonia, intellectual disability (ID), and autism symptomatology. Clinical electroencephalography has shown abnormal sleep physiology, but no studies have characterized sleep behaviors. The present study used the Children's Sleep Habits Questionnaire (CSHQ) in 42 people with dup15q syndrome to examine the clinical utility of this questionnaire and quantify behavioral sleep patterns in dup15q syndrome. Individuals with fully completed forms (56%) had higher cognitive abilities than those with partially completed forms. Overall, caregivers indicated a high rate of sleep disturbance, though ratings differed by epilepsy status. Results suggest that clinicians should use caution when using standardized questionnaires and consider epilepsy status when screening for sleep problems in dup15q syndrome.

P107 Patient self-reported sleep quality, noise and light levels in a tertiary ICU: a prospective observational study

Introduction Sleep is poor in intensive care units (ICU). However, there is limited research examining the causes from the patient perspective, especially in an Australian population. The current study investigated the factors that patients perceive as affecting their sleep in a major Australian tertiary ICU. Methods Patients (n=138, 51F; aged 58.1±16.8 years) completed a survey assessing sleep before and during their ICU stay, factors contributing to poor sleep, and factors that may have improved their sleep in the ICU. Night-time sound (16 nights) and light (28 nights) levels in rooms were also measured. Results Most patients reported good (38%) to very good (25%) sleep quality before their ICU stay, and poor (28%) to very poor (32%) sleep quality in the ICU. Over half (56%) reported an abnormal sleep-wake cycle and most (60%) felt as though they did not obtain sufficient sleep. Noise (54%), pain (50%) and lights (48%) were the top reasons for self-reported poor sleep. Patients felt as though their sleep would have been improved with dimmed lights (64%), a sleeping pill (57%) and closing door/blinds at night (46%). Median (IQR) overnight noise and light levels were 52.8 (51.4–54.6) dB and 39.9 (8.2–90.9) lux respectively. Discussion Of the top three factors that patients perceive to be the primary reasons for poor sleep, two are modifiable (noise and lights). Night-time sound levels exceed standard recommendations and light levels, while mostly low, were higher than indicated for a healthy sleep environment, suggesting that these could be modified to improve patients sleep.

How to manage sleep problems

When you get a good night’s rest, you’re better able to tackle the most challenging dementia issues. On the other hand, when your sleep is poor, even small difficulties can cause you to feel frustrated and irritable. And if that’s true for you with a healthy brain, think about how important sleep is for your loved one with dementia. Poor sleep can cause many problems in those with dementia—not to mention often disrupting your own sleep! Although sleep problems are common in dementia, most of them can be managed without medications. Start by using a sleep log. Work to improve your loved one’s sleep habits and modify their daily routines to improve sleep. Be alert for disorders such as sleep apnea and abnormal sleep movements; let your loved one’s doctor know if you suspect them.

Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome

Background Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12–30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome. Methods To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12). Results Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls. Limitations This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG—routinely ordered for epilepsy monitoring—opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology. Conclusions We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.

Association of Infantile Anorexia with Sleep Pattern and Cognitive Development of Children at Southern Region of Central Java, Indonesia

Background: Cognitive development plays an important role in a child’s life. Cognitive development and sleep patterns can interfere with the brain cell growth related to health and nutrition in children. Many children are reported to have eating difficulty in infantile anorexia. Infantile anorexia is an eating disorder during the children’s period of learning (6 - 36 months of age). The disorder is characterized by extreme refusal of eating, deficiency of growth, and loss of typical appetite. Objectives: This study aimed to determine the association of infantile anorexia at 12 - 36 months of age with cognitive development and sleep patterns in children. Methods: This analytic observational study with a case-control design was conducted on the subjects divided into 40 infantile anorexia children and 40 controls. Infantile anorexia was diagnosed by a trained pediatrician. Cognitive assessment was measured by the Capute Scale test. The Brief Infant Sleep Questionnaire measured the data on children’s sleep patterns. The association of infantile anorexia and children’s cognitive development was analyzed by the chi-square test. Results: The result showed a significant association between infantile anorexia and children’s cognitive development (OR: 52.76; 95% CI: 6.58 - 423.0; P < 0.001). A similar association was also observed between children’s sleep patterns and infantile anorexia (OR: 4.88; 95% CI: 1.80 - 13.21; P < 0.002). Conclusions: The findings of this study demonstrated that children with infantile anorexia are more likely to have impaired cognitive development and abnormal sleep patterns.