Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition.

Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1, and RB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.

Caffeine Enhances Memory Performance in Young Adults during Their Non-optimal Time of Day.

Many college students struggle to perform well on exams in the early morning. Although students drink caffeinated beverages to feel more awake, it is unclear whether these actually improve performance. After consuming coffee (caffeinated or decaffeinated), college-age adults completed implicit and explicit memory tasks in the early morning and late afternoon (Experiment 1). During the morning, participants ingesting caffeine demonstrated a striking improvement in explicit memory, but not implicit memory. Caffeine did not alter memory performance in the afternoon. In Experiment 2, participants engaged in cardiovascular exercise in order to examine whether increases in physiological arousal similarly improved memory. Despite clear increases in physiological arousal, exercise did not improve memory performance compared to a stretching control condition. These results suggest that caffeine has a specific benefit for memory during students' non-optimal time of day - early morning. These findings have real-world implications for students taking morning exams.

Social support, stress and the aging brain.

Social support benefits health and well-being in older individuals, however the mechanism remains poorly understood. One proposal, the stress-buffering hypothesis states social support 'buffers' the effects of stress on health. Alternatively, the main effect hypothesis suggests social support independently promotes health. We examined the combined association of social support and stress on the aging brain. Forty healthy older adults completed stress questionnaires, a social network interview and structural MRI to investigate the amygdala-medial prefrontal cortex circuitry, which is implicated in social and emotional processing and negatively affected by stress. Social support was positively correlated with right medial prefrontal cortical thickness while amygdala volume was negatively associated with social support and positively related to stress. We examined whether the association between social support and amygdala volume varied across stress level. Stress and social support uniquely contribute to amygdala volume, which is consistent with the health benefits of social support being independent of stress.

Hippocampal activity mediates the relationship between circadian activity rhythms and memory in older adults.

Older adults experience parallel changes in sleep, circadian rhythms, and episodic memory. These processes appear to be linked such that disruptions in sleep contribute to deficits in memory. Although more variability in circadian patterns is a common feature of aging and predicts pathology, little is known about how alterations in circadian activity rhythms within older adults influence new episodic learning. Following 10 days of recording sleep-wake patterns using actigraphy, healthy older adults underwent fMRI while performing an associative memory task. The results revealed better associative memory was related to more consistent circadian activity rhythms, independent of total sleep time, sleep efficiency, and level of physical activity. Moreover, hippocampal activity during successful memory retrieval events was positively correlated with associative memory accuracy and circadian activity rhythm (CAR) consistency. We demonstrated that the link between consistent rhythms and associative memory performance was mediated by hippocampal activity. These findings provide novel insight into how the circadian rhythm of sleep-wake cycles are associated with memory in older adults and encourage further examination of circadian activity rhythms as a biomarker of cognitive functioning.

Neurocognitive therapeutics: from concept to application in the treatment of negative attention bias.

There is growing interest in the use of neuroimaging for the direct treatment of mental illness. Here, we present a new framework for such treatment, neurocognitive therapeutics. What distinguishes neurocognitive therapeutics from prior approaches is the use of precise brain-decoding techniques within a real-time feedback system, in order to adapt treatment online and tailor feedback to individuals' needs. We report an initial feasibility study that uses this framework to alter negative attention bias in a small number of patients experiencing significant mood symptoms. The results are consistent with the promise of neurocognitive therapeutics to improve mood symptoms and alter brain networks mediating attentional control. Future work should focus on optimizing the approach, validating its effectiveness, and expanding the scope of targeted disorders.

An examination of the association between chronic sleep restriction and electrocortical arousal in college students.

OBJECTIVE: The deleterious neurocognitive effects of laboratory-controlled short-term sleep deprivation are well-known. The present study investigated neurocognitive changes arising from chronic sleep restriction outside the laboratory. METHODS: Sleep patterns of 24 undergraduates were tracked via actigraphy across a 15-week semester. At the semester beginning, at a midpoint, and a week before finals, students performed the Psychomotor Vigilance Test (PVT) and cortical arousal was measured via event-related potentials (ERP) and resting state electroencephalography (EEG). RESULTS: Average daily sleep decreased between Session 1 and Sessions 2 and 3. Calculated circadian rhythm measures indicated nighttime movement increased and sleep quality decreased from Sessions 1 and 2 to Session 3. Parallel to the sleep/activity measures, PVT reaction time increased between Session 1 and Sessions 2 and 3 and resting state alpha EEG reactivity magnitude and PVT-evoked P3 ERP amplitude decreased between Session 1 and Sessions 2 and 3. Cross-sectional regressions showed PVT reaction time was negatively associated with average daily sleep, alpha reactivity, and P3 changes; sleep/circadian measures were associated with alpha reactivity and/or P3 changes. CONCLUSIONS: Small, but persistent sleep deficits reduced cortical arousal and impaired vigilant attention. SIGNIFICANCE: Chronic sleep restriction impacts neurocognition in a manner similar to laboratory controlled sleep deprivation.

Sleep and sadness: exploring the relation among sleep, cognitive control, and depressive symptoms in young adults.

BACKGROUND: Sleep disturbance is a common feature of depression. However, recent work has found that individuals who are vulnerable to depression report poorer sleep quality compared to their low-risk counterparts, suggesting that sleep disturbance may precede depression. In addition, both sleep disturbance and depression are related to deficits in cognitive control processes. Thus we examined if poor sleep quality predicts subsequent increases in depressive symptoms and if levels of cognitive control mediated this relation. METHODS: Thirty-five undergraduate students participated in two experimental sessions separated by 3 weeks. Participants wore an actigraph watch between sessions, which provided an objective measure of sleep patterns. We assessed self-reported sleep quality and depressive symptoms at both sessions. Last, individuals completed an exogenous cuing task, which measured ability to disengage attention from neutral and negative stimuli during the second session. RESULTS: Using path analyses, we found that both greater self-reported sleep difficulty and more objective sleep stability measures significantly predicted greater difficulty disengaging attention (i.e., less cognitive control) from negative stimuli. Less cognitive control over negative stimuli in turn predicted increased depression symptoms at the second session. Exploratory associations among the circadian locomotor output cycles kaput gene, CLOCK, single nucleotide polymorphism (SNP), rs11932595, as well as sleep assessments and depressive symptoms also are presented. CONCLUSIONS: These preliminary results suggest that sleep disruptions may contribute to increases in depressive symptoms via their impact on cognitive control. Further, variation in the CLOCK gene may be associated with sleep quality.