bioRxiv Science⌕ Search

Biology subjects

Dijk, D.-J.

Publications and source records attributed to Dijk, D.-J..

At least 19 recordsLinked to original sources

Hippocampal stimulation timed to memory reactivation shapes human sleep oscillatory dynamics and consolidation

Memory consolidation during sleep depends on the precisely timed coordination of hippocampal reactivation with cortical slow oscillations and spindles. In humans this coupling has been characterised correlationally, while causal investigations have required intracranial stimulation in restricted patient cohorts or used non-invasive approaches targeting cortical regions, often obscuring the underlying sleep rhythms. Here we stimulated the human hippocampus during sleep for the first time, applying temporal interference stimulation to the left hippocampal head either concurrently with or prior to induced memory reactivation. Stimulation concurrent with reactivation reduced associative memory forgetting relative to mistimed stimulation and enhanced fast spindle amplitude, preserving the association between slow oscillation-spindle coupling and memory. This behavioural benefit was mediated by a distributed, left-lateralised set of spindle and coupling features. Non-invasively engaging deep hippocampal circuits during sleep offers both a means to probe human memory and a scalable basis for intervention where consolidation fails.

neuroscience↗

Resonance-driven enhancement of sleep spindles using thalamic temporal interference stimulation

Sleep spindles are hallmarks of non-rapid eye movement sleep and support memory consolidation yet remain difficult to modulate non-invasively. Combining computational modeling and human sleep recordings, we show that thalamus-targeted temporal interference stimulation (TIS) with a 5Hz envelope increases spindle density via subthreshold resonance in thalamocortical relay neurons. Our results demonstrate a mechanistic framework for the rational design of interventions to selectively augment sleep spindles.

neuroscience↗

Tonic REM sleep EEG components predict better mood, cognition and reduce cortical excitability overnight

Rapid Eye Movement (REM) sleep makes up approximately 20% of sleep in the adult human and is altered in psychiatric and neurodegenerative conditions. REM sleep comprises two substates, during which eye movements do (phasic REM) and do not (tonic REM) occur. Tonic REM makes up 70-90% of REM sleep but its role in regulating brain function, mood and cognition remain underexplored. We investigated how seven nights of insufficient sleep (6 h time in bed), compared to sufficient sleep, alter periodic and aperiodic components of the phasic and tonic REM sleep electroencephalography (EEG), in 542 sleep recordings of 36 young adults. Associations between phasic and tonic REM sleep EEG and mood, cognitive performance, and overnight changes in cortical excitability as indexed by 1/f spectral slopes were assessed. Insufficient sleep predominantly affected tonic REM EEG components, specifically the density of theta, the amplitude, density, and frequency of alpha oscillations and the 1/f slope in the 30 to 45 Hz range. These changes associated with mood and cognitive performances, and with overnight reductions in cortical excitability. These results provide evidence for a role of tonic REM sleep in regulating mood and counteracting cognitive deterioration and excitability changes associated with insufficient sleep.

neuroscience↗

Within and between sleep and cognition: associations in older community dwelling individuals

Cross sectional and interventional studies have demonstrated that sleep has a significant impact on waking brain function including alertness and cognitive performance. Few studies have assessed whether spontaneous night-to-night variation in sleep associates with variation in brain function within an individual. How this compares to the between-individual variation in sleep and cognition and their associations also remains largely unknown. These questions are of particular interest in the context of ageing because both sleep and cognitive abilities are altered in ageing. Furthermore, older people have been reported to be less sensitive to sleep loss. Here we investigated the relationship between sleep and cognition by quantifying associations between intraindividual variation in sleep and cognition as well as associations between interindividual variation in sleep and cognition in 35 cognitively intact older adults (70.8 {+/-} 4.9 years; mean {+/-} SD; 14 females) living in the community. Subjective and actigraphic sleep measures and daily digital assessments of cognition (nine cognitive tests; 19 variables) were obtained over a two-week period. The cognitive test battery probed a wide range of cognitive functions including reaction time, working memory, attention, and problem solving. Principal Component Analysis (PCA) identified four principal sleep components which were labelled Sleep Duration, Sleep Efficiency, Subjective Sleep Quality, and Nap-Effect. Mixed model analyses were conducted with mean and deviation-from-the-mean cognitive variables to quantify how inter- and intra-individual variation in sleep associated with inter and intra individual variation in cognition. Longer sleep duration was associated with faster reaction times in both the inter- and intra-individual analyses and with reduced errors in the inter-individual analyses. Higher sleep efficiency was associated with faster reaction times in both the intra- and inter-individual analyses. By contrast, aspects of cognition relating to learning, visual memory, verbal reasoning, and verbal fluency did not associate with sleep. The data show that in older people some aspects of waking function are sensitive to normal variation in sleep duration and efficiency which implies that interventions that target these aspects of sleep may be beneficial for waking function in ageing.

physiology↗

A clinical grade neurostimulation implant for hierarchical control of physiological activity

Bioelectronic implants for neurostimulation aim to steer disordered neurophysiological processes back towards a healthy state. However, physiology is subject to biological rhythms, including the circadian rhythm and the sleep-wake cycle. These predictable rhythms affect disease symptomatology, biomarkers used in closed-loop therapies, and a physiological systems expected response to stimulation. Therefore, therapeutic devices should incorporate feedforward elements to align algorithm parameters with predictable changes in physiological state, as a parallel of physiological rheostatic control. Here we introduce the DyNeuMo-2c, the first clinical-grade implant capable of delivering closed-loop neurostimulation while flexibly changing its functional configuration according to time of day. The device can chronically measure brain activity and motion state to track potential biomarker patterns in natural, out-of-clinic settings, allowing identification and targeting of patient-specific chronotypes. The system implements a hierarchical control flow, with baseline therapy set by a circadian scheduler, and adaptive policies layered to take effect based on specific biomarkers indicating patient and disease state. Using a benchtop validation setup, we demonstrate that the system has the required capabilities for delivering time-contingent closed-loop therapy in two established clinical use cases: Parkinsons disease and epilepsy. Next, we deploy the system in vivo to deliver closed-loop deep brain stimulation in a healthy non-human primate model of vigilance, highlighting the importance of synchronisation between device operation and physiological state in various conditions (task performance, unconstrained behaviour, and sleep). Time-of-day-dependent adaptation of closed-loop stimulation enabled modulation of both vigilance and behaviour. Overall, the novel device architecture provides a proof-of-concept for delivering time-contingent therapy in chronic therapeutic settings where biological rhythms are of key importance.

neuroscience↗

Circadian and Sleep-Wake Modulation of Functional Connectivity Across Brain Oscillations and States Linked to Cognition in Humans

Sleep and circadian rhythms both contribute to cognitive performance, but the underlying neuronal network- level changes remain unclear. We quantified the contribution of brain state, sleep-pressure dynamics across the sleep-wake cycle, and circadian rhythmicity to electroencephalographic (EEG) functional connectivity (FC) and examined how these network changes relate to cognition. Thirty-four healthy adults completed a 10-day forced-desynchrony protocol to uncouple sleep-wake and endogenous circadian rhythms. From over 1,200 hours of artifact-free EEG, we derived phase-coupling metrics to quantify FC across brain states, thirds-of-the-night (sleep pressure), and circadian phase, and related these network measures to a range of cognitive performance indices. FC differed markedly between brain states, especially in the alpha and sigma bands, and was modulated by sleep history and circadian phase. Principal component analysis revealed both a global and a topographically distributed FC component which responded differentially to sleep pressure. Dissipation of sleep pressure was accompanied by increasing global FC in NREM sleep, and especially in the delta, sigma and beta frequencies, and decreasing global FC in the alpha band. During REM sleep, global FC decreased in nearly all frequency bands with dissipation of sleep pressure. The influence of circadian phase on FC was smaller than that of sleep pressure and varied across brain states. Lower global theta-band FC in NREM and alpha-band FC during wake predicted better alertness and working memory accuracy, an effect modulated by circadian phase. These results suggest that sleep homeostasis and circadian timing interact to stabilize functional brain connectivity in wakefulness, thereby supporting optimal cognitive function. Significance StatementIdentifying how sleep restores neural networks degraded during wakefulness is of significance for understanding sleeps role in maintaining brain function. Here we used a protocol to isolate effects of sleep from effects of circadian rhythmicity on functional connectivity of neural networks and assessed associations with cognitive performance. We found that circadian rhythmicity but in particular the dissipation of sleep pressure had profound effects on global connectivity which were different for NREM sleep, REM sleep and wakefulness and varied across frequency bands. Connectivity measures in the theta, alpha and sleep spindle frequency ranges were associated with cognitive performance. These novel findings provide a new perspective on the nature of the sleep recovery process contributing to the waking performance capability of human brains.

neuroscience↗

Performance of blood-based biomarkers for human circadian pacemaker phase: Training sets matter as much as feature selection methods

Biomarkers are valuable tools in a wide range of human health areas including circadian medicine. Valid, low burden, multivariate molecular approaches to assess circadian phase at scale in people living and working in the real-world hold promise for translating basic circadian knowledge to practical applications. However, standards for the development and evaluation of these circadian biomarkers have not yet been established, even though several publications report such biomarkers and claim that the methods are universal. Here we present a basic exploration of some of the determinants and confounds of blood-based biomarker development for SCN phase by reanalysing publicly available data sets. We compare performance of biomarkers based on three feature selection methods: Partial Least Squares Regression, ZeitZeiger and Elastic Net, as well as performance of a standard set of clock genes. We explore the effects of training sample size and the impact of the experimental protocols from which training samples are drawn and on which performance is tested. Approaches based on small sample sizes used for training are prone to poor performance due to overfitting. Performance to some extent depends on the feature selection method, but at least as much on the experimental conditions from which the biomarker training samples were drawn. Performance of biomarkers developed under baseline conditions do not necessarily translate to protocols that mimic real world scenarios such as shiftwork in which sleep may be restricted or desynchronised from endogenous circadian SCN phase. The molecular features selected by the various approaches to develop biomarkers for SCN phase show very little overlap, although the processes associated with these features have common themes with response to steroid hormones, i.e. cortisol being the most prominent. Overall, the findings indicate that establishment of circadian biomarkers should be guided by established biomarker development concepts and foundational principles of human circadian biology.

bioinformatics↗

Lateralised modulation of posterior alpha oscillations by closed loop auditory stimulation during memory retention

Alpha oscillations have been implicated in the maintenance of working memory representations. Notably, when memorised content is spatially lateralised, the power of posterior alpha activity exhibits corresponding lateralisation during the retention interval, consistent with the retinotopic organisation of the visual cortex. Beyond power, alpha frequency has also been linked to memory performance, with faster alpha rhythms associated with enhanced retention. These findings position alpha oscillations as a promising target for neuromodulation. In this study, we demonstrate that although alpha frequency is not typically lateralised in a retinotopic manner during working memory retention, such lateralisation can be externally induced. Using alpha closed-loop auditory stimulation (CLAS), and leveraging the phase-dependent responsiveness of alpha oscillations to sound, we successfully modulated alpha frequency asymmetrically between the visual cortices. The extent of induced frequency lateralisation was associated with the behavioural asymmetry in task performance.

neuroscience↗

The two-process model: How simple, complex, unique is it from a mathematical perspective?

The two-process model (2pm) of sleep regulation is a conceptual framework and consists of mathematical equations. It shares similarities with models for cardiac, respiratory and neuronal rhythms and falls within the wider class of coupled oscillator models. The 2pm is related to neuronal mutual inhibition models of sleep-wake regulation. The mathematical structure of the 2pm, in which the sleep-wake cycle is entrained to the circadian pacemaker, explains sleep patterns in the absence of 24-h time cues, in different species and in early childhood. Extending the 2pm with a process describing the response of the circadian pacemaker to light creates a hierarchical entrainment system with feedback which permits quantitative modelling of the effect of self-selected light on sleep and circadian timing. The extended 2pm provides new interpretations of sleep phenotypes and provides quantitative predictions of effects of sleep and light interventions to support sleep and circadian alignment in individuals, including those with neurodegenerative disorders.

neuroscience↗

Closed-loop auditory stimulation targeting alpha and theta oscillations during REM sleep induces phase-dependent power and frequency changes

BackgroundAlpha and theta oscillations characterize the waking human electroencephalogram (EEG) and can be modulated by closed-loop auditory stimulation (CLAS). These oscillations also occur during rapid eye movement (REM) sleep, but whether they can be modulated by CLAS is not known. ObjectiveInvestigate whether CLAS can modulate alpha and theta oscillations during REM sleep in a targeted phase-dependent manner. MethodsWe recorded high-density EEG during an extended overnight sleep period in 18 healthy young adults. Auditory stimulation was delivered during both phasic and tonic REM sleep in alternating 6 s ON and 6 s OFF windows. During the ON windows, stimuli were phase-locked to four orthogonal phases of ongoing alpha or theta oscillations detected in a frontal electrode (Fz). ResultsDuring ON windows, the four orthogonal phases of ongoing alpha and theta oscillations were targeted with high accuracy. Alpha and theta CLAS induced phase-dependent changes in power and frequency at the target location. Frequency-specific effects were observed for alpha trough (speeding up) and rising (slowing down) and theta trough (speeding up) conditions. These phase-dependent changes of CLAS were observed during both REM sleep substages, even though the amplitude evoked by auditory stimuli which were not phase-locked was very much reduced in phasic compared to tonic REM sleep. ConclusionsThis study provides evidence that faster REM sleep rhythms can be modulated by CLAS in a phase-dependent manner. This offers a new approach to investigate how modulation of REM sleep oscillations affects the contribution of this vigilance state to brain function. Highlights- REM sleep alpha and theta oscillations can be modulated using phase-locked CLAS - Phase-dependent changes in power and frequency are observed in the target area - Phase-dependent modulation occurs in phasic and tonic REM sleep Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/582907v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@771baborg.highwire.dtl.DTLVardef@1b9b13corg.highwire.dtl.DTLVardef@22e85corg.highwire.dtl.DTLVardef@1c50edc_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Model integration of circadian and sleep-wake driven contributions to rhythmic gene expression reveals novel regulatory principles

Transcriptome studies aim at gaining insight into the molecular pathways underlying biological processes. Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis describe these two processes independently, using separate models such as sinusoidal oscillations and exponential saturating functions. Rhythmically expressed genes are, however, influenced by both processes. We therefore implemented a driven, damped harmonic oscillator model which can accommodate both types of dynamics by varying the degree of damping. This makes it possible to estimate the contribution of circadian and sleep-wake driven influences on the expression of a gene within the framework of a single model. We applied the model to cortex, liver, and blood data obtained in mice and humans. The model reliably captured a wide range of rhythmic dynamics under various experimental conditions, including the long-term amplitude reduction of cortical clock-gene rhythms observed after sleep deprivation. Cortical gene expression was generally influenced more by sleep-wake driven than circadian factors, while the opposite was observed in liver and blood. Importantly, the model suggested that sleep-wake state can alter gene expression with a delayed, long-lasting response not previously considered. Our model further predicted that, perhaps paradoxically, the gain in sleep time after sleep deprivation, delayed re-establishing baseline expression rhythms of intrinsically oscillatory transcripts indicating that similar to insufficient sleep, also excess sleep can impact rhythmic gene expression. Because of the tissue- and gene-specific responses, sleep deprivation led to a profound intra- and inter-tissue desynchronization which in the cortex lasted well beyond phenotypic sleep-wake recovery. The results demonstrate that analyzing rhythmic gene expression must take the complex interactions between circadian and sleep-wake influences into account. The model is a versatile tool with a low number of free parameters to fit and predict gene expression under a variety of conditions relevant to society.

systems biology↗

Mathematical analysis of light-sensitivity related challenges in assessment of the intrinsic period of the human circadian pacemaker

Accurate assessment of the intrinsic period of the human circadian pacemaker is essential for a quantitative understanding of how our circadian rhythms are synchronised to exposure to natural and man-made light-dark cycles. The gold standard method for assessing intrinsic period in humans is forced desynchrony (FD) which assumes that the confounding effect of light on assessment of intrinsic period is removed by scheduling sleep-wake and associated dim light-dark (LD) cycles to periods outside the range of entrainment of the circadian pacemaker. However, the observation that the mean period of free-running blind people is longer than the mean period of sighted people assessed by FD (24.50 {+/-} 0.17 h versus 24.15 {+/-} 0.20 h, p < 0.001) appears inconsistent with this assertion. Here, we present a mathematical analysis using a simple parametric model of the circadian pacemaker with a sinusoidal velocity response curve (VRC) describing the effect of light on the speed of the oscillator. The analysis shows that the shorter period in FD may be explained by exquisite sensitivity of the human circadian pacemaker to low light intensities and a VRC with a larger advance region than delay region. The main implication of this analysis, which generates new and testable predictions, is that current quantitative models for predicting how light exposure affects entrainment of the human circadian system may not accurately capture the effect of dim light. The mathematical analysis generates new predictions which can be tested in laboratory experiments. These findings have implications for managing healthy entrainment of human circadian clocks in societies with abundant access to light sources with powerful biological effects.

neuroscience↗

In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men

Brain structural integrity has been suggested to contribute to the variability in human sleep quality and composition. The associations between sleep parameters and the regional integrity of subcortical structures implicated in sleep-wake regulation remain, however, largely unexplored. The present study aimed at assessing association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem with the variability in the sleep electrophysiology in a large sample of healthy young men (N=321;[~]22y). Generalized Additive Model for Location, Scale and Shape (GAMLSS) was used to seek associations between sleep metrics and Magnetisation Transfer saturation (MTsat) qMRI values, proxy for myelin content. Separate GAMLSS revealed that sleep onset latency and slow wave sleep intensity were significantly associated with MTsat-derived myelin estimates in the brainstem (pcorrected[&le;].03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction - pcorrected[&le;].03), with higher MTsat value linked to better values in the two sleep metrics in the individuals of our sample aged [~]18 to 20y. Similar associations were detected across different parts of the brainstem (pcorrected[&le;].03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the many reticular nuclei of the brainstem essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

neuroscience↗

Multi-night naturalistic cortico-basal recordings reveal mechanisms of NREM slow wave suppression and spontaneous awakenings in Parkinson's disease

BackgroundSleep disturbance is a prevalent and highly disabling comorbidity in individuals with Parkinsons disease (PD) that leads to worsening of daytime symptoms, accelerated disease progression and reduced quality of life. ObjectivesWe aimed to investigate changes in sleep neurophysiology in PD particularly during non-rapid eye movement (NREM) sleep, both in the presence and absence of deep brain stimulation (DBS). MethodsMulti-night (n=58) intracranial recordings were performed at-home, from chronic electrocorticography and subcortical electrodes, with sensing-enabled DBS pulse generators, paired with portable polysomnography. Four people with PD and one person with cervical dystonia were evaluated to determine the neural structures, signals and connections modulated during NREM sleep and prior to spontaneous awakenings. Recordings were performed both ON and OFF DBS in the presence of conventional dopaminergic replacement medications. ResultsWe demonstrate an increase in cortico-basal slow wave activity in delta (1-4 Hz) and a decrease in beta (13-31 Hz) during NREM (N2 and N3) versus wakefulness in PD. Cortical-subcortical coherence was also found to be higher in the delta range and lower in the beta range during NREM versus wakefulness. DBS stimulation resulted in a further elevation in cortical delta and a decrease in alpha (8-13 Hz) and low beta (13-15 Hz) power compared to the OFF stimulation state. During NREM sleep, we observed a strong inverse interaction between subcortical beta and cortical slow wave activity and found that subcortical beta increases prior to spontaneous awakenings. ConclusionsChronic, multi-night recordings in PD reveal opposing sleep stage specific modulations of cortico-basal slow wave activity in delta and subcortical beta power and connectivity in NREM, effects that are enhanced in the presence of DBS. Within NREM specifically, subcortical beta and cortical delta are strongly inversely correlated and subcortical beta power is found to increase prior to and predict spontaneous awakenings. We find that DBS therapy appears to improve sleep in PD partially through direct modulation of cortico-basal beta and delta oscillations. Our findings help elucidate a contributory mechanism responsible for sleep disturbances in PD and highlight potential biomarkers for future precision neuromodulation therapies targeting sleep and spontaneous awakenings.

neuroscience↗

Method to determine whether sleep phenotypes are driven by endogenous circadian rhythmicity or environmental light by combining longitudinal data and personalised mathematical models

Sleep timing varies between individuals and can be altered in mental and physical health conditions. Sleep and circadian sleep phenotypes, including circadian rhythm sleep-wake disorders, may be driven by endogenous physiological processes, exogeneous environmental light exposure along with social constraints and behavioural factors. Identifying the relative contributions of these driving factors to different phenotypes is essential for the design of personalised interventions. The timing of the human sleep-wake cycle has been modelled as an interaction of a relaxation oscillator (the sleep homeostat), a stable limit cycle oscillator with a near 24-hour period (the circadian process), man-made light exposure and the natural light-dark cycle generated by the Earths rotation. However, these models have rarely been used to quantitatively describe sleep at the individual level. Here, we present a new Homeostatic-Circadian-Light model (HCL) which is simpler, more transparent and more computationally efficient than other available models and is designed to run using longitudinal sleep and light exposure data from wearable sensors. We carry out a systematic sensitivity analysis for all model parameters and discuss parameter identifiability. We demonstrate that individual sleep phenotypes in each of 34 older participants (65-83y) can be described by feeding individual participant light exposure patterns into the model and fitting two parameters that capture individual average sleep duration and timing. The fitted parameters describe endogenous drivers of sleep phenotypes. We then quantify exogenous drivers using a novel metric which encodes the circadian phase dependence of the response to light. Combining endogenous and exogeneous drivers better explains individual mean mid-sleep (adjusted R-squared 0.64) than either driver on its own (adjusted R-squared 0.08 and 0.17 respectively). Critically, our model and analysis highlights that different people exhibiting the same sleep phenotype may have different driving factors and opens the door to personalised interventions to regularize sleep-wake timing that are readily implementable with current digital health technology. Author summaryDisrupted sleep has long term health consequences and affects our day-to-day ability to function physically, mentally and emotionally. But what determines when and how long we sleep? It is well-known that daily light exposure patterns determine the timing of the body clock. However, creating mathematical models that can take realistic light exposure patterns and predict plausible sleep timing has been challenging. Furthermore, nearly all previous studies have focused on developing models for average behaviour, yet sleep timing and duration are highly individual. In this paper, we present a simple model that combines sleep regulatory and circadian processes. The model can take individual light exposure patterns and, by fitting physiologically plausible parameters, describe individual mean sleep timing and duration. We test our model on data collected from 34 older participants. Our modelling approach suggests that some of the participants slept late because of physiological factors, while for other individuals, late sleep was a consequence of their light environment. This approach of combining a model with longitudinal data could be implemented in digital health technology such that your smart watch could tell you not only how you slept last night, but also how to change your light environment to sleep better tomorrow.

neuroscience↗

Perfect Timing: Effects of Auditory Stimulation on Alpha Oscillations During Wakefulness and the Transition to Sleep are Phase-dependent in Humans

Alpha oscillations play a vital role in managing the brains resources, inhibiting neural activity as a function of their phase and amplitude, and are changed in many brain disorders. Developing minimally invasive tools to modulate alpha activity and identifying the parameters that determine its response to exogenous modulators, is essential for the implementation of focussed interventions. We introduce Alpha Closed-Loop Auditory Stimulation (CLAS) as an EEG-based method to augment and investigate these brain rhythms in humans with specificity and selectivity, using targeted auditory stimulation. Across three independent studies, we demonstrate that CLAS alters alpha power, frequency, and connectivity in a phase, amplitude and topography-dependent manner. Using a single-pulse-CLAS evoked potentials approach we show that the effects of auditory stimuli on alpha oscillations and resulting evoked potentials can be explained within the theoretical framework of oscillator theory and a phase-reset mechanism. Finally, we demonstrate the functional relevance of our approach by showing that CLAS modulates sleep onset dynamics in an alpha phase-dependent manner.

neuroscience↗

Overlap of expression and alignment of diurnal and circadian rhythmicity in the human blood transcriptome with organ and tissue specific rhythmicity in a non-human primate

BACKGROUNDTwenty-four-hour rhythmicity in transcriptomes of tissues and organs is driven by local circadian oscillators, systemic factors, the central circadian pacemaker, and light-dark cycles. This rhythmicity is to some extent organ- and tissue-specific such that the sets of rhythmic transcripts or their timing are different across tissues/organs. Monitoring rhythmicity of tissues and organs holds promise for circadian medicine, but in humans most tissues and organs are not easily accessible. To investigate the extent to which rhythmicity in the human blood transcriptome reflects rhythmicity in tissues and organs, we compared the overlap and timing of rhythmic transcripts in human blood and rhythmic transcripts in 64 tissues/organs of the baboon. METHODSRhythmicity in the transcriptomes of humans and baboons were compared using set logic, circular cross-correlation, circular clustering, functional enrichment analyses and partial least squares regression. RESULTSOf the 759 orthologous genes that were rhythmic in human blood, 652 (86%) were also rhythmic in at least one baboon tissue. Most of these genes were associated with basic processes such as transcription and protein homeostasis. 109 (17%) of the 652 overlapping rhythmic genes were reported as rhythmic in only one baboon tissue or organ and several of these genes have tissue/organ-specific functions. Analysis of the alignment between baboon and human transcriptomes showed that in these diurnal species, rhythmicity is aligned with the onset, rather than midpoint or end of light period. In both species, the timing of rhythmic transcripts displayed prominent night and day clusters, with genes in the dark cluster associated with translation. The timing of human and baboon transcriptomes was significantly correlated in 25 tissue/organs with an average earlier timing of 3.21 h (SD 2.47 h) in human blood. CONCLUSIONSThe human blood transcriptome contains sets of rhythmic genes that overlap with rhythmic genes of tissues/organs, some of which are tissue/organ-specific, in the baboon. The rhythmic sets vary across tissues/organs but the timing of most rhythmic genes is similar across human blood and baboon tissues/organs. These results have implications for our understanding of the regulation of rhythmicity across tissues/organs and species and development of blood transcriptome-based biomarkers for rhythmicity in tissues and organs.

molecular biology↗

Fatigue, Alertness and Risk Prediction for Shift Workers

Executive summaryO_LIThis report describes the principal outcomes of an Impact Acceleration Account project (grant number EP/I000992/1) between the University of Surrey and Transport for London carried out between Oct. 2019 and Mar. 2020. C_LIO_LIThe aim of the project was to compare the Health and Safety Executive (HSE) Fatigue Risk tool with SAFTE and other more recent models of fatigue, where fatigue here primarily means a reduced ability to function effectively and efficiently as a result of inadequate sleep. C_LIO_LIWe have not sought to discuss the useability of the HSE Fatigue Risk tool or SAFTE since this has been discussed comprehensively elsewhere (e.g. [1, 2]). We have instead focussed on the fundamental principles underlying the models. C_LIO_LIAll current biomathematical models have limitations and make asumptions that are not always evident from the accompanying documentation. Since full details of the HSE Fatigue Risk tool and the SAFTE model are not publicly available, Sections 1 and 2 give a mathematical description of the equations that we believe underlie each of these models. C_LIO_LIA comparison of predictions made by our versions of the HSE and SAFTE equations for one particular shift schedule of relevance to the UK and global tunnelling and construction industries is shown in Section 3. In this comparison, we use data collected durings TfLs Crossrail project by Dragados1. Essentially, both models give broadly the same message for the schedule we looked at, but the ability to display fatigue as it develops within a shift is a strength of SAFTE. C_LIO_LIA summary of the strengths and limitations of the use of these kind of scheduling tools is given in the final Section 4. Limitations include: O_LIModels do not describe fatigue during times when people are not in shift (e.g. driving home). However, they could readily be extended to do so. C_LIO_LIModels assume people start well-rested. This is not always a good assumption and can lead to an under-estimate of fatigue. C_LIO_LIMost models are currently based on population averages, but there are large individual different. It would be possible to further develop models to include uncertainty in fatigue predictions associated with individual differences. C_LIO_LIFew mdels include the light environment, which is important both to promote short-term alertness and facilitate circadian alignment. C_LIO_LIModels are not transparent, which makes them hard to independently validate. C_LIO_LIIt is hard to relate the outputs of current models to measureable outcomes in the field. C_LI C_LIO_LIWe also discuss briefly recent developments in mathematical modelling of fatigue and possible future directions. These include O_LIGuidance on scheduling and education on sleep and fatigue should be considered at least as important as current biomathematical models. C_LIO_LIOnly by analysing and integrating high quality individual data on sleep, fatigue, performance, near misses, accidents, actual shift patterns with models can we develop better models and management systems to reduce fatigue and associated risks. Wearables combined with apps present a great opportunity to collect data at scale but need to be used appropriately. C_LIO_LIThe importance of making time for sleep is not always recognised. Education, early diagnosis of sleep disorders such as sleep apnea, and self-monitoring all have a role to play in reducing fatigue-related risk in the work-place. C_LI C_LIO_LISection 3 and Section 4 may be understood without reading the intermediate more mathematical sections. C_LI

neuroscience↗