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Novel measures of sleep and wake continuity in rat and man.
Get PDFHuman and rodent vigilance states have evolutionarily conserved control mechanisms, which suggests that measures of sleep can translate from the laboratory to the clinic. Continuity is an essential aspect of sleep architecture that facilitates the restoration of both body and mind. Current measures of vigilance state continuity do not align well between species and this prevents accurate translation. Throughout this thesis, survival and transition probability analyses were evaluated for their ability to quantify vigilance state continuity in humans and rats. These techniques produced more effective quantification of sleep architecture than metrics such as wake after sleep onset, number of awakenings and average bout lengths. Two methods for defining a bout were first investigated. In both humans and rats, statistical properties of bouts were characterized using different bout-duration thresholds. It was found that bouts are best modelled with distributions that include a time component. Biological relevance of sleep continuity was also investigated in rats, where bouts of NREM sleep as short as 20 seconds reduced the homeostatic pressure, yet awakenings as short as 10 seconds were enough to disrupt the restorative processes of sleep. Short bouts were therefore an important component of sleep architecture and must be considered when evaluating continuity. Continuity metrics were next used to evaluate sleep restriction in rats and circadian rhythmicity in humans. Both homeostatic and circadian influences exerted significant control of NREM sleep continuity, whilst REM continuity was mostly unaffected. Finally, pharmacological agents were tested and their impact on state continuity effectively translated between species. NREM sleep continuity was not altered by the REM sleep inhibition of SSRI’s which differed to the deficits induced by REM sleep restriction. The main contribution of this thesis is to demonstrate that accurate quantification of vigilance state continuity can improve understanding of sleep architecture and the evaluation of pharmacological agents to deliver better patient outcomes
The impact of sleep-wake interventions on neuropathology and cognition in a mouse model of dementia
Get PDFSleep-wake disturbances are a common neuropsychiatric symptom of dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). However, no standard-of-care therapies are currently systematically prescribed to address these symptoms. Previous studies showed that sleep disruption is a predictor of cognitive impairment and can exacerbate disease progression in AD patients, whilst enhanced sleep can attenuate both cognitive deficits and underlying pathology in preclinical models of dementia. In this thesis, we investigated the impact of sleep-promoting interventions on neuropathology, sleep-wake disturbances and cognitive decline in the rTg4510 mouse model of dementia. We first characterised specific molecular pathways in 6-months-old mice and confirmed sleep and behavioural deficits of this model compared to wild-type controls. Then, we assessed the effect of chronic administration of two drugs: trazodone, a multifunctional drug commonly used off-label as a hypnotic, and a compound with a similar mechanism of action, compared to placebo. Both drugs transiently delayed tau pathology and reduced microglial activation and expression of the microglial Nod-like receptor protein 3 (NLRP3) inflammasome in male rTg4510 mice after 9-weeks. Other pathways involved in microglial activation and tau propagation, such as P38 mitogen-activated protein kinase (P38 MAPK) signalling and components of the Unfolded Protein Response (UPR), were also transiently inhibited by these treatments. In parallel, we explored the impact of chronic treatment on sleep, as well as olfactory and spatial memory. Chronic trazodone treatment rescued electroencephalography (EEG) slowing disturbances and increased rapid-eye movement sleep (REMS) duration, suggesting it can successfully reverse features typically found in AD patients. Trazodone also attenuated early olfactory memory deficits, which was correlated with changes observed during REMS. In addition, voluntary physical activity was assessed as a potential non-pharmacological intervention to treat tauopathies and related cognitive impairment during moderate to severe stages of disease in rTg4510 mice. However, no positive effect was observed after 5-weeks. Altogether, our data provide novel insights to the beneficial role of multitarget pharmacology on underlying neuropathology and related symptomology in AD and other tauopathies
Extrasynaptic GABAA receptors and the local regulation of sleep
No full textGABA (γ-aminobutyric acid) is the main inhibitory transmitter in the mammalian brain. Recent studies emphasise the importance of extrasynaptic GABAA receptors (i.e., GABAA-Rs located outside the synapse) in controlling the excitability of local neuronal circuits. Extrasynaptic GABAA-Rs mediate a persistent tonic inhibitory transmission and the majority contain the δ-subunit. This novel type of transmission plays a key-role in maintaining the excitability of the thalamo-cortical circuits that generate sleep slow waves. Interestingly, drugs enhancing tonic inhibitory transmission induce slow waves. Traditionally, the regulation of the alternation between sleep and waking was considered to be a global brain process, regulated by the interaction of the circadian clock and a homeostatic process keeping track of how long we have been awake and asleep. However, several studies demonstrated that sleep is also regulated in a local, use-dependent manner. Thus, brain regions that are most activated during wakefulness show more slow waves during subsequent sleep. The aim of this project is to investigate the contribution of the δ-GABAA-Rs-mediated tonic transmission to the local, use-dependent regulation of slow wave sleep. We use an established model of local sleep regulation (i.e., unilateral whisker stimulation inducing changes selectively in the corresponding somatosensory cortex) in a mouse model deficient in the GABAA δ-subunit gene. We first investigate whether whisker stimulation during wakefulness alters the expression levels of δ-GABAA-Rs and other components underlying tonic inhibitory transmission in the controlateral somatosensory cortex and thalamus. We will also assess whether these changes are reversed during subsequent sleep and whether they are correlated with changes in sleep slow waves in the electroencephalogram. In addition, to uncover whether tonic inhibitory transmission contributes to the control of sleep regulation by the circadian clock, we will use an established protocol to separate use-dependent and circadian contributions to sleep regulation. Acknowledgements: Supported by BBSRC (BB/I008926/1
Machine Learning Applied to Video Monitoring of Sleep
Get PDFSleep quality is an important determinant of human health and wellbeing and impacts on many aspects of health, ranging from everyday fitness and general alertness to the rate of recovery from a serious illness. Two important indicators of sleep quality are body posture and movements during sleep. Currently, clinical diagnosis of sleep disorders such as sleep apnea or rapid eye movement (REM) sleep behavior disorder (RBD) requires patients to undergo a polysomnography (PSG)-based assessment in a dedicated clinical sleep unit. This involves attaching multiple electrodes to the head and body, which can themselves impact on sleep quality. Additionally, the current standard manual or automated scoring of sleep state lacks a comprehensive quantification of body position during sleep.However, non-contact camera-based sleep monitoring offers an alternative approach to sleep quality assessment that addresses these shortcomings. Nevertheless, these approaches have not been validated against the PSG gold standard or other clinical methods. Such evaluations to date have relied mainly on simulated sleep rather than natural sleep or require subjects to avoid any occlusion from the bedding. These aspects constitute significant limitations for the routine implementation of video monitoring to measure body position and movements during sleep.In this thesis, the design and development of a non-contact monitoring system that automatically analyses body posture and movement by using video data captured from actual sleep using a blanket bed covering are presented. Experimental data are compared to gold standard methods of PSG and manual expert annotation of the video data. Starting with simulated sleep data, a variety of different methodologies were explored based on deep learning for automatic sleep pose detection, including a 4-layer convolutional neural network (CNN) network, two-step deep learning, and combining deep learning with tensor factorisation for the detection of body poses during sleep when poses were occluded by a blanket.Nocturnal sleep was quantified in 12 healthy participants using recordings of the IR camera as well as PSG data in the Surrey sleep laboratory. Using a transfer learning approach applied to IR camera data, supervised machine learning strategies successfully quantified sleep poses of participants covered by a blanket. This represents the first occasion that such a machine learning approach has been used to successfully detect four predefined poses and the empty bed state during 8-10 hour overnight sleep episodes. The Markov Chain transition matrix was also used to quantify sleep behaviour and perform another comparison method against PSG, and manual sleep pose scoring. In a cohort of 12 healthy participants, we found that fine-tuning a ResNet-152 pre-trained CNN network achieved the best performance compared with the standard end-to-end CNN and other pre-trained CNN networks. The method outperforms other video-based methods with an accuracy of 95.1% for sleep pose estimation and outperforms the clinical standard for pose estimation using a PSG position sensor.Unsupervised data-driven pose analysis has also been investigated as a potential avenue of quantifying personalised sleep behaviour. This approach revealed that a participant may have as many as 17 distinct sleep poses during a nocturnal sleep episode. Pilot analysis of the correlation between the sleep poses as well as movement with sleep physiology such as sleep stage, heart rate, and heart rate variability has also been performed. This demonstrates that while sleep pose based on four standard poses and sleep physiology only show low levels of correlation, unsupervised clustering when combined with physiology such as heart rate may offer an alternative approach to resolving sleep states using non-contact strategies. The results of these studies indicate that it is feasible to use video data and machine learning to quantify sleep behaviour
Analysis of brain activity during the sleep-wake cycles of rodents and humans with symbolic dynamic analysis of the electroencephalogram.
Get PDFSleep is an essential physiological phenomenon which is regulated by fundamental sleep-wake cycles. Sleep is formed of non-rapid-eye-movement (NREM) and REM stages where NREM and REM sleep stages alternate with wakefulness in a whole night sleep (i.e., typically consists of several sleep-wake cycles). During sleep, brain is active and the activity also alters with changing vigilance states (VS). Furthermore, physiological or external changes in the brain structure might influence brain activity during sleep. Effects of ageing, sex differences, and pharmacological manipulations have been widely investigated in sleep research using Fourier Transform. However, the use of non-linear analysis techniques might be more suitable in analysing non-linear and non-stationary signals (e.g., electroencephalogram (EEG)). Therefore, non-linear analysis has been used within this PhD with the hypothesis that these methods might reveal hidden characteristics in the changing brain signals that are difficult to detect with traditional EEG power spectral density analysis. The use of non-linear analysis techniques (e.g., symbolic dynamic analysis (SDA)) will allow to further dissect the physiological significance of activity-dependent changes of neuronal networks across sleep-wake cycles, as well as the significance of brain activity patterns during waking, sleep, sleep deprivation (SD), or induced by sleep-promoting drugs and pharmacological treatments.
In this PhD, rodent and human sleep EEG recordings were analysed using SDA methods: Lempel-Ziv complexity (LZC), Permutation Entropy (PE) and Permutation Lempel-Ziv complexity (PLZC). All the methods were able characterise different VS with wakefulness and REM sleep resulting in higher measures of complexity compared to NREM sleep suggesting an active state of the brain in these VS. This was measured in all datasets assisting the hypothesis on the usefulness of these techniques in sleep research by providing the minimum requirement for sleep analysis. In addition to this, SD significantly reduced complexity in the following sleep period supporting the compensation process for the lost sleep by the increased in slow wave activity which was reflected as reduced complexity in this study. Furthermore, a low dose tiagabine administration’s sleep compensation promoting effect was found in mice.
Moreover, ageing was identified as a main effect on changes in brain activity. These changes were more pronounced in the old age where complexity was significantly lower compared to young age. On the one hand, this was found with all three methods and contributing to the hypothesis that these techniques reveal structural dynamic changes due to physiological alterations. On the other hand, no significant differences in complexity across genders were found suggesting the underlying mechanisms to maintain sleep-wake cycles are similar for men and women. This finding with further investigation might corroborate to question the need to use both genders in drug trials. Furthermore, significant changes in brain activity were found at different times of the sleep period highlighting the changes occurring within VS as sleep progresses. This also has an impact on the way sleep stages are scored and investigated which are influenced by different brain activity levels within each VS throughout the entire sleep.
All in all, this study achieved to support its hypothesis of determining the changes in brain activity as a complexity measure by characterising sleep under physiological and pharmacologically induced EEG datasets in mice and in humans. The study was a novel application to analyse sleep in these conditions. However, with further analysis performed on larger datasets, its findings together with surrogate data analysis proved SDA techniques’ robust usability which can complement the gold standard FT analysis in sleep research
Extrasynaptic GABAA receptors and the local regulation of sleep
Get PDFGABA (γ-aminobutyric acid) is the main inhibitory transmitter in the mammalian brain. Recent studies emphasise the importance of extrasynaptic GABAA receptors (i.e., GABAA-Rs located outside the synapse) in controlling the excitability of local neuronal circuits. Extrasynaptic GABAA-Rs mediate a persistent tonic inhibitory transmission and the majority contain the δ-subunit. This novel type of transmission plays a key-role in maintaining the excitability of the thalamo-cortical circuits that generate sleep slow waves. Interestingly, drugs enhancing tonic inhibitory transmission induce slow waves. Traditionally, the regulation of the alternation between sleep and waking was considered to be a global brain process, regulated by the interaction of the circadian clock and a homeostatic process keeping track of how long we have been awake and asleep. However, several studies demonstrated that sleep is also regulated in a local, use-dependent manner. Thus, brain regions that are most activated during wakefulness show more slow waves during subsequent sleep. The aim of this project is to investigate the contribution of the δ-GABAA-Rs-mediated tonic transmission to the local, use-dependent regulation of slow wave sleep. We use an established model of local sleep regulation (i.e., unilateral whisker stimulation inducing changes selectively in the corresponding somatosensory cortex) in a mouse model deficient in the GABAA δ-subunit gene. We first investigate whether whisker stimulation during wakefulness alters the expression levels of δ-GABAA-Rs and other components underlying tonic inhibitory transmission in the controlateral somatosensory cortex and thalamus. We will also assess whether these changes are reversed during subsequent sleep and whether they are correlated with changes in sleep slow waves in the electroencephalogram. In addition, to uncover whether tonic inhibitory transmission contributes to the control of sleep regulation by the circadian clock, we will use an established protocol to separate use-dependent and circadian contributions to sleep regulation. Acknowledgements: Supported by BBSRC (BB/I008926/1
Translational measures of the effects of insufficient sleep on cognition in the rat
Get PDFInsufficient sleep is highly prevalent and associated with deficits in functional wakefulness. Thus, a need remains for pre-clinical evaluation of sleep restriction to develop countermeasures for functional deficits. The overall aim of this thesis was to evaluate translational methods to assess the cognitive consequences of sleep loss in the rat.
We first compared the effects of 11-h sleep restriction induced by three novel non-invasive protocols on attention using a Simple Response Latency task (SRLT). Wakefulness was enforced by cylinder rotation following a Constant, Decreasing or ‘Weibull’ (i.e., modelled on EEG-driven sleep restriction) protocols. While all protocols resulted in sleep loss and attentional deficits, differences in sleep recovery and functional alterations were identified, with the Decreasing and Weibull methods inducing attentional deficits similar to those observed in humans. Many behavioural tasks use food as a reward in rodents, thus we next assessed the interaction of food and sleep restriction. Food-restricted rats displayed resilience in SRLT performance to the effects of 11-h sleep restriction compared to ad libitum-fed rats. By contrast, motivation for food reward value was not altered in a progressive ratio task. We then evaluated the effects of pharmacological treatments to counteract the effects of 11-h sleep restriction. The drugs showed distinct pro-vigilant profiles, with caffeine and modafinil displaying beneficial effects on SRLT performance. A non-pharmacological counter-measure (naps) was unsuccessful in alleviating functional deficits induced by sleep loss. Finally, we applied oxygen amperometry, as a surrogate of neuroimaging, and measured oxygen consumption in the nucleus accumbens during the SRLT. However, data interpretation was limited due to throughput capabilities.
Overall, the data indicated the sleep restriction methodologies provide a translational platform to develop novel pro-vigilant compounds that improve sustained attention. Careful choice of methodologies (i.e., sleep restriction protocols; reward) is important when studying functional deficits induced by sleep loss in rodents
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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