Activities, bioavailability, and metabolism of lipids from structural membranes and oils: Promising research on mild cognitive impairment.
Pérez-Gálvez Antonio,Jarén-Galán Manuel,Garrido-Fernández Juan,Calvo M Visitacion,Visioli Francesco,Fontecha Javier
Concomitant with increased lifespan, large segments of the population are experiencing cognitive decline, which might progress to Alzheimer's disease (AD). Currently, there is no cure for AD and, once the neurodegenerative disorders are established, patients use pharmacologic therapy to slow the progression of the symptoms and require appropriate care to manage their condition. The preclinical stage of neural degeneration that progress through mild cognitive impairment (MCI) before the onset of AD is when it might be possible to introduce behavioral changes and pharma-nutritional interventions that modify the risk factors of MCI conversion to AD. Some food components accumulate in brain tissues, where they play essential roles. Among them, polar lipids, omega 3 fatty acids, and carotenoids appear to work additively or synergistically. Therefore, there is an opportunity to formulate nutraceuticals/functional foods to slow the progression of MCI. In this paper, we review the biochemical bases and recent interventions with bioactive lipids-rich formulations. Based on accumulated evidence, we propose that appropriate large-scale trials are warranted.
Depression in sleep disturbance: A review on a bidirectional relationship, mechanisms and treatment.
Fang Hong,Tu Sheng,Sheng Jifang,Shao Anwen
Journal of cellular and molecular medicine
Sleep disturbance is the most prominent symptom in depressive patients and was formerly regarded as a main secondary manifestation of depression. However, many longitudinal studies have identified insomnia as an independent risk factor for the development of emerging or recurrent depression among young, middle-aged and older adults. This bidirectional association between sleep disturbance and depression has created a new perspective that sleep problems are no longer an epiphenomenon of depression but a predictive prodromal symptom. In this review, we highlight the treatment of sleep disturbance before, during and after depression, which probably plays an important role in improving outcomes and preventing the recurrence of depression. In clinical practice, pharmacological therapies, including hypnotics and antidepressants, and non-pharmacological therapies are typically applied. A better understanding of the pathophysiological mechanisms between sleep disturbance and depression can help psychiatrists better manage this comorbidity.
Sleep and inflammation: partners in sickness and in health.
Irwin Michael R
Nature reviews. Immunology
The discovery of reciprocal connections between the central nervous system, sleep and the immune system has shown that sleep enhances immune defences and that afferent signals from immune cells promote sleep. One mechanism by which sleep is proposed to provide a survival advantage is in terms of supporting a neurally integrated immune system that might anticipate injury and infectious threats. However, in modern times, chronic social threats can drive the development of sleep disturbances in humans, which can contribute to the dysregulation of inflammatory and antiviral responses. In this Review, I describe our current understanding of the relationship between sleep dynamics and host defence mechanisms, with a focus on cytokine responses, the neuroendocrine and autonomic pathways that connect sleep with the immune system and the role of inflammatory peptides in the homeostatic regulation of sleep. Furthermore, I discuss the therapeutic potential of harnessing these reciprocal mechanisms of sleep-immune regulation to mitigate the risk of inflammatory and infectious diseases.
[Sleep, memory and learning].
Acosta María Teresa
Recent studies have demonstrated that while we are sleeping, our brain is very busy processing all information we have acquired along the day. Lack of sleep has shown to produce deficits in memory consolidation and plays an important role in brain development and brain plasticity in the several developmental stages of the human brain. At the cellular level, circadian cycles coordinate complex mechanism that "turn on and off" genes and cellular structures regulating individual cell functions to impact global organ and systems physiological activities. At the end a perfect and coordinated equilibrium in the mental, emotional and physiological is the goal of this complex process. Sleep impacts memory, learning, mood, behavior, immunological responses, metabolism, hormone levels, digestive process and many more physiological functions. We present a review of three basic aspects related with sleep: a. brain electrical activity during the sleep and neuroanatomic correlation with mechanism related with memory and learning; b. circadian cycles and impact in several physiological systems; c some examples of clinical disorders associated with sleep disorders and impact in learning and memory.
Fatigue and disrupted sleep-wake patterns in patients with cancer: a shared mechanism.
Wu Horng-Shiuann,Davis Jean E,Natavio Teofanes
Clinical journal of oncology nursing
The strong and potentially reciprocal relationship between cancer-related fatigue (CRF) and disrupted sleep-wake patterns suggests a possible shared physiologic pathway. A growing body of evidence supports this and shows that abnormalities in the 24-hour rhythm of stress-related hormones may be related to chronic fatigue and sleep disturbances. Aberrations in the hypothalamic-pituitary-adrenal (HPA) axis, the primary neuroendocrine interface responding to stress, induce important biologic and behavioral consequences. HPA aberrations have long been associated with chronic fatigue syndrome. Many overlapping symptoms exist between chronic fatigue syndrome and CRF, including sleep disruption. Therefore, in the absence of knowledge about CRF mechanisms, emerging biologic models from chronic fatigue syndrome may assist in understanding the cause of CRF. Cancer-associated stressors also may alter the circadian functions of HPA-associated neuroendocrine activities, which result in the symptoms of fatigue and disrupted sleep-wake patterns in patients with cancer. Exploring promising physiologic models furthers the knowledge about CRF and disrupted sleep and may foster hypothesis-based studies of mechanisms that underlie apparent overlapping symptoms, providing the basis for new management to improve sleep and lessen fatigue.
Orexin in Respiratory and Autonomic Regulation, Health and Diseases.
Barnett Savannah,Li Aihua
Orexin neurons, located in the hypothalamus, produce orexin-A and orexin-B neuropeptides and send widespread projections throughout the central nervous system, including many nuclei that are critically involved in sleep-wake, cardiorespiratory, and autonomic regulation. Significant progress has been made to better understand the roles of orexins in the control of breathing and autonomic functions since the discovery of orexins in 1998. Orexin neurons are CO /pH chemosensitive and blockade of orexin receptors with orexin receptor antagonists can significantly attenuate ventilatory response to hypercapnia or CO chemoreflex. Animal models with orexin abnormalities, for example, too little or too much, have all been reported to have significant alterations in breathing, central chemoreception (hypercapnic chemoreflex), blood pressure, thermoregulation, and cardiorespiratory responses to stress. More recent studies further show that abnormalities of the orexin system are linked to many neurological disorders in addition to narcolepsy, for example, sleep disorders, neurodegenerative disorders, neurogenic hypertension, and sudden infant death syndrome. These new findings have significantly advanced the knowledge in understanding the underlying mechanism of orexin-associated health and diseases while providing a new pathway for possible treatments. In this article, we will discuss some of the progresses in basic research and in health and diseases. © 2020 American Physiological Society. Compr Physiol 10:345-363, 2020.
[Cognitive Function and Calcium. Ca2+-dependent regulatory mechanism of circadian clock oscillation and its relevance to neuronal function].
Kon Naohiro,Fukada Yoshitaka
Circadian clock generates a variety of biological rhythms such as sleep/wake cycles and blood hormone rhythms. The circadian clock also bolsters daily mental activities. In fact, abnormalities of the circadian rhythms are found in several neurological disorders. The circadian clock has two important functions: (i) a cell-autonomous oscillatory function and (ii) a phase-adjusting function that synchronizes the clock oscillation with environmental cycling conditions such as light/dark cycle. Behavioral rhythms are controlled by the central clock in hypothalamic suprachiasmatic nucleus (SCN). The central clock orchestrates peripheral clocks in the other tissues via neuronal connection and/or actions of humoral factors. The molecular mechanism of the cell-autonomous clock is based on transcriptional feedback regulation of clock genes by their encoded products. Ca2+ is essential for not only the light response of the clock but also the cell autonomous oscillation mechanism. This article provides an overview of recent progress in studies of Ca2+-dependent regulatory mechanism of the molecular clockwork.
Identification of Neurons with a Privileged Role in Sleep Homeostasis in Drosophila melanogaster.
Seidner Glen,Robinson James E,Wu Meilin,Worden Kurtresha,Masek Pavel,Roberts Stephen W,Keene Alex C,Joiner William J
Current biology : CB
Sleep is thought to be controlled by two main processes: a circadian clock that primarily regulates sleep timing and a homeostatic mechanism that detects and responds to sleep need. Whereas abundant experimental evidence suggests that sleep need increases with time spent awake, the contributions of different brain arousal systems have not been assessed independently of each other to determine whether certain neural circuits, rather than waking per se, selectively contribute to sleep homeostasis. Using the fruit fly, Drosophila melanogaster, we found that sustained thermogenetic activation of three independent neurotransmitter systems promoted nighttime wakefulness. However, only sleep deprivation resulting from activation of cholinergic neurons was sufficient to elicit subsequent homeostatic recovery sleep, as assessed by multiple behavioral criteria. In contrast, sleep deprivation resulting from activation of octopaminergic neurons suppressed homeostatic recovery sleep, indicating that wakefulness can be dissociated from accrual of sleep need. Neurons that promote sleep homeostasis were found to innervate the central brain and motor control regions of the thoracic ganglion. Blocking activity of these neurons suppressed recovery sleep but did not alter baseline sleep, further differentiating between neural control of sleep homeostasis and daily fluctuations in the sleep/wake cycle. Importantly, selective activation of wake-promoting neurons without engaging the sleep homeostat impaired subsequent short-term memory, thus providing evidence that neural circuits that regulate sleep homeostasis are important for behavioral plasticity. Together, our data suggest a neural circuit model involving distinct populations of wake-promoting neurons, some of which are involved in homeostatic control of sleep and cognition.
Sleep-Dependent Oscillatory Synchronization: A Role in Fear Memory Consolidation.
Totty Michael S,Chesney Logan A,Geist Phillip A,Datta Subimal
Frontiers in neural circuits
Sleep plays an important role in memory consolidation through the facilitation of neuronal plasticity; however, how sleep accomplishes this remains to be completely understood. It has previously been demonstrated that neural oscillations are an intrinsic mechanism by which the brain precisely controls neural ensembles. Inter-regional synchronization of these oscillations is also known to facilitate long-range communication and long-term potentiation (LTP). In the present study, we investigated how the characteristic rhythms found in local field potentials (LFPs) during non-REM and REM sleep play a role in emotional memory consolidation. Chronically implanted bipolar electrodes in the lateral amygdala (LA), dorsal and ventral hippocampus (DH, VH), and the infra-limbic (IL), and pre-limbic (PL) prefrontal cortex were used to record LFPs across sleep-wake activity following each day of a Pavlovian cued fear conditioning paradigm. This resulted in three principle findings: (1) theta rhythms during REM sleep are highly synchronized between regions; (2) the extent of inter-regional synchronization during REM and non-REM sleep is altered by FC and EX; (3) the mean phase difference of synchronization between the LA and VH during REM sleep predicts changes in freezing after cued fear extinction. These results both oppose a currently proposed model of sleep-dependent memory consolidation and provide a novel finding which suggests that the role of REM sleep theta rhythms in memory consolidation may rely more on the relative phase-shift between neural oscillations, rather than the extent of phase synchronization.
Acute control of the sleep switch in reveals a role for gap junctions in regulating behavioral responsiveness.
Troup Michael,Yap Melvyn Hw,Rohrscheib Chelsie,Grabowska Martyna J,Ertekin Deniz,Randeniya Roshini,Kottler Benjamin,Larkin Aoife,Munro Kelly,Shaw Paul J,van Swinderen Bruno
Sleep is a dynamic process in most animals, involving distinct stages that probably perform multiple functions for the brain. Before sleep functions can be initiated, it is likely that behavioral responsiveness to the outside world needs to be reduced, even while the animal is still awake. Recent work in has uncovered a sleep switch in the dorsal fan-shaped body (dFB) of the fly's central brain, but it is not known whether these sleep-promoting neurons also govern the acute need to ignore salient stimuli in the environment during sleep transitions. We found that optogenetic activation of the sleep switch suppressed behavioral responsiveness to mechanical stimuli, even in awake flies, indicating a broader role for these neurons in regulating arousal. The dFB-mediated suppression mechanism and its associated neural correlates requires expression, suggesting that the acute need to reduce sensory perception when flies fall asleep is mediated in part by electrical synapses.
Basal ganglia beta oscillations during sleep underlie Parkinsonian insomnia.
Mizrahi-Kliger Aviv D,Kaplan Alexander,Israel Zvi,Deffains Marc,Bergman Hagai
Proceedings of the National Academy of Sciences of the United States of America
Sleep disorders are among the most debilitating comorbidities of Parkinson's disease (PD) and affect the majority of patients. Of these, the most common is insomnia, the difficulty to initiate and maintain sleep. The degree of insomnia correlates with PD severity and it responds to treatments that decrease pathological basal ganglia (BG) beta oscillations (10-17 Hz in primates), suggesting that beta activity in the BG may contribute to insomnia. We used multiple electrodes to record BG spiking and field potentials during normal sleep and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in nonhuman primates. MPTP intoxication resulted in severe insomnia with delayed sleep onset, sleep fragmentation, and increased wakefulness. Insomnia was accompanied by the onset of nonrapid eye movement (NREM) sleep beta oscillations that were synchronized across the BG and cerebral cortex. The BG beta oscillatory activity was associated with a decrease in slow oscillations (0.1-2 Hz) throughout the cortex, and spontaneous awakenings were preceded by an increase in BG beta activity and cortico-BG beta coherence. Finally, the increase in beta oscillations in the basal ganglia during sleep paralleled decreased NREM sleep, increased wakefulness, and more frequent awakenings. These results identify NREM sleep beta oscillation in the BG as a neural correlate of PD insomnia and suggest a mechanism by which this disorder could emerge.
[Controlling sleep/wakefulness using optogenetics].
Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology
Optogenetics is a recently developed experimental technique to control the activity of neurons using light. Optogenetics shows its power to reveal the physiological role of specific neural circuits in the brain. In particular, manipulation of a specific type of neurons using optogenetics with high accuracy timing enables us to analyze causality between neural activity and initiation of animal behaviors. However, to manipulate the activity of specific neurons in vivo, there are two critical steps to succeed in manipulation of the neural activity and control of the behavior of individual animals. The first step is an adequate number of molecules of light-activated protein that has to be expressed in the cell membrane of the neurons of interest. The second step is the optical system to illuminate the targeted neurons with enough intensity of light to activate the light-activated protein. We applied optogenetics to hypothalamic peptidergic neurons such as orexin/hypocretin neurons or melanin concentrating hormone (MCH) neurons. These neurons are implicated in sleep/wakefulness regulation. In this mini review, I will show the regulatory mechanism of sleep/wakefulness by these neurons using optogenetics.
Sleep orchestrates indices of local plasticity and global network stability in the human cortex.
Maier Jonathan G,Kuhn Marion,Mainberger Florian,Nachtsheim Katharina,Guo Stephanie,Bucsenez Ulrike,Feige Bernd,Mikutta Christian,Spiegelhalder Kai,Klöppel Stefan,Normann Claus,Riemann Dieter,Nissen Christoph
Animals and humans spend on average one third of their lives in sleep, but its functions remain to be specified. Distinct lines of research propose that sleep promotes local strengthening of information-bearing synapses (plasticity) and global downscaling of synaptic strength (stability) in neural networks-prerequisites for adaptive behavior in a changing environment. However, the potential orchestration of these processes, particularly in humans, needs to be further characterized. Here, we use electrophysiological, behavioral, and molecular indices to noninvasively study cortical plasticity and network stability in humans. We observe indices of local strengthening of prior induced long-term potentiation-like plasticity (paired associative stimulation induced change in motor-evoked potential) and global network stabilization (homeostatic regulation of wake EEG theta activity) after brief periods of nonrapid eye movement sleep compared with wakefulness. The interplay of local sleep slow oscillations and spindle activity, previously related to synaptic refinements during sleep, is identified as a potential mechanism. Our findings are consistent with the notion that sleep-specific brain activity patterns reduce the plasticity-stability dilemma by orchestrating local plasticity and global stability of neural assemblies in the human cortex. Future studies are needed to further decipher the neural mechanisms underlying our indirect observations.
The role of sleep and wakefulness in myelin plasticity.
de Vivo Luisa,Bellesi Michele
Myelin plasticity is gaining increasing recognition as an essential partner to synaptic plasticity, which mediates experience-dependent brain structure and function. However, how neural activity induces adaptive myelination and which mechanisms are involved remain open questions. More than two decades of transcriptomic studies in rodents have revealed that hundreds of brain transcripts change their expression in relation to the sleep-wake cycle. These studies consistently report upregulation of myelin-related genes during sleep, suggesting that sleep represents a window of opportunity during which myelination occurs. In this review, we summarize recent molecular and morphological studies detailing the dependence of myelin dynamics after sleep, wake, and chronic sleep loss, a condition that can affect myelin substantially. We present novel data about the effects of sleep loss on the node of Ranvier length and provide a hypothetical mechanism through which myelin changes in response to sleep loss. Finally, we discuss the current findings in humans, which appear to confirm the important role of sleep in promoting white matter integrity.
Sleep and Wakefulness Are Controlled by Ventral Medial Midbrain/Pons GABAergic Neurons in Mice.
Takata Yohko,Oishi Yo,Zhou Xu-Zhao,Hasegawa Emi,Takahashi Koji,Cherasse Yoan,Sakurai Takeshi,Lazarus Michael
The Journal of neuroscience : the official journal of the Society for Neuroscience
Sleep-wake behavior is controlled by a wide range of neuronal populations in the mammalian brain. Although the ventral midbrain/pons (VMP) area is suggested to participate in sleep-wake regulation, the neuronal mechanisms have remained unclear. Here, we found that nonspecific cell ablation or selective ablation of GABAergic neurons by expressing diphtheria toxin fragment A in the VMP in male mice induced a large increase in wakefulness that lasted at least 4 weeks. In contrast, selective ablation of dopaminergic neurons in the VMP had little effect on wakefulness. Chemogenetic inhibition of VMP GABAergic neurons also markedly increased wakefulness. The wake-promoting effect of the VMP GABAergic neuron ablation or inhibition was attenuated to varying degrees by the administration of dopamine D1 or D2/3 receptor antagonists and abolished by the administration of both antagonists together. In contrast, chemogenetic activation of VMP GABAergic neurons very strongly increased slow-wave sleep and reduced wakefulness. These findings suggest that VMP GABAergic neurons regulate dopaminergic actions in the sleep-wake behavior of mice. Current understanding of the neuronal mechanisms and populations that regulate sleep-wake behavior is incomplete. Here, we identified a GABAergic ventral midbrain/pons area that is necessary for controlling the daily amount of sleep and wakefulness in mice. We also found that these inhibitory neurons control wakefulness by suppressing dopaminergic systems. Surprisingly, activation of these neurons strongly induced slow-wave sleep while suppressing wakefulness. Our study reveals a new brain mechanism critical for sleep-wake regulation.
Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons.
Ito Hisakatsu,Yanase Makoto,Yamashita Akira,Kitabatake Chigusa,Hamada Asami,Suhara Yuki,Narita Michiko,Ikegami Daigo,Sakai Hiroyasu,Yamazaki Mitsuaki,Narita Minoru
BACKGROUND:Several etiological reports have shown that chronic pain significantly interferes with sleep. Inadequate sleep due to chronic pain may contribute to the stressful negative consequences of living with pain. However, the neurophysiological mechanism by which chronic pain affects sleep-arousal patterns is as yet unknown. Although serotonin (5-HT) was proposed to be responsible for sleep regulation, whether the activity of 5-HTergic neurons in the dorsal raphe nucleus (DRN) is affected by chronic pain has been studied only infrequently. On the other hand, the recent development of optogenetic tools has provided a valuable opportunity to regulate the activity in genetically targeted neural populations with high spatial and temporal precision. In the present study, we investigated whether chronic pain could induce sleep dysregulation while changing the activity of DRN-5-HTergic neurons. Furthermore, we sought to physiologically activate the DRN with channelrhodopsin-2 (ChR2) to identify a causal role for the DRN-5-HT system in promoting and maintaining wakefulness using optogenetics. RESULTS:We produced a sciatic nerve ligation model by tying a tight ligature around approximately one-third to one-half the diameter of the sciatic nerve. In mice with nerve ligation, we confirmed an increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep as monitored by electroencephalogram (EEG). Microinjection of the retrograde tracer fluoro-gold (FG) into the prefrontal cortex (PFC) revealed several retrogradely labeled-cells in the DRN. The key finding of the present study was that the levels of 5-HT released in the PFC by the electrical stimulation of DRN neurons were significantly increased in mice with sciatic nerve ligation. Using optogenetic tools in mice, we found a causal relationship among DRN neuron firing, cortical activity and sleep-to-wake transitions. In particular, the activation of DRN-5-HTergic neurons produced a significant increase in wakefulness and a significant decrease in NREM sleep. The duration of NREM sleep episodes was significantly decreased during photostimulation in these mice. CONCLUSIONS:These results suggest that neuropathic pain accelerates the activity of DRN-5-HTergic neurons. Although further loss-of-function experiments are required, we hypothesize that this activation in DRN neurons may, at least in part, correlate with sleep dysregulation under a neuropathic pain-like state.
The comorbidity of insomnia, chronic pain, and depression: dopamine as a putative mechanism.
Finan Patrick H,Smith Michael T
Sleep medicine reviews
Epidemiological, cross-sectional, and prospective studies suggest that insomnia, chronic pain, and depression frequently co-occur and are mutually interacting conditions. However, the mechanisms underlying these comorbid disorders have yet to be elucidated. Overlapping mechanisms in the central nervous system suggest a common neurobiological substrate(s) may underlie the development and interplay of these disorders. We propose that the mesolimbic dopamine system is an underappreciated and attractive venue for the examination of neurobiological processes involved in the interactions, development, exacerbation, and maintenance of this symptom complex. In the present article, studies from multiple disciplines are reviewed to highlight the role of altered dopaminergic function in the promotion of arousal, pain sensitivity, and mood disturbance. We argue that studies aiming to elucidate common factors accounting for the comorbidity of insomnia, chronic pain, and depression should evaluate functioning within the mesolimbic dopaminergic system and its effect on common processes known to be dysregulated in all three disorders.
Toward the Mysteries of Sleep.
The Keio journal of medicine
Although sleep is a ubiquitous behavior in animal species with well-developed central nervous systems, many aspects in the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has triggered an intensive research examining the exact role of the orexinergic and other neural pathways in the regulation of sleep/wakefulness. The orexin receptor antagonist suvorexant, which specifically block the endogenous waking system, has been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >8,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutation in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Since these dominant mutations cause strong phenotypic traits, we expect that the mutated genes will provide new insights into the elusive pathway regulating sleep/wakefulness. Indeed, through a systematic cross-comparison of the Sleepy mutants and sleep-deprived mice, we have recently found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.
Neural Plasticity Is Involved in Physiological Sleep, Depressive Sleep Disturbances, and Antidepressant Treatments.
Zhang Meng-Qi,Li Rui,Wang Yi-Qun,Huang Zhi-Li
Depression, which is characterized by a pervasive and persistent low mood and anhedonia, greatly impacts patients, their families, and society. The associated and recurring sleep disturbances further reduce patient's quality of life. However, therapeutic sleep deprivation has been regarded as a rapid and robust antidepressant treatment for several decades, which suggests a complicated role of sleep in development of depression. Changes in neural plasticity are observed during physiological sleep, therapeutic sleep deprivation, and depression. This correlation might help us to understand better the mechanism underlying development of depression and the role of sleep. In this review, we first introduce the structure of sleep and the facilitated neural plasticity caused by physiological sleep. Then, we introduce sleep disturbances and changes in plasticity in patients with depression. Finally, the effects and mechanisms of antidepressants and therapeutic sleep deprivation on neural plasticity are discussed.
[Sleep and cognitive impairment in neurodegenerative diseases].
Yakovleva O V,Poluektov M G,Lyashenko E A,Levin O S
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova
Sleep and wakefulness disorders are commonly seen in patients with Parkinson's disease, Lewy body dementia and Alzheimer's disease. Sleep provides a lot of functions which sustain normal condition of the brain and sleep disturbances can be one of the factors contributing to the development of neurodegenerative diseases. Sleep and wakefulness disorders can worsen the course of the neurodegenerative process and lead to an increase of symptoms, including cognitive dysfunction. In this review, the relationship between sleep and wakefulness disorders and cognitive impairment as well as clinical forms of sleep and wakefulness disorders and treatment methods in such patients are discussed.
Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness.
Branch Abigail F,Navidi William,Tabuchi Sawako,Terao Akira,Yamanaka Akihiro,Scammell Thomas E,Diniz Behn Cecilia
STUDY OBJECTIVES:Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep. To determine the effects of the orexin neurons on the dynamics of sleep/wake behavior, we analyzed sleep/wake architecture in a novel mouse model of acute orexin neuron loss. METHODS:We used survival analysis and other statistical methods to analyze sleep/wake architecture in orexin-tTA ; TetO diphtheria toxin A mice at different stages of orexin neuron degeneration. RESULTS:Progressive loss of the orexin neurons dramatically reduced survival of long wake bouts, but it also improved survival of brief wake bouts. In addition, with loss of the orexin neurons, mice were more likely to wake during the first 30 sec of nonrapid eye movement sleep and then less likely to return to sleep during the first 60 sec of wakefulness. CONCLUSIONS:These findings help explain the sleepiness and fragmented sleep that are characteristic of narcolepsy. Orexin neuron loss impairs survival of long wake bouts resulting in poor maintenance of wakefulness, but this neuronal loss also fragments sleep by increasing the risk of awakening at the beginning of sleep and then reducing the likelihood of quickly returning to sleep.
Control of sleep and wakefulness in health and disease.
Zeitzer Jamie M
Progress in molecular biology and translational science
Sleep and wake are actively promoted states of consciousness that are dependent on a network of state-modulating neurons arising from both the brain stem and hypothalamus. This network helps to coordinate the occurrence of a sleep state in billions of cortical neurons. In many neurological diseases, there is a specific disruption to one of the components of this network. Under conditions of such disruptions, we often gain an improved understanding of the underlying function of the specific component under nonpathological conditions. The loss or dysfunction of one of the hypothalamic or brain stem regions that are responsible for promotion of sleep or wake can lead to disruptions in sleep and wake states that are often subtle, but sometime quite pronounced and of significant medical importance. By understanding the neural substrate and its pathophysiology, one can more appropriately target therapies that might help the specific sleep disruption. This chapter reviews what is currently understood about the neurobiological underpinnings of sleep and wake regulation and how various pathologies evoke changes in these regulatory mechanisms.
High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.
Lustenberger Caroline,Patel Yogi A,Alagapan Sankaraleengam,Page Jessica M,Price Betsy,Boyle Michael R,Fröhlich Flavio
Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles.
Altered thalamic connectivity in insomnia disorder during wakefulness and sleep.
Zou Guangyuan,Li Yuezhen,Liu Jiayi,Zhou Shuqin,Xu Jing,Qin Lang,Shao Yan,Yao Ping,Sun Hongqiang,Zou Qihong,Gao Jia-Hong
Human brain mapping
Insomnia disorder is the most common sleep disorder and has drawn increasing attention. Many studies have shown that hyperarousal plays a key role in the pathophysiology of insomnia disorder. However, the specific brain mechanisms underlying insomnia disorder remain unclear. To elucidate the neuropathophysiology of insomnia disorder, we investigated the brain functional networks of patients with insomnia disorder and healthy controls across the sleep-wake cycle. EEG-fMRI data from 33 patients with insomnia disorder and 31 well-matched healthy controls during wakefulness and nonrapid eye movement sleep, including N1, N2 and N3 stages, were analyzed. A medial and anterior thalamic region was selected as the seed considering its role in sleep-wake regulation. The functional connectivity between the thalamic seed and voxels across the brain was calculated. ANOVA with factors "group" and "stage" was performed on thalamus-based functional connectivity. Correlations between the misperception index and altered functional connectivity were explored. A group-by-stage interaction was observed at widespread cortical regions. Regarding the main effect of group, patients with insomnia disorder demonstrated decreased thalamic connectivity with the left amygdala, parahippocampal gyrus, putamen, pallidum and hippocampus across wakefulness and all three nonrapid eye movement sleep stages. The thalamic connectivity in the subcortical cluster and the right temporal cluster in N1 was significantly correlated with the misperception index. This study demonstrated the brain functional basis in insomnia disorder and illustrated its relationship with sleep misperception, shedding new light on the brain mechanisms of insomnia disorder and indicating potential therapeutic targets for its treatment.
The Sublaterodorsal Tegmental Nucleus Functions to Couple Brain State and Motor Activity during REM Sleep and Wakefulness.
Torontali Zoltan A,Fraigne Jimmy J,Sanghera Paul,Horner Richard,Peever John
Current biology : CB
Appropriate levels of muscle tone are needed to support waking behaviors such as sitting or standing. However, it is unclear how the brain functions to couple muscle tone with waking behaviors. Cataplexy is a unique experiment of nature in which muscle paralysis involuntarily intrudes into otherwise normal periods of wakefulness. Cataplexy therefore provides the opportunity to identify the circuit mechanisms that couple muscle tone and waking behaviors. Here, we tested the long-standing hypothesis that muscle paralysis during cataplexy is caused by recruitment of the brainstem circuit that induces muscle paralysis during REM sleep. Using behavioral, electrophysiological, and chemogenetic strategies, we found that muscle tone and arousal state can be decoupled by manipulation of the REM sleep circuit (the sublaterodorsal tegmental nucleus [SLD]). First, we show that silencing SLD neurons prevents motor suppression during REM sleep. Second, we show that activating these same neurons promotes cataplexy in narcoleptic (orexin) mice, whereas silencing these neurons prevents cataplexy. Most importantly, we show that SLD neurons can decouple motor activity and arousal state in healthy mice. We show that SLD activation triggers cataplexy-like attacks in wild-type mice that are behaviorally and electrophysiologically indistinguishable from cataplexy in orexin mice. We conclude that the SLD functions to engage arousal-motor synchrony during both wakefulness and REM sleep, and we propose that pathological recruitment of SLD neurons could underlie cataplexy in narcolepsy.
Autonomic regulation during sleep and wakefulness: a review with implications for defining the pathophysiology of neurological disorders.
Fink Anne M,Bronas Ulf G,Calik Michael W
Clinical autonomic research : official journal of the Clinical Autonomic Research Society
Cardiovascular and respiratory parameters change during sleep and wakefulness. This observation underscores an important, albeit incompletely understood, role for the central nervous system in the differential regulation of autonomic functions. Understanding sleep/wake-dependent sympathetic modulations provides insights into diseases involving autonomic dysfunction. The purpose of this review was to define the central nervous system nuclei regulating sleep and cardiovascular function and to identify reciprocal networks that may underlie autonomic symptoms of disorders such as insomnia, sleep apnea, restless leg syndrome, rapid eye movement sleep behavior disorder, and narcolepsy/cataplexy. In this review, we examine the functional and anatomical significance of hypothalamic, pontine, and medullary networks on sleep, cardiovascular function, and breathing.
[Sleep and wakefulness disorders in neurodegenerative diseases].
Yakovleva O V,Poluektov M G,Levin O S,Lyashenko E A
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova
The article reviews the phenomenology of sleep and wakefulness disorders in Parkinson's disease and Alzheimer's disease. Degeneration of sleep and wakefulness centers, secondary effect of other symptoms of diseases and side-effects of drug therapy lead to a widespread prevalence of sleep and wakefulness disturbances in these patients. Along with the review of actual literature concerning mechanisms of development and clinical features of these disorders, the authors discuss principal methods for their treatment.
Brain Circuitry Controlling Sleep and Wakefulness.
Horner Richard L,Peever John H
Continuum (Minneapolis, Minn.)
PURPOSE OF REVIEW:This article outlines the fundamental brain mechanisms that control sleep-wake patterns and reviews how pathologic changes in these control mechanisms contribute to common sleep disorders. RECENT FINDINGS:Discrete but interconnected clusters of cells located within the brainstem and hypothalamus comprise the circuits that generate wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific neurotransmitters, or collections of neurotransmitters, to inhibit or excite their respective sleep- and wake-promoting target sites. These excitatory and inhibitory connections modulate not only the presence of wakefulness or sleep, but also the levels of arousal within those states, including the depth of sleep, degree of vigilance, and motor activity. Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances. SUMMARY:Research has made significant headway in identifying the brain circuits that control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of common sleep disorders and disturbances.
EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness.
Desjardins Marie-Ève,Carrier Julie,Lina Jean-Marc,Fortin Maxime,Gosselin Nadia,Montplaisir Jacques,Zadra Antonio
Study Objectives:Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. Methods:We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient's episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results:Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes' onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Conclusions:Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep.
Differential effects of bifrontal tDCS on arousal and sleep duration in insomnia patients and healthy controls.
Frase Lukas,Selhausen Peter,Krone Lukas,Tsodor Sulamith,Jahn Friederike,Feige Bernd,Maier Jonathan G,Mainberger Florian,Piosczyk Hannah,Kuhn Marion,Klöppel Stefan,Sterr Annette,Baglioni Chiara,Spiegelhalder Kai,Riemann Dieter,Nitsche Michael A,Nissen Christoph
BACKGROUND:Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance. OBJECTIVE/HYPOTHESIS:The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects. METHODS:Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset. RESULTS:Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients. CONCLUSIONS:Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels.
Scalp and Source Power Topography in Sleepwalking and Sleep Terrors: A High-Density EEG Study.
Castelnovo Anna,Riedner Brady A,Smith Richard F,Tononi Giulio,Boly Melanie,Benca Ruth M
STUDY OBJECTIVES:To examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG). METHODS:Fifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system. RESULTS:Scalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1-4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal. CONCLUSIONS:Overall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes.
Disorders of arousal and sleep-related bruxism among Japanese adolescents: a nationwide representative survey.
Itani Osamu,Kaneita Yoshitaka,Ikeda Maki,Kondo Shuji,Yamamoto Ryuichiro,Osaki Yoneatsu,Kanda Hideyuki,Suzuki Kenji,Higuchi Susumu,Ohida Takashi
OBJECTIVE:The main objective of our study was to clarify the prevalence of disorders of arousal (confusional arousals, sleepwalking, sleep terrors) and sleep-related bruxism (teeth grinding) and their associated factors among Japanese adolescents. METHODS:Our study was designed as a cross-sectional sampling survey. The targets were students attending junior and senior high schools throughout Japan. The questionnaire asked for personal data and information on lifestyle, depressive state, and sleep status including the frequency of experiencing disorders of arousal and sleep-related bruxism. RESULTS:A total of 99,416 adolescents responded. The overall response rate was 63.7%, and 98,411 questionnaires were subjected to analysis. The prevalence of disorders of arousal was 7.1% (95% confidence interval [CI], 6.9-7.3%) among boys and 7.7% (95% CI, 7.5-7.9%) among girls. The prevalence of sleep-related bruxism was 2.3% (95% CI, 2.2-2.4%) among boys and 3.0% (95% CI, 2.8-3.2%) among girls. The factors associated with disorders of arousal were the grade in school, smoking habit, alcohol consumption, naptime (min), breakfast habit, participation in club activities, sleep duration, difficulty initiating sleep, nocturnal awakening, early morning awakening, subjective sleep assessment, snoring, decrease in positive feelings, and depression (all p<.001). The factors associated with sleep-related bruxism were gender, smoking habit, nocturnal awakening, snoring, early morning awakening, decrease in positive feelings, and depressive feelings (all p<.001). CONCLUSIONS:If disorders of arousal or sleep-related bruxism are observed in an adolescent, his or her smoking habit, alcohol consumption, sleep status, and depressive state should be considered.
Confusional arousals during non-rapid eye movement sleep: evidence from intracerebral recordings.
Flamand Mathilde,Boudet Samuel,Lopes Renaud,Vignal Jean-Pierre,Reyns Nicolas,Charley-Monaca Christelle,Peter-Derex Laure,Szurhaj William
Study Objectives:Confusional arousals (CA) are characterized by the association of behavioral awakening with persistent slow-wave electroencephalographic (EEG) activity during non-rapid eye movement (NREM) sleep-suggesting that sensorimotor areas are "awake" while non-sensorimotor areas are still "asleep." In the present work, we aimed to study the precise temporo-spatial dynamics of EEG changes in cortical areas during CA using intracerebral recordings. Methods:Nineteen episodes of CA were selected in five drug-resistant epileptic patients suffering incidentally from arousal disorders. Spectral power of EEG signal recorded in 30 non-lesioned, non-epileptogenic cortical areas and thalamus was compared between CA and baseline slow-wave sleep. Results:Clear sequential modifications in EEG activity were observed in almost all studied areas. In the last few seconds before behavior onset, an increase in delta activity occurred predominantly in frontal regions. Behavioral arousal was associated with an increase of signal power in the whole studied frequency band in the frontal lobes, cingulate cortex, insular cortex, and precuneus. Afterwards, a diffuse cessation of very low frequencies (<1 Hz) occurred. Simultaneously, a hypersynchronous delta activity (HSDA) (1-1.5 Hz) arose in a broad network involving medial and lateral frontoparietal cortices, whereas higher frequency activities increased in sensorimotor, orbitofrontal, and temporal lateral cortices. This HSDA was predominantly observed in the inferior frontal gyrus. Conclusions:During CA, the level of activity changed in almost all the studied areas. The embedding of a broad frontoparietal network, especially the inferior frontal gyrus, in an HSDA might explain the participants' altered state of consciousness.