Regulation Of Wakefulness Research Articles

Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1.

Idiopathic hypersomnia is poorly diagnosed in the absence of biomarkers to distinguish it from other central hypersomnia subtypes. Given that light plays a main role in the regulation of sleep and wake, we explored the retinal melanopsin-based pupil response in patients with idiopathic hypersomnia and narcolepsy type 1, and healthy subjects. Twenty-seven patients with narcolepsy type 1 (women 59%, 36 ± 11.5 years old), 36 patients with idiopathic hypersomnia (women 83%, 27.2 ± 7.2 years old) with long total sleep time (> 11/24 hr), and 43 controls (women 58%, 30.6 ± 9.3 years old) were included in this study. All underwent a pupillometry protocol to assess pupil diameter, and the relative post-illumination pupil response to assess melanopsin-driven pupil responses in the light non-visual input pathway. Differences between groups were assessed using logistic regressions adjusted on age and sex. We found that patients with narcolepsy type 1 had a smaller baseline pupil diameter as compared with idiopathic hypersomnia and controls (p < 0.05). In addition, both narcolepsy type 1 and idiopathic hypersomnia groups had a smaller relative post-illumination pupil response (respectively, 31.6 ± 13.9% and 33.2 ± 9.9%) as compared with controls (38.7 ± 9.7%), suggesting a reduced melanopsin-mediated pupil response in both types of central hypersomnia (p < 0.01). Both narcolepsy type 1 and idiopathic hypersomnia showed a smaller melanopsin-mediated pupil response, and narcolepsy type 1, unlike idiopathic hypersomnia, also displayed a smaller basal pupil diameter. Importantly, we found that the basal pupil size permitted to well discriminate idiopathic hypersomnia from narcolepsy type 1 with a specificity=66.67% and a sensitivity=72.22%. Pupillometry may aid to multi-feature differentiation of central hypersomnia subtypes.

The Complex Effects of Light on Metabolism in Humans.

Light is an essential part of many life forms. The natural light-dark cycle has been the dominant stimulus for circadian rhythms throughout human evolution. Artificial light has restructured human activity and provided opportunities to extend the day without reliance on natural day-night cycles. The increase in light exposure at unwanted times or a reduced dynamic range of light between the daytime and nighttime has introduced negative consequences for human health. Light exposure is closely linked to sleep-wake regulation, activity and eating patterns, body temperature, and energy metabolism. Disruptions to these areas due to light are linked to metabolic abnormalities such as an increased risk of obesity and diabetes. Research has revealed that various properties of light influence metabolism. This review will highlight the complex role of light in human physiology, with a specific emphasis on metabolic regulation from the perspective of four main properties of light (intensity, duration, timing of exposure, and wavelength). We also discuss the potential influence of the key circadian hormone melatonin on sleep and metabolic physiology. We explore the relationship between light and metabolism through circadian physiology in various populations to understand the optimal use of light to mitigate short and long-term health consequences.

The Transformation: Power in Persistence and Perspective

The Transformation:Power in Persistence and Perspective Tyler Bendrick We've got another meth napper," my resident stated. With an introduction like that, it is hard not to be immediately labeled as a "difficult patient." Being the only Spanish-speaking person on the team, I, a third-year medical student, became the primary point of contact for this severely injured patient. He was an only-Spanish-speaking, 36-year-old male admitted [End Page 7] to our trauma service after he was hit by a truck while riding his bicycle. Unbeknownst to me at the time, the 14 days I spent caring for this man would become one of the most pivotal learning experiences of my medical school career. It changed not only how I understand and approach "difficult patients" but expanded my knowledge of the complexities and challenges of the current healthcare system and how we, as physicians and healthcare providers, can deliver the best care to patients with low health literacy and limited resources. So, what is a "meth napper?" I questioned. "Well, meth is a super stimulant," my resident explained. "When people are frequent meth users, they get used to functioning normally with high levels of stimulants in their body, reducing the normal regulation of wakefulness. When the amphetamine is removed (such as upon admission to the hospital), the body is left to fend for itself, and thus patients oftentimes sleep for 23 hours a day for about 3 to 5 days while their body works to detox and normalize hormones." As predicted, my new friend, "Joe," was napping when I first went to see him. Thinking back, the word "napping" does not accurately describe his level of somnolence. He was virtually unarousable, and I took to a sternal rub to wake him up at 5 a.m. after his traumatic exploratory laparotomy the night before. Once aroused, he was furious. "Estoy bien. Tengo dolor y tengo hambre," he grunted at me. (I am fine, and I am in pain and hungry!). "Ok, Joe," I replied in Spanish, "I am just going to do a quick exam and you can go back to sleep. We will give you medications for your pain. You had a big surgery on your intestines, so you cannot eat or drink right now. If everything goes well in the next couple of days and you start walking around, we can advance your diet." He begrudgingly let me examine him, never opening his eyes, and I left and went about my day. We continued this routine for five days. I would periodically check on him and usually found him sleeping. When awake, he refused to work with physical therapists, get up and walk or go to the bathroom, shower, use his spirometer, or converse with the nursing staff. He seemed completely disinterested in recovery. About day three, we slowly advanced his diet to clear liquids so he could quench his thirst. Sometimes his wife was there, and she would ask for updates, to which I could only reply, "We have to wait until he is more awake or willing to work with us." I was getting frustrated, as it seemed that his noncompliance was becoming his barrier to discharge. But on day six, everything changed. I went to check on Joe, and he was wide awake, vomiting, and irate. He shouted that he was in incredible pain, and his incision was wet. He was also complaining that he had not eaten in five days, and was insisting that we were starving him. Again, I calmly explained (as I had multiple times a day for the past five days) that his major abdominal surgery prevented us from feeding him until his intestines healed. We were giving him fluids and nutrition through his IV lines, so he was not starving to death. I rushed to get my resident to examine his oozing wound, and after a CT scan and an x-ray, we discovered what we feared: His wound had opened down to the fascia, "dehiscence," as it is called. On top of this, he now had a bowel obstruction, causing his vomiting. His lack of mobility for the past five days had slowed his...

Metabolomics-based Sleepiness Markers for Risk Prevention and Traffic Safety (ME-SMART): a monocentric, controlled, randomized, crossover trial

BackgroundToo little sleep and the consequences thereof are a heavy burden in modern societies. In contrast to alcohol or illicit drug use, there are no quick roadside or workplace tests for objective biomarkers for sleepiness. We hypothesize that changes in physiological functions (such as sleep–wake regulation) are reflected in changes of endogenous metabolism and should therefore be detectable as a change in metabolic profiles. This study will allow for creating a reliable and objective panel of candidate biomarkers being indicative for sleepiness and its behavioral outcomes.MethodsThis is a monocentric, controlled, randomized, crossover, clinical study to detect potential biomarkers. Each of the anticipated 24 participants will be allocated in randomized order to each of the three study arms (control, sleep restriction, and sleep deprivation). These only differ in the amount of hours slept per night. In the control condition, participants will adhere to a 16/8 h wake/sleep regime. In both sleep restriction and sleep deprivation conditions, participants will accumulate a total sleep deficit of 8 h, achieved by different wake/sleep regimes that simulate real-life scenarios. The primary outcome is changes in the metabolic profile (i.e., metabolome) in oral fluid. Secondary outcome measures will include driving performance, psychomotor vigilance test, d2 Test of Attention, visual attention test, subjective (situational) sleepiness, electroencephalographic changes, behavioral markers of sleepiness, changes in metabolite concentrations in exhaled breath and finger sweat, and correlation of metabolic changes among biological matrices.DiscussionThis is the first trial of its kind that investigates complete metabolic profiles combined with performance monitoring in humans over a multi-day period involving different sleep–wake schedules. Hereby, we aim to establish a candidate biomarker panel being indicative for sleepiness and its behavioral outcomes. To date, there are no robust and easily accessible biomarkers for the detection of sleepiness, even though the vast damage on society is well known. Thus, our findings will be of high value for many related disciplines.Trial registrationClinicalTrials.gov Identifier NCT05585515, released on 18.10.2022; Swiss National Clinical Trial Portal SNCTP000005089, registered on 12 August 2022.

Adenosine-independent regulation of the sleep–wake cycle by astrocyte activity

Astrocytes play a crucial role in regulating sleep–wake behavior, and adenosine signaling is generally thought to be involved. Here we show multiple lines of evidence supporting that modulation of the sleep–wake behavior by astrocyte Ca2+ activity could occur without adenosine signaling. In the basal forebrain and the brainstem, two brain regions that are known to be essential for sleep–wake regulation, chemogenetically-induced astrocyte Ca2+ elevation significantly modulated the sleep–wake cycle. Although astrocyte Ca2+ level positively correlated with the amount of extracellular adenosine, as revealed by a genetically encoded adenosine sensor, we found no detectable change in adenosine level after suppressing astrocyte Ca2+ elevation, and transgenic mice lacking one of the major extracellular ATP-adenosine conversion enzymes showed similar extracellular adenosine level and astrocyte Ca2+-induced sleep modulation. Furthermore, astrocyte Ca2+ is dependent primarily on local neuronal activity, causing brain region-specific regulation of the sleep–wake cycle. Thus, neural activity-dependent astrocyte activity could regulate the sleep–wake behavior independent of adenosine signaling.

Maternal Differentiation of Self and Toddlers' Sleep: The Mediating Role of Nighttime Involvement.

Good sleep is essential for optimal development and adaptive functioning. Hence, identifying the factors that shape sleep quality is important. Based on the transactional model of sleep development and drawing on Bowen's concept of differentiation of self (DoS), the present study examined the interrelations between sleep-related parental behavior, child's sleep quality, and mothers' DoS. A community sample of 130 mothers of 24- to 36-month-old children completed the DoS instrument and sleep questionnaires. Lower maternal DoS levels were associated with higher parental sleep-related involvement, both at bedtime and through the course of the night. Using structural equation modeling (SEM), a path analysis model indicates that maternal sleep-related involvement functions as a mediator through which the differentiation of self is related to the sleep characteristics of toddlers. As the links between parenting practices and child sleep reflect bi-directional associations, the conclusion that can be drawn from the present data is that relational aspects, such as those defined and measured by the construct of DoS, contribute to sleep-wake regulation beyond infancy. The data suggest that this construct should be considered in intervention research.

Degradation of STK16 via KCTD17 with Ubiquitin–Proteasome System in Relation to Sleep–Wake Cycle

Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.

The two-process model for sleep–wake regulation: A nonsmooth dynamics perspective

Since its inception four decades ago the two-process model introduced by Borbély has provided the conceptual framework to explain sleep–wake regulation across many species, including humans. At its core, high level notions of circadian and homeostatic processes are modelled with a low dimensional description in the form of a one dimensional nonautonomous and nonsmooth flow, with the rate of change of homeostatic sleep pressure switching at specific times. These events in time can be described by an implicit map from one switching time to another and have given rise to an elegant mathematical description of periodic orbits and their instabilities using the theory of iterated maps. In this paper we show that an equivalent description can be obtained from a direct analysis of the underlying nonsmooth flow. We further show how to construct the Lyapunov exponent of the nonsmooth flow and use this to uncover a more detailed picture of the Arnol’d tongue structure of the model.Given the growing interest in studying networks of sleepers, where interactions may occur continuously throughout the day–night cycle and not just at event times, we advocate for the future use of techniques from nonsmooth dynamical systems in studying networks of the two-process model.

Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor

Orexin receptors are a family of G protein-coupled receptors that consist of two subtypes: orexin-1 receptors (OX1Rs) and OX2Rs. They are expressed throughout the central nervous system and are involved in regulating the sleep-wake cycle. The development of antagonists to orexin receptors has become important in drug discovery because modulation of these receptors can lead to novel treatments for diseases related to the regulation of sleep and wakefulness, such as insomnia. In this study, we determined that the structure of OX2R bound to lemborexant, a dual orexin receptor antagonist (DORA), at 2.89Å resolution. Comparisons of kinetic and dynamic properties of DORAs based on structures and simulations suggest that the enthalpy of molecular binding to receptors and the entropy derived from intramolecular structure can be separately controlled. These results complement existing structural information and allow us to discuss the usefulness of pharmacophore models and target selectivity to OXRs.

Sleep-wake regulation by baroreflex circuitry.

Sleep-wake regulation by baroreflex circuitry.

NREM–REM alternation complicates transitions from napping to non-napping behavior in a three-state model of sleep–wake regulation

The temporal structure of human sleep changes across development as it consolidates from the polyphasic sleep of infants to the single nighttime sleep episode typical in adults. Experimental studies have shown that changes in the dynamics of sleep need may mediate this developmental transition in sleep patterning, however, it is unknown how sleep architecture interacts with these changes. We employ a physiologically-based mathematical model that generates wake, rapid eye movement (REM) and non-REM (NREM) sleep states to investigate how NREM–REM alternation affects the transition in sleep patterns as the dynamics of the homeostatic sleep drive are varied. To study the mechanisms producing these transitions, we analyze the bifurcations of numerically-computed circle maps that represent key dynamics of the full sleep–wake network model by tracking the evolution of sleep onsets across different circadian (∼ 24 h) phases. The maps are non-monotonic and discontinuous, being composed of branches that correspond to sleep–wake cycles containing distinct numbers of REM bouts. As the rates of accumulation and decay of the homeostatic sleep drive are varied, we identify the bifurcations that disrupt a period-adding-like behavior of sleep patterns in the transition between biphasic and monophasic sleep. These bifurcations include border collision and saddle–node bifurcations that initiate new sleep patterns, period-doubling bifurcations leading to higher-order patterns of NREM–REM alternation, and intervals of bistability of sleep patterns with different NREM–REM alternations. Furthermore, patterns of NREM–REM alternation exhibit variable behaviors in different regimes of constant sleep–wake patterns. Overall, the sequence of sleep–wake behaviors, and underlying bifurcations, in the transition from biphasic to monophasic sleep in this three-state model is more complex than behavior observed in models of sleep–wake regulation that do not consider the dynamics of NREM–REM alternation. These results suggest that interactions between the dynamics of the homeostatic sleep drive and the dynamics of NREM–REM alternation may contribute to the wide interindividual variation observed when young children transition from napping to non-napping behavior.

Regulation of wakefulness by astrocytes in the lateral hypothalamus

The lateral hypothalamus (LH) is an important brain region mediating sleep–wake behavior. Recent evidence has shown that astrocytes in central nervous system modulate the activity of adjacent neurons and participate in several physiological functions. However, the role of LH astrocytes in sleep–wake regulation remains unclear. Here, using synchronous recording of electroencephalogram/electromyogram in mice and calcium signals in LH astrocytes, we show that the activity of LH astrocytes is significantly increased during non-rapid eye movement (NREM) sleep-to-wake transitions and decreased during Wake-to-NREM sleep transitions. Chemogenetic activation of LH astrocytes potently promotes wakefulness and maintains long-term arousal, while chemogenetic inhibition of LH astrocytes decreases the total amount of wakefulness in mice. Moreover, by combining chemogenetics with fiber photometry, we show that activation of LH astrocytes significantly increases the calcium signals of adjacent neurons, especially among GABAergic neurons. Taken together, our results clearly illustrate that LH astrocytes are a key neural substrate regulating wakefulness and encode this behavior through surrounding GABAergic neurons. Our findings raise the possibility that overactivity of LH astrocytes may be an underlying mechanism of clinical sleep disorders.

Regulation of wakefulness by GABAergic dorsal raphe nucleus-ventral tegmental area pathway.

The dorsal raphe nucleus (DRN) has previously been proved to be involved in the regulation of the sleep-wake behavior. DRN contains several neuron types, such as 5-HTergic and GABAergic neurons. GABAergic neurons, which are the second largest cell subtype in the DRN, participate in a variety of neurophysiological functions. However, their role in sleep-wake regulation and the underlying neural circuitry remains unclear. Herein, we used fiber photometry and synchronous electroencephalogram (EEG)/electromyography (EMG) recording to demonstrate that DRN GABAergic neurons exhibit high activities during wakefulness and low activities during NREM sleep. Short-term optogenetic activation of DRN GABAergic neurons reduced the latency of NREM-to-wake transition and increased the probability of wakefulness, while long-term optogenetic activation of these neurons significantly increased the amount of wakefulness. Chemogenetic activation of DRN GABAergic neurons increased wakefulness for almost 2 h and maintained long-lasting arousal. In addition, inhibition of DRN GABAergic neurons with chemogenetics caused a reduction in the amount of wakefulness. Finally, similar to the effects of activating the soma of DRN GABAergic neurons, optogenetic stimulation of their terminals in the ventral tegmental area (VTA) induced instant arousal and promoted wakefulness. Taken together, our results illustrated that DRN GABAergic neurons are vital to the induction and maintenance of wakefulness, which promote wakefulness through the GABAergic DRN-VTA pathway.

Role of the paraventricular nucleus of the hypothalamus in sleep–wake regulation

The paraventricular nucleus of the hypothalamus (PVH) acts as a cohesive functional unit that regulates neuroendocrine and autonomic function, complex behavior, and negative emotions after stress. However, how the PVH integrates arousal with these biological functions has only recently been explored. Clinical reports, combined with neurotoxic lesioning, immunochemistry, neuronal activity recordings, and the polysomnographic analyses of genetically modified animals, have revealed that the PVH is important for the control of wakefulness. Here, we review emerging anatomical and neural mechanisms for sleep–wake regulation in the PVH to support its essential role in the promotion and maintenance of wakefulness.

Hunt for mammalian sleep-regulating genes

Genetics is one of the various approaches adopted to understand and control mammalian sleep. Reverse genetics, which is usually applied to analyze sleep in gene-deficient mice, has been the mainstream field of genetic studies on sleep for the past three decades and has revealed that various molecules, including orexin, are involved in sleep regulation. Recently, forward genetic studies in humans and mice have identified gene mutations responsible for heritable sleep abnormalities, such as SIK3, NALCN, DEC2, the neuropeptide S receptor, and β1 adrenergic receptor. Furthermore, the protein kinase A-SIK3 pathway was shown to represent the intracellular neural signaling for sleep need. Large-scale genome-wide analyses of human sleep have been conducted, and many gene loci associated with individual differences in sleep have been found. The development of genome-editing technology and gene transfer by an adeno-associated virus has updated and expanded the genetic studies on mammals. These efforts are expected to elucidate the mechanisms of sleep–wake regulation and develop new therapeutic interventions for sleep disorders.

Mutual Effects of Orexin and Bone Morphogenetic Proteins on Gonadotropin Expression by Mouse Gonadotrope Cells.

Orexin plays a key role in the regulation of sleep and wakefulness and in feeding behavior in the central nervous system, but its receptors are expressed in various peripheral tissues including endocrine tissues. In the present study, we elucidated the effects of orexin on pituitary gonadotropin regulation by focusing on the functional involvement of bone morphogenetic proteins (BMPs) and clock genes using mouse gonadotrope LβT2 cells that express orexin type 1 (OX1R) and type 2 (OX2R) receptors. Treatments with orexin A enhanced LHβ and FSHβ mRNA expression in a dose-dependent manner in the absence of GnRH, whereas orexin A in turn suppressed GnRH-induced gonadotropin expression in LβT2 cells. Orexin A downregulated GnRH receptor expression, while GnRH enhanced OX1R and OX2R mRNA expression. Treatments with orexin A as well as GnRH increased the mRNA levels of Bmal1 and Clock, which are oscillational regulators for gonadotropin expression. Of note, treatments with BMP-6 and -15 enhanced OX1R and OX2R mRNA expression with upregulation of clock gene expression. On the other hand, orexin A enhanced BMP receptor signaling of Smad1/5/9 phosphorylation through upregulation of ALK-2/BMPRII among the BMP receptors expressed in LβT2 cells. Collectively, the results indicate that orexin regulates gonadotropin expression via clock gene expression by mutually interacting with GnRH action and the pituitary BMP system in gonadotrope cells.

The Irrecoverable Loss in Sleep on Weekdays of Two Distinct Chronotypes Can Be Equalized by Permitting a &gt;2 h Difference in Waking Time

Background: Our work/study culture is biased towards the circadian clocks of “morning types”, whereas “evening types” are forced to advance their weekday waking times relative to weekend waking times. Since the experimental research consistently reveals a &gt;2 h difference between these two chronotypes in the positions of their endogenous circadian phases, we hypothesized the necessity to permit a &gt;2 h difference between them in weekday waking times to equalize their irrecoverable loss in sleep on weekdays. Methods: A total of 659 and 1106 participants of online surveys identified themselves as morning and evening types, respectively. The hypothesis was tested by applying a model of sleep–wake regulation for simulating sleep times reported by 245 lecturers of these two types, and by comparison of sleep times of these types among these lecturers and 1520 students. Results: The hypothesis was supported by results showing that, if, on weekdays, an “average” morning type wakes at 6 a.m., the equalization of the weekday sleep loss of the two chronotypes would require the waking time of an “average” evening type to be no earlier than 8 a.m. Conclusions: These results may be implemented in a model-based methodology for the correction of weekday waking times to equalize weekday sleep loss.

Different sensitivity to anesthesia according to ECoG data in dopamine transporter knockout and heterozygous rats

Dopamine in the brain is involved in many important functions, including the regulation of wakefulness. There is also some evidence suggesting that the dopamine function is crucial in anesthetic function. The state of anesthesia is characterized by a change in the level of consciousness and a change in brain electrical activity.Due to impaired mechanisms of dopamine transportation back to the synaptic terminal, dopamine transporter (DAT) knockout and heterozygous rats have increased levels of the extracellular dopamine. In our work, we registered ECoG disturbances in knockout and heterozygous rats, as well as disturbances in tone and activity in acute experiments under the anesthesia Zoletil (tiletamine and zolazepam) from the somatosensory cortex using a NeuroNexus flat multielectrode array to study gamma activity. We also used four low-resistance electrodes to control the slow rhythm.Both low-resistance and high-resistance electrodes showed differences in the ECoG spectrum of heterozygotes and total knockouts from the wild type and from each other. Heterozygous rats for the DAT gene (HET) showed increased rapid beta and gamma activity and decreased slow delta activity, while complete knockouts (KO), on the contrary, showed increased delta activity and decreased beta and gamma activity. Thus, the ECoG spectrum of HET is shifted to the right, while that of KO is shifted to the left. Full knockouts also showed decreased spatial synchronization in the 30–100 Hz gamma range compared to the wild type (WT).It is assumed that sedation of HET and KO is shifted towards opposite directions compared to WT under the same anesthesia conditions.

Study of three wake control strategies for power maximization of offshore wind farms with different layouts

The wake regulation by cooperative yaw control, axis induction control, or their combination can significantly improve the total power output of wind farms. However, a comprehensive study of the three control strategies is still lacking, which hinders their engineering applications. To this end, the optimized yaw angles, induction factors, and total power promotion are systematically compared for the three control strategies on both a regularly arranged wind farm and an irregularly arranged realistic offshore wind farm. The results indicate that all the three strategies work similarly to achieve a net power gain by enhancing the power output of the downstream turbines while slightly downgrading the upstream turbines. For the regularly arranged wind farm, very notable power promotions are obtained in the aligned direction, and all the three control strategies show similar performance, but the promotions almost disappear with a small misalignment. In contrast, power promotion is less sensitive to the wind direction for the irregularly arranged wind farm. The promotion of the yaw control is much more predominate than that of the induction control, and the combined control only slightly outperforms the single yaw control in the realistic wind farm. In the prevailing wind direction, the total power of the realistic wind farm can be increased by 2.1% by the combined control strategy under the wind speed of 6 m/s.

Functional Connectivity Disturbances of the Locus Coeruleus in Chronic Insomnia Disorder.

IntroductionIn recent years, people have gained a profound understanding of chronic insomnia disorder (CID), but the pathophysiological mechanism of CID is still unclear. There is some evidence that the locus coeruleus (LC) is involved in the regulation of wakefulness in CID, but there have been few studies using brain functional imaging. The purpose of this study was to evaluate the resting-state functional connectivity (FC) between the LC and other brain voxels in CID and whether these abnormal FC are involved in the regulation of wakefulness.MethodsA total of 49 patients with chronic insomnia disorder and 47 healthy controls (HC) matched for gender, age, and education were examined with rs-fMRI in this study. The LC was selected as the region of interest, and then seed-based analysis was conducted on the LC and other voxels to obtain the brain regions with abnormal FC. The correlation between the FC value of the abnormal connection area and the clinical scale score was analyzed.ResultsCompared with the HC, the FC between the LC and right precuneus, right posterior cingulate cortex, left middle temporal gyrus, left calcarine, and right superior orbitofrontal cortex was significantly enhanced (p < 0.05, FDR correction), and the functional connectivity signal value between the locus coeruleus and left middle temporal gyrus was positively correlated with the Self-Rating Depression Scale (p = 0.021).ConclusionThe abnormal FC between the LC and multiple brain regions may contribute to a better understanding of the neurobiological mechanism of CID.