Although sleep is a ubiquitous behavior in animal species with central nervous systems, the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has helped reveal neural pathways in the regulation of sleep/wakefulness. Orexin receptor antagonists, which specifically block the endogenous waking system, have 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/EMracG) measurements. We have so far screened >10,000 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 mutations in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Indeed, through a systematic cross-comparison of the Sleepy mutants (with a gain-of-function change in a serine/threonine kinase pathway) and sleep-deprived mice, we have found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.

Characteristics of Upper Airway Resistance in Patients with Catathrenia

Xuemei Gao, Yu Min, Zeliang Hao

Stomatology School and Hospital of Peking University

Catathrenia is a rare sleeping disorder, characterized by a prolonged expiration with a monotonous vocalization resembling groaning. Up to 57 Catathrenia patients were investigated with craniofacial morphology, acoustic analyses, masticatory muscle functions, and nasal breathing function, The groaning episode might derive from the partial or intermittent narrowing of the hypopharynx and reactive forced prolonged expiration to overcome this resistance and the active involvement of the vocal cords.

REM sleep is a fundamental sleep state and plays critical roles in a variety of physiological functions. However, the neuronal circuits that regulate REM sleep remain understood. Here, we showed that lateral pontine tegmentum GABAergic (LPT^GABA) neurons were primarily projection to the sublaterodorsal nucleus (SLD). Optogenetic activation of LPTGABA neurons completely terminated REM sleep and promoted REM-to-NREM sleep transitions through SLD and LH pathway. Furthermore, we found that optogenetic activation of RMTg^GABA neurons immediately converted REM sleep to arousal and initiated NREM sleep via LDT and LH pathway, respectively. Taken together, our findings reveal that LPT and RMTg GABAergic neurons are essential for switching off REM sleep and contribute to conversion from REM to NREM sleep.

Insomnia and narcolepsy are common sleep disorders and are difficult to treat, causing heavy burden to patients, families and the society. In clinical practice, insomnia is normally treated with sedatives-hypnotics, and narcolepsy can be treated with stimulants (such as modafinil), selective serotonin reuptake inhibitors, or gamma hydroxybutyric acid (sodium oxybate). However, many of these drugs may have abuse and addiction potential. Here, we will discuss this problem from three aspects: Firstly, we will perform an overview of sedative-hypnotics and arousal-promoting drugs. Secondly, we will discuss the abuse and addiction problem of sedative-hypnotic and arousal-promoting drugs. Thirdly, we will review the regulatory policies of sedative-hypnotics and arousal-promoting drugs, and provide an outlook for their development.

Astrocytes are involved in a number of brain functions, including sleep-awakening regulation. The results show that the active state of astrocytes, such as calcium concentration, is rhythmic in the 24-hour sleep-awakening cycle. The biomarker level of astrocytes in peripheral blood of patients with chronic insomnia changes, which is related to the severity of insomnia. Astrocytes may also be a target for non-invasive neuroregulation such as transcranial electrical stimulation. This article will report on the progress in these areas.

Sleep-related eating disorder (SRED) is classified as an NREM-related parasomnia characterized by recurrent episodes of dysfunctional eating that occur after an arousal from the main sleep period with partial or complete amnesia for the event, resulting in weight gain from eating high calorie foods and causing various injuries due to consumption of inedible or toxic items. We report a patient with obesity diagnosed sleep-related eating disorder associated with obstructive sleep apnea (OSA).Insisting on applying ventilator leading to weight loss and clinical improvement. Our case may increase awareness among physicians about sleep-related eating disorders.

We reported a case of narcolepsy type 1 (NT1) and epilepsy comorbidity. A 20-y-old girl appeared sudden limbs shaking and unconsciousness after the diagnosis of NT1 for 5 years. The video-electroencephalographic findings showed abnormal epileptic discharges and video-polysomnography showed central hypersomnolence. The patient also had decreased hypocretin-1 concentration in the cerebrospinal fluid and an HLA DQB1*0602 allele. We reviewed the available literature to increase awareness of this rare comorbidity and discuss the treatment and possible coexistence mechanism of NT1 and epilepsy.

A 18-yr-old girl has exhibited more severe daytime sleepiness with 10 years history of narcolepsy.  She became obese quickly after disease onset. Polysomnography demonstrated increased apnea-hypopnea index (AHI) of 3.0, but rapid-eye-movement sleep-predominant central sleep apnea index up to 15.3. Multiple sleep latency tests (MSLT) showed shortened mean sleep latency and five sleep-onset REM period (SOREMP). She was diagnosed with central sleep apnea (CSA) and underwent appropriate positive airway pressure (PAP) . Our patient remains stable and has reported significant benefit from PAP usage. We offer possible neuro-physiological mechanisms herein that could explain the unique findings of this case. 

Unable to lie down

The patient, a 27-year-old male, was hospitalized due to paroxysm chest and abdominal convulsions and unable to lie down for 1 month.  Previous history of hypertension.  Neuropsychological assessment except depression and anxiety. No abnormalities were seen in the head, neck, chest and waist MRI.  Normal EEG, VPSG: Recurrent clonic-clonic twitches in awake supine position, reduced after sleep, relieved in awake sitting position.  A diagnosis of spinal myoclonus propria was made.  Treatment with clonazepam, diazepam and Zonisamide showed no improvement. Discuss the etiology and treatment

A Case Report of Anti-mGluR5 Autoimmune Encephalitis

Yan Chen1, Yanmei Zhu, Jia He, Jiaolin Zheng, Youyang Qu, Haiyan Gou, Yulan Zhu*

Epilepsy and Sleep Disorders Center of the Second Affiliated Hospital of Harbin University

Abstract

Associations between sleep disorders and autoimmune encephalitis have been noted increasingly in recent years. Here we first report a case of acute REM sleep behavior disorder (RBD) accompanied by cognitive impairment which was confirmed as anti-mGluR5 autoimmune encephalitis, in which the CSF anti-mGluR5 IgG was 1:100. The patient’s condition was improved significantly after being treated with methylprednisolone. No recurrence occurred after 6 months of follow-up. It can be concluded that the possibility of autoimmune encephalitis should be considered for acute or subacute sleep disorder with cognitive impairment and the cerebrospinal fluid autoimmune encephalitis antibody should be detected as soon as possible. Additionally, an active immune treatment would help improve prognosis significantly.

A 66-year-old man, a farmer by profession, was referred to us with a history of recurring disturbance of consciousness for the past one year. The attacks started with a loss of consciousness while working，eatting or watching TV, lasted from more than ten minutes to several hours. VEEG showed paroxysmal period more β waves，without epileptic waves. Antiepileptic treatment was ineffective, but he could wake up quickly after Flumazenil intravenous injection.

A 16-year-old female was admitted to hospital due to excessive daytime sleepiness for more than 20 days and was diagnosed for acute disseminated encephalomyelitis. Cranial magnetic resonance imaging (MRI) demonstrated abnormal signal intensity in hypothalamus. Autoimmune encephalitis antibodies and demyelinating antibodies were negative. Multiple sleep latency test results demonstrated an average sleep latency of 2 min and 3 SOREM periods in 4 naps. The CSF hypocretin level was 66.69 pg/ml. She was negative for human leukocyte antigens DQB1*0601(0601,0202). After treatment with steroids and IVIG, the patient’s  hypersomnia significantly improved. According to the literature review, inherited disorders, brain tumors , and head trauma are the three most frequent causes for symptomatic narcolepsy, and ADEM is rare. Most of the Site of onset are in the hypothalamus, and CSF orexin is usually a mild to moderate decline, with some normal levels.

Narcolepsy is a sleep disorder that still not fully recognized by clinicians, and many patients are often misdiagnosed with epilepsy, syncope, or mental disorders. Here we present a 57 year-old-patient diagnosed with narcolepsy , who has typical sleep attacks and cataplexy and has been found short sleep latency and sleep-onset rapid eye movement episodes in Multiple sleep latency test. High-dose corticosteroid therapy have shown some beneficial effects on excessive daytime sleepiness or cataplexy in this patient. The association between narcolepsy and autoimmunity is aslo going to be  discussed in this presentation.

A 13-year-old female admitted to the hospital with the chief complaint of "repeated fainting for 1 month". She had repeated fainting about 1 month ago, and reported that she could hear other people's voices in a daze during the fainting period, and could blink her eyes in response, and woke up on her own for about half an hour to 2 hours. There was no obvious improvement after anti-epileptic and anti-depressive treatment. Neurological examination showed no obvious positive signs. What disease is the patient considering?

Narcolepsy was first described in the medical literature in the 1870’s, but only in the last 20 years have researchers come to understand its true cause. Narcolepsy type 1 (narcolepsy with cataplexy) is caused by severe loss of the orexin/hypocretin neurons in the hypothalamus, most likely from an autoimmune attack on these cells. Dr. Scammell will review how loss of these specific neurons results in sleepiness and cataplexy, and how this appreciation of the importance of the orexin system is now leading to novel, and hopefully highly effective, therapies for people with narcolepsy.

We focused on studying the functional roles of the adenosine A2A and dopamine D1 Receptors (R) in the basal ganglia and obtained following 4 major findings: (1) Nucleus accumbens (NAc) dopamine D1R-expressing neurons are essential in controlling wakefulness; (2) Opposite to the D1R, A2AR made a prominent contribution to sleep control associated with motivation; (3) The ventral pallidal GABAergic neurons control wakefulness associated with motivation; (4) Striatal adenosine A2AR neurons control active-period sleep, whereas striatal D1R neurons play important roles in controlling wakefulness by integrating the up-stream projections and innervation of down-stream pathways. Taken together, we demonstrated that basal ganglia integrate behaviors with sleep/wakefulness via adenosine and dopamine receptors and discussed the impacts of the BG in insomnia and PD.

Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post-mortem brains, we observed 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN) and significantly less CRH-positive fibers in the median eminence, while CRH-neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: i.e. vasopressin, oxytocin, tyrosine hydroxylase and thyrotropin releasing hormone-expressing neurons. Other hypothalamic cell groups, i.e. the suprachiasmatic, ventrolateral preoptic, infundibular and supraoptic nuclei and nucleus basalis of Meynert were unaffected. The surprising selective decrease in CRH-neurons provide novel targets for diagnostics and therapeutic interventions.

Excessive daytime sleepiness (EDS) is one of the commonest symptoms in neurological diseases and could impact on the quality of life by increasing the risk of accidents and generally affecting daily life activities. In this review, we will discuss the variety of causes responsible for EDS in neurological diseases: primary sleep disorders including obstructive sleep apnea-hypopnea syndrome,(OSA),circadian rhythms disorders, Restless leg syndrome  (RLS),periodic limb movement disorder (PLMD),CNS pathological abnormalities in arousal/sleep regulation systems, drugs, and comorbid psychiatric disorder. Among neurological diseases, Stroke, Epilepsy, Dementia, Parkinson disease, Multiple sclerosis, and  Encephalitis; represented a model for these interactions between EDS and neurological diseases.An individualized approach to this symptom in neurological patients should be considered with a focus on the location and nature of lesions. When considering EDS in neurological diseases, close attention to lifestyle and sleep hygiene is advisable. Precise diagnosis and treatment of EDS in neurological disease should be always considered.

Diagnosis and Biomarkers of Central disorders of Hypersomnolence

Jiyou Tang

The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China

Central disorders of Hypersomnolence are a class of sleep spectrum disorders, which is mainly characterized by excessive daytime sleepiness (EDS). Due to the few clinical biomarkers, the diagnosis of EDS requires a combination of comprehensive and personalized evaluation thread and principles. Hence on the basis of scaling qualitative assessment and electrophysiological quantitative diagnosis as well as disease classification, it is potential to find and use intuitive and specific biomarkers to increase the diagnostic accuracy, such as Orexin, melatonin, HLA and brain function imaging, etc.

Psychostimulants such as caffeine and amphetamine constitute the first generation of wake-promoting compounds. Their use and abuse cause well-known medico-social problems e.g., behavioral overexcitation, addiction and cognitive declines. Sleep medicine had long been looking for an awakening pill with preserved cognitive abilities. In the 1980’s, the discovery of modafinil (2nd generation) and its property of enhancing quiet waking in cats through multiple brain targets allows for the first time a successful therapy of hypersomniac symptoms and excessive sleepiness of diverse origins. Yet, it has a limited effect on cataplexy of narcolepsy with 15-25% of patients unresponsive. Ligands acting on specific brain targets are still in high demand in sleep medicine. The wake-promoting histaminergic neurons control their own release, synthesis and activity through a negative feedback on H3-receptors whose inverse agonists have long been known for their wake enhancement in animals. Yet, a clinically-suitable ligand, Pitolisant (必妥利生), has only recently become available, representing the third generation of wake-promoting compounds. This presentation reviews the three generations of wake-promoting therapies with focus on the discovery, mechanisms of action and clinical use of the histamine H3-receptor inverse agonist Pitolisant (必妥利生) and on the pespectives of sleep disorder therapies.

Neuroimaging studies have provided new information about brain abnormalities in narcolepsy patients to explore the pathologic mechanism of through non-invasive research. The main techniques include structural, functional and neurochemical imaging. Recent studies have found that the structural and functional abnormalities located in Hypothalamic secretin neuron projection system, brainstem reticular ascending activating system, emotion-related limbic system and attentional cognitive cortices, which provided important evidence for the changes of neural structure and pathophysiological mechanism of clinical features in narcolepsy.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by discrete episodes of hypersomnia associated with cognitive and behavioral abnormalities. KLS is more typically seen in adolescence than at other ages, and is more common in males than in females. The etiology, pathophysiology, and optimal management of KLS remain uncertain. The significant body of published literature allows consideration of possible aetiological mechanisms, an understanding of which could guide the development of therapeutic strategies. In the last few years advanced neurophysiological and sophisticated neuroimaging methods enabled to expand our knowledge on possible pathophysiological mechanisms which may be playing a role in KLS and establish a laboratory basis for its complex symptomatology. Functional neuroimaging in KLS have evidenced involvement of frontotemporal, thalamocortical and brain stem networks. Although diencephalic abnormalities are a common finding, no consistent pattern has emerged, and these studies have not revealed the mechanism(s) underlying the development of the abnormalities detected. There are currently neither standard biomarkers nor specific imaging study findings, making the diagnosis of KLS a challenge. Further, multimodal functional imaging and new biomarkers are probably necessary to inquire into the KLS pathology.

Sleep disorders and management in Multiple system atrophy

Chun-Feng Liu

Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou

Institute of Neuroscience, Soochow University, Suzhou

Sleep disorders is one of the commonly reported non-motor symptoms in patients with Parkinson's disease (PD) as well as in multiple system atrophy (MSA). A wide range of sleep disorders that include insomnia, excessive daytime sleepiness, rapid eye movement sleep behaviour disorder (RBD), periodic limb movement disorder, and sleep-disordered breathing (SDB). The onset of RBD may predate synucleinopathies (PD and MSA). 88% of patients with MSA had polysomnography(PSG)-confirmed RBD. The proportion is higher than that of PD. Patients with MSA may develop SDB which include obstructive sleep apnea (OSA) and central sleep apnea (CSA). Patients with MSA usually have nocturnal stridor. SDB was associated with a shorter duration of survival in patients with MSA. Continuous positive airway pressure (CPAP) is the gold standard treatment option of OSA and stridor. Bilevel positive airway pressure (BiPAP) may be an appropriate therapy for CSA.However, there is a lack of guidance and consensus on sleep disturbances in MSA. PSG is essential for a confirmatory diagnosis of sleep disturbances in MSA. We should pay attention to PSG examination to determine the optimal solution.

The good sleep states of being are conventionally defined by the simultaneous occurrence of behavioral, neurophysiological and autonomic descriptors. Although conventional/classical sleep classification have contained more than 90 sleep disorders, it is no longer able to define complex clinical syndromes and sleep associated events. So, some scholars suggest that the importance of state dissociation disorders, which are due to the intrusion of features typical of a different state into an ongoing state. Furthermore, status dissociatus also should be taken seriously. In this forum, the speaker will focus on definition, classification and clinical differential diagnosis of state dissociation, status dissociatus and related diseases.

Several lines of evidence support a relationship between disrupted  circadian behavior and neurodegenerative disease. Pathological and imaging studies in Parkinson disease（PD） and Alzheimer disease (AD) have shown abnormalities in brain regions known to regulate circadian rhythms and  circadian abnormalities feature prominently in these disorders. 

Work in rodent models suggests that the relationship between circadian behavior and neurodegeneration may be complex. Transgenic rodent models of PD  and AD show prominent abnormalities of circadian behavior, suggesting that the underlying neurodegenerative processes themselves can cause circadian abnormalities. Conversely, in similar models, it has also been shown that environmental or pharmacological manipulation of sleep and circadian behavior can modify disease progression, suggesting that the relationship may go both ways.

Background and objectives: Early and accurate diagnosis of fatal familial insomnia (FFI) is critical for effective screening, however, this rare disease remains difficult to recognize. This work aimed to propose a new diagnostic criterion for fatal familial insomnia (FFI) with optimal sensitivity, specificity and likelihood ratio.

Methods: An international group of experts was established and 128 genetically confirmed FFI cases and 281 non-FFI prion disease controls are enrolled in the validation process. The new criteria were proposed based on the following steps with 2-round expert consultation: 1) Validation of the 2018 FFI criteria. 2) Diagnostic item selection according to statistical analysis and expert consensus. 3) Validation of the new criteria.

Results: The 2018 criteria for possible FFI had a sensitivity of 90.6%, specificity of 83.3%, the positive likelihood ratio (PLR) of 5.43, and negative likelihood ratio (NLR) of 0.11; the probable FFI criteria had a sensitivity of 83.6%, specificity of 92.9%, the PLR of 11.77, and NLR of 0.18. The new criteria included more specific and/or common clinical features, 2 exclusion items, and summarized a precise and flexible diagnostic hierarchy. The new criteria for possible FFI had a sensitivity of 92.2%, specificity of 96.1%, a PLR of 23.64, and NLR of 0.08, while the probable FFI criteria had a sensitivity of 90.6%, specificity of 98.2%, the PLR of 50.33, and NLR of 0.095. Discussion: A new clinical diagnostic criteria was proposed for FFI, which will be practical at the clinic for early recognition of FFI and differentiation from other prion diseases then help further referral and genetic test.

Narcolepsy is a rare sleep disorder characterized by the main symptom of excessive daytime sleepiness (EDS). The broad variety of medical and psychiatric comorbidities associated with narcolepsy, including sleep-related hallucinations, sleep paralysis, dyssomnia, nightmares, REM sleep behavior disorder, atypical eating disorders, obesity, attention-deficit/hyperactivity disorder (ADHD), psychiatric illnesses such as depression and anxiety. These symptoms may be confused with other diseases and present diagnostic and therapeutic challenges in narcolepsy. Narcolepsy has a significant impact on the quality of life. Currently, the available treatment methods include pharmacotherapy and nonpharmacological strategies. And the behavioral strategies play an important role in the clinical management of narcolepsy.

Insomnia is the most common sleep disorder. About 40% of short-term insomnia disorder develops into chronic insomnia disorder, which has a long-term impact on physical and mental health. Online sleep monitoring and self-help intervention systems have been developed. In addition, several artificial intelligence (AI) programmes have been put in use as interventions for insomnia during recent decades. In this session, we will discuss their advantages and disadvantages, as well as their application experience in The Chinese population.

Adolescence is a critical period for the development of insomnia and many mood problems. Adolescent insomnia seems to have distinct clinical presentation and etiology when compared with that in children and adults. In this presentation, Dr. Jihui Zhang will be presenting the updates in the diagnosis and treatment of adolescent insomnia from his experiences in clinical practice and research. He will also discuss the challenges and directions in this field. 

Our study found that the LED spectrum and sunshine spectrum of the visible light energy treatment system are more than 90% similar, with the sunshine spectrum at different time points as the standard, through the deployment of 7 phosphor materials, to achieve the closest distribution of sunshine spectrum.The first high precision microoptical system converts the LED lattice light source into a large area of parallel beam.To achieve a large area of sky, from top down, into the indoor scene can reflect the consistent effect with the outdoor sunshine environment.

Sleep is one of the most important biorhythms. Sleep is the result of the co-regulation of circadian rhythm and sleep homeostasis. Disruption of circadian rhythms can cause sleep disturbances; Insomnia is a risk factor of depression, which predicts more serious depression and seriously affects the social function of depressed patients. Depression is an independent risk factor for insomnia. The core symptoms of depression are closely related to biorhythm. The higher the severity of biorhythm disorder, the higher the severity of depression. Rhythm sleep and depression are closely correlated with each other. Restoring biorhythm provides a new treatment approach for patients with insomnia and depression, and is expected to bring better clinical treatment outcomes for patients.

Title :Clinical application and latest research progress of Brief Behavioral Treatment for Insomnia(BBT-I)

BBT-I is a short-term, easy-to-operate, evidence-based psychobehavioral treatment for Insomnia. The clinical operation guidelines for BBTI were formally put forward in 2012.

At present, The clinical efficacy of BBTI for insomnia disorders has been proven on improving insomnia related physical discomfort, changing false sleep beliefs and other aspects.

In this report, Professor Gao will introduce the latest clinical application of BBT-I and his team's achievements in the application of BBTI, and share the notes and standardization of using BBT-I technology in clinical practice.

Not all adults with chronic insomnia respond to the recommended therapeutic options of cognitive behavioral therapy and approved hypnotic drugs. Transcranial alternating current stimulation (tACS) may offer a novel potential treatment modality for insomnia. The primary outcome was response rate measured by the Pittsburgh Sleep Quality Index (PSQI) at week 8. Our study showed that the tACS, 20 daily 40-min, 77.5-Hz, 15-mA sessions of active tACS targeting the forehead and both mastoid areas, applied in the present study has potential as an effective and safe intervention for chronic insomnia within 8 weeks.