Afferent Projections to the Calca/CGRP-Expressing Parabrachial Neurons in Mice.

The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons that regulate responses to a variety of interoceptive and cutaneous sensory signals. One lateral PB subpopulation expresses the Calca gene, which codes for the neuropeptide calcitonin gene-related peptide (CGRP). These PB neurons relay signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet their inputs and their neurochemical identity are only partially understood.

The impact of idiopathic hypersomnia on the social lives of young adults.

Objectives: People with idiopathic hypersomnia report significant impairment in their lives due to idiopathic hypersomnia symptoms, and this likely includes an impact on social relationship health. This study investigated the effects of idiopathic hypersomnia on social relationships (friends, romantic, and sexual) during the key developmental period of young adulthood.

Methods: Young adults (N = 106; 18-39years) with idiopathic hypersomnia were recruited through national hypersomnia patient organizations.

Impaired Sleep-Dependent Memory Consolidation in Pediatric Narcolepsy Type 1.

Study Objectives: Disrupted nighttime sleep (DNS) is common in pediatric Narcolepsy type 1, yet its cognitive impact is unknown. As N2 sleep spindles are necessary for sleep-dependent memory consolidation, we hypothesized that Narcolepsy Type 1 impairs memory consolidation via N2 sleep fragmentation and N2 sleep spindle alterations.

Methods: We trained 28 pediatric Narcolepsy Type 1 participants and 27 healthy controls (HC) on a spatial declarative memory task before a nocturnal in-lab polysomnogram and then gave them a cued recall test upon awakening in the morning.

Characterizing disrupted nighttime sleep and associated functional outcomes in youth with narcolepsy type 1.

Study Objectives: Disrupted nighttime sleep (DNS) and sleep instability are common in children and adolescents with Narcolepsy Type 1 (NT1), but optimal objective sleep measures have not been determined. We compared self-reported and objective sleep measures between young people with NT1 and healthy controls (HC) and test the hypotheses that the Wake/N1 Index is the best objective measure of perceived nocturnal wakings vs. other DNS measures reported in the literature and is associated with daytime functional problems.

Cardiovascular Risks in People With Narcolepsy: Expert Panel Consensus Recommendations.

Background: Observational and retrospective studies suggest that people with narcolepsy may have an increased prevalence of cardiovascular and cardiometabolic comorbidities and may be at greater risk for future cardiovascular events. An expert consensus panel was formed to establish agreement on the risk of hypertension and cardiovascular/cardiometabolic disease in people with narcolepsy and to develop strategies to mitigate these risks.

Methods And Results: Experts in sleep medicine and cardiology were selected to participate in the panel.

The nature and magnitude of cognitive impairment in narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia: a meta-analysis.

People with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) often report cognitive impairment which can be quite burdensome but is rarely evaluated in routine clinical practice. In this systematic review and meta-analysis, we assessed the nature and magnitude of cognitive impairment in NT1, NT2, and IH in studies conducted from January 2000 to October 2022. We classified cognitive tests assessing memory, executive function, and attention by cognitive domain.

Impaired cognition in narcolepsy: clinical and neurobiological perspectives.

In addition to well-known symptoms such as sleepiness and cataplexy, many people with narcolepsy have impaired cognition, reporting inattention, poor memory, and other concerns. Unfortunately, research on cognition in narcolepsy has been limited. Strong evidence demonstrates difficulties with sustained attention, but evidence for executive dysfunction and impaired memory is mixed.

Afferent projections to the /CGRP-expressing parabrachial neurons in mice.

The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and cutaneous sensory signals. The lateral PB subpopulation expressing the gene which produces the neuropeptide calcitonin gene-related peptide (CGRP) relays signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet the afferents to these neurons are only partially understood. We mapped the afferent projections to the lateral part of the PB in mice using conventional cholera toxin B subunit (CTb) retrograde tracing, and then used conditional rabies virus retrograde tracing to map monosynaptic inputs specifically targeting the PB neurons.

Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder: a pooled post hoc analysis of two randomized phase 3 clinical studies.

Study Objectives: Post hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal.

Methods: We studied sleep architecture in adults with chronic insomnia disorder from two randomized phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg).

Nociceptor spontaneous activity is responsible for fragmenting non-rapid eye movement sleep in mouse models of neuropathic pain.

Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount.

Harriet Tubman's Hypersomnia: Insights from Historical and Medical Perspectives.

Harriet Tubman, a hero of the abolitionist movement and early civil rights advocate, suffered a head injury in childhood and subsequently developed sleep attacks associated with visions that were extensively documented in historical accounts. Her contemporaries perceived these visions together with unpredictable and unavoidable urges to sleep as manifestations of her deep faith, rather than as symptoms of an illness. While religious perspectives remain crucial to understanding Tubman's sleep-related experiences, some may consider them insufficient in view of modern medical advances.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

Background: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.

Methods: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo.

Number, Duration, and Distribution of Wake Bouts in Patients with Insomnia Disorder: Effect of Daridorexant and Zolpidem.

Background: Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning.

Methods: Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study.

Clinical considerations for the diagnosis of idiopathic hypersomnia.

Idiopathic hypersomnia is a sleep disorder of neurologic origin characterized by excessive daytime sleepiness, with sleep inertia, long, unrefreshing naps, and prolonged nighttime sleep being key symptoms in many patients. Idiopathic hypersomnia is described in the International Classification of Sleep Disorders, 3rd Edition as a central disorder of hypersomnolence with distinct clinical features and diagnostic criteria; however, confirming the diagnosis of idiopathic hypersomnia is often challenging. Diagnosis of idiopathic hypersomnia is based on objective sleep testing and the presence of associated clinical features but may be difficult for clinicians to recognize and correctly diagnose because of its low prevalence, clinical heterogeneity, and symptoms, which are similar to those of other sleep disorders.

Glutamatergic pedunculopontine tegmental neurons control wakefulness and locomotion via distinct axonal projections.

Study Objectives: The pedunculopontine tegmental (PPT) nucleus is implicated in many brain functions, ranging from sleep/wake control and locomotion, to reward mechanisms and learning. The PPT contains cholinergic, GABAergic, and glutamatergic neurons with extensive ascending and descending axonal projections. Glutamatergic PPT (PPTvGlut2) neurons are thought to promote wakefulness, but the mechanisms through which this occurs are unknown.

The impact of narcolepsy on social relationships in young adults.

Study Objectives: Narcolepsy often begins during adolescence and young adulthood, which are crucial periods for social development. The symptoms of narcolepsy likely impact social interactions, but little research has assessed the effects of narcolepsy on social relationships. The current study investigated the impact of narcolepsy on friendships and romantic and sexual relationships.

Orexin neurons inhibit sleep to promote arousal.

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus.

Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase .

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene . Comparing newly generated mouse models for downregulation (models of Angelman syndrome) vs. upregulation (models for autism), we find reciprocal effects of gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity.

Development and Validation of the Pediatric Hypersomnolence Survey.

Background And Objectives: Narcolepsy and idiopathic hypersomnia usually begin in early adolescence, but diagnostic delays ranging from 5 to 10 years are common, affecting disease burden. To improve early identification of these treatable conditions, we developed and validated the Pediatric Hypersomnolence Survey (PHS).

Methods: Content was developed through literature review, patient focus groups, interviews with experts in the field, and field testing.

Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity.

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1.

The Impacts of Age and Sex in a Mouse Model of Childhood Narcolepsy.

Narcolepsy is a sleep disorder caused by selective death of the orexin neurons that often begins in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, episodes of paralysis during wakefulness. Cataplexy is often worse when narcolepsy develops in children compared to adults, but the reason for this difference remains unknown.