Publications

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. We propose the parallel explanation that her sleep attacks, usually attributed to temporal lobe epilepsy, actually represent a hypersomnia that is most consistent with the modern diagnosis of post-traumatic narcolepsy. Using historical analysis as well as current understandings of sleep medicine, we aim to shed light on this under-recognized aspect of Tubman’s life. In addition, this case study allows us to review the potential long-term effects of severe traumatic brain injuries; consider a differential for excessive daytime sleepiness and hypnagogic hallucinations; and familiarize readers with the pathophysiology, diagnosis, and treatment of narcolepsy. Whether her symptoms are viewed through the lens of the past or measured against current biomedical standards, Tubman demonstrated an inspiring ability to persevere despite intrusive sleep episodes and to realize her dreams for the betterment of others.

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

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. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.

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.

Methods: Young adults (18-39 years) with narcolepsy were recruited through national narcolepsy patient organizations. Participants (n = 254) completed an online survey assessing their friendships and romantic and sexual relationships, including communication about their social relationships with medical providers.

Results: All participants (mean age = 28.8 years; 87% female, 92% White/Caucasian) reported that narcolepsy made their social life more challenging. They reported receiving more support from significant others, compared to family or friends (P < .05). Most (80%) indicated that narcolepsy currently impacted their sex life. Only a few participants reported that their providers asked about their social and sex lives, though they wanted providers to ask.

Conclusions: Narcolepsy impacts social functioning in young adults. Many individuals with narcolepsy prioritize single, meaningful, romantic relationships as developing and sustaining new relationships may be challenging. In addition, narcolepsy symptoms impact sexual functioning. Though many participants wanted to discuss their social and sex lives with providers, only a few providers ask. Treatment of narcolepsy in young adulthood should include supporting individuals regarding the impact on social, romantic, and sexual health.

Citation: Davidson RD, Biddle K, Nassan M, Scammell TE, Zhou ES. The impact of narcolepsy on social relationships in young adults. J Clin Sleep Med. 2022;18(12):2751-2761.

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. In addition, some researchers propose that PPTvGlut2 neurons promote locomotion, yet even though the PPT is a target for deep brain stimulation in Parkinson's disease, the role of the PPT in locomotion is debated. We hypothesized that PPTvGluT2 neurons drive arousal and specific waking behaviors via certain projections and modulate locomotion via others.

Methods: We mapped the axonal projections of PPTvGlut2 neurons using conditional anterograde tracing and then photostimulated PPTvGlut2 soma or their axon terminal fields across sleep/wake states and analyzed sleep/wake behavior, muscle activity, and locomotion in transgenic mice.

Results: We found that stimulation of PPTvGlut2 soma and their axon terminals rapidly triggered arousals from non-rapid eye movement sleep, especially with activation of terminals in the basal forebrain (BF) and lateral hypothalamus (LH). With photoactivation of PPTvGlut2 terminals in the BF and LH, this wakefulness was accompanied by locomotion and other active behaviors, but stimulation of PPTvGlut2 soma and terminals in the substantia nigra triggered only quiet wakefulness without locomotion.

Conclusions: These findings demonstrate the importance of the PPTvGluT2 neurons in driving various aspects of arousal and show that heterogeneous brain nuclei, such as the PPT, can promote a variety of behaviors via distinct axonal projections.

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. The testing required for diagnosis of idiopathic hypersomnia also presents logistical barriers, and reliability of objective sleep measures is suboptimal. The pathophysiology of idiopathic hypersomnia remains unknown. In this review, clinical considerations related to the pathogenesis, diagnosis, and management of idiopathic hypersomnia will be discussed, including perspectives from the European Union and United States.

Sensory information is transmitted from peripheral nerves, through the spinal cord, andup to the brain. Sensory information may be modulated by projections from the brain tothe spinal cord, but the neural substrates for top-down sensory control are incompletelyunderstood. We identified a novel population of inhibitory neurons in the mousebrainstem, distinguished by their expression of prodynorphin, which we named LJA5.Here, we identify a similar group of Pdyn+ neurons in the human brainstem, and we definethe efferent and afferent projection patterns of LJA5 neurons in mouse. Using specificgenetic tools, we selectively traced the projections of the Pdyn-expressing LJA5 neuronsthrough the brain and spinal cord. Terminal fields were densest in the lateral and ventro-lateral periaqueductal gray (PAG), lateral parabrachial nucleus (LPB), caudal pressor area,and lamina I of the spinal trigeminal nucleus and all levels of the spinal cord. We thenlabeled cell types in the PAG, LPB, medulla, and spinal cord to better define the specifictargets of LJA5 boutons. LJA5 neurons send the only known inhibitory descending pro-jection specifically to lamina I of the spinal cord, which transmits afferent pain, tempera-ture, and itch information up to the brain. Using retrograde tracing, we found LJA5neurons receive inputs from sensory and stress areas such as somatosensory/insular cor-tex, preoptic area, paraventricular nucleus, dorsomedial nucleus and lateral hypothalamus,PAG, and LPB. This pattern of inputs and outputs suggest LJA5 neurons are uniquelypositioned to be activated by sensation and stress, and in turn, inhibit pain and itch.