Through fundraising events, grant distribution and engagement with the patient community, WUN acts as both a facilitator and an anchor bringing life, stability and encouragement to people affected by Narcolepsy.
Until the late 1990’s, narcolepsy was a complete mystery. Doctors suspected that the problem lay within the hypothalamus, a part of the brain that regulates arousal, sleep, hunger and other functions, but the specific problem was unknown. The discovery that narcolepsy is caused by a loss of the orexin (hypocretin)-producing neurons has substantially improved our understanding of this often-disabling disorder and has enabled researchers to move much closer to better therapies.
With support from Wake Up Narcolepsy, Dr. Scammell’s research group has helped define which brain circuits give rise to cataplexy and sleepiness using mouse models of narcolepsy. Cataplexy is episodes of muscle weakness triggered by strong, generally positive emotions, and Dr. Scammell’s group has found that the amygdala is a key brain region for cataplexy. The amygdala is considered a brain region where “emotion meets motion”. For example, the amygdala helps produce emotional reflexes such as freezing with fear or smiling at a friend. It is now clear that in mice with narcolepsy, positive emotions (in response to tasty treats such as chocolate) are relayed by the amygdala to the brainstem, resulting in episodes of muscle weakness.
The amygdala is a complicated brain region, and Dr. Scammell’s research group will use this generous support from Wake Up Narcolepsy to define just which amygdala neurons mediate cataplexy. They anticipate that this will enable development of drugs that target just this brain circuit without causing side effects. This funding will also help generate crucial pilot data that can leveraged to obtain larger research grants from the National Institutes of Health and other organizations. Ultimately, a better understanding of these brain mechanisms will enable researchers and doctors to develop new methods to improve sleepiness, cataplexy, and other symptoms of narcolepsy.
Genetic predisposition of narcolepsy and a new sleep study diagnostic test
Dr. Emmanuel Mignot and his research team are proud to announce that they have recently completed a World Wide Genome Wide Association study to uncover why narcolepsy develops in some individuals but not others. The study was conducted in regular type 1 narcolepsy patients and also in patients who have developed narcolepsy following vaccination with the anti H1N1 swine flu vaccine pandemrix.
We analyzed multiethnic samples from Asians (Korea, Japan and China), African Americans, and Caucasians (Europe, USA) in 5,501 cases and 23,615 controls to study genetic associations with narcolepsy. We discovered overall significant associations in the HLA locus and in 12 other loci of which 6 are entirely new finings. The new findings include association with the Perforin PRF1, Langherin CD207, SIRPG, IL27 and ZFAND2A genes. Six other associations (T cell receptor TRA, TRB, cathepsin CTSH, interferon receptor IFNAR1, ZNF365 and P2RY11) have been reported in earlier studies. Most interestingly, TRA and CTSH genetic effects were stronger in vaccination-induced narcolepsy, while predisposing effects of IFNAR1, TCRB and CD207 were absent or opposite. Functional analysis in two cohorts revealed a functional role for TRA and TRB variants in regulating usage of TRAJ*24, TRAJ*28 and TRBV*4-2 respectively (P<10-8 ). In addition, we found that the IFNAR1 variant associated with narcolepsy increases response to influenza-A infection in dendritic cells. Finally, we found that partitioned narcolepsy heritability was mediated by immune cells, with functional analysis of ENCODE data indicating enrichment of functional elements in Th17, T regulatory and CD8+ T cells. Together these findings define narcolepsy as an autoimmune disease mediated through T cell receptor signaling, with involvement of influenza A (the flu) as a critical trigger. Interestingly, we are also now learning which genetic effects are related to flu infections (langherin, interferon receptor) versus core to the autoimmune process (PRF1, TCRA, HLA). The research is starting to build a detailed model on how the immune system is causing narcolepsy, with possible preventive applications. This research has been written and will be submitted very soon for publication. Additionally we used machine learning to create a probability score for narcolepsy in individuals suspected of having Type 1 narcolepsy, opening the possibility of diagnosing narcolepsy using an at home nighttime sleep study as opposed to current standard, a daytime nap study following a nocturnal sleep study called the Multiple sleep latency test that lasts 24 hrs. Analysis of sleep currently requires visual inspection by trained scoring technicians. We used neural networks in over 3,000 sleep recordings from 10 locations to automate sleep stage scoring, producing a hypnodensity graph – a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated on 70 subjects assessed by six sleep scorers, forming a more accurate standard for comparison. Our best model performed better than any individual scorer and reached an accuracy of 0.87, while average scorers only reached 0.81. When predictions were weighed by scorer agreement, performance rose to 0.95, indicating a higher consensus in areas of scorer agreement. The method also reliably scores sleep stages down to 5 second epochs instead of the conventional 30 second scoring-epochs. Accuracy did not vary by sleep disorder except for narcolepsy, suggesting scoring difficulties. A narcolepsy biomarker was thus extracted based on unusual sleep-stage overlaps. Validation of the biomarker in an independent dataset of 105 type-1 narcoleptics versus 331 controls and other patients produced a specificity of 0.96 and a sensitivity of 0.91. Similar performances were obtained when tested against a high pretest probability sample of patients with type-2 narcolepsy or idiopathic hypersomnia. Addition of HLADQB1*06:02 typing information (a frequently used genetic marker of type-1 narcolepsy) further increased specificity to 0.99. Our method could reduce costs by decreasing time spent in sleep clinics and automating the diagnosis of narcolepsy. It also opens the possibility of diagnosing narcolepsy using home sleep studies.
This research is under review in nature communication, and also available as a preprint at https://nature-research-under-consideration.nature.com/users/37265-naturecommunications/posts/21655-the-use-of-neural-networks-in-the-analysis-of-sleep-stages-and-thediagnosis-of-narcolepsy
A recent article citing Dr. Mignot’s career in narcolepsy: https://www.theatlantic.com/health/archive/2017/10/narcolepsy-sleep-disorder-stillunsolved/543717/
Thank you for your generous support!
IN THE NEWS – EMMANUEL MIGNOT RECOGNIZED BY THE BREAKTHROUGH PRIZE
Dr. Emmanuel Mignot won a 2023 Breakthrough Prize in Life Sciences for discovering that hypocretin/orexin deficiency causes narcolepsy and for paving the way for the development of new sleep disorder treatments. The prize acknowledges researchers for transformative mathematic discoveries and scientific advances toward understanding living systems and extending human life. This award will further elevate narcolepsy as an important area of sleep and autoimmune research, where many new therapies are currently being developed. The Stanford Center for Narcolepsy is at the forefront of these advancements.
PATHOPHYSIOLOGY
A publication describing new genes associated with type 1 narcolepsy (NT1) in over 5,000 patients across the world has been provisionally accepted in Nature Communications. The work shows that narcolepsy strongly shares autoimmune genes and, in some cases, co-pathology with asthma/allergies. Type 1 diabetes also shares similar genetics, except for the gene DQ0602, which causes susceptibility to narcolepsy but protects against type 1 diabetes. Consequently, very few people with narcolepsy also have type 1 diabetes, even if it runs in the family. In contrast, type 2 diabetes is a common co-occurrence with narcolepsy because of the weight gain associated with both disorders.
Another area of interest is type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). The center has submitted a proposal to study this pathology’s proteomics (7,500 proteins). The goal is to better classify NT2 and IH into subtypes. Classifications have historically been based on a Multiple Sleep Latency Test (MSLT). However, we anticipate greater accuracy when diagnosis of disorders is based on their likely causes: insufficient wake promoting systems, inefficient sleep resulting in sleepiness (profile would look like sleep deprived individuals), or abnormal circadian phase (profile would look like jet lag or shift worker). NT1 will also be included in the study. The center believes that identifying these subtypes will help to treat IH and NT2 more precisely.
The center’s team is also making progress in determining a trigger for type 1 narcolepsy. An increasing amount of data from Dr. Mignot’s laboratory, supported by data from other labs, suggest that narcolepsy can not only be triggered by influenza A/H1N1, but also a subset of influenza B strains. Researchers have
identified a possible commonality between these strains that could explain this process, and the lab will test this hypothesis.
DIAGNOSIS AND MONITORING: BEYOND THE MSLT
Most sleep researchers agree that the Multiple Sleep Latency Test (MSLT)—also referred to as the nap test—is not meaningful when testing for NT2 or IH. It works well for NT1 where patients have cataplexy or low hypocretin. Further, the MSLT measures the ability to fall asleep, but not the struggle many patients experience trying to stay awake. Additionally, the test is done in an artificial environment, which has the potential to yield less accurate results than if it were done in the patient’s home. The development of a comprehensive at-home test would improve the accuracy of diagnostics. Further, it would refine the process of monitoring patient responses to new medications being developed.
To diagnose NT1, Dr. Mignot’s lab found that it is possible to use deep learning/artificial intelligence analysis of nocturnal sleep polysomnography studies instead of the MSLT test, which has ~93% sensitivity and 97% specificity. The team is now extending this work by analyzing more patients with NT1 vs. controls and other hypersomnia (NT2 and IH) at higher resolution (1-second sleep epoch scoring vs. the previous 30-second sleep epoch), using newer statistical techniques for sleep stages, and adding genetic data. In doing this, they found they can now diagnose narcolepsy with 98% sensitivity and specificity, a performance that is superior to the MSLT and allows individuals to be directly and simultaneously screened for narcolepsy when studied for sleep apnea. The study includes over 800 T1N subjects, 100 NT2 subjects, and 200 IH subjects, plus thousands of control subjects with sleep apnea, other sleep problems, and community controls—an unprecedented sample. A follow-up project will scale this new procedure, using tens of thousands of random polysomnography recordings to see if the method can be used to identify misdiagnosed NT1s. With the long-term goal of integrating multiple modalities, the lab will also add proteomic testing (described above) to increase the probability of a precise diagnosis.
Longer term, the solution to diagnosing NT1, NT2 and IH, and monitoring therapeutic response is not just to study nighttime sleep alone, but rather to study both daytime wake/function and nighttime sleep. To do this, we need to start using devices that measure EEG during the day and sleep at night, in real life, for several days in a row. Indeed, daytime sleepiness in hypersomnia includes many different symptoms that differ across patients, such as brain fog, microsleeps, unintended naps, and cognitive difficulties. Using EEG and artificial intelligence during the day, Dr. Mignot’s team hopes to be able to differentiate and measure each event, allowing clinicians to have a complete picture of how an individual is functioning during the day and at night at baseline and after treatment.
THERAPIES
New therapies for narcolepsy and hypersomnia are undergoing clinical trials at Stanford. Together with biopharmaceutical company Takeda, Dr. Mignot’s lab recently published a study showing an infusion of Danavorexton, an orexin agonist (a substance that simulates hypocretin/orexin), helps NT1 patients sustain a nearly average level of wakefulness. This data was extended using the orally available orexin agonist (TAK994) in hundreds of patients, but the clinical trial was interrupted because a few patients developed complications. The lab is now starting a new trial using a different orally available orexin agonist (TAK861) to see if they have the same success rate without complications. Several similar drugs from other companies are set to undergo trials in 2024. Additional trials are underway exploring the effects of new pharmaceuticals and their ability to improve sleep and wake for patients with hypersomnia and narcolepsy. These include a longer lasting formulation of sodium oxybate (Lumriz) from Avadel, antihistamine receptor 3 compounds, and new anticataleptic agents.
LEARN MORE
Please visit Dr. Mignot’s websites which outline his work throughout sleep sciences and narcolepsy. He and his colleagues are hopeful these platforms will attract more like-minded scientists to train and specialize in these areas.
Stanford Center for Narcolepsy
https://med.stanford.edu/narcolepsy.html
Emmanuel Mignot, MD, PhD
Craig Reynolds Professor of Sleep Medicine Director, Stanford Center for Narcolepsy
Mignot Lab @ Stanford mignotlab.com
Dr. Mignot and his colleagues were the first to discover that narcolepsy is an autoimmune disease caused by loss of hypocretin/orexin, a brain chemical needed for staying awake and controlling dreaming. The Stanford Sleep Medicine clinic treats hundreds of narcolepsy patients each year, many of whom volunteer for research studies. Through his work with these volunteers, Dr. Mignot created a database from the records of thousands of patients from multiple ethnic groups, providing an invaluable resource for the field that has led to many breakthroughs. Dr. Mignot’s current research focuses on applications of mobile technology, machine learning, and genetics to the study of sleep and sleep disorders in large population samples. He is the recipient of numerous research grants and honors, including a 2024 Breakthrough Prize in life sciences. Dr. Mignot is co-author of more than 200 original scientific publications and is an active member of several professional and governmental organizations, including the National Academy of Sciences and National Academy of Medicine.
THANK YOU
Thank you for your generous support of narcolepsy research at Stanford Medicine. Through your generosity, Stanford researchers continue to drive the innovative strategies to improve prediction, diagnoses, and treatments. Your gifts fuel the advancements that will change the lives of people with narcolepsy and hypersomnia. They allow researchers to move more rapidly with new discoveries than conventional funding mechanisms.
CONTACT
If you have questions, or if you would like to have a deeper conversation about how you can support this research, please contact:
Ariel Korn
Senior Associate Director, Stanford University Medical Center Development
650.850.1859 ariel.korn@stanford.edu
View Stanford Center for Narcolepsy Research Update 2023-2024 PDF here
Our research team at Boston Children’s Hospital are working on many projects to improve the care of children, adolescent and young adults with narcolepsy. Diagnostic delays in narcolepsy are unfortunately common. We are working on a screening tool that can be used by health care providers and school-based professionals to identify patients with narcolepsy symptoms and direct them towards to appropriate diagnostic tests. We are also working on developing and validating patient-reported outcomes for pediatric narcolepsy. These outcome measures are important to identify what symptoms and functions are important to people with narcolepsy in order to guide treatments. Last, disrupted nighttime sleep (DNS) is a common problem for people with narcolepsy. We are studying DNS in pediatric narcolepsy and assessing its effect on memory, mood, and attention.
Dr. Kiran Maski says, “I am incredibly grateful for the support of Wake Up Narcolepsy, our wonderful research participants, and our dedicated research staff that make this work possible!”
Narcolepsy and idiopathic hypersomnia usually begin in early adolescence, but diagnostic delays ranging 5-10 years are common, impacting disease burden. To improve early identification of these treatable conditions, Dr. Kiran Maski, Boston Children’s, developed and validated the Pediatric Hypersomnolence Survey (PHS). This is a screening tool that can be used in clinical offices and the community to assess sleepy kids and teens. We hope this survey can help triage kids/teens with narcolepsy/idiopathic hypersomnia more directly to sleep medicine providers for timely diagnosis.
Click here to access the survey.
This work was just accepted by the journal Neurology https://pubmed.ncbi.nlm.nih.gov/35314496/.
The development of the PHS was funded by Covery Health Care and Wake Up Narcolepsy.
“With your research funds from last year (2022), we were able to:
AASM Foundation recently provided an update on the 2023 Strategic Research Grant co-funded by Wake Up Narcolepsy.
Strategic Research Grant on Hypersomnolence Update
Prepared for Wake Up Narcolepsy on September 15, 2023
The American Academy of Sleep Medicine Foundation (AASM Foundation) recently partnered with Wake Up Narcolepsy to award a Strategic Research Grant on topics related to narcolepsy because both organizations are passionate about improving the lives of people living with sleep disorders.
As a result of this partnership, the AASM Foundation’s Board of Directors recently approved a $100,000 Strategic Research Grant to principal investigators, Laura Lewis, PhD and Ewa Beldzik, PhD, at Massachusetts Institute of Technology. This grant was funded in collaboration with Wake Up Narcolepsy. Their topic is Imaging the Brainstem and Hypothalamic Activity Underlying Sleepiness-Induced Attention Deficits in Humans.
Broad scientific consensus has called for new biomarkers for hypersomnolence disorders, which is essential to improve their diagnosis and treatment. This project aims to image activity in the brain circuits responsible for sleep-wake regulation and understand how it is linked to cognitive symptoms. This project uses a noninvasive imaging tool, enabling translation to human patients. The AASM Foundation and Wake Up Narcolepsy funding is enabling this research to translate novel MRI-based tools to understand the neural basis of hypersomnolence disorders.
As a partner supporting the AASM Foundation’s Strategic Research Grant program, Wake Up Narcolepsy appointed representatives to participate in the peer-review process, and the organization agreed to co-fund a portion of the grant once approved by the AASM Foundation’s Board of Directors.
The AASM Foundation has distributed more than $25 million in research funding since 1998, and we are proud to partner with organizations like Wake Up Narcolepsy as we work together to champion a bright future in sleep health.
Limbic system-brainstem interactions in cataplexy and REM sleep atonia
Youth Investigator Brandon Toth, Co-Investigator: Christian Burgess, PhD
“Cataplexy often occurs in response to strong, positive emotions; however, despite significant research efforts, it remains unclear what neural mechanisms trigger cataplexy. Muscle tone is regulated by regions of the brainstem, which are directly innervated by neurons in the limbic system, where emotions are processed. The goal of this proposal is to clarify how limbic system-brainstem interactions promote the loss of muscle tone during cataplexy. We will use a combination of cutting edge tools in basic neuroscience, including neural recording and manipulation, in animal models of narcolepsy to investigate these circuits. Understanding the involvement of the limbic system in the regulation of muscle tone will not only open up new avenues of treatment for narcolepsy, but also potentially for other sleep disorders involving abnormal motor control across states, such as REM-sleep behavior disorder.”
Dr. John Peever, PhD
“First and foremost, my lab is grateful for WUN support. The provided funds will allow us to continue addressing the underlying causes of sleepiness and cataplexy in people for narcolepsy. We will use these funds to determine how loss of orexin cells in people with narcolepsy affects brain function. Our goal is to understand how orexin cell loss affects different brain areas to cause sleepiness and narcolepsy.”
The Behavioral Sleep Medicine Lab at Northwestern University, led by Jason Ong, has been very active in research aimed at improving the health-related quality of life in people with narcolepsy and idiopathic hypersomnia. In January 2020, our paper from a study that was funded by WUN was accepted for publication at Behavioral Sleep Medicine. This study involved a series of interviews with PWN to better understand how the symptoms of narcolepsy impact quality of life and to seek patient input on how to provide more relevant mental health services for PWN. In December 2021, we published our first study using a novel cognitive-behavior therapy for hypersomnia (CBT-H) in the Journal of Clinical Sleep Medicine. CBT-H is a 6-session telehealth program using techniques such as following a regular daytime and nighttime schedule, managing depression and anxiety associated with hypersomnia, and improving self-efficacy, which refers to the ability to achieve a goal. We found that 40% of participants showed a significant reduction in depressive symptoms and the telehealth delivery allowed participants from around the US to participate.
In addition to these publications, we have two current projects. One project aims to develop an app specifically designed to monitor and manage symptoms of hypersomnia based on our CBT-H program. The first beta version is nearly ready for testing. The second project is an NIH-funded study examining the use of mindfulness meditation to help reduce depression and anxiety symptoms in people with narcolepsy. This project is currently recruiting participants.
Dr. Jason Ong says, “We greatly appreciate the support from WUN, which has allowed us to carry out and complete these projects during the pandemic. We hope that our work will provide evidence-based strategies using digital and tele-health delivery to improve the mental health and quality of life among PWN.”
1. Helped Masters student finish her Masters in Narcolepsy and depression
2. Started second large study qualitatively evaluating symptoms of Narcolepsy in kids.
3. Published paper on clinical manifestations of Narcolepsy.
4. Adolescent medicine Staff dedicated to the Narcolepsy clinic to help navigate the issues some adolescents face with Narcolepsy.
5. Hosted a family event.
Dr. Indra Narang from Sick Kids-
Clinical Manifestations of Childhood Narcolepsy.
We evaluated symptoms of children who presented with symptoms of Narcolepsy and were
subsequently diagnosed with Narcolepsy. These data were obtained just after diagnosis of Narcolepsy in
33 children prior to any child commencing medications to alleviate their symptoms. The mean age at
diagnosis was 10.4 years, the youngest age being 3.9 years and oldest 17 years of age. All children had
excessive daytime sleepiness. Of these children, 64% had cataplectic facies such as tongue protrusion,
facial droop, facial grimacing and/or head rolling. The remaining 36% had characteristic cataplexy with
muscle weakness of limbs and /or falling to the ground with laughter/excitement. Interestingly, children
with cataplectic facies tended to be younger and had higher body weights. At presentation, the study
also found that 21% of children had hallucinations and 9% had sleep paralysis.
All brain scans (MRI brain) and all testing for epilepsy using an EEG were negative for this group of
children. This study has increased awareness of Narcolepsy in children and highlighted the different
manifestations of Narcolepsy in children. Link to the published study.
Depressive Symptoms, Sleep Patterns and Physical Activity in Adolescents with Narcolepsy
In this study, our group were interested to understand the association between depressive symptoms,
sleep patterns (duration and quality), excessive daytime sleepiness and physical activity in adolescents
with narcolepsy and to compare them to controls. We recruited 30 adolescents with a mean age of 13.8
years diagnosed with Narcolepsy and 30 controls subjects.
Adolescents completed many questionnaires evaluating how 1) sleepy they were 2) the presence of
depressive symptoms, 3) sleep disturbance, 4) physical activity levels. They also used wrist based
actigraphy for one week to measure total sleep time.
This study showed that adolescents with Narcolepsy had more depressive symptoms than adolescents
who did not have Narcolepsy. Depressive symptoms were associated with excessive daytime sleepiness,
more night time sleep disturbance and lower physical activity levels.
This study has re-inforced a multi-disciplinary care approach to adolescents with Narcolepsy ensuring
that mental health issues are addressed early in the consultation process. Further, we have emphasized
the message that improving nocturnal sleep quality and good sleep hygiene as well as promoting
physical activity may provide an opportunity to reduced depressive symptoms in adolescents with
Narcolepsy. This study has not been published yet but is under review.
Qualitative Evaluation of symptoms of Narcolepsy
This study which we have just commenced is evaluating which specific symptoms impact patients with
Narcolepsy. We are also interested to know how these symptoms may affect their daily lives.
WUN Research GrantsWUN offers both unrestricted and restricted grants in several areas of research. |