25.   Andrew S. P. Lim et al., “Sleep Is Related to Neuron Numbers in the Ventrolateral Preoptic/Intermediate Nucleus in Older Adults with and Without Alzheimer’s Disease,” Brain 137 (2014): 2847–61.

  26.   Kirsi-Marja Zitting et al., “Young Adults Are More Vulnerable to Chronic Sleep Deficiency and Recurrent Circadian Disruption Than Older Adults,” Scientific Reports 8 (2018): 11052.

  27.   Daniel Kroeger et al., “Galanin Neurons in the Ventrolateral Preoptic Area Promote Sleep and Heat Loss in Mice,” Nature Communications 9 (2018): 4129.

  28.   Edward C. Harding, Nicholas P. Franks, and William Wisden, “The Temperature Dependence of Sleep,” Frontiers in Neuroscience, April 24, 2019.

  29.   Soňa Nevšímalová et al., “A Contribution to Pathophysiology of Idiopathic Hypersomnia,” Clinical Neurophysiology 53S (2000): 366–70.

  30.   Daniel Aeschbach et al., “A Longer Biological Night in Long Sleepers Than in Short Sleepers,” Journal of Clinical Endocrinology and Metabolism 88 (2003): 26–30.

  31.   Robert J. Thomas and Matt T. Bianchi, “A Circadian Mechanism for Idiopathic Hypersomnia—a Long Biological Night,” Sleep Medicine 74 (2020): 31–32.

  32.   Friedrich K. Stephan and Irving Zucker, “Circadian Rhythms in Drinking Behavior and Locomotor Activity of Rats Are Eliminated by Hypothalamic Lesions,” Proceedings of the National Academy of Sciences 69 (1972): 1583–86.

  33.   Dale M. Edgar, William C. Dement, and C. A. Fuller, “Effect of SCN Lesions on Sleep in Squirrel Monkeys: Evidence for Opponent Processes in Sleep-Wake Regulation,” Journal of Neuroscience 13 (1993): 1065–79.

  34.   David P. Breen, “Hypothalamic Volume Loss Is Associated with Reduced Melatonin Output in Parkinson’s Disease,” Movement Disorders 31 (2016): 1062–66.

  35.   Aleksandar Videnovic et al., “Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson’s Disease,” JAMA Neurology 71 (2014): 463–69.

  36.   K. L. Toh et al., “An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome,” Science 291 (2001): 1040–43; Alina Patke et al., “Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder,” Cell 169 (2017): 203–15.

  37.   Julian Lippert et al., “Altered Dynamics in the Circadian Oscillation of Clock Genes in Dermal Fibroblasts of Patients Suffering from Idiopathic Hypersomnia,” PLoS One 9 (2014): e85255.

  38.   Linus Materna et al., “Idiopathic Hypersomnia Patients Revealed Longer Circadian Period Length in Peripheral Skin Fibroblasts,” Frontiers in Neurology 9 (2018): 424.

  39.   Lucia Pagani et al., “Serum Factors in Older Individuals Change Cellular Clock Properties,” Proceedings of the National Academy of Sciences 108 (2011); 7218–23.

  40.   Brendan M. Gabriel et al., “Disrupted Circadian Oscillations in Type 2 Diabetes Are Linked to Altered Rhythmic Mitochondrial Metabolism in Skeletal Muscle,” Science Advances 7 (2021); William H. Walker et al., “Circadian Rhythm Disruption and Mental Health,” Translational Psychiatry 10 (2020): 28.

  41.   Aditya Ambati et al., “Proteomic Biomarkers of Circadian Time,” Sleep 42S (2019): A17–18; Dasha Cogswell et al., “Identification of a Preliminary Plasma Metabolome-Based Biomarker for Circadian Phase in Humans,” Journal of Biological Rhythms 36 (2021): 369–83.

  42.   Soňa Janáčková et al., “Idiopathic Hypersomnia: A Report of Three Adolescent-Onset Cases in a Two Generation Family,” Journal of Child Neurology 26 (2011): 522–25.

  43.   Michel Billiard and Yves Dauvilliers, “Idiopathic Hypersomnia,” Sleep Medicine Reviews 5 (2001): 351–60.

  44.   In 2002, Emmanuel Mignot’s group described an African American family including seven members with narcolepsy and two with idiopathic hypersomnia. Some DAN family members displayed cataplexy despite having normal hypocretin CSF levels. One with IH, and another with narcolepsy, also did not have the usual HLA risk factor. A search for responsible genes was unproductive, Mignot said. Emmanuel Mignot et al., “The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias,” Archives of Neurology 59 (2002): 1553–62.

  45.   Kris A. Wetterstrand, “DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program,” https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-Data.

  46.   Gregory Costain et al., “Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy,” Neuroscience 418 (2019): 291–310; Siddharth Srivastava et al., “Meta-analysis and Multidisciplinary Consensus Statement: Exome Sequencing Is a First-Tier Clinical Diagnostic Test for Individuals with Neurodevelopmental Disorders,” Genetics in Medicine 21 (2019): 2413–21.

  47.   Taku Miyagawa et al., “A Variant at 9q34.11 Is Associated with HLA-DQB1*06:02 Negative Essential Hypersomnia,” Journal of Human Genetics 63 (2018): 1259–67.

  48.   People with two copies of the risk allele made up 14 percent of the essential hypersomnia cases and 6 percent of the controls (odds ratio 2.63).

  49.   Taku Miyagawa et al., “A Rare Genetic Variant in the Cleavage Site of Prepro-orexin Is Associated with Idiopathic Hypersomnia,” NPJ Genomic Medicine 7 (2022): 29.

  50.   Soňa Nevšímalová et al., “Idiopathic Hypersomnia: A Homogeneous or Heterogeneous Disease?,” Sleep Medicine 80 (2021): 86–91.

  51.   Charles Nunn and David Samson, “Sleep in a Comparative Context: Investigating How Human Sleep Differs from Sleep in Other Primates,” American Journal of Biological Anthropology 166 (2018): 601–12.

  52.   Heming Wang et al., “Genome-wide Association Analysis of Self-Reported Daytime Sleepiness Identifies 42 Loci That Suggest Biological Subtypes,” Nature Communications 10 (2019): 3503.

  53.   Hassan S. Dashti et al., “Genome-wide Association Study Identifies Genetic Loci for Self-Reported Habitual Sleep Duration Supported by Accelerometer-Derived Estimates,” Nature Communications 10: 1100 (2019).

  54.   Yukihide Momozawa and Keijiro Mizukami, “Unique Roles of Rare Variants in the Genetics of Complex Diseases in Humans,” Journal of Human Genetics 66 (2021): 11–23.

  55.   Chris R. Jones et al., “Familial Advanced Sleep-Phase Syndrome: A Short-Period Circadian Rhythm Variant in Humans,” Nature Medicine 5 (1999): 1062–65.

  56.   Kong L. Toh et al., “An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome,” Science 291 (2001): 1040–43.

  57.   Ying Xu et al., “Functional Consequences of a CKIdelta Mutation Causing Familial Advanced Sleep Phase Syndrome,” Nature 434 (2005): 640–44; Arisa Hirano et al., “A Cryptochrome 2 Mutation Yields Advanced Sleep Phase in Humans,” eLife 5 (2016): e16695.

  58.   Luoying Zhang et al., “A PERIOD3 Variant Causes a Circadian Phenotype and Is Associated with a Seasonal Mood Trait,” Proceedings of the National Academy of Sciences 113 (2016): E1536–44; K. C. Brennan et al., “Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase,” Science Translational Medicine 5 (2013): 183ra56–11.

  59.   Lijuan Xing et al., “Mutant Neuropeptide S Receptor Reduces Sleep Duration with Preserved Memory Consolidation,” Science Translational Medicine 11 (2019): eaax2014.

  60.   Ying He et al., “The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals,” Science 325 (2009): 866–70.

  61.   Guangsen Shi et al., “A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors,” Neuron 103 (2019): 1044–55.

  62.   Daniel Aeschbach et al., “Evidence from the Waking Electroencephalogram That Short Sleepers Live Under Higher Homeostatic Sleep Pressure Than Long Sleepers,” Neuroscience 102 (2001): 493–502.

  63.   Karen Weintraub, “Why Do Some People Need Less Sleep? It’s in Their DNA,” Scientific American, October 16, 2019.

  64.   Taku Miyagawa et al., “A Missense Variant in PER2 Is Associated with Delayed Sleep-Wake Phase Disorder in a Japanese Population,” Journal of Human Genetics 64 (2019): 1219–25; Anja Schirmacher et al., “Sequence Variants in Circadian Rhythmic Genes in a Cohort of Patients Suffering from Hypersomnia of Central Origin,” Biological Rhythm Research 42 (2011): 407–16.

  65.   Courtney E. Casale and Namni Goel, “Genetic Markers of Differential Vulnerability to Sleep Loss in Adults,” Genes 12 (2021): 1317.

  12. IMMOBILIZED BY HAPPINESS

    1.   Kiran Maski et al., “Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy,” Journal of Clinical Sleep Medicine 13 (2017): 419–25.

    2.   Ginger Carls et al., “Burden of Disease in Pediatric Narcolepsy: A Claims-Based Analysis of Health Care Utilization, Costs, and Comorbidities,” Sleep Medicine 66 (2020): 110–18.

    3.   Maski et al., “Listening to the Patient Voice in Narcolepsy.”

    4.   Russell Rosenberg and Ann Y. Kim, “The AWAKEN survey: Knowledge of Narcolepsy Among Physicians and the General Population,” Postgraduate Medicine 126 (2014): 78–86.

    5.   Raquel N. Taddei et al., “Diagnostic Delay in Narcolepsy Type 1: Combining the Patients’ and the Doctors’ Perspectives,” Journal of Sleep Research 25 (2016): 709–15.

    6.   Christine Won et al., “The Impact of Gender on Timeliness of Narcolepsy Diagnosis,” Journal of Clinical Sleep Medicine 10 (2014): 89–95.

    7.   Farid R. Talih, “Narcolepsy Presenting as Schizophrenia,” Innovations in Clinical Neuroscience 8 (2011): 30–34.

    8.   Chris Higgins, “I’ve Fallen in Love and I Can’t Get Up,” This American Life, June 4, 2010, https://www.thisamericanlife.org/409/held-hostage/act-three-7.

    9.   Patricia Frerking, “We’re Baaaaa-ack! Or Something,” Sleeping Around: Adventures in Narcolepsy (blog), February 4, 2015, http://sleepingaroundadventuresinnarcolepsy.blogspot.com/2015/02/were-baaaaa-ack-or-something.html.

  10.   Sebastiaan Overeem et al., “The Clinical Features of Cataplexy,” Sleep Medicine 12 (2011): 12–18.

  11.   Fabio Pizza et al., “Clinical and Polysomnographic Course of Childhood Narcolepsy with Cataplexy,” Brain 136 (2013): 3787–95.

  12.   Claire C. Wylds-Wright, Waking Mathilda (Palace Gate, 2017).

  13.   Luis de Lecea et al., “The Hypocretins: Hypothalamus-Specific Peptides with Neuroexcitatory Activity,” Proceedings of the National Academy of Sciences 95 (1998): 322–27; Richard M. Chemelli et al., “Narcolepsy in Orexin Knockout Mice: Molecular Genetics of Sleep Regulation,” Cell 98 (1999): 437–51.

  14.   Shi-Bin Li et al., “Hypothalamic Circuitry Underlying Stress-Induced Insomnia and Peripheral Immunosuppression,” Science Advances 6 (2020): eabc2590.

  15.   From de Lecea’s talk at the 2018 International Symposium on Narcolepsy, Massachusetts.

  16.   Benjamin Boutrel et al., “Role for Hypocretin in Mediating Stress-Induced Reinstatement of Cocaine-Seeking Behavior,” Proceedings of the National Academy of Sciences 102 (2005): 19168–73.

  17.   Thomas C. Thannickal et al., “Opiates Increase the Number of Hypocretin-Producing Cells in Human and Mouse Brain and Reverse Cataplexy in a Mouse Model of Narcolepsy,” Science Translational Medicine 10 (2018): eaao4953.

  18.   Morgan H. James et al., “Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats,” Biological Psychiatry 85 (2019): 925–35.

  19.   Ashley M. Blouin et al., “Human Hypocretin and Melanin Concentrating Hormone Levels Are Linked to Emotion and Social Interaction,” Nature Communications 4 (2013): 1547.

  20.   John Peever and Patrick M. Fuller, “The Biology of REM sleep,” Current Biology 27 (2017): R1237–48.

  21.   Anne Vassalli et al., “Electroencephalogram Paroxysmal Theta Characterizes Cataplexy in Mice and Children,” Brain 136 (2013): 1592–1608.

  22.   Michael S. Aldrich and Ann E. Rogers, “Exacerbation of Human Cataplexy by Prazosin,” Sleep 12 (1989): 254–56.

  23.   Sebastian Overeem, Gert Jan Lammers, and J. Gert van Dijk, “Weak with Laughter,” Lancet 354 (1999): 838.

  24.   Stefano Meletti et al., “The Brain Correlates of Laugh and Cataplexy in Childhood Narcolepsy,” Journal of Neuroscience 35 (2015): 11583–94.

  25.   Louise Bonnet et al., “The Role of the Amygdala in the Perception of Positive Emotions: An ‘Intensity Detector,’ ” Frontiers in Behavioral Neuroscience, July 7, 2015.

  26.   Ramin Khatami, Steffen Birkmann, and Claudio L. Bassetti, “Amygdala Dysfunction in Narcolepsy-Cataplexy,” Journal of Sleep Research 16 (2007): 226–29.

  27.   Carrie E. Mahoney et al., “Cataplexy Triggered by Social Cues: A Role for Oxytocin in the Amygdala,” Sleep 43S (2020): A2.

  28.   Erica Seigneur and Luis de Lecea, “Hypocretin (Orexin) Replacement Therapies,” Medicine in Drug Discovery 8 (2020): 100070.

  13. FRUSTRATING AND MOSTLY FRUITLESS

    1.   Thomas E. Scammell, “The Frustrating and Mostly Fruitless Search for an Autoimmune Cause of Narcolepsy,” Sleep 29 (2006): 601–2.

    2.   David D. Daly and Robert E. Yoss, “A Family with Narcolepsy,” Proceedings of the Staff Meetings of the Mayo Clinic 34 (1959): 313–19. Only three people in this pedigree displayed cataplexy, although others experienced sleep paralysis and hypnogogic hallucinations.

    3.   Robert E. Yoss and David D. Daly, “Hereditary Aspects of Narcolepsy,” Transactions of the American Neurological Association 85 (1960): 239–40.

    4.   Takeo Juji et al., “HLA Antigens in Japanese Patients with Narcolepsy,” Tissue Antigens 24 (1984): 316–19.

    5.   Peter V. Markov and Oliver G. Pybus, “Evolution and Diversity of the Human Leukocyte Antigen (HLA),” Evolution, Medicine and Public Health 1 (2015).

    6.   Emmanuel Mignot et al., “DQB1*0602 and DQA1*0102 (DQ1) Are Better Markers Than DR2 for Narcolepsy in Caucasian and Black Americans,” Sleep 17: S60–67 (1994).

    7.   Yutaka Honda, “Clinical Features of Narcolepsy: Japanese Experiences,” in HLA in Narcolepsy, ed. Y. Honda and T. Juji (Berlin: Springer, 1988), 24–57.

    8.   Emmanuel Mignot, “In Memoriam of Dr Yutaka Honda (1929–2009), a Pioneer in Sleep Medicine and Narcolepsy Research,” Sleep 32: 1528–29 (2009).

    9.   Paul Reading, “The Neurological Sleep Clinic—Part 1—The Sleepy Patient,” Advances in Clinical Neuroscience & Rehabilitation 8 (2008): 6.

  10.   Emmanuel Mignot et al., “HLA DQB1*0602 is Associated with Cataplexy in 509 Narcoleptic Patients,” Sleep 20 (1997): 1012–20.

  11.   Anna Azvolinsky, “In Dogged Pursuit of Sleep,” The Scientist, February 29, 2016, https://www.the-scientist.com/profile/in-dogged-pursuit-of-sleep-33951.

  12.   Henry Nicholls, Sleepyhead (New York: Basic, 2018), 98–111.

  13.   Seiji Nishino et al., “Hypocretin (orexin) Deficiency in Human Narcolepsy,” Lancet 355 (2000): 39–40.

  14.   Thomas C. Thannickal et al., “Reduced Number of Hypocretin Neurons in Human Narcolepsy,” Neuron 27 (2000): 469–74.

  15.   Emmanuel Mignot et al., “The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias,” Archives of Neurology 59 (2002): 1553–62.

  16.   Olivier Andlauer et al., “Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy,” Sleep 35 (2012): 1247–55; Regis Lopez et al., “Temporal Changes in the Cerebrospinal Fluid Level of Hypocretin-1 and Histamine in Narcolepsy,” Sleep 40 (2017): zsw010.

  17.   Birgitte R. Kornum, “Narcolepsy Type 1: What Have We Learned from Immunology?,” Sleep 43 (2020): zsaa055.

  18.   Adi Aran et al., “Elevated Anti-streptococcal Antibodies in Patients with Recent Narcolepsy Onset,” Sleep 32 (2009): 979–83.

  19.   Rebekah H. Borse et al., “Effects of Vaccine Program Against Pandemic Influenza A(H1N1) Virus, United States, 2009–2010,” Emerging Infectious Diseases 19 (2013): 439–48.

  20.   Markku Partinen et al., “Increased Incidence and Clinical Picture of Childhood Narcolepsy Following the 2009 H1N1 Pandemic Vaccination Campaign in Finland,” PLOS One 7 (2012): e33273.

  21.   Yves Dauvilliers et al., “Post-H1N1 Narcolepsy-Cataplexy,” Sleep 33 (2010): 1428–30.

  22.   Louis Jacob et al., “Comparison of Pandemrix and Arepanrix, Two pH1N1 AS03-Adjuvanted Vaccines Differentially Associated with Narcolepsy Development,” Brain Behavior and Immunity 47 (2015): 44–57.