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Neurophysiological correlates of sleep problems in ADHD.

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Neurophysiological correlates of sleep problems in ADHD.

A number of substances are involved in sleep/wake regulation in the brain.

1. Neurotransmitters and sleep/wake regulation

  • Serotonin1234
  • Norepinephrine15
  • Histamine5
  • Acetylcholine65
  • GABA73
  • Glutamate5
  • Dopamine85
    • Selective dopamine reuptake inhibitors may promote wakefulness better than selective norepinephrine reuptake inhibitors in normal and sleep-disordered narcoleptic animals9
    • Severe sleep disturbances are common in people with Parkinson’s disease or Huntington’s disease who have dopaminergic dysfunction1011
    • Dopamine metabolism and dopamine receptor abnormalities are also implicated in excessive daytime sleepiness (e.g., narcolepsy)12
    • Sleep disorders are associated with ADHD13
    • DAT gene variants appear to predispose humans to susceptibility to sleep-wake disorders8
    • Dopamine and melatonin are involved in the regulation of fatigue and sleep.
      The dopaminergic system is influenced by the circadian system.1415
      Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is controlled by dopamine as by melatonin. The retina transmits light information to the suprachiasmatic nucleus, which is the master biological clock. The suprachiasmatic nucleus sends timing information for rhythmic regulation of dopaminergic brain regions and behavior controlled by them (locomotion, motivation). Dopamine produced in the substantia nigra and ventral tegmentum may be rhythmically regulated by the suprachiasmatic nucleus through various neural pathways (including by means of the orexin system or the medial preoptic nucleus of the hypothalamus).16 Orexin deficiency is a possible cause of narcolepsy. Orexin / Hypocretin Light uptake by the retina affects circadian rhythms. Changes in light and light rhythm can affect the circadian rhythm.17
      Dopamine and melatonin inhibit each other.18
      Dopamine is released mainly in the early morning and during the day. Melatonin is inhibited by daylight and released mainly in the evening and at night.19
      A dopamine deficiency (as is typical for ADHD) could therefore cause too little melatonin inhibition. This could possibly explain the severe daytime sleepiness reported by some ADHD sufferers.
      Whether retinal disorders could cause the shifts in chronorhythms common in ADHD and whether these could be a major cause of ADHD are discussed.20

2. Other substances of the brain and sleep-wake regulation

3. Gene variants and sleep-wake rhythm

A homozygous polymorphism in the 3’-flanking region of the clock gene CLK (T3111C) appears to be associated with a posteriorly shifted sleep-wake rhythm and a decreased need for sleep, independent of age, sex, or ethnicity.24.
The longer allele of exon 18 in the PER3 gene is associated with a “morning type”, the shorter allele with an “evening type”. Homozygous carriers of the shorter allele suffer more frequently from difficulties in falling asleep.25
The amino acid exchange T44A in the CSNK1D gene leads to a prolonged circadian rhythm in Drosophila flies, but to a shortened circadian rhythm in mice, as it occurs in mice,26

Polymorphisms in CLK or PER genes are also associated with different sleep-wake rhythms in humans.27

The circadian clocks control28

  • Immune system
  • Virus replication
  • Pharmacokinetics
  • Effectiveness of therapeutics

Remdesivir alters circadian gene expression in primary human dermal fibroblast cultures.28 In subjects without a neuropsychiatric diagnosis who did not exhibit eveningness in chronorhythms, remdesivir caused a slight phase shift in Clock, Per1, and Per2 and significantly altered expression of Bmal1 and Per3. The difference between chronotype and circadian gene expression of Bmal1, Cry1, and Per3 was significant. Remdesivir affected circadian function and shifted chronotype toward eveningness, as is also known from ADHD


  1. Steriade, McCarley (1990): Brainstem control of wakefulness and sleep, S. 185

  2. Roehrs, Carskadon, Dement, Roth (2000): Daytime Sleepiness and Alertness. In: Kryger, Roth, Dement (Hrsg.): Principles and practice of sleep medicine. S. 42

  3. Jones (2000): Basic mechanisms of sleep–wake states In: Kryger, Roth, Dement (Hrsg.): Principles and practice of sleep medicine. S. 134

  4. McGinty, Ronald (2000):Neural Control of Sleep in Mammals. In: Kryger, Roth, Dement (Hrsg.): Principles and practice of sleep medicine. S. 64

  5. McGinty, Ronald (2000):Neural Control of Sleep in Mammals. In: Kryger, Roth, Dement (Hrsg.): Principles and practice of sleep medicine. S. 65

  6. Steriade, McCarley (1990): Brainstem control of wakefulness and sleep, S. 164

  7. Steriade, McCarley (1990): Brainstem control of wakefulness and sleep

  8. Wisor, Nishino, Sora, Uhl, Mignot, Edgar (2001): Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001 Mar 1;21(5):1787-94. doi: 10.1523/JNEUROSCI.21-05-01787.2001. PMID: 11222668; PMCID: PMC6762940.

  9. Nishino, Mao, Sampathkumaran, Shelton (1998): Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online. 1998;1(1):49-61. PMID: 11382857.

  10. Zhang, Ren, Yang, Zhou, Li, Shi, Lu, Sanford, Tang (2019). Sleep in Huntington’s disease: a systematic review and meta-analysis of polysomongraphic findings. Sleep. 2019 Oct 9;42(10):zsz154. doi: 10.1093/sleep/zsz154. PMID: 31328779; PMCID: PMC6783889. METASTUDIE

  11. Wiegand, Möller, Lauer, Stolz, Schreiber, Dose, Krieg (1991): Nocturnal sleep in Huntington’s disease. J Neurol. 1991 Jul;238(4):203-8. doi: 10.1007/BF00314781. PMID: 1832711.

  12. Nishino, Mignot (1997): Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997 May;52(1):27-78. doi: 10.1016/s0301-0082(96)00070-6. PMID: 9185233. REVIEW

  13. Corkum, Moldofsky, Hogg-Johnson, Humphries, Tannock (1999): Sleep problems in children with attention-deficit/hyperactivity disorder: impact of subtype, comorbidity, and stimulant medication. J Am Acad Child Adolesc Psychiatry. 1999 Oct;38(10):1285-93. doi: 10.1097/00004583-199910000-00018. PMID: 10517062.

  14. Parekh, Ozburn, McClung (2015): Circadian clock genes: effects on dopamine, reward and addiction. Alcohol. 2015 Jun;49(4):341-9. doi: 10.1016/j.alcohol.2014.09.034.

  15. Baltazar, Coolen, Webb (2013): Diurnal rhythms in neural activation in the mesolimbic reward system: critical role of the medial prefrontal cortex. Eur J Neurosci. 2013 Jul;38(2):2319-27. doi: 10.1111/ejn.12224.

  16. Mendoza, Challet (2014): Circadian insights into dopamine mechanisms. Neuroscience. 2014 Dec 12;282:230-42. doi: 10.1016/j.neuroscience.2014.07.081.

  17. Wirz-Justice, Wever, Aschoff (2004): Seasonality in freerunning circadian rhythms in man. Naturwissenschaften. 1984 Jun;71(6):316-9.

  18. Green, Besharse (2004): Retinal circadian clocks and control of retinal physiology. J Biol Rhythms. 2004 Apr;19(2):91-102.

  19. Iuvone, Tosini, Pozdeyev, Haque, Klein, Chaurasia (2005): Circadian clocks, clock networks, arylalkylamine N-acetyltransferase, and melatonin in the retina. Prog Retin Eye Res. 2005 Jul;24(4):433-56.

  20. Bijlenga, Vollebregt, Kooij, Arns (2019): The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019 Mar;11(1):5-19. doi: 10.1007/s12402-018-0271-z.

  21. Ehlers, Reed, Henriksen (1986): Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats. Neuroendocrinology. 1986;42(6):467-74. doi: 10.1159/000124489. PMID: 3084988.

  22. McGinty, Ronald (2000):Neural Control of Sleep in Mammals. In: Kryger, Roth, Dement (Hrsg.): Principles and practice of sleep medicine. S. 75

  23. West, Lookingland, Tucker (1997): Regulation of growth hormone-releasing hormone and somatostatin from perifused, bovine hypothalamic slices. II. Dopamine receptor regulation. Domest Anim Endocrinol. 1997 Sep;14(5):349-57. doi: 10.1016/s0739-7240(97)00031-3. PMID: 9347255.

  24. Serretti, Benedetti, Mandelli, Lorenzi, Pirovano, Colombo, Smeraldi (2003): Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2003 Aug 15;121B(1):35-8. doi: 10.1002/ajmg.b.20053. PMID: 12898572. n = 620

  25. Archer, Robilliard, Skene, Smits, Williams, Arendt, von Schantz (2003): A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep. 2003 Jun 15;26(4):413-5. doi: 10.1093/sleep/26.4.413. PMID: 12841365.

  26. Xu, Padiath, Shapiro, Jones, Wu, Saigoh, Saigoh, Ptácek, Fu (2005): Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005 Mar 31;434(7033):640-4. doi: 10.1038/nature03453. PMID: 15800623.

  27. Graw (2019): Genetik, Seite 684

  28. Faltraco, Palm, Coogan, Uzoni, Duwe, Simon, Tucha, Thome (2021): Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD. J Neural Transm (Vienna). 2021 Jul;128(7):1159-1168. doi: 10.1007/s00702-021-02375-3. PMID: 34273024; PMCID: PMC8285716.

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