Sleep problems in ADHD - neurophysiological correlates

Sleep problems in 5-13 year olds with ADHD correlated weakly, but statistically significantly, with maternal mental health problems.¹

Further information on sleep problems can be found here:

• More on the topic Sleep problems with ADHD (as ADHD symptoms) In the chapter Symptoms of ADHD.
• More on the topic (Treatment of) sleep problems with ADHD In the chapter Treatment of ADHD.

• 1. Neurotransmitters and sleep/wake regulation
  • 1.1. Noradrenaline and circadian rhythm
  • 1.2. Stress systems and circadian rhythm
  • 1.3. Dopamine and circadian rhythm
• 2. Cytokines and sleep problems
• 3. Other substances involved in sleep-wake regulation
• 4. EEG peculiarities during sleep in ADHD
  • 4.1. Sleeping spindles
  • 4.2. Gamma connectivity altered during light sleep in ADHD
  • 4.3. Slow waves in the EEG reduced in non-REM deep sleep in ADHD
• 5. Immunological Consequences of Sleep Problems

1. Neurotransmitters and sleep/wake regulation¶

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

• Serotonin²³⁴⁵
• Noradrenaline²⁶
  • Noradrenaline administration into the ventromedial hypothalamus of lean, insulin-sensitive animals, which increased noradrenaline there to the level of obese, insulin-resistant animals, led to complete cardiometabolic syndrome (including leptin resistance) within a few days, with no change in food intake. Additional administration of serotonin intensified this noradrenaline response⁷
• Histamine⁶
• Acetylcholine⁸⁶
• GABA⁹⁴
• Glutamate⁶
• Dopamine¹⁰¹¹
  • Dopamine metabolism and dopamine receptor abnormalities are also involved in excessive daytime sleepiness (e.g. narcolepsy)¹²
  • Selective dopamine reuptake inhibitors promote wakefulness better than selective noradrenaline reuptake inhibitors in normal and narcoleptic animals¹³
  • Severe sleep disorders often occur in people with ADHD or Huntington’s disease who have dopaminergic dysfunction¹⁴¹⁵
  • Sleep disorders are associated with ADHD¹⁶
  • DAT gene variants appear to predispose humans to a susceptibility to sleep-wake disorders¹⁰
  • Dopamine and melatonin are involved in the regulation of tiredness and sleep.
    The dopaminergic system is influenced by the circadian system.¹⁷¹⁸
    Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is controlled by dopamine in the same way as melatonin. The retina transmits light information to the suprachiasmatic nucleus, which is the master biological clock. The suprachiasmatic nucleus sends timing information for the rhythmic regulation of dopaminergic brain regions and the behavior controlled by them (locomotion, motivation). The dopamine produced in the substantia nigra and the ventral tegmentum is possibly rhythmically regulated by the suprachiasmatic nucleus via various neural pathways (including the orexin system or the medial preoptic nucleus of the hypothalamus).¹⁹ Orexin deficiency is a possible cause of narcolepsy. ⇒ Orexin / hypocretin The light absorption of the retina influences the circadian rhythm. Changes in light and light rhythm can affect the circadian rhythm.²⁰
    Dopamine and melatonin inhibit each other.²¹
    Dopamine is mainly released early in the morning and during the day. Melatonin is inhibited by daylight and is mainly released in the evening and at night.²²
    Reduced extracellular dopamine (as is typical of ADHD) could therefore result in insufficient melatonin inhibition. This could possibly explain the severe daytime sleepiness reported by some people with ADHD.
    Disorders of the retina are discussed as to whether they cause the shifts in chronorhythm that are common in ADHD and whether they could be a major cause of ADHD.²³

1.1. Noradrenaline and circadian rhythm¶

Noradrenaline is said to be a key synchronizer of the circadian rhythm. Noradrenaline regulates the nocturnal release of melatonin and circadian gene expression.²⁴²⁵

At the same time, prolonged sleep deprivation appears to cause lasting damage to the locus coeruleus, which would cause permanent damage to the noradrenergic system²⁶

1.2. Stress systems and circadian rhythm¶

Chronic stress (which we believe mediates its symptoms through very similar neurotransmitter shifts to ADHD) often leads to a disorder of the circadian system. More on this at ⇒ Changes in the circadian system due to chronic stress In the article ⇒ Stress damage due to early / prolonged stress in the section ⇒ ADHD as a chronic stress regulation disorder in the chapter ⇒ Stress.

1.3. Dopamine and circadian rhythm¶

The release of dopamine is subject to a circadian rhythm. See under Dopaminergic circadian and ultradian rhythms In the article The 6 dopaminergic systems of the brain in the subsection Dopamine in the section Neurotransmitters in ADHD in the chapter Neurological aspects.

2. Cytokines and sleep problems¶

Sleep problems correlate with increased levels of pro-inflammatory cytokines. Cytokines regulate sleep. Cytokines released by immune cells, particularly interleukin-1β and tumor necrosis factor-α, influence neuronal activity, behavior (including sleep), hormone release, and autonomic function by targeting neuroendocrine, autonomic, limbic, and cortical areas of the CNS.²⁷ One study found elevated inflammatory markers only in women (not men) with sleep problems.²⁸

Sleep deprivation and disturbed sleep lead to increased levels of IL-6, tumor necrosis factor (TNF) (only in men) and C-reactive protein (CRP) compared to undisturbed sleep phases.²⁹³⁰³¹
Sleep problems apparently increase IL-6 and soluble intercellular adhesion molecule (slCAM) even more than severe depression.³²
Sleep deprivation correlates with increased IL-6 levels, although the stimulatory effect of catecholamines on IL-6 secretion is reduced; this change may result from the concomitant reduction in cortisol-induced inhibition, which is eliminated by a lack of cortisol. The stress hormones noradrenaline and CRH also increase IL-6³³

3. Other substances involved in sleep-wake regulation¶

• Melatonin
  For more details, visit ⇒ Melatonin for ADHD In the subsection ⇒ Sleep disorder-related medications for ADHD in the section ⇒ Medication for ADHD - Overview / ⇒ MELATONIN Suitable medication for ADHD in the chapter ⇒ Treatment
• GHRH has a sleep-promoting effect³⁴³⁵
  • The D1 receptor in the bovine hypothalamus mediated a 50% reduction in GHRH release from the hypothalamus in vitro³⁶
• Orexin (hypocretin)⁶
  • Neuropeptide
• Adenosine³⁵
  • Nucleoside
  • Blocks the release of activating neurotransmitters, e.g:
    • Noradrenaline
    • Dopamine
    • Acetylcholine
• Proinflammatory cytokines³⁵
• Prostaglandin D2³⁵
• CRH has a sleep-inhibiting effect³⁴ and impairs deep sleep.³⁷ Sleep problems could therefore be a direct consequence of an overactivated HPA axis.

4. EEG peculiarities during sleep in ADHD¶

There are reports of specific EEG peculiarities in ADHD.³⁸
ADHD correlated with significantly reduced microstate D in the resting EEG and a lower probability of a transition from microstate C to D. However, this was independent of sleep problems.³⁹

4.1. Sleeping spindles¶

While more sleep spindles (higher sigma power) in the EEG correlated with a higher IQ in unaffected people in the light sleep phase (sleep phase 2), fewer sleep spindles correlated with ADHD.⁴⁰

In contrast, another study found increased amplitude, duration, density and activity of slow-wave sleep spindles in children with ADHD.⁴¹

4.2. Gamma connectivity altered during light sleep in ADHD¶

Children with ADHD showed an altered gamma phase delay index in light sleep.⁴²

4.3. Slow waves in the EEG reduced in non-REM deep sleep in ADHD¶

Children and adolescents with ADHD-HI showed a reduction in the EEG power of low-frequency waves from 1 to 4.5 Hz (SWA) in non-REM deep sleep throughout the brain by over 20 % compared to healthy controls. Regular use of stimulants eliminated this deviation. Assuming that SWA reflects synaptic density, this is consistent with previous neuroimaging studies that found smaller gray matter volumes in people with ADHD-HI and their normalization with regular stimulant use.⁴³

5. Immunological Consequences of Sleep Problems¶

Both single and chronic sleep fragmentation increased the mRNA and protein levels of cytokines in the body tissue of mice. Changes in inflammatory responses reflected the activation of stress axes with increased corticosterone and noradrenaline. Treatment with 6-OHDA significantly reduced the inflammation caused by sleep fragmentation. This indicates a regulation of sleep fragmentation-induced inflammation in body tissue by the autonomic nervous system (sympathetic/parasympathetic nervous system).
Chronic sleep fragmentation showed more severe Consequences than single (acute) sleep fragmentation. A one-week recovery from sleep fragmentation sufficiently alleviated the peripheral inflammatory responses, but not the noradrenergic responses.⁴⁴