Sleep Problems in ADHD - Neurophysiological Correlates

Sleep problems in 5- to 13-year-olds with ADHD were weakly but statistically significantly correlated with their mothers’ mental health problems.¹

For more information on sleep problems, click here:

• More on this topic Sleep problems associated with ADHD (as ADHD symptoms) In the chapter on ADHD symptoms.
• More on this topic (Treatment of) Sleep Problems in ADHD In the chapter on the treatment of ADHD.

1. Neurotransmitters and Sleep-Wake Regulation¶

Numerous neurotransmitters are involved in the brain’s sleep-wake regulation.

• Serotonin²³⁴⁵
• Norepinephrine²⁶
  • Administration of norepinephrine into the ventromedial hypothalamus of lean, insulin-sensitive animals—which raised norepinephrine levels there to those of obese, insulin-resistant animals—led within a few days to the full-blown cardiometabolic syndrome (including leptin resistance), while food intake remained unchanged. An additional administration of serotonin enhanced this norepinephrine response.⁷
• Histamine⁶
• Acetylcholine⁸⁶
• GABA⁹⁴
• Glutamate⁶
• Dopamine¹⁰¹¹
  • Abnormalities in dopamine metabolism and dopamine receptors are also involved in excessive daytime sleepiness (e.g., narcolepsy)¹²
  • Selective dopamine reuptake inhibitors promote wakefulness more effectively than selective norepinephrine reuptake inhibitors in both normal and narcoleptic animals¹³
  • Severe sleep disorders frequently occur in people with Parkinson’s disease or Huntington’s disease, who have dopaminergic dysfunction¹⁴¹⁵
  • Sleep disorders are associated with ADHD¹⁶
  • DAT gene variants appear to predispose humans to sleep-wake disorders¹⁰
  • Dopamine and melatonin play a role in regulating fatigue 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 regulated by dopamine in the same way as it is by melatonin. The retina transmits light information to the suprachiasmatic nucleus, which serves as the body’s master biological clock. The suprachiasmatic nucleus sends timing information to regulate the rhythmic activity of dopaminergic brain regions and the behaviors controlled by them (locomotion, motivation). The dopamine produced in the substantia nigra and the ventral tegmental area may be 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 Light exposure to the retina influences the circadian rhythm. Changes in light and light patterns can disrupt the circadian rhythm.²⁰
    Dopamine and melatonin inhibit each other.²¹
    Dopamine is released primarily in the early morning and during the day. Melatonin is suppressed by daylight and is released mainly in the evening and at night.²²
    Reduced extracellular dopamine (as is typical in ADHD) could therefore result in insufficient inhibition of melatonin. This might help explain the severe daytime sleepiness reported by some people with ADHD.
    The discussion focuses on whether retinal disorders cause the shifts in circadian rhythms commonly seen in ADHD and whether these could be a major cause of ADHD.²³

1.1. Norepinephrine and the circadian rhythm¶

Norepinephrine is believed to be a key synchronizer of the circadian rhythm. Norepinephrine regulates nighttime melatonin release as well as circadian gene expression.²⁴²⁵

At the same time, prolonged sleep deprivation appears to cause lasting damage to the locus coeruleus, which would result in permanent damage to the noradrenergic system.²⁶

1.2. Stress Systems and the Circadian Rhythm¶

Chronic stress (which, in our view, manifests its symptoms through neurotransmitter shifts very similar to those seen in ADHD) often leads to a disorder of the circadian system. For more on this, see ⇒ Changes in the circadian system caused by chronic stress In the article ⇒ Damage caused by early-onset or prolonged stress in the section ⇒ ADHD as a chronic stress regulation disorder in the chapter ⇒ Stress.

1.3. Dopamine and the Circadian Rhythm¶

Dopamine release follows a circadian rhythm. For more on this, see 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 are associated with elevated levels of proinflammatory 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 acting on neuroendocrine, autonomic, limbic, and cortical regions of the central nervous system.²⁷ One study found elevated inflammatory markers only in women (not in men) with sleep problems.²⁸

Sleep deprivation and disrupted sleep lead to elevated levels of IL-6, tumor necrosis factor (TNF) (in men only), and C-reactive protein (CRP) compared to periods of undisturbed sleep.²⁹³⁰³¹
Sleep problems appear to increase IL-6 and soluble intercellular adhesion molecule (slCAM) even more than severe depression.³²
Sleep deprivation correlates with elevated IL-6 levels, even though the stimulatory effect of catecholamines on IL-6 secretion is reduced; this change may result from the concurrent reduction in cortisol-induced inhibition, which is absent due to low cortisol levels. The stress hormones norepinephrine and CRH also increase IL-6.³³

3. Other Substances Involved in Sleep-Wake Regulation¶

• Melatonin
  For more information, visit ⇒ Melatonin for ADHD In the subsection ⇒ Sleep-disorder-related medications for ADHD in the section ⇒ Medications for ADHD – Overview / ⇒ Appropriate Medications for ADHD in the chapter ⇒ Treatment
• GHRH promotes sleep³⁴³⁵
  • The D1 receptor in the bovine hypothalamus mediated a 50% reduction in hypothalamic GHRH release in vitro³⁶
• Orexin (hypocretin)⁶
  • Neuropeptide
• Adenosine³⁵
  • Nucleoside
  • Blocks the release of excitatory neurotransmitters, e.g.:
    • Norepinephrine
    • Dopamine
    • Acetylcholine
• Pro-inflammatory cytokines³⁵
• Prostaglandin D2³⁵
• CRH inhibits sleep³⁴ and disrupts deep sleep.³⁷ Sleep problems could therefore be a direct consequence of an overactive HPA axis.

4. EEG Characteristics During Sleep in ADHD¶

There are reports of specific EEG abnormalities associated with ADHD.³⁸
ADHD was associated with a significantly reduced micro-state D in the resting-state EEG and a lower probability of transitioning from micro-state C to D. However, this was independent of sleep problems.³⁹

4.1. Sleep spindles¶

While more sleep spindles (higher sigma power) in the EEG of non-affected individuals during light sleep (sleep stage 2) correlated with a higher IQ, fewer sleep spindles correlated with ADHD.⁴⁰

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

4.2. Gamma Connectivity During Light Sleep Is Altered in ADHD¶

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

4.3. Reduced slow-wave activity on the EEG during deep non-REM sleep in ADHD¶

People with ADHD-HI showed a reduction of more than 20% in EEG power of low-frequency waves ranging from 1 to 4.5 Hz (SWA) across the entire brain during deep non-REM sleep compared to healthy controls. Regular use of stimulants eliminated this difference. Assuming that SWA reflects synaptic density, this finding is consistent with previous neuroimaging studies that found smaller volumes of gray matter in people with ADHD-HI, as well as the normalization of these volumes with regular stimulant use.⁴³

5. Immunological Consequences of Sleep Problems¶

Both acute and chronic sleep fragmentation increased the mRNA and protein levels of cytokines in the body tissues of mice. Changes in inflammatory responses reflected the activation of stress axes, with elevated levels of corticosterone and norepinephrine. Treatment with 6-OHDA significantly reduced the inflammation caused by sleep fragmentation. This suggests that the autonomic nervous system (sympathetic/parasympathetic) regulates sleep-fragmentation-induced inflammation in body tissues.
Chronic sleep fragmentation had more serious consequences than one-time (acute) sleep fragmentation. A one-week recovery period following sleep fragmentation sufficiently alleviated peripheral inflammatory responses, but not noradrenergic responses.⁴⁴

6. Body Temperature and Sleep¶