Sleep problems in ADHD - neurophysiological correlates

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

Sleep problems in 5-13-year-olds with ADHD correlated weakly but statistically significantly with mental health problems in the mother.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. Circadian rhythm and the influence of genes
  • 4.1. Circadian rhythm
  • 4.2. Hours of sunshine/year where you live and ADHD prevalence?
  • 4.3. Gene variants that influence the circadian rhythm
• 5. EEG peculiarities during sleep in ADHD
  • 5.1. Sleeping spindles
  • 5.2. Gamma connectivity altered during light sleep in ADHD
  • 5.3. Slow waves in the EEG reduced in non-REM deep sleep in ADHD
• 6. Immunological consequences of sleep problems

1. Neurotransmitters and sleep/wake regulation¶

• Serotonin²³⁴⁵
• Noradrenaline²⁶
• Histamine⁶
• Acetylcholine⁷⁶
• GABA⁸⁴
• Glutamate⁶
• Dopamine⁹⁶
  • Selective dopamine reuptake inhibitors can promote wakefulness better than selective noradrenaline reuptake inhibitors in normal and sleep-disordered narcoleptic animals¹⁰
  • Severe sleep disorders often occur in people with Parkinson’s disease or Huntington’s disease who have dopaminergic dysfunction¹¹¹²
  • Dopamine metabolism and dopamine receptor abnormalities are also involved in excessive daytime sleepiness (e.g. narcolepsy)¹³
  • Sleep disorders are associated with ADHD¹⁴
  • DAT gene variants appear to predispose humans to a susceptibility to sleep-wake disorders⁹
  • Dopamine and melatonin are involved in the regulation of tiredness and sleep.
    The dopaminergic system is influenced by the circadian system.¹⁵¹⁶
    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).¹⁷ 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.¹⁸
    Dopamine and melatonin inhibit each other.¹⁹
    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.²⁰
    A dopamine deficiency (as is typical of ADHD) could therefore result in insufficient melatonin inhibition. This could possibly explain the severe daytime sleepiness reported by some ADHD sufferers.
    It is discussed whether disorders of the retina could cause the frequent shifts in the chronorhythm in ADHD and whether these could be a significant cause of ADHD.²¹

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.²²²³

At the same time, prolonged sleep deprivation appears to cause lasting damage to the locus coeruleus, which would cause permanent damage to the noradrenergic system²⁴

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 disruption 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 (non-medicinal) administration of stimulants can induce a circadian rhythm in rodents, the so-called methamphetamine-sensitive circadian oscillator (MASCO). This is apparently (also) related to the domapinergically controlled dopamine ultradian oscillator, DUO.²⁵ It is conceivable that the circadian sleep problems in ADHD are linked to the MASCO through dopaminergic connections.

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, affect neuronal activity, behavior (including sleep), hormone release, and autonomic function by targeting neuroendocrine, autonomic, limbic, and cortical areas of the CNS.²⁶ One study found elevated inflammatory markers only in women (not men) with sleep problems.²⁷

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.²⁸²⁹³⁰
Sleep problems apparently increase IL-6 and soluble intercellular adhesion molecule (slCAM) even more than severe depression.³¹
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-6³²

3. Other substances involved in sleep-wake regulation¶

• Melatonin
  For more details, visit ⇒ Melatonin for ADHD In the section ⇒ Medication for ADHD - Overview / ⇒ Suitable medication for ADHD in the chapter ⇒ Treatment and therapy.
• GHRH has a sleep-promoting effect³³³⁴
  • The D1 receptor in the bovine hypothalamus mediated a 50% reduction in GHRH release from the hypothalamus in vitro³⁵
• Orexin (hypocretin)⁶
  • Neuropeptide
• Adenosine³⁴
  • Nucleoside
  • Blocks the release of activating neurotransmitters, e.g:
    • Noradrenaline
    • Dopamine
    • Acetylcholine
• Proinflammatory cytokines³⁴
• Prostaglandin D2³⁴
• CRH has a sleep-inhibiting effect³³ and impairs deep sleep.³⁶ Sleep problems could therefore be a direct consequence of an overactivated HPA axis.

4. Circadian rhythm and the influence of genes¶

4.1. Circadian rhythm¶

The circadian clock, an internal timing system, regulates various physiological processes by generating approximately 24-hour circadian rhythms in gene expression, which translate into rhythms in metabolism and behavior. It is an important regulator of a variety of physiological functions such as metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular and renal functions.

Many human bodily functions are linked to the circadian rhythm:³⁷
02:00 Deepest sleep
04:30 Lowest body temperature
Wake up: Highest cortisol level
07:30 Melatonin release ends
08:00 Highest testosterone level (men)
08:30 Intestinal movements probable
10:30 Maximum vigilance
14:30 Maximum coordination ability
15:30 Fastest reaction time
17.30 Cardiovascular efficiency and muscle strength
18:30 Highest blood pressure
19:00 Highest body temperature
21:00 Start of melatonin secretion
22:30 Suppression of bowel movements

If all these elements occur 1.5 hours later, as in ADHD sufferers with a delayed circadian rhythm, it is understandable that this leads to significant effects and changes compared to normal circadian people (social jet lag).

The circadian clock consists of two main components³⁸

• of the central clock in the suprachiasmatic nucleus (SCN)
• the peripheral clocks that occur in almost all tissues and organ systems

Both central and peripheral clocks can be reset by environmental stimuli that act as timers. The most important zeitgeber for the central clock is light, which is perceived by the retina and transmitted directly to the SCN. The central clock controls the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related signals, so that all clocks are synchronized to the external light-dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression so that a peak in protein expression occurs once every 24 hours to control when a particular physiological process is most active relative to the solar day. Transcription and translation of key clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) play a crucial role in rhythm formation, while delays due to post-translational modifications (PTM) are important for determining the period (tau) of rhythms (tau refers to the period of a rhythm and is the temporal length of a complete cycle).

Diurnal rhythm: synchronized with the day-night cycle
The ultradian and infradian rhythms have a shorter and longer period than 24 hours respectively.

Disruption of circadian rhythms contributes to the pathology of cardiovascular diseases, cancer, metabolic syndromes and ageing.

The core of the molecular mechanism of the circadian clock is a transcription/translation feedback loop (TTFL).

• Positive link in the feedback loop: The transcription factors CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2. They act in the form of a heterodimer and activate the transcription of nuclear clock genes and clock-controlled genes (involved in important metabolic processes) that carry E-box elements (5’-CACGTG-3’) in their promoters.
• The negative links of the feedback loop are the major clock genes: PER1/2/3 and CRY1/2, which are transcriptional repressors and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by inhibiting its activity and thereby negatively regulating their own expression. The CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer also activates the nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and activate and repress ARNTL/BMAL1 transcription, respectively.

The adaptation of the circadian rhythm to changes in light appears to be influenced by various neurotransmitters and active substances:³⁹

• Increased adaptation to light signals (possibly helpful for ADHD or at night during long-term shift work) through
  • 5HT1A autoreceptor agonists
  • Phosphodiesterase 5 inhibitors (PDE5)
• Attenuated adaptation to light signals (possibly helpful for short-term changes in circadian rhythm (pilots) or during the day for long-term shift work) through
  • GABA-B agonists
    • also sedative and sleep-inducing
  • Cannabinoid receptor agonists
    • THC shortens sleep latency, reduces nightmares, improves sleep quality in chronic pain
  • 5HT1B agonists
    • Triptans (e.g. sumatriptan, zolmitriptan)
    • does not promote sleep

4.2. Hours of sunshine/year where you live and ADHD prevalence?¶

One study found a clear correlation between sun intensity (kilowatt hours/square meter/day) and ADHD prevalence. This explained 34 to 57% of ADHD prevalence.⁴⁰ However, a meta-study of 82 studies found no association between solar radiation and ADHD prevalence {Hoffmann MS, Polanczyk GV, Kieling C, Dos Santos IP, Willcutt EG, Rohde LA, Salum GA (2014): Attention-deficit/hyperactivity disorder and solar irradiance: a cloudy perspective. Biol Psychiatry. 2014 Oct 15;76(8):e19-20. doi: 10.1016/j.biopsych.2013.07.044. PMID: 24267411.}}

The amount of sunlight influences D3 production on the one hand and the circadian rhythm on the other.

4.3. Gene variants that influence the circadian rhythm¶

A homozygous polymorphism in the 3’-flanking region of the clock gene CLK (T3111C) is apparently associated with a delayed sleep-wake rhythm and a reduced need for sleep, regardless of age, gender or ethnic origin.⁴¹.
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 difficulty falling asleep.⁴²
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 also occurs in mice,⁴³

Polymorphisms in CLK or PER genes are also associated with different sleep-wake rhythms in humans.⁴⁴

The circadian clocks control⁴⁵

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

5. EEG peculiarities during sleep in ADHD¶

There are reports of specific EEG peculiarities in ADHD.⁴⁶

5.1. 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.⁴⁷

In contrast, another study found an increased amplitude, duration, density and activity of slow-wave sleep spindles in children with ADHD.⁴⁸

5.2. Gamma connectivity altered during light sleep in ADHD¶

Children with ADHD showed an altered gamma phase delay index in light sleep.⁴⁹

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

ADHD-HI-affected children and adolescents 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 ADHD-HI sufferers, as well as their normalization with regular stimulant use.⁵⁰

6. 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.⁵¹