Research advances in children's sleep and vitamin D levels

Liuyan Zhu; Dan Yao

doi:10.6065/apem.2448076.038

Ann Pediatr Endocrinol Metab > Volume 30(1); 2025 > Article

Zhu and Yao: Research advances in children's sleep and vitamin D levels

Review Article

Annals of Pediatric Endocrinology & Metabolism 2025;30(1): 3-10.

Published online: February 28, 2025

DOI: https://doi.org/10.6065/apem.2448076.038

Research advances in children's sleep and vitamin D levels

Liuyan Zhu^1,²

, Dan Yao^1,²

¹Department of Pediatric Health Care, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China

²National Clinical Research Center for Child Health, Hangzhou, China

Address for correspondence: Dan Yao Department of Pediatric Health Care, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China Email: yaoyaof11@zju.edu.cn

Received April 11, 2024 Revised July 26, 2024 Accepted August 5, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In recent years, studies have revealed that vitamin D, a steroid hormone essential for calcium and phosphorus metabolism, also plays a role in sleep. Adequate levels of vitamin D have been linked to improved sleep quality in children and effective prevention of sleep problems. This report is a review and summary of research on the significance of sleep, the stages of children's sleep, and the impact of vitamin D levels on sleep problems. Additionally, this report explores the mechanisms through which vitamin D improves sleep.

Keywords: Sleep, Child, Vitamin D

Highlights

· Vitamin D plays a crucial role in calcium and phosphorus metabolism and is closely linked to children's sleep quality. Research indicates that higher vitamin D levels are associated with improved sleep quality and reduced sleep issues in children.

· The article examines how vitamin D may enhance sleep by regulating neurotransmitters like dopamine, GABA, and serotonin, as well as influencing circadian rhythm-related genes such as BMAL1 and PER2.

· A deficiency in vitamin D can lead to sleep disorders in children, including shorter sleep duration and poorer sleep quality, and may even be linked to obstructive sleep apnea syndrome. Supplementing vitamin D may help alleviate these sleep problems.

Introduction

Sleep plays a crucial role in the process of brain development in children and is essential for physical growth, memory consolidation, executive function, and the immune system [1-5]. The International Classification of Sleep Disorders, Third Edition [6], released by the American Academy of Sleep Medicine in 2014, identifies various sleep disorders including insomnia, sleep-related breathing disorders, excessive daytime sleepiness, and parasomnias. Because of the receipt of a vast amount of information during wakefulness, the brain requires consolidation during sleep. Sleep waves, especially slow waves and spindles, provide an advantageous environment for neuroplasticity in the brain, with slow waves playing a role in memory consolidation [7]. Tononi and Cirelli [8] proposed the synaptic homeostasis hypothesis (SHY) that stated sleep as a fundamental process for maintaining synaptic strength within a certain range. According to the SHY, synaptic connections in many neural circuits increase in strength due to daytime learning, primarily mediated by synaptic potentiation. Stronger synaptic connections require more energy and are prone to saturation. This necessitates synaptic down-scaling, a process that primarily occurs during sleep. The SHY posits that sleep enhances the plasticity of wakefulness, prevents exaggerated brain potentials, and improves signal-to-noise ratio. These ameliorate brain over-saturation states.

Children's sleep is affected by a wide range of factors including changes in sleep structure, sleep regulators, neurobiological mechanisms of sleep, sleep patterns, bed-sharing practices, and sleep disturbances. Other factors that influence children's sleep include interactions among physiological, psychological, social, and environmental factors and deficiencies in vitamins and micronutrients. Emerging evidence highlights a novel role for vitamin D in maintaining and regulating sleep. The relationship between serum 25-hydroxyvitamin D levels and sleep was examined by Geng et al. [9] in a study involving 95 patients with restless leg syndrome (RLS). The participants were categorized into normal and poor sleep groups based on their Pittsburgh Sleep Quality Index (PSQI). Utilizing correlation and regression analyses, the results revealed significantly lower vitamin D levels among individuals in the poor sleep group compared to the normal sleep group. This study reinforces the association between lower vitamin D levels and poorer sleep quality in RLS patients, but a causal link between vitamin D deficiency and RLS has not been established. A systematic review conducted by Abboud et al. [10] evaluated the impact of vitamin D supplementation (VDS) on sleep duration and quality. Their meta-analysis of available data demonstrated a significant decline in the PSQI for patients who underwent VDS; those receiving a placebo did not experience this decline. Because of these findings, we primarily explore the relationship between vitamin D and children's sleep in this report.

Sleep structure

Based on the patterns observed in polysomnography, including electroencephalogram (EEG) results, eye movement assessments, and muscle tone determinations, sleep structure is divided into rapid eye movement (REM) sleep and non- REM (NREM) sleep. Within the first 6 months after birth, NREM sleep is referred to as quiet sleep; and REM sleep is referred to as active sleep. Among infants younger than 3 months, REM sleep predominates. After 6 months, NREM sleep increases. NREM sleep has been divided into stages S1, S2, S3, and S4; but some studies suggest merging S3 and S4 groups. An S1, S2, and S3 classification scheme is now the accepted method for defining NREM sleep. S1 sleep is characterized by a low arousal threshold and is easily disrupted by external stimuli. S2 sleep is characterized by sleep spindles on imaging, and S3 sleep comprises slow-wave sleep (SWS) with a high arousal threshold, minimal susceptibility to external stimuli, and slow respiration and heart rate. Growth hormone secretion is most active during S3.

1. Neuroregulatory mechanisms of sleep-wakefulness

1) Neuroregulatory mechanisms related to wakefulness

The brainstem, hypothalamus, and thalamus provide the main regulatory neural systems for wakefulness [11,12]. The control of sleep and wakefulness is comparable to a switch; specific areas are inhibited during sleep and activated during wakefulness. These areas include the locus coeruleus (LC) and the anterior and posterior hypothalamus. The LC and posterior hypothalamus are activated during wakefulness, and the anterior hypothalamus promotes sleep.

Monoaminergic substances, including norepinephrine (NE), serotonin (5-HT), and dopamine, promote wakefulness and are distributed across the cortex, basal forebrain (BF), lateral hypothalamus (LH), and other brain regions. The LC is an important site for NE production in the forebrain. Its neurons project widely and are influenced by various arousal systems and the brainstem and prefrontal cortex. LC neuron activity peaks during wakefulness, slows during non-REM sleep, and stops during REM sleep. Rats with a damaged LC show decreased wakefulness [13]. Most 5-HT emanates from the midline and dorsal raphe nuclei in the brainstem, which receives inputs from the amygdala, insula, and prefrontal cortex to regulate sleep-wake states and process information from different brain regions [14].

Early research suggested that damage to the raphe nuclei in rodents and felines caused insomnia. This suggested that 5-HT promotes sleep. However, recent studies suggest the opposite, that 5-HT promotes wakefulness [15]. This chemical can stimulate wake-promoting neurons in other brain regions directly or indirectly, and its release is influenced by drugs and light sources. Selective serotonin reuptake inhibitors increase 5-HT release, enhancing alertness in humans and rodents. Light exposure activates 5-HT neurons, possibly mediated by glutamate release, doubling the NREM to REM sleep transition time.

Stimulation of BF neurons promotes wakefulness. This is likely due to acetylcholine- and gamma-aminobutyric acid (GABA)-mediated promotion of cortical activation. Extensive BF lesions can cause slow EEG wave patterns or result in coma [16]. The tuberomammillary nucleus (TMN) is the main source of histaminergic neurons in the brain. During wakefulness, TMN neurons activate regions that promote wakefulness, possibly through the corelease of GABA and indirect stimulation of wakefulness through projection to other subcortical regions [17,18]. Additionally, histaminergic neurons may indirectly stimulate wakefulness by projecting to the midline nuclei in the thalamus and other subcortical regions influencing wakefulness.

Orexin-A and orexin-B are located in the LH and are important neuropeptides for regulating wakefulness [19]. Physical activity or sufficient light increases orexin-A levels, stimulating wake-promoting brain areas. GABAergic neurons in the LH project to the reticular nuclei of the thalamus and can quickly awaken mice from NREM sleep when stimulated by light; darkness, however, prolongs SWS [20]. Orexin neurons produce glutamate and other sleep-inhibitory peptides like dynorphin. Additionally, orexin signals help maintain arousal during stress, challenging tasks, or reward-seeking [21].

2) Neuroregulatory mechanisms related to sleep

During prolonged wakefulness, the body transitions into sleep through a wake-sleep homeostatic response mediated by somnogens like adenosine (AD), prostaglandin D2 (PGD2), interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-α) [22]. These substances act as paracrine mediators of sleep induction and maintain the balance between wakefulness and sleep through a gradual increase during wakefulness. Among these substances, AD is particularly crucial in promoting sleep and is widely dispersed in the BF, cortex, and hippocampus. Astrocytes, regulated by astrocytic kinases [23], are the primary source of AD production. PGD2 may enhance sleep by binding to PGD2 receptors and increasing extracellular AD levels in the BF.

The preoptic area (POA) is an important region for sleep promotion [24]. GABAergic neurons in the ventrolateral (VLPO) and medial (MNPO) POAs promote sleep by inhibiting wakefulness-promoting neurons in the posterior hypothalamus and brainstem. The VLPO primarily maintains NREM sleep, and the MNPO is involved in NREM sleep initiation. GABAergic neurons in the cortical areas promote sleep by inhibiting the parabrachial nucleus. Additionally, BF somatostatin neurons may promote sleep by inhibiting local wakefulness-promoting neurons [25].

REM sleep differs from NREM sleep and requires coordinated cortical activation involving different cell groups in the brainstem, hypothalamus, and POA in addition to hippocampal activity [26]. REM sleep involves coordinated cortical activation and is regulated by interactions between histaminergic and cholinergic neurons. Muscle tone changes are primarily controlled by neurons in the ventromedial medulla. These are influenced by glutamatergic neurons in the adjacent spinal tract nucleus of the trigeminal nerve. During REM sleep, GABAergic neurons inhibit neurons in the ventral periaqueductal gray (vlPAG) and lateral pontine tegmentum (LPT) areas, while neurons in the sublaterodorsal nucleus (SLD) are activated and project to the ventromedial medulla. These provide a pathway to inhibit motor neuron activity. The dorsal paragigantocellular nucleus inhibits LC neurons.

In summary, the regulation of NREM sleep, REM sleep, and wakefulness involves complex neural network and neurotransmitter activities and interactions. The VLPO POA promotes maintenance of wakefulness or sleep, whichever is being experienced. Reciprocal inhibitory circuits between REM sleep-promoting neurons in the SLD and REM sleep-inhibiting neurons in the vlPAG and LPT areas regulate REM sleep. These interactions ensure the transitions among wakefulness, NREM sleep, and REM sleep.

The neurological mechanisms of vitamin D in the brain

1. Synthesis and metabolism of vitamin D in the brain

Vitamin D is a steroid hormone and an important regulator of calcium and phosphate metabolism. Vitamin D exists primarily as 25-hydroxyvitamin D3 (25(OH)D3) and its activated form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The primary source of vitamin D is sunlight. Exposure to ultraviolet B radiation converts 7-dehydrocholesterol in skin tissue into 25(OH)D3 [27]. Studies [28] have shown that in vitro glial cells can promote the conversion of 25(OH)D3 into 1,25(OH)2D3. The level of 1,25(OH)2D3 in the central nervous system correlates with plasma 25(OH)D3 levels. The most important enzyme involved in vitamin D breakdown and metabolism, CYP24A1, is present in primary rat glial cells and human brain astrocytes. Vitamin D enhances the expression of CYP24A1 in a dose-dependent manner [29,30]. The vitamin D receptor (VDR) was identified in the hippocampus of healthy individuals and in patients with Alzheimer or Huntington disease. In addition to the hippocampus, VDRs are present in calbindin-28k cells in the brain and cerebellum. Strong immunohistochemical expression of VDR in the substantia nigra of mouse and human brains suggests a role for vitamin D in dopaminergic neurons [31]. VDR first appears in embryonic dopamine neurons on embryonic day 12, and its expression gradually increases until adulthood. Additionally, VDR expression in oligodendrocytes and 1,25(OH)2D3 can promote the differentiation of adult neural stem cells into oligodendrocytes and the maturation of oligodendrocyte progenitor cells (OPCs) [32].

Vitamin D regulates neuronal excitability in the brain through several mechanisms: regulation of regular firing, duration of action potentials, intrinsic excitability, and sensitivity to neurotransmitters such as GABA receptors and N-methyl-D-aspartate receptors [33]. Furthermore, vitamin D can upregulate the synthesis of neurotrophins such as nerve growth factor, neurotrophin 3, and glial cell-derived neurotrophic factor [34] and downregulate neurotrophin 4 synthesis. Therefore, vitamin D may influence neuronal development through multiple pathways.

Astrocytes regulate cortical states, acting in an interactive information network system. Astrocytes activate neurons through the release of neurotransmitters, provide energy substrates to neurons, and clear glutamate to restore ion balance after neuronal depolarization [35]. Research by Bellesi et al. [36] on cortical astrocyte activities during different states of arousal indicated that astrocytic gene expression and ultrastructure differ during wakefulness and sleep. Approximately 1.4% of astrocytes remain in a state of alertness with substantially greater gene upregulation during wakefulness.

Based on that research, we compiled a table to enhance comprehension of the impact of neurotransmitters in the brain and the influence of vitamin D on sleep (Table 1).

2. Vitamin D effects on sleep

In recent years, research has demonstrated that, in addition to regulating calcium and phosphate metabolism, vitamin D regulates the circadian rhythm of sleep in humans [37]. The role of vitamin D in the sleep-wake cycle was first proposed by Stumpf and Jennes [38] in 1984, who observed a steroid hormone anatomical model using the Allocortex Limbic Brainstem Core model. The study suggested that steroid hormones control the endocrine autonomic regulatory system in all species. This system extends to the hypothalamus-preoptic-septal regions through the brainstem from the cervical spinal cord to the medulla, pons, and midbrain. This endocrine system is involved in functions such as sleep, respiration, cardiovascular function, reproduction, metabolism, and digestion. Vitamin D, a typical steroid hormone, is at the core of this endocrine system. The vitamin D-regulated endocrine system follows the Multiple Activation of Heterogeneous Systems concept; and intracellular vitamin D receptors are located in the pituitary gland, hypothalamus, and brainstem.

Yong et al. [39] recently speculated that vitamin D deficiency may have long-term effects on sleep duration. That research group found that patients with low cord blood vitamin D levels at birth had an increased risk of insufficient sleep (less than 10.5 hours per night) during preschool years (ages 2 to 5–6 years). Furthermore, an objectively measured sleep study using actigraphy showed that higher concentrations of serum 25(OH)D were associated with longer night sleep duration [40]. Research on adults with sleep disorders revealed that a 50,000-unit vitamin D supplement every 2 weeks for 8 weeks improved self-reported sleep scores, increasing sleep duration and subjective sleep quality [41]. A systematic meta-analysis showed that 25(OH)D levels below 20 ng/mL are associated with low sleep efficiency and short sleep duration [37]. A cross-sectional study examining 800 Chinese adolescents aged 8 to 14 years demonstrated a positive association between serum 25-(OH) vitamin D levels and sleep duration. Additionally, 25-(OH) vitamin D deficiency emerged as an independent predictor of insufficient sleep in Chinese primary and secondary school students [42]. Several studies have shown a strong association between vitamin D deficiency and obstructive sleep apnea, especially in adults; and continuous positive airway pressure has an effect on vitamin D balance in adult men with obstructive sleep apnea [43,44]. Al-Shawwa et al. [45] confirmed a link between vitamin D deficiency and shorter sleep duration and poorer sleep quality in children. Interestingly, those researchers demonstrated that vitamin D deficiency was not related to early awakening but was due to a reduced ability to initiate sleep. This suggests a potential connection between vitamin D and the body's internal clock and provides a theoretical basis for further research on the role of vitamin D deficiency in sleep disorders [45].

The results of these studies suggest that insufficient vitamin D can influence children's sleep. However, the specific mechanisms by which vitamin D affects sleep are not fully understood.

3. Possible mechanisms of the effect of vitamin D on sleep

The exact mechanisms by which vitamin D influences sleep regulation are not clear, but one hypothesis is that the mechanism is related to the lack of vitamin D in important areas of the brainstem that regulate sleep [43]. VDRs are expressed in regions such as the anterior and posterior hypothalamus, substantia nigra, central gray matter of the midbrain, interpeduncular nucleus, and nuclei involved in sleep regulation such as the pontine reticular and raphe nuclei. These areas contain pacemaker cells that play important roles in the initiation and maintenance of sleep [46]. Vitamin D target cells are also present in the BF, periventricular hypothalamic area, and POA, which are involved in melatonin synthesis. Vitamin D regulates the conversion of tryptophan to 5-hydroxytryptophan by regulating the activity of tryptophan hydroxylases-2. When the VDRE gene is expressed, 5-hydroxytryptophan is metabolized to 5-HT and melatonin is produced [47] and promotes sleep. In addition, 5-hydroxytryptamine plays a crucial role in the initiation and maintenance of sleep in children, promoting and maintaining SWS and influencing the sleep-wake cycle [48]. Vitamin D is involved in circadian rhythm regulation [49,50] in adipocytes; and 1,25-dihydroxycholecalciferol controls the expression of BMAL1 and PER2, the human brain's "clock" genes. The protein 1α-hydroxylase is activated by vitamin D and is expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Therefore, vitamin D may affect these "clock" genes. Also, 25-hydroxylase and 24-CYP24A1, controllers of vitamin D degradation, are expressed in the brain.

The 24-hour sleep-wake cycle is regulated by light and natural light-dark cycles through a central biological clock in the SCN of the hypothalamus via retinal receptors. Peripheral sensors are then affected through hormonal and neural pathways. Since light affects both vitamin D synthesis and circadian rhythms, vitamin D may regulate circadian rhythms by acting on VDRs in the brain [51].

Additionally, the distribution of VDR in the human brain is similar to that in rodents [46], present in cortical and subcortical regions involved in sleep regulation. These regions are the frontal cortex, which regulates normal sleep physiology; the cingulate cortex, which is involved in sleep-related respiratory and blood pressure changes and is associated with sleep apnea; the dentate gyrus, which is an adult neurogenic site related to sleep deprivation; the raphe nucleus, which is associated with insomnia and idiopathic REM sleep behavior disorder; the anterior hypothalamus, especially the suprachiasmatic and periventricular nuclei, which are closely connected to efferent neural pathways and receive signals from efferent neural pathways; and the VLPO, which regulates NREM sleep [52].

Vitamin D deficiency causes discomfort during sleep, shortens sleep duration, and leads to decreased sleep quality. Vitamin D deficiency can cause nonspecific pain and noninflammatory skeletal muscle diseases [53] that secondarily result in poor sleep quality. The mechanism may be related to the elevation of inflammatory mediators such as TNF-α, IL-1, and PGD2, all of which are involved in sleep regulation. Vitamin D inhibits the release of IL-1, a promoter of astrocytic PGD2 production, and TNF-α.

Over 50% of children experience sleep disturbances, and 1% to 5% are affected by obstructive sleep apnea (OSA) [54]. Suitable oral VDS can improve behavior and cognitive impairments in children with obstructive sleep apnea hypopnea syndrome (OSAHS), highlighting the link between vitamin D deficiency and OSAHS [55]. Reduced levels of 25(OH) vitamin D were correlated with higher OSA-18 questionnaire scores and larger lymphoid tissue size in children undergoing tonsillectomy [56]. Inflammatory cytokines can cause muscle disorders like tonsillar hypertrophy and rhinitis, raising the risk of upper airway obstruction during sleep and leading to OSAHS. This heightened risk contributes to sleep disturbances and excessive daytime sleepiness [57]. According to Deniz et al. [58], alterations in the genotypes of VDR and VDBP genes can cause changes in serum vitamin D levels, ultimately worsening OSAHS. The study indicates that VDR can segregate the retinoic acid receptor-related orphan receptor gamma t (RORγt) coactivator Runx1; this results in RORγt transcriptional activity suppression and subsequent inhibition of Th17 cell differentiation [59]. Vitamin D plays a crucial role in the immune system; and 1,25(OH)2D3, an active form of vitamin D, exerts its effects by directly targeting CD4 [60].

Additionally, compared to individuals without sleep deprivation, those with reduced total sleep time reported higher levels of spontaneous daytime somatic pain symptoms and lower pain thresholds, suggesting a bi-directional relationship between pain and sleep [61]. Sleep deprivation-induced hyperalgesia is associated with elevated inflammation markers such as IL-1, IL-6, and the NE release mediator IL-2. NE activates β-adrenergic receptors, participating in sleep regulation [62-64]. Furthermore, adequate levels of vitamin D can alleviate idiopathic pain caused by statins; VDS in patients with statin-induced myalgia relieves pain symptoms and improves nighttime sleep quality [65]. Low vitamin D level is an adjunct factor to aromatase inhibitors in the mediation of musculoskeletal pain, and VDS can improve the effectiveness of drug therapy [66]. A cohort study found that more than half of subjects with nonspecific musculoskeletal pain had vitamin D deficiency (25(OH)D < 20 ng/mL) [67].

In summary, vitamin D deficiency may cause sleep disturbances by influencing melatonin secretion, changing light exposure-regulated circadian rhythms, causing related skeletal diseases, and affecting sleep through associated factors such as chronic somatic pain symptoms caused by changes in inflammatory mediators.

Conclusion

Adequate sleep plays a crucial role in the healthy development of children, and vitamin D level can influence achievement of adequate sleep. Ensuring optimal levels of vitamin D is especially important for healthy sleep patterns in children. However, the exact mechanism by which vitamin D affects children's sleep remains unclear and requires further research.

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contribution

Conceptualization: LZ, DY; Writing - original draft: LZ; Writing - review & editing: DY

Table 1.

Interactions between vitamin D and neurotransmitters and their impact on sleep

Neurotransmitter	Interaction mechanism	Impact on sleep
Dopamine	Dopamine is present in the cerebral cortex, basal forebrain, and locus coeruleus. Dopamine in specific brain regions promotes alertness through enhanced synaptic transmission. Vitamin D-targeted cells in the basal forebrain regulate dopamine secretion.	Dopamine is a neurotransmitter that promotes wakefulness and attention during the sleep-wake cycle. While dopamine has sleep-promoting effects, elevated levels can cause insomnia.
Gamma-aminobutyric acid (GABA)	Vitamin D regulates the activity of GABA receptors, moderating neural excitability.	GABA is primarily active during non-REM sleep, promoting deep sleep phases.
Serotonin	Vitamin D promotes the synthesis of serotonin, regulating the sleep-wake cycle.	Serotonin is crucial for regulating sleep rhythms and states of wakefulness.
Glutamate	Vitamin D influences neurotransmission through modulation of glutamate receptor sensitivity.	Glutamate plays a crucial role in wakefulness and REM sleep.
Orexin-a	Increased synthesis of vitamin D stimulates the production of orexin-a, which enhances brain activity and delays the onset of sleep.	Orexin-a plays a crucial role in stimulating the brain to awaken from NREM sleep.
Adenosine	Astrocytes contain the enz yme CYP24A1. CYP24A1 metabolizes vitamin D. Vitamin D increases the expression of CYP24A1 in a dose-dependent manner. Adenosine acts as a paracrine mediator to induce sleep.	Astrocytic kinase regulates adenosine to promote sleep.
Neurotrophin-3 (NT-3)	Vitamin D enhances the production of neurotrophic factor 3, which promotes the proliferation of oligodendrocyte precursor cells and increases neuronal activity, aiding in remyelination.	Elevated NT-3 levels stimulate neuronal activity and contribute to wakefulness.

REM, rapid eye movement; NREM, non-REM.

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