Chronobiology in Paediatric Neurological and Neuropsychiatric Disorders: Harmonizing Care with Biological Clocks

Headaches, particularly migraines and tension-type headaches, are among the most common neurological complaints in paediatric patients [31,32]. Emerging evidence underscores the significant influence of circadian rhythms on these conditions [21]. Migraines, in particular, exhibit a pronounced circadian pattern, often peaking in the early morning and late afternoon [33]. This temporal occurrence is associated with fluctuations in key neurohormones, including cortisol, melatonin, and serotonin, all of which follow circadian cycles [34]. Notably, reduced evening melatonin levels are frequently observed in paediatric migraine sufferers, suggesting that circadian misalignment may contribute to migraine onset [35].

The hypothalamus, specifically the suprachiasmatic nucleus (SCN), has also been implicated in the pathogenesis of migraines [36,37]. Increased hypothalamic activity has been documented during the prodromal phase of migraine attacks, suggesting that dysfunction in this circadian-regulated region could trigger migraine episodes [37]. Disruptions in melatonin secretion, governed by the SCN and produced by the pineal gland, further exacerbate sleep disturbances in children with migraines, particularly those with comorbid conditions such as insomnia [38]. Moreover, research indicates a higher prevalence of evening chronotype (a preference for later sleep and wake times) among children with migraines, a sleep pattern linked to poor sleep quality and increased headache frequency [39].

Both sleep regulation and migraine mechanisms share common neurochemical and neuroanatomical pathways. Dysregulation of neurotransmitters like serotonin and dopamine, which are involved in both sleep-stage transitions and the early symptoms of migraines (e.g., yawning, mood changes), underscores the shared pathophysiology between these processes [37]. Circadian disruptions, including irregular sleep schedules and night-time light exposure, suppress melatonin production, worsening both sleep quality and migraine frequency [40].

Research also indicates a relationship between early childhood sleep disturbances, such as colic, and the subsequent development of migraines [41,42,43,44,45]. Several studies have shown that infantile colic, traditionally seen as a gastrointestinal issue, could actually reflect a disruption in sleep patterns, increasing the risk of migraines in later childhood [43]. One review found that infant colic is associated with an increased odds ratio of developing migraines, pointing to shared pathophysiological mechanisms, probably related to the regulation of circadian rhythms [46]. This evidence emphasizes the importance of addressing early sleep disturbances, such as infant colic, to potentially mitigate the risk of chronic headache disorders linked to biorhythm imbalances [47].

Sleep disturbances are frequently reported in children with migraines, including insomnia, parasomnias, and obstructive sleep apnoea (OSA) [44,45]. Studies indicate that parasomnias, such as sleepwalking and night terrors, affect up to 30% of paediatric migraine sufferers, a rate significantly higher than that observed in the general population [44,45]. Additionally, OSA (a well-established cause of morning headaches) is prevalent among children with migraines [48].

The complex interplay between circadian rhythms, sleep disorders, and paediatric migraines highlights the need for a comprehensive approach to diagnosis and treatment. The overlap in brain structures and neurochemical pathways involved in both sleep regulation and migraine pathophysiology suggests a shared biological foundation. By addressing circadian misalignment and improving sleep quality, clinicians can better manage paediatric migraines.

Paediatric epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures in children, often with multifactorial causes that range from genetic to structural abnormalities [49]. Its impact extends beyond seizures, affecting cognitive, behavioural, and sleep functions [50]. Understanding how biological rhythms influence epilepsy is crucial, especially in paediatric populations where brain development is ongoing. Circadian rhythms play a central role in modulating epileptic activity. While sleep disorders are commonly observed in children with epilepsy, the relationship between circadian rhythms and seizure patterns offers a further framework for understanding and managing the condition [22].

Seizures in paediatric epilepsy exhibit distinct temporal patterns, strongly influenced by the circadian cycle. These rhythms govern various neurophysiological processes, including cortical excitability, which in turn modulates the likelihood of seizure occurrence. For example, generalized seizures in children are more likely to occur in the early morning following sleep, while certain focal seizures, such as those arising from the frontal lobe, occur predominantly at night [51]. The underlying mechanism involves circadian genes like BMAL1 and CLOCK, which regulate the excitability of neurons and thus influence seizure thresholds [52,53].

In paediatric cases, these circadian influences are even more pronounced because the developing brain is particularly sensitive to changes in the sleep–wake cycle [54]. Seizure activity tends to follow the natural fluctuations of cortical excitability that occur throughout the day, with specific epilepsy syndromes showing different peaks in seizure frequency [55].

The overlap between circadian rhythms and sleep disorders in paediatric epilepsy suggests that these conditions may share common regulatory pathways [22]. The disruption of circadian rhythms often leads to disturbances in sleep patterns, which can manifest as insomnia or hypersomnia in children with epilepsy [56]. These circadian misalignments not only predispose individuals to seizures but also impair the regulation of sleep–wake cycles, resulting in chronic sleep disturbances [57]. The circadian clock also interacts with the mTOR signalling pathway, which has been implicated in both epileptogenesis and sleep regulation [52,53]. Moreover, the type of epilepsy may also determine the severity and nature of sleep disruptions. For instance, children with sleep-related hypermotor epilepsy (SHE) often experience particularly pronounced disturbances in sleep architecture, including frequent nocturnal awakenings and abnormal motor activity during sleep [58]. The presence of comorbid sleep disorders, such as OSA or insomnia, further complicates epilepsy management and can lower quality of life [59].

A better understanding of how these two systems interact can lead to more effective therapeutic strategies. As research continues to unravel the connections between circadian biology and epilepsy, there is great potential for improving the management and quality of life for children living with this challenging condition.

According to the World Health Organization, autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impairments in social interaction, communication, the presence of rigid or repetitive behaviours, and differences in the perception of sensory stimuli [60]. Over recent decades, increasing evidence has pointed toward a significant role of circadian rhythm disruptions in ASD, with wide-reaching effects on both the core symptoms of autism and the overall quality of life [20]. Chronobiology has become a growing area of interest in understanding ASD pathophysiology, focusing on the molecular mechanisms that underlie circadian dysregulation and its impact on cognitive, behavioural, and physiological processes [61]. The molecular foundation of circadian rhythms involves a set of core clock genes, including CLOCK, BMAL1, PER1-3, and CRY1-2, which participate in transcriptional–translational feedback loops (TTFLs) that generate rhythmic oscillations in gene expression and protein synthesis [62].

In ASD, dysregulation of circadian rhythms is a pervasive issue that is associated with both molecular and behavioural abnormalities. Melatonin and cortisol have been found to exhibit abnormal rhythmicity in individuals with ASD [63]. Melatonin is essential for regulating sleep–wake cycles and is typically secreted in response to darkness. Studies have consistently shown reduced nocturnal melatonin levels and a blunted circadian rhythm of melatonin secretion in individuals with ASD [64]. This reduction is not only correlated with sleep disturbances but also linked to broader behavioural symptoms, such as social interaction difficulties and heightened anxiety [65]. It is important to note that individuals with autism who also experience seizures often display an abnormal melatonin rhythm, which has been linked to electroencephalogram (EEG) changes [66]. Moreover, individuals with autism appear to be highly sensitive not only to disruptions in external environmental rhythms but also to internal physiological changes. For example, some female adolescents with autism are prone to epileptic seizures around the 14th day of their menstrual cycle, coinciding with a peak in luteinizing hormone (LH) levels [63]. This highlights a chain of events where disturbances in biological rhythms, compounded by heightened sensitivity to environmental stimuli, can increase arousal and physiological stress, ultimately triggering seizures in some children with autism [67].

Similarly, cortisol, a hormone that follows a diurnal cycle, is often dysregulated in ASD. While cortisol typically peaks in the morning and decreases throughout the day, individuals with ASD often display a blunted or abnormal cortisol rhythm, which may contribute to the hyperarousal and stress reactivity seen in these patients [68]. These hormonal disruptions suggest that circadian rhythm dysfunction may be a core feature of ASD, influencing not only sleep but also emotional regulation and social behaviour [20].

On a molecular level, ASD is associated with the dysregulation of several pathways involved in circadian rhythm regulation [69]. One of the most studied pathways is the canonical WNT/β-catenin pathway, which plays a crucial role in both neurodevelopment and the regulation of circadian rhythms [70,71,72].

Dysregulation of this pathway has been implicated in the metabolic reprogramming observed in ASD. Upregulation of WNT/β-catenin signalling has been linked to aberrant brain development, including altered neuronal connectivity and synaptic plasticity, both of which are specific features of autism [70,73]. Moreover, the WNT/β-catenin pathway interacts with circadian clock genes, suggesting that disruptions in this pathway may contribute to the circadian abnormalities seen in ASD [70,73].

CLOCK and BMAL1 drive the expression of PER and CRY genes, essential components of the circadian feedback loop [74,75]. In ASD, mutations or dysregulation of these circadian genes have been observed: for example, the PER1 gene, which is critical for the sleep–wake transition, has been found to be mutated in some individuals with ASD [76]. These mutations are thought to disrupt the normal oscillatory behaviour of circadian clocks, leading to abnormalities in sleep patterns, hormone secretion, and potentially other physiological rhythms [63].

Moreover, genetic studies have pointed to mutations in circadian regulators such as NR1D1 (Rev-erbα), a gene that inhibits BMAL1 expression and modulates circadian cycles [62]. Disruption of these pathways leads to the widespread circadian dysfunction seen in ASD, further emphasizing the importance of molecular chronobiology in understanding the disorder [77].

The clinical implications of circadian dysregulation in autism extend beyond sleep disturbances, influencing a range of behavioural symptoms [78]. Individuals with ASD often exhibit increased sensitivity to environmental stimuli, repetitive behaviours, and social withdrawal. These symptoms may be exacerbated by the disrupted synchronization of internal clocks with external environmental cues, such as the light–dark cycle [20].

One key manifestation of circadian disruption in ASD is sleep disturbance, which is reported in up to 80% of children with the condition [64]. Common sleep-related issues include delayed sleep onset, frequent nocturnal awakenings, reduced total sleep time, and early morning awakenings. Sleep disturbances not only worsen daytime behavioural issues such as irritability and hyperactivity but also interfere with cognitive development and learning, making them a critical area for intervention [65].

Moreover, sleep problems in ASD have been correlated with increased severity of repetitive behaviours and reduced social engagement [79]. For example, Goldman et al. (2011) assessed the relationship between sleep and behaviour in 1784 children aged from 2 to 18 years with a confirmed diagnosis of ASD [79]. Their findings indicated that poor sleepers exhibited a higher incidence of behavioural problems compared to good sleepers, with over three-quarters of the children reporting issues with attention and social interactions [79]. Internal desynchronization caused by circadian misalignment may aggravate repetitive motor behaviours and insistence on sameness, as individuals with ASD struggle to adapt to changes in their external or internal environments [68].

Given the profound impact of circadian dysfunction on ASD, chronotherapeutic interventions have emerged as a promising avenue for treatment.

Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity [80,81]. However, beyond these core symptoms, recent research highlights the significant role that circadian rhythm disruptions play in the pathophysiology and symptomatology of ADHD [23,82,83].

The circadian system plays a crucial role in regulating the body's daily physiological, behavioural, and cognitive processes [84].

ADHD is increasingly being recognized as a disorder with significant circadian dysregulation [85]. Several studies have shown that individuals with ADHD exhibit disturbances in their circadian rhythm, particularly in relation to their sleep–wake cycles [86]. One of the most common findings is a phase delay, where individuals experience a delay in their endogenous circadian markers, such as dim light melatonin onset (DLMO) [83,87]. In individuals with ADHD, the secretion of melatonin often occurs later in the evening, resulting in delayed sleep onset, reduced sleep duration, and difficulty waking in the morning [85,87].

The phase delay observed in ADHD aligns with a preference for eveningness, or "night owl" behaviour, a chronotype that is more prevalent in individuals with the disorder [83,88,89]. Studies using measures such as the Morningness–Eveningness Questionnaire (MEQ) and the Munich Chronotype Questionnaire (MCTQ) consistently show that ADHD patients tend to score higher on eveningness [87,90]. In the general population, eveningness is associated with altered emotionality, and ADHD-related traits such as apathetic, volatile, and disinhibited temperaments are linked to evening orientation, as is sensation-seeking behaviour [91]. This phase delay not only affects sleep patterns but also exacerbates core ADHD symptoms, such as inattention, hyperactivity, and impulsivity, particularly during the daytime when optimal cognitive function is required [88,89].

Light exposure is the primary external cue that synchronizes the circadian clock with the external environment, a process known as entrainment [86]. Light influences circadian rhythms through a pathway that involves intrinsically photosensitive retinal ganglion cells (ipRGCs), which detect changes in ambient light and relay this information to the SCN [92]. In individuals with ADHD, there may be alterations in light sensitivity or reduced exposure to natural light, which can disrupt the normal entrainment of circadian rhythms [83,85]. This misalignment between internal circadian rhythms and external environmental cues can lead to a range of behavioural and cognitive disruptions [88,89].

Interestingly, it has been suggested that individuals with ADHD may have a diminished sensitivity to morning light, which further contributes to delayed circadian phase [83]. This has significant implications for therapeutic interventions aimed at realigning the circadian clock in ADHD patients [23,86].

Several studies have identified polymorphisms in clock genes that are associated with both ADHD symptoms and circadian phase delays [85,93]. For instance, single nucleotide polymorphisms (SNPs) in the CLOCK and PER3 genes have been linked to increased eveningness and delayed sleep onset in ADHD populations [87,88,89]. These genetic variants may alter the normal functioning of the molecular clock, leading to the chronobiological disturbances seen in ADHD [83].

Moreover, disruptions in the regulation of dopamine, that plays a key role in ADHD, have also been linked to circadian rhythm dysfunction [87,93,94]. Dopamine release is under circadian control, and alterations in dopaminergic pathways can affect both circadian timing and the expression of ADHD symptoms [83,88,89]. Circadian and dopaminergic systems are closely interconnected in the regulation of attention, impulsivity, and behaviour [86].

Chronotype, which refers to an individual's preference for morning or evening activity, is strongly influenced by circadian rhythms [83,88,89]. In ADHD, the tendency toward a later chronotype has been associated with impaired cognitive performance during the morning hours [81]. This has important implications for both educational and occupational settings, where individuals with ADHD may struggle to perform at their best due to misaligned circadian timing [88,89]. Furthermore, subtype differences in the prevalence of sleep-onset insomnia have been indicated, with a decreased number of adults with the inattentive ADHD subtype displaying symptoms of sleep-onset insomnia compared to other subtypes [95]. Inattentive subtype patients not suffering from sleep-onset insomnia exhibited longer sleep duration and more stable sleep–wake rhythms compared to those with sleep-onset insomnia [96]. This aligns with previous reports that inattentive subtypes of ADHD are sleepier during the day and sleep for longer durations at a time, with dysregulation of the melatonin rhythm potentially mediating these associations [95,97].

Studies have shown that individuals with ADHD who have a later chronotype exhibit poorer performances in working memory, sustained attention, and executive function tasks, particularly in the early part of the day [83,85]. This misalignment between cognitive demand and circadian alertness contributes to the characteristic difficulties that are commonly seen in this population [88,89].

While much of the research on ADHD and circadian rhythms focuses on sleep, it is important to recognize that circadian disruption in ADHD affects a wide range of physiological processes beyond the sleep–wake cycle [81,92]. For example, Bijlenga et al. (2013) have recently postulated that the higher than expected prevalence of photophobia in ADHD may reflect a deficit in non-visual photic transmission associated with the circadian system, and that such a change could lead to the phase alterations observed in this conditions [98]. Circadian disturbance is further implicated in ADHD by findings that seasonal affective disorder (SAD), a form of depression intimately linked to circadian dysfunction [99], is significantly comorbid with this population [93,95,98,100]. For example, hormonal rhythms, including cortisol secretion, which follows a diurnal pattern, may be disrupted in ADHD [83,101].

There is evidence of blunted cortisol rhythms, which may contribute to daytime fatigue and cognitive difficulties [87]. Sex differences in the stress response have been identified in childhood ADHD, with elevated early morning cortisol levels in boys and decreased levels in girls [102].

Furthermore, circadian dysregulation in ADHD can affect metabolic processes, mood regulation, and cardiovascular function, all of which are under circadian control [81,92]. The pervasive nature of circadian dysfunction in ADHD underscores the importance of considering chronobiological factors in both the diagnosis and treatment of the disorder [83].

Post-traumatic stress disorder (PTSD) in children and adolescents is a significant mental health condition that arises after exposure to traumatic events [103]. This condition is marked by symptoms of re-experiencing, avoidance, hyperarousal, and mood alterations, all of which impair daily functioning [80]. Factors such as the type of trauma, the developmental timing of exposure, gender, pubertal development, social context, and psychopathology are hypothesized to contribute to the divergent findings in PTSD outcomes [104,105,106].

Emerging research highlights the role of circadian rhythm dysregulation, offering new insights into the chronobiological aspects of PTSD in younger populations [24]. Circadian rhythms are significantly affected in children with PTSD, often manifesting as delayed sleep phases and attenuated circadian amplitude [107]. Studies using actigraphy demonstrate that these children have more disrupted circadian rhythms compared to controls, with delayed sleep onset and irregular physical activity patterns during the day [108,109]. Children who experience early-onset trauma, particularly those who develop PTSD, often exhibit robust circadian rhythms with hyperactivity, while those without PTSD show attenuated rhythms [107]. Dysregulation of these rhythms may exacerbate PTSD symptoms and contribute to long-term psychiatric complications, such as depression and anxiety [110,111].

The hypothalamic–pituitary–adrenal (HPA) axis, responsible for regulating the body's stress response, is deeply intertwined with circadian rhythms. In children with PTSD, the typical circadian pattern of cortisol secretion can be significantly disrupted [112]. Some studies have found elevated afternoon and evening cortisol levels in children with PTSD, indicating a flattened diurnal slope of cortisol secretion [113,114]. This flattening of cortisol rhythms has been linked to sustained hyperarousal and a heightened stress response, worsening PTSD symptoms such as sleep disturbances, mood dysregulation, and emotional resilience, together with difficulties with concentration and cognitive functioning [106,115,116,117,118].

The timing and type of trauma play a crucial role in the development of PTSD. Children exposed to chronic stress or multiple traumatic events are more likely to develop severe PTSD symptoms and show profound circadian rhythm disturbances [119]. For example, the timing of first trauma exposure has been associated with different diurnal secretion patterns in boys and girls [120,121].

The developmental stage at the time of trauma exposure also critically influences cortisol dysregulation. Younger children, especially those under 10, tend to have higher cortisol levels post-trauma compared to adolescents [122]. These elevated cortisol levels in younger children may be associated with hyperarousal and heightened stress reactivity, while adolescents tend to exhibit variable cortisol responses to trauma [122,123].

Cortisol profiles differ between children and adults with PTSD. In adults, studies often report low or normal baseline cortisol levels, whereas children frequently have elevated cortisol levels, especially in the evening [122,124]. Although cortisol levels in paediatric patients may normalize over time, noradrenaline concentrations often remain high, contributing to sustained hyperarousal [125,126].

Sleep disturbances are common and persistent in children and adolescents with PTSD, affecting more than 50% of patients after a traumatic event [109,127]. These disturbances include insomnia, nightmares, night terrors, fragmented sleep, and altered sleep architecture, particularly in rapid eye movement (REM) sleep [128]. Nightmares, in particular, are a hallmark of PTSD, affecting 50% to 80% of children after trauma [129,130].

Polysomnographic studies indicate that children with PTSD experience increased sleep fragmentation, elevated wake-after-sleep onset (WASO), and micro-arousals, all of which correlate with PTSD severity [109,131]. Additionally, environmental stressors exacerbate these disturbances, suggesting that interventions should include environmental considerations and psychoeducation for both children and their parents [131,132].

Gender plays a critical role in how PTSD manifests in relation to chronobiology and biorhythm. Studies consistently show that girls are more susceptible to trauma-related cortisol dysregulation and sleep disturbances than boys [133]. This heightened vulnerability is partly attributed to hormonal changes during puberty that interact with the HPA axis [134]. Girls with PTSD often exhibit elevated cortisol levels in response to trauma-related stimuli, linked to re-experiencing and hyperarousal symptoms [112]. Longitudinal increases in cortisol levels have been associated with higher anxiety in adolescent girls [135]. Similarly, Trickett et al. (2010) observed that girls who experienced trauma showed different developmental trajectories in cortisol regulation compared to boys, potentially influencing PTSD outcomes [136]. Furthermore, Luo et al. (2012) collected hair samples from adolescent girls exposed to a devastating earthquake in China [137]. Compared to controls, girls in the quake area had elevated cortisol levels for several months following the event. Subsequently, girls who developed PTSD diverged, exhibiting markedly lower hair cortisol levels compared to trauma-exposed girls without PTSD [137]. In contrast, boys may show lower morning cortisol levels, reflecting hypoactivation of the HPA axis [106]. These gender differences underscore the need for tailored, gender-specific approaches to PTSD treatment. Circadian rhythm dysregulation is a core feature of paediatric PTSD, contributing to the severity and persistence of the disorder. Altered cortisol patterns, delayed chronotypes, and long-term disruptions of the HPA axis highlight the importance of considering chronobiological factors in the diagnosis and treatment of PTSD in younger populations.

Potential consequences of biorhythm dysregulation in paediatric neurological and neuropsychiatric disorders are shown in Figure 1.