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Abstract

Background

Time in headache disorders is crucial for diagnosis and gives insight into headache pathophysiology.

Objective

To summarize published studies which describe timing processes in both attack presentation (onset, duration) and disease characterization (age of onset, evolution over time) in primary headache disorders and link to pathophysiology.

Methods

A comprehensive search was conducted through Ovid MEDLINE(R) and PubMed, focusing on English-language articles from 1946 to 2023 to write the review. The International Classification of Headache Disorders, 3rd edition provided the framework for the review of primary headache disorders (migraine, tension-type headache and cluster headache).

Results

Attack presentation: Migraine attacks exhibit significant circadian and infradian rhythms, influenced by hormonal levels, light sensitivity, and hypothalamic activation. Tension-type headache lacks clear chronobiological patterns, with limited understanding of its underlying mechanisms. Cluster headache displays a distinct circannual pattern, with attacks often occurring at night and relevant involvement of the hypothalamus. Disease characterization: Age of onset exhibits the earliest peak in migraine; frequency and typical features of primary headache disorders decrease over time.

Conclusion

This comprehensive analysis of time patterns in primary headache disorders underscores their role in phenotyping, understanding and treating primary headache disorders, offering promising avenues for advancing and tailoring headache management.

Graphical abstract

This is a visual representation of the abstract.

Keywords

chronobiology headache disorders circadian rhythms cluster headache migraine tension-type headache

Introduction

The relevance of timing processes is ubiquitous in medical conditions and can be traced through the millennia (1). The study of cyclical biological phenomena and disease evolution with time are relevant topics to headache medicine (2). Chronobiology-the branch of biology concerned with cyclical physiological phenomena-explains the most renowned biological rhythms —circadian cycles—, encompassing physiological and behavioral changes primarily influenced by light and darkness; ultradian rhythms, varying from minutes to less than 24 h (i.e., diurnal variations or headache appearing at a specific time of the day) and infradian rhythms (i.e., lunar phase, seasonal alterations or menstrual cycle) are relevant to headache disorders (2,3).

Accurate identification of attack duration and time of onset is essential for proper diagnosis, particularly migraine and cluster headache (CH) in line with the chronobiology-based criteria outlined in the International Classification of Headache Disorders, 3rd edition (ICHD-3) (4). Hence, a comprehensive grasp of chronobiological features holds significant implications for both education and treatment decisions (4).

However, the concept of time in headache medicine extends beyond the chronobiology of attacks, encompassing the entire disease process. Time affects biological systems, as seen in disease onset and evolution, with significant clinical implications. For example, recognition of the age of disease onset aids in diagnosis, particularly as a ‘red-flag’ for secondary headache disorders (5). Similarly, the time span in which disease progression occurs may be informative of undertreatment or due to the presence of secondary conditions. Consequently, time in terms of both the attack and disease is pivotal to multiple aspects (pathophysiology, diagnosis and treatment) of headache disorders. (6). In this review, we summarize the relevance of time in headache regarding both the attack duration and the disease characterization as well as the possible underlying pathophysiological explanations in primary headache disorders.

Methods

This is a comprehensive review focusing on the most relevant aspects of time in headache: chronobiology of attack presentation and disease evolution, considering only English-language articles published in scientific journals and chapters of English-language books. We searched the articles through Ovid MEDLINE(R) and Pubmed using the queries or a combination of the queries: ‘Migraine Disorders’, ‘Migraine’, ‘Cluster Headache’, ‘Tension Type Headache’, ‘Headache Disorders’, ‘Headache’, ‘Chronobiology Disorders’, ‘Chronobiology Phenomena’, ‘Mediators’, ‘Pathophysiology’, between 1946 and 2023. For every selected article, we first evaluated the abstract to determine its relevance to the work and then reviewed the full text. We read through the references of the articles to identify any other relevant publications. Data were organized and analyzed qualitatively.

Results

The implication of timing in attacks presentation (duration, onset in terms of circadian/infradian rhythmicity) and disease characterization (age of onset and evolution over time), as well as the possible underlying pathophysiological explanations are included in Tables 1–5 and summarized in Figure 1.

Figure 1.

Vignette of primary headache disorders and their chronobiology. A. Chronobiology features of selected primary headache disorders. F; female, M; Male. TTH; Tension-type headache. B. Key central circadian structures and timing of attacks. Under photic stimulation, input to suprachiasmatic nucleus (SCN) directly via retinohypothalamic tract (RHT), and indirectly via intergeniculate leaflet (IGL) and geniculohypothalamic tract (GHT), ultimately SCN efferents target pineal gland (PG) via vasoactive intestinal peptide (VIP). Non-photic inputs to SCN include RN and IGL. C. Seasonal variation of primary headache bouts (stylized). Peak presentation: refers to the time of day. Created in biorender.com

Table 1.

Attack presentation regarding duration of the main primary headache disorders.

Primary headache	Duration of attack	Peripheral markers mediating duration of attacks	Central mechanisms mediating duration of attacks	Attack genes/mediators	Ref
Migraine	Range: 4-72 hAverage hours in EM under 50 years:Non-perimenstrual women: 16 (15–17) hPerimenstrual women: 23 (21–24) hMen: 14 (13–15) h.Shorter duration in children. Longer durations in women with EM and CM compared to men.	Sex hormones (menstruation).The drop in estrogen levels contributes to brain excitability and therefore activation of the trigeminal system.	Hypothalamus activation.The salience network primarily involving the insulae and cingulate cortex.Electroencephalography (EEG) slowing.	Vascular inflammatory markers.Pentraxin-3 levels are higher in individuals with shorter attack duration (<12 h).The G10 T (intron 23) genotype.It has been associated with longer attack duration.Polymorphisms in oxidative stress related genes.They have been associated with migraine attack duration including rs1050450 in the Glutathione Peroxidase 1 (GPX1) gene, possibly to be due to a reduced anti-oxidative activity.	(4,7,–17)
TTH	Range: 30 min and 7 days.eTTH: 30 mins - 7 days; cTTH: Hours to days, or unremitting.	Myofascial trigger point. Treatment of myofascial trigger point can modulate the nociceptive input to the caudal trigeminal nucleus which can be diminished, leading to a reduction in central sensitivity and ultimately improving TTH duration.	In TTH alpha2-adrenergic mechanism.	Putative role of alpha 2 agonist.	(4,18–25)
CH	15–180 mins.Longer durations observed in women and patients with comorbid migraine.	–			(4,26–28)

TTH: Tension-Type Headache; CH: Cluster Headache; eTTH: episodic Tension-Type Headache; cTTH: Chronic Tension-Type Headache; –No data; Ref: references.

Table 2.

Attack presentation regarding onset during the day in primary headache disorders.

Time onset during the day	Predominant day time	Circadian peripheral/external mechanisms	Circadian brain MRI structures involved	Circadian genes/mediators	Ref
Migraine	Great variability has been observed, although predominantly morning onset.Morning onset: 6:00 −12:00 am-.Nighttime/early morning onset: 00:00 −6:00 am).Other studies did not find any specific time preference for attack onset or the time preference is closer to the early afternoon.In pediatric population predominately in the afternoon or morning, related to school related stress. In the elderly, predominantly at night.	Triggers.Stress related to work can be more pressing in the morning or early afternoon.Differences in the circadian pacemaker.The chronotype (morning/evening) is associated with attack onset respectively.Insomnia.Sleep disturbances happening the night prior to the attack are associated with morning onset.	The hypothalamus and, specially, the suprachiasmatic nucleus, are important regulators of sleep and circadian mechanisms that occur during an attack.	Higher morning plasma cortisol levels are linked to circadian rhythmicity.	(29,–37)
TTH	No predominant day or nighttime.	–	–	–	(36,38)
CH	Predominantly night attacks, with great variability.Studies have reported times of 9pm −11pm, and also during midnight, 2am and early morning.	Daytime naps can be triggers but nocturnal sleep has been reported to induce attacks in 80% of patients.Lay down after a stressful situation has also been reported as a trigger.	The suprachiasmatic nucleus (SCN), positioned in the anterior of the hypothalamus adjusts the circadian clock to consider fluctuations exhibited in light is the main brain structure involved in CH attacks onset.Light is identified by rod and cone photoreceptors and intrinsically photosensitive retinal ganglion cells (ipRGCs). IpRGCs recognize light and transmit signals via the retinohypothalamic tract to the SCN, which lead to induced expression of clock circadian genes and related changes to the circadian rhythm.Moreover, activation in ipsilateral inferior hypothalamic grey matter has been observed in PET studies in patients with CCH and active pain.	Genes involved in circadian rhythm, namely, CLOCK, HCRTR2 and PER3, may play a role in CH attack onset.Expression of PER1 and PER2 CLOCK genes which are involved in the circadian rhythm.Two recently studied genome-wide association studies (GWAS) have identified four loci, two of which involve genes associated with circadian rhythm which are the MER proto-oncogene, tyrosine kinase, and four and a half LIM domains 5.	(39,–52)

Abbreviations: TTH: Tension-Type Headache; CH: Cluster Headache; PET: Positron emission tomography; –No data; Ref: references.

Table 3.

Attack presentation regarding onset happening in bouts in primary headache disorders.

Bouts	Predominant season	Seasonal /Circannual mechanisms	Seasonal /Circannual brain MRI structures involved	Seasonal genes/mediators	Ref
Migraine	Regarding seasonal variability they are less strong compared to circadian rhythmicity.The light season being the most common time for attacks to occur but is mostly relevant in patients with MA, according to Norwegian studies. Peaks in November to January were observed as well as a nadir in July (13,22), while other studies have pointed towards autumn and spring.	Changes in light. Patients with MA can be triggered by light changes.Changes in triggers.Sleep routine during light season, school stress and allergic rhinoconjunctivitis in the springtime -specially in children-, play a role in seasonal/circannual mechanisms.Moreover, seasonal variability has been associated with more cranial autonomic symptoms.	The hypothalamus, specifically the suprachiasmatic nucleus, similar to circadian rhythmicity, is vital in seasonal/circannual pattern.Moreover, the pineal gland, responsible for releasing melatonin and controlled by the hypothalamus, might also play a role.		(4,53,–56)
TTH	No predominant season time	–	–	–	–
Cluster Headache	Attacks occur in a circannual pattern, predominantly during spring and autumn, with summer, generally having lower reports of CH bouts.	Photoperiodism, changing of daylight length.Bouts tend to occur based on daylight patterns annually. Fluctuations in daylight length has shown to increase onset of cluster period, shortly succeeding the longest and shortest days of the year.Climate conditions and patterns had a differing effect on cluster periods. Previous cold or warm periods may shape the onset of cluster attacks.	Hypothalamus. In the anterior section of the hypothalamus, a detection of increased grey matter volume, ipsilaterally, was recognized in ECH and CCH studied patients, compared to the control group. The location in which the irregularities were seen, in the suprachiasmatic nucleus is linked to biological patterns and rhythms - further indicating and giving rise to the circannual phenomenon in CH.	Vitamin D deficiency . It is prevalent amongst CH patients. Some studies have shown that patients with lower serum vitamin D levels tend to have cluster attacks winter to spring.	(40,42,44–52,58)

Abbreviations: TTH: Tension-Type Headache; CH: Cluster Headache; MA: Migraine with Aura. Ref: references.

Table 4.

Disease characterization based on age of onset of primary headache disorders.

Age	Type of Study	Age of onset	Mechanisms/explanations underlying age of onset	Authors, year / country (Ref)
Migraine	Cross-sectional, Survey.	The peak incidence based on age of onset: 20 to 24 years in women and 15 to 19 years in men.The median age of onset: 25 years in women and 24 years in men.	Environmental factors. The higher prevalence of migraine among individuals with lower income may indicate the impact of environmental factors on both the initiation and persistence of the disease. Genetic influence. The observation that a younger age of migraine onset in affected individuals predicts familial clustering of migraine suggests a potential genetic influence on the onset or persistence of migraine during early life.	Stewart et al., 2008 / USA (59)
TTH	Cross-sectional	Mean age of onset: 29.1 years (29.8 years in men and 28.5 years in women).Median age of onset: 25 years (30 years in men and 24.5 years in women)	Not specified.	Taga et al., 2015 / Italy (60)
CH	Cross-sectional	Mean age of onset: 29.7 years in men and 30.3 years in women.	Sex-dependent endocrine and/or genetic regulatory mechanisms, possibly of hypothalamic origin, are likely to be involved, along with environmental and related to changes in lifestyle.	Ekbom et al., 2002 / Sweden (61)

Abbreviations: TTH: Tension-Type Headache; CH: Cluster Headache. Ref: references.

Table 5.

Disease characterization based on the evolution over time of primary headache disorders.

	Type of Study	Ages (years)	Follow up period (years)	Population (initial, follow up)	Headache Evolution	Authors, year/ (Ref)
Migraine	Retrospective cohort study	<18	n/a	359	* Children (≤12 yr) having shorter duration (<4hr, 72% vs. 62%), less bilateral pain (78% vs. 82%), more nausea (81% vs. 70%), and vomiting (52% vs. 32%) compared to adolescent (>12 yr).	Wilcox et al., 2018 (62)
	Retrospective cohort study	16–80	n/a	1009	* 50 + age group showed a “lesser acute migraine attack” showing greater ability to function during headache attack.	Kelman, 2006 (63)
	Cohort follow up study	11.6 ± 3.1	10	142, 84	46%, migraine persists74%, TTH14%, migraine free	Galinski et al., 2015 (64)
	Cohort follow up study	2–15	25	118, 88	33%, remission41%, retained diagnosis26%, evolved into different headache (10% of migraine to TTH, 5% of TTH to migraine)	Lopes et al., 2022 (65)
	Follow up of nationwide, community-based prevalence study	18–65	5	5323, 3001 (migraine, 438)	16% remission43% retained diagnosis of migraine6% transition to probable migraine 12% transition to probable TTH23% transition to TTH	Oguz Akarsu et al., 2020 (66)
TTH	Follow up of nationwide, community-based prevalence study	18–65	5	5323, 3001 TTH, 266)	29% remission32% retained diagnosis of TTH18% transition to probable TTH6% transition to probable migraine15% transition to migraine	Oguz Akarsu et al., 2020 (66)
TTH	Retrospective study	6–18	n/a	989 (241, TTH)	* Comparing young children (6–12 yr) and adolescents (13–18 yr): No differences in frequency, intensity, laterality, characteristics of pain	Genizi et al., 2021 (67)
CH	Prospective observational study	29–82	5.0–15.7	42	* 33%, remission* Mean age of remission: 42 yr	Lee et al., 2018 (68)
Hypnic headache	Retrospective	Not available	n/a	40	* Age onset: 44–86 years old* Time onset: 01:00 to 5:30AM	Tariq et al., 2016, (69)

Abbreviations: TTH: tension-type headache. CH: Cluster Headache.

Attacks presentation

Attack duration

The duration of the headache attack is currently defined by the time between pain initiation and termination, which differs among primary headache disorders (4).

Migraine

The ICHD-3 states that the duration of a migraine attack ranges between 4–72 h (4). However, the average duration for treated migraine attacks ranges between 30–42 h with a large heterogenicity (7). Migraine patients suffer from longer attacks than other headache types (8). Besides that, attack duration differs regarding sex and migraine type — episodic (EM) vs chronic migraine (CM) — (7,9). Studies have shown a significantly longer attack duration in women compared to men, especially in perimenstrual migraine attacks (10). The median duration for patients with EM under 50 years old was lower in men than women, in both non-perimenstrual and menstrual attacks (7). Moreover, median headache duration was longer for patients of all ages with CM— in which it might be more difficult to define a beginning and an end of the attack due to a certain degree of continuous pain—, patients with medication overuse headache, and attacks in women, averaging 44.4 (17.9–79.0) hours. This was followed by non-perimenstrual attacks in women (7). The longer attack duration in patients with the chronic subtype may indicate that sensitization mechanisms can drive the differences in attack duration between different patient groups. Deciphering to what extent chronobiological variation as opposed to degree of sensitization contributes to duration of attacks can be difficult to elucidate, although central and peripheral mechanisms have been linked to attack duration.

At a peripheral level, it has been proposed that variations in estrogen levels during menstruation may influence attack duration in women by affecting brain excitability (11). At a central level, changes in brain function such as electroencephalography (EEG) slowing and asymmetry of the alpha frequency with a negative correlation with alpha peak frequency, and activation of anterior hypothalamic structures seen through MRI images have been associated with longer attack duration (12,13). Moreover, higher levels of vascular inflammatory markers such as pentraxin-3 (PTX-3) levels have been found in individuals with shorter attack duration (<12 h) (14). Several nitric oxidase synthase gene polymorphisms have been associated with migraine risk and the G10 T (intron 23) genotype specifically has been associated with longer attack duration while the endothelial nitric oxidase synthase G894 T TT genotype was more common in migraine patients with attack duration longer than 24 h (15,16). Additionally, polymorphisms in oxidative stress related genes have also been associated with migraine attack duration including rs1050450 in the Glutathione Peroxidase 1 (GPX1) gene (17) with putative anti-oxidative activity. Though genetic links have been found to attack duration, the influence of medication usage and sensitization due to chronicity on attack duration cannot be overlooked. Many genetic studies have not been replicated and show conflicting results such as the endothelial nitric oxidase G894 T genotype (16). Additionally, many of the studies did not take medication usage and migraine chronicity into account. Chronobiology is likely to have less influence on attack duration than on timing of attacks. Therefore, a complex interplay of peripheral and central biological, as well as environmental factors with an impaired control of start-stop mechanisms, including higher inflammation, hormonal fluctuations and polymorphisms in oxidative stress genes, sensitization, and medication use likely underlies a longer duration of migraine attacks.

Tension-type headache

The ICHD-3 states that the duration of tension-type headache (TTH) lasts from 30 min to seven days (4), relating to patients with episodic TTH. However, in patients with chronic TTH the duration ranges between hours to days or unremitting (4).

Regarding the pathophysiological mechanisms underlying the duration of the attacks in TTH, the literature is scarce (18,19). Treatment of the myofascial trigger point leads to reduction of the nociceptive input to the caudal trigeminal nucleus and therefore central sensitivity decreases, resulting in an improvement in TTH duration (20,21).

The presence of a TTH nocturnal onset might point towards other comorbid conditions such as sleep apnea or bruxism in which have been reported to be associated with frequent episodic TTH, without an effect on attack duration or chronobiology (22,23).

Moreover, in TTH, alpha2-adrenergic mechanisms may be the underlying pathophysiology (24). Therefore, it is plausible to hypothesize that targeting central sensitization through peripheral treatments aimed at these trigger points in TTH, along with modulation of alpha2-adrenergic mechanisms, may contribute to reducing TTH duration.

Cluster headache

Cluster headache (CH) attack duration, typically described as lasting 15–180 min (4), exhibits longer duration in women with migraine associated symptoms . However, to date, there is no clear evidence of the peripheral or central mechanisms implicated in CH attack duration.

Hypnic headache

Hypnic headache attacks last from 15 min to up to 3–4 h (4). This duration is like that of CH however, they are not associated with cranial autonomic symptoms or restlessness.

Attack onset regarding circadian rhythmicity

The onset of a headache attack refers to the moment when the first headache-associated symptoms appear. The onset of these initial symptoms may be determined by the circadian rhythm among certain primary headache disorders (4).

Migraine

Migraine attacks may follow a diurnal rhythmicity between 6:00–12:00am, although several studies have either not found a specific diurnal preference or had predominance of attacks in the early afternoon or night time (29–33). In patients over 55 years old they commonly occur during the night.

Regarding the factors underlying the diurnal rhythmicity of migraine attacks, the occurrence of environmental triggers throughout the day, such as variations of light, and the more extreme morning and evening chronotype — individual variations in preference and performance across different times of the day — (32), are associated with attack onset (35). Moreover, insomnia or sleep problems the night prior to the attack are associated with morning onset though it is unclear whether it could be a prodromal symptom . Biological mechanisms such as a morning rise in cortisol levels and a potentially different setting of the circadian pacemaker among migraineurs might play a role in diurnal rhythmicity (34). Among brain structures involved, hypothalamic activation is seen during the pre-ictal phase of migraine . The most important neuronal center for controlling the biological clock is in the hypothalamus, known as the suprachiasmatic nucleus (SCN), which helps attune the molecular clocks throughout the body based on outside stimuli such as light exposure and lifestyle. Therefore, circadian rhythmicity in migraine patients is influenced by triggers, chronotype and hypothalamic activation, correlating with the timing of migraine attacks.

Tension-type headache

In TTH no time preference of headache attack has been identified nor linked to chronotype . Moreover, limited circadian data exist . In short, the mechanism of the chronobiology of the TTH attack has not yet been elucidated.

Cluster headache

In patients with CH attacks that occur at night, generally between 9pm and 2am which can be detected by actigraphy, they have a more specific pattern compared to migraine (38,–41). Moreover, in patients with CH daytime naps, nocturnal sleep and lay down after a stressful situation have been reported as triggers, pointing towards the hypothalamus governing the attack biology, especially in patients noting diurnal rhythmicity that reported sleep as an attack activator (42). Therefore, concerning the pathophysiological mechanisms underlying CH, the suprachiasmatic nucleus (SCN) plays a key role in adjusting the circadian clock to consider fluctuations exhibited in light received by the retina (43). Cluster headache (CH) is associated with REM sleep, often occurring 90 min after sleep onset, coinciding with the first REM phase and linked to orexinergic system fluctuations (6). A Positron emission tomography (PET) study revealed CCH patients in active pain state compared to control patients had activation in the ipsilateral inferior hypothalamic grey matter (44). Although migraine also has hypothalamus involvement, it is believed to be one of the key factors regarding circadian rhythm in CH. Regarding other mediators and genes involved in headache onset, a number of studies explored genes identified to have a role in circadian rhythm, namely, CLOCK (45,46), which is central to the maintenance of circadian rhythms; HCRTR2 which plays a role in sleep regulation and the stabilization of wakefulness (47,48); and PER3 component of the circadian clock, contributing to the regulation of sleep-wake cycles. Moreover, two recent genome-wide association studies have identified four loci, two of which involve genes associated with circadian rhythms . These genes are the MER proto-oncogene, tyrosine kinase (MERTK), and four and a half LIM domains 5 involved in cellular processes like regulation of immune responses and signal transduction . A relevant region on chromosome 2 is located with an intronic area of the MERTK gene. Essentially, MERTK activates the cAMP-responsive element binding protein (CREB) pathway, which is vital in the regulation and control of the light entrainment and timing of the SCN, which is a key element in CH biology. Collectively, the pathophysiology of CH onset involves nocturnal timing linked to circadian rhythms, with the suprachiasmatic nucleus in the hypothalamus playing a pivotal role, alongside genetic factors like CLOCK, HCRTR2, PER3, MER proto-oncogene, tyrosine kinase, and FHL5, influencing sleep regulation, immune responses, and neural activation.

Hypnic headache

Headaches occur at least four nights/week, usually at a consistent time each night (4).

Attacks onset regarding infradian rhythmicity

The initiation of a headache bout is the time when the first attack of a group of attacks occurs. Attack onset may be determined by the infradian rhythm among certain primary headache disorders (4).

Migraine

In addition to diurnal rhythms, infradian rhythms characterized by seasonal variation also play a role in the frequency and severity of migraine attacks and disease progression . The seasonal fluctuation in attack frequency might be attributable to changes in the presence of attack triggers (stress/work) throughout the year . Moreover, a higher incidence of migraine with aura attacks during light seasons has been reported, highlighting a potential connection to light variations as well as with temperature . Besides that, pure menstrual migraine with or without aura occurring in a predictable pattern exclusively in the perimenstrual period (from −2 to +3 days), and menstrual-related migraine with or without aura occurring both perimenstrual and at other times of the menstrual cycle also highlight the importance of the infradian rhythmicity in migraine (4).

Regarding the underlying pathophysiological mechanisms, the brain structures involved in migraine, specifically the sensitivity of the hypothalamus to light and behavior also provides a strong connection to seasonal variability. The pathophysiology of menstrual migraine is thought to be primarily linked to hormonal fluctuations, especially the decline in estrogen levels preceding menstruation which modulates pain perception and inflammatory responses resulting in a heightened sensitivity to migraine triggers. This sensitivity can lead to the activation of various pathways in the brain associated with migraine attacks, such as cortical spreading depression and trigeminovascular system activation (4). Therefore, seasonal variations influence migraine frequency likely due to changes in trigger presence such as stress and light exposure but also due to hypothalamic sensitivity to light and brain structures involved in migraine and hormonal changes implicated in these infradian rhythms.

Tension-type headache

The evidence supporting the cyclic nature of tension-type headaches remains insufficient. To date, the relationship between infradian rhythmicity and TTH evolution is unknown.

Cluster headache

In CH, attacks occur with an infradian circannual pattern as they follow the same onset pattern annually, especially during spring and autumn with the lowest reported CH bouts in summer (39,41,57). Photoperiodism, changing of daylight length, and bouts tend to occur based on daylight patterns annually (57). Fluctuations in daylight length have been shown to increase the onset of cluster period, shortly succeeding the longest and shortest days of the year (70). Climate conditions and patterns had a differing effect on cluster periods. Previous cold or warm periods may shape the onset of cluster attacks (70). Moreover, patients tend to report cluster bouts during November and fewer occurrences of cluster during the summer months, with greater daylight (42). Additionally, some evidence shows that there are greater CH populations further away from the equator (71). This further alludes to the influence of daylight hours in the prevalence of cluster and thus, the circadian rhythm is pivotal in the involvement of CH pathophysiology (72).

In CH, in the anterior section of the hypothalamus, the SCN, a detection of increased grey matter volume, ipsilaterally, was recognized in episodic CH (eCH) and chronic CH (CCH) studied patients, compared to the control group, further indicating and giving rise to the circannual phenomenon in CH (73). Apropos the SCN, its relationship with light offers interesting information. Illumination passing through the retina influences the SCN (74). Light is detected via cone and rod photoreceptors Furthermore, intrinsically photosensitive retinal ganglion cells (ipRGCs), which are sensitive to blue light further detect external light and transmit signals through the retinohypothalamic (RHT) tract to the SCN (74). After light signals have been received, SCN neurons are activated and thus, induce the expression of clock genes PER1 AND PER2, which are involved in the circadian rhythm and thus, subsequent changes in the circadian rhythm (75).

Among mediators, lower vitamin D is prevalent amongst CH patients with attacks from Winter to Spring (58) although no correlation has been found between CH and three SNPs in vitamin D receptor gene (58).

The characteristics of the attack regarding duration and time onset and bouts, as well as possible pathophysiological explanations underlying specific duration of the attacks are included in Tables 2 and 3.

Disease characterization

Age of onset

Migraine

The one-year prevalence of migraine is 15% in the general population, with a female-to-male ratio of 3:1 (76). Half of migraine patients report migraine onset before the age of 25 (median age of onset of 25 years in women and 24 years in men) (59). There is an association of early onset with higher attack frequency in the long-term, so it is considered a negative prognostic factor (77). Migraine prevalence rates increase in girls from puberty onward (78). Although the specific interplay and mechanisms between hormones and the age of migraine onset are complex and incompletely understood, there is evidence that hormonal factors, especially estrogen fluctuations, may influence migraine onset and remission (79). Moreover, migraine has a strong familial aggregation, with twin and family studies estimating its heritability at 35%- 60% (80).

Tension-type headache

The one-year prevalence of episodic TTH and chronic TTH is estimated at 38- 85%, and 0.9–2.2%, respectively and the peak prevalence is estimated at age 35–39 (81,82). Age of onset does not seem to differ between men and women (60) while TTH prevalence tends to be slightly higher in women with a female-to-male ratio of 1.2:1 (83). This points to a lower influence of hormones in TTH compared to migraine.

According to two twin studies, the heritability of TTH varies with the presence of concomitant migraine, with a higher heritability in those without concomitant migraine (84). However, in contrast to genetic research on migraine, specific genes predisposing to TTH are unknown, and age of onset in relation to family history has not been studied so far. However, an onset at > 50 years of age is considered a red flag for secondary headache, similarly to other primary headache conditions (83).

Cluster headache

The one-year prevalence of CH is estimated at 53 per 100,000 and males are predominantly affected with the overall sex ratio being 4:1 (male to female) (61). Numerous studies have reported mean age of onset, ranging from 27.2 to 33.9 years (85,86). Age of onset is younger for episodic than for chronic CH and tends to be younger in men (61). Reported age of diagnosis shows 6–9 years of delay from age of onset (85).

Family and twin studies have long suggested a genetic basis of CH, which has been confirmed by recent Genome-wide association studies (GWAS) analyses (49,50); whether genetic determinants influence the age of onset of CH still needs to be investigated.

Several studies indicate a high prevalence of cigarette smoking in CH patients, linking smoking history to an earlier age of onset (87). A Korean study reported a significantly lower age at onset in the never-smoker group compared to the ever-smoker group (27.1 ± 12.9 vs. 30.6 ± 10.9, p = 0.024) (87). An analysis from the United States Cluster Headache Survey indicated that patients without tobacco exposure were significantly more likely to develop CH at ages 40 and younger, while the exposed sufferers were significantly more likely to develop CH at 40 years and older (88). This suggests that patients developing CH at younger age without tobacco exposure have a more innate genetic susceptibility, while in patients developing CH at an older age, toxicity of tobacco exposure altering hypothalamus-based neurotransmitter function might play a more important pathophysiological role (87,88). Table 4 includes disease characterization based on age of onset.

Evolution of primary headache disorders

Migraine

The characteristics and clinical features of migraine vary with age (7,62). The duration of migraine attacks in children is shorter than in adolescents and adults, often bilateral, and accompanied by vomiting and nausea (62). Children with migraine are more likely to have experienced infantile colic than those without migraine (73% vs. 27%) (89). Longitudinal studies of 10 to 25 years in pediatric migraine show a decrease in frequency, duration, and intensity of attacks with a remission rate of 14–35% during the follow-up period (64,65). As individuals transit from adult to elderly lesser migraine features and better functioning during headache attacks are observed (63). Moreover, the patterns of headaches may shift slightly towards the back of the head or exhibit more bilaterally, as well as happening at night (90) or having headache with TTH features (8,65,66). Additionally, the emergence of migraine onset during the night appears to be an age-related feature, appearing in the course of the disease (30).

In migraine, natural rhythms appear to worsen as the disease becomes chronic in some patients, losing the pattern, and conversely, when properly treated, they improve and there is a lower incidence of attacks, possibly causing an epigenetic regulation of these regulatory centers (91).

Tension-type headache

During childhood, the prevalence of tension type headache varies highly depending on age. The prevalence increases with age, 6–38% in preschoolers, 38–50% in school aged children and 75% in adolescents (92). However, there are no differences between children and adolescents in frequency, intensity, laterality, characteristics of pain (67). After the peak prevalence at 30–39 years, the frequency of TTH tends to decrease as age increases (93). They typically present with bilateral and moderate intensity, lacking distinct features. It is known that TTH exhibits a higher remission rate than migraine as individuals transition from adolescence to adulthood (90).

Cluster headache

A long-term follow-up of untreated patients showed decreased CH features including side-locked unilaterality, autonomic symptoms and diurnal rhythmicity and 33% remission at mean age of 42.3 years (range of 27–65) (68).

Other primary headaches

Although only limited data were available for evolution of other primary headaches, most showed a high remission rate over time (Table 5).

Importance of time in headache: Therapeutics and research

A detailed understanding of chronobiology is required to both accurately phenotype and diagnose primary headache disorders, and aid in the identification of secondary pathologies. As described in Tables 1–4, timing is both critical in positive diagnosis and consideration of ‘red-flags’ (5). In eCH, an understanding of the circannual pattern will not only reduce treatment burden, but modelling periods of chrono-risk may also provide the opportunity for precision management (6). Moreover, understanding the natural evolution of migraine allows us to tailor therapy to an individual's age.

Time may also have an impact on the efficacy of therapy in migraine. In a randomized trial of exercise in migraine, synchrony of the timing of the intervention with exercise performance determined efficacy (94). There are conflicting clinical reports on the impact of timing of onabotulinumtoxinA injection on efficacy (95,96). The relationship between chronobiology and efficacy of therapy is largely unexamined in trial design. Moreover, “Time is brain,” advocating for prompt migraine treatment, leads to better outcomes. Earlier triptans use and shorter CM durations predict better acute and positive onabotulinumtoxinA responses (97,98). Additionally, the APPRAISE trial showed that early erenumab treatment in EM yields enhanced, lasting efficacy and better safety and adherence compared to standard oral preventatives (99).

Finally, chronobiology is pivotal in research (Table 6). Genetic studies have identified CLOCK gene loci in CH, while pre-clinical studies have provided insights on the effect of treatment on circadian gene expression (45,46). Clinically, understanding the cycle of disease is pivotal to the success of clinical trials (100).

Table 6.

Summary of attack rhythmicity, age of onset, evolution and possible pathophysiology in prevalent primary headache disorders.

	Time in relation to attack			Time in relation to disease		Pathophysiology
	Attack duration	Attack Onset	Bouts	Age of onset	Evolution	Pathophysiology
Migraine	4–72 h	Variable; predominantly diurnalOlder patients may have night attacks	Variable dependent on triggers. Light seasons in migraine with aura.	Peak: 20–24 years	Decrease in frequency, duration and intensity over time. Increase in duration in the elderly	Hormonal fluctuations, brain changes in function, genetic factors, inflammation, oxidative stress
TTH	30 min- 7 days	Not circadian rhythm	Not ultradian rhythm	Peak: 30–39 years	Higher remission rate compared to migraine	Myofascial trigger, adrenergic mechanism, limited understanding
CH	15–80 min	9pm-2am	Spring and autumn	Mean: 27–33 years	Decreased features over time, remission rate	Hypothalamic involvement, circannual pattern, genetic factors, smoking

Abbreviations: TTH: Tension-Type Headache. CH: Cluster Headache.

Conclusions

The exploration of time in headache disorders unveils intricate patterns intertwined with the attack and disease evolution in primary headaches. From the diurnal rhythms guiding migraine attacks to the circannual fluctuations defining CH bouts, understanding these temporal intricacies is indispensable for accurate diagnosis, tailored treatment, and precision management. In fact, the use of preventive treatments which help to restore these timing processes in headache disorders should not be delayed.

This comprehensive review underscores the significance of time in headache in primary headache disorders unraveling their pathophysiological underpinnings. As we delve deeper into the timing processes of headaches, novel insights emerge, offering promising avenues for improved clinical research designs and personalized therapeutic interventions, which may enhance efficacy and precision in our approach to patient care, marking a significant advancement in headache management.

Clinical implications

The exploration of chronobiology reveals intricate patterns in attack duration, onset, disease age of onset, and evolution in primary headaches, from diurnal rhythms guiding migraine attacks to circannual fluctuations defining cluster headache bouts.

Migraine attacks exhibit significant diurnal and infradian rhythms, influenced by melatonin levels, light sensitivity, and hypothalamic activation; several gene polymorphisms have been associated with migraine attack duration.

Tension-type headache lacks clear chronobiological patterns, with limited understanding of its underlying mechanisms.

Cluster headache displays a distinct circannual pattern, with attacks often occurring at night and relevant involvement of the hypothalamus.

Understanding temporal intricacies is indispensable for accurate diagnosis, tailored treatment, and precision management in primary headache disorders.

Footnotes

Acknowledgements

We thank the International Headache Society (IHS) board for organizing the International Headache Academy of the International Headache Society (IHS-iHEAD) working group.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research,authorship,and/or publication of this article: A.G.M. reports that within the prior 36 months has received speaker honoraria from TEVA,Lilly and Altermedica.

J.C.R reports in the last 36 months he has received honoraria for education presentations for Abbvie,Novartis and Viatris. He has served on medical advisory boards for Pfizer,Viatris and Lilly. His institution has received funding for research grants,clinical trials and projects supported by the International Headache Society,Brain Foundation,Lundbeck,Abbvie,Pfizer and Aeon.

F.H.,F.J.O.,H.G.,T.C.S.,M.C.D.,U.A.,H.H.,J.M.K.,reports no conflict of interests.

K.S.L reports personal fees from Teva and Acticor Biotech.

E.C. has received received honoraria from Novartis,Chiesi,Lundbeck,Medscape.

P.P.R. reports that within the prior 36 months,having received honoraria as a consultant and speaker for: AbbVie,Amgen,Biohaven,Chiesi,Eli Lilly,Lundbeck,Medscape,Novartis,Pfizer and Teva. Her research group has received research grants from Novartis,Teva,AbbVie,EraNET Neuron,RIS3CAT FEDER,AGAUR,ISCIII,International Headache Society;has received funding for clinical trials from Alder,Amgen,Biohaven,Eli Lilly,Lundbeck,Novartis,Teva. She is the Honorary Secretary of the International Headache Society. She is a member of the Clinical Trials Guideline Committee of the International Headache Society. She serves as an associate editor for Cephalalgia,Headache,The Journal of Headache and Pain,Neurologia,and Revista de Neurologia . She is the founder of

. P.P.R. does not own stocks from any pharmaceutical company.

Funding

The authors disclosed receipt of the following financial support for the research,authorship,and/or publication of this article: No funding was received to write this paper. Funding was received from the Instituto de Salud Carlos III (ISCIII),European Union (ESF+),and FEDER funds according to O.A.,M.P. de 13 de diciembre de 2023 through a Juan Rodes Fellowship (JR23/00005) and national research project (PI24/01085) to A.G.M.,and Juan Rodes Fellowship (JR23/00065) to E.C. K.S.L. is participant in the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health at Charité (BIH).

Author's contribution

A.G.M. and P.P.R. made substantial contributions to the conception,design and revised the work. J.C.R.,F.H. and E.C. supervised the main working groups. The rest of authors drafted the work. All authors approved the submitted version.

ORCID iDs

Alicia Gonzalez-Martinez

Jason C. Ray

Faraidoon Haghdoost

Usman Ashraf

Heewon Hwang

Edoardo Caronna

Patricia Pozo-Rosich

Tuba Cerrahoğlu Sirin

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Time and headache: Insights into timing processes in primary headache disorders for diagnosis,underlying pathophysiology and treatment implications

Abstract

Background

Objective

Methods

Results

Conclusion

Keywords

Introduction

Methods

Results

Attacks presentation

Attack duration

Migraine

Tension-type headache

Cluster headache

Hypnic headache

Attack onset regarding circadian rhythmicity

Migraine

Tension-type headache

Cluster headache

Hypnic headache

Attacks onset regarding infradian rhythmicity

Migraine

Tension-type headache

Cluster headache

Disease characterization

Age of onset

Migraine

Tension-type headache

Cluster headache

Evolution of primary headache disorders

Migraine

Tension-type headache

Cluster headache

Other primary headaches

Importance of time in headache: Therapeutics and research

Conclusions

Clinical implications

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

Author's contribution

ORCID iDs

References