Circadian rhythm and hypothalamus-related symptoms of migraine: A prospective study

doi:10.21203/rs.3.rs-1638529/v1

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Circadian rhythm and hypothalamus-related symptoms of migraine: A prospective study

https://doi.org/10.21203/rs.3.rs-1638529/v1

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Background: Hypothalamic symptoms and circadian rhythm in migraine are controversial。To use WeChat as a survey tool to explore the correlation between hypothalamus-related symptoms and migraine attacks and examine the circadian cycle of migraines.

Methods: This prospective study enrolled migraine patients at the Headache Specialty Clinic, Neurology Department of Shandong Provincial Hospital, from November 2018 to January 2020. Each patient was required to report the migraine attack via WeChat for 3 months. At 08:00 every day, the WeChat mass texting function was used to send an inquiry about migraines in the past 24 h. If yes, a questionnaire was issued to obtain the details. The participants were assigned to the low (LFM) (≤5 days/month) and high (HFM) (>5 days/month) frequency migraine groups.

Results: 162 participants completed the study. A total of 2875 migraine attacks were recorded. The HFM group showed more attacks at night (37.8% vs. 5.7%) and before dawn (25.5% vs. 7.9%) compared with the LFM group, while the LFM group had more attacks in the morning (53.5% vs. 11.7%) (P<0.001). Generally speaking, the two groups showed a reverse attack trend. Yawning was more frequent in the prodromal phase; facial sweating, conjunctival congestion, neck stiffness, photophobia, runny nose, nasal obstruction, and emotional changes were more frequent in the headache phase; inattention and fatigue were more frequent in the postdrome phase (all P<0.001).

Conclusions: HFM and LFM display different migraine attack temporal patterns. Hypothalamus-related non-headache symptoms were present in all phases of migraine attacks. The rates of non-headache symptoms were significantly different in different phases.

migraine

hypothalamus

circadian rhythm

non-headache symptom.

Migraine is a common neurological disorder, but its pathogenesis is poorly understood. Although headache is the most predominant symptom of migraine, migraine includes many non-headache symptoms that are being increasingly recognized [1]. Non-headache symptoms are present in the whole process of a migraine attack and are the most obvious in the prodromal and postdrome phases [1]. The diversity of non-headache symptoms in migraine suggests that multiple parts of the central nervous system are involved in migraine attacks, among which the hypothalamus is one of the most concerning parts [2–6].

The close association between the hypothalamus and migraine is related to its structure and function: 1) neuroendocrine center that links neuroregulation with humoral regulation, 2) regulating center of the autonomic nerve involved in body temperature, food intake, reproduction, circadian regulations, and other activities, 3) involved in the emotional regulation through the relationship with the limbic system, and 4) extensive connections with other brain regions [7]. Thus, the hypothalamus has long been considered to play an important role in migraine attacks and maintenance [8, 9].

Conjunctival congestion, lacrimation, nasal obstruction, runny nose, palpebral edema, and forehead/facial sweating are common autonomic symptoms during migraine attacks [10–12]. The central role of the hypothalamus in autonomic nervous function and homeostasis indicates that it might be involved in the autonomic nervous response of migraine [2, 4]. For many migraine patients, the initial symptom during the attack is the “prodromal symptom” before the headache. The most commonly reported prodromal symptoms before headache are fatigue, inattention, emotional changes, yawning, neck stiffness, phonophobia, and nausea [1, 8, 13–17]. An important hypothesis about the prodromal symptoms of migraine is related to hypothalamic activity [18, 19].

Yawning is an ancient behavior in biological development, involving multiple neurotransmitters, including dopamine [20]. Studies have shown that yawning results from dopamine acting on dopamine receptors on the hypothalamic-pituitary axis [11]. Yawning is one of the most predictive prodromal symptoms of migraine [12]. Therefore, dopamine might play an important role in the early phases of a migraine attack. The hypothalamus may be the source of dopamine in the initial symptoms of migraine [6]. Another common prodromal symptom is neck stiffness. The A11 nucleus in the posterior hypothalamus can inhibit the nociceptive information transmitted by the trigeminal nerve mediated by dopamine D2 and 5HT 1B/1D receptors [21]. If hypothalamic dysfunction occurs in the early phases of migraine, this inhibitory effect will attenuate or disappear, leading to increased nociceptive information transmitted by the trigeminal nerve. The connection between the trigeminal nerve and the C1 and C2 cervical nerves results in neck muscular contraction and stiffness, often considered neck discomforts [22].

The hypothalamus, especially the suprachiasmatic nucleus, controls the circadian rhythms such as sleep-wake, appetite, metabolism, and temperature regulation [23]. Studies have shown that migraine attacks have obvious circadian rhythm patterns, predominantly in the morning and at noon [24]. The circadian rhythm disorders caused by time difference or shift work can easily induce migraine attacks [25]. Still, the above findings remain controversial, and it has been suggested that most migraine attacks have no specific circadian rhythm characteristics [26].

The smartphone is becoming widespread, and the instant chat tool WeChat has the characteristics of being easy to use and allowing smooth communication. It can timely provide the time of migraine attack and related symptoms, reduce recall bias, and has high credibility in the collected data. In this setting, the present study aimed to use WeChat as a survey tool to explore the correlation between hypothalamus-related symptoms and migraine attacks and examine the circadian cycle of migraines. By studying the correlation between migraine and the hypothalamus, it could help to understand the pathogenesis of migraine better and seek new treatment options, providing a basis for further understanding the pathogenesis of migraine.

Study design and participants

This prospective study enrolled migraine patients at the Headache Specialty Clinic, Neurology Department of Shandong Provincial Hospital, from November 2018 to January 2020. The present study was reviewed and approved by the Institutional Review Board of Shandong Provincial Hospital. Before the study, the patients were informed of the study objectives, methods, significances, and risks in detail. The subjects voluntarily participated in the study and gave written informed consent. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

The inclusion criteria were 1) meeting the diagnostic criteria for migraine from The International Classification of Headache Disorders, 3rd edition (ICHD-3) [1], and 2) using the WeChat app function proficiently and being able to timely send and reply to messages. The exclusion criteria were 1) secondary headache, 2) mental illness or history of drug abuse, 3) pregnant women, or 4) < 6 years of education.

Study methods

The WeChat app (Tencent, Shenzhen, China) that was current during the study was version 6.7.3 and was compatible with Android and Apple iOS8+. Each participant was required to scan the WeChat QR code of the investigator’s mobile phone and add the investigator as a friend. Each participant received training on common hypothalamus-related symptoms of migraine. Every day at 08:00 am, the participants were asked whether there was a migraine attack in the past 24 h through the mass texting function of WeChat. If the participant did not reply, the message was sent again in the afternoon on the same day to remind the participant. When a headache occurred, the participants were encouraged to send a message immediately. Regardless of whether headaches occurred, all participants needed to reply to the investigator’s messages. The participants were allowed to take non-steroidal anti-inflammatory drugs to manage headaches, acute triptans, and preventive drugs such as topiramate and flunarizine. When studying the circadian rhythm, according to the research methods of de Tommaso et al. [26], the participants were assigned to the LFM group (duration of headache per month ≤ 5 days) and HFM group (duration of headache per month > 5 days) based on the number of migraine attacks per month.

Outcome measures

Outpatient survey: Two professionally trained headache physicians investigated the general characteristics of the participants, including age and educational level, the course of migraine, monthly headache frequency, visual analog scale (VAS), presence or absence of aura, duration of headache (hours), and menstrual cycle. The VAS score was 0–10 points, and the pain scoring criteria included grades 0–10: 0 indicated no pain, and 10 the most severe pain imaginable; 1–3 points indicated mild and bearable pain, 4–6 points indicated bearable pain affecting sleep, and 7–10 points indicated gradually severe and unbearable pain.

WeChat survey: If the participant reported migraine symptoms on WeChat, an inquiry was made about the onset and ending time of the headache, clinical characteristics such as pain intensity, location of pain, exacerbation or not after exercise, nausea, vomiting, photophobia, and phonophobia, presence or absence of non-headache symptoms such as yawning, neck stiffness, fatigue, and inattention, and autonomic symptoms such as conjunctival congestion, lacrimation, nasal obstruction, runny nose, palpebral edema, and forehead/facial sweating. The attack phase and duration were recorded. The definition criteria of migraine attack [1] were 1) moderate to severe headache (VAS ≥ 4 points), 2) throbbing or swelling pain with a duration of 4–72, 3) accompanied by nausea and/or vomiting, phonophobia, and photophobia, and 4) headaches aggravated by daily activities. The prodromal phase of migraine was defined as 24 h before the migraine-related headache [8]. The postdrome phase of migraine was defined as within 72 h after the migraine-related headache disappeared [14].

Statistical analysis

All statistical analyses were performed with SAS 9.4 (SAS Institute, Cary, NY, USA). The continuous data were presented as means ± standard deviations and analyzed using the independent-samples t-test or analysis of variance. Categorical data were presented as n (%) and analyzed using the chi-square test. Two-sided P-values < 0.05 were considered statistically significant.

Baseline characteristics of participants

A total of 230 migraine patients were recruited, but 32 were excluded because they had no attacks for 3 consecutive months, and 36 were withdrawn because they did not reply to the messages in time. Thus, 162 participants completed the study (Fig. 1). The age range was 18–60 years (mean, 38.5 ± 12.4) years. Among them, 44 were males, and 118 were females. There were 51 participants with chronic migraine (CM), 101 with migraine without aura (MO), 10 with migraine with aura (MA), 16 with menstrual-related migraine (MRM), and seven with pure menstrual migraine (PMM). In the LFM group (n = 93), there were 21 males and 72 females, with an age range of 18–59 (mean, 35.8 ± 9.8) years, and a total of 1039 attacks. In the HFM group (n = 69), there were 15 males and 54 females, with an age range of 18–60 (mean, 40.15 ± 12.24) years, and a total of 1834 attacks. The daily response rate on WeChat exceeded 80%. A total of 2873 migraine attacks were recorded. The general characteristics of the participants are shown in Table 1.

Table 1

Baseline characteristics of the participants
Characteristics	n = 162
Age (years), mean ± SD	38.5 ± 12.4
Males/females	44/118
Migraine type, n (%)
CM	51 (19.1)
MO	101 (62.3)
MA	10 (6.2)
PMM	7 (4.3)
MRM	16 (9.9)
Frequency group, n (%)
LFM	93 (57.4)
HFM	69 (42.6)
Course of headache (years), mean ± SD	7.8 ± 2.5
Attack frequency (days/month), mean ± SD	10.6 ± 6.3
VAS score, mean ± SD	7.3 ± 2.5
CM: chronic migraine; MO: migraine without aura; MA: migraine with aura; MRM: menstrual-related migraine; PMM: pure menstrual migraine; LFM: low-frequency migraine; HFM: high-frequency migraine.

Changes in circadian rhythms

The time distribution results of the migraine attacks according to frequency are shown in Table 2. The HFM group showed more attacks at night (37.8% vs. 5.7%) and before dawn (25.5% vs. 7.9%) compared with the LFM group, while the LFM group had more attacks in the morning (53.5% vs. 11.7%) (P < 0.001). Generally speaking, the two groups showed a reverse attack trend (Fig. 2).

Table 2

Time distribution of the migraine attacks according to frequency
Attack time, n (%)	LFM (n = 96)	HFM (n = 69)	P
Morning	560 (53.5)	214 (11.7)	< 0.001
Afternoon	342 (32.9)	474 (26.0)
Night	54 (5.7)	688 (37.8)
Before dawn	83 (7.9)	458 (25.5)
Note: before dawn: 00:00–05:59; morning: 06:00–11:59; afternoon: 12:00–17:59; and night: 18:00–23:59. LFM: low-frequency migraine; HFM: high-frequency migraine.

Hypothalamus-related symptoms during migraine attacks

In each phase of migraine attacks, there were significant differences in hypothalamic-related non-headache symptoms (Table 3, all P < 0.0001). Yawning was more frequent in the prodromal phase. Facial sweating, conjunctival congestion, neck stiffness, photophobia, runny nose, nasal obstruction, and emotional changes were more frequent in the headache phase. Inattention and fatigue were more frequent in the postdrome phase.

Table 3

Hypothalamus-related symptoms during migraine attacks (n = 2875)
Symptom, n (%)	Prodromal phase	Headache phase	Postdrome phase	P
Inattention	1351 (46.9)	1571 (54.6)	1955 (68.0)	< 0.001
Fatigue	1722 (59.9)	1866 (64.9)	2156 (74.7)	< 0.001
Facial sweating	230 (8.0)	531 (18.5)	144 (5.0)	< 0.001
Palpebral edema	61 (2.1)	172 (5.9)	76 (2.6)	< 0.001
Conjunctival congestion	288 (10.0)	575 (20.0)	115 (4.0)	< 0.001
Yawning	1431 (49.7)	1221 (42.4)	920 (32.0)	< 0.001
Neck stiffness	1283 (44.6)	1361 (47.3)	776 (27.0)	< 0.001
Photophobia	468 (16.3)	1581 (54.9)	441 (15.4)	< 0.001
Runny nose	57 (1.9)	230 (8.0)	29 (1.0)	< 0.001
Nasal obstruction	431 (15.0)	728 (25.3)	141 (4.9)	< 0.001
Emotional changes	1218 (42.4)	2156 (74.9)	1554 (54.1)	< 0.001

Some symptoms of migraine appear to be related to the hypothalamus [18, 19]. The hypothalamus is related to the circadian cycle, but a circadian cycle in migraines is controversial [24, 26]. Therefore, this study aimed to use WeChat as a survey tool to explore the correlation between hypothalamus-related symptoms and migraine attacks and examine the circadian cycle of migraines. The results indicate that HFM and LFM display different migraine attack temporal patterns. Hypothalamus-related non-headache symptoms were present in all phases of migraine attacks. The rates of non-headache symptoms were significantly different in different phases.

Many diseases have specific circadian rhythms. For example, acute myocardial infarction, sudden cardiac death, and ischemic stroke mainly occur in the morning [16]. A study suggested that migraine attacks have circadian rhythms, with the incidence in the morning being higher than in other periods [17]. Another study showed many attacks in the morning and around noon, suggesting a double-peak phenomenon [24]. On the other hand, it has been reported that most migraine patients have no specific circadian rhythms [26]. The present study suggests that migraine does not show a circadian rhythm when considering all participants. But when classified as LFM and HFM, migraine attacks displayed specific patterns. In LFM, the migraine attacks were more frequent from 06:00 in the morning and reached a peak around 08:00–09:00 to decrease gradually in the afternoon, with few attacks between 18:00 and 05:59 the next morning. On the other hand, the trend of the HFM group was opposite to that of the LFM group. The attack rate was lower in the morning, gradually increasing in the afternoon, and the attack rate was higher at night.

Changes in migraine circadian rhythm are closely associated with triggers. Hypersomnia, sleep deprivation, hard light, noise, unpleasant odor, and stress are common triggers of migraines [27]. Between 06:00 and 11:59, in addition to hypersomnia and sleep deprivation, most triggers are present. Especially in Shandong Province, work usually starts at 08:00, so the work pressure is high, which may be one reason for the high incidence of paroxysmal migraine attacks. The incidence of LFM attack is decreased significantly after 18:00, which may be related to emotional relaxation at the end of the workday. Low attack frequency at night and before dawn may be related to sleep. Indeed, sleep is a common strategy to relieve migraines [28].

On the other hand, the frequency of attacks in HFM was relatively high at night and before dawn and might be related to sleep disorders. Most (68%-84%) patients with CM have sleep disorders and report insomnia every day or almost every day [29], while the incidence of insomnia in patients with PM is only 38% [29]. In addition, the incidence of daytime somnolence in migraine, especially CM, was significantly increased [30]. Daytime somnolence in CM might be the reason for the low attack frequency in the morning.

The suprachiasmatic nucleus of the hypothalamus is a key structure that regulates the human circadian rhythm [31]. Thus, the hypothalamus plays an important role in the changes of the circadian rhythm of migraines [2]. The hypothalamus might be involved in the chronic progression of migraine [5], and hypothalamic dysfunction might also cause the change in the circadian rhythm of migraine [32]. Therefore, the interaction between the external environment (i.e., headache triggers) and the hypothalamic circadian rhythm might be the reason for the formation and change of the circadian rhythm in migraine. The differences in circadian rhythms between the LFM and HFM groups were significant, so it was speculated that the change in circadian rhythm might be a sign of migraine chronicity.

Migraine is often accompanied by a variety of non-headache symptoms before and after the onset that also affects the patients’ daily work and quality of life [33]. Hypothalamus-related non-headache symptoms are common in migraine patients, even in children [34]. The present study suggests that autonomic symptoms were obvious in the prodromal and headache phases, especially in the headache phase, mainly manifesting as nasal obstruction, runny nose, photophobia, palpebral edema, and conjunctival congestion. In the postdrome phase, the incidence was significantly reduced. Some non-specific symptoms such as fatigue, inattention, and neck stiffness continued to be higher. Although these symptoms are not as obvious as headaches, they also affect patients’ work and study and often led to disability. Non-headache symptoms of migraine mainly occur in the prodromal and postdrome phases [35], as observed in the present study. Autonomic symptoms such as nasal obstruction and runny nose mainly occur in the prodromal and headache phases of migraine, and the incidence is lower in the postdrome phase. It suggests that the nuclei related to the autonomic nerve of the hypothalamus are mainly activated in the prodromal and headache phases.

The pathogenesis of hypothalamus-related non-headache symptoms remains unclear, and some might be related to hypothalamic neurosecretory function. Neuropeptide Y (NPY) is a neurotransmitter secreted by the hypothalamus and is involved in food intake and appetite regulation, pain, and circadian rhythm [36]. NPY can cause blood glucose fluctuation through appetite regulation, leading to hypothalamic dysfunction, ultimately resulting in the non-headache symptoms of migraine [37]. Orexin (or hypocretins) is another hypothalamic neuropeptide. The secretion of orexin has an obvious circadian rhythm. The secretion increases during wakefulness and decreases during sleep [38]. It is considered to play a central role in the smooth transition between sleep and wakefulness. Orexin can directly stimulate monoaminergic and cholinergic hypothalamic brainstem networks in the locus coeruleus to promote wakefulness [3, 39, 40]. Reduced orexin can lead to sleep regulation disorders such as narcolepsy [41]. Hypothalamic orexin fibers have been confirmed to project directly and indirectly through the gray matters around the midbrain to the trigeminal cervical complex in the brainstem and regulate the conduction of trigeminal nociceptive signals [42]. These neuroendocrine functions might lead to symptoms such as fatigue, emotional instability, and inattention. A generally accepted hypothesis is that symptoms such as yawning and nausea are associated with dopamine, and dopamine receptor antagonists can reverse these symptoms [43], which might be related to that dopamine can act on the active site of the hypothalamic-pituitary axis [44]. Many hypothalamus-mediated migraine-related symptoms might be triggered by a series of persistent nociceptive information from the meninges. These pain signals reach the limbic system and hypothalamus through the spinal trigeminal nucleus, leading to non-headache symptoms [45, 46]. Neurons and nuclei in the hypothalamus receive numerous direct nociceptive inputs through the trigeminohypothalamic tract (THT) [46]. These hypothalamic neurons or nuclei have the functions of regulating body temperature, food and water intake, sleep, and circadian rhythm [47], and are closely associated with autonomic nerves, endocrine, and homeostasis, which result in migraine-related symptoms (such as food desire and loss) such as loss of appetite, fatigue, paresthesia, easy depression, irascibility, and other symptoms [48].

An innovation of the present study was using the social app WeChat to explore the circadian rhythm of migraine attacks and non-headache symptoms related to the hypothalamus. The present study used the LFM and HFM classification instead of paroxysmal migraine and chronic migraine and revealed specific migraine patterns.

Still, the present study has some limitations. First, the present study enrolled 162 patients with 2875 attacks, but the sample size is still small, especially patients with MA and menstrual migraine, so that no related subgroup analysis could be conducted. Second, due to higher requirements on patients’ educational level, older or illiterate patients were not enrolled, which may cause a selection bias.

HFM and LFM display different migraine attack temporal patterns. Hypothalamus-related non-headache symptoms were present in all phases of migraine attacks. The rates of non-headache symptoms were significantly different in different phases. These results might provide some insight into the management of migraines.

HFM

high frequency migraine

LFM

low frequency migraine

THT

trigeminohypothalamic tract

5-HT

Serotonin

ICHD-3

International Classification of Headache Disorders, 3rd edition

chronic migraine

migraine without aura

migraine with aura

MRM

menstrual-related migraine

PMM

pure menstrual migraine

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Shandong Provincial Hospital. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from the patients.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

QD: Software, Formal Analysis, Investigation, Resources, Data Curation, Writing Original Draft Preparation, Writing Review and Editing, Visualization, Project Administration. CC: Conceptualization, Methodology, Supervision, Funding Acquisition. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

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Circadian rhythm and hypothalamus-related symptoms of migraine: A prospective study

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Abstract

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Background

Material And Methods

Study design and participants

Study methods

Outcome measures

Statistical analysis

Results

Baseline characteristics of participants

Changes in circadian rhythms

Hypothalamus-related symptoms during migraine attacks

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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