Circadian Features of Cluster Headache and Migraine: A Systematic Review, Meta-analysis, and Genetic Analysis

Abstract

Background and objectives: Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.

Methods: A librarian created search criteria in MEDLINE Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Separate from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWASs) of headache, a nonhuman primate study of CCGs in a variety of tissues, and recent reviews of brain areas relevant in headache disorders. Altogether, this allowed us to catalog circadian features at the behavioral level (circadian timing, time of day, time of year, and chronotype), systems level (relevant brain areas where CCGs are active, melatonin and corticosteroid levels), and cellular level (core circadian genes and CCGs).

Results: For the systematic review and meta-analysis, 1,513 studies were found, and 72 met the inclusion criteria; for the genetic analysis, we found 16 GWASs, 1 nonhuman primate study, and 16 imaging reviews. For cluster headache behavior, meta-analyses showed a circadian pattern of attacks in 70.5% (3,490/4,953) of participants across 16 studies, with a clear circadian peak between 21:00 and 03:00 and circannual peaks in spring and autumn. Chronotype was highly variable across studies. At the systems level, lower melatonin and higher cortisol levels were reported in cluster headache participants. At the cellular level, cluster headache was associated with core circadian genes CLOCK and REV-ERBα, and 5 of the 9 cluster headache susceptibility genes were CCGs. For migraine behavior, meta-analyses showed a circadian pattern of attacks in 50.1% (2,698/5,385) of participants across 8 studies, with a clear circadian trough between 23:00 and 07:00 and a broad circannual peak between April and October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in participants with migraine and even lower during an attack. At the cellular level, migraine was associated with core circadian genes CK1δ and RORα, and 110 of the 168 migraine susceptibility genes were CCGs.

Discussion: Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiologic foundation for circadian-targeted research into these disorders.

Trial registration information: The study was registered with PROSPERO (registration number CRD42021234238).

Figure 1. Circadian Rhythms

(A) The 24-hour circadian transcriptional-translational feedback loop. Full gene names: CLOCK = circadian locomotor output cycles kaput; NPAS2 = neuronal PAS domain protein 2; BMAL1 = brain and muscle ARNT like 1; PER = period; CRY = cryptochrome; REV-ERB = reverse strand of erb; ROR = retinoid acid–related orphan receptor; CK1 = casein kinase 1; GSK3 = glycogen synthase kinase 3. (B) The suprachiasmatic nucleus (green) acts as a master clock, coordinating the clocks of other brain areas and other organs through neuronal connections and hormones (especially corticosteroids and melatonin). (C) Peak timing of physiologic processes and neurologic diseases and chronotype sleep patterns.

Figure 2. Quality Assessment

NIH quality assessment tools for case series studies (top), case-control studies (middle), and observational cohort and cross-sectional studies (bottom). Color codes: green indicates yes, not applicable, good quality rating, and fair quality rating; yellow indicates unclear or cannot determine; red indicates no or poor quality rating. One study (Romo-Nava 2010) had headache data that received a poor quality rating (although this rating is not a reflection of its other data); this study was excluded from the systematic review and meta-analysis. Details are available in eTable 2 (links.lww.com/WNL/C709).

Figure 3. Flow Diagrams for Each Phase of This Study

GWAS = genome-wide association study; FHM = familial hemiplegic migraine; ICHD1 = International Classification of Headache Disorders, first edition (published in 1988). *Ten studies measured non-neurologic features in cluster headache or migraine, specifically the circadian features of the heart rate, blood pressure, reflexes, epinephrine, sodium, cyproheptadine, or tweets about headaches.

Figure 4. Meta-analysis of Predictable Timing of Participants With Cluster Headache for (A) the Presence or Absence of a Circadian Pattern, (B) the Circadian Pattern of a Participant Hour by Hour, or (C) the Circannual Pattern of a Participant Month by Month

Rayleigh test data (in red) are shown for mean, length, and p value. The average time across all participants (red arrows) was 0.01 hours and 10.61 months or 00:01 on October 19. Both the hour-by-hour and month-by-month data were significantly different between cluster headache and migraine (Watson 2 test p < 0.01). Of note, a single participant could respond once for A but multiple times for B or C. Additional analysis, including bar graphs, circadian 4-hour blocks, circannual seasons, individual contributions from each study, and raw data, is available in eFigures 1 and 2 (links.lww.com/WNL/C704 and links.lww.com/WNL/C705) and eTables 7–9 (links.lww.com/WNL/C709).

Figure 5. Clock-Controlled Genes for Cluster Headache Genes (First Column) and the Specific Tissues in Which They Cycle (First Row)

Tissues from red (prefrontal cortex) to blue (thalamus) were determined to be relevant in the pathophysiology of cluster headache (tissues colored shades of purple were not relevant). For the full uncondensed dataset, see eTable 12 (links.lww.com/WNL/C709). Cbl = cerebellum. *The other brain areas category consists of 3 tissues (habenula, olfactory bulb, and mammillary body) that were not mentioned as relevant in the pathophysiology of cluster headache.

Figure 6. Meta-analysis of Predictable Timing of Participants With Migraine for (A) the Presence or Absence of a Circadian Pattern, (B) the Circadian Pattern of Attacks Hour by Hour, or (C) the Circannual Pattern of Attacks Month by Month

Rayleigh test data (in red) is shown for mean, length, and p value. The average time across all attacks (red arrows) was 14.13 hours and 7.4 months or 14:08 on July 12. Both the hour-by-hour and month-by-month data were significantly different between cluster headache and migraine (Watson 2 test p < 0.01). Of note, a single participant could respond once for A but multiple times for B or C. Additional analysis, including bar graphs, circadian 2-hour blocks, individual contributions from each study, and raw data, is available in eFigures 3 and 4 (links.lww.com/WNL/C706 and links.lww.com/WNL/C707) and eTables 7–9 (links.lww.com/WNL/C709).

Figure 7. Clock-Controlled Genes for Migraine (First Column) and the Specific Tissues in Which They Cycle (First Row)

Given the numerous genes involved in migraine, here we show a subset, namely all migraine genes that cycle in the thalamus, hypothalamus, brainstem, or cerebellum (green and blue). For the full uncondensed dataset, including genes that cycle in only cortical and subcortical areas, see eTable 14 (links.lww.com/WNL/C709). Tissues from red (prefrontal cortex) to blue (thalamus) were determined to be relevant in the pathophysiology of migraine (tissues colored shades of purple were not relevant). Cbl = cerebellum. *The other brain areas category consists of 3 tissues (habenula, olfactory bulb, and mammillary body) that were not mentioned as relevant in the pathophysiology of migraine.