By Dara G. Jamieson, MD
Clinical Associate Professor of Neurology, Weill Cornell Medical College
The hypothalamus plays a regulatory role in both migraine and cluster headaches. However, the two headache types have distinctive clinical features, characteristic areas of resting state functional connectivity on magnetic resonance imaging, and different genetic chronobiological associations.
Messina R, Sudre CH, Wei DY, et al. Biomarkers of migraine and cluster headache: Differences and similarities. Ann Neurol 2023;93:729-742.
Benkli B, Kim SY, Koike N, et al. Circadian features of cluster headache and migraine: A systematic review, meta-analysis, and genetic analysis. Neurology 2023; Mar 29. doi: 10.1212/WNL.0000000000207240. [Online ahead of print].
The quest for specific headache biomarkers, both imaging and genetic, advances the understanding of headache pathophysiology and refines headache treatments, both preventive and acute. Messina et al identified magnetic resonance imaging (MRI) biomarkers for migraine and cluster headaches by examining clinical, functional, and structural MRI data from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Images obtained on a 3T MRI were preprocessed and analyzed to obtain brain volumetric, white matter (WM) fractional anisotropy, WM mean diffusivity, cerebral blood flow, and resting state functional connectivity maps. The imaging-based differentiation of patients with headache from controls was strong in both patients with migraine (89%) and cluster headache (98%). A combination of MRI and clinical criteria differentiated between migraine and cluster headache with an increased accuracy of 99%, as compared to 78% with brain imaging alone.
Restlessness and more severe pain with cluster headaches were the most important clinical features in discriminating between the two groups of headache patients. The most discriminative MRI patterns in distinguishing headache patients from controls included brain resting state functional connectivity networks of the hypothalamus and the periaqueductal gray (PAG) region. The functional connectivity in the left PAG had a positive correlation with movement sensitivity, phonophobia, and nausea/vomiting and a negative correlation with cranial autonomic symptoms and pain severity. The left thalamic network was the most discriminative MRI feature in distinguishing migraine from cluster headache; the MRI analysis revealed a lower functional interaction between the left thalamus and parietal regions in patients with cluster headache, as compared to patients with migraine. Messina et al noted that functional imaging biomarkers involving hypothalamic and PAG networks were found in both headache types, and that the thalamocortical pathway differentiated between the two types.
Benkli et al determined that cluster headache and migraine have circadian features at cellular, systems, and behavioral levels, and that chronobiological genetic markers distinguish them. The mind and body respond to the environment in a repetitive, approximately 24-hour cycle, with diurnal variations within that circadian pattern. Core clock genes, present in virtually every cell type, show daily fluctuations in expression, leading to synchronization with other cells so that organs and brain nuclei have their own rhythms in a circadian transcriptional-translational feedback loop, overseen by the suprachiasmatic nucleus (SCN) in the hypothalamus.
Both the endogenous biological rhythms and the exogenous cues, which are known as zeitgebers (“time givers”), such as light and eating, regulate the body’s circadian rhythm. The circadian features of cluster headache (e.g., predictable timing, association with the core clock genes CLOCK and CRY1) are more widely recognized than are the circadian patterns of migraine. However, perturbations of zeitgebers and mutations in a core clock gene (CK1d) are associated with migraine.
Benkli et al performed a systematic review/meta-analysis of circadian data in cluster headache and migraine focusing on the timing of headache attacks and chronotype (i.e., the body’s natural inclination to be awake or asleep at certain times in a 24-hour cycle). They also performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes, or CCGs) by cross-referencing genome-wide association studies of cluster headache and migraine genes, a study of all CCGs, and recent review articles of relevant brain areas for cluster headache and migraine. The analysis found that a circadian pattern of attacks was more common in cluster headache (70.5%) than in migraine (50.1%). Cluster headache had a clear circadian peak between 21:00-03:00; migraine had a clear circadian trough between 23:00-07:00. Chronotype was highly variable in both headache types. Although the association with specific CCGs differed by headache type (cluster: CLOCK and REV-ERBa; migraine: CK1d and RORa), the majority of the susceptibility genes were CCGs in both headache types.
COMMENTARY
Both of these studies of cluster headache and migraine, one examining MRI and clinical features and the other examining the genetics of their chronobiology, reveal significant pathophysiological and clinical overlap between the two headache types. The relatively low (78%) diagnostic accuracy of the MRI model in discriminating between cluster headache and migraine patients reflects the coexistence of the two types of headaches, as well as their common pathophysiological mechanisms and genetic predisposition. Both Messina et al and Benkli et al emphasize the importance of the central regulatory role of the hypothalamus, which has been well recognized in cluster headache, but less well known with migraine. The study by Messina et al “showed a significant functional interaction between the hypothalamus and brain areas implicated in pain control and visual processing in both migraine and cluster headache patients studied outside their headache attacks.” The circadian rhythm of headache types is genetically mediated at a cellular level but regulated at a brain level by the hypothalamic SCN.
The finding that cluster and, to a lesser degree, migraine, both are highly circadian emphasizes what headache sufferers know intrinsically, that disruption of their routine (i.e., perturbations of zeitgebers) is a strong trigger for headache. Avoidance of circadian disruption and use of circadian-based treatments (such as taking medications at certain times of the day) are easy modifications that may prevent circadian-based headaches. However, rather than adjustment of the daily cycle, it may be alterations in the expression of the multiple genes that regulate the headaches’ circadian pattern that ultimately lead to the prevention of circadian-sensitive headaches.
