Characteristics of locus coeruleus functional connectivity network in patients with comorbid migraine and insomnia

Abstract

Background: Migraine and insomnia are prevalent conditions that often co-occur, each exacerbating the other and substantially impacting the quality of life. The locus coeruleus (LC), a brainstem region responsible for norepinephrine synthesis, participates in pain modulation, sleep/wake cycles, and emotional regulation, rendering it a potential nexus in the comorbidity of migraine and insomnia. Disruptions in the LC-noradrenergic system have been hypothesized to contribute to the comorbidities of migraine and insomnia, although neuroimaging evidence in humans remains scarce. In this study, we aimed to investigate the intrinsic functional connectivity (FC) network of the LC in patients with comorbid migraine and subjective chronic insomnia and patients with migraine with no insomnia (MnI) using resting-state functional magnetic resonance imaging (rs-fMRI) and seed-based FC analyses.

Methods: In this cross-sectional study, 30 patients with comorbid migraine and chronic insomnia (MI), 30 patients with MnI, and 30 healthy controls (HCs) were enrolled. Participants underwent neuropsychological testing and rs-fMRI. The LC-FC network was constructed using seed-based voxel-wise FC analysis. To identify group differences in LC-FC networks, voxel-wise covariance analysis was conducted with sex and age as covariates. Subsequently, a partial correlation analysis was conducted to probe the clinical relevance of aberrant LC-FC in patients with MI and MnI.

Results: Except for the insomnia score, no other significant difference was detected in demographic characteristics and behavioral performance between the MI and MnI groups. Compared with HCs, patients with MI exhibited altered LC-FC in several brain regions, including the dorsomedial prefrontal cortex (DMPFC), anterior cerebellum, dorsolateral prefrontal cortex (DLPFC), thalamus, and parahippocampal gyrus (PHG). Lower FC between the LC and DLPFC was associated with greater insomnia severity, whereas higher FC between the LC and DMPFC was linked to longer migraine attack duration in the MI group.

Conclusion: Our findings reveal the presence of aberrant LC-FC networks in patients with MI, providing neuroimaging evidence of the interplay between these conditions. The identified LC-FC alterations may serve as potential targets for therapeutic interventions and highlight the importance of considering the LC-noradrenergic system in the management of MI.

Keywords: Functional connectivity; Insomnia; Locus coeruleus; Migraine.

Fig. 1

Correlation matrix of clinical features and behavioral assessment in pooled migraine, MnI, and MI groups. Abbreviations: MnI: patients with migraine with no insomnia; MI: patients with comorbid migraine and insomnia; Duration: duration of disease; Frequency: frequency of disease; Attack duration: attack duration of each migraine; VAS: mean Visual Analogue Scale; HIT-6: Headache Impact Test six; PSQI: Pittsburgh Sleep Quality Index; SDS: Zung self-depression scale; SAS: Zung self-anxiety scale

Fig. 2

Group differences in LC-FC network among three groups (GRF correction, Voxel level p < 0.005, cluster level p < 0.05, cluster size > 35). A. the group difference brain regions in left LC-FC network. B. the group difference brain regions in the right LF-FC network. Abbreviations: GRF: Gaussian Random Field; LC-FC: locus coeruleus functional connectivity; HC: healthy control; MnI: patients with migraine with no insomnia; MI: patients with comorbid migraine and insomnia; STG: superior temporal gyrus; MTG: middle temporal gyrus; aCbm: anterior cerebellum lobe; SMA: supplementary motor area; PHG: parahippocampal gyrus; DLPFC: dorsolateral prefrontal cortex; DMPFC: dorsomedial prefrontal cortex; MOG: middle occipital gyrus

Fig. 3

Relationship between altered LC-FC strength and behavioral features in pooled migraine, MI, and MnI groups. The PSQI score was negatively associated with the FC between the left LC and right PHG (A), left STG/MTG (B), right LC, and right caudate (C) in the pooled migraine groups. The PSQI score was positively associated with the FC between the left LC and right DLPFC in the MI but not the MnI group (D). The disease duration was negatively associated with the FC between the right LC and right caudate in the pooled migraine groups (E). The attack duration is positively associated with the FC between the right LC and the right DMPFC in the MI but not the MnI group (F). Abbreviations: LC-FC: locus coeruleus functional connectivity; MI: patients with comorbid migraine and insomnia; MnI: patients with migraine with no insomnia; PSQI: Pittsburgh Sleep Quality Index; PHG: parahippocampal gyrus; STG: superior temporal gyrus; MTG: middle temporal gyrus; DLPFC: dorsolateral prefrontal cortex; DMPFC: dorsomedial prefrontal cortex