Comorbid Migraine, Insomnia Linked to Aberrant Locus Coeruleus Functional Connectivity

A recent study found aberrant locus coeruleus functional connectivity (LC-FC) networks in patients with comorbid migraine and insomnia.¹

“These findings offer novel perspectives on the neuroimaging mechanisms underlying [comorbid migraine and insomnia],” wrote investigators, led by Changlin Wang, from the department of neurology at The First Affiliated Hospital of Anhui Medical University in China.

Migraine and insomnia often co-occur and exacerbate the other condition.² The locus coeruleus is a brainstem region responsible for norepinephrine synthesis and modulates pain, sleep/wake cycles, and emotional regulation.¹ It is believed this region is a possible nexus in the comorbidity of migraine and insomnia; people have hypothesized that disruptions in the locus coeruleus- noradrenergic system contribute to the comorbidities of migraine and insomnia.

However, there is limited neuroimaging evidence on this connection in humans. Investigators sought to investigate the intrinsic functional connectivity network of the locus coeruleus in patients with comorbid migraine and insomnia, as well as in patients with migraine and no insomnia. The team evaluated the functional connectivity through resting-state functional magnetic resonance imaging and seed-based analyses.

The cross-sectional study included 30 patients with comorbid migraine and chronic insomnia, 30 patients with migraine and no insomnia, and 30 healthy controls. Participants with migraine had no significant difference in behavioral performance and demographic characteristics, including age, sex, or education levels, between those with and without insomnia (P > .05). They also did not have significant differences in headache-related features, such as duration, frequency, attack duration, VAS, HIT score, and depression.

Compared with healthy controls, participants with migraines had greater SAS and SDS scores (P < .001). The scores were not significantly different between participants with and without insomnia (P > .05).

Investigators found patients with comorbid migraine and insomnia demonstrated altered LC-FC in several brain regions, including the dorsomedial prefrontal cortex, anterior cerebellum, dorsolateral prefrontal cortex, thalamus, and parahippocampal gyrus.

The team found a Pittsburgh Sleep Quality Index (PSQI) score is negatively correlated with the left LC-FC in the right parahippocampal gyrus (P = .0006). This indicates a lower functional connectivity between the locus coeruleus and the dorsolateral prefrontal cortex is linked to a greater insomnia severity.

“This finding suggests that LC-DLPFC connectivity may be a potential biomarker of sleep disturbance in patients with [comorbid migraine and insomnia],” investigators wrote.

The team also noted a positive correlation between PSQI and the right LC-FC in the caudate (P = .03), which demonstrates worse sleep quality is linked to greater connectivity in the caudate.

Additionally, greater functional connectivity between the locus coeruleus and the dorsomedial prefrontal cortex was associated with a longer migraine attack among participants with comorbid migraine and insomnia (P = .036).

“The observed enhanced functional connectivity between the LC and cerebellum may suggest alterations in trigeminal nociceptive processing and pain modulation within the LC in patients with MI,” investigators wrote. “However, further research is needed to confirm these potential mechanisms.”

Investigators wrote the study was limited by its cross-sectional design and the small sample size. They also added the study was limited by only conducting the MRIs from 4 pm to 10 pm as individuals with insomnia may have increased hyperarousal and anxiety closer to their typical sleep time. Completing the MRIs later in the day may have impacted the functional data.

Other key limitations included using subjective insomnia measures rather than objective measures such as polysomnography and using 3T fMRI which lacks the resolution for small subcortical structures, are key limitations.

“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 [comorbid migraine and insomnia],” investigators concluded.

References

1. ^{Wang C, Chen S, Cheng Z, et al. Characteristics of locus coeruleus functional connectivity network in patients with comorbid migraine and insomnia. J Headache Pain. 2024;25(1):159. Published 2024 Sep 27. doi:10.1186/s10194-024-01877-1}
2. ^{Grossi, G. Chronic Migraine and Insomnia Have a Strong Bidirectional Relationship. HCPLive. October 11, 2022. https://www.hcplive.com/view/chronic-migraine-insomnia-strong-bidirectional-relationship. Accessed October 9, 2024.}