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. 2025 Apr 7;26(1):69.
doi: 10.1186/s10194-025-02009-z.

Limbic system abnormalities in episodic cluster headache: a 7T MRI multimodal study

Xinyu Wang #  1 , Luhua Zhang #  1 , Yongqin Xiong  1 , Mengmeng Hou  1 , Shuhua Zhang  2 , Caohui Duan  1 , Song Wang  1 , Xiaoyu Wang  1   3 , Haoxuan Lu  1 , Jiayu Huang  1 , Yan Li  1 , Zhixuan Li  1 , Zhao Dong  4 , Xin Lou  5   6
Affiliations

Limbic system abnormalities in episodic cluster headache: a 7T MRI multimodal study

Xinyu Wang et al. J Headache Pain. .

Abstract

Background: Although the limbic system has long been thought to be involved in the pathophysiology of cluster headache, inconsistencies in imaging studies of episodic cluster headache (eCH) patients and limited understanding of the specific regions within the limbic system have prevented a full explanation of its involvement in the disease. Therefore, we performed multimodal imaging analysis using 7 T MRI with the aim of exploring structural-functional abnormalities in subregions of the limbic system and their relationship with clinical features.

Methods: In this cross-sectional study, we employed 7T MRI to investigate structural (volumetric) and functional (fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo)) alterations in limbic subregions (hypothalamus, thalamus, amygdala, hippocampus) among 69 in-bout but outside the attacks eCH patients and 63 healthy controls (HCs). Automated volumetry and resting-state functional MRI analyses were performed after adjusting for age, Generalized Anxiety Disorder scale, sex (and intracranial volume when evaluating volumetric measures). Then functional-structural coupling indices were computed to assess network-level relationships.

Results: In eCH patients, volumes in right anterior inferior and right posterior of hypothalamus, left molecular_layer_hippocampal-head, left lateral-nucleus and left Central-nucleus on the headache side, as well as left tuberal inferior and left tuberal superior of hypothalamus, and right parasubiculum on the contralateral side were significantly altered compared with HCs (P < 0.05). Additionally, the volume of the right anterior inferior was positively correlated with the duration of last headache episode. After false discovery rate correction, widespread alterations in fALFF and ReHo values were observed among hypothalamic, thalamic, hippocampal, and amygdalar subregions, some of which correlated with clinical measures. Furthermore, the structure-function coupling indices in the right anterior inferior and the left lateral geniculate nucleus on the headache side differed significantly between eCH patients and HCs.

Conclusions: Our findings demonstrate that in-bout but outside the attacks eCH patients present anatomical and functional maladaptation of the limbic system. Moreover, the observed dissociation between localized abnormalities and largely preserved network coupling-except in the hypothalamus and thalamus-suggests that these two regions may be particularly susceptible to eCH-related dysfunction, while broader brain networks retain compensatory capacity in pathological states. These findings refine potential neuromodulation targets and highlight the value of ultrahigh-field imaging in eCH research.

Keywords: 7T MRI; Amygdala; Episodic cluster headache; Hippocampus; Hypothalamus; Structure-function coupling; Thalamus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Chinese PLA General Hospital in accordance with the ethical principles of the Declaration of Helsinki. (S2023-459-01). Consent for publication: All authors consent for the publication. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Sagittal, coronal, and axial ROIs used to calculate functional and structural indices are indicated: light blue for the thalamus, yellow and red for the hypothalamus, dark blue for the left hippocampus and amygdala, and green for the right hippocampus and amygdala. L, left; R, right
Fig. 2
Fig. 2
The volume of the right anterior inferior hypothalamus on the headache side was positively correlated with the duration of the last headache episode
Fig. 3
Fig. 3
Correlation between functional values and clinical parameters. A A significant negative correlation between the fALFF values in left-subiculum-head on the headache side and cluster period duration; B A significant correlation between the ReHo values of different brain regions on the headache side and cluster period duration; C A significant negative correlation between ReHo values of left-anterior superior on the headache side and headache intensity; D A significant positive correlation between the ReHo values of left-Central-nucleus on the headache side and PHQ_9; E A significant positive correlation between the ReHo values of right_VLP on the contralateral side and cluster period duration; F A significant correlation between the ReHo values of different brain regions on the contralateral side and PHQ_9
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References

    1. May A (2005) Cluster headache: pathogenesis, diagnosis, and management. Lancet 366(9488):843–855. 10.1016/S0140-6736(05)67217-0 - PubMed
    1. Burish MJ, Pearson SM, Shapiro RE, Zhang W, Schor LI (2021) Cluster headache is one of the most intensely painful human conditions : results from the international cluster headache questionnaire. Headache 61(1):117–124. 10.1111/head.14021 - PMC - PubMed
    1. Headache Classification Subcommittee of the International Headache Soc i. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004 24 Suppl 1:9-160. 10.1111/j.1468-2982.2003.00824.x - PubMed
    1. Russell MB (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3(5):279–283. 10.1016/S1474-4422(04)00735-5 - PubMed
    1. Serafini RA, Pryce KD, Zachariou V (2020) The mesolimbic dopamine system in chronic pain and associated affectiv e comorbidities. Biol Psychiatry 87(1):64–73. 10.1016/j.biopsych.2019.10.018 - PMC - PubMed

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