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The abnormally increased functional connectivity of the locus coeruleus in migraine without aura patients

BMC Research Notes volume 17, Article number: 330 (2024) Cite this article

Abstract

Background

The neurovascular theory is thought to be one of the main pathological mechanisms of migraine. Locus coeruleus (LC) is a major node in the neurovascular pathway. Exploring the functional network characteristics of LC in migraine without aura (MwoA) patients can help us gain insight into the underlying neural mechanisms in MwoA patients.

Methods

In this study, we used resting-state functional magnetic resonance imaging (rsfMRI) and a functional connectivity (FC) approach to explore the functional characteristics of LC in MwoA patients. 17 healthy controls (HCs) and 28 MwoA patients were included in the study. FC was calculated based on rsfMRI data collected by a 3T MRI scanner. General linear model were used to compare whether there were differences in LC brain networks between the two groups. We also utilized logistic regression to explore the role of LC functional networks in the clinical diagnosis of MwoA.

Results

After general linear analysis, MwoA patients displayed increased FC from right LC to the left lingual and calcarine sulcus, as well as to the right frontal medial gyrus/orbit part, when compared with HCs. The results of the logistic regression showed that the LC FC signals were 81% accurate in distinguishing MwoA from the HCs.

Conclusion

Our results demonstrated that patients with MwoA exhibited significant LC FC differences in the brain areas associated with visual and cognitive function. Understanding the changes in the LC brain network in MwoA patients can provide us with new ideas to understand the pathological mechanisms of MwoA.

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Introduction

Migraine is a common recurrent headache disorder characterized by a throbbing headache that typically occurs on one side of the head, although it can affect both sides. It is often accompanied by symptoms such as nausea, vomiting, and sensitivity to light and sound [1]. Migraine without aura (MwoA) is the most common type of migraine, accounting for approximately 80% of cases [1]. Migraine without aura is a recurrent headache, typically unilateral and throbbing mainly in the frontotemporal region, with attacks lasting between 4 and 72 h [1, 15]. Compared to migraine with aura, MwoA has a higher frequency of attacks and can seriously affect the work and life of the patient [2].

Locus coeruleus (LC) is located in the medial nucleus of the trigeminal nerve bundle and is also a major node in the neurovascular pathway [3, 4]. The LC is closely involved in the regulation of pain and stress-related disorders [5]. Acute pain triggers a strong LC stress response and LC activity produces pain promotion, anxiety, increased memory aversion and behavioural hopelessness at the level of the spinal cord, prefrontal cortex and amygdala [5]. Exploring the functional network characteristics of LC in MwoA patients can help us gain insight into the underlying neural mechanisms in MwoA patients [6].

Resting-state functional magnetic resonance imaging (rsfMRI) detects functional brain activity by measuring changes in blood oxygen levels in the brain. RsfMRI has been used extensively in the study of brain mechanisms in patients with migraine. Functional connectivity (FC) research has focused on the resting state, and FC reflects shared connectivity patterns across multiple brain states by characterising statistical associations between neural time series [7,8,9,10,11,12]. Studies based on rsfMRI and functional connectivity (FC) also showed increased FC between hypothalamus and LC in patients with migraine [7]. After transcutaneous auricular vagus nerve stimulation, the patients with migraine showed a significant increase in FC between the LC and the right temporoparietal junction and the left secondary somatosensory cortex [8]. Gollion et al. [9] used T1 neuromelanin-sensitive-weighted 3T MRI to study the content of neuromelanin, a by-product of LC norepinephrine synthesis in MwoA patients, and there was no difference in neuromelanin contrast between MwoA patients and healthy controls in LC.

Abnormalities in the occipital lobe, the visual functional region, have been widely reported in patients with migraine [10]. Messina et al. [11] used structural MRI images to explore cortical changes in patients with migraine. They found that patients with migraine showed decreased cortical thickness and surface area in areas of pain processing. But in areas of executive function and visuomotor processing, patients with migraine showed increased cortical thickness and surface area, when compared to control subjects. Ozkan et al. [12] found that patients with migraine with visual aura had a much higher frequency of occipital bending than patients with migraine without aura. Abnormalities in occipital lobe metabolites in patients with migraine have also been identified in studies of magnetic resonance spectroscopy imaging. Reduced levels of N-acetylaspartate indicating neuronal loss were found in the occipital cortex and thalamus of MwoA patients [13, 14].

However, to the best of our knowledge, there are no studies using rsfMRI and FC to explore LC functional connectivity patterns in MwoA patients. The aim of the present study was to examine alterations in the features of LC FC in MwoA patients using rsfMRI, by comparing with healthy controls (HCs). We hypothesized that, relative to HCs group, the MwoA group would display altered LC FC in brain regions associated with the neurovascular hypothesis, such as the occipital lobe [11,12,13,14].

Materials and methods

Patients

The study recruited 28 MwoA patients and 17 HCs between March and October of 2014 from headache ambulatory. According to International Headache Society criteria [15], the diagnosis of definite MwoA was made by two neurologist specialists in headache disorders who were blinded to MRI and neuropsychological findings (Headache Classification Committee of the International Headache, 2013) [15]. The control subjects were recruited from local communities and had no history of neurological diseases. Exclusion criteria included: (i) no headache attacks in the three days preceding the scan, on the day of the scan, or in the three days following the scan; (ii) no history of substance abuse or prophylactic drug use; (iii) no psychotic disorder; there are no contraindications to MRI scanning; (iv) Female subjects who are not pregnant or menstruating; no migraines or headaches and did not take any chronic treatments. The Local Ethics Committee approved the study protocol in accordance with the Helsinki Declaration (approval number: 2017-R006). All participants provided their written informed consent for the study.

MRI scanning

All subjects underwent a functional fMRI scan with an 8-channel head coil on a 3 T MRI scanner (Achieva X-series, Philips Medical, Best, the Netherlands). T2*-weighted echo-planar images were acquired for the functional scan with the following parameters: 35 axial slices, thickness/gap = 4/0 mm, in-plane resolution = 80 × 80, repetition time (TR) = 2000 ms, echo time (TE) = 35 ms, flip angle = 90°, and FOV = 240 × 240 mm2. Each functional imaging had 240 volumes. During image acquisition, we instructed patients to remain still and close their eyes [16].

Data preprocessing

SPM12 (http://www.fil.ion.ucl.ac.uk/spm) and DPABI v6.0 (http://rfmri.org/DPABI) were used for data preprocessing. The following preprocessing steps were taken: discarding the first ten volumes, slice timing and head motion correction, spatial normalization to Montreal Neurological Institute (MNI) space with a resampling resolution of 3 × 3 × 3 mm3, spatial smoothing with a 6-mm Gaussian kernel along all three directions, linear trend removal, and temporal bandpass filtering (0.01–0.08 Hz). Finally, the resulting images were cleaned up by regressing out the head motion parameters, the cerebral spinal fluid signal, and the white-matter signal. Subjects with a head motion of more than 2.0 mm translation or a rotation of more than 2.0° in any direction were excluded.

LC resting-state functional connectivity analysis

Using an atlas-based method, we imported the Automated Anatomical Labeling 3 template with DPABI and two separate LC seeds (one per hemisphere) were created in the MNI space [17] (Fig. 1). For each participant, the Pearson’s correlation coefficient was calculated between the average seed time-series and the other time-series of whole-brain voxels. To confirm the normal distribution of correlation images, Fisher’s Z-transform was applied to Pearson’s correlation maps.

Fig. 1
figure 1

Three-dimensional localization of locus coeruleus in a high-resolution structural image. The left locus coeruleus is shown in red and the right locus coeruleus is shown in blue

Full size image

Statistical analysis

We used the non-parametric Mann-Whitney U-test to compare the age and education of the two groups as a way of determining whether there was a statistical difference. We used the chi-square test to compare the gender composition of the two groups.

Using REST (http://www.restfmri.net/), we conducted statistical analysis. The individual normalized FC maps were analyzed voxel-by-voxel between the two groups using a general linear model. We regressed out the mean relative head motion displacements, age, and gender as covariates to minimize the impact of confounding variables in the statistical analysis. The statistical map that resulted from multiple comparisons had a p value of 0.05 (adjusted for multiple comparisons by AlphaSim, with a cumulative individual voxel p-value of 0.005 and a cluster size of > 25 voxels).

Relationship of LC FC with clinical variables

The Z value of the aberrant brain areas and the clinical scores of MwoA patients were correlated using Spearman’s rank to look at the relationship between the FC values and clinical variables (duration, frequency and visual analogue scale.) in MwoA patients.

Clinical diagnostic analysis

We used logistic regression to explore the role of LC functional networks in the clinical diagnosis of MwoA. We extracted mean FC signals from differential brain regions of the LC brain network. We built a binomial logistic regression model using matlab function fitglm. The independent variables were the mean FC signals in the differential brain regions and the response variables were category (MwoA = 1, HC = 0). Then, the established logistic regression model was used to calculate the posterior probability of different class classifications. Finally, we calculated the Area Under the Curve value and sketched the Receiver Operating Characteristic curve using the matlab function perfcurve.

Results

Demographic and clinical data

Age (z = -0.270, P = 0.7873), sex distribution (χ2 = 2, P = 0.3431), and years of schooling (t = 0.973, P = 0.2030) did not significantly differ between the two groups.

Table 1 presents specifics of the demographic information and corresponding testing.

Table 1 Demographic and clinical data
Full size table

Abnormal LC FC values in the MwoA group

There was no difference in brain networks of the left LC in the MwoA group compared to HCs. MwoA patients displayed higher FC from the right LC to the left lingual, calcarine sulci, and the right frontal medial gyrus/orbit part (ORBmid.R). (Figs. 2; Table 2).

Table 2 Brain regions with significantly different FC values with the right locus coeruleus in the MwoA group compared with the HCs group
Full size table
Fig. 2
figure 2

Brain regions showing the increased right locus coeruleus functional connectivity values in the MwoA compared with HCs groups

Full size image

Correlations of LC FC with clinical variables

We did not find any correlations between the LC FC values and the clinical variables.

Results of the logistic regression model

The results of the logistics regression showed that LC FC signals were 81% classification accuracy in distinguishing MwoA and HCs (Fig. 3).

Fig. 3
figure 3

Receiver Operating Characteristic plot of the logistics regression of the LC FC signal used to differentiate between MwoA and HCs. Area Under the Curve value is 0.8130

Full size image

Discussion

In this study, we examined resting-state LC FC in MwoA and HCs groups using rsfMRI data. Compared with the HC groups, the MwoA group showed increased FC from the right LC to the left lingual gyrus, calcarine sulcus, and the right frontal medial gyrus/orbit part. We used logistic regression to build a classification model to determine the ability of LC FC signals to distinguish between MwoA and HCs. The results of the logistic regression showed that the LC FC signals were 81% accurate in distinguishing between MwoA and HCs.

The brain regions where we found significant differences were located in the occipital lobe. Experiments in rats showed that significant enhancement of Fos immunoreactivity in the caudal nucleus of the trigeminal nerve, LC, parabrachial nucleus and median suture nucleus after injurious trigeminal nerve stimulation with capsaicin [18]. Locus coeruleus may also directly modulate trigeminal spinal tract nucleus neurons, leading to alpha2-adrenoceptor-dependent cerebral hypoperfusion, a known trigger for cortical spreading depression (CSD) [5]. In addition, loss of cortical norepinephrine upstream signal will hyperexcite LC and lower the CSD threshold. While, the CSD hypothesis refers to an inhibitory band of neuroelectrical activity originating in the occipital lobe caused by noxious stimuli, which extends at a rate of 2 to 5 mm/min into the adjacent cortex and is accompanied by spreading oligemia [19]. Vagus nerve stimulation activates glutamate receptor-mediated tropomyosin kinase B signaling in the nucleus of the solitary tract, regulates serotonergic and norepinephrinergic innervation of the cerebral cortex to inhibit CSD and cortical neuroinflammation, thereby reducing clinical symptoms in migraine patients [20].

Both the lingual gyrus and the calcarine sulcus are located in the occipital lobe and are associated with visual functional. Studies show that increased blood flow to visually relevant brain areas and brainstem neurotransmitter-related brain areas is one of the pathological mechanisms of migraine [3]. The lingual gyrus is mainly responsible for visual processing, especially letter processing [21]. The Independent Component Analysis-based approach also showed that MwoA patients had an increased FC in the lingual gyrus [22]. In a negative emotion picture stimuli fMRI study, patients with migraine showed a stronger activation in lingual gyrus [21].

The calcarine sulcus belongs to the primary visual cortex and is the primary site of detection of direct visual information [23]. In an arterial spin labeling study, MwoA patients showed increased cerebral blood flow connectivity between the left calcarine sulcus and the ORBmid.R [24]. The right lingual gyrus and left calcarine sulcus had a decreased component activity in patients with MwoA compared with HCs. Meanwhile, the values of the left calcarine sulcus were positively correlated with visual analogue scale scores [25]. The graph analysis was used to model the brain connectome of MwoA and HCs. Difference in brain regions between the two groups was located primarily within the occipital lobe, including middle occipital gyrus and calcarine sulcus [26]. The LC-occipital cortex pathway is involved in the regulation of visual sensory processing [27]. Our results suggested that patients with migraine are hypersensitive to visual stimuli and that the visual cortex is in a state of high arousal. The hypersensitive state of inhibition of the LC-occipital cortex pathway can alleviate the clinical symptoms of patients with migraine.

We identified functional network abnormalities in the right LC of MwoA patients. About 60% of LC neurons recorded during CSD showed abnormal bursts of activity [28]. CSD-related burst activity may lead to reduced excitability of the dendritic membrane of LC neuronal bodies and the release of large amounts of norepinephrine from LC via a large number of axonal side branches, thus playing a role in the functional changes in brain neurons associated with CSD [28]. There is a link between lower levels of N-acetylaspartate (NAA), a marker of axonal damage, in the right LC in early relapsing-remitting multiple sclerosis and auditory selective attentional dysfunction [29]. Our study suggests that there may be laterality in the functional network of the LC in MwoA patients.

We found no correlation between brain function signals and clinical scales. The small sample size affects the statistical robustness and correlation analysis of the results. In addition, the pain-related scales collected in the study were inadequate. Only VAS scales were collected, but scales such as the Numeric Rating Scale, the Migraine Disability Assessment Questionnaire and the Headache Impact Assessment Scale were not collected [30].

There are several limitations to this study. First, the results of this study should be replicated in a larger cohort. Smaller samples reduce the test-retest reliability of resting-state functional magnetic resonance imaging study results. Second, our study did not examine whether the predictive model was specific for migraine or whether pain conditions such as chronic low back pain or fibromyalgia showed the same variability. Third, Patients with migraine often have some psychobehavioural symptoms, such as depression. In future studies, we will need to collect psychobehavioural scales to address the impact of altered brain mechanisms on psychobehavioural symptoms in patients with migraine [31]. Finally, we excluded the effects of medication use and psychiatric disorders when enrolling patients, but studies have shown that there is a potential association between diet, stress and exercise and migraine, and that the influencing factors need to be further refined when enrolling patients in the future [32,33,34].

Conclusions

In the current study, we compared the patterns of the LC FC in MwoA and HCs groups. Our results showed that patients with MwoA exhibited significant LC FC differences in the brain areas associated with visual and cognitive function when compared with HCs. These findings enhance our understanding of the functional mechanism of the LC brain network in patients with MwoA.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

LC:

Locus coeruleus

MwoA:

Migraine without aura

rsfMRI:

Resting-state functional magnetic resonance imaging

FC:

Functional connectivity

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Acknowledgements

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Funding

The Key Project of Medical Science Research of Hebei Province (20200002) (to JM Chen).

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Author notes

  1. Bangli Shen and Jinming Cheng contributed equally to this work.

Authors and Affiliations

  1. Department of Algiatry of the Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China

    Bangli Shen

  2. Department of Neurology, The Hebei General Hospital, Shijiazhuang, 050050, Hebei, China

    Jinming Cheng

  3. Department of Radiology of the Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China

    Xiaoyuan Wu & Xiaozheng Liu

  4. Department of Neurology, Xingtai people’s Hospital, Xingtai, 054000, Hebei, China

    Xi Zhang

  5. Department of Neurology of the Second Affiliated hospital, Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Zhihong Wang

  6. Wenzhou Key Laboratory of Structural and Functional Imaging, Wenzhou, 325027, Zhejiang, China

    Xiaozheng Liu

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Contributions

“ZHW and XZL conceptualized the study design. BLS and JMC analyzed the fMRI data and wrote the main manuscript text. XYW and XZ did the formal analysis and validated the statistical analysis. ZHW, XZL and all authors reviewed the manuscript.”

Corresponding authors

Correspondence to Zhihong Wang or Xiaozheng Liu.

Ethics declarations

Ethics approval and consent to participate

The Local Ethics Committee of the Second Affiliated Hospital of Hebei Medical University approved the study protocol in accordance with the Helsinki Declaration in 2017/02/09 (approval number: 2017-R006). All participants provided their written informed consent for the study.

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Not Applicable.

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The authors declare no competing interests.

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Shen, B., Cheng, J., Zhang, X. et al. The abnormally increased functional connectivity of the locus coeruleus in migraine without aura patients. BMC Res Notes 17, 330 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13104-024-06991-6

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ISSN: 1756-0500

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