Altered perfusion changes of the locus coeruleus in patients with chronic migraine: a pilot 3D-PCASL study

doi:10.21203/rs.3.rs-4804884/v1

Numerous studies demonstrated that the locus coeruleus (LC)was activated by acute nociceptive pain and played important role during the maintenance of chronic pain. The purpose of the study was to assess the morphology and cerebral blood flow (CBF) changes of LC in chronic migraine(CM) patients and to explore their correlation with CM clinical features using three-dimensional pseudo-continuous arterial spin labeling(3D PCASL), aiming to provide a better understanding of LC role in CM pathophysiology. Thirteen patients diagnosed of CM at Department of Neurology, Hainan Hospital of Chinese PLA General Hospital from May 2020 to June 2021 were prospectively included and fifteen age and sex-matched normal controls (NCs) were enrolled. All the participants received psycho-neurological assessment and undertook brain structural and 3D PCASL MRI examination. Volume and CBF alterations were assessed, correlation analysis with clinical scores were undertaken, and the receiver operating characteristic (ROC) curves analysis were conducted between groups. No statistical differences were found in the total volumes of LC between CM patients and NCs (P > 0.05). Compared with the NCs, the CBF in bilateral LC were lower in the CM patients, and the decrease in the right side has significant statistical value(P = 0.031). Correlation analysis revealed a negative association between the CBF of LC with duration of the disease (years). ROC curves analysis showed that the curve area for the CBF of the right LC was 0.749(95% CI 0.563–0.935), and the optimal cut-off point of value, sensitivity, and specificity for distinguishing CM from NC was 49.67 ml/100mg.min, 0.53 and 0.92, respectively. Hypoperfusion of bilateral LC was observed in CM. The altered CBF value of LC was negatively correlated with the disease duration. LC perfusion may hold promise as a potential early diagnostic imaging biomarker for CM.

Chronic migraine

Locus coeruleus

Perfusion imaging

Brain Magnetic Resonance Imaging

Arterial spin labeling

Chronic migraine (CM) is a disabling brain disorder with no effective management approaches. CM sufferers have frequent attacks, usually occurring on ≥ 15 days/month for more than 3 months(HIS,2013), and comprised of approximately1.4-2.2% of the global population. Due to high attack frequency and symptom severity, CM imposes significant burdens on personals as well as society(Burch et al,2019). The underlying pathophysiology leading to migraine chronification is poorly understood and remains an evolving area of research.

The locus coeruleus-norepinephrine (LC-NE) system in the brainstem innervates extensive areas throughout the brain and is involved in regulation of a variety of neuropsychiatric disorders. To date, interest in imaging the LC in vivo and in evaluating its potential as biomarkers has always been omnipresent. Nevertheless, LC is a tiny nucleus(14.5mm in length and 2.5 mm in thickness) and poses great challenge to researchers in defining its function(Fernandes et al, 2012). With advances in neuroimaging, several structural and functional MRI studies have revealed altered volume and functional connectivity of LC in healthy aging, patients with Alzheimer’s disease (AD)( Castellanos et al, 2015), Parkinson’s disease(Theofifilas et al, 2017) and depression(Bernard et al,2011).

Current research and viewpoints(Chen et al,2020) report that LC is a crucial pain regulation center not only at brain structural level but also at brain function level. An emerging body of research indicates that(Vila-Pueyo et al,2019 and Suarez-Pereira et al,2022) noradrenergic neurons in the LC participate in the development and maintenance of analgesic effects in episodic migraine. While as the pain prolongs, that is in CM, LC function shifts from pain inhibition to pain facilitation. The elaborate mechanism underling migraine chronification as well as functional transition of LC in CM remained unclear.

While the cerebral blood flow changes are reported as sensitive and reliable spatial predictors to the dynamic neural activity, we propose that the cerebral perfusion alteration might account for the functional impairment with LC and the bidirectional modulation of pain. To address the hypothesis, we employed an advanced segment technique, that is the three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) to automatically measure the LC CBF alteration to elucidate the hypothesis.

Participants

This study employed 13 chronic migraine (CM) sufferers without comorbidity and 15 sex- and age-matched NCs. Migraine patients were consecutively recruited from Hainan Hospital of Chinese PLA General Hospital from May 2020 to June 2021. Diagnosis of CM fulfilled the criteria of International Classification of Headache Disorders, 3rd edition. Patients with chronic somatic or psychiatric disorders, age under 18 or above 60 were excluded. The study was approved by the ethics committee of the Chinese PLA General Hospital.

Clinical assessment

Adequate information about the study, its risks and benefits were provided and the participants voluntarily agree to participate. Psychometric properties and severity of anxiety and depression were assessed by Hamilton Anxiety Scale (Matza et al ,2010)(HAMA) and Hamilton Depression Scale (Zimmerman et al,2013)(HAMD). Montreal Cognitive Assessment (MoCA) Beijing Version (www.mocatest.org), and General Sleep Disturbance Scale (GSDS) (Lee 2007)were employed to evaluate cognition and sleep quality respectively. Disease duration (DD) and the Visual Analogue Scale (VAS) were recorded. Migraine Disability Assessment (Hung et al, 2006)(MIDAS) assessing the impact of headache was acquired. Higher scores indicated increased symptom severity and larger burden.

MRI Acquisition

Participants were required to stop having psychostimulants at least 12 hours to avoid neurological excitement. Imagine was performed on a GE 3.0 T MR scanner (DISCOVERY MR750, GE Healthcare, Milwaukee, WI, USA) with a conventional eight-channel quadrature head coil.

Firstly, axial three-dimensional T1-weighted fast spoiled gradient recalled echo (3D T1-FSPGR) sequence generating 360 slices were acquired under the following parameters : echo time (TE) = 3.0 ms, flip angle = 15°, field of view (FOV) = 25.6 cm×25.6 cm, Matrix = 256×256, slice thickness = 1mm, number of acquisition = 1, repetition time (TR) = 7.0 ms. Then, axial pseudo-continuous arterial spinal labelling (PCASL) tagging scheme with a 3D interleaved spiral fast spinal echo (FSE) readout (3D spiral FSE ASL) generating 50 CBF slices were run with different parameters: TR/TE = 5128 ms/15.9 ms, flip angle = 111°, FOV = 20cm×20cm, x, y matrix = 1024 × 8 (spiral acquisition), slice thickness = 3.0 mm, labeling duration was 1.5 s, and post-labeling delay time (PLD) was 1.5 s.

Image processing

All MR data were preprocessed using Statistical Parametric Mapping 12 (SPM 12) (http://www.fil.ion.ucl.ac.uk/spm/) running under MATLAB 7.6 (The Mathworks, Natick, MA, USA) environment. The image processing included following steps: (1) The raw brain structures (3D T1-FSPGR) were segmented and then generated inverse deformation field (IDF), and then IDF was applied to the LC template (Edlow et al, 2012)in order to generate the individual LC (Fig. 1); (2) The raw CBF images (as source images) were coregistered with raw T1 image (3D-FSPGR) (as reference images) and then generated warped CBF images (wCBF); (3) Based on the individual LC, the CBF value and volume of LC could be extracted from the wCBF and raw 3D T1-FSPGR respectively.

Statistical Analysis

We first performed intergroup comparisons in age, HAMA, HAMD, MoCA, GSDS, total volume of LC, and total CBF using one-way analysis of variance test(ANOVA). An independent samples t-test was employed to compare intergroup differences in DD and MIDAS. Partial correlation analyses were performed between the volumes and CBF of LC and the clinical parameters of CM patients. In our study, the discriminative capability of the LC perfusion for distinguishing CM from NC groups was evaluated. The receiver-operating characteristic(ROC) curves were generated based on CBF of LC, and the area under the curve (AUC) was recognized with reasonable diagnostic valuable when AUC set at > 0.7.

Demographics and Clinical characteristics

A total of 28 participants (13 CM patients and 15 NC) were enrolled in this study (Table 1). All the patients in the CM group were examined in the headache interictal period. The CM patients and NC were matched in age and sex. The median disease duration of the migraine was 8 years, ranging 3 to 30 years. The average MIDAS score was 102.62, demonstrating severe disability caused by CM. All the patients reported VAS score greater than 6, with an average of 7.77, suggesting the pain was severe. Anxiety were significantly more common in the CM patients (P = 0.005), with average HAMA score of 22.31 ± 12.05, indicating CM patients were comorbid with moderate anxiety. Cognitive function as measured by MoCA was lower in CM patients than NC (P = 0.058). The average MoCA score in CM group was 23.38 ± 4.95, which is lower than 26, implying mild cognitive impairment.

Table 1

The clinical characteristics of CM and NC
	CM(n = 13)	NC(n = 15)	P value
Age(years)	40.69 ± 8.60	38.00 ± 9.56	0.443
Sex(F/M)	13(9/4)	15(11/4)	1.000
HAMA	22.31 ± 12.05	9.73 ± 3.39	0.003
HAMD	16.46 ± 10.58	15.73 ± 2.92	0.814
MoCA	23.38 ± 4.98	26.47 ± 2.42	0.058
VAS	7.77 ± 1.36	NA	NA
MIDAS	102.62 ± 47.53	NA	NA
DD(years)	8(3,30)^a	NA	NA
CM, chronic migraine; NC, normal control; ^aMedian(minimum value, maximum value); NA, not available.

Comparison of the LC volume and perfusion

No statistical difference was found in the total LC volume among CM patients and NC (P > 0.05). Greater LC volume was detected in the right side in both groups, but the difference has no statistical significance (Table 2). Compared with NC, decreased CBF was detected in both sides of LC in CM patients, especially in the right side. The average CBF in the CM patients were 43.91 ± 6.21 ml/100mg.min, while the average CBF in the NC groups were 51.27 ± 10.11 ml/100mg.min (P = 0.031) (Fig. 2).

Table 2

Volume and CBF analysis of LC among CM and NC CM, chronic migraine; NC, normal control; LC, locus coeruleus.
	CM(n = 13)	NC(n = 15)	P value
LC_L_Volume	1.11 ± 0.47	1.09 ± 0.36	0.921
LC_R_Volume	1.29 ± 0.53	1.36 ± 0.37	0.690
LC_L_CBF^a	44.19 ± 6.42	50.42 ± 10.2	0.069
LC_R_CBF^a	43.91 ± 6.21	51.27 ± 10.11	0.031

CM, chronic migraine; NC, normal control; LC, locus coeruleus.

^aml/100mg/min.

Correlation Analysis of the volume and CBF of LC With the Clinical Variables

Correlation analysis showed that both sides of CBF in LC were negatively correlated with the duration of the migraine(years) (Table 3).

Table 3

Correlation analysis of the volume and CBF of LC with the clinical variables in CM
	LC_L_CBF		LC_R_CBF		LC_L_Volume		LC_R_Volume
	r	P-value	r	P-value	r	P-value	r	P-value
HAMA	-0.271	0.182	-0.289	0.136	0.172	0.381	-0.230	0.239
HAMD	0.022	0.911	0.021	0.914	0.039	0.843	-0.506	0.006
MoCA	0.098	0.619	0.149	0.450	-0.229	0.242	0.049	0.804
DD	0.738	0.004	0.745	0.003	-0.372	0.211	-0.075	0.807
VAS	0.111	0.719	-0.007	0.983	0.202	0.509	0.042	0.892
GSDS	0.254	0.403	0.182	0.551	0.085	0.781	-0.508	0.077
MIDAS	0.463	0.111	0.425	0.148	-0.372	0.210	-0.227	0.456
CM, chronic migraine; LC, locus coeruleus; r, correlation coefficient; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Scale; MoCA, Montreal Cognitive Assessment; DD, disease duration; VAS, Visual Analog Scale; GSDS, General Sleep Disturbance Scale; MIDAS, Migraine Disability Assessment Scale.

ROC Curve Analysis of LC CBF for CM diagnosis

In distinguishing patients with CM from NC, CBF of the right side of LC had the highest AUC of 0.749(95% CI 0.563–0.935), indicating good discriminative power. The cut-off value was 54 ml/100mg.min with sensitivity 80% and specificity 69%, which showed a pronounced differentiation potential(Table 4 and Fig. 3 ).

Table 4

ROC analysis of the LC perfusion
	Left LC	Right LC
CBF value^a	44.19 ± 6.42	43.91 ± 6.21
AUC (95%CI)	0.705 (0.505–0.905)	0.749 (0.563–0.935)
Cut-off value^a	49.67	54.00
Sensitivity	0.53	0.80
Specificity	0.92	0.69
^aml/100mg/min; LC, locus coeruleus; CBF, cerebral blood flow; AUC, the area under receiver operating characteristic curve; CI, confidence interval.

In the current study, the LC volume was not altered in chronic migraineurs, but hypoperfusion was detected in both sides of LC. ROC analysis revealed the decreased CBF had high specificity for the diagnosis of CM and was negatively correlated with the disease course. That is, as the duration of migraine sustained, LC blood flow declined annually. Dysfunction of LC-NE system associated with chronic pain has been reported mostly in animals(Suto et al,2014). To the best of our knowledge, this is the first study investigating volume and CBF changes within the LC in chronic migraineurs. Our results demonstrated that LC perfusion changes might have clinical correlations and diagnostic implications for CM.

Imaging with quantitative neuromelanin-sensitive magnetic resonance imaging (NM-MRI) have observed LC volume decrease in PD and AD patients. We observed no statistical difference in the overall LC volume in chronic migraineurs. Given the small size of LC(14.5mm in length and 2.5 mm in thickness)³, it is not surprising to detect no volumetric differences between groups. With the advances of neuroimaging(Alipour et al,2023), 7T sequences MRI with potential advantage when visualizing small structures such as the LC(O'Callaghan et al,2021) may provide better detectable contrast between the LC and surrounding tissue.

In this study, we could see decreased LC perfusion in CM patients in comparison with normal control. The CBF value was automatically measured via 3D-pCASL. ASL has several advantages compared to earlier performed dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI)( Zhang et al, 2022), including a consistent spatial resolution, allowing for detection of small perfusion differences, noninvasive that it does not require the injection of contrast agents, can be repeated, and can be completely quantified. Compared with PET and SPECT, ASL is less expensive without ionizing radiation exposure(Dolui et al,2020).The importance of ASL has been well validated in the study of cerebral blood flow(Zhang et al,2023; Li et al,2022; Tang et al,2023; Liu et al,2022).

The cerebral blood flow most closely correlated with postsynaptic neural activity(Poplawsky et al,2021). Whether the observed decrease in blood flow reflects an inhibition of LC neural activity needs to be further assessed by electrophysiological study. Other commonly accepted explanations include the presence of some degree of interictal cerebrovascular dysregulation in migraineurs(Arkink et al,2011). Frequent migraine attacks affected the whole body vasculature(Kurth& Dodick,2015; Tepper, 2014). When the peripheral blood flow changes, LC-NE neurons which was under control of afferent from the cardiovascular system(Elam,1984) could mediate cerebral vasoconstriction and redistribution of blood. Emerging body of research demonstrated that specific activation of LC cause vasoconstriction and generate frequency-dependent reduction in intracranial blood flow via alpha 2-adrenceptor mechanism(Denuelle et al, 2008) it is not known whether the same process happens within the LC of migraine patients. Thus, treatments targeting the LC-NA pathway therefore may have the potential to delay or prevent CM-related pathology.

Our correlation analysis identified that the decreased blood flow was negatively correlated with the disease course. That is, as the duration of migraine sustained, LC blood flow declined annually. Another study also revealed that the extent of cerebral perfusion could negatively predicted the pain intensity(Bakhtadze et al,2012). Larger sample size as well as longitudinal re-measurements of the same patient group, to see further CBF changes and to clarify the relation between perfusion changes and clinical features may be needed.

Currently, there is no consensus on which clinical and neuroimaging biomarkers for, despite the increasing research evidence about the clinical and cerebral microstructural and blood flow alterations associated with migraine. Our ROC analysis revealed the decreased CBF showed a fair diagnostic efficacy for the diagnosis of CM.

CM exhibits multifactorial clinical features, and has a high incidence of cognitive and emotional deficits in comparison to episodic migraine(Katsarava et al,2012). In fact, depression and painful symptoms commonly occur together. The presence of pain especially moderate to severe pain which impairs function, and/or is refractory to treatment is associated with more lower quality of life and worse mood. In consistency with these findings, our current study confirmed that the chronic migraineurs were comorbid with moderate anxiety and mild cognitive impairment. It is hard to clarify whether it is the migraine that leads to anxiety or whether co-occurring anxiety predisposes an individual to be more sensitive to pain. Whatever, our research provide evidence that the subtle nucleus perfusion alteration might have clinical correlation with the dural disorder or the vicious cycle of comorbidity. Treatment of anxiety and migraine simultaneously might have implications for better outcomes.

Based on findings from the current research, it is reasonable to speculate that the cerebrovascular changes of LC might represent a pathological overlap that lead to migraine chronification and altered emotional disorders and cognitive deficits.

Although our study is meaningful, we recognize that there are some limitations. Firstly, the sample size is small. Secondarily, in addition to the LC-NE system, the cerebral metabolic factors produced during migraine attacks including arachidonic acid metabolites, potassium, nitric oxide, and CO might could also be integrated to modulate the regional CBF. Whether the hypoperfusion of LC was involved in CM pathophysiology, that is contributing to altered function shifting from pain inhibition to pain facilitation and chronification, remains unclear. Further studies may expand the sample size to better elucidate the alteration of the LC in neuroimaging findings.

This study identifies alteration of LC regional cerebral brain flow (CBF) in CM patients. The CBF of LC is negatively correlated with the disease duration of chronic migraineurs. Decreased blood flow at the LC site has predictive value for the diagnosis of CM and the LC-noradrenergic system might be a potential target for future treatments for CM.

Ethical approval

The study has been approved by the Ethics Committee of PLA General Hospital. The study was conducted following the Declaration of Helsinki.

Consent to participate

Informed consent was obtained from all study participants. Legally Authorized Representatives of illiterate participants provided informed consent for the study.

Funding declaration

None

Consent to publication

All the authors agreed to publish this article. Competing interests The authors declare no competing interests.

Availability of data and materials

The data and code that support the findings of this study are available from the corresponding author upon reasonable request.

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No competing interests reported.

Altered perfusion changes of the locus coeruleus in patients with chronic migraine: a pilot 3D-PCASL study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Participants

Clinical assessment

MRI Acquisition

Image processing

Statistical Analysis

Results

Demographics and Clinical characteristics

Comparison of the LC volume and perfusion

Correlation Analysis of the volume and CBF of LC With the Clinical Variables

ROC Curve Analysis of LC CBF for CM diagnosis

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1