Structural and functional brain changes in perimenopausal women who are susceptible to migraine: a study protocol of multi-modal MRI trial

As a common headache disorder, migraine is characterized by recurrent headache attacks accompanied with symptoms including nausea and vomiting [1]. According to the World Health Organization (WHO), migraine is considered as one of the most disabling and burdensome diseases [2, 3]. In general, adult females experience migraine attacks twice more than males, and although men and women reported similar headache severity and frequency, women reported more migraine related symptoms [4, 5].

This gender difference is mainly caused by the difference in sex hormone. Estrogen quantities are relatively stable in men and undergo a much more gradual decline with age as compared with women [6]. For example, previous studies revealed that migraine is closely linked to the menopausal period of women, and one of the most prominent triggers is the sudden decline of estrogen [7‐9]. Estrogen can bind to its receptors of nucleus or cytoplasm in the brain, and then exert its function of pain transmission by gene transcription and protein synthesis [10]. However, this procedure would be disturbed by the sudden drop of estrogen in perimenopausal period, which would furtherly result in the susceptibility to migraine [6].

Since the decline of estrogen begins in perimenopausal period, giving hormone replacement therapy (HRT) in this period is considered as an effective method to treat migraine [11, 12]. To avoid the abuse and overuse of HRT which could cause some severe unpleasant complications, those women should be given the lowest effective dose of medication [13, 14]. However, headache is a subjective feeling, and effective diagnostic system is still lacked for quantifying the degree of migraine, which could result in the abuse and overuse of HRT in treating this disease.

In the past two decades, functional magnetic resonance imaging (fMRI) technique has become an indispensable tool in migraine research and has greatly contributed to our understanding of migraine pathophysiology [15‐17]. It could show anatomic and functional cerebral transformations associated with the clinical evolution and could be applied to most individuals without adverse effects. Maleki et al. found that female migraineurs have thicker posterior insula and precuneus cortices as compared with both male migraineurs and healthy controls of both sexes [18]. Compared to healthy controls, Kim and colleagues revealed a reduction of gray matter (GM) density in migraineurs, including insula, motor/premotor, prefrontal, cingulate, posterior parietal, and orbitofrontal cortex [19]. Huang et al. found reduced fractional anisotropy (FA) in the right frontal of migraine patients by using a tract-based spatial statistics (TBSS) method, which means the microstructure of white matter (WM) in that region is impaired [20]. Liu et al. found that the resting-state functional connectivity (FC) was disrupted in patients with long-term migraine through the method of graph theory [21]. However, these researches are all focused on both male and female patients at all ages, which contributes little to quantify the degree of migraine in perimenopausal women. According to our knowledge, no previous studies had researched the imaging abnormality of perimenopausal women who are susceptible to the decline of estrogen. Since estrogen plays a pivotal role in pain transmission in our brain [10], we thus raised the current hypothesis that brain structure and function of these women who are susceptible to estrogen drop exhibit unique characteristic changes in multi-modal images.

Consequently, we would like to conduct a prospective clinical trial to investigate the imaging abnormalities in these susceptible perimenopausal women. At the beginning, perimenopausal women around who had migraine will be recruited from the pain clinic of our hospital. Perimenopausal women around who did not have migraine will be recruited as healthy controls (HC) from the local community. Then, these subjects will undergo a series of multi-modal MRI brain scans and neuropsychology scales to assess the mental and physical state of these subjects. Multi-modal MR images of these two groups of subjects will be compared to find significant features as objective biomarkers.

The flowchart of the current trial is described in Fig. 1.

Multi-modal imaging features of perimenopausal women who are susceptible to estrogen decline will be acquired. Imaging sequences will include 3D-BRAVO, DKI, RS-BOLD and 3D-pCASL. Imaging features for assessment will include volumetric characteristics, white matter integrity, functional characteristics, topological properties and perfusion properties. Clinical information, such as information of migraine, headache level, MIDAS score, SAS, SDS, MMSE, MoCA and SF-36 will also be acquired for assessment.

The structural imaging could reflect the long-term impact of migraine on the brain structure, including GM volume and WM integrity. VBM has been pervasively used to investigate structural changes in migraine in the last decade. Some of them observed significant GM abnormalities in several brain regions of migraine patients [30‐32], including right superior temporal gyrus, right inferior frontal gyrus and left precentral gyrus etc., but the result in other studies were not significant [33‐35]. Two recent meta-analysis considered that migraine could cause GMV changes, and these changes were related to gender [36]. The integrity of WM is usually measured by calculating several parameters of its diffusional ability, such as MD, MK and FA. Several previous studies had compared these parameters between migraine patients and healthy controls, and they found significant increases or decreases in brain regions like thalami, corpus callosum and internal capsule [37‐40]. Previous studies had also investigated the difference of WM integrity between migraine patients with and without aura and between ictal and interictal period [37, 41]. In addition, imaging researches about WM integrity in children or adolescent who have migraine had also been conducted [42, 43]. In the current study, we hope that the long-term impact of the susceptibility of estrogen drop on brain structure could also be reflected in structural imaging.

The functional imaging could reflect the impact of migraine on the brain activity, including neural activity and perfusion condition. RS-BOLD signal had attracted considerable attention in migraine patient to examine potential alterations of brain induced by recurrent migraine attacks. In migraine patients, previous studies have detected various alterations regarding functional connectivity in pain related regions including the periaqueductal gray area (an important region involved in nociceptive processing) [44], as well as insular which is stronger functionally coupled to the dorsal caudal pons and periaqueductal gray area than healthy controls [45]. Other recent studies have reported changed ReHo, ALFF/fALFF or FC in the executive control network [46, 47], and the default mode network [35]. In addition, the functional topologic properties of migraineurs were also observed in precentral gyrus, anterior cingulate gyrus, thalamus and etc. [21, 48]. Previous researches had identified CBF abnormalities as an imaging biomarker in migraineurs, but these CBF studies were all based on single-photon emission computed tomography (SPECT), which is invasive and difficult to generalize in clinical trial [49, 50]. Recently, ASL is an emerging MRI sequence that can be easily performed without contrast injection or any side effects. Some recent studies stressed the significant abnormalities in somatosensory cortex or other brain regions of migraineurs [51, 52], while one study declared that they didn’t see and significant changes [53]. We hope that the impact of the susceptibility of estrogen drop on brain activity could also be reflected in functional imaging.