This study found that MwoA patients had decreased volume but increased ReHo in MRN. Besides, the MRN with both structural and functional alteration had increased resting state functional connectivity with PAG in MwoA patients. However, the correlation analysis showed that the VBM and Reho values of the MRN were not correlated with headache frequency, headache intensity, disease duration, SAS or SDS. This structural and functional neuroimaging study supports the involvement of MRN in the pathophysiology of migraine.
Regional homogeneity (Reho) is a method that applies Kendall’s coefficient of concordance to resting-state BOLD fMRI data in order to measure the similarity of the time series of a given voxel to those of its nearest neighbors in a voxel-wise way [19], which could reflect the local synchronization of spontaneous neural activity, hierarchical organization of the brain and neurodevelopmental factors[25]. Voxel-based morphometry (VBM) is a computational approach to neuroanatomy that measures differences in local concentrations of brain tissue, through a voxel-wise comparison of multiple brain images[18], which could reflect tissue atrophy or expansion[26]. Both Reho and VBM are data-driven analysis methods, which could reflect the functional and structural status in vivo. Studies using Reho[27_ 30] or VBM[31_ 35] alone for patients with migraine have been reported. However, not all studies reported consistent, stable and replicable findings. To our knowledge, this is the first neuroimaging study combining Reho, VBM and FC to explore the concurrent functional and structural differences in migraineurs, which may provide specific and more reliable insights into the unfolding brain’s adaptive or maladaptive changes in migraineurs.
It is widely accepted that migraine involves activation and sensitization of trigeminovascular pathways[36], as well as brainstem and diencephalic nuclei[37]. This study found that MwoA patients had a concurrent brain structural and functional alteration in MRN. MRN is located in the brainstem, extending from the caudal edge of the superior cerebellar peduncles to the motor nucleus of the Vth cranial nerve[38]. Previous studies report that MRN plays a critical role in the regulation of hippocampal activity and is likely involved in memory consolidation processes[39], depression[40] and anxiety[41]. Besides, MRN is also an important brain region in the human ascending arousal system, which is related with consciousness maintenance and its disorders such as fatigue and sleep disturbance[24]. In migraine patients, recent transcranial sonography studies reported that a hypoechogenic MRN correlated to a higher migraine attack frequency[42] and depression[43]. MRN is the main source of 5-hydroxytryptamine (5-HT, also known as serotonin) in the brain[44]. Serotonin is a neurotransmitter that is affected by many physical and emotional processes, including depression, mood, social functioning, exercise, and diet[45]. In migraineurs, decreased levels of serotonin have been observed[46]. Serotonin receptors have been found on the trigeminal nerve and cranial vessels and their agonists especially triptans are effective in migraine treatment[47]. Although there is a growing body of evidence for a direct role for dysfunctions of central 5-HT and MRN availability in migraine, the exact and specific action of endogenous 5-HT system and MRN in migraine continues to be the focus of active investigation[42, 43, 48].
In order to further explore the MRN’s correlation with other brain regions in migraineurs, Rs-FC analysis was applied by taking the region in MRN as the seed. This study found that the MRN had increased functional connectivity with PAG in migraineurs relative to HS. Previous animal neuroanatomy studies reported that the afferences for MRN mainly came from the limbic system, while the efferences were mainly to the lateral cortex, hypothalamus, amygdala, hippocampus, and medial cortex[38]. Some studies also report that MRN contribute serotoninergic projections to both the PAG (especially ventrolateral PAG) and the superior colliculus, the neural circus of which is related with a brain aversive system and pain modulation[49, 50]. The PAG plays a central role in descending pain modulatory system and is closely associated with opioid analgesia[51]. Animal studies also showed that descending modulation of the trigeminocervical complex (TCC), through the ventrolateral PAG and rostral ventromedial medulla, could cause the activation of ‘on’ cells and the inhibition of ‘off’ cells in the rostral ventromedial medulla, which seems to be critical for activation of TCC and development of migraine headache[37, 52, 53]. Taken together, this structural and functional neuroimaging study provide a more reliable evidence supporting the involvement of MRN in the pathophysiology of migraine.
There are several potential limitations in this study. 1) HS did not have SAS and SDS examined, which may have left the depression and anxiety level uncontrolled for migraineurs in this study. 2). This study primarily focused on the headache frequency, headache intensity and disease duration in migraineurs, with the symptoms such as allodynia, fatigue and sleep disturbances unrecorded. 3) This is a descriptive, not a mechanistic study.