This study investigated the large-scale resting-state functional connectivity of the whole brain in migraine without aura during interictal phase by using FCD analysis. Migraineurs showed altered lFCD or dFCD in the dlPFC, OFG, HP, PHG, MTG, precuneus, SMC, and cerebellum, some of which were more apparent in CM compared with EM. The FCD values in the HP, OFG, MTG, SMC, and precuneus correlated with migraine frequency, indicating that abnormal functional interactions may reflect migraine symptom severity. Consistent with a previous FCD study on EM, more widespread group-differences were observed in lFCD than dFCD. Although the exact biological mechanism of lFCD remains unclear, it is analogous to regional homogeneity (ReHo), a measure thought to reflect the efficiency of coordinated neuronal activity and used to assess local brain functional alterations.
Compared with HC, both EM and CM showed reduced lFCD in the bilateral dlPFC. In support of our results, multiple migraine studies consistently reported decreased ReHo in the dlPFC in EM compared with HC[11, 16, 17]. However, the current study extended previous findings of altered brain function in the dlPFC to CM. The dlPFC is involved in cognitive evaluation, working memory, opioid analgesia, and play a critical role in mediation attenuation of pain perception via cognitive control mechanisms. Therefore, our finding of lFCD reduction in the dlPFC may suggest disrupted pain modulation in different subtypes of migraine without aura. We also found increased lFCD in the right cerebellum in both migraine groups compared to HC. The cerebellum plays an important role in human nociception and modulating of pain perception[22–24]. Previous studies have found an increased prevalence of ischemic lesions in the cerebellar posterior lobe. In addition, relatively consistent findings of reduced gray matter volume were reported in the cerebellum in EM and CM [26–28]. Collectively, increased lFCD in the cerebellum in our study may indicate common ineffective inhibition of pain perception in EM and CM.
Our data revealed that lFCD of the OFG in EM was higher than that in HC, but was lower than that in EM. Additionally, in the CM versus HC comparison, we found increased dFCD in the right OFG which positively associated with migraine frequency across all patients. Therefore, the results indicated both local and distant functional connectivity abnormalities in this region and the alterations may progress with repeated migraine attacks. Supporting our results, a MRI study on EM reported increased ReHo in patients compared to HC. Zhao et al. also found increased ReHo in EM without aura, which was more profound in patients with long-term disease duration than those with short-term disease duration. Concerning remote functional connection, Tian et al. reported enhanced OFG connectivity with the right nucleus accumbens in EM relative to HC. The OFG also showed increased functional connectivity with the hypothalamus and amygdala in CM compared with EM or HC [31, 32]. The OFG is proposed to participate in sensory integration, decision making, expected reward and punishment, especially response inhibition[33, 34]. Stimulation, both pain and pleasure, has been reported to elicit opioid release in the OFG. A recent resting-state MRI study found increased regional brain activity in the OFG in migraineurs after verum acupuncture. Furthermore, persistent orbitofrontal hypofunction was reported to be associated with medication overuse headache, and decreased gray matter of this region was predictive of poor response to treatment. We speculated that higher FCD in the OFG may be adaptive mechanism associated with affective and cognitive response in migraine.
In this study, EM showed increased and decreased lFCD in the HP/PHG as compared with HC and CM, respectively. Furthermore, compared with HC, EM had higher dFCD in the right PHG while CM showed higher dFCD in the right HP and PHG/TP. Interestingly, both lFCD and dFCD in the right HP positively correlated with migraine frequency. The current findings were partially supported by two prior studies reporting increased ReHo in the HP/PHG in EM compared to HC[17, 29]. However, in contrast to our results, Gao et al. found lower lFCD in bilateral HP in the EM versus HC comparison. The discrepancy may result from different option regarding global-signal regression in data preprocessing. With respect to interregional functional connectivity, increased PHG connectivity with multiple regions have been repeatedly observed in EM relative to HC[30, 39]. By contrast, migraineurs showed both increased and decreased HP connectivity compared to HC. Nevertheless, our findings was supported by a DTI study based on graph theory approaches by showing that excessive network integration of the HP in migraineurs predicted poor placebo effect and may contribute to the development and maintenance of persistent migraine. We recently found that migraine frequency negatively associated with gray matter volume in the right HP/PHG. The HP is involved in learning and memory formation, as well as pain-related attention and anxiety, and stress response[42, 43]. The PHG is closely functionally related to HP, and plays a role in memory and emotional response. Overall, our finding of greater FCD in the HP/PHG in patients with higher headache frequency may be compensatory changes for structural atrophy, reflecting insufficient inhibitory feed back to HPA axis, delayed shutdown and overactivation of stress responses.
We also found increased lFCD in the left MTG in the EM versus HC comparison, and decreased lFCD in the left SMC and bilateral precuneus in the CM versus HC comparison. Moreover, migraine frequency negatively associated with lFCD in the MTG, PreCG, and precuneus across all patients, indicating that patients with higher migraine frequency had lower lFCD in these regions. Supporting our results, Zhang et al. reported decreased ReHo and degree centrality in the primary somatosensory cortex and premotror cortex in migraine without aura. Reduced ReHo in the precuneus was also observed in female EM patients relative to HC. Interestingly, another resting-state MR study revealed ReHo reduction in the precuneus only in migraineurs with long-term disease duration. The authors also found higher ReHo in the MTG in patients with short-term disease duration but lower ReHo in this region in patients with long-term disease duration. Thus, it was possible that distinct functional plasticity may exist in the MTG in migraineurs with different disease burden. More studies are needed to verify this hypothesis, though it was partially in accordance with our findings of increased lFCD in EM but a negative relationship between migraine frequency and lFCD in this region. The postcentral gyrus predominantly participates in sensory-discriminative pain processing. The precuneus is involved in spatial orientation and sensory information processing and interpretation. The MTG is related to language and semantic memory processing as well as multimodal sensory integration. Motor cortex stimulation has been reported to be a potential tool to centrally modulate chronic pain, although its role in pain is not completely understood. Collectively, altered lFCD in the MTG, precuneus and SMC may be associated with disrupted mutlisensory integration, nociceptive information processing, and pain modulation in migraine.