There are numerous challenges in discerning the directionality or specificity of the changes in functional connectivity between the SMN and other regions, especially in patients with MwoA. In this study, we extracted the distribution of SMN and identified abnormal neural activity of bilateral PoCG and left MCC unique to patients with MwoA. Specifically, the SMN in episodic patients with MwoA exhibited abnormal inflow or outflow influences on multiple functional networks and headache dysregulation related to clinical characteristics (e.g., headache frequency and duration). Our findings are in agreement with prior evidence of a disrupted SMN functional connectivity in migraineurs without aura [6], thus providing new insights into multi-sensory modulation in migraine processing. Moreover, we demonstrate that these effective functional abnormalities are independent of structural and microstructural changes.
In the current study, we found higher neural activity in bilateral PoCG, decreased effective functional connectivity from the right PoCG to the left MTG, as well as increased effective functional connectivity from the primary visual cortex (the calcarine sulcus and cuneus) to the right PoCG. The calcarine sulcus and cuneus are core regions of the primary visual network in the brain, and therefore, the present findings suggest that functional abnormalities between the SMN and visual network are specifically altered in patients with MwoA. Indeed, previous migraine studies have showed that altered activity within the sensory-related cortex, including SMN and visual cortex, results in dysfunction associated with affective, cognitive or pain processing [19,20]. Moreover, previous study has shown altered function associated with nociceptive processing and cognitive impairment within the MTG in migraineurs [21]. Furthermore, a longitudinal investigation [22] showed that the morphological alteration of the visual cortex was significantly associated with migraine progression, especially in the calcarine sulcus and cuneus. Our findings also showed increased brain activity of the right PoCG, which is positively correlated with the headache frequency, and demonstrated functional deficits to compensate recurrent pain stimuli. Therefore, the abnormal effective functional connectivity between the SMN and visual cortex may be part of the pathological mechanism of failure to filter the unpleasant signals or lower the threshold to somatosensory stimuli in the visual pathway. Besides, the pain-induced task-state study demonstrated that episodic migraineurs had hyperactivation of the somatosensory cortex in the interictal phase [22]. These results are in line with the ones obtained from our analysis. However, Wang [8] and Zhao [24] et al. reported opposite resting-state neural activity of the bilateral PoCG in migraineurs with all headache subphases by low-frequency oscillations and regional homogeneity approaches to reflect the spontaneous neural function of the brain. In addition, an electroencephalography-related study [25] demonstrated higher desynchronization and power overlying the primary sensorimotor cortex in the preictal phase compared to the interictal phase, with no significant differences between interictal migraineurs and HCs. The heterogeneity of the migraineurs phase and the use of different neuroimaging methods might explain the discrepancy between the studies. Taken together, migraine is a chronic and periodic disorder of the central nervous system related to cortical and subcortical networks alterations of disrupting brain homeostasis and amplifying the intensity of sensory stimuli[26]. Further longitudinal investigation of how physiological changes within the migraine cycle is crucial to acquire a more complete understanding of the neuropathological mechanisms behind the headache attack.
Compared with the HCs, migraineurs without aura showed changed effective functional connectivity from the left PoCG to many pain-related areas, such as precuneus [5,27]. This region has been demonstrated to be crucial in the DMN [28]. The DMN, one of the core brain networks that is activated when at a rest state, plays a pivotal role in discriminative, cognitive and perceptive functions of pain [20,21,29]. Moreover, the precuneus participates in the discrimination of sensory perception of pain [30] and the brainstem-thalamus-cortex circuit which modulates pain intensity [31] in the migraineurs. Our data found the increased brain functional connectivity from the right precuneus to left PoCG was negatively correlated with HIT scores, indicating that the dysfunction between the primary somatosensory cortex and DMN could disrupt the neural transmission pathway of regulation involved in sensory perception of pain. Whereas, the decreased brain functional connectivity from the left PoCG to right precuneus has a positive modulatory effect on the headache duration, suggesting that the long-term and repetitive migraine headache attacks could lead to somatosensory cortex compensatory or dysfunctional changes. These observations showed that influences between the left somatosensory cortex and DMN play a role in functional adaption along migraine progressing.
The current study also observed that, in resting state, there is decreased activity of the left MCC, a key region connected to circuits mediating cognitive control, nociceptive perception and multisensory integration [32,33]. Particularly, it is suggested that the consecutive hyperactivation of the MCC could alleviate the neuropathic pain, but the hypoactivity of the MCC may diminish the pain inhibitory abilities, corresponding to the present findings [32]. This study provided evidence for functional changes from the left MCC to the left insula, which is localized near to the limbic system, subcortical network and anterior DMN, and may trigger pain processing adjustments in multiple instinct brain networks. The insula is a component of the SN (a pivotal large-scale intrinsic network associated with perceiving) related to the processing and integration of internal and external stimuli [34]. There are similar views on the contributions of MCC-associated networks spanning several cortical and subcortical networks to regulate the pain perception and processing. Notably, the pathway from the MCC to insula has been proven to be able to gate nociceptive hypersensitivity and amplify perception in the context of nociception [35]. Hence, the SMN-insula effective functional connectivity modulates the switching to the task processing. Since the SMN and insula are key regions of the trigeminovascular modulatory system, a pain inhibiting system, disrupted activity of these regions may lead to a dysfunctional pain inhibition pathway, thus contributing to the hypersensitivity of pain and migraine. Moreover, we found increased effective functional connectivity from the SMN to right PCL and negative correlation between the functional connectivity strength and HIT scores, similar to the results of previous Rs-fMRI study. Zhang et al. found weaker functional connectivity between the SMN and PCL in migraineurs without aura [6]. Thus, this pattern of the PCL dysfunction would induce abnormal sensorimotor integration, and as a possible abnormal neurophysiological mechanism in interictal MwoA.
In addition, one notable aspect revealed by this study is that the SMN subregions could be influenced by abnormal inputs from or outputs to the putamen, a component of the striatum. Literature has shown that the striatum affects the neuronal pathways underlying the inhibition effect of nociceptive stimulation [36]. These effects are mediated by the striatal dopamine D2 receptors which are associated with pain inhibitory circuitry of the caudal trigeminal nucleus [37]. The abnormal interaction of the putamen has been shown to trigger many independent components [38], justifying the hypothesis that transmission of pain is complex and multidimensional [39]. Since the cortico-striato-thalamo-cortical loop affects many neurological disorders [40], the results suggested that perturbation of the striato-cortical circuit may suppress the inhibitory function on the nociceptive reflex. Furthermore, the chronic pain and mood disorders have been proven to share common neuroanatomical substrates including the stratum [41].The dysfunction of the striatum in chronic pain could disrupt the mesolimbic dopamine pathways and play a role in the pathogenesis of chronic pain and mood comorbidity [42]. Although no correlation between the brain dysfunction and the anxiety and depression scores was discovered in this study, MwoA patients showed higher measurement scores about anxiety and depression than HCs. Together with the previous evidence, we highlight the importance of putamen in pain-related processing as well as in the regulation of mood disorders comorbid with chronic pain syndromes.
Our study, however, used a small sample size. Therefore, a large sample size might be needed to enhance our data repeatability and reliability. In addition, the heterogeneity of the participants, such as the etiology, headache severity, disease duration, or neuropsychiatric comorbidity could result in neural activity biasness. Moreover, the pharmacological effects could play a pivotal role in the striato–thalamic–orbitofrontal pathway associated with pathogenesis of migraine and contribute to the abnormal brain function [37,43]. The number of analgesic drugs consumed in a month should be carefully taken into account, meriting a more detailed study in the future. Besides the functional alterations, more studies are required to investigate the possibility of structural connectivity involved in SMN.