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 activityofbilateral PoCG,left ROL/insula, and bilateral SMA unique to patients with MwoA.Specifically, the SMN in episodic patients with MwoA exhibited abnormal inflow or outflow influence on multiple functionalnetworks andheadachedysregulation related to clinical characteristics (e.g., headache impact and duration).Our findings are in agreement with prior evidence of a disrupted SMN functional connectivity in migraineurs without aura, thusprovidingnew insightsinto 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 foundhigher neural activityin bilateral PoCG, decreased functional connectivity from the right PoCG to the contralateralcalcarinesulcus, as well asincreased connectivity intensity from the visual cortex (left calcarine sulcus and right 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 networkare 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[17,18].Our findings also show increased brain activity of the right PoCG, which negatively regulate the headache impact intensity, and functional deficitsthat fail to compensate recurrent endogenous and exogenous pain stimuli or inhibitnociceptive signals in the interictal period.Previous longitudinal investigationshowed thatthe morphological alteration of the visual cortex was significantly associated with migraine progression, especially in the calcarine sulcus and cuneus. In agreement, our results demonstratefunctional influences from the right PoCG tothe left calcarine sulcus positively correlated with disease course and prior structural plasticity.
However, Wang et al. reported opposite neuralactivity of the bilateral PoCG by low-frequency oscillations approach to reflect the spontaneous neural function of the brain. In addition, an electroencephalography-related study 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.Therefore, the abnormal effective functional connectivity between the SMN and visual cortex may be part of the pathological mechanismof failure to filter the unpleasant signals or lower the threshold to somatosensory stimuli in the visual pathway.Furthermore, our resting-state fMRI study also showed the abnormal effective connectivity from the left inferior OFC to the right PoCG in migraineurs without aura compared to HC. The OFC, a segment of the advanced processing center and a key function to the regulation of negative feedback, might constitude the cognitive function, regulation of emotions, psychiatric disorders and inhibitory control. The heightened effective connectivity might be interpreted as a dysfunctional inhibitory response to malaise signals.Our demonstration of positive functional coupling between the primary somatosensory cortex and the OFC may also infer the possible role of the OFC in migraine.
Compared with the HCs, migraineurs without aura showed changed effective connectivity from the left PoCG to many pain-related areas, such as theMTG, angular gyrus,precuneus, and IPL[5,22].These regions have been demonstrated to be crucial in the default mode network (DMN). The DMN, one of the core brain networks that is activatedwhen ata rest state, plays a pivotal role in discriminative, cognitive and perceptive functions of pain[18,24-26].Previous studies have shownaltered functionassociated with nociceptive processing and cognitive impairment,within the angular gyrus and MTG in migraineurs.Moreover, the precuneus participates in thediscrimination of sensory perception of pain and the brainstem-thalamus-cortex circuit which modulates pain intensity in the migraineurs. Our datafound thatthe increased brain function in the left PoCG hasa negative modulatoryeffect in the frequency of headache attacks.Thus, our results indicated that the dysfunction between the primary somatosensory cortex and DMNmay disrupt the neural transmission pathway of discrimination and intensity involved in sensory perception of pain. Besides, long-term and repetitive migraine headache attacks may lead to somatosensory cortex compensatory or dysfunctional changes. These observations agree with our data which showed that influence from the left somatosensory cortex to 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 ROL/insula, near to the limbic system, subcortical network and anterior DMN, which may trigger pain processing adjustments in multiple instinct brain networks.The insula isa component of the salient network (SN,a pivotal large-scale intrinsic network associated with perceiving) which process and integrate internal and external stimuli.Similarly, a resting-state fMRI study reported that insular cortex demonstrated abnormal functional connectivity to DMNencoding headache severity in migraineurs.Whereas, high SN function occurs when the mind is engaged in specific tasks, rise in DMN activity does not depend on external stimulation. Hence, the ROL/insula-DMN functional connectivity modulates the switching between self-monitoring and task processing.In addition, the operculum, which contains the secondary sensory cortex, is another key region involved in the processing of sensory information.Previous studies have shown that the secondary sensory cortex and insulacould provideinformation about the intensity, cognition and spatial discriminative pain pathways of nociceptive stimulus in migraine[8,18].The ROL/insulahas been proposed to be involved in the multi-network sensory integration of pain. It predominantly mediates the intensityand signals ascending the spinothalamic tracts of the pain processing system[32-34].Furthermore, the decreased effective connectivity from theleft IPL to the left ROL/insula may support the impaired function and lower inhibition power of DMN, and hypersensitive responses to external sensory inputs.Since the SMN and DMN 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 thehypersensitivity of pain and migraine.
In addition, we observed that the SMNsubregionscould be influencedby abnormalinputs from the putamen and the caudate nucleus, components of the striatum.Literature has shownthat thestriatumaffects the neuronal pathways underlying the inhibition effect of nociceptive stimulation. These effect is mediated bythe striatal dopamine D2 receptorswhich are associated with pain inhibitory circuitry ofthe caudal trigeminal nucleus.The abnormal interaction of the putamen has been shown to trigger many independent components, justifying the hypothesis that transmission of pain is complex and multidimensional. Moreover, the SMA contributes to response selection and nociceptive generation in MwoA[7,9].Furthermore, since the cortico-striato-thalamo-cortical loop affects many neurological disorders , we speculated that perturbation of the striato-cortical circuit may suppress the inhibitory function on the nociceptive reflex.Together with the previous evidence, we highlight the importance of stratum and SMA in pain- and movement-related processing as well as in the regulation of migraine and other chronic pain syndromes[38,39]. The information transformation and transmission pathway corresponds toboth ventral and dorsal streams specialized in processing the intensity of painful stimuli. This pattern of increased effective connectivity indicates that the putamen may influence the activity of somatosensory cortex in discriminating pain experience, thus, its potential and vitalrole in shaping of the pain perception. Our findings explain the dysregulation between the putamen and sensory cortex in migraine headaches.
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. Besides the functional alterations, more studies are required to investigate the possibility of structural connectivity involved in SMN.