Atypical functional connectivity between the anterior cingulate cortex and other brain regions in a rat model of recurrent headache

Migraine is the most common primary headache disorder and has high socioeconomic and personal costs.1 Migraine was ranked as the sixth leading cause of disability worldwide in the Global Burden of Disease Survey and the leading cause of disability in those under 50 years of age.2,3 Classified as a subset of migraine, chronic migraine (CM) is defined as headaches on ≥15 days/month. In approximately 2.5% of patients with episodic migraine (EM), the condition transitions to CM annually.4 CM imposes a greater burden, with disability scores nearly twice as high as those in EM.5 Except for the difference in headache-day frequency between EM and CM, there are two important indicators of progression to CM. Repeated migraine attacks may lead to central sensitization via the chronic stimulation of central pain pathways. As a symptomatic manifestation of central sensitization, cutaneous allodynia was defined as innocuous stimuli perceived as painful. The majority of migraineurs develop cutaneous allodynia during migraine attacks, and some have persistent sensitization even during the interictal phase.6,7 Cutaneous allodynia is more frequent and severe in CM than in EM; it is associated with female sex, headache frequency, increased body mass index, disability, and depression.8 Cutaneous allodynia may indicate migraine progression.4 Hyperalgesia during the interictal period is also regarded as an indicator of success in the preparation of animal models of CM.9 Major non-headache indicators associated with CM include anxiety, depression, and other affective disorders.10 Clinical and epidemiological studies have demonstrated that migraine has a bidirectional relationship with depression and anxiety.11,12 Migraineurs have a more than four-fold relative risk of developing depression compared with patients without migraine.13 Most CM rats show depression- and anxiety-like behaviors.14 However, functional brain changes related to the indicators of progression to CM remain unclear. The anterior cingulate cortex (ACC) is a key structure involved in various higher brain functions, such as nociception, chronic pain, cognition, and emotions.15 Migraineurs had concordant decreases in the gray matter volume in the ACC, and the decreased gray matter volume was related to the estimated frequency of headache attacks in a meta-analysis.16 Activation in the ACC was also found in migraine patients.16 A CM group showed greater activation in the ACC on laser stimulus compared with both controls and migraine without aura (MWA) patients.17 Noxious trigeminal heat stimulation in migraine patients after external trigeminal neurostimulation induced a significantly reduced BOLD response in the ACC.18 A molecular-level study revealed altered N-acetyl aspartate/creatinine in the ACC in migraine patients.19 Taken together, these findings indicate that the ACC plays an important role in the pathogenesis of migraine, especially CM. The ACC is involved in chronic neuropathic pain and its associated anxiety.20 Nevertheless, the functional changes in the ACC that occur in migraine remain unknown. Functional connectivity (FC) is a descriptive measure of the spatiotemporal correlations among distinct cerebral regions.21 Resting-state functional connectivity (rs-FC) shows co-activation of brain regions during the resting state and reveals the functional brain changes involved in the pathogenesis of diseases. Therefore, in this study, we used functional magnetic resonance imaging (fMRI) to investigate rs-FC based on the ACC in migraine model rats. We prepared animal models that mimic EM and CM via inflammatory soup (IS) infusions in the dura mater of rats at different frequencies.22 We hypothesized that there would be atypical FC of the ACC with (1) central pain pathways in the ictal stage in the low-frequency IS-stimulated group and (2) brain areas related to nociception, emotion processing, and pain modulation in the high-frequency IS-stimulated group, and (3) that cutaneous allodynia would be related to higher pain-modulating cortical areas.