Triple network disruption in medication overuse headache: functional signatures and clinical impact

Chronic migraine with medication overuse headache (CM-MOH) is a disabling neurological condition. CM-MOH is associated with functional impairment and high prevalence of psychiatric comorbidities. Neuroimaging research showed alterations in large-scale brain networks in chronic pain disorders. Among these, the so-called “triple network model” -Default Mode Network (DMN), Salience Network (SN), and Central Executive Network (CEN)- has garnered attention for its critical role in cognitive and emotional regulation. Dysregulation within and between these networks has been implicated in various chronic pain, substance abuse, and affective disorders. However, the role of triple network functional connectivity alterations in CM-MOH remains poorly understood. This study aims to investigate alterations in functional connectivity (FC) both within and between the triple networks and whole brain, and to explore how these neural changes relate to the clinical and psychiatric characteristics of CM-MOH. This case-control study, 91 patients with CM-MOH and 35 healthy controls underwent clinical, neuropsychological, and resting-state fMRI assessments as part of the CM-MIND study. Patients were classified by type of medication overuse (triptans, NSAIDs, polyabusers). FC within and between the DMN, SN, and CEN, as well as whole-brain FC, was analyzed. Associations with clinical and psychiatric features (including allodynia, medication intake, anxiety, and depression) were examined using between-group comparisons and regression analyses. Compared to healthy controls, CM-MOH patients exhibited increased extra-network DMN and SN FC with sensorimotor regions, most pronounced in triptan abusers who also showed CEN-motor alterations. Moreover, SN nodes were associated with reduced global and local efficiency. Allodynia severity was associated with increased SN-sensorimotor and decreased DMN intra-network FC, while higher anxiety correlated with reduced DMN-amygdala/putamen FC. Migraine chronification and higher medication intake were linked to increased DMN and SN FC with temporal-occipital regions. Notably, polyabusers showed SN-CEN disconnection and concurrently enhanced coupling of both networks with temporo-occipital regions as an effect of medication intake. Our results suggest that CM-MOH involves maladaptive connectivity of the triple network model. Alterations in FC, mainly in SN and DMN, and in CEN to a lesser extent, might be associated with migraine chronification and pain embodiment, while altered CEN interactions might be associated with medication overuse.