To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.

Background & Aims Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). Methods We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level−dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. Results Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls—an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level−dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. Conclusions Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF₁) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional–arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state–trait anxiety and hypothalamic–pituitary–adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional–arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF₁signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF₁receptor antagonism for patients with stress-sensitive disorders.