BOLD repetition enhancement in the orbitofrontal cortex during complex visuospatial processing in migraine without aura: a shift in periaqueductal gray - cortical coupling?

Visual discomfort and sensory overload are common complaints in migraine patients without aura (MwoA), even between attacks, yet their neural basis remains poorly understood. We aimed to explore brain activation patterns in response to complex visuospatial tasks with higher ecological validity by using functional magnetic resonance imaging in migraine patients without aura. Fifty-nine right-handed female participants (30 interictal MwoA and 29 non-headache controls, aged 18–46 years) were included in the study. Subjects completed visually demanding fMRI tasks, which were designed based on aversive visuals that are frequently encountered in daily routine. Participants were asked to locate a target presented within either a high-frequency grating or a crowded geometric array in two runs while undergoing an fMRI scan. Both behavioral, clinical, and neuroimaging data were analyzed to examine repetition-related neural dynamics. A complex visual task induced higher BOLD activations in salience, executive control, and dorsal attention networks, particularly in visual areas, in migraine without aura patients compared to non-headache sufferers. Unlike controls, migraine patients exhibited repetition enhancement in the orbitofrontal cortex and the periaqueductal gray. Repetition suppression is impaired in higher-order visual areas of LOC, Pulvinar, and IPS compared to the control group. Reaction time and initial learning ability were comparable in the two groups; however, the accuracy rate decreased towards the end of the second run. Changes in the accuracy rate were positively correlated with changes in the OFC BOLD signal. Increased photophobia correlated with BOLD activation changes in the periaqueductal gray, the lateral occipital cortex, and the insula in migraine. Lack of repetition suppression in higher-order cortical and thalamic visual areas, and repetition enhancement in the OFC and PAG, are novel findings in migraine. Orbitofrontal activation correlated with task performance, indicating increased effortful top-down control to sustain accuracy, despite substantial metabolic demands, in migraine patients without aura. The enhanced BOLD activation in higher-order visual processing, along with reduced accuracy performance during repetition, may also reflect a prolonged reliance on aerobic glycolysis to meet neuronal energy demands. Abnormal engagement of pain-modulatory regions during visual processing suggests that sensory input is processed as aversive rather than neutral. These results provide a network-level explanation in which disrupted sensory gating and altered cortico-midbrain interactions impair predictive suppression, contributing to cognitive fatigue, sustained sensory gain, and visual hypersensitivity in migraine without aura.