Mesocorticolimbic circuitry in episodic migraine: reward- and punishment-related responses and resting-state connectivity

Clinical evidence suggests an involvement of the dopaminergic system in migraine pathophysiology; however, its functional role remains poorly understood. We investigated neurofunctional alterations within mesocorticolimbic/dopaminergic circuits in individuals with episodic migraine compared with healthy controls. We employed a Monetary Incentive Delay (MID) fMRI task to assess mesocorticolimbic function during reward and loss anticipation in individuals with episodic migraine (n = 25) and control subjects (n = 27). Group differences in task-related activity were examined within core mesocorticolimbic regions, including the ventral tegmental area, nucleus accumbens, and medial prefrontal cortex, focusing on the anticipation phase, which has been widely suggested to be sensitive to dopaminergic signaling. Resting-state fMRI was additionally used to assess intrinsic functional connectivity within the same regions. Repeated-measures ANCOVA indicated reduced mesocorticolimbic activity during anticipation in migraine patients compared with controls. Logistic regression analyses further showed that loss anticipation–related activity discriminated between the two groups. Planned contrasts revealed reduced responses specifically within the nucleus accumbens and ventral tegmental area during loss anticipation. Exploratory analyses showed an association between mesocorticolimbic activity during loss anticipation and the self-reported attack-related pain intensity, although this did not survive correction for multiple comparisons. No significant associations were observed between loss anticipation–related activity with affective symptom severity (BDI, STAI). Supporting these results, resting-state fMRI analyses further revealed altered nucleus accumbens–prefrontal functional connectivity in migraine patients. Overall, the observed pattern suggests that individuals with episodic migraine are characterized by a reduction in mesocorticolimbic responsivity, mainly involving the ventral tegmental area and the nucleus accumbens, during reward/loss anticipation processes, but with a preferential reduction in negative-valence (loss) anticipation. These task-related alterations are embedded within an altered nucleus accumbens–prefrontal pathway evident at rest. Together, these findings are consistent with a disturbance of mesocorticolimbic function in episodic migraine, potentially involving dopaminergic mechanisms.