Migraine is a common disabling neurological condition, characterized by severe recurrent headaches, accompanied by several neurological and autonomic symptoms [1]. Its pathophysiology involves peripheral nociceptive signals and complex central alterations from the trigemino-vascular system, neurotransmitter systems, and central pain modulation regions [1].

Some neuroimaging studies have provided evidence of central dysfunction in migraine population, reporting pain-induced brain alterations and suggesting a dysregulation of pain facilitation and inhibition processes [2]. Resting-state fMRI (rs-fMRI) studies have further revealed widespread disrupted functional connectivity (FC) across multiple cortical and subcortical regions and networks implicated in sensory, cognitive, and affective aspects of pain [3–6].

Novel migraine preventive treatments acting on Calcitonin Gene Related Peptide (CGRP) pathway have shown remarkable efficacy in clinical practice [7]. CGRP, plays a major role in migraine pathophysiology by promoting meningeal vessels dilation, local neurogenic inflammation, thereby releasing pro-nociceptive mediators that enhance pain transmission and sensitivity. Two main classes of CGRP-targeting treatments are available: monoclonal antibodies (mAbs anti-CGRP; e.g., erenumab, galcanezumab) directed against CGRP or its receptor, and small-molecule CGRP receptor antagonists, gepants [7]. In this context, atogepant, a recently approved gepant theapeutic drug, has demonstrated high safety, tolerability, and efficacy in migraine prevention. Clinical evidence shows a rapid and robust preventive effect, with 60–80% of patients achieving a ≥ 50% reduction in monthly migraine episodes within three months, and up to ~ 50% reaching complete remission at one year [8–10].

Only few neuroimaging studies have investigated whether anti-CGRP mAbs could modify brain activity. For erenumab, Schwedt et al. showed changes in network FC efficiency and central processing of extracranial painful stimuli involving cingulate and frontal cortices, putamen, and periaqueductal gray in treatment responders [11]. For galcanezumab, reduction FC between the somatosensory, motor, and insular cortices in responders was observed [12], moreover, a decreases hypothalamic activation stronger in responders was observed [13]. By contrast, no neuroimaging evidence are available for gepants. Whereas mAbs act mainly peripherally and have limited blood-brain barrier (BBB) permeability [14], the degree of BBB penetration of gepant is still unclear, and this leaves open the question of its potential central neurofunctional involvement. Moreover, since migraine pathophysiology involves multiple neurotransmitter systems, including serotonin, which contributes to migraine generation, and dopamine, which has been associated with prodromal symptoms such as yawning and nausea, understanding how anti-CGRP treatments modulate neurotransmitter activity may provide new insights into their central mechanisms of action [15, 16].

On these grounds, this longitudinal study aimed to investigate the effects of a 12-week atogepant treatment on resting state brain FC and on FC modulated by the spatial distribution of different neurotransmitter receptors in a cohort of episodic migraine (EM).

In this study, we observed that 12-week atogepant treatment in EM patients is associated with significant changes in the brain’s FC at rest and dopamine-related FC within the mesocorticolimbic system, accompanied by a sizable clinical improvement, in both MMD and MAM, consistently with atogepant efficacy data [10]. Furthermore, we also observed a concomitant decrease in allodynia, a marker of central sensitization. This is partly consistent with previous findings which showed marked decrease in ASC-12, [29, 30], for example with erenumab [31], where this effect was attributed to prolonged suppression of peripheral nociceptive input. Our findings therefore may suggest that atogepant may similarly modulate central sensitization mechanisms.

Longitudinal ROI-to-ROI analyses showed a pattern of increased connectivity at T1, involving the right SFG, bilateral putamen, left pallidum, left ACC, and bilateral PCC. Importantly, greater the longitudinal increase in ACC-PCC connectivity, the larger the improvement in MDD, MAM, and allodynia scores after treatment, linking FC modulation with clinical response. All these regions participate in different aspects of the neural processing of the pain experience, with either pain-facilitating or pain-inhibiting functions and show functional alterations in migraine patients [1–3, 32].

The SFG emerged as the node showing the largest number of post-treatment connectivity changes with other ROIs, indicating a central role in the network reorganization. This finding should be considered alongside previous data [33] reporting reduced connectivity between the dorsolateral prefrontal cortex and several cortical and basal ganglia regions, including the putamen, in EM patients. Given the critical involvement of SFG in pain modulation, both findings point to a dysfunction of descending pain-control pathways both interictally and in relation to treatment-related reorganization. In this framework, the increased frontal-putaminal connectivity observed after atogepant may reflect a strengthening of interictal fronto-striatal coupling and a reinforcement of top-down pain modulation mechanisms.

The SFG also showed longitudinally increased connectivity with the ACC, which in turn exhibited enhanced connectivity with the PCC, suggesting an atogepant-related strengthening of frontal-anterior cingulate-posterior cingulate interactions. Within this axis, the ACC plays a central role: it integrates the sensory, emotional, and motivational components of the pain experience, contributes to autonomic regulation, and acts as a key node of descending pain-control pathways [34–36]. The PCC, on the other hand, is a core hub of the default mode network, involved in the conscious experience of pain [36]. Together with the superior frontal cortex, these regions form a network implicated in higher-order modulation of nociceptive processing. Findings from migraine cohorts further highlight the relevance of these midline regions. Consistent structural and functional alterations were reported in the prefrontal cortex, ACC, and PCC [1, 37–40]. These functional abnormalities include reduced interictal metabolism in both cingulate regions, particularly in the ACC, where lower metabolic activity correlates with longer disease duration and higher attack frequency [41] as well as altered FC. In particular, stronger coupling between the PCC, ACC, and medial prefrontal regions has been associated with more efficient conditioned pain modulation [42], whereas pain catastrophizing corresponds to reduced activation of these same nodes [43]. Resting-state ACC-PCC [44] and PCC [43] connectivity has also been negatively correlated with pain intensity, and patients with cutaneous allodynia exhibit heightened cingulate responses to painful stimulation [44], reinforcing the role of this pathway is critical for endogenous pain regulation and central sensitization in migraine.

In this context, the increase in frontal-ACC-PCC connectivity observed in our cohort, and the ACC-PCC FC association with reductions in MMD, MAM, and allodynia, suggests that atogepant may help restore the functional balance of this midline regulatory system.

Interestingly, the regions identified in our study (i.e. frontal areas, cingulate cortex, and putamen) overlap with those showing increased connectivity in response to painful stimulation in patients who responded to an 8-week erenumab treatment compared with non-responders [11]. Considering that erenumab and atogepant targets both the CGRP receptor, these converging findings raise the possibility of a similar, albeit likely indirect, central mechanism of action underlying therapeutic response [35, 37, 40].

With respect to neurotransmitter-related FC, we observed increased dopamine-related connectivity in the mesocorticolimbic dopaminergic system (D1 receptor and DAT transporter), in a cluster located in the medial orbitofrontal cortex, a key node region of the mesocorticolimbic circuit, that contributes to pain modulation by integrating the affective and motivational dimensions of painful stimuli and by exerting inhibitory coupling with regions involved in nociceptive information processing [45]. Alterations of this dopaminergic pathway have already been described in migraine, where mesocorticolimbic FC alterations associated with dopamine availability have been previously reported in EM patients, suggesting a dopaminergic contribution to pain processing and affective response to pain [46]. Importantly, similar patterns have been observed across chronic pain conditions. Reduced dopamine synthesis and release, together with gray matter volume loss of its major nodes, have been observed [47]. Likewise, disrupted mesocorticolimbic connectivity has been associated with central pain sensitization and chronification in conditions such as chronic low back pain [48]. Based on these observations, the dopamine-related FC increases observed here may reflect a normalization of altered mesocorticolimbic dynamics, suggesting that atogepant may exert part of its therapeutic effect by directly or indirectly normalizing disrupted dopaminergic connectivity patterns, restoring adaptive pain processing mechanisms.

Although atogepant antagonism of the CGRP receptor is well established, the extent to which atogepant crosses the BBB remains uncertain. Both gepants and mAbs exhibit limited BBB permeability and are therefore believed to exert their therapeutic effects outside the central nervous system (CNS) [49, 50]. For mAbs, the prevailing view is that their reduction of peripheral activation afferents, may secondarily influence central brain regions involved in pain perception, salience processing, and descending inhibitory control [11–14, 51, 52]. On the other hand, even small quantities reaching the CNS may still contribute to treatment response [14]. Although slightly higher in BBB penetration, a similar mechanism is plausible even for gepants.

In this framework, the clinical improvements observed in our cohort together with the longitudinal increases in connectivity across regions involved in multiple dimensions of pain processing, including the mesocorticolimbic dopaminergic system, may reflect indirect central modulation mediated by atogepant resulting from reduced peripheral nociceptive drive. Further work is needed to clarify whether atogepant, and gepants broadly, exert central actions directly or predominantly through peripheral CGRP-receptor blockade and comparative studies with mAbs will be crucial to clarify exact mechanisms of anti-CGRP therapies.

Limitations

Our findings should be considered in light of some limitations. First, our sample size of EM patients was modest, although homogeneous, reflecting the explorative nature of the study. Second, the follow-up period was limited to 12 weeks. While this interval aligns with standard clinical practice, longer observation may help clarify the extent and durability of atogepant CNS effects. Third, this was a cohort study, and therefore we cannot completely exclude that the observed variations in brain connectivity are the solely effect of atogepant administration. Studies with a control condition could further explore the specific neuromodulation activity of atogepant.

In this study, we provide the first evidence of longitudinal FC changes in brain regions involved in pain processing and within the dopaminergic mesocorticolimbic system in EM patients after 12 weeks of atogepant treatment. These findings may reflect direct or indirect central neurofunctional adaptations associated with clinical improvement. A deeper understanding of such central changes could offer new insights into the mechanism underlying successful preventive therapies for migraine.

Data may be made available upon reasonable request to corresponding author.