Dopaminergic Regulation of Reward System Connectivity Underpins Pain and Emotional Suffering in Migraine

Abstract

Purpose It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues. Patients and Methods We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [ 11 C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed. Results Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS). Conclusion Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.

Alterations in Effective Connectivity of the Hippocampus in Migraine without Aura

“… 21 Recently, a study focusing on the reward system revealed weaker FC between the right nucleus accumbens and hippocampus in patients with EM. 22 In one study examining the contribution of genotype to hippocampal FC changes in female patients with EM, Liu et al found no significant interaction effect for disease and catechol-O-methyltransferase genotype, but reported decreased FC between hippocampus and multiple brain regions including the mPFC, insula and amygdala in EM patients with val homozygote. 16 Chong et al found stronger structural covariance between the hippocampus and cortico-limbic regions in migraine.…”

Functional magnetic resonance imaging in migraine: A systematic review

“…In subjects with migraine, the amygdala displayed increased rs-FC to middle occipital gyrus (26), middle cingulate cortex (100), right insula (61), and left precuneus (100) compared to HC. Decreased amygdala rs-FC compared to HC was found with orbitofrontal cortex (26), right nucleus accumbens (119), inferior occipital gyrus, and middle occipital gyrus (100). Altered amygdala rs-FC was also demonstrated between different types of migraine: between episodic migraine and chronic migraine (for a number of connected areas) (100), as well as between chronic migraine with and without medication overuse (for FC between bilateral amygdala) (127).…”

“…The rs-FC of hippocampus was decreased to some areas (hypothalamus [31], right nucleus accumbens [119], inferior parietal gyrus and supplementary motor area [26]) and increased to other areas (hypothalamus [53], cerebellar and occipital areas [26]) compared to HC. rs-FCD of hippocampus was found increased in chronic migraine (123) as well as decreased in migraine without aura (55) compared to HC.…”

“…Overall, findings regarding rs-FC of cingulate cortex were heterogeneous. While some studies found heightened rs-FC of anterior cingulate cortex (to lingual gyrus [132], middle temporal gyrus and right frontal pole [131]) in subjects with migraine compared to HC, other studies demonstrated reduced rs-FC of anterior cingulate cortex (to anterior insula [27], right nucleus accumbens [119], periaqueductal grey [58], prefrontal cortex [69], and posterior cingulate cortex [69]) in migraine without aura compared to HC. For the posterior cingulate cortex, some studies showed decreased rs-FC (to medial prefrontal cortex [27], primary somatosensory cortex, temporal, parietal, and frontal areas [132]) in migraine without aura compared to HC.…”

Meditation practice, mindfulness and pain-related outcomes in mindfulness-based treatment for episodic migraine

“…Specifically, the mesolimbic system (i.e., neurons in the ventral tegmental area that project to the nucleus accumbens [NAc], thalamus, amygdala and hippocampus) and its cortical projections (i.e., to the anterior cingulate cortex, ventromedial prefrontal cortex [vmPFC] and orbitofrontal cortex) are activated in the context of approach and avoidance behaviors, respectively (Cardinal et al, 2002;Salamone, 1994;Salamone & Correa, 2012). Individuals with chronic pain show general deficits in mesocorticolimbic functioning and associated reward processing (Loggia et al, 2014) with the degree of reward system dysfunction correlating with pain severity (Kim et al, 2021).…”