Mesocorticolimbic Pathways Encode Cue-Based Expectancy Effects on Pain

Abstract

Expectation interacting with nociceptive input can shape the perception of pain. It has been suggested that reward-related expectations are associated with the activation of the ventral tegmental area (VTA), which projects to the striatum (e.g., nucleus accumbens [NAc]) and prefrontal cortex (e.g., rostral anterior cingulate cortex [rACC]). However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. In this study, we leveraged a visual cue conditioning paradigm with a long pain anticipation period and collected magnetic resonance imaging (MRI) data from 30 healthy human subjects (14 females). At the within-subject level, whole-brain functional connectivity (FC) analyses showed that the mesocortical pathway (VTA-rACC FC) and the mesolimbic pathway (VTA-NAc FC) were enhanced with positive expectation but inhibited with negative expectation during pain anticipation period. Mediation analyses revealed that cue-based expectancy effects on pain were mainly mediated by the VTA-NAc FC, and structural equation modeling showed that VTA-based FC influenced pain perception by modulating pain-evoked brain responses. At the between-subject level, multivariate pattern analyses demonstrated that gray matter volumes in the VTA, NAc, and rACC were able to predict the magnitudes of conditioned pain responses associated with positive and/or negative expectations across subjects. Our results therefore advance the current understanding of how the reward system is linked to the interaction between expectation and pain. Furthermore, they provide precise functional and structural information on mesocorticolimibic pathways that encode within-subject and between-subject variability of expectancy effects on pain. Significance StatementStudies have suggested that reward-related expectation is associated with the activation of the VTA, which projects to the striatum and prefrontal cortex. However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. Using multimodality MRI and a visual cue conditioning paradigm, we found that the functional connectivity and gray matter volumes in key regions (the VTA, NAc, and rostral ACC) within the mesocorticolimbic pathways encoded expectancy effects on pain. Our results advance the current understanding of how the reward system is linked to the interaction between expectation and pain, and provide precise functional and structural information on mesocorticolimbic pathways that encode expectancy effects on pain.

Pain and social decision-making: New insights from the social framing effect

“…In addition, regarding the impact of emotion on decision-making (see Section 3), an unsolved problem is whether empathy and guilt elicited by pain in others modulate decision-making directly (as suggested by the risk-as-feeling hypothesis) or through cognitive evaluation (as suggested by the affect-as-information hypothesis). Finally, our findings indicate a close relationship between reward processing and pain processing, which has been acknowledged recently and needs to be explored further [156,157].…”

The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review

“…The VTA, a part of the DAergic system, is composed of mesolimbic DA neurons that project to the NAc and mPFC [ 59 , 60 ]. It is involved in various physiological functions such as pain processing and motivation [ 59 ].…”

“…The shell is the outer region innervated by DAergic neurons and is closely related to the mesolimbic system. It has been identified as playing a profound role in motivation and pain modulation pathways [ 60 , 69 ]. In contrast, the NAc core region, which connects to the caudate-putamen and striatum, is involved in goal-directed behaviors [ 70 , 71 ].…”

A mutant vesicular stomatitis virus with reduced cytotoxicity and enhanced anterograde trans-synaptic efficiency

“…Ventral tegmental area (VTA) is an important brain region with complex output neural networks, which performs diverse functions in reward, cognition, motivation, and aversion [38][39][40]. VTA neurons project to the lateral septal nucleus (LS), the nucleus accumbens (ACB), the caudoputamen (CP), the habenula, the amygdala, the dorsal nucleus raphe (DR), the prefrontal cortex (PFC), the anterior cingulate area (ACA), and the somatomotor areas (MO), among other regions [41][42][43][44][45][46]. To examine anterograde trans-synaptic ability of Mutant-VSV, the Mutant-VSV and WT-VSV were injected into the VTA region of mouse brain, and the brain slices were prepared at 3 DPI and 5 DPI.…”