Exploring the Influence of Synaptic Density and Anxiety on Pain Perception: Evidence from a 11CUCB-J PET Imaging Study

• Published in: The international journal of neuropsychopharmacology
• Main Authors: Moisieienko, Karina, Asch, Ruth H, Davis, Margaret T, Pietrzak, Robert H, Esterlis, Irina
• Format: Journal Article
• Language: English
• Published: 13.06.2025
• ISSN: 1469-5111; 1469-5111
• DOI: 10.1093/ijnp/pyaf040

Structural and functional brain alterations may be associated with pain and anxiety. We hypothesized that synaptic density (measured in vivo with [11C]UCB-J and positron emission tomography quantification of synaptic vesicle SV2A) alterations may play a role in higher pain sensitivity, and that this relationship may be mediated by anxiety symptoms.BACKGROUNDStructural and functional brain alterations may be associated with pain and anxiety. We hypothesized that synaptic density (measured in vivo with [11C]UCB-J and positron emission tomography quantification of synaptic vesicle SV2A) alterations may play a role in higher pain sensitivity, and that this relationship may be mediated by anxiety symptoms.Twenty-one mentally and medically healthy subjects (11 males, 10 females; age 45.1 ± 16.9 years) participated in imaging, acute pain [cold pressor test (CPT)] and anxiety (State-Trait Anxiety Inventory) assessments. SV2A density was quantified as regional volumes of distribution (VT) using a one-tissue compartment model with a plasma input function. SV2A density was assessed in five regions of interest (ROIs) that were previously shown to be associated with pain: dorsolateral prefrontal cortex (DLPFC), amygdala, anterior cingulate cortex (ACC), fusiform gyrus, and cerebellum.METHODSTwenty-one mentally and medically healthy subjects (11 males, 10 females; age 45.1 ± 16.9 years) participated in imaging, acute pain [cold pressor test (CPT)] and anxiety (State-Trait Anxiety Inventory) assessments. SV2A density was quantified as regional volumes of distribution (VT) using a one-tissue compartment model with a plasma input function. SV2A density was assessed in five regions of interest (ROIs) that were previously shown to be associated with pain: dorsolateral prefrontal cortex (DLPFC), amygdala, anterior cingulate cortex (ACC), fusiform gyrus, and cerebellum.State anxiety was positively correlated with pain sensitivity (r = 0.60, p=.004). Significant negative correlations were observed between pain sensitivity and SV2A density in cerebellum (r = -0.67, p=.001), fusiform gyrus (r = -0.66, p=.001), DLPFC (r = -0.63, p=.002), and ACC (r = -0.58, p=.006). Mediation analysis revealed a significant indirect effect of cerebellar synaptic density on pain sensitivity through state anxiety symptoms (B = -0.77, 95% CI [-1.89, -0.04]), accounting for 33% of the total effect. For the fusiform gyrus, the direct effect on pain sensitivity remained significant after controlling for anxiety symptoms (B = -1.67, p=.020), while the indirect effect through anxiety symptoms was not significant (B = -0.43, 95% CI [-1.44, 0.37]).RESULTSState anxiety was positively correlated with pain sensitivity (r = 0.60, p=.004). Significant negative correlations were observed between pain sensitivity and SV2A density in cerebellum (r = -0.67, p=.001), fusiform gyrus (r = -0.66, p=.001), DLPFC (r = -0.63, p=.002), and ACC (r = -0.58, p=.006). Mediation analysis revealed a significant indirect effect of cerebellar synaptic density on pain sensitivity through state anxiety symptoms (B = -0.77, 95% CI [-1.89, -0.04]), accounting for 33% of the total effect. For the fusiform gyrus, the direct effect on pain sensitivity remained significant after controlling for anxiety symptoms (B = -1.67, p=.020), while the indirect effect through anxiety symptoms was not significant (B = -0.43, 95% CI [-1.44, 0.37]).Results provide the first known in vivo evidence that lower synaptic (SV2A) density is associated with greater pain sensitivity, particularly in the fusiform gyrus and cerebellum. Mediation analyses revealed that state anxiety partially mediated the relationship between cerebellar synaptic density and pain sensitivity, while having an additive - but not mediating - effect on the relationship between fusiform synaptic density and pain sensitivity.CONCLUSIONResults provide the first known in vivo evidence that lower synaptic (SV2A) density is associated with greater pain sensitivity, particularly in the fusiform gyrus and cerebellum. Mediation analyses revealed that state anxiety partially mediated the relationship between cerebellar synaptic density and pain sensitivity, while having an additive - but not mediating - effect on the relationship between fusiform synaptic density and pain sensitivity.