Amygdalar Functional Connectivity Differences Associated With Reduced Pain Intensity in Pediatric Peripheral Neuropathic Pain

Abstract

Background: There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation. Objective: To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP. Methods: This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11–18 years with clinical features of chronic peripheral NeuP (n = 17), recruited from a tertiary clinic, relative to healthy adolescents (n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences. Results: Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (PFDR<0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males (r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females (r = −0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory. Conclusions: Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible.