Enhanced amygdala-frontal operculum functional connectivity during rest in women with chronic neck pain: Associations with impaired conditioned pain modulation

Abstract

Background: Chronic neck pain is a leading cause of disability worldwide, affecting the lives of millions of people. Research investigating functional brain alterations in relation to somatosensory function is necessary to better understand mechanisms underlying pain development and maintenance in individuals with chronic neck pain, yet remains scarce. This case-control study aimed to examine resting-state functional connectivity alterations and associations with pain outcomes, self-reported central sensitization-related symptoms and quantitative sensory testing (QST) measures in patients with chronic non-traumatic (idiopathic/CINP) neck pain and chronic traumatic (whiplash associated/CWAD) neck pain compared to pain-free controls.

Methods: Resting-state functional magnetic resonance images were acquired in 107 female participants (38 CINP, 37 CWAD, 32 healthy controls). After data pre-processing, seed-to-seed analyses were conducted focusing on resting-state functional connectivity involving pre-defined regions of interest that have previously been observed to be structurally or functionally altered and/or associated with pain-related measures in this patient population.

Results: Findings demonstrate enhanced left amygdala functional coupling during rest with the left frontal operculum in women with CINP and CWAD compared to controls. This increased resting-state functional connectivity was associated with more self-reported symptoms related to central sensitization and decreased efficacy of conditioned pain modulation. Furthermore, enhanced connectivity between the left amygdala and left frontal orbital cortex, and between the left pallidum and the left frontal operculum was observed only in patients with CWAD compared to healthy controls. In patients, additional associations between local hyperalgesia and enhanced connectivity between the left superior parietal cortex and the left and right precentral gyrus were found.

Conclusions: In line with our hypotheses, patients with CWAD showed the most pronounced alterations in resting-state functional connectivity, encompassing subcortical limbic (amygdala) and basal ganglia (pallidum), and ventral frontal regions (frontal operculum, orbitofrontal cortex) when compared to CINP and controls. Findings are generally in line with the idea of a continuum, in absence of significant group differences across CINP and CWAD. Enhanced amygdala-frontal operculum functional connectivity was the most robust and only connectivity pair in the cluster that was associated with QST (i.e., dynamic QST; endogenous pain inhibition), and that was observed in both patient groups. In addition, independent of group differences, enhanced resting-state functional connectivity between superior parietal cortex (involved in attention) and primary motor cortex was associated with static QST (i.e., greater local hyperalgesia). Taken together, our findings show a key role for enhanced amygdala-ventral frontal circuitry in chronic neck pain, and its association with diminished endogenous pain inhibition further emphasizes the link between cognitive-affective and sensory modulations of pain in women with chronic non-traumatic and traumatic neck pain.

Keywords: Chronic idiopathic neck pain; Chronic whiplash associated disorders; Pain processing; Quantitative sensory testing; Resting-state functional connectivity.

Fig. 1

Self-reported pain-related outcomes (n = 100), self-reported symptoms related to CS (n = 100), and QST measures (n = 98) across groups. Box plots and values of individual participants are presented. Significant values reflect results of post-hoc pairwise comparisons of one-way ANOVA or Kruskal-Wallis test. Main effects of group are not depicted for visual simplicity. All p values are Bonferroni corrected. *= p < .05, **= p < .01, ***= p < .005. CS: central sensitization, QST: quantitative sensory testing, NDI: Neck Disability Index.

Fig. 2

rsFC pairs showing a significant main effect of group (p-FDR < 0.05) (A). Statistics refer to the pairwise group comparisons. *= p < .05, ***= p < .001. p values are Bonferroni corrected. Amy: Amygdala, l: left, OFC: Orbitofrontal cortex, FO: frontal operculum, rsFC: resting-state functional connectivity. Scatterplots of associations between rsFC showing group differences and CPM (taking CINP and CWAD together), and for associations with CSI taking CINP and CWAD separately because of significant interaction effect with group (B).

Fig. 3

Scatterplots of associations between higher local pressure hyperalgesia (i.e., decreased PPTs), and increased rsFC between left superior parietal cortex and respectively right and left precentral gyrus at the level of all selected regions in patients with chronic whiplash associated disorders (CWAD) and chronic idiopathic neck pain (CINP). PPT: pressure pain threshold, rsFC: resting-state functional connectivity.

Fig. 4

Overview of ROIs showing significant group differences in rsFC between CINP and CWAD patients and pain-free controls, and ROIs involved in significant associations between rsFC across all selected regions and local hyperalgesia within CINP and CWAD patients. ROIs: regions of interest, rsFC: resting-state functional connectivity, CS: central sensitization, CINP: chronic idiopathic neck pain, CWAD: chronic whiplash associated disorders.