Background and aims: Previous research revealed differences in pain outcomes and central sensitization between patients with trauma-induced chronic whiplash associated disorders (CWAD) and patients with non-traumatic chronic idiopathic neck pain (CINP). Also, structural brain alterations have been observed in CWAD compared to CINP and healthy controls, which were related to maladaptive pain cognitions and central sensitization (CS). Functional brain alterations and their relationship with pain outcomes and CS, on the other hand, have not yet been investigated in this population. This study therefore aimed to examine resting-state functional connectivity (rsFC) alterations and associations with disability, pain, pain cognitions, and CS in CINP and CWAD patients compared to pain-free controls. 

Methods: Resting-state functional magnetic resonance images were acquired in 107 female participants (38 CINP, 37 CWAD, 32 controls). After data pre-processing, seed-to-seed rsFC analyses were conducted in the CONN toolbox. 17 regions of interest were selected as seed regions. These seeds are implicated in (chronic) pain and observed to be structurally altered in previous studies in this patient population. Targets were all frontal, parietal and subcortical regions, and the periaqueductal gray (PAG). All regions were extracted from the Harvard-Oxford cortical and subcortical atlas, except for the PAG (coordinate-based). Potential rsFC group differences were examined. Within regions showing a main effect of group, associations with disability, pain intensity, pain cognitions and measures of CS were examined. Also, within the patient group, associations were investigated between measures of CS and rsFC between all seeds and targets. Age was included as covariate in the analyses. For the main effect of group, an FDR correction was applied (p-FDR < .05), and a Bonferroni correction was performed for pairwise group comparisons. 

Results: A significant main effect of group was observed in rsFC between the left amygdala and respectively left frontal operculum (b=.09; p-FDR= .04) and right inferior frontal triangularis (b=.09; p-FDR = .04). Pairwise group comparisons revealed that patients with CWAD showed increased rsFC between left amygdala and respectively left frontal operculum (p= .001) and right inferior frontal triangularis (p= .003) compared to controls. Furthermore, patients with CINP also showed increased rsFC between the left amygdala and right inferior frontal triangularis (p= .02) compared to controls. No rsFC group differences were observed between patients with CWAD and CINP.
Zooming into these group differences, we observed that across the patient group (taking CINP and CWAD together), increased rsFC between left amygdala and left frontal operculum was furthermore associated with more self-reported CS symptoms (r= .28; p= .02) and decreased efficacy of conditioned pain modulation (r= -.29; p= .03). 
At the whole-brain level (all selected regions), increased strength of rsFC between the anterior cingulate gyrus and right frontal operculum cortex was furthermore associated with lower pressure pain thresholds at the quadriceps muscle (r= -.40; p-FDR = .04) across the patient group. In addition, more self-reported symptoms of CS were associated with increased strength of rsFC between the left thalamus and respectively right insular cortex (r= .36; p-FDR= .002), right central operculum (r= .34; p-FDR = .01), and left postcentral gyrus (r= .42; p-FDR = .01). 

Conclusions: These findings are the first to demonstrate increased amygdala functional coupling during rest with regions in the ventrolateral prefrontal cortex in both women with CINP and CWAD compared to healthy controls. No rsFC differences were observed between the traumatic and non-traumatic chronic neck pain group. The increased rsFC between the amygdala and the frontal operculum was related to more self-reported symptoms of CS and decreased efficacy of endogenous pain inhibition. In addition, other associations between increased rsFC of various pain-related regions of interest and more signs of CS were observed. The altered amygdala-prefrontal cortex rsFC may be involved in the pathophysiology of CWAD and CINP. Further prospective longitudinal studies are warranted, and future research should explore whether therapy reverses these brain alterations.

ALTERED RESTING-STATE FUNCTIONAL CONNECTIVITY IN WOMEN WITH TRAUMATIC AND NON-TRAUMATIC CHRONIC NECK PAIN COMPARED TO PAIN-FREE WOMEN: ASSOCIATIONS WITH PAIN OUTCOMES AND CENTRAL SENSITIZATION?