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

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.