The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

Key points Heart Rate Variability (HRV) is associated with descending pain modulation as measured by the Conditioned Pain Modulation paradigm (CPM) There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC) CPM scores are also associated with vmPFC grey matter (GM) The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM Our data provide new evidence of interactions between ANS and descending pain mechanisms. Abstract There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between 'pressure-only' and 'pressure+cold' stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart Rate Variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of LF-HRVnu-CPM association. CPM response magnitude was also negatively with vmPFC GM volumes. Our multi-modal approach, using behavioural, physiological, and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. Abstract figure. The aim of this study is to investigate which brain regions mediate the association between the Autonomic Nervous System (ANS) and descending pain modulating mechanisms. To achieve so, healthy controls underwent a Conditioned Pain Modulation paradigm, with the aim to explore the functioning of their descending pain modulating mechanisms. In a subgroup of these participants, we also acquired structural and functional MRI data, alongside with physiological data (i.e. Heart Rate Variability during cold pain). Overall, we observed that the CPM response was negatively associated with ventro-medial prefrontal cortex grey matter (vmPFC) and positively associated with the strength of functional connectivity between the periaqueductal gray area (PAG) and the vmPFC. Importantly, PAG-vmPFC functional connectivity mediated the strength of the association between HRV and CPM. This article is protected by copyright. All rights reserved.