Sustained perturbation in functional connectivity induced by cold pain

Abstract

Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes is varied and inconsistent between cohorts. Increases and decreases in connectivity strength in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how other networks are effected, for example, descending pain control networks, remains unknown. Whether connectivity changes relate to peripherallymediated nociceptive afferent input, represent coping strategies or are sequelae of chronic pain, e.g. anxiety/depression, is also unknown. Here, we examined FC changes in response to experimentally-administered tonic cold pain in healthy volunteers as a means of disambiguating the nature of connectivity changes. We assessed FC prior to, during, and following tonic cold painful stimulation in four seed regions: ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG) and recorded subjectively reported pain using a computerised visual analogue scale. We saw DMN FC changes during painful stimulation and that internetwork communication between the rAI and sgACC seeds with the vmPFC became less anti-correlated during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations largely persisted during a 6-minute recovery period following cessation of the painful stimulus. Observed FC changes related to the magnitude of individuals' subjectively reported pain. We provide new insights into FC changes during and following tonic coldpain and suggest that some FC changes observed in chronic pain patients may relate to the presence of an ongoing afferent peripheral drive.

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks

“…During the scanning session, participants underwent three consecutive resting-state fMRI blocks, each of 6 min duration: a baseline resting condition ("Baseline"), and a prolonged noxious cold stimulation ("Cold-pain") and a post-cold recovery session. For this study, data from the first two blocks were analyzed, whilst the results of the last block are presented in Makovac et al (2019). To elicit pain, 2 • C cold-water was circulated via a custom-made aluminum thermode (4 × 20 cm) applied to the volar surface of the participants' left forearm, via a high capacity (700W) solid state circulating chiller unit (Thermotek RC22A750) employed to deliver stable temperature control of the afferent stimulation over time.…”

“…In our original experimental paradigm, the "cold-pain" resting state session was followed immediately by a further "post-cold" session (see Makovac et al, 2019), which precluded the provision of an intermediate subjective response to the prolonged noxious stimulation. To circumvent this, each participant's subjective experience of cold pain was explored in a further post-scanning session.…”

“…The cingulate-seed was located at MNI xyz = (2, 8, 38) (7 mm spherical radius; right dACC) and the PAG ROI at MNI xyz = (0, −30, −1) (3 mm spherical radius). Our ROIs were based on results from pre-existing data acquired by our group (Makovac et al, 2019) and previously published examples of the dACC (Kong et al, 2010a;Duerden and Albanese, 2013;Wilcox et al, 2015) and the PAG (Kong et al, 2010b;Zyloney et al, 2010;Mainero et al, 2011). Functionally, we chose these two regions because of their known involvement in both pain processing and ANS control (see Supplementary Material S4 for a Neurosynth -https://neurosynth.org/ -based meta-analysis of pain-related and ANS-related studies, S4).…”

“…Functional connectivity of the dACC increased in the Coldpain condition with clusters in the contralateral rostral ACC, superior frontal gyrus, and the frontal pole (Figure 2A and Table 2). Upon noxious cold stimulation, functional connectivity of the PAG with the precuneus increased [results reported in Makovac et al (2019)].…”

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

“…During the scanning sessions, participants underwent three FC MRI scans, each of six minutes in duration: a baseline; a cold-pain and a post-cold recovery block. The investigation of the post-cold recovery phase aimed at identifying pain-related carry over effects and the results from this analysis have been reported elsewhere (Makovac et al, 2019). A multi-echo resting-state fMRI (rs-fMRI) approach was adopted to mitigate problems related to paininduced movements, which are an important source of non-BOLD artifacts in pain studies (Dipasquale et al, 2017;Moayedi, Salomons, & Atlas, 2018;Siegel et al, 2016).…”