A Novel Investigation of an In-Scanner Alternative to the Cold Pressor Test in Healthy Individuals

Abstract

The cold pressor task (CPT) is widely used to study tonic pain during acute and chronic conditions and is often used as a conditioning stimulus to activate descending pain control systems. However, logistical challenges in magnetic resonance imaging (MRI) limit its application, hindering the understanding of CPT's neural dynamics. To address this, we acquired resting-state functional MRI (fMRI) data from 30 healthy participants before, during and after immersion in gelled-cold water, the closest in-scanner alternative to date to CPT for prolonged stimulation. Participants provided subjective pain intensity ratings after each scan, as well as average pain perceived during noxious stimulation, using a numeric rating scale (NRS). Following fMRI, participants rated their pain continuously during identical tonic noxious stimulation of the contralateral hand using a visual analogue scale (VAS). We employed three complementary methods to examine changes in brain function across fMRI conditions: a data-driven approach via independent component analysis (ICA), seed-to-whole-brain connectivity analysis with the periaqueductal grey (PAG) as seed and spectral dynamic causal modelling (spDCM) to explore effective connectivity changes across the dorsal anterior cingulate cortex (dACC), anterior insulae (AI), thalamus and PAG. NRS scores were significantly higher following tonic cold compared to baseline and recovery conditions. Continuous VAS reflected sustained mild-to-moderate pain over 6 min, with average VAS scores not significantly differing from NRS ratings recorded in the scanner. ICA identified engagement of descending pain control and sensorimotor networks during pain, with the latter persisting during recovery. Seed-based analysis revealed a disengagement between the PAG and cortical/subcortical regions involved in pain processing, such as the dACC, midcingulate cortex, AI, intraparietal sulcus and precuneus. Finally, spDCM revealed tonic pain neural signature was most likely characterised by top-down inhibitory and bottom-up excitatory connections. This study establishes the cold gelled-water paradigm as a potential in-scanner alternative to CPT. By uncovering key neural dynamics of CPT, we provide new insights into the brain and brainstem mechanisms of tonic cold pain paradigms routinely used in psychophysical pain studies.