Figure 1. Hierarchy of specific and non-specific components of the brain response to acute pain and approach for identifying pain-specific responses.

A. Brain responses to pain are composed of four hierarchical components of processing, illustrated in concentric rings from most general (outer pink circle) to most specific (inner red semi-circle): 1) domain-general responses to any sensations regardless of the sensory modality of the stimulus (e.g. arousal, attention, salience, valence), 2) processing of somatosensory information regardless of nociception (e.g. intensity, location, and modality), 3) processing of nociceptive information, regardless of pain perception; and 4) pain-specific responses (i.e. those that track the subjective pain experience).

B. Here we illustrate a potential fMRI analysis pipeline that leverages autonomic nervous system (ANS) isolate pain-specific BOLD responses. Step 1 depicts a conventional fMRI analysis that models only standard nuisance regressors (e.g., motion, global signal, spikes, intercepts). If correlations between BOLD responses and subjective pain are evaluated, results are unlikely to be specific to pain. Step 2 depicts a design matrix that incorporates additional regressors (in color) corresponding to temperature effects (left, blue) and the timeseries of recorded autonomic measures (right, green), such as skin conductance (SCR) or pupillary response (PR), alongside nuisance regressors. This design matrix thereby accounts for differences in arousal (non-specific response) and nociception. Residual associations between brain activity and subjective pain can therefore be evaluated (Steps 3 and 4), which are more likely to be specific to pain.