Abstract

Pain and somatosensory processing involves an interaction of multiple neuronal networks. One result of these complex interactions is the presence of differential responses across brain regions that may be incompletely modeled by a straightforward application of standard general linear model (GLM) approaches based solely on the applied stimulus. We examined temporal blood oxygenation-level dependent (BOLD) signatures elicited by two stimulation paradigms (brush and heat) providing innocuous and noxious stimuli. Data were acquired from 32 healthy male subjects (2 independent cohorts). Regional time courses and model-free analyses of the first cohort revealed distinct temporal features of the BOLD responses elicited during noxious versus innocuous stimulation. Specifically, a biphasic (dual peak) BOLD signal was observed in response to heat but much less so in response to brush stimuli. This signal was characterized by a stimulus-locked response along with a second peak delayed by approximately 12.5 s. A cross-validation error analysis determined a modified design matrix comprising two explanatory variables (EVs) as a parsimonious means to model the biphasic responses within a GLM framework. One EV was directly derived from the stimulation paradigm (EV1), while the second EV (EV2) was EV1 shifted by 12.5 s. The 2EV GLM analysis enabled a more detailed characterization of the elicited BOLD responses, particularly during pain processing. This was confirmed by application of the model to a second, independent cohort[AU1]. Furthermore, the delayed component of the biphasic response was strongly associated with the noxious heat stimuli, suggesting that this may represent a sensitive fMRI link of pain processing.