Disentangling linear and nonlinear brain responses to evoked deep tissue pain

Abstract

Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional MRI, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region’s functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least five different, regionally-specific activity profiles in the brain. Linearly increasing (e.g., primary somatosensory/motor cortex, insulae) and intensity-independent (e.g., secondary somatosensory cortex) activation was noted in traditional pain processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (e.g., posterior cingulate cortex), linearly decreasing (e.g., contralateral inferior parietal lobule), and quadratic (U-shaped; e.g., medial prefrontal cortex). The latter observation suggests that: 1) different DMN subregions exhibit functional heterogeneity and 2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities in order to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

Pain-related autonomic response is modulated by the medial prefrontal cortex: An ECG–fMRI study in men

“…The physiological significance of pain-related BOLD-signal change within certain brain regions is still unclear, which is particularly true for deactivations. Most of the previous studies focused predominantly on pain-evoked brain activations, while deactivations were relatively neglected until recently [22,26]. The pain-related deactivation of MPFC observed in the present study also indicate, that not only activations (across the "pain matrix") but-as other studies have also proposed-the investigation of deactivations might yield a better understanding of central pain processing [22].…”

Disrupted Brain Circuitry for Pain‐Related Reward/Punishment in Fibromyalgia

“…Of note, we were able to observe these brain responses even if the stimuli used had a longer duration (i.e., 46 – 74 sec) than most published fMRI pain studies. Still, the lack of activation within the primary somatosensory cortex (which we have previously observed with cuff pain stimuli of shorter duration (21)) could be due to the length of stimulation. During the relief anticipation period (Figure 4), FM patients exhibited decreased brain activation compared to controls, as they activated visual areas (likely in response to the processing of the visual cue) but, unlike healthy volunteers, failed to activate S1/M1, SPL, ventro- and dorso-lateral prefrontal and fronto-insular cortices.…”

“…Interestingly, brain responses to pain anticipation were significantly reduced in FM patients. Cuff pain stimuli (Figure 3) evoked brain activity changes in regions frequently observed as activated (thalamus, insula/frontal operculum, S2, DLPFC, basal ganglia and cerebellum) or deactivated (medial prefrontal cortex) during experimental pain (21, 26), which were statistically indistinguishable across groups in whole-brain analyses. Of note, we were able to observe these brain responses even if the stimuli used had a longer duration (i.e., 46 – 74 sec) than most published fMRI pain studies.…”

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks

“…Notably, the role of the DMN in pain perception has remained under debate. Deactivations of the DMN during pain were reported in early imaging studies (40,41), but recent studies suggest a more nuanced view in which the DMN responds nonlinearly or even activates during pain (42,43). In any pain study, attention likely fluctuates on a trial-to-trial basis variably in different individuals.…”