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 magnetic resonance imaging, 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 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, 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 (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, 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 to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

Figure 1. (A) Experiment trial design. (B) Legendre polynomial transformations

These transformations were applied to pain ratings in order to produce independent regressors for the fMRI general linear model.

Figure 2. Psychophysical results

Bars represent mean ± SD.

Figure 3. Group statistical maps for the (A) Constant, (B) Linear and (C) Quadratic stimulus-response curves

The gray insert displays the results of the direct searches in a priori regions (see Methods). SI/MI = primary somatosensory/motor cortex, SII = Secondary somatosensory cortex, pINS = posterior insula, aINS = anterior insula, MCC = middle cingulate cortex, HF = Hippocampal formation, thal. = thalamus, MPFC = medial prefrontal cortex, VLPFC = ventrolateral prefrontal cortex, LTC = lateral temporal cortex, cereb. = cerebellum, PCC = posterior cingulate cortex, Rsp = retrosplenial cortex, precun. = precuneus, IPL = inferior parietal lobule, SPL = superior parietal lobule, SMA = supplementary motor area, preSMA = pre-supplementary motor area, cun. = cuneus, NAc = nucleus accumbens.

Figure 4. Representative regions for each of the five activity patterns identified

(A) S2, (B) PCC/Rsp, (C) right SI/MI, (D) right IPL and (E) MPFC were selected as representative regions for the Constant+, Constant−, Linear+, Linear− and Quadratic contrasts, respectively. The left, middle and right panels show the masks used to extract the % signal change, the S-R curves, and the averaged peristimulus plots, respectively. In the scatterplots, brain response to innocuous stimuli (‘p0’, not modeled in the GLM) is represented by cyan circles. Error bars represent SEM. For acronyms and abbreviations, see Figure 3 caption.

Figure 5. Multifaceted DMN response to pain

Surface representation data demonstrate pain intensity independent deactivation (Constant−) in regions described as DMN ‘core’ areas, as well as bilateral perirolandic cortices (green arrows). In the scatterplots, the activity changes evoked by innocuous stimuli (‘p0’, not modeled in the GLM) are represented by cyan circles. X axes = pain intensity ratings, Y axes = % BOLD signal change. Error bars represent SEM. For acronyms and abbreviations, see Figure 3 caption. Using functional magnetic resonance imaging, this study identifies five different, regionally-specific activity profiles in the brain in response to seven levels of pain stimulation.