Etienne Vachon-Presseau

The Stress Model of Chronic Pain: Evidence from Basal Cortisol and Hippocampal Structure and Function in Humans.

Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations administered in 16 patients with chronic back pain and 18 healthy control subjects. Results showed that patients with chronic back pain have higher levels of cortisol than control subjects. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus, a region involved in anticipatory anxiety and associative learning. Importantly, path modelling-a statistical approach used to examine the empirical validity of propositions grounded on previous literature-revealed that the cortisol levels and phasic pain responses in the parahippocampal gyrus mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the sustained endocrine stress response observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states.

Cerebral Regulation of Facial Expressions of Pain

Facial expression of affective states plays a key role in social interactions. Interestingly, however, individuals differ substantially in their level of expressiveness, ranging from high expressive to stoic individuals. Here, we investigate which brain mechanisms underlie the regulation of facial expressiveness to acute pain. Facial responses, pain ratings, and brain activity (BOLD-fMRI) evoked by noxious heat and warm (control) stimuli were recorded in 34 human volunteers with different degrees of facial expressiveness. Within-subject and between-subject variations in blood oxygenation level-dependent (BOLD) responses were examined specifically in relation to facial responses. Pain expression was inversely related to frontostriatal activity, consistent with a role in downregulating facial displays. More detailed analyses of the peak activity in medial prefrontal cortex revealed negative BOLD responses to thermal stimuli, an effect generally associated with the default mode network. Given that this negative BOLD response was weaker in low expressive individuals during pain, it could reflect stronger engagement in, or reduced disengagement from, self-reflective processes in stoic individuals. The occurrence of facial expressions during pain was coupled with stronger primary motor activity in the face area and—interestingly—in areas involved in pain processing. In conclusion, these results indicate that spontaneous pain expression reflects activity within nociceptive pathways while stoicism involves the active suppression of expression, a manifestation of learned display rules governing emotional communication and possibly related to an increased self-reflective or introspective focus.

Corticolimbic anatomical characteristics predetermine risk for chronic pain

SEE TRACEY DOI101093/BRAIN/AWW147 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Mechanisms of chronic pain remain poorly understood. We tracked brain properties in subacute back pain patients longitudinally for 3 years as they either recovered from or transitioned to chronic pain. Whole-brain comparisons indicated corticolimbic, but not pain-related circuitry, white matter connections predisposed patients to chronic pain. Intra-corticolimbic white matter connectivity analysis identified three segregated communities: dorsal medial prefrontal cortex-amygdala-accumbens, ventral medial prefrontal cortex-amygdala, and orbitofrontal cortex-amygdala-hippocampus. Higher incidence of white matter and functional connections within the dorsal medial prefrontal cortex-amygdala-accumbens circuit, as well as smaller amygdala volume, represented independent risk factors, together accounting for 60% of the variance for pain persistence. Opioid gene polymorphisms and negative mood contributed indirectly through corticolimbic anatomical factors, to risk for chronic pain. Our results imply that persistence of chronic pain is predetermined by corticolimbic neuroanatomical factors.

Acute Stress Contributes to Individual Differences in Pain and Pain-Related Brain Activity in Healthy and Chronic Pain Patients

Individual differences in pain sensitivity and reactivity are well recognized but the underlying mechanisms are likely to be diverse. The phenomenon of stress-induced analgesia is well documented in animal research and individual variability in the stress response in humans may produce corresponding changes in pain. We assessed the magnitude of the acute stress response of 16 chronic back pain (CBP) patients and 18 healthy individuals exposed to noxious thermal stimulations administered in a functional magnetic resonance imaging experiment and tested its possible contribution to individual differences in pain perception. The temperature of the noxious stimulations was determined individually to control for differences in pain sensitivity. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared with their basal levels collected over 7 consecutive days, suggesting normal hypothalamic–pituitary–adrenal axis reactivity to painful stressors in CBP patients. Critically, after controlling for any effect of group and stimulus temperature, individuals with stronger cortisol responses reported less pain unpleasantness and showed reduced blood oxygenation level-dependent activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness. Psychophysiological interaction analysis further revealed that higher stress reactivity was associated with reduced functional connectivity between the aMCC and the brainstem. These findings suggest that acute stress modulates pain in humans and contributes to individual variability in pain affect and pain-related brain activity.

The multilevel organization of vicarious pain responses: Effects of pain cues and empathy traits on spinal nociception and acute pain

&NA; The shared‐representation model of empathy suggests that vicarious pain processes rely partly on the activation of brain systems underlying self‐pain in the observer. Here, we tested the hypothesis that self‐pain may be facilitated by the vicarious priming of neural systems underlying pain perception. Pictures illustrating painful agents applied to the hand or the foot (sensory information), or painful facial expressions (emotional information) were shown to 43 participants to test the effects of vicarious pain on the nociceptive flexion reflex (NFR) of the lower limb and pain intensity and unpleasantness produced by transcutaneous electrical stimulation applied over the sural nerve. Results confirmed the expected priming effects of vicarious pain on spinal and perceptual processes. However, for comparable pain intensity and arousal evoked by the pain pictures, the facilitation of the NFR and the self‐pain unpleasantness measurements was more robust in response to pictures depicting pain sensory compared to emotional information. Furthermore, the facilitation of the NFR by pain pictures was positively correlated with the empathy trait of the observer. In contrast, the change in perceived shock‐pain intensity was negatively correlated with empathic traits. This dissociation implies that low‐level vicarious priming processes underlying pain facilitation may be downregulated at higher pain‐processing stages in individuals reporting higher levels of empathy. We speculate that this process contributes to reducing self–other assimilation and is necessary to adopt higher‐order empathic responses and altruistic behaviors. A priming effect of vicarious pain and individuals’ empathic traits on self‐pain processing at different levels of the neuraxis is revealed.

Neural processing of sensory and emotional-communicative information associated with the perception of vicarious pain☆

The specific neural processes underlying vicarious pain perception are not fully understood. In this functional imaging study, 20 participants viewed pain-evoking or neutral images displaying either sensory or emotional-communicative information. The pain images displayed nociceptive agents applied to the hand or the foot (sensory information) or facial expressions of pain (emotional-communicative information) and were matched with their neutral counterparts. Combining pain-evoking and neutral images showed that body limbs elicited greater activity in sensory motor regions, whereas midline frontal and parietal cortices and the amygdala responded more strongly to faces. The pain-evoking images elicited greater activity than their neutral counterparts in the bilateral inferior frontal gyrus (IFG), the left inferior parietal lobule (IPL) and the bilateral extrastriate body area. However, greater pain-related activity was observed in the rostral IPL when images depicted a hand or foot compared to a facial expression of pain, suggesting a more specific involvement in the coding of somato-motor information. Posterior probability maps enabling Bayesian inferences further showed that the anterior IFG (BA 45 and 47) was the only region showing no intrinsic probability of activation by the neutral images, consistent with a role in the extraction of the meaning of pain-related visual cues. Finally, inter-individual empathy traits correlated with responses in the supracallosal mid/anterior cingulate cortex and the anterior insula when pain-evoking images of body limbs or facial expressions were presented, suggesting that these regions regulated the observers affective-motivational response independent from the channels from which vicarious pain is perceived.

The Emotional Brain as a Predictor and Amplifier of Chronic Pain

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain—that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.

Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700

Dispositional empathy modulates vicarious effects of dynamic pain expressions on spinal nociception, facial responses and acute pain

Pain communication is thought to promote automatic vicarious self‐protective responses as well as empathic concern towards others’ suffering. This duality was recently highlighted in a study showing that highly empathic individuals display increased vicarious facilitation of low‐level pain processing (nociceptive flexion reflex, NFR) combined with an unexpected reduced facilitation of self‐pain perception (pain ratings) while viewing static pictures evoking pain in others. The present study sought to test further the moderating effects of dispositional empathy on vicarious responses induced by viewing dynamic pain expressions. Twenty‐four healthy volunteers viewed 1‐s videos showing different levels of pain expression before noxious electric shocks were delivered to the sural nerve. Viewing stronger pain expressions generally increased shock–pain unpleasantness ratings, the amplitude of the NFR, and facial responses (corrugator muscle) to the noxious stimulation. However, self‐pain ratings (intensity and unpleasantness) increased less or were reduced following clips of pain expression in individuals scoring higher on the Empathy Quotient. These results suggest that vicarious processes facilitate low‐level defensive responses, while the experience of self‐pain and the associated negative affect may be partly tuned‐down by higher‐order empathic processes.

Global disruption of degree rank order: a hallmark of chronic pain.

Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic pain conditions. We used resting-state functional MRI data to analyze the brain connectome at varying scales and densities. In three chronic pain conditions, we observe disrupted kD, in proportion to individuals’ pain intensity, and associated with community membership disruption. Additionally, we observe regional degree changes, some of which were unique to each type of chronic pain. Subjects with recent onset of back pain exhibited emergence of kD only when the pain became chronic. Similarly, in neuropathic rats kD emerged weeks after injury, in proportion to pain-like behavior. Thus, we found comprehensive cross-species evidence for chronic pain being a state of global randomization of functional connectivity.