Turning on the alarm: the neural mechanisms of the transition from innocuous to painful sensation

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49oC) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid- cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum

Cognitive behavioral training reverses the effect of pain exposure on brain-network activity

Repeated sensory exposures shape the brain's function and its responses to environmental stimuli. An important clinical and scientific question is how exposure to pain affects brain network activity and whether that activity is modifiable with training. We sought to determine whether repeated pain exposure would impact brain-network activity and whether these effects can be reversed by cognitive behavioral training (CBT). Healthy subjects underwent 8 experimental sessions on separate days where they received painful thermal stimuli. They were randomly assigned to groups receiving either CBT (Regulate group, n=17) or a non-pain-focused treatment (Control group, n=13). Before and after these sessions, participants underwent functional MRI (fMRI) during painful stimulation and at rest. The effect of repeated pain over time in the Control group was a decrease in the neurotypical pain-evoked default mode network (DMN) deactivation. The Regulate group did not show these DMN effects but rather had decreased deactivation of the right ventrolateral prefrontal cortex (R vlPFC) of the executive control network. In the Regulate group, reduced pain-evoked DMN deactivation was associated with greater individual reduction in pain intensity and unpleasantness over time. Finally, the Regulate group showed enhanced resting functional connectivity between areas of the DMN and executive control network over time, compared to the Control group. Our study demonstrates that trainable cognitive states can alter the effect of repeated sensory exposure on the brain. The findings point to the potential utility of cognitive training to prevent changes in brain network connectivity that occur with repeated pain experience

The “pain matrix” in pain-free individuals

Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals,1,2 and is now considered a candidate biomarker for pain in medicolegal settings and a tool for drug discovery. The pain-specific interpretation of such functional magnetic resonance imaging (fMRI) responses, although logically flawed,3,4 remains pervasive. For example, a 2015 review states that “the most likely interpretation of activity in the pain matrix seems to be pain.”4 Demonstrating the nonspecificity of the pain matrix requires ruling out the presence of pain when highly salient sensory stimuli are presented. In this study, we administered noxious mechanical stimuli to individuals with congenital insensitivity to pain and sampled their brain activity with fMRI. Loss-of-function SCN9A mutations in these individuals abolishes sensory neuron sodium channel Nav1.7 activity, resulting in pain insensitivity through an impaired peripheral drive that leaves tactile percepts fully intact.5 This allows complete experimental disambiguation of sensory responses and painful sensation

Attending work with chronic pain is associated with higher levels of psychosocial stress

Background & Aims Much is known about the impact of pain in terms of medical costs and missed work. Less is known about its associations when individuals are present for work. This study examines “presenteeism” by analysing the psychosocial costs of pain in the workplace, using the 2015 European Working Conditions Survey (EWCS). Methods We conducted cross-sectional analysis of 2,384 individuals with chronic pain, and 2,263 individuals without pain (matched by age and sex), using data from the European Working Condition Survey (2015). We compared groups in terms of the following psychosocial factors: Supervisor Support, Job Responsibility, Team Cohesion, Discrimination, Threats/Abuse, Job Competency, Job Reward, Sexual Harassment, Stress, and Job Security. The groups were also compared in terms of days lost due to illness. Results People with pain were 64% less likely to view their job as rewarding (OR .61, 95% CI .57-.65), 47% more likely to be subjected to threats/abuse in the workplace (OR .68, 95% CI .63-.73), 30% more likely to report poor supervisor support (OR .77, 95% CI .73-.82), and 28% more likely to perceive discrimination in the workplace (OR .78, 95% CI .71-.85). People with pain missed approximately 9 more days of work per year than the non-pain respondents

Neural emotion regulation circuitry underlying anxiolytic effects of perceived control over pain.

Anxiolytic effects of perceived control have been observed across species. In humans, neuroimaging studies have suggested that perceived control and cognitive reappraisal reduce negative affect through similar mechanisms. An important limitation of extant neuroimaging studies of perceived control in terms of directly testing this hypothesis, however, is the use of within-subject designs, which confound participants' affective response to controllable and uncontrollable stress. To compare neural and affective responses when participants were exposed to either uncontrollable or controllable stress, two groups of participants received an identical series of stressors (thermal pain stimuli). One group ("controllable") was led to believe they had behavioral control over the pain stimuli, whereas another ("uncontrollable") believed they had no control. Controllable pain was associated with decreased state anxiety, decreased activation in amygdala, and increased activation in nucleus accumbens. In participants who perceived control over the pain, reduced state anxiety was associated with increased functional connectivity between each of these regions and ventral lateral/ventral medial pFC. The location of pFC findings is consistent with regions found to be critical for the anxiolytic effects of perceived control in rodents. Furthermore, interactions observed between pFC and both amygdala and nucleus accumbens are remarkably similar to neural mechanisms of emotion regulation through reappraisal in humans. These results suggest that perceived control reduces negative affect through a general mechanism involved in the cognitive regulation of emotion

Functional connectivity of the amygdala is linked to individual differences in emotional pain facilitation

The amygdala is central to emotional processing of sensory stimuli, including pain. Because recent findings suggest that individual differences in emotional processes play a part in the development of chronic pain, a better understanding of the individual patterns of functional connectivity that makes individuals susceptible to emotionally modulated facilitation of pain is needed. We therefore investigated the neural correlates of individual differences in emotional pain facilitation using resting-state functional magnetic resonance imaging (rs-fMRI) with an amygdala seed. Thirty-seven participants took part in 3 separate sessions, during which pain sensitivity was tested (session 1), participants underwent rs-fMRI (session 2), and emotional pain modulation was assessed (session 3). The amygdala served as seed for the rs-fMRI analysis, and whole-brain voxel-wise connectivity was tested. Pain modulatory scores were entered as regressor for the group analysis. Stronger connectivity of the amygdala to S1/M1, S2/operculum, and posterior parietal cortex at rest characterized individuals who showed greater pain facilitation by negative emotions. When comparing the amygdala networks associated with pain unpleasantness and with pain-intensity modulation, most of the identified areas were equally related to either pain rating type; only amygdala connectivity to S1/M1 was found to predict pain-intensity modulation specifically. We demonstrate that trait-like patterns of functional connectivity between amygdala and cortical regions involved in sensory and motor responses are associated with the individual amplitude of pain facilitation by negative emotional states. Our results are an early step toward improved understanding of the mechanisms that give rise to individual differences in emotional pain modulation

The structural and functional connectivity neural underpinnings of body image

How we perceive our bodies is fundamental to our self-consciousness and our experience in the world. There are two types of interrelated internal body representations—a subjective experience of the position of a limb in space (body schema) and the subjective experience of the shape and size of the limb (body image). Body schema has been extensively studied, but there is no evidence of the brain structure and network dynamics underpinning body image. Here, we provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger-stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants' susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances

Do “central sensitization” questionnaires reflect measures of nociceptive sensitization or psychological constructs? Protocol for a systematic review

Introduction: Central sensitization (CS) was first defined in animal studies to be increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state. Recently, the concept of CS has been adopted in clinical assessments of chronic pain, but its diagnosis in humans has expanded to include the enhancement of a wide range of nociceptive, sensory, and emotional responses. Many poorly understood pain disorders are referred to as “central sensitivity syndrome,” a term associated with a broad range of hypervigilant sensory and emotional responses. Diagnosis often involves a review of medical records and an assessment of behaviour, emotional disposition, and overall sensitivity of a patient. Obviously, these assessments are unable to directly capture the responsiveness of nociceptive neurons. The purpose of this review is to ascertain whether self-report questionnaires associated with central sensitization and the diagnosis of central sensitivity syndrome are associated with enhanced nociceptive responses or whether they more validly measure sensitivity in a broader sense (ie, including emotional responses). Methods: Following the PRISMA guidelines, a detailed search of studies that involve the Central Sensitization Inventory or Pain Sensitivity Questionnaire correlated with either nociceptive sensory tests (quantitative sensory testing) or emotional hypervigilance (anxiety, depression, stress, etc) will be conducted on MEDLINE, PsychINFO, and Web of Science. Perspective: The review is expected to synthesize correlations between sensitivity questionnaires and nociceptive or emotional sensitivity to determine whether these questionnaires reflect a broadened understanding of the term “central sensitization.

Is pain “all in your mind”? Examining the general public’s views of pain

By definition, pain is a sensory and emotional experience that is felt in a particular part of the body. The precise relationship between somatic events at the site where pain is experienced, and central processing giving rise to the mental experience of pain remains the subject of debate, but there is little disagreement in scholarly circles that both aspects of pain are critical to its experience. Recent experimental work, however, suggests a public view that is at odds with this conceptualisation. By demonstrating that the public does not necessarily endorse central tenets of the “mental” view of pain (subjectivity, privacy, and incorrigibility), experimental philosophers have argued that the public holds a more “body-centric” view than most clinicians and scholars. Such a discrepancy would have important implications for how the public interacts with pain science and clinical care. In response, we tested the hypothesis that the public is capable of a more “mind-centric” view of pain. Using a series of vignettes, we demonstrate that in situations which highlight mental aspects of pain the public can, and does, recognize pain as a mental phenomenon. We also demonstrate that the public view is subject to context effects, by showing that the public’s view is modified when situations emphasizing mental and somatic aspects of pain are presented together