Brain activity sustaining the modulation of pain by empathetic comments.

Empathetic verbal feedback from others has been shown to alleviate the intensity of experimental pain. To investigate the brain changes associated with this effect, we conducted 3T-fMRI measurements in 30 healthy subjects who received painful thermal stimuli on their left hand while overhearing empathetic, neutral or unempathetic comments, supposedly made by experimenters, via headsets. Only the empathetic comments significantly reduced pain intensity ratings. A whole-brain BOLD analysis revealed that both Empathetic and Unempathetic conditions significantly increased the activation of the right anterior insular and posterior parietal cortices to pain stimuli, while activations in the posterior cingulate cortex and precuneus (PCC/Prec) were significantly stronger during Empathetic compared to Unempathetic condition. BOLD activity increased in the DLPFC in the Empathetic condition and decreased in the PCC/Prec and vmPFC in the Unempathetic condition. In the Empathetic condition only, functional connectivity increased significantly between the vmPFC and the insular cortex. These results suggest that modulation of pain perception by empathetic feedback involves a set of high-order brain regions associated with autobiographical memories and self-awareness, and relies on interactions between such supra-modal structures and key nodes of the pain system.

Functional imaging of pain.

Brain functional imaging has been applied to the study of pain since 1991. Then, a plethora of studies around the world looking at pain sensations and their brain correlates was published. Four kinds of studies can be distinguished: i) A first set investigated brain responses to noxious heat stimulations (above the pain threshold) relative to an equivalent warm innocuous stimulation (below the pain threshold). The aim of these studies was to identify the pattern of brain regions involved in the nociceptive processes and they may be considered as descriptive studies rather than explanative studies. Their value was to list for the first time every brain structure that might be playing a role. ii) Secondly, several experimental investigations have explored brain activations when subjects are confronted with unpleasant situations such as seeing or imagining other people in pain (e.g. empathy for pain). Obviously, feeling pain and representing others suffering share a common brain network, indicating that a large part of the regions showing intensity changes are not specific to nociception. iii) The third set of imaging studies is aimed at investigating the functional and structural brain abnormalities that may account for clinical pain states. Unfortunately, a relatively small number of studies provide clear findings that do not allow drawing convincing and generalized conclusions. iv) The last set of studies focused on the modulation of pain experience in humans. Several research groups conducted projects on different factors known to alter pain perception and their associated brain processes with the objective of identifying one or more key regions capable of controlling the pain sensation. In the same vein, investigations have been performed around pain therapies. From the clinician's point of view, it may be seen as complementary to assess pain and analgesic processes. All these aspects of pain research with functional imaging are considered below, including attempts to understand the functional significance of each of the observed activations. v) A special focus will be dedicated to new sophisticated approaches, vi) applied to neuroimaging (e.g. graph theory). These promising techniques and recent electrophysiological investigations bring additional information to our understanding of pain/analgesic processes, particularly for temporal dynamics and connectivity between brain regions.

The posterior insular-opercular cortex: An access to the brain networks of thermosensory and nociceptive processes?

In spite of systematic investigations, the existence of a specific cortex that could encode for the intensities of somatosensory stimuli, including within nociceptive ranges, is still a matter of debate. The present consensus is that pain is expressed in a distributed network made of thalamus, SII, insula, ACC, and, less consistently, SI. Here we argument that there must be an entrance to this network. The common denominator to every functional imaging study is that the subjects can distinguish between noxious and non-noxious stimuli, or between two different intensities of noxious stimuli. This is associated with a consistent activation of the insula-SII cortices while activations in other brain areas may be missing or sub-significant. In other words, the operculo-insular cortex activations are the most robust pain-related activations across studies, whatever the manipulation of the pain components, except the discriminative one. Intra-cerebral recordings also pointed out this piece of cortex as being able to encode for pain intensity. As a last physiological argument, stimulating directly the brain with small intensities standardized electrical shocks elicited pain sensations selectively if the electrode was in the operculo-insular cortex. Human models of disease confirmed that epileptic discharges in the insular cortex can produce ictal pain. Insular epilepsy (or propagation of discharges to the insular cortex) is the only focal epilepsy to be possibly associated with painful symptoms. Finally, unique and focal lesions of the posterior operculo-insular cortices were able to remove (or at least to impair) thermosensory and nociceptive functions. Thus, the operculo-insular area can be presented as the only area in the brain to respond to the features of a primary thermosensory and nociceptive cortex. This area is likely to be the starting point of the nociceptive-related networks. Future investigations are necessary to determine how this "pain symphony" between these different brain areas is temporally orchestrated. Developments of new targets for functional neurosurgery could benefit of such localized and initiating processes, for instance focal neurostimulations.

Does an observer's empathy influence my pain? Effect of perceived empathetic or unempathetic support on a pain test.

The physiological and behavioural effects of empathy for other's pain have been widely investigated, while the opposite situation, i.e. the influence on one's pain of empathetic feedback from others, remains largely unexplored. Here, we assessed whether and how empathetic and unempathetic comments from observers modulate pain and associated vegetative reactions. In Study 1, conversations between observers of a pain study were recorded by professional actors. Comments were prepared to be perceived as empathetic, unempathetic or neutral, and were validated in 40 subjects. In a subsequent pain experiment (Study 2), changes in subjective pain and heart rate were investigated in 30 naïve participants who could overhear the empathetic or unempathetic conversations pre-recorded in study 1. Subjective pain was significantly attenuated when hearing empathetic comments, as compared to both unempathetic and neutral conditions, while unempathetic comments failed to significantly modulate pain. Heart rate increased when hearing unempathetic remarks and when receiving pain stimuli, but heart acceleration to nociceptive stimulation was not correlated with pain ratings. These results suggest that empathetic feedback from observers has a positive influence on pain appraisal and that this effect may surpass the negative effect of unempathetic remarks. Negative remarks can either trigger feelings of guilt or induce irritation/anger, with antagonistic effects on pain that might explain inter-individual variation. As in basal conditions heart rate and pain perception are positively correlated, their dissociation here suggests that changes in subjective pain were linked to a cognitive bias rather than changes in sensory input.