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Editorial |

Pain Perception Multiple Matrices or One?

Paul Geha, MD1,2; Stephen G. Waxman, MD, PhD3,4
[+] Author Affiliations
1Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
2John B. Pierce Laboratory, New Haven, Connecticut
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
4Neurorehabilitation Research Center, Veterans Affairs Hospital, West Haven, Connecticut
JAMA Neurol. 2016;73(6):628-630. doi:10.1001/jamaneurol.2016.0757.
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Acute or transient pain activates a large set of brain regions, including thalamus, primary and secondary somatosensory areas, insula, anterior cingulate cortex (ACC), and periaqueductal gray matter, areas collectively referred to as the pain matrix, with variable activation of striatum (dorsal and ventral), amygdala, and medial and dorsolateral prefrontal cortex (Figure).1 Activity in areas of the pain matrix has been consistently observed in hundreds of studies irrespective of the modality used to elicit nociceptive input (eg, thermal heat, painful pressure, intramuscular injections, visceral balloon inflation), leading some investigators to propose that this matrix of regions mediates the conscious perception of pain.2 In addition to the consistency of activation across studies, proponents of the pain matrix advance the argument that subjective reports of pain intensity correlate with neural response magnitude within some areas of the pain matrix, mainly insula and ACC, and suggest as a corollary that modulation of pain experience leads to a corresponding modulation of the neural response within the pain matrix. More recently, Wager et al3 added strength to these arguments by showing, using a machine-learning approach, that a weighted pattern of brain activity within the areas presented in the Figure in red can be derived from one group of individuals and used to predict pain intensity in a new group or can differentiate somatosensory pain from nonnoxious thermal heat or the pain of social rejection. The pain matrix has therefore been considered sufficient to generate the conscious perception of pain elicited by peripheral nociceptive input via A delta and C fibers. However, serious challenges have been raised against this view. In a series of experiments using nociceptive, somatosensory, auditory, and visual stimuli, Mouraux et al4 demonstrated that activation within the pain matrix is multimodal rather than pain specific, and they suggested that the magnitude of neural activation can be explained by the saliency of the stimulus independent of modality. Using evoked potentials, the same authors had previously demonstrated how the context of nociceptive stimulus presentation, eg, comparing repetitive monotonous stimuli vs novel stimuli, can decorrelate the brain response in ACC and insula from the perceived pain intensity, providing counterexamples to the concept of the pain matrix.5 More recently, they showed that patterns of brain activity elicited in response to nociceptive, visual, tactile, or auditory stimuli derived from the noncorresponding primary sensory cortex, eg, response to pain derived from the auditory cortex or the visual cortex, is sufficient to differentiate between different types of peripheral input, including pain.6 These results suggest that even the traditional view of primary sensory cortices, let alone large-scale matrices like the pain matrix, being specialized in processing information exclusively from 1 sensory modality has to be abandoned for a more multisensory or multimodal view.

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Brain Areas Activated by Painful Stimulation

Nociceptive input is relayed from peripheral C fibers and A delta fibers via second-order neurons in the spinal cord either directly (fibers shown in purple) to cortical areas like the medial prefrontal cortex (mPFC) or indirectly (fibers shown in green) via subcortical nuclei like the thalamus (Thal), the periaqueductal gray matter (PAG), the striatum (including the ventral striatum [VS] and the dorsal striatum), the amygdala (Amy), or the parabrachial nucleus (not shown). The thalamus in turn relays pain signals via direct projections to the primary somatosensory cortex (SI) and secondary somatosensory cortex (SII), insula (Ins), and anterior cingulate cortex (ACC). Brain areas shown in red collectively depict the pain matrix. Brain areas shown in blue are often activated during functional magnetic resonance imaging experiments in response to painful stimulation, although less consistently than the components of the pain matrix. Large areas of the prefrontal cortex are often activated in response to pain; the mPFC encodes the subjective value of pain and the dorsolateral prefrontal cortex (DLPFC) mediates executive control and decision making. DRG indicates dorsal root ganglion.

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