Here, a quantitative assessment of brain regions involved in human processing of pain, and a unique comparison of brain activations in patients with pain and healthy individuals, was performed using ALE. The insula, ACC, SII, and thalamus were commonly activated by pain, irrelevant of pain modality or stimulated body part, both in patients and healthy individuals. The high predominance of insular and ACC activations in our analyses furthers their role as key regions for the experience of pain. Our results are also made available as a spatial brain mask for free download and use in future neuroimaging analyses, eg, when analyses are confined to the core pain network or when independently and functionally defined pain areas for region of interest analyses are desired.
In line with recent data suggesting that the insula plays a fundamental role in human pain,11,58 we report robust likelihood of activations of the entire insula during pain, with peaks in the anterior insula (AI). Although the dorsal-posterior insula has been described as the cortical representation of incoming nociceptive signals,11 the AI has been associated with the integration of emotional and interoceptive states.10,46 For example, exposure to noxious stimuli may induce the activation of both the posterior and anterior insula, whereas the subjective evaluation of these stimuli is represented in the AI.31 Based on the significant likelihood of activating the insula across pain modalities, with peaks in the AI, we suggest that the AI is an essential component for the subjective experience of pain. Previous ALE meta-analyses also found insular involvement in pain processing,15,36,43 with peaks in anterior, middle, and the posterior insula. Yet, is there coherence between experimental studies suggesting that the posterior insula plays a fundamental role in pain and ALE analyses suggesting that the AI is key for pain processing? It has been suggested that the posterior insula is a nonspecific way station for sensory input and coding of stimulus intensity, rather than a specific pain center,13 as opposed to the evaluative role of the AI. Hence, the 2 regions reflect different aspects of pain processing. Neuroanatomical studies support the notion that the right AI is part of an afferent path for interoceptive representations of pain and homeostatic drive.9 The AI is thereby thought to provide meta-representations of the state of the body, or “the feeling self”, combined with motivational drive for bodily protection.9 Involvement of the AI in cognitive meta-representations of pain has also been found in studies of empathy for pain where the AI is activated both by one's own pain and by watching pain in others.47,60 Interestingly, Ochsner et al.47 found that the right AI was more engaged during the processing of one's own pain than watching others' pain.47 Combined with the central role of the AI suggested here, the AI could be essential for attributing pain to one's own body.
Patients' less likelihood to activate key nociceptive regions may seem counterintuitive because patients have persistent pain. One methodological explanation could be that patients' relatively lower likelihood to activate, eg, the AI and cingulate gyrus, indicates a ceiling effect, as patients have constant noxious input to nociceptive brain regions and are thus not able to display additional activation during added experimental pain.36 Furthermore, recent data suggest that the transition from acute to chronic pain entails a shift from lateral (sensory-discriminative) to medial (affective-motivational) neural activity.3 Our results may thus support the hypothesis that chronic pain involves decreased sensory and enhanced emotional processes because ALE differences were also found in the thalamus, a region with a significantly less likelihood of pain activation in patients. For several different categories of patients with pain, there are reports of thalamic structural changes,14,53,59 attenuated thalamic activity during rest,34,41 and attenuated pain-evoked activations.26,33 Our results thereby support the notion that pain pathophysiology may involve thalamocortical dysrhythmia.6,30,37 According to the dysrhythmia theory, thalamocortical disruption may lead to disturbances of sensation, motor performance, cognition, and ultimately, to disabling chronic disorders, such as chronic pain. In a longitudinal neuroimaging study,27 where fibromyalgia patients were scanned before and after treatment with cognitive behavioral therapy, there was increased connectivity between the thalamus and lateral prefrontal cortex compared to waitlist controls. Because chronic pain is associated with disrupted thalamocortical connectivity, the increase in thalamocortical connectivity may reflect a normalization of pain pathophysiology.
We found that patients had a less likelihood to activate parts of the middle-frontal gyrus, possibly reflecting patients' decreased activation of the brain's pain inhibitory network.26,28 The prefrontal cortex is a key region for pain inhibition, eg, during reappraisal of pain and placebo analgesia,48,64 suggesting that the attenuated activation of the frontal gyrus in patients may represent decreased pain inhibition. Yet, our results were inconclusive, as patients displayed an increased likelihood of activating some parts of the prefrontal cortex, whereas the same structure had a decreased likelihood of activation on the right side. Because the laterality and specificity of the different prefrontal subregions during noxious stimulation is not fully understood, further studies of the role of the prefrontal cortex in pain chronification are needed.
In this study, we only included data originating from publications reporting their results using 3D coordinates within a standardized stereotactic space. Although studies assessing links between brain areas and pain processing in patients with localized lesions are very informative and, some argue, with a stronger causality, they fall outside the scope of this statistical meta-analysis. Future attempts should be made to quantify lesion extensions in coordinate space and merge the information with that from coordinate-based inference studies to render a more inclusive meta-analysis.
The results from the present study suggest that (1) insular and ACC activation are central for pain perception and (2) functional differences in pain processing between patients with chronic pain and healthy individuals may explain behavioral differences and further our understanding of pain pathology, especially when pain is viewed as a homeostatic function or as a transition from lateral (sensory) to medial (emotional) processing of pain.
The authors have no conflicts of interest to declare.
This material is based on work supported by a grant from the Knut and Alice Wallenberg Foundation (KAW 2012.0141) awarded to J. N. Lundström. Johnson & Johnson Inc provided partial salary support during the data collection phase. C. Regenbogen is supported by a postdoctoral fellowship of the DAAD (German Academic Exchange Service). J. Frasnelli is supported by grants from the Research Center of Sacré-Coeur Hospital, Montréal, the University of Québec in Trois-Rivières, the Natural Sciences and Engineering Research Council (Canada), and the Fonds de Recherche du Québec—Santé. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors thank Dr Marco Loggia for valuable comments on a previous version of this manuscript as well as Kajsa Forsberg and Anna Sjöholm Norling for assisting in data collection and extraction.
Supplemental Digital Content
Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A239.
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