In this study, we investigated fMRI signal changes evoked by heat pain in a relatively large cohort of subjects. As expected, we found that the application of noxious stimuli produces not only activations within the ‘pain matrix’ [2
], but also widespread deactivations. Since negative BOLD responses have been shown to correlate with decreases in neuronal activity [34
], and therefore do not merely represent a vascular epiphenomenon, the results from this and other studies appear to suggest that a large network of areas in the brain decreases its activity during pain. These fMRI signal decreases were observed in so-called ‘core regions of the default network’ [4
], such as bilateral MPFC, posterior cingulate cortex / precuneus, parahippocampus / hippocampus and lateral temporal cortex, as well as in brain regions not traditionally associated with the DMN, such as lateral occipital gyri, premotor area, superior frontal gyrus and contralateral S1 / M1.
The DMN is a widespread network of brain structures which appears to be engaged when individuals are left to think to themselves undisturbed, and was shown to reduce its activity during the execution of a wide variety of goal-oriented behaviors [4
]. Although its specific functions are currently under debate, two leading hypotheses have been recently formulated [4
]. According to the ‘sentinel hypothesis,’ this network would support broad monitoring of the external environment in the absence of attention-demanding stimuli. Our data do not seem to support this hypothesis. In fact, if the pain-related deactivations were due to the interruption of the broad monitoring of the external environment, then increasing levels of pain would have to be associated with increasing deactivations. To our surprise, however, LOW pain stimuli induced deactivations in a much larger network of brain regions than HIGH pain ().
A second hypothesis, the ‘internal mentation hypothesis’, poses that the DMN would support internally directed cognitive activity that is largely detached from the external world, and specifically have a role in ‘constructing dynamic mental simulations based on personal past experiences such as used during remembering, thinking about the future, and generally when imagining alternative perspectives and scenarios to the present’ [4
]. Our observation that higher pain is associated with lower deactivations might be compatible with the this hypothesis: in fact, due to the threat that intensely painful stimuli pose to the organism, it is possible that high pain leads subject to instinctively mentally explore ‘alternative scenarios’ in order to prepare for an escape from pain. This exploration of potential solutions to the current threat might partially counteract the DMN inhibition induced by the incoming stimulation, particularly for intensely painful stimuli. Alternatively, the observed differences in the extent and magnitude of deactivations might relate to differences in the cognitive load across stimulus intensities. In fact, as we have previously reported [27
], evaluating the painfulness of a stimulus is more effortful, and requires a more extensive activation of pain evaluative networks, for mild to moderate stimuli, than for high intensity stimuli.
Although most imaging studies published to date focus on BOLD activations, pain-induced fMRI or PET deactivations have been reported [3
]. In several of these studies the deactivations were either simply interpreted in terms of cross-modal inhibition, or briefly reported and not further discussed. Some others, however, indicate that deactivations might play a more prominent role in central processing of pain (e.g., [19
]). Interestingly, some studies have reported stronger deactivations with increasing pain [6
], in brain areas where we observed that HIGH pain was associated with lesser deactivation than LOW pain (e.g., posterior cingulate/precuneus or medial prefrontal areas). We currently have no hypotheses to explain this apparent discrepancy, and future experiments will need to clarify this issue. However, by illustrating that activations and deactivations can, at least in some circumstances, have a different relation with stimulus intensity, our results suggest that activations and deactivations might underlie different aspects of the pain experience.
When we compared the fMRI responses to LOW and HIGH pain in male and female subjects, we observed that males showed stronger activations than females in several areas (LOW pain: left insula / operculum; HIGH pain: bilateral insula / operculum, S2, thalamus, rostral and dorsal ACC, left brain stem, MPFC, and right DLPFC). These results are in line with other studies showing generally stronger pain related activations in male subjects [3
]. However we did not observe any gender differences in deactivations, whereas stronger pain-related deactivations in females have been previously reported [3
In support of the functional dissociation between BOLD increases and decreases are the results of the correlational and functional connectivity analyses. The correlational analysis on the fMRI signals of different brain regions during different pain levels showed that 1) the activity of regions showing fMRI signal increases were in general significantly correlated; 2) the activity of pain-activated regions was not correlated with that pain-deactivated regions 3) within the regions showing fMRI signal decreases, those traditionally classified as belonging to DMN (PCC, vMPFC, dMPFC, PCC/precuneus, bilateral lateral temporal cortex) were significantly correlated, whereas 4) the left and right lateral occipital brain regions were significantly correlated with each other, but their relation with other deactivated areas depended on the level of painful stimulation. The latter observations appear to indirectly support the view that there are different mechanisms underlying fMRI signal decrease in pain perception processes.
To further investigate the functional connection between different brain regions observed in fMRI group analysis, we performed a functional connectivity analysis on the resting state data collected at the beginning of the fMRI scan session in a subset of our subjects. Four brain regions showing fMRI signal increase were selected: ACC, left S1, right insula and S2. Traditionally, it is believed that S1 and S2 belong to lateral pain system, whereas ACC and anterior insula belong to medial pain system. Our results seem to provide some support to this notion. In fact, S1 displayed synchronous activity with bilateral S1/M1, mid-cingulate cortex, posterior insula / S2, and occipital cortex, but not with ACC, one of the brain regions most consistently associated with affective dimension of pain [39
]. Placing a seed in the left S2 also achieved similar results. When we used ACC as the seed region, significant synchronous activity was observed in several brain regions including bilateral ACC, mid-cingulate cortex, bilateral anterior / middle insula, thalamus, caudate, orbital PFC, LPFC, cerebellum, but not in S1 or S2. Similar results were obtained with the anterior insula.
Among the regions showing fMRI signal decrease during administration of pain, several core areas of the default network, such as the vMPFC, PCC and left lateral temporal cortex, displayed synchronous activity at rest. The functional connectivity maps for areas outside the DMN, however, appeared rather different from that of DMN: for instance, we observed that the activity of the right lateral occipital gyrus was significantly synchronous with that of bilateral lateral and medial occipital cortex, and left lateral temporal cortex. These results, along with those of the correlational analyses, suggest functional dissociation between lateral occipital cortex and other regions deactivated during painful stimulation, possibly supporting the notion that the mechanisms behind deactivations within and outside the default network might be of different nature (e.g., task-dependant vs task-independent; [16
In conclusion, we report that pain stimuli induce robust, widespread, intensity dependent (HIGH pain > LOW pain) fMRI signal increases across the pain matrix. In addition, the noxious stimuli induce a simultaneous decrease in activation in several brain regions, including some of the ‘core structures’ of the DMN. In contrast to what we observe with the signal increases, the extent and magnitude of brain deactivation is greater for LOW than HIGH pain stimuli. Furthermore, correlation analyses indicate that the activity of areas displaying pain-evoked changes in the same direction is highly correlated, though there are no significant correlations between brain activations and deactivations. The functional dissociation between activated and deactivated networks is further supported by functional connectivity analyses, which show that spontaneous activity fluctuations are significantly correlated across areas displaying pain-induced changes of the same direction, but not of the opposite direction. Since our results show the absence of a linear relationship between pain-induced activations and deactivations, we propose that these brain signal changes may underlie different aspects of the pain experience.