We present the first direct evidence of linkage between elevated intrinsic brain connectivity and spontaneous pain intensity in FM. We applied ICA to resting state fMRI data and found that FM patients had greater connectivity within the rEAN and between the DMN and the insular cortex a brain region linked to evoked pain processing. Furthermore, our data directly links spontaneous pain report at the time of the scan to the degree of both rEAN and DMN connectivity to the insula. Our findings have implications for underlying brain mechanisms of endogenous clinical pain in FM, potentially pointing towards “markers” for disease progression. More broadly, these findings have implications for how subjective experiences such as pain arise from a complex interplay amongst multiple brain networks.
Our results strongly implicate the insular cortex as being a key node in the elevated intrinsic connectivity in FM patients. Patients demonstrated greater DMN connectivity to the left anterior, middle, and posterior insula. Furthermore, FM participants with greater spontaneous pain levels displayed increased intrinsic connectivity between both the DMN and rEAN and insular cortex. Many studies have found insular involvement in the multidimensional (sensory, affective, cognitive) pain state. This insula is one of the most commonly activated brain regions in neuroimaging studies of acute experimental pain (35
). The posterior insula has been associated with sensory intensity encoding (36
), while the anterior insula may be more strongly related to affective dimensions of pain, such as anticipatory anxiety related to pain (37
). However, the insula does not just process pain signals, and has been implicated in multiple association processes related to both interoceptive (38
) and exteroceptive salience (18
). In fact, it has been hypothesized that the insula integrates subcortical homeostatic information, such as that arising from a pain state (39
), into a higher-order cognitive and affective conscious state of awareness (40
). Our data supports this view as ratings of spontaneous pain were correlated to increased insular connectivity in brain networks (DMN, EAN) known to support cognition.
Intrinsic connectivity between the posterior insula and DMN areas such as the PCC has been shown to exist even in healthy subjects (41
). Substantial positive DMN connectivity to the posterior insula was also noted for both FM and HC in our analysis. This suggests that existing links between the DMN and insula may be hyperactive in FM patients. This hyperactive connectivity has been suggested by proton magnetic resonance spectroscopy (H-MRS) studies in FM patients’ where posterior insula glutamate levels appear to be elevated (42
). Future studies should also explore increased glutamate concentrations within the DMN, as we found increased intrinsic DMN connectivity for FM patients. In addition, greater DMN-insular resting connectivity could lead to altered DMN response to external sensory input for FM, something that was found for chronic low back pain patients responding to cognitive/visual tasks (43
It is also interesting to speculate that pain related reorganization of ICNs associated with working memory and attention (EAN) provides a potential neurobiological mechanism to the known cognitive deficits in FM patients (for review of FM-related dyscognition see (20
)). Perhaps not-coincidentally, these deficits appear to be focused on working memory and attention, and are particularly exacerbated with increasing distraction. Notably, FM patients’ cognitive deficits correlate more with their pain than with psychiatric co-morbidities (e.g. depression, anxiety, sleep disruption), as shown by a recent study by Dick et al. (44
). Our results indicate that insula-rEAN connectivity for FM increases with increasing levels of spontaneous pain. Interestingly, PAG-rEAN connectivity decreases
with increasing pain, consistent with the hypothesis that cognitive controls for descending inhibition (anti-nociception) might modulate FM pain levels. We suggest that the insula, which is intimately involved with multidimensional aspects of pain processing, becomes more hyper-connected to the rEAN with increasing pain levels for FM, diverts resources away from normal rEAN functioning, thereby leading to deficits in working memory and attention.
We found altered intrinsic connectivity in the right, but not left, EAN. ICA commonly separates the EAN into a right and left lateralized network (14
). Laterality in working memory and attention tasks has been noted in previous neuroimaging studies (45
) and lesions of the iPS typically result in spatial attention deficits when localized to the right side (46
). This laterality corroborates our suggestion that altered intrinsic rEAN connectivity may play a role in dyscognition in FM patients. Future studies should explore the significance of right, versus left, EAN connectivity in FM patients.
Another interesting finding was that the differences between FM and HC groups in DMN and EAN connectivity were driven entirely by the FM group and not HC. While this result could indicate that the observed differences were either the consequence or the cause of lingering chronic pain, it certainly supports the growing body of evidence that FM, and likely other chronic pain syndromes, are accompanied by altered brain neurophysiology. Moreover, this result was qualitatively similar to recent reports of altered ICN connectivity in patients with other forms of chronic pain (47
). Specifically, Cauda et al. reported enhanced resting DMN connectivity within DMN component regions (precuneus, IPL), sensorimotor (bilateral thalamus and insula), and cognitive / evaluative pain modulatory regions (dlPFC). However our findings substantially add to this inter-group comparison, as we found that the degree of DMN connectivity was associated with state-specific pain report at the time of the scan - an important finding as it specifically links intrinsic functional connectivity to the chronic pain state. The specificity of our results was buttressed by the fact that a control brain network, the MVN (not previously implicated in FM pathology), did not display altered intrinsic connectivity. Thus, our findings of altered brain connectivity appear to not be widespread, but are localized to DMN and rEAN intrinsic connectivity networks.
Other neuroimaging approaches have also attempted to evaluate the brain correlates of spontaneous clinical pain. Positron emission tomography (PET) with opioid binding agents has found that FM patients have decreased binding potential within the nucleus accumbens, which correlated with increasing spontaneous pain (48
). An H-MRS study found that reductions in resting glutamate concentration in the posterior insula are associated with reductions in clinical FM pain report (49
). Finally, continuous on-line patient report of spontaneous pain fluctuation was used to guide fMRI statistical analysis and found that fMRI signal in the medial-prefrontal cortex (MPFC) correlates with spontaneous pain intensity (1
). Our results add to this growing literature on neural correlates of chronic pain. The MPFC is a cardinal node of the DMN, and our results point to increased intrinsic DMN connectivity to the insula, with increasing connectivity directly correlated with increasing levels of spontaneous clinical pain in FM patients.
There are a number of limitations to our findings that should be discussed. First, our results were derived strictly from FM patients and may not generalize to other chronic pain states, a possibility we are currently evaluating. However qualitatively similar findings have been observed in neuropathic pain patients (47
), thus our results likely do have some generalizability. Furthermore, all of our participants were female, leaving open the possibility that FM pathophysiology may in fact be different for male patients. Finally, some of our FM patients were taking medications during the time of the scan (see Supplementary Table 1
), thus some findings may have been influenced by pharmacological modulation of neural connectivity. For ethical reasons, subjects were not asked to titrate down their existing pain medications for this study. However, none of our patients were taking opioid medications, and as the effects of other (e.g. SSRI, SNRI) medications on intrinsic brain connectivity are unknown, they should be explored in future studies. Larger studies, which could group participants by medication usage, can also address this issue.
In conclusion, we find direct evidence of disrupted intrinsic connectivity within multiple brain networks in FM patients. These findings are in agreement with other brain imaging results which indicate that individuals with FM have altered brain function (5
). Emerging evidence suggests that FM pain may be mediated by central nervous system hyperexcitability rather than peripheral pathology. Our results clearly show that individuals with FM have greater connectivity between multiple brain networks and the insular cortex – a brain region previously linked with evoked pain processing and hyperexcitability in FM. Our data also demonstrate that intrinsic connectivity to the insula is directly associated with increasing spontaneous pain. Hence, our approach represents a novel step forward in finding the neural correlates of spontaneous clinical