Dynamic Pain Connectome Functional Connectivity and Oscillations Reflect Multiple Sclerosis Pain

Rachael L. Bosma; Junseok A. Kim; Joshua C. Cheng; Anton Rogachov; Kasey S. Hemington; Natalie R. Osborne; Jiwon Oh; Karen D. Davis


Pain. 2018;159(11):2267-2276. 

In This Article


This study has provided novel insight into the NP features in patients with MS through the lens of the relationship between MS pain and cross-network functional reorganization within the dynamic pain connectome. Our key findings were that: (1) approximately 50% of patients with MS experienced pain and sensory features of mixed NP, (2) patients with mixed NP had abnormal cross-network connectivity between the salience and DMNs, (3) all patients exhibited a disruption in brain signal variability between the SN and the ascending nociceptive pathway, but only patients with mixed NP have disrupted brain signal variability between the SN and descending pain-modulation pathway, (4) patients exhibited amplified regional neural variability in the DMN, and (5) abnormalities in sFC and brain signal variability were related to the degree of interference of pain on activities of daily living. Therefore, our study indicates that SN cross-network communication is dysfunctional in patients with MS pain, and the degree of abnormality reflects both features of NP and how much pain interferes in daily functioning.

We examined cross-network sFC to explore pain-related alterations in network organization and found that MS patients with mixed NP have abnormally high SN-DMN connectivity. The right temporoparietal junction, a key node of the SN, detects relevant stimuli from the environment and coordinates other brain networks, such as the DMN, to generate a behavioral response.[15,44,56] By contrast, the DMN is active during internally directed, self-referential thought and suppressed when attention is externally engaged.[19,38] In healthy individuals, the activity between the SN and the DMN is anticorrelated. Disruptions in this cross-network anticorrelation can been identified in several chronic pain conditions and the degree of sFC abnormality is related to pain symptoms.[2,24,46] In the current study, we found that a disruption in SN-DMN anticorrection was present only in the mixed NP group, and across all patients with MS, the degree of abnormality was related to pain interference scores. In mixed NP pain, the relationship between the SN and DMN may be altered due to the experience of salient fluctuating pain and greater pain interference. Acute pain experienced by healthy individuals is salient and able to allocate attention away from internal thought, thereby suppressing the DMN. By contrast, in patients with chronic pain, ongoing mixed NP pain may actually cause thoughts to be more directed towards pain. This is consistent with evidence from patients with temporomandibular disorder in which sFC within the DMN corresponded to rumination about pain.[37] Furthermore, salience network-DMN cross-network sFC abnormalities are also evident in patients with posttraumatic stress disorder[52,53] and are related to inattention symptoms in attention deficit hyperactivity disorder (ADHD).[36] This suggests that SN-DMN sFC abnormalities are not specific to pain, but rather that over time, the continuous experience of salient symptoms become ingrained in internal thought and alters attention. Thus, SN-DMN abnormalities in MS patients with mixed NP likely reflect an alteration in the neural salience–pain relationship.

The organization of brain networks and the relationship between networks have typically been described using static measures of FC, which assume that these measures remain stable in the resting-state brain over time.[29,57] However, it is now known that the relationship between brain regions is dynamic and can fluctuate over time.[29] Therefore, here we also examine the salience–pain relationship using measures of dFC to understand whether SN-ascending nociceptive or SN-descending modulation pathways are dynamically altered in MS pain. We found that although SN-ascending nociceptive pathway dFC was increased in patients, patients with mixed NP had a decreased SN-descending dFC. It is important to note that our sFC and dFC findings were distinct and that only dFC measures were sensitive to differences in patients vs controls or between mixed NP and non-NP subgroups in these brain regions. Findings of dFC but not sFC differences are consistent with previous studies that have demonstrated that the most dynamic connections are intermodular and those with low sFC.[57] Therefore, using measures of dFC provides additional insight into MS pain-related functional reorganization of the salience–pain relationship. Abnormalities in the dynamic relationship between SN-ascending and SN-descending modulation pathway may reflect alterations in "the balance between efficient information processing and metabolic expenditure."[57] In HCs, higher dFC between the salience network and executive control networks has been shown to reflect a greater ability to prioritize a cognitive task over a pain stimulus.[12] Thus, in patients with higher pain severity and interference, the SN may "overcoordinate" or "overengage" with the ascending nociceptive pathway as a result of or, alternatively, as a driver of the barrage of painful and salient input experienced by these patients. Conversely, MS patients with mixed NP had a decrease in dFC between the SN-descending modulation pathway. This may reflect an inability of the SN to dynamically engage with the descending modulation system to respond to ongoing pain. Therefore, the relationship between dFC and pain is likely network-specific and context-specific. Previous studies have demonstrated that dFC measures are sensitive to variability in behaviour.[12,28] Because pain fluctuates over time and mixed NP is highly dynamic, measures of brain dynamics within the dynamic pain connectome may capture dynamics in pain perception. However, future studies that acquire continuous measures of ongoing pain or more thoroughly measure the temporal dimension of pain are required to resolve the precision with which measures of dFC track pain fluctuations.

Measures of sFC and dFC inform how regions and networks of the brain are communicating with one another; an additional consideration is the baseline neural variability at a regional level. Using measures of BOLD variability, we found that patients with MS had greater BOLD variability (sw3) in the DMN. This is inconsistent with our hypothesis and deviates from findings in HCs in whom greater BOLD variability was associated with lower pain sensitivity and better pain-coping.[49] However, it is consistent with previous findings that describe increased power in regions of the DMN in patients with chronic lower back pain.[1] BOLD signal variability could reflect regional cortical excitability.[1,3,21] Enhanced variability in the DMN could therefore reflect increased engagement in internal thoughts and rumination about pain. In chronic pain, this increase in DMN baseline activity could in part account for the inability to suppress this network when engaging in an external task.[2] Default mode network BOLD variability (sw3) was also predictive of pain interference scores; we suggest that the inability to disengage from thoughts on pain likely consumes attentional resources and disrupts the ability to fully engage in day-to-day activities.

There are several limitations to this study. We found that patients had higher depression scores than controls, and patients with mixed NP had slightly higher (although largely overlapping) depression scores compared with non-NP patients. Depression is highly comorbid in chronic pain conditions and the neurobiological underpinnings are overlapping.[6] Therefore, as it is difficult to separate the effects of depression vs pain on the brain, the results presented here may also, in part, be influenced by the depression. Age and disease severity are also known to alter brain function. However, our supplementary analyses (available online as supplemental digital content at http://links.lww.com/PAIN/A617) suggested that our results did not change when controlling for age and that disease severity was not related to our findings (Supplementary Table 1, available online as supplemental digital content at http://links.lww.com/PAIN/A617). Another potential confound is the level of drowsiness or vigilance in our resting state scan because these factors are known to influence measures of dFC.[40] We did not assess this and therefore are unable to control for or remove the effects of vigilance in our study. However, we also do not have any evidence that there would be systematic group difference in vigilance that could account for our results. Therefore, any effect of vigilance likely adds noise to our data that obscures our results, rather than inflate them. Of note, the variance of the dynamic conditional correlation, which we use as our measure of dFC, has been shown to be scan–rescan reliable,[13] which alleviates some of the concerns regarding noise confounds on this measure. Finally, patients were not required to stop taking medications; the potential physiological effects of these medications on the BOLD fMRI signal are unknown in this study.

Altogether, our findings reveal that the relationship between salience and pain is disrupted in patients with MS pain. This is reflected in abnormalities in brain communication of the salience network—specifically SN-DMN sFC, SN-ascending, and SN-descending dFC, and also BOLD variability in the DMN that relate to pain interference and mixed NP pain features. Disruption in the salience–pain relationship is evident in a number of different chronic pain conditions including diabetic neuropathy[9] and lower back pain.[24] Therefore, these phenomena are a hallmark across chronic pain conditions, suggesting that the neural underpinnings of MS pain can also be described by a functional reorganization in key regions of the dynamic pain connectome.