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

Abstract and Introduction


Pain is a prevalent and debilitating symptom of multiple sclerosis (MS); yet, the mechanisms underlying this pain are unknown. Previous studies have found that the functional relationships between the salience network (SN), specifically the right temporoparietal junction a SN node, and other components of the dynamic pain connectome (default mode network [DMN], ascending and descending pathways) are abnormal in many chronic pain conditions. Here, we use resting-state functional magnetic resonance imaging and measures of static and dynamic functional connectivity (sFC and dFC), and regional BOLD variability to test the hypothesis that patients with MS have abnormal DMN-SN cross-network sFC, dFC abnormalities in SN-ascending and SN-descending pathways, and disrupted BOLD variability in the dynamic pain connectome that relates to pain inference and neuropathic pain (NP). Thirty-one patients with MS and 31 controls completed questionnaires to characterize pain and pain interference, and underwent a resting-state functional magnetic resonance imaging scan from which measures of sFC, dFC, and BOLD variability were compared. We found that (1) ~50% of our patients had NP features, (2) abnormalities in SN-DMN sFC were driven by the mixed-neuropathic subgroup, (3) in patients with mixed NP, dFC measures showed that there was a striking change in how the SN was engaged with the ascending nociceptive pathway and descending modulation pathway, (4) BOLD variability was increased in the DMN, and (5) the degrees of sFC and BOLD variability abnormalities were related to pain interference. We propose that abnormal SN-DMN cross-network FC and temporal dynamics within and between regions of the dynamic pain connectome reflect MS pain features.


Chronic pain is a prevalent and debilitating symptom of multiple sclerosis (MS); however, the mechanisms underlying MS-related pain are not well understood.[18,22,23,31,47] Past investigations of MS pain have focused on neuropathic pain (NP) and have used structural magnetic resonance imaging (MRI) to link lesion characteristics to pain symptoms with inconclusive results.[50] However, pain is not due to activity in one specific brain area, but arises from the coordination and dynamics across several brain networks that comprise the dynamic pain connectome (ascending nociceptive and descending modulation pathways, salience network [SN] and default mode network [DMN]).[33,34] We posit that MS pain, both NP and non-neuropathic pain (non-NP), can arise from functional abnormalities of the dynamic pain connectome; however, we expect these abnormalities to be distinct for patients with NP vs non-NP because their pains have different features.

The right temporoparietal junction (rTPJ) is a key node of the salience network and is known to direct attention to changes in sensory input and coordinates brain activity to facilitate a behavioural response.[15,35] In patients with chronic pain, the rTPJ is functionally disrupted[7,24] and abnormal communication between the rTPJ and other regions of the salience network with other regions within the dynamic pain connectome has been described.[3,24,26,27] Thus, functional deficits of the salience-pain neural systems may be a hallmark of chronic pain. Therefore, chronic pain in patients with MS is likely due to be related to aberrant cross-network functional connectivity between the rTPJ (a node of the SN) and other regions of the dynamic pain connectome. Furthermore, because pain demands attentional resources and causes disability, these brain abnormalities likely also contribute to the pain interference in daily function.

Previous examination of within network brain abnormalities in MS pain used static measures of functional connectivity (sFC) and found dysfunction in the DMN in patients with MS pain.[51] However, emerging evidence suggest that brain communication across regions does not remain static across time, but rather is intrinsically dynamic between intermodular regions (ie, SN-ascending nociceptive or SN-descending modulation pathways) and reflects the ability to switch between states.[11,28,29,33,34,57] For example, greater salience network–control network dynamics was also associated with the prioritization of a cognitive task over pain.[12] Furthermore, we have recently demonstrated that greater regional brain flexibility (BOLD variability) was related to greater pain-coping and less pain sensitivity.[49] However, whether dynamic communication between (dynamic functional connectivity [dFC]) or within (BOLD variability) regions subserves optimal function or is a sign of dysfunction is unknown and may depend on the particular context.

In the current study, resting-state functional magnetic resonance imaging (rsfMRI) and measures of sFC, dFC, and BOLD variability were used to test the hypothesis that patients with MS have abnormal: (1) DMN-SN cross-network sFC, (2) SN-ascending and SN-descending pathways' dFC, and (3) BOLD variability in the dynamic pain connectome that relates to pain inference and NP.