Disruptions in cortical circuit connectivity distinguish widespread hyperalgesia from localized pain

Abstract

Introduction: This study aims to investigate the interregional functional connectivity in chronic back pain patients with widespread hyperalgesia, patients with localized back pain, and pain-free controls using stimulus-evoked high-density EEG recordings.

Methods: We conducted high-density EEG recordings to compare the functional connectivity and betweenness centrality between these groups.

Results: Compared with controls, chronic pain patients showed altered functional connectivity between regions that process cognitive information and regions that process sensory or affective information. Widespread hyperalgesia, however, is further differentiated from localized pain by decreased inter-hemispheric connectivity of sensory and affective areas and increased intra-hemispheric connectivity between sensory and cognitive cortices. Graph-theoretic analysis showed that whereas chronic pain is associated with decreased centrality of prefrontal, orbitofrontal, and cingulate areas, widespread hyperalgesia is distinguished by increased centrality of prefrontal and insular areas.

Discussion: Together, our results show that although widespread hyperalgesia shares certain features with localized pain, it is further characterized by distinct cortical mechanisms.

Keywords: EEG; chronic low back pain; chronic pain; functional connectivity; hyperalgesia; pain mechanisms; pain phenotyping.

Figure 1

Characterization of patients with widespread hyperalgesia using high-density electroencephalography (EEG) recordings. (A) Patients experiencing chronic low back pain, further characterized into those with only localized pain and those with widespread hyperalgesia (see Materials and Methods), as well as pain-free controls underwent EEG recordings. (B) Patients with widespread hyperalgesia show increased sensitivity to both 32 mN stimulus and 256 mN stimulus to the dorsum of their hand. Unpaired t-test, p ≤ 0.05 (*). p ≤ 0.01 (**), p ≤ 0.001 (***) and p ≤ 0.0001 (****). (C) Resting-state EEG was collected, including 5-minute intervals with eyes open and 5-minutes with eyes closed. Additionally, EEG recordings were performed during the application of pinprick stimuli (32 mN vs. 256 mN) to the dorsum of the right hand. (D) EEG data was analyzed and source localization was performed to isolate cortical areas known to play prominent roles in pain processing (regions of interest, ROIs). These include the primary somatosensory cortex (S1), insula (IC), anterior cingulate cortex (ACC; including rostral ACC or rACC and dorsal ACC or dACC), medial orbitofrontal cortex (mOFC), and dorsolateral prefrontal cortex (dlPFC). Figure creation was assisted by biorender.com.

Figure 2

Disrupted mean connectivity across functionally grouped cortical networks are found in chronic pain patients. Left columns: FC between grouped cortical networks in patients with chronic low back pain (n = 24); middle columns: FC between grouped cortical networks in pain-free controls (n = 19); right columns: matrix comparing mean FC in patients with chronic low back pain vs. pain-free controls (red indicates higher mean connectivity in chronic low back pain patients as compared to controls, blue indicates lower mean connectivity in chronic low back pain patients as compared to controls, p-values displayed on matrix indicate statistically significant differences between the two mean connectivities). (A) Noxious mechanical stimulation with 256 mN resulted in increased debiased weighted phase lag index (dwPLI) between cognitive-processing cortical areas and the sensory cortex that is contralateral to the stimulus (p = 0.016), but decreased FC between cognitive areas and the ipsilateral sensory cortex (p = 0.041) in the beta band of the chronic low back pain group as compared to pain-free controls. (B) Noxious stimulation resulted in increased dwPLI connectivity between right hemisphere cognitive processing regions and left hemisphere affective processing regions in the high-gamma band (p = 0.0388) of the chronic low back pain group as compared to pain-free controls.

Figure 3

Unique features in mean connectivity across functionally grouped cortical networks in patients with widespread hyperalgesia. Left columns: FC between grouped cortical networks in patients with widespread hyperalgesia (n = 12); middle columns: FC between grouped cortical networks in patients with localized pain (n = 12); right columns: matrix comparing mean FC in patients with widespread hyperalgesia vs. patients with localized pain (red indicates higher mean connectivity in widespread hyperalgesia patients as compared to localized pain patients, blue indicates lower mean connectivity in widespread hyperalgesia patients as compared to localized pain patients, p-values displayed on matrix indicate statistically significant differences between the two mean connectivities). (A) Noxious mechanical stimulation with 256 mN resulted in decreased inter-hemispheric dwPLI connectivity between the sensory cortices and affective cortices (p = 0.011, p = 0.0496) in the alpha band of the widespread hyperalgesia group as compared to the chronic localized pain group. (B) Noxious stimulation resulted in increased dwPLI connectivity between the cognitive processing regions and the sensory cortex that is ipsilateral to stimulus in the beta band (p = 0.021) of the widespread hyperalgesia group as compared to the chronic localized pain group.

Figure 4

Chronic pain is characterized by changes in node centrality in theta, beta, and high-gamma frequency oscillations. (A) Noxious mechanical stimulation with 256 mN resulted in decreased centrality of the right hemisphere dorsolateral PFC in the theta band (p = 0.0302), (B) Noxious stimulation decreased centrality of the left hemisphere medial OFC (p = 0.0095) and increased centrality of the right hemisphere dorsal ACC (p = 0.0269) in the beta band. (C) Noxious stimulation decreased centrality of the left hemisphere rostral ACC in the high-gamma band (p = 0.0441) in the chronic low back pain group (n = 24) as compared to pain-free controls (n = 19). Data are shown as mean +/− SEM.

Figure 5

Select features in node centrality further characterize widespread hyperalgesia from localized pain. (A) Noxious mechanical stimulation with 256 mN resulted in increased centrality of the right hemisphere dorsolateral PFC in the theta band (p = 0.016). (B) Noxious stimulation decreased centrality of the right hemisphere rostral ACC (p = 0.0275) and increased centrality of the right hemisphere insular cortex (p = 0.0483) in the beta band. (C) Noxious stimulation decreased centrality of the right hemisphere rostral ACC in the low-gamma band (p = 0.0024) in patients with widespread hyperalgesia (n = 12) as compared to patients with localized pain (n = 12). Data are shown as mean +/− SEM.