Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex

Abstract

Introduction: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN).

Methods: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN.

Results: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Keywords: Capsaicin-heat pain model; Central sensitization; Descending pain modulatory network; Parabrachial nuclei; Periaqueductal gray; Seed-driven functional connectivity.

Fig. 1.

(A) In study 1, 18 participants experienced a pain-free resting state scan and 40 min later experienced the same resting state scan while experiencing thermal allodynia induced by capsaicin. (B) In study 2, 40 participants experienced a pain-free resting state scan and then 40 min later experienced the same resting state scan while experiencing thermal allodynia induced by capsaicin. Scans used in the analysis in the present report are demarcated in red. Abbreviations: WDT – warmth detection threshold; HPT – heat pain threshold; MSIT – multi-source interference task (Bush and Shin, 2006); DTI – diffusion tensor imaging; ASL – arterial spin label; MPRAGE – magnetization prepared rapid acquisition gradient echo. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).

Fig. 2.

(A) Ratings of prolonged tonic pain intensity during C-HP, the first arrow is when the thermode increased to the target temperature and the temperature increased 0.5 °C at each subsequent arrow (n = 32). (B) Warmth detection thresholds (WDT) and heat pain thresholds (HPT) taken before and after exposure to the C–HP model (n = 32); ** - p = 0.0002; *** - p < 0.0001. (C) Mean intensity of pain descriptors from the SF-MPQ-2, where percentages above each bar represent percentage of participants endorsing pain descriptor with any non-zero rating (n = 36). Error bars are 95% confidence intervals.

Fig. 3.

(A) Correlation between normalized pain intensity and functional connectivity between subgenual anterior cingulate cortex and periaqueductal gray during the pain-free (blue circles) and tonic pain states (red triangles). (B) Correlation between normalized pain intensity and functional connectivity between right parabrachial nucleus and periaqueductal gray during the pain-free (blue circles) and tonic pain states (red triangles). Shaded areas correspond to 95 percent confidence bounds. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).

Fig. 4.

Contrast maps of tonic pain state > pain-free state of seed-driven functional connectivity from (A) left amygdala complex seed (B) left parabrachial complex seed and (C) right parabrachial complex seed. n = 50; minimum cluster size 270 mm³; p-value threshold 0.001. Axial and sagittal labels are in MNI coordinates.

Fig. 5.

Pain intensity covariation with seed-driven functional connectivity maps of (A) right amygdala complex seed during pain-free state immediately before and (B) left amygdala complex seed during tonic pain. n = 50; minimum cluster size 270 mm³; p-value threshold 0.001. Axial and sagittal labels are in MNI coordinates.