The periaqueductal gray in chronic low back pain: dysregulated neurotransmitters and function

Figures

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  Figure 1.. Overview of the study design and the CPM and experimental pressure pain sensitivity assessment. Main outcomes of interest are highlighted in bold. Red crosses indicate locations at which PPTs were assessed, ie, over the erector spinae muscle within the lower back (most painful area) and at the thenar eminence of the nondominant hand (pain-free, remote area). The CPMSHAM paradigm was only performed at the nondominant hand. CPM, conditioned pain modulation; CS, conditioning stimulus; 1H-MRS, proton magnetic resonance spectroscopy; HADS, hospital anxiety and depression scale; PCS, pain catastrophizing scale; PPT, pressure pain threshold; TS, test stimulus.

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  Figure 2.. 1H-MRS VOI placement and acquired spectra. (A) The VOI was placed according to anatomical landmarks such as the cerebral aqueduct. The yellow box represents the nominal size of the VOI (11 × 15 × 18 mm3 [AP × LR × FH]). Blue-shaded areas represent the VSS bands. The unshaded area within the yellow box represents the final VOI size (8.8 × 10.2 × 12.2 mm3). (B) Representative single spectrum (SNR = 19, FWHM H2O = 5.1 Hz, FWHM NAA = 4.9 Hz, age = within 53.5 years [median age of the cohort] ± 5). (C) Overlaid single spectra together with the group average (bold) for CLBP patients (purple) and controls (turquoise). The schematic brain was adapted from Servier Medical Art (smart.servier.com). AP, anterior–posterior; CLBP, nonspecific chronic low back pain; FWHM, full width at half maximum; FH, foot–head; 1H-MRS, proton magnetic resonance spectroscopy; LR, left–-right; NAA, N-acetylaspartate; SNR, signal-to-noise ratio; VOI, volume of interest; VSS, very selective saturation.

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  Figure 3.. Lower Glx/GABA in CLBP patients driven by decreased Glx and increased GABA. The raincloud plots show the raw data (coloured dots), means and 95% confidence intervals (black dots and bars), and probability distributions (vertical “clouds”) of Glx/GABA (A) and Glx and GABA separately (B) for CLBP patients (purple) and controls (turquoise). *P < 0.05, **P < 0.01. CLBP, nonspecific chronic low back pain; GABA, γ-aminobutyric acid; Glx, glutamate + glutamine.

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  Figure 4.. Inhibitory CPM effects on PPTs in CLBP patients and pain-free controls. (A) PPT changes in controls in response to the CPM (blue) and the CPMSHAM (white) paradigm performed at the nondominant hand (pain-free, remote area). Data are presented as PPT values at each timepoint of the 2 paradigms (left panel) and as absolute parallel (PPT before − PPT during) and sequential (PPT before − PPT after) PPT changes in response to the 2 paradigms (ΔPPT; right panel). (B) PPT values before and during the cold water bath reflecting parallel CPM effects at the lower back (most painful area) and at the nondominant hand of CLBP patients (purple) and controls (turquoise). (C) Group comparison of relative parallel CPM effects (CPM ΔPPT), ie, ([PPT before − PPT during]/PPT before) × 100, at the lower back and at the nondominant hand. Negative absolute and relative ΔPPTs reflect inhibitory effects, and positive values reflect facilitatory effects. The dotted line depicts a null effect. The plots represent the raw data (coloured semitransparent dots), means (coloured dots), and 95% confidence intervals (black bars). **P < 0.01, ***P < 0.001. CLBP, nonspecific chronic low back pain; CPM, conditioned…

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  Figure 5.. Associations of Glx/GABA, Glx, and GABA with experimental pressure pain sensitivity. (A-C) visualize the results of the linear models testing cohort differences in associations of Glx/GABA, Glx, and GABA with experimental pressure pain sensitivity, ie, PPTs. Pearson correlations reflect the models' effects of interest, ie, the “experimental pressure pain sensitivity × cohort” interaction effect (significant for Glx/GABA and GABA in the lower back and the nondominant hand) and the main effect of “experimental pressure pain sensitivity” (significant for Glx in the lower back). (A) shows Pearson correlations between Glx/GABA and PPTs at the lower back (most painful area) and at the nondominant hand (pain-free, remote area) for CLBP patients (purple) and controls (turquoise), (B) shows Pearson correlations between Glx and PPTs at both areas for the pooled sample (CLBP patients + controls), ie, main effect, and (C) shows Pearson correlations between GABA and PPTs at both areas for CLBP patients and controls. Solid lines represent significant Pearson correlations. CLBP, nonspecific chronic low back pain; PPT, pressure pain threshold.

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  Figure 6.. Associations of parallel CPM effects with clinical pain intensities. Spearman correlations between relative parallel CPM effects (CPM ΔPPT) and average clinical pain intensities over the past 4 weeks (average clinical pain), ie, “trait” pain, and within-CPM-session clinical pain (CPM-session clinical pain), ie, “state” pain. Upper panels show ranked data representative of Spearman correlations. To help with interpretability, the raw data are shown in the lower panels. Negative relative CPM ΔPPTs reflect inhibitory CPM effects, and positive relative CPM ΔPPTs reflect facilitatory CPM effects. The dotted line depicts a null CPM effect. CLBP, nonspecific chronic low back pain; CPM, conditioned pain modulation; NRS, numeric rating scale; PPT, pressure pain threshold.

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  Figure 7.. Clinical evidence for altered amygdala–medial prefrontal cortex (mPFC)–PAG connectivity patterns in chronic pain and potential consequences for PAG-driven descending pain inhibition. Summary of resting-state functional connectivity (rsFC) studies that found altered rsFC,11,13,15,41,44,74,81,83 altered effective rsFC (effFC),43 and altered task rsFC (taskFC; during observation of harmful activities)47 in the amygdala–mPFC–PAG circuit in chronic pain patients compared with pain-free controls. Altered supratentorial input to the PAG might be associated with dysregulated PAG metabolites and PAG-driven descending inhibition, such as the decreased Glx/GABA and the lacking association between Glx/GABA and experimental pressure pain sensitivity in CLBP patients observed in this study. Here, the anterior cingulate cortex was considered to be part of the mPFC.57 The schematic brain and spinal cord were adapted from Servier Medical Art (smart.servier.com). CLBP, nonspecific chronic low back pain; GABA, γ-aminobutyric acid; Glx, glutamate + glutamine; PAG, periaqueductal gray.