Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Abstract

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.

Tracking sensory system atrophy and outcome prediction in spinal cord injury

“…Alterations in structure and function in these areas14, 18, 55, 56 have been associated with impaired sensory processing and sensory discomfort in patients with SCI 22. Similar to findings in the spinal cord, myelin‐sensitive R1 and MT paralleled the volumetric changes observed in the thalamus, cerebellum, and medulla oblongata comprising the dorsal columns.…”

Chronic Pain: We Should Not Underestimate the Contribution of Neural Plasticity

“…99 This alteration was not present in those with spinal cord injury without pain or with less severe pain, and provides evidence that proliferation of glia and glial activation within the cortex may contribute to the maintenance of neuropathic pain.…”

“…One caveat that should be mentioned is that most of these studies have not taken patient comorbidities into account and some have revealed structural changes in non-neuromatrix regions, so such reorganisation may not always be pain-specific. 91 Changes in concentration of specific brain metabolites have been demonstrated in neuromatrix regions of people with chronic low back pain, 92-95 CRPS, 96,97 spinal cord injury, 98,99 and post-herpetic neuralgia. 97 In fact, it was some of this early work using magnetic resonance spectroscopy that lead to the hypothesis that morphological changes may be present in the brain.…”

“…The clinical importance of such findings is evident in that the concentration of metabolites related to glutamate and NAA in people with spinal cord injury was able to distinguish between those with pain and those without. 98,99 Reduced concentration of these specific metabolites reflects a loss of neurons or neuronal dysfunction in specific neuromatrix regions. It has been speculated that this arises through a neurodegenerative processes due to enhanced neural activity in these regions in people with long-term pain.…”

“…The intensity of current or ongoing pain has been correlated with primary somatosensory cortex reorganisation in CRPS, 107,110 spinal cord injury, 111 and phantom limb pain. 152 Others have reported that cortical metabolite concentrations 98,99 and the extent of atrophy of the insula 89 correlate with pain intensity. Stronger evidence of a relationship between pain and cortical plasticity has been shown in a few longitudinal studies.…”