Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 7, 100038
eCollection

Biological and Behavioral Markers of Pain Following Nerve Injury in Humans

Affiliations

Biological and Behavioral Markers of Pain Following Nerve Injury in Humans

S A Holmes et al. Neurobiol Pain.

Abstract

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Summary of study. Diagram showing the different sites of evaluation used in the current investigation and the location of injury. For each measure, a list of the extracted parameters is outlined as well as the methods used.
Fig. 2
Fig. 2
Peripheral nerve measures. (Left) A schematic is outlined showing the recording window and its position within the leg as well as representations of the sciatic, tibial and fibular nerves using schematic and tractography representations. Recordings were taken from both the left and right legs. (Middle) Findings from the diffusion weighted imaging analysis using fractional anisotropy as well as other diffusion measures (Right). * Indicates a significant difference (p < 0.05) in a regression model controlling for the recorded leg (left or right) and the location of injury (left or right ankle). HTY = Healthy; ANK = Ankle Injury.
Fig. 3
Fig. 3
Genetic profiling analysis. (A) Heat map of 33 differentially expressed genes from saliva of injury patients vs. control subjects. Supervised analysis of gene profiling data from ankle injury patients and control subjects. The genes with multiple test corrected p value <0.05 and absolute change >2 folds were considered significantly and differentially expressed. In each heat map, rows depict differentially expressed genes and columns depict individual subjects. The relative expression level of genes is shown using a pseudocolor scale from −3 to +3 (green represents down regulation and red represents up regulation). (B) Pathways enrichment analysis of genes that are differentially expressed in saliva from ankle injury patients compared to controls. This analysis depicts the significant effect on multiple stress and inflammation pathways including DNA Damage, Neuroinflammation, AMPK and ATM signaling. Pathways with multiple test corrected p value <0.05 were considered significant. (C) Top regulatory molecules (orange) significantly altered in injury group as compared to controls. Lines ending in an arrow represent amplification and those ending in a flat line represent an inhibitory connection. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Cortical thickness measures. Comparing cortical thickness between the healthy control and ankle injury cohorts. Each highlighted brain region depicts a significant difference between subject groups at the FDR-corrected level of 0.05. Red = greater thickness in healthy controls; Blue = greater thickness in ankle injury cohort. All significant brain regions are ported in the table below along with the size of the cluster and center of gravity reported in Talairach coordinates. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
Circular diagrams presenting tractography of white matter pathways. Significant differences between healthy control and ankle injury cohorts are highlighted within each ring. Rings represent output from all 18 white matter pathways (inside of ring) with individual points reflecting subject values (outside of ring). White matter tracts (right side) from an exemplar subject show the five tracts with significant group differences. R = right hemisphere; L = Left hemisphere.
Fig. 6
Fig. 6
Integrated Cross Modal Analysis. Coherence/correlation maps indicating a relationship between brain or inflammatory marker or self-reported measures (healthy vs. patients). The analysis shows differences in patterns within the heatmap for genes evaluated (A), structural brain regions (B), peripheral nerve measures (C) and psychological/self-reported measures (D). A stronger relationship is indicated by the increase in (blue-purple) vs. a weaker relationship (no-color). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 7
Fig. 7
Proposed cascade model of nerve stretch injury. Results from this investigation are integrated into a proposed model to understand how acute findings may relate to chronic pain processes.

Similar articles

See all similar articles

Cited by 1 article

References

    1. Alexander A.L., Lee J.E., Lazar M., Field A.S. Diffusion tensor imaging of the brain. Neurotherapeutics. 2008:26. - PubMed
    1. Androulakis X.M., Krebs K.A., Jenkins C., Maleki N., Finkel A.G., Rorden C., Newman R. Central executive and default mode network intranetwork functional connectivity patterns in chronic migraine. J. Neurol. Disord. 2018;6(5) - PMC - PubMed
    1. Angin M., Sharma S., King M., Murooka T.T., Ghebremichael M., Mempel T.R., Addo M.M. HIV-1 infection impairs regulatory T-cell suppressive capacity on a per-cell basis. J. Infect. Dis. 2014;210(6):899–903. - PMC - PubMed
    1. Apkarian A.V., Reckziegel D. Peripheral and central viewpoints of chronic pain, and translational implications. Neuroscience Letters. 2018 - PMC - PubMed
    1. Baron R., Maier C., Attal N., Binder A., Bouhassira D., Cruccu G., Treede R.-D. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain. 2017;158(2):261–272. - PMC - PubMed
Feedback