Corticostriatal functional connectivity predicts transition to chronic back pain

Journal name:
Nature Neuroscience
Volume:
15,
Pages:
1117–1119
Year published:
DOI:
doi:10.1038/nn.3153
Received
Accepted
Published online

The mechanism of brain reorganization in pain chronification is unknown. In a longitudinal brain imaging study, subacute back pain (SBP) patients were followed over the course of 1 year. When pain persisted (SBPp, in contrast to recovering SBP and healthy controls), brain gray matter density decreased. Initially greater functional connectivity of nucleus accumbens with prefrontal cortex predicted pain persistence, implying that corticostriatal circuitry is causally involved in the transition from acute to chronic pain.

At a glance

Figures

  1. Changes in global and regional gray matter density over 1 year.
    Figure 1: Changes in global and regional gray matter density over 1 year.

    (a) SBPr patients (in contrast with SBPp patients) exhibited decreases in pain intensity with time. Horizontal bars represent range of times for each visit in each group (SBPp, black; SBPr, gray; healthy controls, white); orange lines are the mean. Pain duration at visit 1 was not different between the groups (SBPp, 14.08 ± 0.97 weeks; SBPr, 12.36 ± 1.04 weeks; unpaired t test, t = 1.68, P = 0.16). VAS, visual analog scale. (b) Gray matter volume only decreased in time in SBPp patients (group × visit, F6,147 = 3.23, P < 0.01). (c) Whole-brain voxelwise repeated-measures ANOVA for gray matter density changes in time for SBPp patients. Regions (red-yellow) that significantly changed in gray matter density included bilateral NAc, insula and left sensorimotor cortex (Supplementary Table 3). L, left; R, right. (d) ROI analyses for right NAc and right insula showed decreased gray matter only in SBPp patients. +P < 0.05, ++P < 0.01, within group comparison to visit 1; *P < 0.05, **P < 0.01 comparison to healthy controls at corresponding time. Error bars represent s.e.m.

  2. Functional connectivity of NAc and insula.
    Figure 2: Functional connectivity of NAc and insula.

    (a) Whole-brain voxelwise contrast of NAc (green) functional connectivity (links) between SBPp and SBPr patients. SBPp showed (red-yellow) significantly stronger positive connections between NAc and mPFC at both visits (P < 0.05). (b) Average total number of voxels exhibiting positive (z(r) > 0.25) and negative (z(r) < −0.25) links to NAc. Positive functional connections were larger in SBPp patients at both visits. (Group F1,34 = 8.80, P < 0.01). (c) In SBPp patients, the number of NAc positive links correlated with affective pain (computed from the affective descriptors of McGill pain questionnaire at the day of the scan) at both visits. (d) Whole-brain voxelwise contrast of insula (green) functional connectivity. SBPp showed decreased negative correlations between insula dorsolateral PFC and posterior cingulate cortex in time (group × visit, F1,34 = 4.04, P < 0.05). (e) Positive and negative links to insula. SBPp patients showed decreased negative links at visit 4. (f) In SBPp patients and at visit 4, the number of negative links to insula was related to insula gray matter density (left) and to pain intensity (right). *P < 0.05 in comparison with healthy controls, ++P < 0.01, within group comparison. Error bars represent s.e.m.

  3. mPFC-NAc functional connectivity predicts pain chronification.
    Figure 3: mPFC-NAc functional connectivity predicts pain chronification.

    (a) Location and coordinates of the mPFC and NAc seeds that we used. (b) mPFC-NAc functional connectivity in SBPp patients was higher than that in SBPr patients in separate fMRI scans. (c) ROC curves and discrimination probabilities (D, area under ROC curve) for predicting pain persistence at visits 2, 3 and 4 using mPFC-NAc at visit 1′ (unbiased estimate). (d) In a separate validation group (n = 13), mPFC-NAc strengths at visit 1 (inset) and ROC and D values at visit 1 predicted persistence of pain at visit 4. *P < 0.05, **P < 0.001. Error bars represent s.e.m.

References

  1. Apkarian, A.V., Hashmi, J.A. & Baliki, M.N. Pain 152, S49S64 (2011).
  2. Chou, R. & Shekelle, P. J. Am. Med. Assoc. 303, 12951302 (2010).
  3. Woolf, C.J. & Salter, M.W. Science 288, 17651769 (2000).
  4. Baliki, M.N., Schnitzer, T.J., Bauer, W.R. & Apkarian, A.V. PLoS ONE 6, e26010 (2011).
  5. Yarkoni, T., Poldrack, R.A., Nichols, T.E., Van Essen, D.C. & Wager, T.D. Nat. Methods 8, 665670 (2011).
  6. Baliki, M.N. et al. J. Neurosci. 26, 1216512173 (2006).
  7. Baliki, M.N., Geha, P.Y., Fields, H.L. & Apkarian, A.V. Neuron 66, 149160 (2010).
  8. Baliki, M.N., Geha, P.Y. & Apkarian, A.V. J. Neurophysiol. 101, 875887 (2009).
  9. Isnard, J., Magnin, M., Jung, J., Mauguière, F. & Garcia-Larrea, L. Pain 152, 946951 (2011).
  10. Seminowicz, D.A. et al. J Neurosci 31, 75407550 (2011).
  11. Ungless, M.A., Magill, P.J. & Bolam, J.P. Science 303, 20402042 (2004).
  12. Seymour, B. et al. Nature 429, 664667 (2004).
  13. Zubieta, J.K. et al. J. Neurosci. 25, 77547762 (2005).
  14. Johansen, J.P. & Fields, H.L. Nat. Neurosci. 7, 398403 (2004).
  15. Chanda, M.L. et al. J. Pain 12, 792800 (2011).
  16. Smith, S.M. & Nichols, T.E. Neuroimage 44, 8398 (2009).
  17. Baliki, M.N., Geha, P.Y., Apkarian, A.V. & Chialvo, D.R. J. Neurosci. 28, 13981403 (2008).
  18. Fox, M.D. et al. Proc. Natl. Acad. Sci. USA 102, 96739678 (2005).

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Author information

Affiliations

  1. Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

    • Marwan N Baliki,
    • Bogdan Petre,
    • Souraya Torbey,
    • Kristina M Herrmann,
    • Lejian Huang &
    • A Vania Apkarian
  2. Department of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

    • Thomas J Schnitzer
  3. Department of Neurology and the Ernest Gallo Clinic & Research Center, University of California, San Francisco, Emeryville, California, USA.

    • Howard L Fields
  4. Departments of Anesthesia and Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

    • A Vania Apkarian

Contributions

M.N.B. conducted the experiment, analyzed the data and prepared and wrote the manuscript. B.P. contributed to data collection and analysis. S.T. recruited subjects and conducted the experiment. K.M.H. contributed to data collection. L.H. performed data quality control. T.J.S. recruited subjects and edited the manuscript. H.L.F. wrote the manuscript. A.V.A. designed and supervised the experiment and wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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Supplementary information

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  1. Supplementary Text and Figures (2M)

    Supplementary Figures 1–9 and Supplementary Tables 1–4

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