Brain Imaging and Behavior

, Volume 8, Issue 4, pp 506–516 | Cite as

Preliminary differences in peripheral immune markers and brain metabolites between fatigued and non-fatigued breast cancer survivors: a pilot study

  • Suzanna Maria ZickEmail author
  • Heather Zwickey
  • Lisa Wood
  • Bradley Foerster
  • Tohfa Khabir
  • Benjamin Wright
  • Eric Ichesco
  • Ananda Sen
  • Richard Edmund Harris
Original Research


Persistent cancer-related fatigue (PCRF) is one of the most troubling side-effects of breast cancer (BC) treatment. One explanatory model for PCRF is sickness behavior, which is a set of adaptive responses including sleepiness and depressed mood in reaction to an inflammatory trigger. Prior research has investigated differences in inflammatory cytokines between fatigued and non-fatigued BC survivors, but no study has examined differences in brain metabolites. Differences in inflammatory markers, and brain metabolites using proton magnetic resonance spectroscopy were evaluated within 16 fatigued and 13 non-fatigued BC survivors. Fatigued BC survivors had significantly higher ratios of two markers derived from brain metabolites; namely (a) creatine, normalized to total creatine (creatine + phosphocreatine (Cr/tCr)) ratio (P = 0.03) and (b) glutamate + glutamine (Glx) to N-acetyl-aspartate (NAA) ratio (P = 0.01) in the posterior insula compared to non-fatigued breast cancer survivor. Further, serum IL-6 was increased in fatigued women compared to non-fatigued women (P = 0.03), Using receiver operator curves (ROC) we determined that the posterior insula Glx/NAA ratio was the best predictor of fatigue with an overall area under the receiver operating characteristic curve (AUROC) of 79 %, with a sensitivity of 81 % and a specificity of 69 %. However, posterior insula Glx/NAA, Cr/tCr and serum IL-6 were not significantly correlated with one another implying the possibility of independent biological mechanisms for PCRF rather than an interrelated mechanism as represented by the sickness behavior model. This study provides novel preliminary evidence of several distinct neurobiological changes in the posterior insula associated with PCRF in BC survivors. Future, longitudinal studies are needed to explore these distinct biological phenomena where changes through time in peripheral immune markers and brain metabolites are examined to determine if they correlate with changes in fatigue.


Magnetic resonance spectroscopy Persistent fatigue Breast cancer survivors Creatine Glutamate Cytokines C-reactive protein Posterior insula Anterior insula Anterior cingulate Occipital cortex 



This research was supported by grants from the Ronald P. and Joan M. Nordgren Cancer Research Fund and the University of Michigan National Institutes of Health Clinical and Translational Awards (CTSA) grant number UL1RR024986.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments described in this manuscript comply with the current laws of the country in which they were performed.


  1. Alexander, S., Minton, O., Andrews, P., & Stone, P. (2009). A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome. European Journal of Cancer, 45(3), 384–392.PubMedCentralPubMedCrossRefGoogle Scholar
  2. Allen, P. J. (2012). Creatine metabolism and psychiatric disorders: does creatine supplementation have therapeutic value? Neuroscience and Biobehavioral Reviews, 36(5), 1442–1462.PubMedCentralPubMedCrossRefGoogle Scholar
  3. American Cancer Society. (2012). Cancer treatment and survivorsip facts & figures 2012–2013. In A. C. Society (Ed.), Atlanta, Georgia.Google Scholar
  4. Benveniste, H., Zhang, S., Reinsel, R. A., Li, H., Lee, H., Rebecchi, M., et al. (2012). Brain metabolomic profiles of lung cancer patients prior to treatment characterized by proton magnetic resonance spectroscopy. International Journal of Clinical and Experimental Medicine, 5(2), 154–164.PubMedCentralPubMedGoogle Scholar
  5. Berger, A. M., Kuhn, B. R., Farr, L. A., Lynch, J. C., Agrawal, S., Chamberlain, J., et al. (2009). Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue. Psychooncology, 18(6), 634–646.PubMedCrossRefGoogle Scholar
  6. Bjelland, I., Dahl, A. A., Haug, T. T., & Neckelmann, D. (2002). The validity of the hospital anxiety and depression scale. An updated literature review. Journal of Psychosomatic Research, 52(2), 69–77.PubMedCrossRefGoogle Scholar
  7. Bokemeyer, M., Ding, X. Q., Goldbecker, A., Raab, P., Heeren, M., Arvanitis, D., et al. (2011). Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. Gut, 60(3), 370–377.PubMedCrossRefGoogle Scholar
  8. Boksem, M. A., & Tops, M. (2008). Mental fatigue: costs and benefits. Brain Research Reviews, 59(1), 125–139.PubMedCrossRefGoogle Scholar
  9. Bower, J. E. (2005). Prevalence and causes of fatigue after cancer treatment: the next generation of research. Journal of Clinical Oncology, 23(33), 8280–8282.PubMedCrossRefGoogle Scholar
  10. Bower, J. E. (2008). Behavioral symptoms in patients with breast cancer and survivors. Journal of Clinical Oncology, 26(5), 768–777.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Bower, J. E., Ganz, P. A., Aziz, N., & Fahey, J. L. (2002). Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine, 64(4), 604–611.PubMedCrossRefGoogle Scholar
  12. Bower, J. E., Ganz, P. A., Aziz, N., Fahey, J. L., & Cole, S. W. (2003). T-cell homeostasis in breast cancer survivors with persistent fatigue. Journal of the National Cancer Institute, 95(15), 1165–1168.PubMedCrossRefGoogle Scholar
  13. Bower, J. E., Ganz, P. A., Irwin, M. R., Kwan, L., Breen, E. C., & Cole, S. W. (2011). Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? Journal of Clinical Oncology, 29(26), 3517–3522.PubMedCentralPubMedCrossRefGoogle Scholar
  14. Brooks, J. C., Roberts, N., Whitehouse, G., & Majeed, T. (2000). Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome. British Journal of Radiology, 73(875), 1206–1208.PubMedCrossRefGoogle Scholar
  15. Cameron, B. A., Bennett, B., Li, H., Boyle, F., Desouza, P., Wilcken, N., et al. (2012). Post-cancer fatigue is not associated with immune activation or altered cytokine production. Annals of Oncology. doi: 10.1093/annonc/mds108.PubMedCentralGoogle Scholar
  16. Castillo, M. (2007). Spectroscopy evidence of diffuse brain abnormalities in patients with epileptogenic foci. American Journal of Neuroradiology, 28(6), 1076–1077.CrossRefGoogle Scholar
  17. Chang, Y. J., Lee, J. S., Lee, C. G., Lee, W. S., Lee, K. S., Bang, S. M., et al. (2007). Assessment of clinical relevant fatigue level in cancer. Support Care Cancer, 15(7), 891–896.PubMedCrossRefGoogle Scholar
  18. Chaudhuri, A., Condon, B. R., Gow, J. W., Brennan, D., & Hadley, D. M. (2003). Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport, 14(2), 225–228.PubMedCrossRefGoogle Scholar
  19. Collado-Hidalgo, A., Bower, J. E., Ganz, P. A., Cole, S. W., & Irwin, M. R. (2006). Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clinical Cancer Research, 12(9), 2759–2766.PubMedCrossRefGoogle Scholar
  20. Craig, A. D. (2010). The sentient self. Brain Structure and Function, 214(5–6), 563–577.PubMedCrossRefGoogle Scholar
  21. Craig, A. D. (2011). Significance of the insula for the evolution of human awareness of feelings from the body. Annals of the New York Academy of Sciences, 1225, 72–82.PubMedCrossRefGoogle Scholar
  22. Dantzer, R. (2001). Cytokine-induced sickness behavior: mechanisms and implications. Annals of the New York Academy of Sciences, 933, 222–234.PubMedCrossRefGoogle Scholar
  23. Dantzer, R., & Kelley, K. W. (2007). Twenty years of research on cytokine-induced sickness behavior. Brain, Behavior, and Immunity, 21(2), 153–160.PubMedCentralPubMedCrossRefGoogle Scholar
  24. Filosa, A., Paixao, S., Honsek, S. D., Carmona, M. A., Becker, L., Feddersen, B., et al. (2009). Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neuroscience, 12(10), 1285–1292.PubMedCentralPubMedCrossRefGoogle Scholar
  25. Fletcher, M. A., Zeng, X. R., Barnes, Z., Levis, S., & Klimas, N. G. (2009). Plasma cytokines in women with chronic fatigue syndrome. Journal of Translational Medicine, 7, 96.PubMedCentralPubMedCrossRefGoogle Scholar
  26. Friedman, S. D., Shaw, D. W., Ishak, G., Gropman, A. L., & Saneto, R. P. (2010). The use of neuroimaging in the diagnosis of mitochondrial disease. Developmental Disabilities Research Reviews, 16(2), 129–135.PubMedCrossRefGoogle Scholar
  27. Gelinas, C., & Fillion, L. (2004). Factors related to persistent fatigue following completion of breast cancer treatment. Oncology Nursing Forum, 31(2), 269–278.PubMedCrossRefGoogle Scholar
  28. Harris, R. E., Sundgren, P. C., Craig, A. D., Kirshenbaum, E., Sen, A., Napadow, V., et al. (2009). Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis and Rheumatism, 60(10), 3146–3152.PubMedCentralPubMedCrossRefGoogle Scholar
  29. Hart, B. L. (1988). Biological basis of the behavior of sick animals. Neuroscience and Biobehavioral Reviews, 12(2), 123–137.PubMedCrossRefGoogle Scholar
  30. Hawkins, R. A. (2009). The blood–brain barrier and glutamate. American Journal of Clinical Nutrition, 90(3), 867S–874S.PubMedCentralPubMedCrossRefGoogle Scholar
  31. Hedberg, T. G., & Stanton, P. K. (1996). Long-term plasticity in cingulate cortex requires both NMDA and metabotropic glutamate receptor activation. European Journal of Pharmacology, 310(1), 19–27.PubMedCrossRefGoogle Scholar
  32. Kesler, S. R., Watson, C., Koovakkattu, D., Lee, C., O’Hara, R., Mahaffey, M. L., et al. (2013). Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy. Brain Imaging and Behavior. doi: 10.1007/s11682-013-9228-1.PubMedGoogle Scholar
  33. Kim, S. H., Son, B. H., Hwang, S. Y., Han, W., Yang, J. H., Lee, S., et al. (2008). Fatigue and depression in disease-free breast cancer survivors: prevalence, correlates, and association with quality of life. Journal of Pain and Symptom Management, 35(6), 644–655.PubMedCrossRefGoogle Scholar
  34. Lee, B. N., Dantzer, R., Langley, K. E., Bennett, G. J., Dougherty, P. M., Dunn, A. J., et al. (2004). A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation, 11(5), 279–292.PubMedCrossRefGoogle Scholar
  35. Liu, L., Mills, P. J., Rissling, M., Fiorentino, L., Natarajan, L., Dimsdale, J. E., et al. (2012). Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy. Brain, Behavior, and Immunity, 26(5), 706–713.PubMedCentralPubMedCrossRefGoogle Scholar
  36. Lopez Zunini, R. A., Scherling, C., Wallis, N., Collins, B., Mackenzie, J., Bielajew, C., et al. (2012). Differences in verbal memory retrieval in breast cancer chemotherapy patients compared to healthy controls: a prospective fMRI study. Brain Imaging and Behavior. doi: 10.1007/s11682-012-9213-0.Google Scholar
  37. Maddock, R. J., & Buonocore, M. H. (2012). MR spectroscopic studies of the brain in psychiatric disorders. Current Topics in Behavioral Neurosciences. doi: 10.1007/7854_2011_197.PubMedGoogle Scholar
  38. Maier, S. F. (2003). Bi-directional immune-brain communication: implications for understanding stress, pain, and cognition. Brain, Behavior, and Immunity, 17(2), 69–85.PubMedCrossRefGoogle Scholar
  39. Mathew, S. J., Mao, X., Keegan, K. A., Levine, S. M., Smith, E. L., Heier, L. A., et al. (2009). Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR in Biomedicine, 22(3), 251–258.PubMedCrossRefGoogle Scholar
  40. Matsui, K., Jahr, C. E., & Rubio, M. E. (2005). High-concentration rapid transients of glutamate mediate neural-glial communication via ectopic release. Journal of Neuroscience, 25(33), 7538–7547.PubMedCrossRefGoogle Scholar
  41. Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R., & Sharma, P. L. (2013). Excitotoxicity: bridge to various triggers in neurodegenerative disorders. European Journal of Pharmacology, 698(1–3), 6–18.PubMedCrossRefGoogle Scholar
  42. Mendoza, T. R., Wang, X. S., Cleeland, C. S., Morrissey, M., Johnson, B. A., Wendt, J. K., et al. (1999). The rapid assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer, 85(5), 1186–1196.PubMedCrossRefGoogle Scholar
  43. Moffett, J. R., Ross, B., Arun, P., Madhavarao, C. N., & Namboodiri, A. M. (2007). N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Progress in Neurobiology, 81(2), 89–131.PubMedCentralPubMedCrossRefGoogle Scholar
  44. Montazeri, A. (2008). Health-related quality of life in breast cancer patients: a bibliographic review of the literature from 1974 to 2007. Journal of Experimental & Clinical Cancer Research, 27, 32.CrossRefGoogle Scholar
  45. Myers, J. S. (2008). Proinflammatory cytokines and sickness behavior: implications for depression and cancer-related symptoms. Oncology Nursing Forum, 35(5), 802–807.PubMedCrossRefGoogle Scholar
  46. Nakanishi, S. (1992). Molecular diversity of glutamate receptors and implications for brain function. Science, 258(5082), 597–603.PubMedCrossRefGoogle Scholar
  47. Provencher, S. W. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine, 30(6), 672–679.PubMedCrossRefGoogle Scholar
  48. Puri, B. K., Counsell, S. J., Zaman, R., Main, J., Collins, A. G., Hajnal, J. V., et al. (2002). Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatrica Scandinavica, 106(3), 224–226.PubMedCrossRefGoogle Scholar
  49. Rawson, E. S., & Venezia, A. C. (2011). Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids, 40(5), 1349–1362.PubMedCrossRefGoogle Scholar
  50. Reid-Arndt, S. A., Hsieh, C., & Perry, M. C. (2010). Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psychooncology, 19(5), 535–544.PubMedCentralPubMedCrossRefGoogle Scholar
  51. Reuter-Lorenz, P. A., & Cimprich, B. (2013). Cognitive function and breast cancer: promise and potential insights from functional brain imaging. Breast Cancer Research and Treatment, 137(1), 33–43.PubMedCrossRefGoogle Scholar
  52. Reyngoudt, H., Achten, E., & Paemeleire, K. (2012). Magnetic resonance spectroscopy in migraine: what have we learned so far? Cephalalgia. doi: 10.1177/0333102412452048.PubMedGoogle Scholar
  53. Ronnback, L., & Hansson, E. (2004). On the potential role of glutamate transport in mental fatigue. Journal of Neuroinflammation, 1(1), 22.PubMedCentralPubMedCrossRefGoogle Scholar
  54. Savic, I., Thomas, A. M., Ke, Y., Curran, J., Fried, I., & Engel, J., Jr. (2000). In vivo measurements of glutamine + glutamate (Glx) and N-acetyl aspartate (NAA) levels in human partial epilepsy. Acta Neurologica Scandinavica, 102(3), 179–188.PubMedCrossRefGoogle Scholar
  55. Schifitto, G., Deng, L., Yeh, T. M., Evans, S. R., Ernst, T., Zhong, J., et al. (2011). Clinical, laboratory, and neuroimaging characteristics of fatigue in HIV-infected individuals. Journal for Neurovirology, 17(1), 17–25.CrossRefGoogle Scholar
  56. Schubert, C., Hong, S., Natarajan, L., Mills, P. J., & Dimsdale, J. E. (2007). The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain, Behavior, and Immunity, 21(4), 413–427.PubMedCrossRefGoogle Scholar
  57. Segerstrom, S. C., & Miller, G. E. (2004). Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychological Bulletin, 130(4), 601–630.PubMedCentralPubMedCrossRefGoogle Scholar
  58. Starkweather, A. R., Lyon, D. E., & Schubert, C. M. (2011). Pain and Inflammation in women with early-stage breast cancer prior to induction of chemotherapy. Biological Research for Nursing. doi: 10.1177/1099800411425857.PubMedCentralPubMedGoogle Scholar
  59. Tittle, M. B., McMillan, S. C., & Hagan, S. (2003). Validating the brief pain inventory for use with surgical patients with cancer. Oncology Nursing Forum, 30(2), 325–330.PubMedCrossRefGoogle Scholar
  60. Wallimann, T., Wyss, M., Brdiczka, D., Nicolay, K., & Eppenberger, H. M. (1992). Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochemistry Journal, 281(Pt 1), 21–40.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Suzanna Maria Zick
    • 1
    Email author
  • Heather Zwickey
    • 2
  • Lisa Wood
    • 3
  • Bradley Foerster
    • 4
    • 5
  • Tohfa Khabir
    • 1
  • Benjamin Wright
    • 1
  • Eric Ichesco
    • 6
  • Ananda Sen
    • 7
  • Richard Edmund Harris
    • 6
  1. 1.Department of Family MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Helfgott Research InstituteOregon Health Sciences UniversityPortlandUSA
  3. 3.MGH Institute of Health Professions, School of NursingNational College of Natural MedicineBostonUSA
  4. 4.Department of RadiologyVA Ann Arbor Healthcare SystemAnn ArborUSA
  5. 5.Ann Arbor VA Healthcare SystemAnn ArborUSA
  6. 6.Department of AnesthesiologyUniversity of MichiganAnn ArborUSA
  7. 7.Department of Family MedicineUniversity of MichiganAnn ArborUSA

Personalised recommendations