Effect of blast-related mTBI on the working memory system: a resting state fMRI study

  • Kathleen F. PagulayanEmail author
  • Eric C. Petrie
  • David G. Cook
  • Rebecca C. Hendrickson
  • Holly Rau
  • Melissa Reilly
  • Cindy Mayer
  • James S. Meabon
  • Murray A. Raskind
  • Elaine R. Peskind
  • Natalia Kleinhans


Reduced working memory is frequently reported by Veterans with a history of blast-related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory.


Traumatic brain injury Resting state fMRI Working memory Auditory consonant trigrams test Veterans Blast injury Neuropsychology 



This work was supported by Career Development Award #IK2CX000516 from the United States (U.S.) Department of Veterans Affairs Clinical Science Research and Development Service, Merit Review #I01 RX000521 from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service, the U.S. Department of Veterans Affairs Medical Research Service, as well as VA Northwest Network MIRECC and University of Washington Royalty Research Fund.

The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Compliance with ethical standards

Conflict of interest

Author Raskind has received consultant fees from Takeda Pharmaceuticals and Merck Pharmaceuticals. Author Peskind has received consultant fees from Takeda, Merck, Aramis, and Eli Lilly. Author Meabon is Chief Operations Officer for Neurogenix Pharmaceuticals, Inc. Authors Cook, Hendrickson, Kleinhans, Mayer, Pagulayan, Petrie, Rau, and Reilly declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2018_9987_MOESM1_ESM.docx (370 kb)
ESM 1 (DOCX 369 kb)
11682_2018_9987_MOESM2_ESM.docx (190 kb)
ESM 2 (DOCX 190 kb)


  1. Baddeley, A. (1996). The fractionation of working memory. Proceedings of the National Academy of Sciences, 93(24), 13468–13472.CrossRefGoogle Scholar
  2. Belanger, H. G., & Vanderploeg, R. D. (2005). The neuropsychological impact of sports-related concussion: a meta-analysis. Journal of the International Neuropsychological Society, 11(4), 345–357.CrossRefGoogle Scholar
  3. Belanger, H. G., Kretzmer, T., Yoash-Gantz, R., Pickett, T., & Tupler, L. A. (2009). Cognitive sequelae of blast-related versus other mechanisms of brain trauma. Journal of the International Neuropsychological Society, 15(1), 1–8.CrossRefGoogle Scholar
  4. Belanger, H. G., Kretzmer, T., Vanderploeg, R. D., & French, L. M. (2010). Symptom complaints following combat-related traumatic brain injury: relationship to traumatic brain injury severity and posttraumatic stress disorder. Journal of the International Neuropsychological Society, 16(1), 194–199.CrossRefGoogle Scholar
  5. Bohnen, N., Jolles, J., & Twijnstra, A. (1992). Neuropsychological deficits in patients with persistent symptoms six months after mild head injury. Neurosurgery, 30(5), 692–695 discussion 695-696.PubMedGoogle Scholar
  6. Bonavita, S., Sacco, R., Della Corte, M., Esposito, S., Sparaco, M., d'Ambrosio, A., et al. (2015). Computer-aided cognitive rehabilitation improves cognitive performances and induces brain functional connectivity changes in relapsing remitting multiple sclerosis patients: an exploratory study. Journal of Neurology, 262(1), 91–100.CrossRefGoogle Scholar
  7. Cerasa, A., Gioia, M. C., Valentino, P., Nistico, R., Chiriaco, C., Pirritano, D., et al. (2013). Computer-assisted cognitive rehabilitation of attention deficits for multiple sclerosis: a randomized trial with fMRI correlates. Neurorehabilitation and Neural Repair, 27(4), 284–295.CrossRefGoogle Scholar
  8. Chen, S. H., & Desmond, J. E. (2005). Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task. Neuropsychologia, 43(9), 1227–1237.CrossRefGoogle Scholar
  9. Chen, C. J., Wu, C. H., Liao, Y. P., Hsu, H. L., Tseng, Y. C., Liu, H. L., et al. (2012). Working memory in patients with mild traumatic brain injury: functional MR imaging analysis. Radiology, 264(3), 844–851.CrossRefGoogle Scholar
  10. Damoiseaux, J. S., Rombouts, S. A., Barkhof, F., Scheltens, P., Stam, C. J., Smith, S. M., et al. (2006). Consistent resting-state networks across healthy subjects. Proceedings of the National Academy of Sciences, 103(37), 13848–13853.CrossRefGoogle Scholar
  11. Daniels, J. K., McFarlane, A. C., Bluhm, R. L., Moores, K. A., Clark, C. R., Shaw, M. E., et al. (2010). Switching between executive and default mode networks in posttraumatic stress disorder: alterations in functional connectivity. Journal of Psychiatry and Neuroscience, 35(4), 258–266.CrossRefGoogle Scholar
  12. De Giglio, L., Tona, F., De Luca, F., Petsas, N., Prosperini, L., Bianchi, V., et al. (2016). Multiple sclerosis: changes in thalamic resting-state functional connectivity induced by a home-based cognitive rehabilitation program. Radiology, 280(1), 202–211.CrossRefGoogle Scholar
  13. Desmond, J. E., Gabrieli, J. D., Wagner, A. D., Ginier, B. L., & Glover, G. H. (1997). Lobular patterns of cerebellar activation in verbal working-memory and finger-tapping tasks as revealed by functional MRI. Journal of Neuroscience, 17(24), 9675–9685.CrossRefGoogle Scholar
  14. Drag, L. L., Spencer, R. J., Walker, S. J., Pangilinan, P. H., & Bieliauskas, L. A. (2012). The contributions of self-reported injury characteristics and psychiatric symptoms to cognitive functioning in OEF/OIF veterans with mild traumatic brain injury. Journal of the International Neuropsychological Society, 18(3), 576–584.CrossRefGoogle Scholar
  15. Filippi, M., Riccitelli, G., Mattioli, F., Capra, R., Stampatori, C., Pagani, E., et al. (2012). Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures--an explorative study. Radiology, 262(3), 932–940.CrossRefGoogle Scholar
  16. Fox, M. D., & Greicius, M. (2010). Clinical applications of resting state functional connectivity. Frontiers in Systems Neuroscience, 4, 19.PubMedPubMedCentralGoogle Scholar
  17. Frenchman, K., Fox, A., & Mayberry, M. (2005). Neuropsychological studies of mild traumatic brain injury: a meta-analytic review of research since 1995. Journal of Clinical and Experimental Neuropsychology, 27, 334–351.CrossRefGoogle Scholar
  18. Galarneau, M. R., Woodruff, S. I., Dye, J. L., Mohrle, C. R., & Wade, A. L. (2008). Traumatic brain injury during Operation Iraqi Freedom: Findings from the United States Navy-Marine Corps Combat Trauma Registry. Journal of Neurosurgery, 108(5), 950–957.Google Scholar
  19. Gathercole, S., Alloway, T., Kirkwood, H., Elliot, J., & Holmes, J. (2008). Attentional and executive function behaviours in children with poor working memory. Learning and Individual Differences, 18, 214–223.CrossRefGoogle Scholar
  20. Gordon, S. N., Fitzpatrick, P. J., & Hilsabeck, R. C. (2011). No effect of PTSD and other psychiatric disorders on cognitive functioning in veterans with mild TBI. The Clinical Neuropsychologist, 25(3), 337–347.CrossRefGoogle Scholar
  21. Gorges, M., Muller, H. P., Lule, D., Consortium, L., Pinkhardt, E. H., Ludolph, A. C., et al. (2015). To rise and to fall: functional connectivity in cognitively normal and cognitively impaired patients with Parkinson's disease. Neurobiology of Aging, 36(4), 1727–1735.CrossRefGoogle Scholar
  22. Guskiewicz, K. M., McCrea, M., Marshall, S. W., Cantu, R. C., Randolph, C., Barr, W., et al. (2003). Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA concussion study. Journal of the American Medical Association, 290(19), 2549–2555.CrossRefGoogle Scholar
  23. Habas, C., Kamdar, N., Nguyen, D., Prater, K., Beckmann, C. F., Menon, V., et al. (2009). Distinct cerebellar contributions to intrinsic connectivity networks. Journal of Neuroscience, 29(26), 8586–8594.CrossRefGoogle Scholar
  24. Heaton, R. K., Marcotte, T. D., Mindt, M. R., Sadek, J., Moore, D. J., Bentley, H., et al. (2004). The impact of HIV-associated neuropsychological impairment on everyday functioning. Journal of the International Neuropsychological Society, 10(3), 317–331.CrossRefGoogle Scholar
  25. Hillary, F. G. (2008). Neuroimaging of working memory dysfunction and the dilemma with brain reorganization hypotheses. Journal of the International Neuropsychological Society, 14(4), 526–534.CrossRefGoogle Scholar
  26. Hillary, F. G., Roman, C. A., Venkatesan, U., Rajtmajer, S. M., Bajo, R., & Castellanos, N. D. (2015). Hyperconnectivity is a fundamental response to neurological disruption. Neuropsychology, 29(1), 59–75.CrossRefGoogle Scholar
  27. Jao, T., Schroter, M., Chen, C. L., Cheng, Y. F., Lo, C. Y., Chou, K. H., et al. (2015). Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy. Neuroimage, 122, 332–344.CrossRefGoogle Scholar
  28. Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage, 17(2), 825–841.CrossRefGoogle Scholar
  29. Kay, T. (1993). Neuropsychological treatment of mild traumatic brain injury. Journal of Head Trauma Rehabilitation, 8(3), 74.CrossRefGoogle Scholar
  30. Keren-Happuch, E., Chen, S. H., Ho, M. H., & Desmond, J. E. (2014). A meta-analysis of cerebellar contributions to higher cognition from PET and fMRI studies. Human Brain Mapping, 35(2), 593–615.CrossRefGoogle Scholar
  31. Kirschen, M. P., Chen, S. H., Schraedley-Desmond, P., & Desmond, J. E. (2005). Load- and practice-dependent increases in cerebro-cerebellar activation in verbal working memory: an fMRI study. Neuroimage, 24(2), 462–472.CrossRefGoogle Scholar
  32. Koso, M., & Hansen, S. (2006). Executive function and memory in posttraumatic stress disorder: a study of Bosnian war veterans. European Psychiatry, 21(3), 167–173.CrossRefGoogle Scholar
  33. Kroenke, K., Spitzer, R. L., & Williams, J. B. W. (2001). The PHQ-9: Validity of a brief depression severity measure. Journal of General Internal Medicine, 16(9), 606–613.CrossRefGoogle Scholar
  34. Kumar, S., Rao, S. L., Chandramouli, B. A., & Pillai, S. (2013). Reduced contribution of executive functions in impaired working memory performance in mild traumatic brain injury patients. Clinical Neurology and Neurosurgery, 115(8), 1326–1332.CrossRefGoogle Scholar
  35. Lemieux, L., Salek-Haddadi, A., Lund, T. E., Laufs, H., & Carmichael, D. (2007). Modelling large motion events in fMRI studies of patients with epilepsy. Magnetic Resonance Imaging, 25(6), 894–901.CrossRefGoogle Scholar
  36. Louapre, C., Perlbarg, V., Garcia-Lorenzo, D., Urbanski, M., Benali, H., Assouad, R., et al. (2014). Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study. Human Brain Mapping, 35(9), 4706–4717.CrossRefGoogle Scholar
  37. McAllister, T. W., Saykin, A. J., Flashman, L. A., Sparling, M. B., Johnson, S. C., Guerin, S. J., et al. (1999). Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. Neurology, 53(6), 1300–1308.CrossRefGoogle Scholar
  38. McAllister, T. W., Sparling, M. B., Flashman, L. A., Guerin, S. J., Mamourian, A. C., & Saykin, A. J. (2001). Differential working memory load effects after mild traumatic brain injury. Neuroimage, 14(5), 1004–1012.CrossRefGoogle Scholar
  39. McAllister, T. W., Flashman, L. A., Sparling, M. B., & Saykin, A. J. (2004). Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review. Brain Injury, 18(4), 331–350.CrossRefGoogle Scholar
  40. McDowell, S., Whyte, J., & D'Esposito, M. (1997). Working memory impairments in traumatic brain injury: evidence from a dual-task paradigm. Neuropsychologia, 35(10), 1341–1353.CrossRefGoogle Scholar
  41. Meabon, J. S., Huber, B. R., Cross, D. J., Richards, T. L., Minoshima, S., Pagulayan, K. F., et al. (2016). Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction. Science Translational Medicine, 8(321), 321ra6.CrossRefGoogle Scholar
  42. Mendez, M. F., Owens, E. M., Reza Berenji, G., Peppers, D. C., Liang, L. J., & Licht, E. A. (2013). Mild traumatic brain injury from primary blast vs. blunt forces: post-concussion consequences and functional neuroimaging. NeuroRehabilitation, 32(2), 397–407.PubMedGoogle Scholar
  43. Nelson, N. W., Hoelzle, J. B., Doane, B. M., McGuire, K. A., Ferrier-Auerbach, A. G., Charlesworth, M. J., et al. (2012). Neuropsychological outcomes of U.S. veterans with report of remote blast-related concussion and current psychopathology. Journal of the International Neuropsychological Society, 18(5), 845–855.CrossRefGoogle Scholar
  44. Newsome, M. R., Durgerian, S., Mourany, L., Scheibel, R. S., Lowe, M. J., Beall, E. B., et al. (2015). Disruption of caudate working memory activation in chronic blast-related traumatic brain injury. Neuroimage: Clinical, 8, 543–553.CrossRefGoogle Scholar
  45. O'Neil, M.E., Carlson, K.F., Storzbach, D., Brenner, L.A., Freeman, M., Quinones, A.R., Motu'apuaka, M., & Kansagara, D. (2014). Factors associated with mild traumatic brain injury in veterans and military personnel: a systematic review. Journal of the International Neuropsychological Society, 1–13.Google Scholar
  46. Owen, A. M., McMillan, K. M., Laird, A. R., & Bullmore, E. (2005). N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Human Brain Mapping, 25(1), 46–59.CrossRefGoogle Scholar
  47. Peskind, E. R., Petrie, E. C., Cross, D. J., Pagulayan, K., McCraw, K., Hoff, D., et al. (2011). Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war veterans with persistent post-concussive symptoms. Neuroimage, 54(Suppl 1), S76–S82.CrossRefGoogle Scholar
  48. Petrie, E. C., Cross, D. J., Yarnykh, V. L., Richards, T., Martin, N. M., Pagulayan, K., et al. (2014). Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans. Journal of Neurotrauma, 31(5), 425–436.CrossRefGoogle Scholar
  49. Rabinak, C. A., Angstadt, M., Welsh, R. C., Kenndy, A. E., Lyubkin, M., Martis, B., et al. (2011). Altered amygdala resting-state functional connectivity in post-traumatic stress disorder. Frontiers in Psychiatry, 2, 62.CrossRefGoogle Scholar
  50. Robinson, M. E., Lindemer, E. R., Fonda, J. R., Milberg, W. P., McGlinchey, R. E., & Salat, D. H. (2015). Close-range blast exposure is associated with altered functional connectivity in veterans independent of concussion symptoms at time of exposure. Human Brain Mapping, 36(3), 911–922.CrossRefGoogle Scholar
  51. Roth, R., Isquith, P., & Gioia, G. (2005). Behavioral rating inventory for executive function-adult version. Lutz: Psychological Assessment Resources.Google Scholar
  52. Sacco, R., Bonavita, S., Esposito, F., Tedeschi, G., & Gallo, A. (2013). The contribution of resting state networks to the study of cortical reorganization in MS. Multiple Sclerosis International, 2013, 857807.CrossRefGoogle Scholar
  53. Samuelson, K. W., Neylan, T. C., Metzler, T. J., Lenoci, M., Rothlind, J., Henn-Haase, C., et al. (2006). Neuropsychological functioning in posttraumatic stress disorder and alcohol abuse. Neuropsychology, 20(6), 716–726.CrossRefGoogle Scholar
  54. Sastre-Garriga, J., Alonso, J., Renom, M., Arevalo, M. J., Gonzalez, I., Galan, I., et al. (2011). A functional magnetic resonance proof of concept pilot trial of cognitive rehabilitation in multiple sclerosis. Multiple Sclerosis Journal, 17(4), 457–467.CrossRefGoogle Scholar
  55. Selnes, O. A. (2002). Neurocognitive aspects of medication adherence in HIV infection. Journal of Acquired Immune Deficiency Syndrome, 31(Suppl 3), S132–S135.CrossRefGoogle Scholar
  56. Shaw, M. E., Moores, K. A., Clark, R. C., McFarlane, A. C., Strother, S. C., Bryant, R. A., et al. (2009). Functional connectivity reveals inefficient working memory systems in post-traumatic stress disorder. Psychiatry Research, 172(3), 235–241.CrossRefGoogle Scholar
  57. Shura, R. D., Rowland, J. A., & Miskey, H. M. (2016). Auditory consonant trigrams: a psychometric update. Archives of Clinical Neuropsychology, 31(1), 47–57.CrossRefGoogle Scholar
  58. Smits, M., Dippel, D. W., Houston, G. C., Wielopolski, P. A., Koudstaal, P. J., Hunink, M. G., et al. (2009). Postconcussion syndrome after minor head injury: brain activation of working memory and attention. Human Brain Mapping, 30(9), 2789–2803.CrossRefGoogle Scholar
  59. Sripada, R. K., King, A. P., Garfinkel, S. N., Wang, X., Sripada, C. S., Welsh, R. C., et al. (2012). Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder. Journal of Psychiatry and Neuroscience, 37(4), 241–249.CrossRefGoogle Scholar
  60. Stoodley, C. J., & Schmahmann, J. D. (2009). Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage, 44(2), 489–501. Scholar
  61. Stuss, D. T., Stethem, L. L., & Poirier, C. A. (1987). Comparison of three tests of attention and rapid information processing across six age groups. The Clinical Neuropsychologist, 1, 139–152.CrossRefGoogle Scholar
  62. Stuss, D. T., Stethem, L. L., Hugenholtz, H., & Richard, M. T. (1989). Traumatic brain injury: a comparison of three clinical tests, and analysis of recovery. The Clinical Neuropsychologist, 3, 145–156.CrossRefGoogle Scholar
  63. Terrio, H., Brenner, L. A., Ivins, B. J., Cho, J. M., Helmick, K., Schwab, K., et al. (2009). Traumatic brain injury screening: preliminary findings in a US Army brigade combat team. Journal of Head Trauma Rehabilitation, 24(1), 14–23.CrossRefGoogle Scholar
  64. Thames, A. D., Kim, M. S., Becker, B. W., Foley, J. M., Hines, L. J., Singer, E. J., et al. (2011). Medication and finance management among HIV-infected adults: the impact of age and cognition. Journal of Clinical and Experimental Neuropsychology, 33(2), 200–209.CrossRefGoogle Scholar
  65. Tomasi, D., Chang, L., Caparelli, E. C., & Ernst, T. (2007). Different activation patterns for working memory load and visual attention load. Brain Research, 1132(1), 158–165.CrossRefGoogle Scholar
  66. Tombaugh, T. (1996). Test of Memory Malingering (TOMM). New York: Multi-Health Systems.Google Scholar
  67. Vasterling, J. J., Brailey, K., Constans, J. I., & Sutker, P. B. (1998). Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology, 12(1), 125–133.CrossRefGoogle Scholar
  68. Wall, S. E., Williams, W. H., Cartwright-Hatton, S., Kelly, T. P., Murray, J., Murray, M., et al. (2006). Neuropsychological dysfunction following repeat concussions in jockeys. Journal of Neurology, Neurosurgery, and Psychiatry, 77(4), 518–520.CrossRefGoogle Scholar
  69. Weathers, F. W., Huska, J. A., & Keane, T. M. (1991). PCL-M for DSM-IV. Boston: National Center for PTSD – Behavioral Science Division.Google Scholar
  70. Weathers, F. W., Litz, B. T., Herman, D. S., Huska, J. A., & Keane, T. M. (1993). The PTSD Checklist (PCL): Reliability, validity, and diagnostic utility. Paper presented at the 9th Annual Conference of the ISTSS, San Antonio, TX.Google Scholar
  71. Wechsler, D. (2001). Wechsler test of adult reading manual. San Antonio: Psychological Corp.Google Scholar
  72. Zhang, D., & Raichle, M. E. (2010). Disease and the brain's dark energy. Nature Reviews Neurology, 6(1), 15–28.CrossRefGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Kathleen F. Pagulayan
    • 1
    • 2
    Email author
  • Eric C. Petrie
    • 1
    • 2
  • David G. Cook
    • 3
    • 4
    • 5
  • Rebecca C. Hendrickson
    • 1
  • Holly Rau
    • 1
  • Melissa Reilly
    • 6
  • Cindy Mayer
    • 1
  • James S. Meabon
    • 1
    • 2
  • Murray A. Raskind
    • 1
    • 2
  • Elaine R. Peskind
    • 1
    • 2
  • Natalia Kleinhans
    • 6
  1. 1.VA Northwest Network Mental Illness, Research, Education, and Clinical Center (MIRECC)VA Puget Sound Health Care SystemSeattleUSA
  2. 2.Department of Psychiatry and Behavioral SciencesUniversity of Washington School of MedicineSeattleUSA
  3. 3.Department of Medicine (Division of Gerontology and Geriatric Medicine)University of Washington School of MedicineSeattleUSA
  4. 4.Department of PharmacologyUniversity of Washington School of MedicineSeattleUSA
  5. 5.VA Puget Sound Health Care System, Seattle Division, Geriatric Research, Education, and Clinical Center (GRECC)SeattleUSA
  6. 6.Department of RadiologyUniversity of Washington School of MedicineSeattleUSA

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