Abstract
There is a need to improve the understanding of the neurobiological underpinnings of traumatic brain injury (TBI). Individuals with TBI experience comorbidities such as posttraumatic stress disorder (PTSD) with considerable symptom overlap including depression and hyperarousal, confounding the ability to identify specific TBI-related brain changes. The aims of the current study were to investigate hippocampal and amygdalar volumes in Veterans with TBI with (TBI + PTSD, n = 32) and without (TBI - PTSD, n = 25) PTSD. Shape analysis was employed to reveal any relationship between the hippocampus and depressive symptoms in TBI subgroups. 32 TBI + PTSD, 25 TBI - PTSD, and 25 age-matched healthy male Veterans underwent an MRI scan on a 3 Tesla scanner and a clinical evaluation. The TBI + PTSD and the TBI + hyperarousal (met criteria for the hyperarousal symptom cluster, regardless of PTSD diagnosis) subgroup had trend-level larger left amygdalar volume than the TBI - PTSD subgroup and the TBI - hyperarousal subgroup, respectively. However, there was no significant difference between the TBI group as a whole and healthy controls (HC). There was a significant negative correlation between the Hamilton Rating Scale for Depression score (HAM-D) and left hippocampal volume and a positive correlation between the HAM-D score and left amygdalar volume in the TBI group. Left hippocampal volume was correlated with the HAM-D score only in the TBI + PTSD and not in TBI - PTSD subgroup. Shape analyses revealed a significant correlation between the HAM-D score and the CA1 and subiculum regions of the left hippocampus. Our results suggest that the amygdala may be a neuroanatomical correlate in mediating PTSD-like symptoms in Veterans with TBI. The results of shape analysis suggest that alterations in the CA1 and subiculum subregions of hippocampus may have a role in depression and PTSD.
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References
Anderson, C. V., Wood, D. M., Bigler, E. D., & Blatter, D. D. (1996). Lesion volume, injury severity, and thalamic integrity following head injury. Journal of Neurotrauma, 13(2), 59–65. https://doi.org/10.1089/neu.1996.13.59.
Arciniegas, D. B., Topkoff, J. L., Rojas, D. C., Sheeder, J., Teale, P., Young, D. A., Sandberg, E., Reite, M. L., & Adler, L. E. (2001). Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury. The Journal of Neuropsychiatry and Clinical Neurosciences, 13(2), 213–221. https://doi.org/10.1176/jnp.13.2.213.
Ariza, M., Serra-Grabulosa, J. M., Junque, C., Ramirez, B., Mataro, M., Poca, A., et al. (2006). Hippocampal head atrophy after traumatic brain injury. Neuropsychologia, 44(10), 1956–1961. https://doi.org/10.1016/j.neuropsychologia.2005.11.007.
Averill, C. L., Satodiya, R. M., Scott, J. C., Wrocklage, K. M., Schweinsburg, B., Averill, L. A., Akiki T. J., Amoroso T., Southwick S. M., Krystal J. H., Abdallah C. G. (2017). Posttraumatic stress disorder and depression symptom severities are differentially associated with hippocampal subfield volume loss in combat veterans. Chronic Stress (Thousand Oaks), 1, https://doi.org/10.1177/2470547017744538.
Belanger, H. G., Uomoto, J. M., & Vanderploeg, R. D. (2009). The veterans health Administration's (VHA's) Polytrauma system of care for mild traumatic brain injury: Costs, benefits, and controversies. The Journal of Head Trauma Rehabilitation, 24(1), 4–13. https://doi.org/10.1097/HTR.0b013e3181957032.
Bigler, E. D., Blatter, D. D., Anderson, C. V., Johnson, S. C., Gale, S. D., Hopkins, R. O., & Burnett, B. (1997). Hippocampal volume in normal aging and traumatic brain injury. AJNR. American Journal of Neuroradiology, 18(1), 11–23.
Bigler, E. D., Anderson, C. V., & Blatter, D. D. (2002). Temporal lobe morphology in normal aging and traumatic brain injury. AJNR. American Journal of Neuroradiology, 23(2), 255–266.
Bigler, E. D., Abildskov, T. J., Wilde, E. A., McCauley, S. R., Li, X., Merkley, T. L., Fearing, M. A., Newsome, M. R., Scheibel, R. S., Hunter, J. V., Chu, Z., & Levin, H. S. (2010). Diffuse damage in pediatric traumatic brain injury: A comparison of automated versus operator-controlled quantification methods. Neuroimage, 50(3), 1017–1026. https://doi.org/10.1016/j.neuroimage.2010.01.003.
Bolzenius, J. D., Wade, B. S. C., Velez, C. S., Drennon, A. M., Cooper, D. B., Kennedy, J. E., Reid, M. W., Bowles, A. O., Thompson, P. M., Gutman, B., Lewis, J. D., Ritter, J. L., York, G. E., Bigler, E. D., & Tate, D. F. (2018). Relationships between subcortical shape measures and subjective symptom reporting in US Service members with mild traumatic brain injury. The Journal of Head Trauma Rehabilitation, 33(2), 113–122. https://doi.org/10.1097/htr.0000000000000379.
Bremner, J. D., Randall, P., Scott, T. M., Bronen, R. A., Seibyl, J. P., Southwick, S. M., Delaney, R. C., McCarthy, G., Charney, D. S., & Innis, R. B. (1995). MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. The American Journal of Psychiatry, 152(7), 973–981. https://doi.org/10.1176/ajp.152.7.973.
Calder, A. J., Lawrence, A. D., & Young, A. W. (2001). Neuropsychology of fear and loathing. Nature Reviews. Neuroscience, 2(5), 352–363. https://doi.org/10.1038/35072584.
Carlson, K. F., Kehle, S. M., Meis, L. A., Greer, N., Macdonald, R., Rutks, I., et al. (2011). Prevalence, assessment, and treatment of mild traumatic brain injury and posttraumatic stress disorder: A systematic review of the evidence. The Journal of Head Trauma Rehabilitation, 26(2), 103–115. https://doi.org/10.1097/HTR.0b013e3181e50ef1.
Cole, J., Toga, A. W., Hojatkashani, C., Thompson, P., Costafreda, S. G., Cleare, A. J., Williams, S. C., Bullmore, E. T., Scott, J. L., Mitterschiffthaler, M. T., Walsh, N. D., Donaldson, C., Mirza, M., Marquand, A., Nosarti, C., McGuffin, P., & Fu, C. H. (2010). Subregional hippocampal deformations in major depressive disorder. Journal of Affective Disorders, 126(1–2), 272–277. https://doi.org/10.1016/j.jad.2010.03.004.
Corrigan, J. D., & Bogner, J. (2007). Initial reliability and validity of the Ohio State University TBI identification method. The Journal of Head Trauma Rehabilitation, 22(6), 318–329. https://doi.org/10.1097/01.htr.0000300227.67748.77.
Davis, M., & Whalen, P. J. (2001). The amygdala: Vigilance and emotion. Molecular Psychiatry, 6(1), 13–34.
Defense, & Center, V. B. I. (2012). DoD worldwide numbers for TBI. Defense and Veterans Brain Injury Center, Silver Spring Maryland.
Depue, B. E., Olson-Madden, J. H., Smolker, H. R., Rajamani, M., Brenner, L. A., & Banich, M. T. (2014). Reduced amygdala volume is associated with deficits in inhibitory control: A voxel- and surface-based morphometric analysis of comorbid PTSD/mild TBI. BioMed Research International, 2014, 691505. https://doi.org/10.1155/2014/691505.
Dixon, K. J. (2017). Pathophysiology of traumatic brain injury. Physical Medicine and Rehabilitation Clinics of North America, 28(2), 215–225. https://doi.org/10.1016/j.pmr.2016.12.001.
Duvernoy, H. M. (2005). The human Hippocampus: Functional anatomy, vascularization and serial sections with MRI 3rd edition. American Journal of Neuroradiology, 26(10), 2702.
Faul, M., Xu, L., Wald, M., & Coronado, V. (2010). Traumatic brain injury in the United States: Emergency department visits, hospitalizations and deaths.
First, M. B., Spitzer, Robert L, Gibbon Miriam, and Williams, Janet B W (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. New York: Biometrics Research, New York State Psychiatric Institute.
Geuze, E., Vermetten, E., & Bremner, J. D. (2005). MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Molecular Psychiatry, 10(2), 160–184. https://doi.org/10.1038/sj.mp.4001579.
Hamilton, M. (1959). The assessment of anxiety states by rating. The British Journal of Medical Psychology, 32(1), 50–55.
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56–62.
Hoge, C. W., McGurk, D., Thomas, J. L., Cox, A. L., Engel, C. C., & Castro, C. A. (2008). Mild traumatic brain injury in U.S. soldiers returning from Iraq. The New England Journal of Medicine, 358(5), 453–463. https://doi.org/10.1056/NEJMoa072972.
Huang, Y., Coupland, N. J., Lebel, R. M., Carter, R., Seres, P., Wilman, A. H., & Malykhin, N. V. (2013). Structural changes in hippocampal subfields in major depressive disorder: A high-field magnetic resonance imaging study. Biological Psychiatry, 74(1), 62–68. https://doi.org/10.1016/j.biopsych.2013.01.005.
Isikli, S., Ugurlu, O., Durmusoglu, E., Kizilates, G., Kitis, O., Ozan, E., et al. (2013). Altered hippocampal formation shape in first-episode depressed patients at 5-year follow-up. Journal of Psychiatric Research, 47(1), 50–55. https://doi.org/10.1016/j.jpsychires.2012.08.022.
Ji, J., & Maren, S. (2008). Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear. Learning & Memory, 15(4), 244–251. https://doi.org/10.1101/lm.794808.
Kaplan, G. B., Leite-Morris, K. A., Wang, L., Rumbika, K. K., Heinrichs, S. C., Zeng, X., Wu, L., Arena, D. T., & Teng, Y. D. (2018). Pathophysiological bases of comorbidity: Traumatic brain injury and post-traumatic stress disorder. Journal of Neurotrauma, 35(2), 210–225. https://doi.org/10.1089/neu.2016.4953.
Karl, A., Schaefer, M., Malta, L. S., Dorfel, D., Rohleder, N., & Werner, A. (2006). A meta-analysis of structural brain abnormalities in PTSD. Neuroscience and Biobehavioral Reviews, 30(7), 1004–1031. https://doi.org/10.1016/j.neubiorev.2006.03.004.
Kim, G. H., Lee, J. H., Seo, S. W., Kim, J. H., Seong, J. K., Ye, B. S., Cho, H., Noh, Y., Kim, H. J., Yoon, C. W., Oh, S. J., Kim, J. S., Choe, Y. S., Lee, K. H., Kim, S. T., Hwang, J. W., Jeong, J. H., & Na, D. L. (2015). Hippocampal volume and shape in pure subcortical vascular dementia. Neurobiology of Aging, 36(1), 485–491. https://doi.org/10.1016/j.neurobiolaging.2014.08.009.
LeDoux, J. E. (2000). Emotion circuits in the brain. Annual Review of Neuroscience, 23, 155–184. https://doi.org/10.1146/annurev.neuro.23.1.155.
Lindqvist, D., Mueller, S., Mellon, S. H., Su, Y., Epel, E. S., Reus, V. I., Rosser, R., Mahan, L., Mackin, R. S., Yang, T. T., & Wolkowitz, O. M. (2014). Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls-preliminary findings. Psychiatry Research, 224(3), 168–174. https://doi.org/10.1016/j.pscychresns.2014.09.002.
Maller, J. J., Thomson, R. H., Pannek, K., Bailey, N., Lewis, P. M., & Fitzgerald, P. B. (2014). Volumetrics relate to the development of depression after traumatic brain injury. Behavioural Brain Research, 271, 147–153. https://doi.org/10.1016/j.bbr.2014.05.047.
Maren, S. (1999). Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats. Behavioral Neuroscience, 113(2), 283–290.
McDonald, B. C., Saykin, A. J., & McAllister, T. W. (2012). Functional MRI of mild traumatic brain injury (mTBI): Progress and perspectives from the first decade of studies. Brain Imaging and Behavior, 6(2), 193–207. https://doi.org/10.1007/s11682-012-9173-4.
McGlade, E., Rogowska, J., & Yurgelun-Todd, D. (2015). Sex differences in orbitofrontal connectivity in male and female veterans with TBI. Brain Imaging and Behavior, 9(3), 535–549. https://doi.org/10.1007/s11682-015-9379-3.
McKinnon, M. C., Yucel, K., Nazarov, A., & MacQueen, G. M. (2009). A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. Journal of Psychiatry & Neuroscience, 34(1), 41–54.
Morey, R. A., Gold, A. L., LaBar, K. S., Beall, S. K., Brown, V. M., Haswell, C. C., Nasser, J. D., Wagner, H. R., McCarthy, G., & Mid-Atlantic MIRECC Workgroup. (2012). Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group. Archives of General Psychiatry, 69(11), 1169–1178. https://doi.org/10.1001/archgenpsychiatry.2012.50.
Nugent, A. C., Luckenbaugh, D. A., Wood, S. E., Bogers, W., Zarate, C. A., Jr., & Drevets, W. C. (2013). Automated subcortical segmentation using FIRST: Test-retest reliability, interscanner reliability, and comparison to manual segmentation. Human Brain Mapping, 34(9), 2313–2329. https://doi.org/10.1002/hbm.22068.
O'Mara, S. (2006). Controlling hippocampal output: The central role of subiculum in hippocampal information processing. Behavioural Brain Research, 174(2), 304–312. https://doi.org/10.1016/j.bbr.2006.08.018.
Palacios, E. M., Sala-Llonch, R., Junque, C., Fernandez-Espejo, D., Roig, T., Tormos, J. M., Bargallo, N., & Vendrell, P. (2013). Long-term declarative memory deficits in diffuse TBI: Correlations with cortical thickness, white matter integrity and hippocampal volume. Cortex, 49(3), 646–657. https://doi.org/10.1016/j.cortex.2012.02.011.
Patenaude, B., Smith, S. M., Kennedy, D. N., & Jenkinson, M. (2011). A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage, 56(3), 907–922. https://doi.org/10.1016/j.neuroimage.2011.02.046.
Ross, D. E. (2011). Review of longitudinal studies of MRI brain volumetry in patients with traumatic brain injury. Brain Injury, 25(13–14), 1271–1278. https://doi.org/10.3109/02699052.2011.624568.
Schneiderman, A. I., Braver, E. R., & Kang, H. K. (2008). Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: Persistent postconcussive symptoms and posttraumatic stress disorder. American Journal of Epidemiology, 167(12), 1446–1452. https://doi.org/10.1093/aje/kwn068.
Shenton, M. E., Hamoda, H. M., Schneiderman, J. S., Bouix, S., Pasternak, O., Rathi, Y., Vu, M. A., Purohit, M. P., Helmer, K., Koerte, I., Lin, A. P., Westin, C. F., Kikinis, R., Kubicki, M., Stern, R. A., & Zafonte, R. (2012). A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging and Behavior, 6(2), 137–192. https://doi.org/10.1007/s11682-012-9156-5.
Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155. https://doi.org/10.1002/hbm.10062.
Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T. E., Johansen-Berg, H., et al. (2004). Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 23(Suppl 1), S208–S219. https://doi.org/10.1016/j.neuroimage.2004.07.051.
Stein, M. B., & McAllister, T. W. (2009). Exploring the convergence of posttraumatic stress disorder and mild traumatic brain injury. The American Journal of Psychiatry, 166(7), 768–776. https://doi.org/10.1176/appi.ajp.2009.08101604.
Suvak, M. K., & Barrett, L. F. (2011). Considering PTSD from the perspective of brain processes: A psychological construction approach. Journal of Traumatic Stress, 24(1), 3–24. https://doi.org/10.1002/jts.20618.
Tae, W. S., Kim, S. S., Lee, K. U., Nam, E. C., Choi, J. W., & Park, J. I. (2011). Hippocampal shape deformation in female patients with unremitting major depressive disorder. AJNR. American Journal of Neuroradiology, 32(4), 671–676. https://doi.org/10.3174/ajnr.A2367.
Tate, D. F., & Bigler, E. D. (2000). Fornix and hippocampal atrophy in traumatic brain injury. Learning & Memory, 7(6), 442–446.
Tate, D. F., Wade, B. S., Velez, C. S., Drennon, A. M., Bolzenius, J., Gutman, B. A., et al. (2016). Volumetric and shape analyses of subcortical structures in United States service members with mild traumatic brain injury. Journal of Neurology, 263(10), 2065–2079. https://doi.org/10.1007/s00415-016-8236-7.
Tate, D. F., Wade, B. S. C., Velez, C. S., Drennon, A. M., Bolzenius, J. D., Cooper, D. B., Kennedy, J. E., Reid, M. W., Bowles, A. O., Thompson, P. M., Gutman, B. A., Lewis, J. D., Ritter, J. L., York, G. E., & Bigler, E. D. (2018). Subcortical shape and neuropsychological function among U.S. service members with mild traumatic brain injury. Brain Imaging and Behavior, 13, 377–388. https://doi.org/10.1007/s11682-018-9854-8.
Tomaiuolo, F., Carlesimo, G. A., Di Paola, M., Petrides, M., Fera, F., Bonanni, R., et al. (2004). Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: A T1 weighted MRI study. Journal of Neurology, Neurosurgery, and Psychiatry, 75(9), 1314–1322. https://doi.org/10.1136/jnnp.2003.017046.
Travis, S., Coupland, N. J., Silversone, P. H., Huang, Y., Fujiwara, E., Carter, R., Seres, P., & Malykhin, N. V. (2015). Dentate gyrus volume and memory performance in major depressive disorder. Journal of Affective Disorders, 172, 159–164. https://doi.org/10.1016/j.jad.2014.09.048.
Van Boven, R. W., Harrington, G. S., Hackney, D. B., Ebel, A., Gauger, G., Bremner, J. D., et al. (2009). Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder. Journal of Rehabilitation Research and Development, 46(6), 717–757.
Vanderploeg, R. D., Belanger, H. G., & Curtiss, G. (2009). Mild traumatic brain injury and posttraumatic stress disorder and their associations with health symptoms. Archives of Physical Medicine and Rehabilitation, 90(7), 1084–1093. https://doi.org/10.1016/j.apmr.2009.01.023.
Videbech, P., & Ravnkilde, B. (2004). Hippocampal volume and depression: A meta-analysis of MRI studies. The American Journal of Psychiatry, 161(11), 1957–1966. https://doi.org/10.1176/appi.ajp.161.11.1957.
Wade, B. S., Valcour, V. G., Wendelken-Riegelhaupt, L., Esmaeili-Firidouni, P., Joshi, S. H., Gutman, B. A., et al. (2015). Mapping abnormal subcortical brain morphometry in an elderly HIV+ cohort. Neuroimage Clin, 9, 564–573. https://doi.org/10.1016/j.nicl.2015.10.006.
Warner, M. A., Youn, T. S., Davis, T., Chandra, A., Marquez de la Plata, C., Moore, C., Harper, C., Madden, C. J., Spence, J., McColl, R., Devous, M., King, R. D., & Diaz-Arrastia, R. (2010). Regionally selective atrophy after traumatic axonal injury. Archives of Neurology, 67(11), 1336–1344. https://doi.org/10.1001/archneurol.2010.149.
Wechsler, D. (2011). Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II). San Antonio: NCS Pearson.
Woon, F. L., & Hedges, D. W. (2008). Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: A meta-analysis. Hippocampus, 18(8), 729–736. https://doi.org/10.1002/hipo.20437.
Woon, F. L., & Hedges, D. W. (2009). Amygdala volume in adults with posttraumatic stress disorder: A meta-analysis. The Journal of Neuropsychiatry and Clinical Neurosciences, 21(1), 5–12. https://doi.org/10.1176/jnp.2009.21.1.5.
Woon, F. L., Sood, S., & Hedges, D. W. (2010). Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: A meta-analysis. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34(7), 1181–1188. https://doi.org/10.1016/j.pnpbp.2010.06.016.
Yurgil, K. A., Barkauskas, D. A., Vasterling, J. J., Nievergelt, C. M., Larson, G. E., Schork, N. J., Litz, B. T., Nash, W. P., Baker, D. G., & Marine Resiliency Study Team. (2014). Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty marines. JAMA Psychiatry, 71(2), 149–157. https://doi.org/10.1001/jamapsychiatry.2013.3080.
Zatzick, D. F., Rivara, F. P., Jurkovich, G. J., Hoge, C. W., Wang, J., Fan, M. Y., Russo, J., Trusz, S. G., Nathens, A., & Mackenzie, E. J. (2010). Multisite investigation of traumatic brain injuries, posttraumatic stress disorder, and self-reported health and cognitive impairments. Archives of General Psychiatry, 67(12), 1291–1300. https://doi.org/10.1001/archgenpsychiatry.2010.158.
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This study was supported by funds from Merit Review 5101 CX000253-02 and VISN 19 MIRECC (The Mental Illness Research, Education and Clinical Centers), Salt Lake City, UT, USA.
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Bae, S., Sheth, C., Legarreta, M. et al. Volume and shape analysis of the Hippocampus and amygdala in veterans with traumatic brain injury and posttraumatic stress disorder. Brain Imaging and Behavior 14, 1850–1864 (2020). https://doi.org/10.1007/s11682-019-00127-2
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DOI: https://doi.org/10.1007/s11682-019-00127-2