Emerging Approaches to Neurocircuits in PTSD and TBI: Imaging the Interplay of Neural and Emotional Trauma

  • Andrea D. SpadoniEmail author
  • Mingxiong Huang
  • Alan N. Simmons
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 38)


Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) commonly co-occur in general and military populations and have a number of overlapping symptoms. While research suggests that TBI is risk factor for PTSD and that PTSD may mediate TBI-related outcomes, the mechanisms of these relationships are not well understood. Neuroimaging may help elucidate patterns of neurocircuitry both specific and common to PTSD and TBI and thus help define the nature of their interaction, refine diagnostic classification, and may potentially yield opportunities for targeted treatments. In this review, we provide a summary of some of the most common and the most innovative neuroimaging approaches used to characterize the neural circuits associated with PTSD, TBI, and their comorbidity. We summarize the state of the science for each disorder and describe the few studies that have explicitly attempted to characterize the neural substrates of their shared and dissociable influence. While some promising targets in the medial frontal lobes exist, there is not currently a comprehensive understanding of the neurocircuitry mediating the interaction of PTSD and TBI. Future studies should exploit innovative neuroimaging approaches and longitudinal designs to specifically target the neural mechanisms driving PTSD-TBI-related outcomes.


Diffusion tensor imaging (DTI) fMRI Functional neuroimaging Magnetic resonance imaging Magnetoencephalography (MEG) Neuroimaging Positron-emission tomography (PET) Posttraumatic stress disorder PTSD Traumatic brain injury (TBI) 



The authors appreciate the contributions of Michelle Liu to the literature search. Dr. Spadoni’s VA salary is supported by a Career Development Award and Dr. Simmons’ VA salary is supported by a Merit Award through the VA Clinical Science Research and Development Service. Additional support was generously provided by the VA Center for Excellence in Stress and Mental Health.


  1. Abe O, Yamasue H, Kasai K, Yamada H, Aoki S, Iwanami A, Ohtani T, Masutani Y, Kato N, Ohtomo K (2006) Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism. Psychiatry Res Neuroimaging 146:231–242CrossRefGoogle Scholar
  2. Adams JH (1982) Diffuse axonal injury in non-missile head injury. Injury 13:444–445PubMedCrossRefGoogle Scholar
  3. Aoki Y, Inokuchi R, Gunshin M, Yahagi N, Suwa H (2012) Diffusion tensor imaging studies of mild traumatic brain injury: a meta-analysis. J Neurol Neurosurg Psychiatry 83:870–876PubMedPubMedCentralCrossRefGoogle Scholar
  4. Arfanakis K, Haughton VM, Carew JD, Rogers BP, Dempsey RJ, Meyerand ME (2002) Diffusion tensor MR imaging in diffuse axonal injury. Am J Neuroradiol 23(5):794–802PubMedGoogle Scholar
  5. Ashburner J, Friston KJ (2000) Voxel-based morphometry – the methods. NeuroImage 11:805–821PubMedCrossRefGoogle Scholar
  6. Assemlal HE, Tschumperle D, Brun L, IEEE (2007) Fiber tracking on HARDI data using robust ODF fields. In: 2007 I.E. international conference on image processing, vol 1–7, pp 1261–1264Google Scholar
  7. Badre D, Frank MJ (2012) Mechanisms of hierarchical reinforcement learning in cortico-striatal circuits 2: evidence from fMRI. Cereb Cortex 22:527–536PubMedCrossRefGoogle Scholar
  8. Ball GJ, Gloor P, Schaul N (1977) The cortical electromicrophysiology of pathological delta waves in the electroencephalogram of cats. Electroencephalogr Clin Neurophysiol 43:346–361PubMedCrossRefGoogle Scholar
  9. Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A (2000) In vivo fiber tractography using DT-MRI data. Magn Reson Med 44:625–632PubMedCrossRefGoogle Scholar
  10. Bazarian JJ, Donnelly K, Peterson DR, Warner GC, Zhu T, Zhong JH (2013) The relation between posttraumatic stress disorder and mild traumatic brain injury acquired during Operations Enduring Freedom and Iraqi Freedom. J Head Trauma Rehabil 28:1–12PubMedCrossRefGoogle Scholar
  11. Beaulieu C (2002) The basis of anisotropic water diffusion in the nervous system – a technical review. NMR Biomed 15:435–455PubMedCrossRefGoogle Scholar
  12. Beckmann CF, DeLuca M, Devlin JT, Smith SM (2005) Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc B-Biol Sci 360:1001–1013CrossRefGoogle Scholar
  13. Bonnelle V, Ham TE, Leech R, Kinnunen KM, Mehta MA, Greenwood RJ, Sharp DJ (2012) Salience network integrity predicts default mode network function after traumatic brain injury. Proc Natl Acad Sci U S A 109:4690–4695PubMedPubMedCentralCrossRefGoogle Scholar
  14. Brenner LA, Ladley-O’Brien SE, Harwood JEF, Filley CM, Kelly JP, Homaifar BY, Adler LE (2009) An exploratory study of neuroimaging, neurologic, and neuropsychological findings in veterans with traumatic brain injury and/or posttraumatic stress disorder. Mil Med 174:347–352PubMedCrossRefGoogle Scholar
  15. Buchsbaum MS, Simmons AN, DeCastro A, Farid N, Matthews SC (2015) Clusters of low F-18-fluorodeoxyglucose uptake voxels in combat veterans with traumatic brain injury and post-traumatic stress disorder. J Neurotrauma 32:1736–1750PubMedCrossRefGoogle Scholar
  16. Bullmore E, Sporns O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 10:186–198PubMedCrossRefGoogle Scholar
  17. Cernak I, Wang Z, Jiang J, Bian X, Savic J (2001) Cognitive deficits following blast injury-induced neurotrauma: possible involvement of nitric oxide. Brain Inj 15:593–612PubMedCrossRefGoogle Scholar
  18. Chen S, Li L, Xu B, Liu J (2009) Insular cortex involvement in declarative memory deficits in patients with post-traumatic stress disorder. BMC Psychiatry 9:39PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cohen D (1968) Magnetoencephalography – evidence of magnetic fields produced by alpha-rhythm currents. Science 161:784–786PubMedCrossRefGoogle Scholar
  20. Craig AD (2003) Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 13:500–505PubMedCrossRefGoogle Scholar
  21. Craig AD (2009) How do you feel – now? The anterior insula and human awareness. Nat Rev Neurosci 10:59–70PubMedCrossRefGoogle Scholar
  22. Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis – I. Segmentation and surface reconstruction. NeuroImage 9:179–194PubMedCrossRefGoogle Scholar
  23. Davenport ND, Lim KO, Armstrong MT, Sponheim SR (2012) Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury. NeuroImage 59:2017–2024PubMedCrossRefGoogle Scholar
  24. Davenport ND, Lim KO, Sponheim SR (2015) White matter abnormalities associated with military PTSD in the context of blast TBI. Hum Brain Mapp 36:1053–1064PubMedCrossRefGoogle Scholar
  25. Delgado MR, Nearing KI, LeDoux JE, Phelps EA (2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 59:829–838PubMedPubMedCentralCrossRefGoogle Scholar
  26. Depue BE, Olson-Madden JH, Smolker HR, Rajamani M, Brenner LA, Banich MT (2014) Reduced amygdala volume is associated with deficits in inhibitory control: a voxel- and surface-based morphometric analysis of comorbid PTSD/Mild TBI. Biomed Res Int 2014:691505PubMedPubMedCentralCrossRefGoogle Scholar
  27. Dickie EW, Brunet A, Akerib V, Armony JL (2011) Neural correlates of recovery from post-traumatic stress disorder: a longitudinal fMRI investigation of memory encoding. Neuropsychologia 49:1771–1778PubMedCrossRefGoogle Scholar
  28. Diwakar M, Harrington DL, Maruta J, Ghajar J, El-Gabalawy F, Muzzatti L, Corbetta M, Huang MX, Lee RR (2015) Filling in the gaps: anticipatory control of eye movements in chronic mild traumatic brain injury. Neuroimage Clin 8:210–223PubMedPubMedCentralCrossRefGoogle Scholar
  29. Dretsch MN, Lange RT, Katz JS, Goodman A, Daniel TA, Deshpande G, Denney TS, Iverson GL, Robinson JL (2017) Examining microstructural white matter in active duty soldiers with a history of mild traumatic brain injury and traumatic stress. Open Neuroimaging J 11:46–57CrossRefGoogle Scholar
  30. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang YY, Gautier C, Mathis C (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387PubMedCrossRefGoogle Scholar
  31. Eierud C, Craddock RC, Fletcher S, Aulakh M, King-Casas B, Kuehl D, LaConte SM (2014) Neuroimaging after mild traumatic brain injury: review and meta-analysis. Neuroimage Clin 4:283–294PubMedPubMedCentralCrossRefGoogle Scholar
  32. Elsinga PH, Hatano K, Ishiwata K (2006) PET tracers for imaging of the dopaminergic system. Curr Med Chem 13:2139–2153PubMedCrossRefGoogle Scholar
  33. Engdahl B, Leuthold AC, Tan HRM, Lewis SM, Winskowski AM, Dikel TN, Georgopoulos AP (2010) Post-traumatic stress disorder: a right temporal lobe syndrome? J Neural Eng 7(6):066005PubMedCrossRefGoogle Scholar
  34. Etkin A, Wager TD (2007) Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164:1476–1488PubMedPubMedCentralCrossRefGoogle Scholar
  35. Fani N, King TZ, Jovanovic T, Glover EM, Bradley B, Choi K, Ely T, Gutman DA, Ressler KJ (2012) White matter integrity in highly traumatized adults with and without post-traumatic stress disorder. Neuropsychopharmacology 37:2740–2746PubMedPubMedCentralCrossRefGoogle Scholar
  36. Felmingham K, Williams LM, Kemp AH, Liddell B, Falconer E, Peduto A, Bryant R (2010) Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder. J Abnorm Psychol 119:241–247PubMedCrossRefGoogle Scholar
  37. Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based analysis – II: inflation, flattening, and a surface-based coordinate system. NeuroImage 9:195–207PubMedCrossRefGoogle Scholar
  38. Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB (2010) Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol Psychiatry 68:433–441PubMedPubMedCentralCrossRefGoogle Scholar
  39. Frasure-Smith N, Lesperance F, Talajic M (1995) The impact of negative emotions on prognosis following myocardial infarction: is it more than depression? Health Psychol 14:388–398PubMedCrossRefGoogle Scholar
  40. Friston KJ, Penny W (2003) Posterior probability maps and SPMs. NeuroImage 19:1240–1249PubMedCrossRefGoogle Scholar
  41. Friston KJ, Frith CD, Fletcher P, Liddle PF, Frackowiak RSJ (1996) Functional topography: multidimensional scaling and functional connectivity in the brain. Cereb Cortex 6:156–164PubMedCrossRefGoogle Scholar
  42. Friston KJ, Trujillo-Barreto N, Daunizeau J (2008) DEM: a variational treatment of dynamic systems. NeuroImage 41:849–885PubMedCrossRefGoogle Scholar
  43. Gean AD (1994) Imaging of head trauma. Raven Press, New YorkGoogle Scholar
  44. Gentry LR, Godersky JC, Thompson B, Dunn VD (1988) Prospective comparative study of intermediate-field MR and CT in the evaluation of closed head trauma. AJR 150:673–682PubMedCrossRefGoogle Scholar
  45. Georgopoulos AP, Tan HRM, Lewis SM, Leuthold AC, Winskowski AM, Lynch JK, Engdahl B (2010) The synchronous neural interactions test as a functional neuromarker for post-traumatic stress disorder (PTSD): a robust classification method based on the bootstrap. J Neural Eng 7:16011PubMedCrossRefGoogle Scholar
  46. Gewirtz JC, McNish KA, Davis M (2000) Is the hippocampus necessary for contextual fear conditioning? Behav Brain Res 110:83–95PubMedCrossRefGoogle Scholar
  47. Gloor P, Ball G, Schaul N (1977) Brain lesions that produce delta waves in the EEG. Neurology 27:326–333PubMedCrossRefGoogle Scholar
  48. Goetz P, Blamire A, Rajagopalan B, Cadoux-Hudson T, Young D, Styles P (2004) Increase in apparent diffusion coefficient in normal appearing white matter following human traumatic brain injury correlates with injury severity. J Neurotrauma 21:645–654PubMedCrossRefGoogle Scholar
  49. Haacke EM, Brown RW, Thompson MR, Venkatesan R (1999) Magnetic resonance imaging: physical principles and sequence design. Wiley-Liss, New YorkGoogle Scholar
  50. Hamalainen M, Hari R, Ilmoniemi RJ, Knuutila J, Lounasmaa OV (1993) Magnetoencephalography – theory, instrumentation, and applications to noninvasive studies of the working human brain. Rev Mod Phys 65:413–497CrossRefGoogle Scholar
  51. Hayes JP, Hayes SM, Mikedis AM (2012) Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol Mood Anxiety Disord 2:9PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA (2008) Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 358:453–463PubMedCrossRefGoogle Scholar
  53. Huang MX, Dale AM, Song T, Halgren E, Harrington DL, Podgorny I, Canive JM, Lewis S, Lee RR (2006) Vector-based spatial-temporal minimum L1-norm solution for MEG. NeuroImage 31:1025–1037PubMedCrossRefGoogle Scholar
  54. Huang MX, Theilmann RJ, Robb A, Angeles A, Nichols S, Drake A, D'Andrea J, Levy M, Holland M, Song T, Ge S, Hwang E, Yoo K, Cui L, Baker DG, Trauner D, Coimbra R, Lee RR (2009) Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients. J Neurotrauma 26:1213–1226PubMedCrossRefGoogle Scholar
  55. Huang MX, Nichols S, Robb A, Angeles A, Drake A, Holland M, Asmussen S, D’Andrea J, Chun W, Levy M, Cui L, Song T, Baker DG, Hammer P, McLay R, Theilmann RJ, Coimbra R, Diwakar M, Boyd C, Neff J, Liu TT, Webb-Murphy J, Farinpour R, Cheung C, Harrington DL, Heister D, Lee RR (2012) An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. NeuroImage 61:1067–1082PubMedCrossRefGoogle Scholar
  56. Huang MX, Huang CW, Robb A, Angeles A, Nichols SL, Baker DG, Song T, Harrington DL, Theilmann RJ, Srinivasan R, Heister D, Diwakar M, Canive JM, Edgar JC, Chen YH, Ji ZW, Shen M, El-Gabalawy F, Levy M, McLay R, Webb-Murphy J, Liu TT, Drake A, Lee RR (2014a) MEG source imaging method using fast L1 minimum-norm and its applications to signals with brain noise and human resting-state source amplitude images. NeuroImage 84:585–604PubMedCrossRefGoogle Scholar
  57. Huang MX, Nichols S, Baker DG, Robb A, Angeles A, Yurgil KA, Drake A, Levy M, Song T, Mclay R, Theilmann RJ, Diwakar M, Risbrough VB, Ji ZW, Huang C, Chang DG, Harrington DL, Muzzatti L, Canive JM, Edgar JC, Chen YH, Lee RR (2014b) Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury. Neuroimage Clin 5:109–119PubMedPubMedCentralCrossRefGoogle Scholar
  58. Huang MX, Yurgil KA, Robb A, Angeles A, Diwakar M, Risbrough VB, Nichols SL, McLay R, Theilmann RJ, Song T, Huang CW, Lee RR, Baker DG (2014c) Voxel-wise resting-state MEG source magnitude imaging study reveals neurocircuitry abnormality in active-duty service members and veterans with PTSD. Neuroimage Clin 5:408–419PubMedPubMedCentralCrossRefGoogle Scholar
  59. Huang CW, Huang MX, Ji ZW, Swan AR, Angeles AM, Song T, Huang JW, Lee RR (2016a) High-resolution MEG source imaging approach to accurately localize Broca’s area in patients with brain tumor or epilepsy. Clin Neurophysiol 127:2308–2316PubMedCrossRefGoogle Scholar
  60. Huang MX, Harrington DL, Robb Swan A, Angeles Quinto A, Nichols S, Drake A, Song T, Diwakar M, Huang CW, Risbrough VB, Dale A, Bartsch H, Matthews S, Huang JW, Lee RR, Baker DG (2016b) Resting-state magnetoencephalography reveals different patterns of aberrant functional connectivity in combat-related mild traumatic brain injury. J Neurotrauma 34:1412–1426PubMedCrossRefGoogle Scholar
  61. Huang MX, Risling M, Baker DG (2016c) The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury. Psychoneuroendocrinology 63:398–409PubMedCrossRefGoogle Scholar
  62. Huettel SA, Song AW, McCarthy G (2004) Functional magnetic resonance imaging. Sinauer Associates, SunderlandGoogle Scholar
  63. Hulkower MB, Poliak DB, Rosenbaum SB, Zimmerman ME, Lipton ML (2013) A decade of DTI in traumatic brain injury: 10 years and 100 articles later. Am J Neuroradiol 34:2064–2074PubMedCrossRefGoogle Scholar
  64. Jorge RE, Acion L, White T, Tordesillas-Gutierrez D, Pierson R, Crespo-Facorro B, Magnotta VA (2012) White matter abnormalities in veterans with mild traumatic brain injury. Am J Psychiatr 169:1284–1291PubMedCrossRefGoogle Scholar
  65. Josephs O, Turner R, Friston K (1997) Event-related fMRI. Hum Brain Mapp 5:243–248PubMedCrossRefGoogle Scholar
  66. Kandel ERS, James H, Jessell TM, Siggelbaum SA, Hudspeth AJ, Mack S (2013) Principles of neural science, 5th edn. McGraw-Hill, New YorkGoogle Scholar
  67. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A (2006) A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 30:1004–1031PubMedCrossRefGoogle Scholar
  68. Kato T, Nakayama N, Yasokawa Y, Okumura A, Shinoda J, Iwama T (2007) Statistical image analysis of cerebral glucose metabolism in patients with cognitive impairment following diffuse traumatic brain injury. J Neurotrauma 24:919–926PubMedCrossRefGoogle Scholar
  69. Kelmendi B, Adams TG, Southwick S, Abdallah CG, Krystal JH (2017) Posttraumatic stress disorder: an integrated overview of the neurobiological rationale for pharmacology. Clin Psychol Sci Pract 24:281–297CrossRefGoogle Scholar
  70. Kim MJ, Lyoo IK, Kim SJ, Sim M, Kim N, Choi N, Jeong DU, Covell J, Renshaw PF (2005) Disrupted white matter tract integrity of anterior cingulate in trauma survivors. Neuroreport 16:1049–1053PubMedCrossRefGoogle Scholar
  71. King AP, Abelson JL, Britton JC, Phan KL, Taylor SF, Liberzon I (2009) Medial prefrontal cortex and right insula activity predict plasma ACTH response to trauma recall. NeuroImage 47:872–880PubMedCrossRefGoogle Scholar
  72. Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD (2005) Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 88:79–86PubMedCrossRefGoogle Scholar
  73. Kitayama N, Brummer M, Hertz L, Quinn S, Kim Y, Bremner JD (2007) Morphologic alterations in the corpus callosum in abuse-related posttraumatic stress disorder. J Nerv Ment Dis 195:1027–1029PubMedPubMedCentralCrossRefGoogle Scholar
  74. Kuhn S, Gallinat J (2013) Gray matter correlates of posttraumatic stress disorder: a quantitative meta-analysis. Biol Psychiatry 73:70–74PubMedCrossRefGoogle Scholar
  75. Le Bihan D, Breton E, Lallemand D, Grenier P, Cabanis E, Laval-Jeantet M (1986) MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 161:401–407PubMedCrossRefGoogle Scholar
  76. Leahy RM, Mosher JC, Spencer ME, Huang MX, Lewine JD (1998) A study of dipole localization accuracy for MEG and EEG using a human skull phantom. Electroencephalogr Clin Neurophysiol 107:159–173PubMedCrossRefGoogle Scholar
  77. Lei D, Li KM, Li LJ, Chen FQ, Huang XQ, Lui S, Li J, Bi F, Gong QY (2015) Disrupted functional brain connectome in patients with posttraumatic stress disorder. Radiology 276:818–827PubMedCrossRefGoogle Scholar
  78. Levin HS, Wilde E, Troyanskaya M, Petersen NJ, Scheibel R, Newsome M, Radaideh M, Wu T, Yallampalli R, Chu ZL, Li XQ (2010) Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae. J Neurotrauma 27:683–694PubMedCrossRefGoogle Scholar
  79. Levine B, Cabeza R, McIntosh AR, Black SE, Grady CL, Stuss DT (2002) Functional reorganisation of memory after traumatic brain injury: a study with H(2)(15)0 positron emission tomography. J Neurol Neurosurg Psychiatry 73:173–181PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lewine JD, Davis JT, Bigler ED, Thoma R, Hill D, Funke M, Sloan JH, Hall S, Orrison WW (2007) Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J Head Trauma Rehabil 22:141–155PubMedCrossRefGoogle Scholar
  81. Li L, Lei D, Huang X, Suo X, Xiao F, Kuang W, Li J, Bi F, Lui S, Kemp GJ, Sweeney JA, Gong Q (2016a) White matter abnormalities in post-traumatic stress disorder following a specific traumatic event. EBioMedicine 4:176–183PubMedPubMedCentralCrossRefGoogle Scholar
  82. Li L, Sun G, Liu K, Li M, Li B, Qian SW, Yu LL (2016b) White matter changes in posttraumatic stress disorder following mild traumatic brain injury: a prospective longitudinal diffusion tensor imaging study. Chin Med J 129:1091–1099PubMedPubMedCentralCrossRefGoogle Scholar
  83. Liberzon I, Sripada CS (2008) The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 167:151–169PubMedCrossRefGoogle Scholar
  84. Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA (1999a) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11:11–17PubMedCrossRefGoogle Scholar
  85. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, Koeppe RA, Fig LM (1999b) Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 45:817–826PubMedCrossRefGoogle Scholar
  86. Lindemer ER, Salat DH, Leritz EC, McGlinchey RE, Milberg WP (2013) Reduced cortical thickness with increased lifetime burden of PTSD in OEF/OIF veterans and the impact of comorbid TBI. Neuroimage Clin 2:601–611PubMedPubMedCentralCrossRefGoogle Scholar
  87. Linnman C, Zeffiro TA, Pitman RK, Milad MR (2011) An fMRI study of unconditioned responses in post-traumatic stress disorder. Biol Mood Anxiety Disord 1:8PubMedPubMedCentralCrossRefGoogle Scholar
  88. Lopez KC, Leary JB, Pham DL, Chou YY, Dsurney J, Chan L (2017) Brain volume, connectivity, and neuropsychological performance in mild traumatic brain injury: the impact of post-traumatic stress disorder symptoms. J Neurotrauma 34:16–22PubMedPubMedCentralCrossRefGoogle Scholar
  89. MacDonald CL, Johnson AM, Cooper D, Nelson EC, Werner NJ, Shimony JS, Snyder AZ, Raichle ME, Witherow JR, Fang R, Flaherty SF, Brody DL (2011) Detection of blast-related traumatic brain injury in U.S. military personnel. N Engl J Med 364:2091–2100CrossRefGoogle Scholar
  90. MacDonald C, Johnson A, Cooper D, Malone T, Sorrell J, Shimony J, Parsons M, Snyder A, Raichle M, Fang R, Flaherty S, Russell M, Brody DL (2013) Cerebellar white matter abnormalities following primary blast injury in US military personnel. PLoS One 8:e55823CrossRefGoogle Scholar
  91. Matthews SC, Strigo IA, Simmons AN, O'Connell RM, Reinhardt LE, Moseley SA (2011) A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without major depression after blast-related concussion. NeuroImage 54(Suppl 1):S69–S75PubMedCrossRefGoogle Scholar
  92. Menon V (2011) Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci 15:483–506PubMedCrossRefGoogle Scholar
  93. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL (2009) Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 66:1075–1082PubMedPubMedCentralCrossRefGoogle Scholar
  94. Mohammadian M, Roine T, Hirvonen J, Kurki T, Ala-Seppala H, Frantzen J, Katila A, Kyllonen A, Maanpaa HR, Posti J, Takala R, Tallus J, Tenovuo O (2017) High angular resolution diffusion-weighted imaging in mild traumatic brain injury. Neuroimage Clin 13:174–180PubMedCrossRefGoogle Scholar
  95. Molina ME, Isoardi R, Prado MN, Bentolila S (2010) Basal cerebral glucose distribution in long-term post-traumatic stress disorder. World J Biol Psychiatry 11:493–501PubMedCrossRefGoogle Scholar
  96. Morey RA, Haswell CC, Selgrade ES, Massoglia D, Liu CL, Weiner J, Marx CE, Cernak I, McCarthy G, Grp MW (2013) Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans. Hum Brain Mapp 34:2986–2999PubMedCrossRefGoogle Scholar
  97. Nakayama N, Okumura A, Shinoda J, Nakashima T, Iwama T (2006) Relationship between regional cerebral metabolism and consciousness disturbance in traumatic diffuse brain injury without large focal lesions: an FDG-PET study with statistical parametric mapping analysis. J Neurol Neurosurg Psychiatry 77:856–862PubMedPubMedCentralCrossRefGoogle Scholar
  98. Naumova AV, Akulov AE, Khodanovich MY, Yarnykh VL (2017) High-resolution three-dimensional macromolecular proton fraction mapping for quantitative neuroanatomical imaging of the rodent brain in ultra-high magnetic fields. NeuroImage 147:985–993PubMedCrossRefGoogle Scholar
  99. Nelson MD, Tumpap AM (2017) Posttraumatic stress disorder symptom severity is associated with left hippocampal volume reduction: a meta-analytic study. CNS Spectr 22:363–372PubMedCrossRefGoogle Scholar
  100. Newsome MR, Durgerian S, Mourany L, Scheibel RS, Lowe MJ, Beall EB, Koenig KA, Parsons M, Troyanskaya M, Reece C, Wilde E, Fischer BL, Jones SE, Agarwal R, Levin HS, Rao SM (2015) Disruption of caudate working memory activation in chronic blast-related traumatic brain injury. Neuroimage Clin 8:543–553PubMedPubMedCentralCrossRefGoogle Scholar
  101. Newsome MR, Mayer AR, Lin XD, Troyanskaya M, Jackson GR, Scheibel RS, Walder A, Sathiyaraj A, Wilde EA, Mukhi S, Taylor BA, Levin HS (2016) Chronic effects of blast-related TBI on subcortical functional connectivity in veterans. J Int Neuropsychol Soc 22:790–792PubMedCrossRefGoogle Scholar
  102. Niogi SN, Mukherjee P (2010) Diffusion tensor imaging of mild traumatic brain injury. J Head Trauma Rehabil 25:241–255PubMedCrossRefGoogle Scholar
  103. Norman KA, Polyn SM, Detre GJ, Haxby JV (2006) Beyond mind-reading: multi-voxel pattern analysis of fMRI data. Trends Cogn Sci 10:424–430PubMedCrossRefGoogle Scholar
  104. O’Doherty DCM, Chitty KM, Saddiqui S, Bennett MR, Lagopoulos J (2015) A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder. Psychiatry Res Neuroimaging 232:1–33CrossRefGoogle Scholar
  105. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87:9868–9872PubMedPubMedCentralCrossRefGoogle Scholar
  106. Okie S (2005) Traumatic brain injury in the war zone. N Engl J Med 352:2043–2047PubMedCrossRefGoogle Scholar
  107. Patel R, Spreng RN, Shin LM, Girard TA (2012) Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies. Neurosci Biobehav Rev 36:2130–2142PubMedCrossRefGoogle Scholar
  108. Paulus MP, Stein MB (2006) An insular view of anxiety. Biol Psychiatry 60:383–387PubMedCrossRefGoogle Scholar
  109. Penny W, Friston K (2003) Mixtures of general linear models for functional neuroimaging. IEEE Trans Med Imaging 22:504–514PubMedCrossRefGoogle Scholar
  110. Peres JF, Foerster B, Santana LG, Fereira MD, Nasello AG, Savoia M, Moreira-Almeida A, Lederman H (2011) Police officers under attack: resilience implications of an fMRI study. J Psychiatr Res 45:727–734PubMedCrossRefGoogle Scholar
  111. Petrie EC, Cross DJ, Yarnykh VL, Richards T, Martin NM, Pagulayan K, Hoff D, Hart K, Mayer C, Tarabochia M, Raskind MA, Minoshima S, Peskind ER (2014) Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans. J Neurotrauma 31:425–436PubMedPubMedCentralCrossRefGoogle Scholar
  112. Phelps EA, LeDoux JE (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48:175–187PubMedCrossRefGoogle Scholar
  113. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285PubMedCrossRefGoogle Scholar
  114. Portnow LH, Vaillancourt DE, Okun MS (2013) The history of cerebral PET scanning from physiology to cutting-edge technology. Neurology 80:952–956PubMedPubMedCentralCrossRefGoogle Scholar
  115. Povlishock JT, Coburn TH (1989) Morphopathological change associated with mild head injury. Oxford University Press, New YorkGoogle Scholar
  116. Povlishock JT, Katz DI (2005) Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil 20:76–94PubMedCrossRefGoogle Scholar
  117. Rabinak CA, Angstadt M, Welsh RC, Kenndy AE, Lyubkin M, Martis B, Phan KL (2011) Altered amygdala resting-state functional connectivity in post-traumatic stress disorder. Front Psychol 2:62Google Scholar
  118. Rauch SL, Shin LM, Phelps EA (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research – past, present, and future. Biol Psychiatry 60:376–382PubMedCrossRefGoogle Scholar
  119. Robb Swan A, Nichols S, Drake A, Angeles A, Diwakar M, Song T, Lee RR, Huang MX (2015) Magnetoencephalography slow-wave detection in patients with mild traumatic brain injury and ongoing symptoms correlated with long-term neuropsychological outcome. J Neurotrauma 32:1510–1521PubMedPubMedCentralCrossRefGoogle Scholar
  120. Sartory G, Cwik J, Knuppertz H, Schurholt B, Lebens M, Seitz RJ, Schulze R (2013) In search of the trauma memory: a meta-analysis of functional neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD). PLoS One 8(3):e58150PubMedPubMedCentralCrossRefGoogle Scholar
  121. Schaul N, Gloor P, Ball G, Gotman J (1978) The electromicrophysiology of delta waves induced by systemic atropine. Brain Res 143:475–486PubMedCrossRefGoogle Scholar
  122. Scheid R, Preul C, Gruber O, Wiggins C, von Cramon DY (2003) Diffuse axonal injury associated with chronic traumatic brain injury: evidence from T2*-weighted gradient-echo imaging at 3 T. AJNR 24:1049–1056PubMedGoogle Scholar
  123. Schuff N, Zhang Y, Zhan W, Lenoci M, Ching C, Boreta L, Mueller SG, Wang Z, Marmar CR, Weiner MW, Neylan TC (2011) Patterns of altered cortical perfusion and diminished subcortical integrity in posttraumatic stress disorder: an MRI study. NeuroImage 54:S62–S68PubMedCrossRefGoogle Scholar
  124. Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatr 160(8):1516–1518PubMedCrossRefGoogle Scholar
  125. Shin YB, Kim SJ, Kim IJ, Kim YK, Kim DS, Park JH, Yeom SR (2006) Voxel-based statistical analysis of cerebral blood flow using Tc-99m ECD brain SPECT in patients with traumatic brain injury: group and individual analyses. Brain Inj 20:661–667PubMedCrossRefGoogle Scholar
  126. Simmons AN, Matthews SC (2012) Neural circuitry of PTSD with or without mild traumatic brain injury: a meta-analysis. Neuropharmacology 62:598–606PubMedCrossRefGoogle Scholar
  127. Simmons AN, Paulus MP, Thorp SR, Matthews SC, Norman SB, Stein MB (2008) Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry 64:681–690PubMedPubMedCentralCrossRefGoogle Scholar
  128. Simmons A, Strigo IA, Matthews SC, Paulus MP, Stein MB (2009) Initial evidence of a failure to activate right anterior insula during affective set shifting in posttraumatic stress disorder. Psychosom Med 71:373–377PubMedPubMedCentralCrossRefGoogle Scholar
  129. Simmons AN, Fitzpatrick S, Strigo IA, Potterat EG, Johnson DC, Matthews SC, Orden KF, Swain JL, Paulus MP (2012) Altered insula activation in anticipation of changing emotional states: neural mechanisms underlying cognitive flexibility in special operations forces personnel. Neuroreport 23:234–239PubMedCrossRefGoogle Scholar
  130. Simmons AN, Norman SB, Spadoni AD, Strigo IA (2013) Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder. Psychother Psychosom 82:382–389PubMedCrossRefGoogle Scholar
  131. Smith ME (2005) Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15:798–807PubMedCrossRefGoogle Scholar
  132. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TEJ (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31:1487–1505PubMedCrossRefGoogle Scholar
  133. Sorg SF, Schiehser DM, Bondi MW, Luc N, Clark AL, Jacobson MW, Frank LR, Delano-Wood L (2016) White matter microstructural compromise is associated with cognition but not posttraumatic stress disorder symptoms in military veterans with traumatic brain injury. J Head Trauma Rehabil 31:297–308PubMedPubMedCentralCrossRefGoogle Scholar
  134. Spielberg JM, McGlinchey RE, Milberg WP, Salat DH (2015) Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans. Biol Psychiatry 78:210–216PubMedCrossRefGoogle Scholar
  135. Sponheim SR, McGuire KA, Kang SS, Davenport ND, Aviyente S, Bernat EM, Lim KO (2011) Evidence of disrupted functional connectivity in the brain after combat-related blast injury. NeuroImage 54:S21–S29PubMedCrossRefGoogle Scholar
  136. Sripada RK, King AP, Garfinkel SN, Wang X, Sripada CS, Welsh RC, Liberzon I (2012a) Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder. J Psychiatry Neurosci 37:241–249PubMedPubMedCentralCrossRefGoogle Scholar
  137. Sripada RK, King AP, Welsh RC, Garfinkel SN, Wang X, Sripada CS, Liberzon I (2012b) Neural dysregulation in posttraumatic stress disorder: evidence for disrupted equilibrium between salience and default mode brain networks. Psychosom Med 74:904–911PubMedPubMedCentralCrossRefGoogle Scholar
  138. Stamatakis EA, Wilson JT, Hadley DM, Wyper DJ (2002) SPECT imaging in head injury interpreted with statistical parametric mapping. J Nucl Med 43:476–483PubMedGoogle Scholar
  139. Stein MB, McAllister TW (2009) Exploring the convergence of posttraumatic stress disorder and mild traumatic brain injury. Am J Psychiatry 166:768–776PubMedCrossRefGoogle Scholar
  140. Stein MB, Kessler RC, Heeringa SG, Jain S, Campbell-Sills L, Colpe LJ, Fullerton CS, Nock MK, Sampson NA, Schoenbaum M, Sun X, Thomas ML, Ursano RJ (2015) Prospective longitudinal evaluation of the effect of deployment-acquired traumatic brain injury on posttraumatic stress and related disorders: results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Am J Psychiatry 172:1101–1111PubMedPubMedCentralCrossRefGoogle Scholar
  141. Strigo IA, Simmons AN, Matthews SC, Grimes EM, Allard CB, Reinhardt LE, Paulus MP, Stein MB (2010) Neural correlates of altered pain response in women with posttraumatic stress disorder from intimate partner violence. Biol Psychiatry 68:442–450PubMedCrossRefGoogle Scholar
  142. Tanielian TL, Jaycox L (2008) Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. RAND Corporation, Santa MonicaGoogle Scholar
  143. Thompson PM, Stein JL, Medland SE et al (2014) The ENIGMA consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging Behav 8:153–182Google Scholar
  144. Tuch DS (2004) Q-ball imaging. Magn Reson Med 52:1358–1372PubMedCrossRefGoogle Scholar
  145. Vasterling JJ, Verfaellie M, Sullivan KD (2009) Mild traumatic brain injury and posttraumatic stress disorder in returning veterans: perspectives from cognitive neuroscience. Clin Psychol Rev 29:674–684PubMedCrossRefGoogle Scholar
  146. Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD (2003) Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 54:693–702PubMedPubMedCentralCrossRefGoogle Scholar
  147. Videbech P, Ravnkilde B (2015) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatr 161(11):1957–1966CrossRefGoogle Scholar
  148. Villarreal G, Hamilton DA, Graham DP, Driscoll I, Qualls C, Petropoulos H, Brooks WM (2004) Reduced area of the corpus callosurn in posttraumatic stress disorder. Psychiatry Res Neuroimaging 131:227–235CrossRefGoogle Scholar
  149. Wang EW, Huang JH (2013) Understanding and treating blast traumatic brain injury in the combat theater. Neurol Res 35:285–289PubMedCrossRefGoogle Scholar
  150. Wilde EA, Hunter JV, Newsome MR, Scheibel RS, Bigler ED, Johnson JL, Fearing MA, Cleavinger HB, Li X, Swank PR, Pedroza C, Roberson GS, Bachevalier J, Levin HS (2005) Frontal and temporal morphometric findings on MRI in children after moderate to severe traumatic brain injury. J Neurotrauma 22:333–344PubMedCrossRefGoogle Scholar
  151. Wilde EA, Chu Z, Bigler ED, Hunter JV, Fearing MA, Hanten G, Newsome MR, Scheibel RS, Li X, Levin HS (2006) Diffusion tensor imaging in the corpus callosum in children after moderate to severe traumatic brain injury. J Neurotrauma 23:1412–1426PubMedCrossRefGoogle Scholar
  152. Worsley KJ, Evans AC, Marrett S, Neelin P (1992) A 3-dimensional statistical-analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 12:900–918PubMedCrossRefGoogle Scholar
  153. Yarnykh VL, Bowen JD, Samsonov A, Repovic P, Mayadev A, Qian PQ, Gangadharan B, Keogh BP, Maravilla KR, Henson LKJ (2015) Fast whole-brain three-dimensional macromolecular proton fraction mapping in multiple sclerosis. Radiology 274:210–220PubMedCrossRefGoogle Scholar
  154. Yeh PH, Wang BQ, Oakes TR, French LM, Pan H, Graner J, Liu W, Riedy G (2014) Postconcussional disorder and PTSD symptoms of military-related traumatic brain injury associated with compromised neurocircuitry. Hum Brain Mapp 35:2652–2673PubMedCrossRefGoogle Scholar
  155. Yurgil KA, Barkauskas DA, Vasterling JJ, Nievergelt CM, Larson GE, Schork NJ, Litz BT, Nash WP, Baker DG, Team MRS (2014) Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty marines. JAMA Psychiat 71:149–157CrossRefGoogle Scholar
  156. Zhang J, Mitsis EM, Chu K, Newmark RE, Hazlett EA, Buchsbaum MS (2009) SPM and cluster counting analysis of [18F] FDG-PET imaging in traumatic brain injury. J Neurotrauma 27(1):35–49CrossRefGoogle Scholar
  157. Zhang L, Zhang Y, Li LJ, Li ZX, Li WH, Ma N, Hou CL, Zhang ZJ, Zhang ZQ, Wang LF, Duan L, Lu GM (2011) Different white matter abnormalities between the first-episode, treatment-naive patients with posttraumatic stress disorder and generalized anxiety disorder without comorbid conditions. J Affect Disord 133:294–299PubMedCrossRefGoogle Scholar
  158. Zhang L, Li W, Shu N, Zheng H, Zhang Z, Zhang Y, He Z, Hou C, Li Z, Liu J, Wang L, Duan L, Jiang T, Li L (2012) Increased white matter integrity of posterior cingulate gyrus in the evolution of post-traumatic stress disorder. Acta Neuropsychiatrica 24:34–42PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Andrea D. Spadoni
    • 1
    • 2
    Email author
  • Mingxiong Huang
    • 3
    • 4
  • Alan N. Simmons
    • 1
    • 2
  1. 1.Research ServiceVA San Diego Healthcare SystemSan DiegoUSA
  2. 2.Department of PsychiatryUniversity of California, San DiegoLa JollaUSA
  3. 3.Radiology and Research ServicesVA San Diego Healthcare SystemSan DiegoUSA
  4. 4.Department of RadiologyUniversity of California, San DiegoLa JollaUSA

Personalised recommendations