Volume 46, Number 6, 2009 JRRDJRRD Pages 717–756 Journal of Rehabilitation Research & Development Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder Robert W. Van Boven, MD, DDS;1* Greg S. Harrington, PhD;1 David B. Hackney, MD;2 Andreas Ebel, PhD;3 Grant Gauger, MD;4 J. Douglas Bremner, MD;5 Mark D’Esposito, MD;6 John A. Detre, MD;7 E. Mark Haacke, PhD;8 Clifford R. Jack Jr, MD;9 William J. Jagust, MD;10 Denis Le Bihan, MD, PhD;11 Chester A. Mathis, PhD;12 Susanne Mueller, MD;3 Pratik Mukherjee, MD;13 Norbert Schuff, PhD;3 Anthony Chen, MD;13–14 Michael W. Weiner, MD3,13 1The Brain Imaging and Recovery Laboratory, Central Texas Department of Veterans Affairs (VA) Health Care System, Austin, TX; 2Harvard Medical School, Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA; 3University of California, San Francisco (UCSF) Center for Imaging of Neurodegenerative Diseases, VA Medical Center, San Francisco, CA; 4UCSF, San Francisco VA Medical Center, San Francisco, CA; 5Emory Clinical Neuroscience Research Unit, Emory University School of Medicine, Atlanta VA Medical Center, Atlanta, GA; 6Henry H. Wheeler Jr Brain Imaging Center, Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA; 7Center for Functional Neuroimaging, Department of Neurology and Radiology, University of Pennsylvania, Philadelphia, PA; 8The Magnetic Resonance Imaging Institute for Biomedical Research, Wayne State University, Detroit, MI; 9Mayo Clinic, Rochester, MN; 10Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA; 11NeuroSpin, CEA-Saclay, Gif-sur-Yvette, France; 12PET Facility, University of Pittsburgh, Pittsburgh, PA; 13UCSF, San Francisco, CA; 14Program in Rehabilitation Neuroscience, San Francisco VA Medical Center, San Francisco, CA Abstract—Improved diagnosis and treatment of traumatic ADC = Apparent Diffusion Coefficient; ADNI = Alzheimer’s brain injury (TBI) and posttraumatic stress disorder (PTSD) are Disease Neuroimaging Initiative; ANT = Attention Network needed for our military and veterans, their families, and society Task; ASL = arterial spin labeling; BOLD = blood oxygen at large. Advances in brain imaging offer important biomarkers dependent level; CA = cornu ammonis; CAPS = Clinician- of structural, functional, and metabolic information concerning Administered PTSD Scale; CBF = cerebral blood flow; CBT = the brain. This article reviews the application of various imag- cognitive-behavior therapy; Cho = choline; CNS = central ner- ing techniques to the clinical problems of TBI and PTSD. For vous system; Cr = creatine; CT = computed tomography; DG = TBI, we focus on findings and advances in neuroimaging that dentate gyrus; D-MRI = diffusion magnetic resonance imaging; hold promise for better detection, characterization, and monitor- DTI = diffusion tensor imaging; EPI = echo-planar imaging; ing of objective brain changes in symptomatic patients with FA = fractional anisotropy; FDG = fluorodeoxyglucose; fMRI = combat-related, closed-head brain injuries not readily apparent functional magnetic resonance imaging; LDFR = long-delay free by standard computed tomography or conventional magnetic recall; mI = myo-inositol; MR = magnetic resonance; MRI = resonance imaging techniques. magnetic resonance imaging; MRS = magnetic resonance spec- troscopy; MRSI = magnetic resonance spectroscopic imaging; Key words: diagnosis, diffusion tensor imaging, fMRI, neuroim- NAA = N-acetylaspartate; OIF/OEF = Operation Iraqi Freedom/ aging, OIF/OEF, posttraumatic stress disorder, PTSD, TBI, trau- Operation Enduring Freedom; PCS = postconcussion syndrome; matic brain injury, veterans. *Address all correspondence to Robert W. Van Boven, MD, DDS; Mild Traumatic Brain Injury Clinic, Irwin Army Community Hospital, 600 Caisson Hill Road, Fort Riley, Abbreviations: Aβ = amyloid-β; ACC = anterior cingulate cor- KS 66442; Email: [email protected] tex; ACR = anterior corona radiata; AD = Alzheimer disease; DOI:10.1682/JRRD.2008.12.0161 717 718 JRRD, Volume 46, Number 6, 2009 Abbreviations (continued): PET = positron emission tomogra- disorders, or in otherwise healthy persons. However, phy; PIB = Pittsburgh Compound B; PTSD = posttraumatic improving the sensitivity of neuroimaging to subtle brain stress disorder; PW-MRI = perfusion-weighted magnetic reso- perturbations and combining these objective measures nance imaging; QA = quality assurance; rCBV = regional cere- with careful clinical characterization of patients may facili- bral blood volume; ROI = region of interest; RT = reaction time; tate better understanding of the neural bases and treatment SNR = signal-to-noise ratio; SPECT = single photon emission of the signs and symptoms of mild TBI. computed tomography; SWI = susceptibility-weighted imaging; For combat-related PTSD, the clinical manifestations TBI = traumatic brain injury; UCSF = University of California, include not only intrusive recurrent memories and hyper- San Francisco; UF = uncinate fasciculus. vigilance but also nonspecific symptoms, including insom- nia, concentration difficulties, irritability, impaired decision- making abilities, and memory problems. Moreover, overlap TRAUMATIC BRAIN INJURY AND of symptoms and the comorbidities of PTSD, TBI, depres- POSTTRAUMATIC STRESS DISORDER: sion, and their sequelae (e.g., sleep deprivation, drug or “INVISIBLE WOUNDS” alcohol abuse) make assessment, diagnosis, and manage- ment of these patients very difficult. As in the case of TBI, Improved diagnosis and treatment of traumatic brain objective and specific biological or anatomical markers injury (TBI) and posttraumatic stress disorder (PTSD) are would be invaluable in the diagnosis of PTSD. Neuroimag- needed for our military and veterans, their families, and ing assays could also aid in the monitoring and evaluation of society at large. According to a RAND Corporation study treatment approaches. In addition, these data may also pro- based on screening questionnaire data, nearly one out of vide information on brain vulnerability to subsequent injury five Operation Iraqi Freedom/Operation Enduring Free- and help establish guidelines for safe return to duty. dom (OIF/OEF) servicemembers (300,000) are estimated Brain imaging offers an important class of biomarkers to experience symptoms of PTSD or depression and more because of its ability to obtain structural, functional, and than 320,000 OIF/OEF servicemembers have sustained a metabolic information concerning the brain with various TBI [1]. Similarly, 23 percent (907/3,973) of a returning X-ray CT, magnetic resonance (MR) imaging (MRI), and brigade combat team were clinician-identified to have a positron emission tomography (PET) scanning techniques. history of TBI [2]. CT remains an extremely valuable and the most commonly The majority of cases of TBI in civilian and combat- utilized imaging modality. It is very sensitive to fractures related settings are categorized as “mild,” a category based of the skull and facial bones and can rapidly assess the pos- primarily on the characteristics of the acute sequelae follow- sible need for urgent neurosurgical interventions, such as ing the injury. The criteria for the classification of mild can evacuation of hematomas [4]. MRI has exquisite soft- vary, but the Department of Defense/Department of Veter- tissue contrast and also can measure function and metabo- ans Affairs March 2009 Clinical Practice Guideline has lism. Various PET scanning techniques can measure brain adopted the following criteria: (1) brief loss of conscious- function and amyloid deposition. ness (30 minutes or less), (2) brief alteration of conscious- This article reviews the application of various imaging ness (up to 24 hours), (3) posttraumatic amnesia for 0 to techniques to the clinical problems of TBI and PTSD. For 1 days, or (4) Glasgow Coma Score (best score within the TBI, we focus on findings and advances in neuroimaging first 24 hours) of 13 to 15 (15 = normal), and (5) a normal- that hold promise for better detection, characterization, and appearing brain on computed tomography (CT) scan [344]. monitoring of objective brain changes in symptomatic In contrast to civilian TBIs due to falls, sports, etc., patients with combat-related, closed-head brain injuries nearly 70 percent of combated-related TBIs are a result of not readily apparent by standard CT or conventional MRI blast “plus” injuries, i.e., the effects of blast plus another techniques. modality [3]. In mild TBI, the underlying pathology is not well understood and the lesion(s) may be subtle, scattered, varied, and, as indicated above, not detected on conven- OVERVIEW: NEUROIMAGING IN TRAUMATIC tional brain CT studies. Further diagnostic challenges are BRAIN INJURY posed by virtue of the varied and nonspecific postconcus- sion symptoms (e.g., concentration problems, irritability, Advanced neuroimaging techniques are finding headaches) that are also found in PTSD, depression, sleep increased use in the study of TBI. Whereas CT and standard 719 VAN BOVEN et al. Neuroimaging of TBI and PTSD MRI structural images can readily demonstrate large focal MRI (PW-MRI) has shown that regions of both normal- contusions or bleeds, diffuse axonal injury may be detected appearing and contused brain may have an abnormal indirectly by brain volume loss (volumetric analysis) or dif- regional cerebral blood volume (rCBV) and that alterations fusion tensor imaging (DTI). DTI studies have shown in rCBV may play a role