Diffusion-Tensor Imaging Findings and Cognitive Function Following Hospitalized Mixed-Mechanism Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Published:April 20, 2017DOI:



      To undertake a systematic review and meta-analysis of the relationship between microstructural damage and cognitive function after hospitalized mixed-mechanism (HMM) mild traumatic brain injury (mTBI).

      Data Sources

      PsycInfo, EMBASE, and MEDLINE were used to find relevant empirical articles published between January 2002 and January 2016.

      Study Selection

      Studies that examined the specific relationship between diffusion tensor imaging (DTI) and cognitive test performance were included. The final sample comprised previously medically and psychiatrically healthy adults with HMM mTBI.

      Data Extraction

      Specific data were extracted including mTBI definitional criteria, descriptive statistics, outcome measures, and specific results of associations between DTI metrics and cognitive test performance.

      Data Synthesis

      Of the 248 original articles retrieved and reviewed, 8 studies met all inclusion criteria and were included in the meta-analysis. The meta-analysis revealed statistically significant associations between reduced white matter integrity and poor performance on measures of attention (fractional anisotropy [FA]: d=.413, P<.001; mean diffusivity [MD]: d=−.407, P=.001), memory (FA: d=.347, P<.001; MD: d=−.568, P<.001), and executive function (FA: d=.246, P<.05), which persisted beyond 1 month postinjury.


      The findings from the meta-analysis provide clear support for an association between in vivo markers of underlying neuropathology and cognitive function after mTBI. Furthermore, these results demonstrate clearly for the first time that in vivo markers of structural neuropathology are associated with cognitive dysfunction within the domains of attention, memory, and executive function. These findings provide an avenue for future research to examine the causal relationship between mTBI-related neuropathology and cognitive dysfunction. Furthermore, they have important implications for clinical management of patients with mTBI because they provide a more comprehensive understanding of factors that are associated with cognitive dysfunction after mTBI.


      List of abbreviations:

      DAI (diffuse axonal injury), DTI (diffusion tensor imaging), FA (fractional anisotropy), HMM (hospitalized mixed-mechanism), MD (mean diffusivity), MRI (magnetic resonance imaging), mTBI (mild traumatic brain injury)
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        • Cassidy J.D.
        • Carroll L.J.
        • Peloso P.M.
        • et al.
        Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
        J Rehabil Med. 2004; : 28-60
        • Voss J.D.
        • Connolly J.
        • Schwab K.A.
        • Scher A.I.
        Update on the epidemiology of concussion/mild traumatic brain injury.
        Curr Pain Headache Rep. 2015; 19: 32
        • Blumbergs P.C.
        • Scott G.
        Staining of amyloid precursor protein to study axonal damage in mild head injury.
        Lancet. 1994; 344: 1055
        • Blumbergs P.C.
        • Scott G.
        • Manavia J.
        • Wainwright H.
        • Simpson D.A.
        • McLean A.J.
        Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury.
        J Neurotrauma. 1995; 12: 565-572
        • Bigler E.D.
        Neurobiology and neuropathology underlie the neuropsychological deficits associated with traumatic brain injury.
        Arch Clin Neuropsychol. 2003; 18: 595-621
        • Bigler E.D.
        Neuroimaging biomarkers in mild traumatic brain injury (mTBI).
        Neuropsychol Rev. 2013; 23: 169-209
        • Assaf Y.
        • Pasternak O.
        Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review.
        J Mol Neurosci. 2008; 34: 51-61
        • Aoki Y.
        • Inokuchi R.
        • Gunshin M.
        • Yahagi N.
        • Suwa H.
        Diffusion tensor imaging studies of mild traumatic brain injury: a meta-analysis.
        J Neurol Neurosurg Psychiatry. 2012; 83: 870-876
        • Bigler E.D.
        Neuropsychology and clinical neuroscience of persistent post-concussive syndrome.
        J Int Neuropsychol Soc. 2008; 14: 1-22
        • Kinnunen K.M.
        • Greenwood R.
        • Powell J.H.
        • et al.
        White matter damage and cognitive impairment after traumatic brain injury.
        Brain. 2011; 134: 449-463
        • Alexander M.P.
        Mild traumatic brain injury: pathophysiology, natural history, and clinical management.
        Neurology. 1995; 45: 1253-1260
        • Messe A.
        • Caplain S.
        • Paradot G.
        • et al.
        Diffusion tensor imaging and white matter lesions at the subacute stage in mild traumatic brain injury with persistent neurobehavioral impairment.
        Hum Brain Mapp. 2011; 32: 999-1011
        • Hughes D.G.
        • Jackson A.
        • Mason D.L.
        • Berry E.
        • Hollis S.
        • Yates D.W.
        Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: correlation with neuropsychological tests and delayed recovery.
        Neuroradiology. 2004; 46: 550-558
        • Karr J.
        • Areshenkoff C.N.
        • Garcia-Barrera M.A.
        The neuropsychological outcomes of concussion: a systematic review of meta-analyses on the cognitive sequelae of mild traumatic brain injury.
        Neuropsychology. 2014; 28: 321-336
        • Kurca E.
        • Sivak S.
        • Kucera P.
        Impaired cognitive functions in mild traumatic brain injury patients with normal and pathologic magnetic resonance imaging.
        Neuroradiology. 2006; 48: 661-669
        • McCauley S.R.
        • Wilde E.A.
        • Barnes A.
        • et al.
        Patterns of early emotional and neuropsychological sequelae after mild traumatic brain injury.
        J Neurotrauma. 2014; 31: 914-925
        • Barker-Collo S.
        • Jones K.
        • Theadom A.
        • et al.
        Neuropsychological outcome and its correlates in the first year after adult mild traumatic brain injury: a population-based New Zealand study.
        Brain Inj. 2015; 29: 1604-1616
        • Mathias J.L.
        • Beall J.A.
        • Bigler E.D.
        Neuropsychological and information processing deficits following mild traumatic brain injury.
        J Int Neuropsychol Soc. 2004; 10: 286-287
        • Genova H.M.
        • DeLuca J.
        • Chiaravalloti N.
        • Wylie G.
        The relationship between executive functioning, processing speed, and white matter integrity in multiple sclerosis.
        J Clin Exp Neuropsychol. 2013; 35: 631-641
        • Voelbel G.T.
        • Genova H.M.
        • Chiaravalotti N.D.
        • Hoptman M.J.
        Diffusion tensor imaging of traumatic brain injury review: implications for neurorehabilitation.
        NeuroRehabilitation. 2012; 31: 281-293
        • Gosselin N.
        • Bottari C.
        • Chen J.K.
        • et al.
        Electrophysiology and functional MRI in post-acute mild traumatic brain injury.
        J Neurotrauma. 2011; 28: 329-341
        • Mayer A.R.
        • Bellgowan P.S.
        • Hanlon F.M.
        Functional magnetic resonance imaging of mild traumatic brain injury.
        Neurosci Biobehav Rev. 2015; 49: 8-18
        • Silverberg N.D.
        • Gardner A.J.
        • Brubacher J.R.
        • Panenka W.J.
        • Li J.J.
        • Iverson G.L.
        Systematic review of multivariable prognostic models for mild traumatic brain injury.
        J Neurotrauma. 2015; 32: 517-526
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • Group P.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535
        • Borenstein M.
        • Hedges L.V.
        • Higgins J.P.
        • Rothstein H.R.
        Introduction to meta-analysis.
        John Wiley & Sons, Chichester, West Sussex, UK2009
        • Carroll L.
        • Cassidy J.D.
        • Holm L.
        • Kraus J.
        • Coronado V.
        Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
        J Rehabil Med. 2004; : 113-125
        • Lezak M.D.
        Neuropsychological assessment.
        Oxford Univ Pr, Oxford, New York2004
        • Strauss E.
        • Sherman E.M.
        • Spreen O.
        A compendium of neuropsychological tests: administration, norms, and commentary.
        Oxford Univ Pr, Oxford, New York2006
        • Viswanathan M.
        • Ansari M.T.
        • Berkman N.D.
        • et al.
        Assessing the risk of bias of individual studies in systematic reviews of health care interventions.
        in: Methods guide for effectiveness and comparative effectiveness reviews. Agency for Healthcare Research and Quality (U.S.), Rockville2012 (AHRQ Publication No. 12-EHC047-EF)
        • Higgins J.P.
        • Green S.
        Cochrane handbook for systematic reviews of interventions.
        Wiley-Blackwell, Chichester2008
        • Sanderson S.
        • Tatt I.D.
        • Higgins J.P.
        Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography.
        Int J Epidemiol. 2007; 36: 666-676
        • Mayer A.R.
        • Ling J.
        • Mannell M.V.
        • et al.
        A prospective diffusion tensor imaging study in mild traumatic brain injury.
        Neurology. 2010; 74: 643-650
        • Miles L.
        • Grossman R.I.
        • Johnson G.
        • Babb J.S.
        • Diller L.
        • Inglese M.
        Short-term DTI predictors of cognitive dysfunction in mild traumatic brain injury.
        Brain Inj. 2008; 22: 115-122
        • Veeramuthu V.
        • Narayanan V.
        • Kuo T.L.
        • et al.
        Diffusion tensor imaging parameters in mild traumatic brain injury and its correlation with early neuropsychological impairment: a longitudinal study.
        J Neurotrauma. 2015; 32: 1497-1509
        • Grossman E.J.
        • Jensen J.H.
        • Babb J.S.
        • et al.
        Cognitive impairment in mild traumatic brain injury: a longitudinal diffusional kurtosis and perfusion imaging study.
        AJNR Am J Neuroradiol. 2013; 34 (S1-S3): 951-957
        • Holli K.K.
        • Waljas M.
        • Harrison L.
        • et al.
        Mild traumatic brain injury: tissue texture analysis correlated to neuropsychological and DTI findings.
        Acad Radiol. 2010; 17: 1096-1102
        • Kumar R.
        • Gupta R.K.
        • Husain M.
        • et al.
        Comparative evaluation of corpus callosum DTI metrics in acute mild and moderate traumatic brain injury: its correlation with neuropsychometric tests.
        Brain Inj. 2009; 23: 675-685
        • Xiong K.
        • Zhu Y.
        • Zhang Y.
        • et al.
        White matter integrity and cognition in mild traumatic brain injury following motor vehicle accident.
        Brain Res. 2014; 1591: 86-92
        • Niogi S.N.
        • Mukherjee P.
        • Ghajar J.
        • et al.
        Structural dissociation of attentional control and memory in adults with and without mild traumatic brain injury.
        Brain. 2008; 131: 3209-3221
        • Bracht T.
        • Linden D.
        • Keedwell P.
        A review of white matter microstructure alterations of pathways of the reward circuit in depression.
        J Affect Disord. 2015; 187: 45-53
        • Bigler E.D.
        • Maxwell W.L.
        Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings.
        Brain Imaging Behav. 2012; 6: 108-136
        • Dodd A.B.
        • Epstein K.
        • Ling J.M.
        • Mayer A.R.
        Diffusion tensor imaging findings in semi-acute mild traumatic brain injury.
        J Neurotrauma. 2014; 31: 1235-1248
        • Toth A.
        • Kovacs N.
        • Perlaki G.
        • et al.
        Multi-modal magnetic resonance imaging in the acute and sub-acute phase of mild traumatic brain injury: can we see the difference?.
        J Neurotrauma. 2013; 30: 2-10
        • Kwok F.Y.
        • Lee T.M.
        • Leung C.H.
        • Poon W.S.
        Changes of cognitive functioning following mild traumatic brain injury over a 3-month period.
        Brain Inj. 2008; 22: 740-751
        • O'Jile J.R.
        • Ryan L.M.
        • Betz B.
        • et al.
        Information processing following mild head injury.
        Arch Clin Neuropsychol. 2006; 21: 293-296
        • Farquharson S.
        • Tournier J.D.
        • Calamante F.
        • et al.
        White matter fiber tractography: why we need to move beyond DTI.
        J Neurosurg. 2013; 118: 1367-1377
        • Hulkower M.B.
        • Poliak D.B.
        • Rosenbaum S.B.
        • Zimmerman M.E.
        • Lipton M.L.
        A decade of DTI in traumatic brain injury: 10 years and 100 articles later.
        AJNR Am J Neuroradiol. 2013; 34: 2064-2074
        • Pertab J.L.
        • James K.M.
        • Bigler E.D.
        Limitations of mild traumatic brain injury meta-analyses.
        Brain Inj. 2009; 23: 498-508
        • Levin H.S.
        • Diaz-Arrastia R.R.
        Diagnosis, prognosis, and clinical management of mild traumatic brain injury.
        Lancet Neurol. 2015; 14: 506-517
        • Sabet A.A.
        • Christoforou E.
        • Zatlin B.
        • Genin G.M.
        • Bayly P.V.
        Deformation of the human brain induced by mild angular head acceleration.
        J Biomech. 2008; 41: 307-315
        • Zhang L.
        • Yang K.H.
        • King A.I.
        Biomechanics of neurotrauma.
        Neurol Res. 2001; 23: 144-156
        • Hulley S.B.
        • Cummings S.R.
        • Browner W.S.
        • Grady D.G.
        • Newman T.B.
        Designing clinical research.
        Lippincott Williams & Wilkins, 2013