2013 BiglerA

Neuropsychol Rev (2013) 23:169209 DOI 10.
1007/s11065-013-9237-2
REVIEW
Neuroimaging Biomarkers in Mild Traumatic Brain Injury (mTBI)

Erin D. Bigler
Received: 18 February 2013 / Accepted: 7 August 2013 / Published online: 24 August 2013 # Springer Science+Business Media New York 2013
Abstract Reviewed herein are contemporary neuroimaging methods that detect abnormalities associated with mild traumatic brain injury (mTBI). Despite advances in demonstrating underlying neuropathology in a subset of individuals who sustain mTBI, considerable disagreement persists in neuropsychology about mTBI outcome and metrics for evaluation. This review outlines a thesis for the select use of sensitive neuroimaging methods as potential biomarkers of brain injury recognizing that the majority of individuals who sustain an mTBI recover without neuroimaging signs or neuropsychological sequelae detected with methods currently applied. Magnetic resonance imaging (MRI) provides several measures that could serve as mTBI biomarkers including the detection of hemosiderin and white matter abnormalities, assessment of white matter integrity derived from diffusion tensor imaging (DTI), and quantitative measures that directly assess neuroanatomy. Improved prediction of neuropsychological outcomes in mTBI may be achieved with the use of targeted neuroimaging markers.
Keywords Mild Traumatic Brain Injury (mTBI) . Concussion . Neuropsychology . Neuroimaging . Biomarkers . Neuropathology . Brain damage . Cognitive and neurobehavioral sequelae Abbreviation ACR ANAM CC CT CTE CVLT DAI DKI DMN DOI DSS DTI EF EN FE FLAIR fMRI GCS GM GRE GWI LDFR LOC M MCI MR MRI MRS MS mTBI Anterior corona radiata Automated neurological assessment metrics Corpus callosum Computed tomography Chronic traumatic encephalopathy California verbal learning test Diffuse axonal injury Diffusion kurtosis imaging Default mode network Day-of-injury Disability status scale Diffusion tensor imaging Executive function Executive network Finite element Fluid attenuated inversion recovery Functional magnetic resonance imaging Glasgow coma scale Gray matter Gradient recalled echo Gulf war illness Long delay free recall Loss of consciousness Mean Mild cognitive impairment Magnetic resonance Magnetic resonance imaging Magnetic resonance spectroscopy Multiple sclerosis Mild traumatic brain injury
E. D. Bigler (*) Department of Psychology, Brigham Young University, 1001 SWKT, Provo, UT 84602, USA e-mail: erin_bigler@byu.edu E. D. Bigler Neuroscience Center, Brigham Young University, Provo, UT, USA E. D. Bigler Magnetic Resonance Imaging Research Facility, Brigham Young University, Provo, UT, USA E. D. Bigler Department of Psychiatry, University of Utah, Salt Lake City, UT, USA E. D. Bigler The Brain Institute of Utah, University of Utah, Salt Lake City, UT, USA
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Neuropsychol Rev (2013) 23:169209
mcTBI OI PCS PTA RAS RAVLT RT SD or s.d. SDMT SWI TBI TBSS UF WHO WM WMHs
Mild complicated traumatic brain injury Orthopedically injured Post-concussion(al) syndrome Post-traumatic amnesia Reticular activating system Rey auditory verbal learning test Reaction time Standard deviation Symbol digit modality test Susceptibility weighted imaging Traumatic brain injury Tract-based spatial statistics Uncinate fasciculus World Health Organization White matter White matter hyperintensities
Introduction A simplified view of concussionthe mildest form of traumatic brain injury (TBI)is that although it is an acute brain injury any residuals from a concussion are short-lived physiological aberrations without lasting neurological sequelae. Indeed, the majority of concussions run a benign course with spontaneous return to baseline level of function without any systematic treatment. In the absence of an enduring neurological deficit, the neuropsychological argument has been made that any post-concussion cognitive or behavioral change in function does not reflect permanent neuropathology. Reasons behind these assumptions are that indisputably the majority of those who experience a mild TBI (mTBI)1 return to pre-injury baseline and resume typical function, at least based on traditional neuropsychological measures (Rohling et al. 2011). Transient perturbation of neuronal physiology seems a likely explanation and fits well with the majority of positive outcomes documented in mTBI research. Throughout the 1980s and early 1990s, apparent confirmation of no identifiable gross neuropathology was the conclusion of the majority of mTBI cases who underwent computed tomography (CT) or magnetic resonance imaging (MRI) (see Bigler and Snyder 1995). However, given the delicate nature of neuronsespecially axons with diameters of just a few
Definition of concussion and mTBI remains controversial and definitional issues have been discussed by Bigler (2008), but for this review the terms concussion and mTBI are used interchangeably. Based on the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force (p. 1637, Menon et al. 2010).
micronsneuropathologists have still considered the likelihood of neuronal damage in mTBI (see Blennow et al. 2012). The mechanical deformation from stretching, twisting and shearing actions brought on by head impact and acceleration/deceleration of the brain during the event that caused the concussion at least transiently alters cellular morphology and function. For example, Peerless and Rewcastle speculated in 1967 that .concussion depends upon varying degrees of damage to the axon as well as the neuron. The current definition of concussionimmediate loss of consciousness with rapid and complete recovery of cerebral functionshould not exclude the fact that a small number of neurons may have been permanently disconnected or have perished. (Peerless and Rewcastle 1967, p. 577). It is now the 21st century and although advanced neuroimaging methods in the living individual are not capable of matching histological precision, they do permit detection of neuropathological findings at the millimeter to sub-millimeter level and technologically are far advanced over techniques of just a decade ago. Contemporary neuroimaging permits in vivo studies of the injured brain, acutely as well as chronically and prospectively, with techniques that more directly examine cerebral microstructure. Moreover, precise biomechanical finite element (FE) studies empirically show where the greatest strains occur in the brain when subjected to headimpact or acceleration/deceleration movement, as depicted in Fig. 1 from Chatelin et al. (2011). As shown in Fig. 1, these regions of greatest axonal elongation, stress and strain occur in the very regions where acute magnetic resonance (MR) diffusion tensor imaging (DTI) changes are well documented in mTBI during both the acute and chronic phase (see also Chu et al. 2010; Metting et al. 2013). Current neuroimaging methods now demonstrate that a subgroup of mTBI patients have more than a transient physiological disruption in neural function showing identifiable underlying neuropathology (Bigler and Maxwell 2012; Gonzalez and Walker 2011; Kasahara et al. 2012; Kim et al. 2013; Lewine et al. 2007; Lipton et al. 2012; Matthews et al. 2012; Messe et al. 2011; 2012; Niogi and Mukherjee 2010; Wada et al. 2012). This review examines the current status of advanced neuroimaging findings in neuropsychological outcome research on mTBI. Neuroimaging improvements have resulted in a number of techniques that appear to be sensitive in detecting subtle pathology associated with mTBI (Benson et al. 2012; Kou et al. 2010; Niogi and Mukherjee 2010). Because of the objectivity that accompanies neuroimaging and image analysis techniques, neuroimaging findings may serve a biomarker role for the investigation of cognitive and neurobehavioral outcome from mTBI (Kou et al. 2010). Candidate neuroimaging biomarkers of mTBI are listed in Table 1 and introduced below. This review will only address structural imaging techniques and not functional neuroimaging metrics that also may
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From Chatelinet al. 2011
From Chu et al. 2010

Fig. 1 (Top ) Pictorial description of the neuroimaging steps in developing a finite element (FE) model to map diffusion information demonstrating where greatest axonal deformation occurs in the brain as a consequence of trauma. The final image on the right shows the most vulnerable areas to be corpus callosum, deep WM tracts of both cerebral hemispheres and the brainstem. From Chatelin et al. (2011) and used with permission from the Journal of the Mechanical Behavior of Biomedical Materials and Elsevier Publishing. (Bottom Left ). Red depicts regions of abnormal diffusion tensor imaging (DTI) findings within 6 days of sustaining an
From Metting et al.2013

mTBI. Note that where these changes occur match the prediction based on where the greatest axonal elongation strain occurs. From Chu et al. (2010) used with permission from American Society of Neuroradiology. (Bottom Right ). During the chronic phase of mTBI the colorized regions depict where group DTI differences are found in mTBI compared with non-injured controls used with permission from Metting et al. (2013). Note how the chronic findings are also predicted by the loci of greatest strain as shown in the FE modeling by Chatelin et al. (2011)
have implications for biomarker roles in mTBI (see Bryer et al. 2013; Zhou and Lui 2013); nor will this review deal with any treatment outcome factors that may come from improved neuroimaging biomarker identification of mTBI. To highlight the various points made in this review, individual cases with mTBI with several types of neuroimaging abnormalities will be presented. From a clinical neuropsychological perspective, clinical decision making must occur on an individual basis all-the-while understanding what group data analyses may show. Where individual cases are used in this review, they were carefully selected to reflect findings based on larger studies and not just case studies.
Candidate Neuroimaging Biomarkers Numerous magnetic resonance (MR) techniques currently identify trauma-related neuropathology (Duhaime et al. 2012; Hunter et al. 2012). The MR imaging (MRI) method known as diffusion tensor imaging (DTI; Fox et al. 2013) has become the most sensitive and predictive MRI metric in mTBI research (Niogi and Mukherjee 2010). DTI is an established neuroimaging procedure used diagnostically and in research across a variety of neurological diseases and disorders, especially those that predominantly influence white matter (WM) integrity (Alexander et al. 2007; Chanraud et al. 2010; Chapman et al. 2012; Sundgren et al. 2004; Travers et al. 2012; Wycoco et al. 2013; Zappala et al. 2012). As will be discussed in this review, mTBI may be viewed as a disruption in WM neural networks (Mayer et al. 2012a; Pandit et al. 2013; Shumskaya et al. 2012; Stevens et al. 2012; L. Tang et al. 2011; Voelbel et al. 2012), where damage or disruption of myelin integrity and oligodendrocytes may characterize much of the pathology that comes from TBI when chronic problems persist (Maxwell 2013). The key element in networks is pathways (Catani and Thiebaut de Schotten 2012), and fundamental to all pathways is axon integrity . In regard to contemporary neuroimaging, DTI provides the best
Table 1 Potential MRI biomarkers of mTBI Imaging modality SWI FLAIR Measures Hypointensities reflective of blood by-products (i.e. hemosiderin) WMHs indicating WM signal abnormality and/or increased perivascular space
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visualization and MR metrics of water diffusion that directly assess axon integrity (Mori et al. 2012). Indeed, the research and clinical applications of DTI are well established, including its use in providing in vivo visualization and analysis of WM integrity in mTBI (see Huston and Field 2013). DTI and mTBI In a review specific to DTI and TBI, Hulkower et al. (2013) conclude that, DTI effectively differentiates patients with TBI and controls, regardless of the severity and timeframe following injury. (in press, e-pub page1). The Hulkower et al. review was based on the first 100 published DTI studies that examined the ability of DTI to detect differences between controls and TBI and included over 30 studies that specifically assessed mTBI. As an index of WM integrity DTI metrics may serve as biomarkers of the health of WM connections in mTBI (Bigler and Bazarian 2010; Ling et al. 2012; Niogi and Mukherjee 2010; Kou et al. 2010; Bigler 2013). For neuroimaging findings to serve as biomarkers in TBI, including mTBI, there must be neuropathological confirmation of the relationship between what is observed from neuroimaging with that viewed histologically (Bigler and Maxwell 2011). Animal studies of TBI with in vivo DTI metrics, compared to histological confirmation, provide the necessary neuropathological foundation to infer in the living human what a particular DTI finding may mean at the histological level (see Bennett et al. 2012; Hylin et al. 2013; Budde et al. 2011). Likewise, in cases of epilepsy and cerebral neoplasm, there is pre-surgical and post-surgical confirmation of how DTI changes relate to damaged neural tissue (Abdullah et al. 2013; Liu et al. 2013). Given the status of DTI research and clinical findings, DTI is one of several neuroimaging methods that meet criteria for use as a biomarker of WM integrity. Specific to mTBI, in a study that examined only corpus callosum (CC) DTI findings, Aoki et al. (2012) demonstrated in a meta-analysis of 15 mTBI studies, that DTI consistently demonstrated differences between mTBI groups and controls. The consistency of these findings across studies allowed Aoki et al. (2012) to conclude that DTI metrics were sufficient to detect white matter damage in the CC of mTBI patients. (p. 870). Aoki et al. focused on the CC because of its vulnerability in mTBI to stretch and strain (Bayly et al. 2012; McAllister et al. 2012), but also other studies have shown the vulnerability of other long coursing tracts in the brain like the superior longitudinal fasciculus and tracts within frontal and temporal lobe regions (Shenton et al. 2012). Biomechanics of what produces an mTBI likely relate to a variety of outcome differences (Breedlove et al. 2012), and sports concussion is certainly in a different class from auto-pedestrian head injuries that produce mTBI. Nonetheless, even in sports concussion, which may produce the mildest of injuries, DTI is capable of distinguishing those with significant parenchymal injury and those without, at least in the acute and early sub-acute stages
(Bazarian et al. 2012; Cubon et al. 2011; Gardner et al. 2012; Koerte et al. 2012a; Maugans et al. 2012; Slobounov et al. 2012; Virji-Babul et al. 2013). Other Neuroimaging with Biomarker Potential: Hemosiderin, White Matter Hyperintensities (WMH), and Regional and Whole Brain Atrophy Several other candidate measures as neuroimaging biomarkers of mTBI, as listed in Table 1, include detection of hemosiderin (a by-product of blood degradation with paramagnetic properties detectable by MRI) as an indication of shear-force injury, currently best detected using susceptibility weighted imaging (SWI; Benson et al. 2012). As will be discussed below, cerebral microvasculature is just as small and delicate as neural tissue and therefore susceptible to deformation injury where petechial hemorrhage may attend mTBI (see Bigler 2004). In individuals with no risk factors for cerebrovascular disease and under 50 years of age, MRI detection of hemosiderin is unlikely unless there is injury or disease (Hunter et al. 2012; Kubal 2012; Sharp and Ham 2011). In 52 children with orthopedic injury only, no child had hemosiderin deposition detected whereas in the 41 children with mTBI, Bigler et al. (2013a) found that 12 children had hemosiderin. As with the detection of hemosiderin, the presence of WM signal abnormalitiesreferred to as WM hyperintensities (WMHs)are less common in individuals under 50 years as well (Hopkins et al. 2006), but have been noted to occur with increased frequency in TBI (Bigler et al. 2013a; Marquez de la Plata et al. 2007). Another imaging technique that involves WM is diffusion kurtosis imaging (DKI; Zhuo et al. 2012); this provides another metric shown to be affected in mTBI (Grossman et al. 2012a). In this technique, because of biological constraints in normal tissue, water diffusion metrics (e.g., kurtosis imaging) should have a rather uniform distribution but the shape of the distribution deviates when damage occurs. Small focal contusions occur in mTBI and may result in focal areas of atrophy (Bigler et al. 2013a). Regions of focal atrophy may be quantified as may whole brain volumetric changes. Indeed, longitudinal volumetric studies that provide quantitative metrics show whole brain volume loss over time in mTBI subjects (MacKenzie et al. 2002; Ross et al. 2012; Zhou et al. 2013). Neuroimaging biomarkers in mTBI neuropsychological outcome research could be applied in numerous ways. For example, Sorg et al. (2013) examined 30 war veterans with a history of mTBI (on average more than 2 years post injury) with a subgroup of 13 showing impaired neuropsychological performancedefined as performance at least one standard deviation below the meanon at least one executive function (EF) measure. Figure 2 plots out DTI detected WM differences that related to reduced EF performance in the mTBI group, showing that these regions of reduced EF performance corresponded with reduced WM integrity in the ventral prefrontal WM, posterior cingulum bundle, genu, and splenium
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Fig. 2 Atlas-based region of interest (ROI) placement and group comparisons of fractional anisotropy (FA) values depicting where significant differences occurred in mTBI patients with reduced EF. Placement of the tract-based special statistics (TBSS)-derived white matter skeleton regions of interest in standard space on a T1 image. Note in each case of reduced EF, FA is also reduced although not always significant. Also, most importantly, note that in all comparisons no significant FA differences were observed between controls and those with intact EF. Colors reflect different ROIs of white matter (WM) tracts. Note : AIC=anterior internal capsule; Ant. Cing.=anterior cingulum bundle; DPFWM=dorsal prefrontal white matter; EF = executive functions; FA= fractional
anisotropy; HC=healthy controls; PIC=posterior internal capsule; Post. Cing. = posterior cingulum bundle; ROI=region of interest; TBSS=tractbased spatial statistics; VPFWM=ventral prefrontal white matter. Error bars represent standard error of the mean. aP corrected<.10, bP corrected <.05. Used with permission from Sorg et al. (2013) and Wolters Kluwer/ Lippincott Publishers. Note once again the overlap of where significant DTI differences occur in relation to what was shown in Fig. 1, but now by examining neuropsychological outcome specific to white matter (WM) tracts, a clearer picture emerges as to where pathology affects cognitive performance
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of the CC. These are all well-known regions that participate in EF networks and likewise, vulnerable to mechanical deformation during head injury (Chatelin et al. 2011). Relevantly, the Sorg et al. study basically replicates similar observations in mTBI research involving these brain regions and EF, as reported by others (Jorge et al. 2012; Wada et al. 2012). Taking this approach the neuroimaging DTI biomarker findings provide novel information about brain-behavior relations that could never be gleaned from just the neuropsychological data, since group averaging neuropsychological test findings may obscure those with impairment. As another example, Hellyer et al. (2012) took a different approach using DTI and other MR metrics assessed through machine learning to first segregate TBI patients, the majority of whom had mTBI and no visible abnormality on the scan from controls. The MRI-based machine learning classifier extracted just from the CC achieved 86 % correct classification of those with TBI, the majority of whom had mTBI. In turn, these classifiers positively related to impairments in EF and speed of processing. A different MR biomarker approach from that of Sorg et al. (2013) but with convergence, demonstrating the added information that neuroimaging provides for understanding the neural basis of mTBI effects on cognition. The presence of DTI findings in cases of mTBI has also been used to predict outcome. For example, Rao et al. (2012) obtained DTI at 1 month post-injury where frontotemporal DTI findings related to clinically significant depression assessed at 1 year post injury. Messe et al. (2011; 2012) used DTI findings in the subacute (821 days) timeframe compared to chronic phase (~6 months) where persistence in abnormal DTI findings was associated with persistence of post-concussion syndrome (PCS). These examples demonstrate ways in which neuroimaging studies may serve as biomarkers of brain injury to identify individuals with mTBI who have demonstrable neuroimaging findings. The traditional criterion variable of mTBI, the injury itself, constitutes an unreliable marker of any behavioral or cognitive sequelae (Bigler et al. 2013c). Further, transient pathophysiological effects dominate mTBI but are comingled with structural and enduring pathology in a minority of those injured. Therefore, the fact of having sustained an mTBI in no way can distinguish the two, and therefore, the injury itself when traditionally classified as only an event that has occurred cannot identify who does or does not have persistent pathology. One could argue that there is abundant neuropsychological literature that supports the transient nature of mTBI with no lasting effect (Carroll et al. 2004b; Larrabee et al. 2013; Rohling et al. 2011); but all of this prior literature is based almost entirely on the assumption that the eventthe concussive injury itselfis a sufficient independent variable that characterizes the injury. Likewise, all of the post-mTBI symptoms that constitute what has been referred to as the post-
concussive syndrome (PCS) overlap with myriad other neurological and neuropsychiatric signs and symptoms and therefore, their lack of any specificity renders PCS criteria incapable as effectively serving as a bio-behavioral marker of mTBI. If, as is now being shown, neuroimaging methods demonstrate residual neural findings in some who have sustained mTBI then the mere classification of mTBI by the event that produced it will lead to erroneous conclusions. This review examines the potential role that neuroimaging biomarkers of brain pathology can play in the next decade of mTBI outcome research (Kan et al. 2012; Walker and Tesco 2013). Much of the confusion over mTBI sequelae is attributable to the absence of reliable biomarkers of brain injury. Only a brief historical perspective of mTBI will be offered here, as numerous other reviews have covered much of that material in great detail (see Prigatano and Gale 2011; Bigler 2008; Ruff 2011; Iverson 2005). Likewise, the history of neuroimaging in mTBI and contemporary methods, including underlying MR physics, has been reviewed elsewhere (see Shenton et al. (2012). Most of this review will focus on methods of structural neuroimaging, but there is also a large body of mTBI research on functional neuroimaging techniques, especially functional MRI (fMRI) and MR spectroscopy (MRS), which will not be reviewed here but has been by Slobounov et al. (2012) and Bryer et al. (2013). At the outset of this review, it is categorically stated that the majority of those who sustain an mTBI display and/or experience symptoms that are brief and run a benign course, including what occurred to this author.2 This review is concerned only with the minority of mTBI subjects who have sustained an injury which may no longer constitute a simple transient event (Bigler et al. 2013b).
Opposing Views of mTBI: Neuroimaging Biomarkers Will Help Resolve Controversies To put the Peerless and Rewcastles speculation of axonal damage in mTBI into context, their 1967 publication became the classic paper that established the concept of the WM shear lesion in TBI; that, in turn, became the foundation for the
I sustained a sports-related concussion playing high school football in 1966. I must have displayed significant PTA and confusion on the sideline because I was taken to the emergency room for evaluation and subsequently hospitalized overnight for observation. I am amnestic to those events, but it was recorded on an 8 mm tape. However, I recovered rapidly, as the injury was on a Friday and I practiced Monday and played in the next game on the following Friday. This, of course, was long before return-to-play guidelines but for me, post-concussion symptoms were minimal and short lived.
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concept of diffuse axonal injury (DAI, see Adams et al. 1982). The term shear lesion that is now commonplace nomenclature in the neuropsychological literature of TBI began with this Peerless and Rewcastle (1967) publication. Specific to mTBI, and coincidentally in 1967, Taylor also reviewed the topic of post-concussional sequelae outlining core clinical features of the post -concussional syndrome (PCS), which nearly three decades later would become labeled post -concussional disorder by DSM-IV standards (DSM-5 has dropped mention of PCS, instead using the major or mild neurocognitive disorder due to TBI as the qualifier). Taylors opening statement acknowledged a 100 year strident debate as to whether PCS was a residual of brain injury, manifestation of psychogenic problems, or something malingered. Almost 50 years since that publication the debate continues just as strongly, especially in the field of neuropsychology. The debate is not about acute concussive effects, as there is uniform agreement that the acute effects alter brain function. Indeed, especially within the realm of sports concussion, welldesigned neuropsychological studies have unequivocally demonstrated consistent acute neurocognitive and neurobehavioral effects of a concussion (McCrea 2007), as well as indisputable evidence of acute electrophysiological aberrations associated with concussion (Arciniegas 2011; Shaw 2002), along with development of reproducible animal models of concussion and its acute neuropathological effects (Chen et al. 2012b; Hylin et al. 2013). Likewise, there is minimal debate about the fact that the majority who sustain mTBI do recover (or, at least return to baseline; see Mott et al. 2012; Vasterling et al. 2012; Rona 2012). A principal debate centers on whether mTBI results in residual neuropathological changes in some as manifested by persistence of neurocognitive and neurobehavioral deficits 3 months or longer after mTBI. The camp that views mTBI as a transient physiological event with no lasting sequelae is captured by Geiffensteins statement that mTBI is a self-contained condition that resolves quickly without special treatment, a generally accepted conclusion by fair-minded neuropsychologists (see Carone and Bush 2013, p. xiii). As another example of this perspective, Boone (2013) states, The field [referring to neuropsychology] as a whole is taking the position that there is no long-term cognitive consequence from mTBI (p. 275). The other camp contends that most who experience mTBI recover and return to pre-injury baseline as measured by traditional neuropsychological assessment methods. However, as Ponsford et al. (2011) observed in a longitudinal study involving adults who sustained mTBI, some did exhibit ongoing impairment in memory function after 3 months and that at least a proportion of these mTBI participants did have subtle residual cognitive sequelae 3 months post-injury (p. 945). With some studies estimating 6 % to 35 % occurrences on the incidence of PCS in children after TBI, Barlow
et al. (2010) found in a prospective longitudinal cohort of 670 children (aged 018 years) who presented to the emergency room and assessed to have sustained mTBI, that 13.7 % had persisting symptoms at 3 months or longer post-injury when compared to a consecutive case-controlled cohort of 197 children who sustained an extra-cranial injury but were not diagnosed with mTBI. Similarly, in a prospective cohort study of concussion (all types) and resolution of symptoms that enrolled 280 patients (1122 years old) over a 12 month period, Eisenberg et al. (2013) showed that 15 % remained symptomatic at 3 months. In an adult sample, followed up to 14 years post TBI, that contained a substantial number of patients with mTBI, McMillan et al. (2012) found persistence of disability based on the Glasgow Outcome Scale-Extended. In another study, Levin et al. (2012) identified 102 mTBI patients at baseline within 4 days of injury and tracked them for 3 months compared to similarly tracked orthopedically injured (OI) controls. At 3 months using a conservative cut-point for symptom endorsement of PCS, about 10 % of the mTBI sample had PCS compared to under 2 % of the OI subjects. At 3 months mTBI patients in the Levin et al. study did differ from OI controls on a computer-based measure of processing speed but not on traditional neuropsychological measures. The studies above, and others (see also Dean and Sterr 2013; Kumar et al. 2013; Pontifex et al. 2012; Tallus et al. 2013), show that some with mTBI endorse and display persisting cognitive and neurobehavioral problems beyond 3 months. However, are the problems specific to brain injury or related to some other factor? There is abundant literature that discusses a host of pre-morbid personality and emotional factors that may predispose the individual who sustains an mTBI to misattribute residual symptoms to the injury rather than a pre-existing condition (Silver 2012). A fundamental problem with this is that misattribution assumes absence of pathology that could explain the symptom. Without some independent biomarker as to potential bona fide neural damage, a true distinction between accurate or misattributed perception in mTBI is impossible. Some criticize the mTBI neuropsychological literature because of not controlling for depression, litigation and effort, but Heitger et al. (2009) controlled for all of these factors and observed subtle cognitive deficits associated with mTBI after 6 months. Hanten et al. (2012) in a well-designed, within subjects longitudinal study of mTBI compared to OI and non-injured controls that tracked 59 mTBI patients (cognitive testing at <1 week, 1, and 3 months post-injury), all with no CT abnormalities on the day of injury (DOI) scan, found persisting memory problems to 3 months in some of those with mTBI. Konrad et al. (2011) examined 33 mTBI patients on average 6 years post-injury, all of whom passed symptom validity testing but nonetheless demonstrated persisting, chronic cognitive and emotional dysfunction. Dean and Sterr
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(2013) have also controlled for these factors finding residual subtle cognitive impairments associated with mTBI beyond 3 months post injury. The Hanten et al. (2012) and Hellyer et al. (2012) studies are particularly relevant for this review because they underscore the significance of advanced neuroimaging findings in mTBI for understanding neuropsychological outcome after 3 months post injury. The Hanten et al. investigation was longitudinal, obtained baseline imaging within 96 h, and followed up at 1 and 3 months post-injury. The study also included OI subjects as well as non-injured controls that were all imaged with high-field 3-Tesla MRI. Of the 59 (32 %) mTBI subjects, 19 had identifiable trauma-related pathology on follow-up MRI, even though none had identifiable DOI CT abnormalities. Even though MRI findings were based only on qualitative ratings by a neuroradiologist, clinically identifiable pathology involving the frontal lobes was associated with persisting deficit in an EF working memory task in the mTBI patients (see also the study by Raz et al. 2011 that shows MRI correlates with impaired EF performance in mTBI as well as Fig. 2 from Sorg et al. 2013). In the Hellyer et al. (2013) investigation the MRI classifier not only distinguished mTBI subjects, as well as those with more severe injury, from controls but also related to performance on EF measures in TBI patients on average almost 3 years post injury. These studies support that underlying pathology occurs in some who sustain an mTBI. Unlike what is emerging with contemporary neuroimaging, past measures that have been used clinically and in research with mTBI are too coarse to be effective biomarkers. Day-ofinjury (DOI) CT and even traditional markers of injury severity such as loss of consciousness (LOC) or post -traumatic amnesia (PTA), are poor predictors of outcome when Glasgow Coma Scale (GCS) scores are in the mild 1315 range (Smits et al. 2007). Further, even identifiable abnormalities on a DOI CT scan have limited predictive ability for mTBI, likely because they under detect the number and type of abnormalities (Smits et al. 2007). Past restrictions in mTBI research design (see full discussion of design issues as reviewed by Bigler et al. 2013c), plus the problems of how mTBI groups should be properly composed (Luoto et al. 2012), combined with the absence of a reliable mTBI biomarker, have resulted in major limitations in fully understanding mTBI outcomes. As summarized nearly two decades ago by Cipolotti and Warrington (1995), if neuropsychological assessment is to provide unique information about a condition and its relationship to underlying neurological impairment, there must be a method to independently define the pathophysiology or brain damage of that condition or objectively rule it out. In other words, to use neuropsychological measures as dependent variables to characterize a disorder, the independent variable reflecting neurological impairment must be specific to the
condition being examined. Once established, hypotheses about how brain impairment or damage that may selectively disrupt some components of a cognitive or behavioral system can then be examined. This is how neuropsychology has demonstrated neurocognitive and neurobehavioral correlates with other major neurological and neuropsychiatric disorders. To date this approach has not been applied to mTBI because there has been no independent marker of brain pathology, other than the event of having sustained a mild head injury. Abundant mTBI studies exists on the lack of neuropsychological findings of mTBI, but almost all of those studies have used the injury itself as the only independent factor to classify the mTBI condition. If the fact of sustaining an mTBI is insufficient to identify a neural condition with potential lasting sequelae, then the event by itself becomes an inadequate criterion related to outcomewhat is needed is a biomarker that identifies those with neural changes from the mTBI event. Therefore, this review turns to the neuropathology of mTBI and first asks a basic question: Are there discernible abnormalities that can be demonstrated in mTBI using contemporary neuroimaging? If so how should they be characterized as independent variables in studying neuropsychological outcome? The current review assumes basic understanding and background in neuroimaging and neuropathology of TBI, which has been covered in other reviews (Chanraud et al. 2010; Travers et al. 2012; Wilde et al. 2012; Hunter et al. 2012). It must be emphasized again that this is not a discussion of all who have sustained an mTBI because the assumption is that likely the majority have only experienced a transient event and advanced neuroimaging techniques would be negative in such individuals. Thus, the assumption that guides this review is that these pathological neuroimaging markers of mTBI will only be found in a subset of individuals with mTBI.
Neuropathology of mTBI From a neuropathological standpoint, TBI can be viewed on a continuum and as summarized by Graham and Lantos (2002) shear and tensile strains at the axonal level are the most important single factors contributing to the severity of brain damage in any patient who sustains a blunt head injury because it occurs at the moment of injury (p.867). Chatelin et al. (2011), integrating various MRI methods including DTI, developed FE biomechanical models to experimentally examine shear and tensile strains at different injury severity levels. Their results have particular relevance to understanding mTBI because they illustrate, as previously shown in Fig. 1, where the greatest axonal shear/strain effects occur in TBI corona radiata, corpus callosum, and brainstem. Given that information, and turning to acute imaging, as shown by Chu et al. (2010), knowing where the shear-strain effects are greatest predicts where DTI findings are most likely to acutely
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occur in mTBI (see Fig. 1, lower left panel), as well as where abnormalities will be chronically identified, as shown in Fig. 1 (lower right panel and Metting et al. 2013). The study by Tang et al. (2012) demonstrates the continuum or range of MR diffusion tensor findings in TBI. These investigators examined TBI patients from mild to severe compared to a control sample. As shown in Fig. 3, when the TBI subjects were compared to controls, there were significant and quite uniformly reduced fractional anisotropy (FA) values throughout brain WM, but particularly the corpus callosum and all areas as identified by Chatelin et al. (2011). However, basically within these same regions when severity was graded from mild to severe, the degree of FA changes related specifically to severity of injury with general conformation to where the changes occurred in comparison to the control sample. If one accepts that WM damage can be viewed on a continuum, studying moderate to severe forms of TBI may provide insight and understanding of milder forms of TBI. Other biomechanical studies show that the shear-strain relationship on WM is directly proportional to the severity of injury (Bayly et al. 2012). From this perspective, tensile strain may distort the axon and if this occurs within appropriate levels of tolerance, only physiological disruption results. This physical effect may be transient or may have subclinical relevance for understanding mTBI, since in the majority of
Fig. 3 a Fractional anisotropy (FA) comparisons between control and mild to moderate TBI subjects using voxel by voxel TBSS analysis (p < 0.05). Yellow: Control>mild to moderate TBI. Lower FA (yellow ) reflects extensive WM abnormalities. b Correlation analysis of FA and severity scores using voxel by voxel TBSS results comparing mild to severe TBI subjects (p <0.05). Blue: significant negative correlations between FA and severity. These findings demonstrate that as severity increases from mild to severe TBI so do DTI differences. Used with permission from Tang et al. (2012) and Springer-Verlag. Note ; FA= fractional anisotropy; TBSS=tract-based spatial statistics
those who sustain an injury full return to baseline is the norm, lending credence that reversibility of acute mTBI effects occurs in the majority (Parkinson 1992). Nonetheless, such a physical effect has the potential of initiating complex molecular and metabolic pathologies (Choe et al. 2012), along with cellular inflammatory reactions (Loov et al. 2013). Furthermore, there are a host of non-traumatic reversible encephalopathies that present with acute disturbances in physiologic functioning only to exhibit complete restoration of function as homeostasis returns resulting in no apparent sequelae including neuropsychological (Bavikatte et al. 2010; Pula and Eggenberger 2008). The fact that recovery meaning return to presumed baselineoccurs in disorders like reversible encephalopathies lends support to transient and mutable physiological changes associated with mTBI that may not have a permanent effect. Experimentally, in vitro and in vivo mTBI models show how physiological disruption may occur on a continuum followed by recovery and restoration (Greer et al. 2012; Johnson et al. 2012b). In this sense restoration implies a rebuilding where neural repair restores unimpaired functioning. Regardless of how function is returned to its normal state, much of the injury in mTBI may result in no lasting neuropathological effect. Traumatic axonal injury or TAI can be modeled from subtle physiological perturbation on the mildest end of injury, which may have no lasting effect, to distinct axonal damage that does result in histologically identified anatomical changes, which if to a sufficient degree will result in structural damage making macroscopic detection possible with advanced neuroimaging methods. Both animal and human studies also demonstrate that neuropathological changes are directly related to injury severity (Colgan et al. 2010; Mao et al. 2010; Maxwell et al. 2010; Rostami et al. 2012; Turner et al. 2013). Animal studies of blast injury can manipulate damage parameters that go from no discernible parenchymal effects verified by histological analysis to presence of edema, microhemorrhages, and neuronal changes (Risling et al. 2011; Saljo et al. 2011)in particular WM pathology (Park et al. 2012). Human blast-related TBI studies document WM pathology in military personnel exposed to such forces (Mac Donald et al. 2013, 2011). Quantitative neuroimaging studies demonstrate parenchymal volume loss linearly related to injury severity from mild to severe (Levine et al. 2008; Wilde et al. 2006; Ghosh et al. 2009). All of this supports the view that TBI neuropathology occurs on a continuum. From this perspective, understanding more severe TBI provides a framework for understanding the mildest of injuries and how pathology may be expressed in mTBI. Turning to the seminal neuropathological contributions of Strich (1956) and Peerless and Rewcastle (1967), as neuropathologists who studied more severe traumatic brain injuries, they viewed the brains microscopic environment and recognized the delicate and vulnerable nature of an axon when
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presented with traumatic forces including blunt trauma and acceleration/deceleration. Although Strich (1956) examined only severe cases of brain injury and individuals who died within 6 weeks post-injury, she reviewed various anecdotal neuropathological studies and made observations implicating neuronal damage in concussion, reporting the possibility that it may play a part [referring to neuronal injury], should be borne in mind (p. 184). Following this, Peerless and Rewcastle (1967) speculated that concussion could result in damage to the axon as well as the neuron and then indicated that such damage may disconnect the neuron (p. 577). These speculations happened to be confirmed a year later by Oppenheimer (1968) and his case study identified as J.M. Oppenheimers findings occurred before the introduction of the GCS rating method (see Teasdale and Jennett 1974), and therefore the definition of concussion or mTBI at that time was dependent upon the clinical description by Oppenheimer. The case study J.M was described as having been struck by a motor scooter and stunned yet apparently did not lose consciousness, but did have 10 to 15 min of retrograde amnesia and anterograde amnesia of about 20 min (Oppenheimer 1968). He had a parietal scalp bruise, but no skull fracture and no neurological signs (p. 301). Unfortunately however, he did sustain a chest injury in the accident, including multiple rib fractures that ultimately proved fatal. He also had a longstanding history of being bronchitic, and died of chest complications 13 days after the injury (p. 301). When J.M.s brain was microscopically examined, the following was observed at autopsy: The brain looked entirely normal except for a tiny softening in the lateral sulcus on one side of the midbrain. There was no vascular disease, and no sign of brain swelling. Histologically, there was some myelin destruction and numerous axonal retraction bulbs in the midbrain lesion. Nine blocks, from various parts of the brain, were stained for microglia. In every block, at least one microglial cluster was found (Oppenheimer 1968, p.301) While Oppenheimer was the first to provide this amount of neuropathological detail in an mTBI patient, others have confirmed such post-mortem observations as well (see Bigler 2004; Bigler and Maxwell 2012; Blumbergs et al. 1994; McKee et al. 2010, 2012). Figure 4 shows classic neuropathology of axonal damage, beading and axon bulb formation; indeed the types of pathologies that Peerless and Rewcastle (1967) observed in more severe TBI was found at post-mortem in an mTBI patient who succumbed not to TBI but to chest-pulmonary injury from the impact (see Bigler and Maxwell 2012). However, the classic pathology of shear injury and axon beading and degradation, when it occurs in mTBI, is only one facet of the potential mTBI pathologies that may occur. For example, in an mTBI patient who died from a
Fig. 4 A medium power light micrograph of part of a central white matter tract from a patient who suffered mTBI with complications and died from respiratory failure as a result of thoracic injuries 18 h after entry to hospital. The field is part of a paraffin section labeled for -amyloid precursor protein, a marker for axonal injury. The irregular, orange profiles represent axons within which focal loss of fast axonal transport has resulted in abnormal accumulation of the amyloid protein. The purple circles are the nuclei of glial supporting cells and are probably mostly oligodendrocytes. Within this field are a range of types of abnormal axons which represent different stages in the pathological cascade culminating in secondary axotomy. Injured axons form axonal swellings (*) on either side of the focus of loss of axonal transport. Axonal swellings continue to increase in diameter as a result of continued anterograde and retrograde axonal transport and a constriction occurs (black arrows ) at some point within the axonal swelling. The axon undergoes secondary axotomy thereat and separates into fragments. The regions of increased axonal caliber are then at the ends of the fragments and are referred to as axonal degeneration bulbs (white arrows ). The axonal fragment now separated from the neuronal cell body then degenerates. From Bigler and Maxwell (2012) used with permission from Springer. The inset in the lower left shows the classic line drawings from Peerless and Rewcastle (1967) used with permission from the Canadian Medical Association. The line drawing shows different stages of axonal beading from none in (A) to extensive beading and axonal fragmentation in (D). Note how the beading reflective of axonal damage is distinctly observed in the photomicrograph from the mTBI subject (black arrows )
heart attack several months post-injury, Bigler (2004) demonstrated both macrophages and hemosiderin were present in WMmicro-bleeds likely from trauma with macrophages indicative of neuroinflammatory processes (Bigler 2013). Presence of hemosiderin is a blood by-product from degraded blood, in TBI considered a residual from shearing of the microvasculature or breakdown of the vascular wall from trauma (Benson et al. 2012), and a distinct marker of TAI detected by MRI (Scheid et al. 2006). Two MR methods are sensitive in detecting edema and microhemorrhages: 1) DTI, for neuroinflammation, and 2) gradient recalled echo (GRE) sequences, in particular susceptibility weighted imaging (SWI), for microhemorrhages. Certain DTI metrics, like fractional anisotropy (FA), are sensitive to inflammation, because with inflammation a restriction in water dispersion occurs. FA is a DTI metric
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reflective of water diffusion, on a scale of 0.0 to 1.0, with normative values typically within a midrange. FA that is too low may reflect WM degradation (intracellular water mixes with extracellar because axon membranes do not effectively constrain water or are absent) and FA too high, may reflect edema because water diffusion is constrained (Chanraud et al. 2010; Shenton et al. 2012). Elevated FA may occur when water dispersion is restricted because of regional or more generalized swelling. As already shown in Fig. 1 (lower left panel), acute inflammation in mTBI occurs in characteristic regions vulnerable to damage (see Chu et al. 2010). With regards to detecting microhemorrhages and trauma-related vascular pathology, as mentioned, the SWI sequence is particularly sensitive with microhemorrhages and indicators of hemosiderin deposition occurring within the same regions of vulnerability (Turtzo et al. 2012; Benson et al. 2012). A most important factor with traumatically induced micro-bleeds is that they may evolve over hours to 12 days post-injury (Oehmichen et al. 2003). Given CT limitations in detecting blood and the fact that in mTBI a CT scan, if done at all, is typically the first scan performed, usually within an hour or two of coming into the emergency department (ED), and therefore blood or blood byproducts may not be observed in the initial imaging as demonstrated in Fig. 5 (also see Bigler 2008). Graham and Lantos (2002) provide a rationale for viewing TBI on a continuum, emphasizing the vulnerability of axons,
Fig. 5 Negative day of injury (DOI) computed tomography (CT) imaging is shown in the two axial images on the top left. Approximately 6 weeks post-injury, follow-up MRI demonstrated hemosiderin deposition (dark splotches ) within the deep right frontal lobe (bottom left coronal image ). These abnormalities persisted 5 years post-injury reflected as white matter hyperintensities (WMHs) on the FLAIR sequence in the right frontal region as well as the hemosiderin deposition. All axial scans are in radiological orientation where right is on the viewers left
the delicate nature of blood vessels in the brain, and the microvascular damage that can result from trauma (see also Fujita et al. 2012; Sangiorgi et al. 2013). Damage from TBI affects both brain parenchyma and blood vessels, which when sheared or damaged in ways where blood may leak into the parenchyma, leave degraded blood by-products in the form of hemosiderin potentially detectable by MRI. Figure 6 shows the detection of hemosiderin in the region of the forceps minor in a child with mTBI associated with a high velocity impact sports concussion that had normal conventional neuroimaging in the ED. As with the case presented in Fig. 5, a healthy individual without cardiovascular or cerebral vascular risk factors under the age of 30 at the time of injury would not be expected to have any hemosiderin deposition identified on imaging. Figure 6 depicts pathology (hemosiderin deposition) detected after a sports accident where the significance of the impact dynamics can be less substantial than in motor vehicle accidents. Here, DTI demonstrates reduced connectivity in the frontal region, likely a consequence of the mTBI although no pre-injury baseline imaging was available for compariosn. In addition to the shear/strain effects on blood vessels, TBI at the moderate-to-severe level of injury severity is a wellknown cause of deficits in vascular autoregulation (Yokobori et al. 2011). Using transcranial Doppler testing of dynamic cerebral autoregulation, Junger et al. (1997) demonstrated in mTBI patients 48 h post-injury that eight out of 29 (28 %) demonstrated poorly functioning or absent cerebral autoregulation versus none of the controls (p. 425). In professional boxers with suspected chronic brain injury from multiple concussive as well as sub-concussive blows to the head, impaired cerebral hemodynamics has been demonstrated (Bailey et al. 2013). Cerebral autoregulation is key to blood flow dynamics that subserve neural function that generates cognition and behavior (Logothetis 2008). Therefore, even if neural tissue is not damaged, if precisely regulated vascular flow does not occur normally, because of vascular injury deficits may arise. Interestingly, Pomschar et al. (2013) have shown in mTBI that some develop abnormal intracranial venous drainage patterns, speculating that microvascular damage in mTBI alters vascular compliance adversely influencing venous drainage. Likewise, Metting et al. (2013) used perfusion CT on the DOI scan to identify blood flow and infer edema in cases of mTBI, which in turn, also related to DTI outcome months post-injury (see also Metting et al. 2010, 2009). One of their interpretations on the effects of mTBI is that it disrupts the vascular autoregulation by damaging the perivascular nerve network (see Ueda et al. 2006). A variety of abnormal fMRI findings have been reported in mTBI (Johnson et al. 2012a; Slobounov et al. 2011b; Chen et al. 2012a), and some form of subtle vascular pathology alone and/or in combination with neuronal pathology may be responsible for such findings. Regardless, from a structural imaging perspective, presence of hemosiderin in the mTBI
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Fig. 6 Hemosiderin deposition (black arrow ) detected with susceptibility weighted imaging (SWI) in an older child who sustained an mTBI in a sporting accident. Day-of-injury (DOI) computed tomography (CT) scan was negative. Diffuse tensor imaging (DTI) tractography (right image ) shows reduced frontal projection of aggregate tracts within the superior
anterior frontal region (arrow ). Color reflects DTI convention where blue reflects vertically oriented tracts, green indicates anterior-posterior orientated tracts and warm colors (orange-red) reflect tracts that are laterally oriented. Axial MR images are not in radiological perspective, because of the 3-D image presentation. Right is on the viewers right
patient may not only infer TAI but disrupted vascular integrity (Scheid et al. 2006). As already indicated traumatic axonal injury or TAI may be the better term to use with regards to understanding all pathological effects that relate to axonal damage from trauma (see discussion of this point by Bigler and Maxwell 2012), but regardless of whether the DAI or TAI term is used, in mTBI when focal WM abnormalities are visibly present, they are best detected in the fluid attenuated inversion recovery (FLAIR) sequence (Marquez de la Plata et al. 2007; an example of a trauma-related FLAIR signal abnormality is shown in Fig. 5). The distribution of hyperintense foci on FLAIR imaging or the hypointense hemosiderin signal on GRE/SWI in TBI reflecting DAI/TAI pathology is shown in Fig. 7 from Chatelin et al. (2011). While the Fig. 7 illustration is based on
all levels of severity, the distribution of these types of lesions as observed in mTBI is identicallesions at the gray/white margins, deep white matter, and corpus callosum. In the Bigler et al. (2013a) study that included 41 children with mild complicated TBI (mcTBI; defined as some type of positive neuroimaging typically on initial CT imaging) all of whom had GCS of 1315 but on CT had evidence of skull fracture, small contusion or some form of hemorrhage or edema, 12 (29.3 %) had identifiable hemosiderin deposition on follow-up MRI at least 6 months post-injury. Given that these observations were based on standard GRE sequence and not SWI, where sensitivity in detecting hemosiderin is 23 times greater, indicates that this is an under estimate in the number of TAI-type findings in mcTBI (see Benson et al. 2012). Nonetheless, even with these limitations almost one-
Fig. 7 Chatelin et al. (2011) summarized the location and distribution of diffuse axonal injury (DAI) pathology based on several neuroimaging and postmortem studies to show white matter (WM) pathology in deep tracts within each hemisphere, corpus callosum, and upper brainstem as indicated by black stars. Bar graphs represent a simple frequency count of
visually identifiable abnormalities. Note the frequent occurrence of DAI within the frontal and temporal lobes. Red stars signify abnormalities in deep WM regions and black indicates cortical and corpus callosum loci. Used with permission from the Journal of the Mechanical Behavior of Biomedical Materials and Elsevier publishing
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third of mcTBI patients have a marker of TAI when MRI is performed yet there are no systematic large-scale neuropsychological outcome studies in the literature that specifically have studied this type of lesion mapping and mTBI. Animal models of mTBI can provide a direct comparison between neuroimaging and histological confirmation of neuroimaging findings and confirm presence of neuropathology even at the mild end of TBI severity (Dewitt et al. 2013). The shape of the animal brain, especially the rodent brain and skull are very different from the human and therefore the precise biomechanics of human brain injury cannot exactly be duplicated in animal models (Spain et al. 2010). Porcine models that more directly mimic the human brain have been developed (Sullivan et al. 2013) and probably hold the greatest promise for improved understanding of mTBI neuropathology based on neuroimaging findings integrated with histological confirmation and its effect on cognition and behavior (see Browne et al. 2011). These animal models provide histopathological confirmation of what may be observed with in vivo neuroimaging in the human with TBI, including mTBI (see Budde et al. 2011; Turtzo et al. 2012). Although involving multiple concussive blows to the head, ante-mortem imaging in those individuals with suspect chronic traumatic encephalopathy (CTE) is providing the neuroimaging background for improved understanding of the postmortem histopathology of CTE (Baugh et al. 2012; Handratta et al. 2010). Hart et al. (2013) and Strain et al. (2013) have found cognitive deficits and depression in older retired National Football League (NFL) players compared to healthy controls, associated with WM-defined DTI findings. Likewise, Lehman et al. (2012) found three times higher rates of neurodegenerative mortality in retired NFL players and CTE has been established in NFL players (McKee et al. 2010, 2012). There are more unknowns than what is known about sports-related CTE, but the possibilities of this being a latent phenomenon of mTBI raises sobering questions and means the very best in research design should be applied to studying mTBI and potential relations with CTE (see Victoroff 2013) and other forms of neurodegeneration (Lee et al. 2013). Nonetheless, abnormal WM findings have been reported in physician-observed concussion from hockeyrelated injury as well as soccer players without symptomatic concussion, but with history of head and soccer ball impact (Koerte et al. 2012b, a; Lipton et al. 2013). The presumed relationships with such findings are the history of concussion and sub-concussive injuries. While CTE may require multiple concussive and sub-concussive blows to the head, each blow occurs within the realm of mTBI. Taken together, the animal and human literature on mTBI provides support for the use of advanced neuroimaging methods, that effectively detect various common brain pathologies in some who have sustained mTBI, and these should become biomarkers for future mTBI investigations related to neuropsychological outcome.
Absence of Biomarkers of mTBI Lead to Psychogenic Explanations As pointed out by Taylor in 1967, during the chronic phase after concussion, on conventional neurological testing, there are no abnormal signs on physical examination (p. 67). Without any objective marker of neurological impairment, psychological explanations naturally came to the forefront. Indeed, returning to Taylor (1967), he continues: I have yet to read an article on the subject of post concussional sequelae in the British literature which does not contain the words litigation or psychogenic in the first dozen lines. Even a critical leading article about post-traumatic headache, written in April 1966, which concluded that treatment was not easy but was well worthwhile, contained the statement that in at least two-thirds of the patients there is a psychogenic element. This is certainly an advance on a similar leader of 1961, which said: Above all, the general physician . . . should find it advisable to refer a patient to the psychiatrist as soon as possible . . . and concluded: In the ultimate analysis it [accident neurosis] is a social disease and a function of industrial morale. (p. 67) Taylor was referring to Millers classic papers on accident neurosis (Miller 1961a, b, 1962; Miller and Cartlidge 1972), where at best residual effects from concussion were portrayed by Miller as a functional disorder characterized by neurosis in the title. At worst, residual effects that persisted from concussion were considered by Miller as feigned, malingered impairments associated with secondary gain, especially when litigation was involved. For Miller, attribution to cellular damage as having any part to do with PCS was simply unsupported speculation (Miller 1961a, p. 992). Miller was a neurologist and in the pre-neuroimaging era, objective neurological findings, particularly those pathognomonic for damaged neural systems (i.e., an abnormal reflex, hemiplegia) were the only objective findings worthy of clinical demonstration of neurological damage or impairment short of something being observed at the time of neurosurgery or autopsy. Understandably, the patient with mTBI and an entirely normal clinical neurological examination would not be suspected to have any underlying impairment. Indeed, one of the classic and influential psychodynamic textbooks at the time of Miller s publications, Laughlins (1956) The Neuroses in Clinical Practice , characterized all neuroses following trauma, including concussion, as merely neurotic reactions which have been attributed to or which follow a situational traumatic event . (p.633). Specific to residual effects from concussion, Laughlin writes that Evidence could not be found to validate scientifically the theories of an organic basis., rather a large body of data has been accumulated clearly establishing the basic
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psychologic origins of the symptoms commonly seen in connection with these reactions (p.635). Without an independent biomarker of brain injury, the natural conclusion is captured by the title of Jacobsons (1995) review, The post - concussional syndrome : Physiogenesis , psychogenesis and malingering : An integrative model . Macleod (2010); Evans (2010) and Obermann et al. (2010), all provide updated reviews and perspectives of the functional versus the organic versus the malingering symptoms that may be associated with mTBI. For example, as reflected in the article titlePost concussion syndrome : The attraction of the psychological by the organic Macleod (2010) makes the case that following concussion the potentially malignant influences of psychosocial factors can compound the organic state since there is invariably a psychological component to any physical disease (p. 1035). Neuropsychological assessment entered the debate in 1974 when Gronwall and Wrightson (1974a) demonstrated reduced neuropsychological test performance in a group of individuals with concussion dependent on task complexity and attention demands (see also Gronwall and Wrightson 1974b, 1975). Gronwall and Wrightson and countless other investigators have been attempting to characterize PCS symptoms, especially, inability to carry out normal work, poor concentration, fatigue, irritability, and headache (p. 605), since the original 1974 publications. Gronwall and Wrightson were immediately criticized (see their commentaries in Gronwall et al. 1990; Wrightson and Gronwall 1999) and the controversy continues to this day (see Temme et al. 2013). However, there would likely not be controversy, or less of it, if objective measures of neural abnormalities could be demonstrated with mTBI. The problem centers on the fact that PCS symptoms are simply not specific to having sustained a concussion; they occur from diverse sources and, in the individual with a history of head injury, are influenced by a host of pre-injury as well as post-injury factors (Silver et al. 2009; Silver 2012). Given these ambiguities it is no surprise that neuropsychological outcome studies provide such a confusing picture. Although memory impairment as a symptom following mTBI is commonplace (Ruff et al. 2009), memory complaints are ubiquitous symptoms across numerous neurological and neuropsychiatric disorders. Similarly, given the complexity of neural systems that underlie memory, diverse structures and pathways have the potential to influence memory performance on a neuropsychological task. Indeed, similar arguments can be made about all symptoms/problems that form PCSnone are unique to having sustained an mTBI and none have a unique neural underpinning that would be specific to mTBI. Unless there is some type of biomarker to link the symptom complaint (i.e., problems with memory, fatigue, inability to concentrate, etc.) to the presenting problem and history, and to which neural system is being affected, it becomes a statistical quagmire to find relationships. As argued in this review, one
potential solution, or at least an improvement in research design, would be to use neuroimaging as a type of biomarker to define mTBI subgroups with common pathology. As already shown in Fig. 2, this was the approach taken by Sorg et al. (2013). In addition, this is captured in the study by Niogi et al. (2008) which examined mTBI patients who underwent DTI as well as neuropsychological examination. A critical pathway for memory involves the uncinate fasiculus (UF; see Nestor et al. 2012) and Fig. 8 shows the relation of UF integrity based on FA and memory performance. Note in Fig. 8 that the long delay free recall (LDFR) trial of the California Verbal Learning Test (CVLT; Delis et al. 2000) positively relates with FA in the UF, but not in the anterior corona radiata (ACR). A variety of factors may contribute to reduced memory performance and UF integrity as the UF is part of language and emotional processing networks and not just memory (Catani et al. 2012), but the point is that it was the UF that related to memory impairment in mTBI. Furthermore, note that over half of the mTBI subjects performed well within normative ranges of the standardization sample. So, unless the right pathway is examined in mTBI patients with possible perturbation of that pathway related to a particular function, no group relationship would be found. No two mTBI patients will ever have identical pathology; therefore, this limits how omnibus whole-brain neuroimaging metrics would be sensitive in detecting where unique pathology may reside in mTBI (however, see Kim et al. 2013). Geary and colleagues (2010, 2011) similarly demonstrated the importance of the UF in memory in mTBI but also examined a novel way of assessing list-learning using the CVLT (Delis et al. 2000) in an mTBI sample. In 35 controls and 40 mTBI subjects, Trial 1 was the only trial that reached significance, but the mean (M ) and standard deviation (SD ) values were clinically unimpressive (Control: M =7.63, SD =2.06; mTBI: M =6.58, SD =1.84); no other CVLT comparisons were significant including no GroupList interaction. In a traditional sense these would be interpreted as potentially meaningless and inconsequential clinical findingsthat is, no neuropsychological effect from mTBI. However, the correlation between UF and CVLT was significant (it should also be noted that the superior longitudinal fasciculus was also significant, likely a reflection of attentional networks in memory), reflecting a distinct relation between reduced verbal learning and UF integrity. Another example comes from Little et al. (2010), but this study focused on executive functioning tasks and examined DTI metrics of thalamic integrity. Again, only those with abnormally low FA exhibited reduced neuropsychological functioning. In these investigations if neuropsychological tests were group averaged, irrespective of neuroimaging findings, none or just a few and clinically unimpressive differences would be observed. Geary et al. (2010) concluded, Most
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Fig. 8 Two cognitive functions are specifically associated with white matter (WM) microstructure in two distinct regions (uncinate fasciculus [UF] and anterior corona radiata [ACR]) in adults with mild TBI. a Correlation of memory performance and average bilateral UF fractional anisotropy (FA) in both hemispheres (r =0.52, p <0.001). b The ACR FA does not correlate significantly with long delay free recall (LDFR)
memory (r = 0.057, p =0.725). c The UF FA does not correlate significantly with attentional control (r =0.133; p =0.41). d Correlation of attentional control measured by conflict score and the left ACR FA were significant (r =0.47; p =0.001). This shows that cognitive effects from mTBI may be region and task specific. From Niogi et al. (2008) and used with permission from Oxford University Press
critically, the finding of diminished recall for Trial 1 was observed in well-motivated (i.e., as assessed by effort measures), nonlitigating, nondepressed, and gainfully employed individuals many years after sustaining a mild TBI (p. 514), and that patients with mTBI demonstrated, diminished verbal learning that is not often interpreted in standard neuropsychological assessment. (p. 506). Traditional neuropsychological methods did not distinguish the groups. Psychogenic interpretations of mTBI effects have been dependent upon the absence of neurogenic explanations. However, there has been no systematic assessment that has pitted the so-called psychogenic versus neurogenic where advanced neuroimaging has been used. Had not advanced neuroimaging techniques been used, the interpretations of the memory problems in the mTBI patients described in the studies by Niogi et al. (2008), Geary et al. (2010, 2011) and Little et al. (2010), could have been given a psychogenic description. Without definitive biomarkers of brain injury in mTBI, one should be skeptical of its proof and influence on cognition and behavior (see M. P. Alexander 1998). However, skepticism over mTBI sequelae should form the foundation for critical, hypothesis driven research using the best in technology, not just the rejection of the existence of the problem, especially when the issues of underlying neuropathology have not been determined.
False Distinction of Mild Complicated Traumatic Brain Injury or mcTBI Since its introduction as a clinical neuroimaging method, MRI has proven to be superior in detecting abnormalities associated with any type of TBI (H. S. Levin et al. 1987). However, routine DOI clinical neuroimaging is almost exclusively done with CT because the procedure is quick, clinically sensitive to neurosurgically important abnormalities, readily detects skull fracture and can be done on patients with life support equipment or metallic fragments in the head or body (Hunter et al. 2012). Likewise, interpretation is typically based solely on clinical judgment of the radiologist, with no quantitative measures applied. As might be expected, presence of DOI CT abnormality in mTBI has been associated with increased levels of neurobehavioral and neurocognitive sequelae (de Guise et al. 2010; Kashluba et al. 2008; Mounce et al. 2012; Iverson et al. 2000), although this is not always observed in mTBI samples (Lange et al. 2012; Deepika et al. 2012). Because of the objectivity of DOI CT abnormalities indicating presence of parenchymal injury, as noted before, this classification became known as mild complicated TBI or mcTBI. This specific classification clearly identifies those mTBI patients with a definitive traumatic abnormality on the DOI CT scan, but the problem with this distinction is that because it is
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only CT based, it substantially underestimates the true presence and type of TBI abnormalities. Figure 9 is from a recent study by Yuh et al. (2012) that depicts the results from a prospective, multi-center study of mTBI that included 135 patients who received early CT imaging and MRI within 39 days post-injury. Clinically, CT identified lesions in the form of contusion, hemorrhage, or edema were found in approximately 25 % (numbers consistent with other studies as reviewed by Yuh et al. 2012) but note, over 40 % were identified with MRI. As reported by these investigators, CT was especially poor at identifying axonal injury. As important as Yuh et al. (2012) study is in demonstrating how frequently neuroimaging abnormalities are found in mTBI, a particular limitation of this investigation is that it used conventional MRI and only examined T1, T2, T2*GRE and FLAIR sequences and clinical readings. The SWI sequence is superior to standard GRE sequences in detecting hemosiderin, where comparative studies show a two-tothreefold increase in detection of abnormalities with SWI over standard GRE (Benson et al. 2012). Yuh et al. did not include quantitative analyses at different post-injury time-points, which show a high yield in detecting differences in mTBI beyond just clinical findings (see Toth et al. 2013). Notably, none of the mTBI patients in the Toth et al. study had abnormalities on DOI scanning, and clinical interpretation of the MRI findings was likewise negative. Only when the neuroimaging data were subjected to quantitative analyses, were differences detected. It should be noted that Toth et al. at 1 month post-injury, in their longitudinal, within subjects design, showed a mean 1 % volume reduction in overall brain
Fig. 9 Incidence of computed tomography (CT) vs. magnetic resonance imaging (MRI) traumatic brain injury common data element (TBI-CDE) abnormalities in 135 study participants with mTBI. For MRI evidence of contusion and MRI evidence of hemorrhagic axonal injury, progressively darker shades of red indicate larger numbers of lesions (gray legend). Study participants with CT evidence of brain contusion had, in most cases, evidence of one or two hemorrhagic contusions, with no CT demonstrating more than 3 convincing brain contusions. CT showed evidence of hemorrhagic axonal injury in 3 of 135 study participants, all with 1 to 3 foci of injury. Permission to be reproduced from Yuh et al. (2012) and Wiley
volume and a 3.4 % increase in ventricular volume in individuals with mTBI. Both changes were statistically significant (p <.05). In the acute phase, quantitative metrics using DTI, like FA may identify differences from controls in more than 90 % of mTBI subjects (Wilde et al. 2008). Likewise, several mTBI studies have shown that DTI findings over 3 months post-injury assist in identifying those with persistent neurobehavioral and neurocognitive sequelae and, in turn, relate to those who remain symptomatic (see Ling et al. 2012; Mayer et al. 2012a, 2011, 2012b; Messe et al. 2011, 2012). When DOI CT is compared with conventional MRI, as shown in the studies reported above it may detect only half or fewer of the abnormalities visibly present with MRI. Further, with the greater sensitivity of SWI and DTI in detecting abnormalities, conservatively within any mTBI sample with reportedly normal CT, somewhere from one-quarter to a third of those will have abnormalities detected with MRI. An example of a normal DOI CT but abnormal MRI appears in Fig. 5, demonstrating the importance of follow-up neuroimaging in mTBI even in the absence of any CT findings on the DOI scan. This young adult university student was struck by a car and thrown into the curb. Positive LOC of short duration was independently verified by an observer at the scene. Emergency department (ED) assessment indicated a GCS of 13 but a negative CT. She was discharged from the hospital the following day; however, upon returning to her graduate studies she complained of substantial problems with attention and memory. Follow-up MRI demonstrated multiple regions of hemosiderin deposition within the frontal white matter. Furthermore, these abnormalities remained essentially unchanged over the next 5 years, demonstrating their permanency. All past markers of mTBI such as LOC, DOI CT findings, PTA, GCS, and PCS symptoms have limitations, with LOC, PTA and GCS only reflecting indirect measures of possible neuropathology. Even clinical categorical ratings that are determined to reveal no abnormalities on conventional clinical MRI cannot detect what quantitative analyses can (Toth et al. 2013). As such, only a confusing picture of mTBI outcome would come from incomplete or ineffective markers like GCS, or positive CT assessed in the ED used to define the event that represents mTBI; such is the state of neuropsychological investigations of mTBI. A host of psychological variables may be at play as sequelae to mTBI (McNally et al. 2013). Before psychogenic theories are invoked to explain the effects of mTBI, objective and controlled investigation of potential structural and functional neuropathologies predictive of outcome is essential (Blaine et al. 2013). An example of the potential misapplication of psychogenic interpretations for poorly identified illness comes from military service men and women who served in the Gulf War in the early 1990s and developed Gulf War Illness (GWI). When
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first reported GWI was widely touted as a classic psychogenic illness within the somatoform category of disorders (Gronseth 2005); however, neuroimaging studies using techniques like DTI have shown WM pathology in some individuals with GWI that relate to subjective symptoms like fatigue and pain (Rayhan et al. 2013). Such findings call into question umbrella-type psychogenic classifications until potential neuropathological explanations are ruled out.
Limitations in Detecting Neuropsychological Impairment in TBI The most common problems from TBI are residual deficits in cognitive speed, visuoconstruction, attention, and memory abilities (Millis et al. 2001). The study by Bendlin et al. (2008) provides an ideal example in the demonstration of residual neuropsychological effects of TBI combined with the most common areas of damage, in particular WM changes based on DTI metrics (see Fig. 10). Note how the abnormalities depicted in Fig. 10 overlap with predicted areas of damage as shown in Figs. 1 and 7. Inclusion criteria in this investigation involved documented positive loss of consciousness, positive DOI CT scan and a GCS of at least 13 with initial MRI obtained around 2 months post-injury, with follow up around 1 year post-injury. Thus, the Bendlin et al. research included mcTBI participants, although the overall sample would be characterized as a moderate-to-severe TBI group. The control sample consisted of age and education matched participants without injury. Figure 11 summarizes the neuropsychological findings. Neuropsychological results are presented in z -score format with the 0.0 horizontal line indicating the control reference zscore. Clearly notable is the distinct influence that sub-acute brain injury has on speed of processing when first assessed but by 1 year post-injury, improved functioning occurs across the
board, including processing speed with all domains functioning approximately 0.5 to 1.0 SD below control levels. Figure 10 indicates that the brain was damaged as this TBI cohort exhibited degenerative changes from the sub-acute time of initial testing (2 months post-injury) to follow-up (1 year). It is instructive to note that the greatest neuropathological changes occurred in WM, in the areas predicted by DAI/TAI studies (see Figs. 1, 2, 3 and 7: note the overlap with areas acutely and chronically seen with just mTBI) and that WM damage related most to the cognitive deficits (see also Farbota et al. 2012b from this same group; and Farbota et al. 2012a). Concomitant with the neurodegenerative changes resulting in both gray matter (GM) and WM atrophy (defined as volume loss), all domains of cognitive functioning exhibited improvements over time. However, despite improvements in cognitive functioning with time in a mostly moderate-to-severe TBI sample, as a group no cognitive function returned to presumed baseline as reflected by the control 0.0 z -score. From a psychometric standpoint the extent of cognitive impairment during the chronic phase seems to hover at around 0.5 of a standard deviation difference. Translating this to effect size differences, in TBI, including mcTBI with known gross neuropathological changes, neurocognitive function in most domains would reflect on average medium effect size differences in comparison to a non-brain injured control sample. If only medium effect size differences occur in mostly moderateto-severe TBI with quantifiable brain volume loss from the brain injury, what does this mean for those who sustain mTBI, where pathology may be much more subtle? Does this not mean that in using traditional neuropsychological measures that the expected effect-size differences would be small or minimal, if present at all (see discussion by Bigler et al. 2013c)? In some studies involving moderate TBI, neuropsychological test findings cannot be differentiated from controls or those with mTBI, even in those with positive neuroimaging
Fig. 10 Neuroimaging findings depicting the extent of gray matter (GM) and white matter (WM) damage in the Bendlin et al. (2008) study, showing changes (volume loss) from 2-months post-injury to 12 months. The TBI group showed extensive WM volume decline over time (shown in hot colors ), in addition to a few regions of GM volume decline, including the thalamus and bilateral pallidum (shown in winter colors ).
Patients also showed GM volume decline over time in the cingulum, right post-central gyrus, supplementary motor area, right precentral gyrus, and bilateral putamen (areas not shown here). Results are shown in neurological orientation (left is left). Color bars reflect t -statistics. Permission to reproduce from Elsevier and the authors
186 Fig. 11 Summary neuropsychological results from Bendlin et al. (2008) organized by general domain of cognitive function. Note : COWAT= Controlled Oral Word Association Test; Trails A=Trail Making Test, Part A, Trails B= Trail Making Test, Part B; LN Sequence=Letter Number Sequence; CVLT=California Verbal Learning Test, Tot=total, SD=short delay, LD=long delay; BVMT=Brief Visuospatial Memory Test. Control performance was standardized with the z -score statistic, showing that the initial assessment at approximately 2-months postinjury reflects the most significant deficits, which by a year postinjury while improved, still is below the control reference level. Modified from Bendlin et al. 2008, courtesy of Drs. Bendlin and Johnson
imaging findings (Lange et al. 2012). Does this not mean that the neuropsychological technique being used to assess cognition in mTBI needs to be critiqued? As noted, the CVLT memory task was sensitive to differences on Trial 1, but on average this amounted to less than one fewer word retained in the mTBI group on the 16-item word list [Little et al. (2010) and Geary et al. (2010)]. Heitger et al. (2009) found a significantly lower retention of the distractor list on the Rey Auditory Verbal Learning Test (RAVLT; Rey 1958) in a group of symptomatic mTBI patients but in real terms this amounted, on average, to less than one word recalled by the PCS symptomatic mTBI group compared with the symptomatic (again, effort and depression were controlled for). Ponsford et al. (2011) examined memory performance at 1 week and 3 months post-mTBI using the ImPACT computerized assessment method (Iverson et al. 2003) and observed a significant difference at 3 months on a visual composite memory measure; however, the reported effect size difference was small at 0.25. Again, from a clinical perspective these are negligible to minimal differences for the clinical neuropsychologist to detect with traditional neuropsychological measures in the individual with mTBI. Therefore, not only will the neuropathological substrate of mTBI be subtle for neuroimaging techniques to detect, but the neuropsychological effects will also be as equally subtle if traditional methods are used. Figure 12 graphically shows this problem in an mTBI case of a 17.5 year-old mTBI patient by plotting out CVLT-II performance over trials. This individual had initial negative
CT but positive follow-up MRI with multiple hemosiderin deposits noted particularly in the frontal area (this case is discussed in Bigler 2004). The patient complained of memory problems but as graphically depicted in Fig. 12, only on Trial 2 of the CVLT-II does this patient perform outside the range of the normative sample, and on that trial only deviates less than one word. Without the positive neuroimaging reflecting abnormalities within known memory/attentional networks, such findings from traditional neuropsychological test results may simply be overlooked. The memory problems associated with mTBI may simply not be assessed by these traditional neuropsychological measures or they may simply be silent anomalies.
Between Subject Heterogeneity of mTBI Neuropathology: If No Two TBIs are Ever Identical, How can a Uniform Neuropsychological Outcome be Expected? Given the uniqueness of individual brains, combined with the unique circumstances and biomechanics of any brain injury (Watanabe et al. 2012)especially the random nature of injuriesit is unlikely that two brain injuries could ever be identical (Rosenbaum and Lipton 2012). Even with the detailed controls and experimental rigor of animal TBI models, Turtzo et al. (2012) showed using an identical rat strain mechanically injured in exactly the same fashion with a controlled cortical impact methodidentifiable pathology was
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Fig. 12 Performance on the California Verbal Learning Test (CVLT) in an mTBI patient with negative day-of-injury (DOI) computed tomography (CT) but positive magnetic resonance imaging (MRI) with multiple hemosiderin deposits within the frontal and temporal lobes. Patient CVLT-II performance (black diamond ) is plotted in comparison to CVLT-II normative data (gray bars ) from the test manual. Note that the patients performance, while on the low end of the normative distribution in each trial, only drops below 1 standard deviation (s.d.) of the comparison sample on Trial 2 in List A Immediate. This case is adapted from Bigler (2004)
have mcTBI-related focal pathology, but the marked differences in the distribution of macroscopically identified lesions are evident. Simple overview of this illustration and the nonoverlapping nature of the lesions would implicate nonoverlapping neuropathological influences likely resulting in different neurobehavioral consequences because different neural pathways and networks were damaged in these mcTBI patients. Based on DTI-derived atlases (see Catani et al. 2012), lesions from any MRI sequence or CT scan can be overlaid, where various inferences can be made about specific pathways and neural systems that may be disrupted or affected as shown in Fig. 14. Taking two of the cases from Fig. 13 and applying the Catani and Thiebaut de Schotten (2012) atlas, the identifiable lesions disrupt different pathways. Without using quantitative neuroimaging methods to identify abnormalities and aggregate mTBI subjects into similar groups, why would there be any neuropsychological expectation that similar deficits in cognitive and neurobehavioral functioning would emerge simply by having mTBI subjects within a group only defined by having sustained an mTBI? The lesions in Fig. 14a would affect the cingulum bundle and the uncinate, along with occipitofrontal fasciculi and interhemispheric pathways across the genu; whereas in case Fig. 14b, the coup -contre coup lesions would have likely influenced both the superior and inferior occipitofrontal fasciculi. Locus of such pathology undoubtedly will differentially affect cognition. Different lesion patterns with each mTBI case would likely influence neuropsychological outcome in unique ways. Mixture of lesions and outcomes has the potential to washout effects that otherwise are present within mTBI subgroups. Returning to the Niogi et al. (2008; see Fig. 8) investigation, it is only when memory is considered within the context of the UF integrity, that mTBI related memory impairments become apparent, and then only within a subset of those with a history of mTBI.
never identical. Similarly, Sullivan et al. (2013) in a porcine model demonstrated that sagittal rotations were most likely to injure axons, sparing those in other planes. With human FE modeling using individual MRI configured brain anatomy, no two injuries could be identically simulated (see Bayly et al. 2012). The mcTBI component of the study by Bigler et al. (2013a) found no case where any of the lesions (areas of focal encephalomalacia, hemosiderin deposit, or WM signal abnormality) perfectly overlapped. The major inference of this is reflected in Fig. 13 from four mTBI cases from this study, three with a GCS of 15 and one a GCS score of 14. These cases were selected for this illustration as they unequivocally
The Concept of Mild Cognitive Impairment and Neuropsychology In terms of injury classification of TBI, mild, moderate and severe categorization has been the standard since the origination of the GCS metric in 1974. There is no dispute concussion is a TBI and, provided that no disruption or change in level of consciousness moves the GCS measure below a 13, that this level of TBI constitutes the mildest of injuries. If level of injury is effectively described as ranging from mild to severe and if all TBI is on a continuum, as argued in this review, why would the potential for residual cognitive effects stop at the moderate range of TBI? As already stated, animal models of TBI may be graded from no discernible
188 Fig. 13 Four cases of pediatric mild TBI (mTBI) showing different locations of focal lesions selected from the study by Bigler et al. (2013a, b, c). All had mTBI and only the participant in the lower right (d ) had a Glasgow Coma Scale (GCS) of 14 with the rest having GCS scores of 15. Note the complete lack of overlap of any focal lesion. The children in C and D are highlighted in Fig. 14 to show how different pathways are affected. a , c and d are T2-weighted images and show areas of old focal surface contusions with increased CSF signal and B is a fluid attenuated inversion recovery (FLAIR) sequence where the red arrow points to a white matter (WM) hyperintensity
pathophysiological or neurobehavioral effects, to showing increasingly impaired cognitive performance with underlying injury severity and neuropathology. With neuroimaging and electrophysiological studies consistently showing WM pathology and abnormalities in connectivity in mTBI (Morey et al. 2012; Tallus et al. 2013; Smits et al. 2011; Kirov et al. 2013; Messe et al. 2013), combined with animal models and human studies from multiple concussions showing histologically confirmed brain pathology (McKee et al. 2010, 2012; Wall et al. 2006), why would it not be expected that such pathology adversely affects cognition and behavior? Historically, psychological theory of cognitive impairment, regardless of etiology, consistently has been reported in terms of mild, moderate-to-severe impairments in comparison to some normative sample (Bornstein et al. 1987). This has been established for all disorders, be it stroke, degenerative disease, demyelinating disorders, epilepsy, etc., in order to characterize neurocognitive effects of the disorder (Beghi et al. 2006; Grau-Olivares and Arboix 2009; Snyder et al. 2011; Waldstein and Wendell 2010). The argument of this review is that mild neurocognitive and neurobehavioral sequelae do occur with mTBI and should be characterized as such. And further, although a rather benign clinical course of full return of function in mTBI is the norm, neuroimaging methods that
provide objective indicators of underlying neuropathology should assist in better characterization of the neurocognitive and neurobehavioral outcomes of mTBI. Subjective Symptoms and the Term Mild Maybe the biggest obstacle with the mild classification within the field of neuropsychology comes with the subjectivity and nondescript nature of so many of mTBI symptoms. Much has been written about subjective symptoms in mTBI because of their co-occurrence with so many other neurological and neuropsychiatric conditions (Chaput et al. 2009; Iverson et al. 2010; Jakola et al. 2007; Kennedy et al. 2007; Macleod 2010). This, coupled with issues related to research design of mTBI studies, led the 2004 World Health Organization (WHO) to label much of the research in mTBI problematic (see Carroll et al. 2004a). Without a definitive biomarker that differentiates etiology of symptoms from other disorders, it should be no surprise that studies that examine group outcome in mTBI, mostly endorse biopsychosocial models, some of which minimize or do not discuss any underlying neuropathology (see discussions by Silver 2012; Silver et al. 2009; van Veldhoven et al. 2011; Williams et al. 2010). On the other hand, expression of a subset of symptoms associated with mTBI may be psychogenic (Mounce et al.
Neuropsychol Rev (2013) 23:169209 Fig. 14 a Sagittal views of the pathology demonstrated in subject 13-D is compared to the Catani and Thiebaut de Schotten (2012) atlas. Note that from this atlas, pathways involving the anterior cingulum bundle along with projecting interhemispheric pathways from the genu of the corpus callosum would be affected by this lesion distribution. [Outline Notes : Red =corpus callosum, Mauve= overlap of cingulum with corpus callosum tracts, Blue=uncinate fasciculus] b Axial views of the pathology demonstrated in subject 13-B. Note that this is the T2-weighted image in the upper left which clearly shows the WM hyperintensity as was visualized in the fluid attenuated inversion recovery (FLAIR) image in Fig. 13. The bottom left image is a gradient recalled echo (GRE) sequence and shows distinct presence of hemosiderin. Note these pathologies would influence the inferior fronto-occipital fasciculus (Green Outline ) and superior longitudinal fasciculus (Green ). Different lesions affect different pathways and networks
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2012; Macleod 2010); however, a search for underlying neuropathology should be undertaken before the psychogenic label is considered. While subjective symptoms may be the bane of neuropsychology in terms of understanding mTBI (McLean et al. 2009), understanding the nature of subjective symptoms have played a key element of what occurs during the prodrome of
neurodegenerative disease. For example, when turning to the literature on aging and dementia, neuroticism was once considered simply a trait not linked in any way with dementia. However, life stressors as well as early-in-life neuroticism and depression have a relationship with the development of dementia, potentially via stress-mediated neuroinflammation factors (Wilson et al. 2007).
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Similarly, ill-defined prodromal cognitive complaints in older individuals with subjective memory symptoms do relate to who develops mild cognitive impairment (MCI) and converts to Alzheimers disease (Jessen et al. 2010; Reisberg et al. 2010). Subjective symptoms also appear to be harbingers of progressive change in other conditions, for example, multiple sclerosis (Marrie et al. 2005), Lupus erythematosus (Denburg et al. 2003), Parkinsons disease (Bugalho and Oliveira-Maia 2012; Skogar et al. 2012). Most relevant to mTBI is that recently Lafrance and colleagues (2013) found that history of TBI was a significant risk factor in development of psychogenic nonepileptic seizures. It seems intuitive for all neurological and neuropsychiatric disorders that factors heralding vulnerabilities for developing depression and anxiety-based disorders provide a backdrop reflecting a different brain at the time of sustaining an mTBI than the brain without such vulnerabilities. Likewise, any of these pre-existing vulnerabilities probably diminishes the resources and resiliencies postinjury in coping with the effects of mTBI. In the case of psychogenic epilepsy, some diminished capacity for emotional coping because of the brain injury may be the path for increased maladaptive emotional adjustment post-injury, resulting in the phenomena of pseudoseizures as found in the Lafrance et al. (2013) study. Of course, all of the disorders just mentioned (i.e., epilepsy) have their own definitive biomarkers, which then assist in ferreting out how subjective symptoms/complaints may relate to the disorder. Without biomarkers for mTBI as offered by advanced neuroimaging methods, the problems circle back to the imprecision of measuring subjective complaints and no method to tie them to what may be bona fide neuropathology or absence thereof. Subjective symptoms will remain nondescript and likely not be helpful in discriminating mTBI patients from other conditions nor useful in predicting who achieves good versus poor recovery. Well-designed neuroimaging studies or studies based on other validated biomarkers are needed to address this issue systematically (Zetterberg et al. 2013). For example, Chen et al. (2007) demonstrated a relationship between persisting symptoms and PCS following mTBI and different fMRI activation patterns in prefrontal regions in mTBI subjects. Bigler and Bazarian (2010) argue that studying persisting symptoms combined with neuroimaging biomarkers must be the next line of research examining the effects of mTBI, including emotional outcome and occurrence of non-specific symptoms. The Problem of Measuring What may be Mild in Neuropsychological Outcome Using traditional neuropsychological measures, one of the biggest challenges in clinical neuropsychology may be determining what the mild neurocognitive effects of any disorder are, including mTBI. This problem was introduced in the discussions involving Figs. 2, 5, 8, and 11. In a stroke study that has in its title the detection of subtle
memory impairment and attentional deficits., Duffin et al. (2012) show on average, that stroke patients thought to have suffered a mild [italics added] cerebrovascular accident, exhibited significantly reduced retention on the RAVLT of approximately one word. Note this is the same level of reduced performance that Geary et al. (2010, 2011), Little et al. (2010), and Heitger et al. (2009) found in mTBI on list retention tasks like the RAVL or CVLT. Although significant, a one or two word less retention on a 15-item word list can only be viewed as a subtle, slight difference. Returning to the Bendlin et al. (2008) study, it shows that effect size differences overall on cognitive performance >12 months post-TBI in mostly moderate-to-severe TBI patients with neuroimaging documented atrophy is only about 0.5. This translates to an expected difference per trial on measures like the CVLT or RAVLT of approximately one less word recalled. If those with well documented structural damage exhibit this kind of subtleness to their cognitive profile on traditional neuropsychological tests, what kind of impairment would be detected in the mTBI patient with mild cognitive problems? An even more important issue is alluded to by Millis (2009) with the following statement: cognitive tests do not directly measure cognition: they measure behavior from which we make inferences about cognition (p.2410). Neuropsychological measures of cognition only permit inferences to be made about brain function (see Lezak et al. 2012). This becomes an even more important issue when attempting to detect subtle deficits, given the controlled assessment environment that does not mimic a naturalistic setting. The majority of clinically administered neuropsychological tests that are performed use highly regimented standardized presentations of auditory and visual stimuli, with hand-recording of responses and their tabulation for scoring and interpreting all done within a rigid administration of items, with no extraneous stimuli or sound. Likewise, potential differences are as good as are the comparative norms and normative samples. This problem is distinctly demonstrated in the mTBI case presented in Fig. 5. The college student previously depicted in Fig. 5 had participated in a variety of routine working memory tasks as a volunteer participant for fMRI cognitive neuroscience research projects before she was injured. Therefore, pre-injury data were available on not only her cognitive performance but her fMRI activation patterns in response to the cognitive probes (see Wu et al. 2010a; Allen et al. 2011). When reassessed more than a year post-injury and having completed her degree and with full-time employment, although still with lingering PCS, cognitively on the paper-and-pencil and computer based tasks she was able to perform at similar levels as pre-injury. However, using an event-related fMRI paradigm where performance (response latency) was assessed in milliseconds, reflective of true neural processing speed, her
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performance level was slower by about ~135 milliseconds. Accuracy had not changed at all, only slowed processing. Thus, traditional neuropsychological test findings were not tapping underlying neural deficits and what the patient was subjectively experiencing. She struggled with attentional processes, speed and working memory, and as can be viewed in Fig. 5 had distinct frontal pathology (hemosiderin and WMHs) within known networks associated with attention, speed of processing and working memory, confirming the likelihood that her mTBI related complaints were neurogenic.
Evolutionary Influences on Recovery from mTBI Survivability from a concussion is true across the animal kingdom. There are numerous animal models of mTBI (Biasca and Maxwell 2007; Cohen et al. 2007; Leker et al. 2002; Shaw 2002; Weber 2007), all demonstrating good recovery of basic functioning following mTBI in distinct contrast to moderate-to-severe TBI. In terms of the natural recovery of function, most extensively studied in the athlete, basic motor, sensory and cerebellar functions predictably are the first affected and likewise, the first to come back on-line. Evolutionarily, that makes sense because in the brutish fightflight world of our ancestors, if you were on the losing end of fisticuffs, one would need to sufficiently recover motor ability to flee (see Bigler 2012) or survival was unlikely (Masel and DeWitt 2010). Likewise, in earlier eras to remain part of a human clan, mobility was certainly a key factor as well. From a cognitive perspective, the concussed individual is capable of
performing basic mental tasks even in the earliest stages of recovery, just not as efficiently. But in earlier times from a survival perspective memory demands would likely have been much more naturalistic than what occurs with the modern challenges of todays technologically sophisticated world, and therefore, potentially not as noticeable. Anatomically, there is likely a straightforward explanation for differential evolutionary effects on motor over cognitive recovery. Figure 15 shows the mostly vertically organized motor and sensory tracts of the corticospinal and spinocortical systems and cerebellar tracts. Efferent and afferent pathways of these systems that pass through the upper brainstem (compare to Fig. 16) have a common location associated with the reticular activating system (RAS). One look at the narrow trajectory, see red arrows in Fig. 16, of these pathways through this upper midbrain region, see horizontal red lines in Fig. 16, shows the unique confluence of these tracts in relationship to the large and weighty cerebral hemispheres. Furthermore, the upper brainstem remains more rigid being held in position by the skull base than the cerebral hemispheres, and is tethered to the spinal cord that is tightly held within the spinal column. By definition, any effect at this upper brainstem level must be minimal in mTBI or otherwise the individual is left with longer duration coma and thus a lower GCS than the minimal post-resuscitation 13 score required for mTBI classification. Any prolonged disruption of the RAS would lead to longer duration coma and persistence of disorders of consciousness (Jellinger 2013). So, by definition these neural systems cannot be seriously damaged in order to survive the brain injury and remain classified as an mTBI.
Fig. 15 The corticospinal and spinocortical tracts are oriented vertically with afferent and efferent pathways coursing through the brainstem. In contrast the interhemispheric pathways of the corpus callosum and the intrahemispheric pathways of the inferior occipitofrontal fasciculus have
very different trajectories. Adapted with permission from Catani and Thiebaut de Schotten 2008 and Elsevier. See also Catani and Thiebaut de Schotten (2012).
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Fig. 16 The left cerebral hemisphere is shown in the upper left as a 3-D rendered view from T1-weighted magnetic resonance imaging (MRI). The upper middle panel shows the much smaller brainstem (outlined flesh-tone) with the ventricular system shown in aquamarine for orientation. Notice the smallness of the brainstem in relation to the cerebral hemisphere, as well as the central location of the brainstem in relation to the cerebral hemisphere. Mid-sagittal T1-weighted MRI is shown in the upper right panel. Particularly small is the midbrain region, outlined by the horizontal red lines in the upper right image. Lower left is a coronal
T1-weighted image that shows the small midbrain and brainstem in comparison to the large cerebral hemispheres, and then highlighted with the middle panel, with the arrows pointing to the region of the cerebral peduncle and where the corticospinal tracts pass. Lower right panel shows a lateral view of the corpus callosum superimposed on the 3-D brain from the upper left, showing the orientation of projecting fibers. Colors represent aggregate tract orientationblue=vertically oriented tracts, green= anteriorly-posteriorly orientated tracts and warm colors (orange -red )= side-to-side or laterally projecting tracts
However, as shown in Figs. 15 and 16 the long coursing WM inter- and intra-hemispheric pathways are oriented quite differently from the primary motor and somatosensory pathways and are, therefore (see Figs. 6 and 16 and compare the orientations of the fiber tracts that make up the corpus callosum and inferior occipito-frontal fasciculus), differentially influenced by shear-strain effects and interhemispheric connections. Pathology within these inter-and intra-hemispheric WM tracts would less likely influence motor function but differentially influence cognitive ability, in particular working memory, attention and speed of processing. Hence, in mTBI the injured individual returns to baseline motoric and sensory processing ability before cognitive functions return.
in unarmed combatants, presumed to be present as a reflection of concussion history, and when such findings are within the gray-white junction or adjacent to the corpus callosum, the
Within-Subject Heterogeneity of mTBI Lesions, Their Specificity and Neuropathology Given the prior discussion of inter-subject heterogeneity in mTBI combined with evolutionary adaptability of mTBI, what about within subject variability of lesions in mTBI? Figures 17 and 18 are from a single mTBI patient with WM hyperintensities (WMH). While WMH may be a normal variant and certainly not specific to TBI (see Hopkins et al. 2006; Iverson et al. 2011), in an otherwise healthy individual who experiences mTBI, their presence may reflect white matter damage (Benson et al. 2012; Shenton et al. 2012). WMH may also represent vulnerability indicators since they are associated with disorders like depression (Kempton et al. 2011), where pre-existing depression increases the likelihood of persisting symptoms following mTBI (Silver et al. 2009). Orrison et al. (2009) demonstrated WMH with increased rates
Fig. 17 [View this image in conjunction with Fig. 18]. The FLAIR image in the upper right shows a distinct white matter hyperintensity (WMHs, red arrow ) in the frontal white matter (WM). Plotting the location of all WMHs (as shown in yellow ) in the 3-D DTI surface rendered image of the brain (diffusion scan images are fuzzy, and that is why this image represents just a smooth surface outline of the brain), in the upper left shows the multiple distribution of WMHs. However, using tract-based spatial statistics (TBSS), differences in WM, compared to a normative sample, exhibit a somewhat different distribution of WM findings as shown in red in the 3-D view (ventricular system is shown in aquamarine for orientation purposes)
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Fig. 18 [View this image in conjunction with Fig. 17]. White matter hyperintensities (WMHs, yellow ) and tract-based spatial statistics (TBSS) white matter (WM) differences ( red ) in an mTBI subject are superimposed on tubular generated diffuse tensor imaging (DTI) tracts for ease in visualizing the tract, showing how depending on which tract is being examined, the WM finding occurs within different tracts. Note :
White=corpus callosum, Purple=arcuate fasciculus, Orange=uncinate fasciculus, Blue=corticospinal and spinocortical tracts, Dark Green= inferior occipito-frontal fasciculus, Light Green=occipito-temporal fasciculus, Lightest Green=Cingulum Bundle. Different techniques that highlight different types of WM findings depend on the imaging sequence and the method used to identify the difference
likelihood of these signal abnormalities reflecting brain pathology from trauma is increased (Bigler and Maxwell 2011). WMHs are best seen on the FLAIR sequence as shown in Fig. 17 (see also Figs. 5 and 13 and previous discussion of T2 and FLAIR identified WMH). Another method for assessing WM integrity based on DTI findings is a technique that uses what is referred to as tract based spatial statistics or TBSS (Grossman et al. 2012b). In comparison with a normative sample, location of statistically significant deviations in DTI metrics can be identified using TBSS, pathological differences that do not necessarily match where FLAIR-identified WMHs are located as shown in Figs. 17 and 18 (see also Dineen et al. 2009). This distinctly demonstrates that these two MRI-derived WM findings WMH and DTI tract abnormalitiesin this mTBI patient likely represent different aspects of WM anatomy. When WMH were simultaneously plotted in conjunction with TBSS derived differences and overlaid on various white matter fasciculi, the heterogeneity of how such findings may influence different neural substrates is immediately evident as shown in Fig. 18. Because abnormalities findings like WMH occur in the normal population, even in children (see Bigler et al. 2013a), their presence alone cannot be considered an unequivocal biomarker of injury. However, because TBI is likely to occur in an individual under 40 years of age, presence of WMH in younger individuals has a low base rate as do indicators for micro-bleeds (see Potchen et al. 2013), although the likelihood of these findings becomes much more frequent after age
60 (Pettersen et al. 2008). For example, in a sample of orthopedically injured children with no brain insult, had no evidence of hemosiderin although two had WMH (Bigler et al. 2013a). Whether these WMH were trauma-related in any way is unknown, but likely were just normal variants or incidental findings (Katzman et al. 1999; Vernooij et al. 2007) that predated the mTBI. If between -subject heterogeneity reflects the unique differences between subjects in terms of injury biomechanics and dynamics (along with genetic, pre-injury, and complex-postinjury factors), then the within -subject heterogeneity of how and where lesions may influence neural systems, is just as complex. What becomes evident when these lesions are plotted is not just whether a lesion is present, but whether the lesion significantly disrupts a network.
mTBI, Networks, and Resiliency Consistently, the neurocognitive effects of TBI have been shown to result in slower speed of processing and disruptions in the central EF working memory system (Ciaramelli et al. 2006; Willmott et al. 2009). While a full discussion of attentional and working memory networks is beyond the scope of this review, what has been referred to as the default mode network (DMN) has become fundamental in understanding the effects of TBI on memory, attention, and processing speed (see Arenivas et al. 2012; Bonnelle et al. 2012; Palacios et al.
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2012; Zhou et al. 2012). Of particular relevance to mTBI, the DMN, in part, relies on patent and efficient pathways between parietal and frontal cortices during engagement involving attentional tasks. These are some of the longest intrahemispheric pathways, but also require interhemispheric integration via the corpus callosum. This means that as a consequence of deformation/shear/strain influences that occur during TBI, the DMN is especially vulnerable to injury, even at the level of an mTBI. Andrews-Hanna et al. (2010) derived a simplified network involving aspects of the DMN as shown in Fig. 19. What is critical about this figure is the interrelationship between key brain structures involving medial temporal lobe memory regions (hippocampus), with intra- and interhemispheric pathways linking the entirety of the memory network including the fornix and cingulum bundle. All of these brain regions in the DMN are particularly vulnerable to the biomechanical and neuropathological effects of TBI (Bigler 2007). In association with the DMN, as partly shown in Fig. 19, are key connections, like the cingulum bundle (Wu et al. 2010b), which receives input from the hippocampus via the mammillary bodies and anterior thalamus. Figure 20, from Bonnelle et al. (2011) shows that in TBI lower FA, likely reflecting abnormal WM integrity of the cingulum bundle, was associated with slower reaction time. In addition to the study by Bonnelle et al., others investigations that included mTBI subjects, some of which exclusively examined only
mTBI subjects, have demonstrated that disruptions in the DMN relates to neurocognitive sequelae in TBI (Zhang et al. 2012; Johnson et al. 2012a; Sharp et al. 2011; Caeyenberghs et al. 2012; Mayer et al. 2012a). From a cognitive symptom perspective, attention deficits along with disrupted emotional regulation are commonplace in mTBI. As shown in the above mentioned studies WM pathology within the DMN related to TBI, especially that which influences both cortical-cortical and corticolimbic connections may play a central role in the evolution of symptoms of memory and emotional dysfunction following mTBI. The Human Connectome work of Van den Heuvel and Sporns (2011) has emphasized critical hubs and nodes in what they refer to as rich-club connections within major networks. If damage does not involve a major hub or node, then the brain probably has greater resiliency in re networking around the lesion. However, returning to Fig. 19 from Andrews-Hanna et al., if the anterior medial prefrontal cortex is damaged, such damage takes out eight critical links within the network. As Moretti et al. (2012) have shown, disruptions of a hub have farreaching ipsilateral as well as contralateral adverse influences. Damage in mTBI outside the rich-club network may have minimal to no effect and permit the brain to re-wire. However, any type of lesion disrupting a socalled rich-club network could have widespread influence, even though the lesion itself is small and localized.
Fig. 19 a and b As demonstrated in the study by Andrews-Hanna et al. (2010), the functional connectivity of the default mode network comprises a midline core and two distinct subsystems, as shown in d (dorsal medial and medial temporal). c Depicts the functional correlation strengths between 11 regions and all color codes reflect in bolder lines the systems with stronger relationships. Note : aMPFC= anterior medial prefrontal cortex, PCC=posterior cingulate cortex, dMPFC=dorsal medial prefrontal cortex, TPJ=temporoparietal junction, LTC=lateral temporal cortex, TempP=temporal pole, vMPFC=ventral MPFC, pIPL= posterior inferior parietal lobule, Rsp=retrosplenial cortex, PHC= parahippocampal cortex, HF+= hippocampal formation. Reproduced with permission from Elsevier
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Fig. 20 Sustained attention as measured by reaction time was found to be correlated with cingulum bundle structure in TBI as shown by Bonnelle et al. (2011). Notice how this system involves the default mode network and extensive connectiveness of what was previously shown in Fig. 19. a Sagittal view (x =8) of the reference component selected for the functional connectivity analysis. Anterior and posterior midline nodes of the default mode network (DMN) are shown in warm colors, and the midline node within the executive network (EN) is shown in blue. The right
cingulum bundle connecting the posterior and anterior parts of the DMN is shown in green. b Fractional anisotropy (FA) of the cingulum bundle in patients is plotted against the change in reaction time (RT) between the first and the last part of the task (N =28). Measures are age normalized, i.e., age was regressed out from the measures using a linear regression, where residuals were saved as standardized values. Reproduced with permission from the Society for Neuroscience
Are Traditional Neuropsychological Metrics Used in mTBI Assessment Insensitive to the Cognitive and Neurobehavioral Effects of the Injury? With the emergence of clinical neuropsychology in the late 1960s, early 1970s neuropsychological methods were considered the gold standard for diagnosing mTBI (see Boll and Barth 1983; Barth et al. 1983). The premise was that the neurocognitive effects of mTBI were detected when neuropsychological test performance deviated below some assumed baseline or established norm. However, once factors such as age, education, time post-injury plus pre-injury psychosocial variables, post-injury variables such as pain, sleep disorder, fatigue and emotional functioning were all considered, the complexity of the problem of mTBI assessment with only neuropsychological tests became evident (Silver 2012; Silver et al. 2009). Within-subject designed sports concussion studies that obtained pre-injury measures and then assessed neuropsychological status post-injury, convincingly demonstrated that some traditional neuropsychological methods were sensitive in detecting acute effects of mTBI. However, over time these standard neuropsychological measures could show a return to baseline, all-the-while electrophysiological and neuroimaging findings may not, and subjectively, mTBI patients continue to report PCS (Prichep et al. 2012; Gardner et al. 2012; Henry et al. 2011; Talavage et al. 2013; Slobounov et al. 2011a, b). At 4 months post-injury using DTI, neuroimaging abnormalities have been detected in mTBI, yet minimal-to-no neuropsychological differences were found on standard clinical measures (Ling et al. 2012). The question reverts to whether
this is an absence of any residual neuropsychological effect, even though structural pathology may be present, or is it the lack of sensitivity of the test attempting to define a neurocognitive correlate? All of this implicates an insensitivity of traditional neuropsychological methods in detecting subtle abnormal neurological states that may exist in mTBI. Levin et al. (2012) showed in a study that obtained initial post-injury mTBI MRI findings within 24 to 96 h, then at 1 week, 1 month and 3 months that traditional speed of processing measures like the Symbol Digit Modalities Test (SDMT; Smith 1992) did not distinguish lasting sequelae, only computerized reaction time (RT), or Codesub Reaction Time, the speed of processing task from the Automated Neuropsychological Assessment Metrics (ANAM, Reeves et al. 2002) remained significantly different after 3 months. Traditional neuropsychological administration of the SDMT is paper-and-pencil with time measured in seconds. Codesub RT is measured in milliseconds (msecs; Cernich et al. 2007). Millisecond processing speed is more representative of real-time neural processing (Momjian et al. 2003) and potentially the type of task that best distinguishes between those with mTBI and controls (Hartikainen et al. 2010). In typical, developed, non-injured control subjects cognitive tasks that pit speed versus accuracy show match versus mismatch performance to differ between the 100200 msec range (Ho et al. 2012). All timed traditional neuropsychological measures assess speed with a manually controlled stopwatch. Stopwatch accuracy either between trials or between raters for an identical event is about 100 msec (Vicente-Rodriguez et al. 2011). Measuring in seconds rather than msecs and the error
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introduced by turning on and off a hand initiated timer would obscure any subtle differences in true neural processing speed potentially induced by mTBI. Combining this error variance with only small-to-medium and often non-significant differences in traditional neuropsychological test performance, even in moderate-to-severe TBI as demonstrated by Bendlin et al. (2008), suggests that traditional neuropsychological assessment methods will be even less sensitive in detecting what may be genuine cognitive, yet subtle differences in those with mTBI. Brenner et al. (2010) examined 45 soldiers with well documented history of presumed blast-related mTBI divided into two groupsone that became asymptomatic and the other remained symptomatic, yet neuropsychological measures could not differentiate the groups. Brenner et al. offer the following conclusion, standard neuropsychological assessment may not increase understanding about impairment associated with mTBI symptoms (p. 160). The longitudinal study by Heitger et al. (2009) conducted in New Zealand, has been referred to several times in this review because of the quality of the experimental design. It demonstrated the exact same findings as Brenner et al., matching two groups on injury severity and all aspects of injury demographics where, at 6 months and beyond, one group had recovered and was asymptomatic, but the other group remained symptomatic. In the symptomatic group, neuropsychological testing identified deficits in only 5 of the 36 subjects despite all being symptomatic from a PCS standpoint. Heitger and colleagues concluded, This limited ability of neuropsychological testing to document ongoing impairment in brain function in mCHI [mild closed head injury; their term rather than mTBI, as used in this review] was also reflected in our results (p. 2865). Abnormalities in eye-movement in the form of slower eyetracking did demonstrate consistent differences in the symptomatic mTBI group, reliably differentiating symptomatic from non-symptomatic mTBI subjects. Such findings raise important questions about locus of abnormality and whether traditional neuropsychological measures are designed to detect such subtle abnormalities (Grindel 2006). For example, in the Heitger et al. (2009) study the deficits in eye-tracking in the symptomatic mTBI group were considered to be of upper brainstem origin. There are no traditional neuropsychological tests that directly assess eyemovements or upper brainstem function. Of course, the upper brainstem is contiguous with the ventral diencephalon and likewise, in addition to the ascending RAS that interfaces the brainstem with the thalamus, there is the diffuse thalamic projection system; all of which are important in arousal, attention, and habituation, and potentially injured in TBI (Lifshitz and Lisembee 2012). Neuropsychological measures may detect impairments in attention/concentration and working memory, but such techniques have no ability to localize
the origin of the deficit. Fortunately, using neuroimaging as a biomarker of thalamic integrity, there are now several studies of mTBI patients showing abnormal connectivity and resting state activity within the thalamus that relate to cognitive impairment (Grossman et al. 2012b; Nathan et al. 2012; Yang et al. 2012; Raz et al. 2011; L. Tang et al. 2011; Grossman et al. 2012a; Gosselin et al. 2011; Little et al. 2010). Because of the central role played by the thalamus any small perturbation at this brain level could have potential widespread cortical effects (Izhikevich and Edelman 2008). Nonetheless, without neuroimaging or some electrophysiological measure of upper brainstem and/or thalamic integrity, neuropsychological techniques are limited in distinguishing deficits associated with the type of pathology that might be present in these areas without independent confirmation via neuroimaging. So, what can it mean in an mTBI patient if neural processing is disrupted by 50 to 100 msec when engaging attentional networks, such as the DMN? Mayer et al. (2009) demonstrated that an mTBI group, which did not significantly differ from controls on traditional neuropsychological measures of attention or memory, was significantly slower to disengage and reorient to an auditory attention task. As a group, the mTBI participants were slower by the 50100 msec range, times below detection with traditional neuropsychological measures. Given the increased likelihood of WM pathology associated with mTBI and the subtleness of injury effects, especially at a thalamic level, neuropsychology as a field needs to rethink the use of traditional neuropsychological methods to study the mildest forms of brain injury. Traditional methods would not be sensitive in detecting real-world processing deficits that could influence processing speed, arousal, and attention/concentration. For a variety of reasons clinical neuropsychology has been slow to embrace techniques like computer and virtual-based methods that may have much greater application in detecting subtle impairments, including those associated with mTBI (Schultheis et al. 2002; Slobounov et al. 2011a; Parsons et al. 2011; Armstrong et al. 2012; Campbell et al. 2009). In addition to the demonstration by Brenner et al. (2010) that traditional neuropsychological measures failed to differentiate bona fide cases of mTBI with residual symptoms; Geary et al. (2010) acknowledge at the outset of their investigation that while mTBI patients often report chronic memory problems, traditional neuropsychological assessments often fail to find evidence for such complaints (p. 514). What some have done within neuropsychology is to conclude that performance in many of these patients, despite their complaints, is within the range of normal or a normative sample, and therefore does not represent a deficit or any type of brain impairment. Instead of considering that the traditional neuropsychometric approach may be insensitive in detecting deficits and searching for diagnostic solutions,
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neuropsychology as a field has been too quick to dismiss these complaints as merely functional noise that is cognitively inconsequential. Why has it Been so Challenging to Accept That Some mTBIs Result in Lasting Sequelae? Butler et al. (2009) provide a most interesting account in Neuropsychology Review of how the conflict in American medicine between the disciplines of psychiatry and neurology, delayed the recognition of cognitive dysfunction in multiple sclerosis (MS). In the last two decades, well designed neuropsychological studies have unquestionably demonstrated neurocognitive deficits as part of the spectrum of impairments associated with MS. Interestingly, as Butler et al. point out, a major reason why cognitive impairment was late in being recognized could be attributed to researchers using an insensitive metric the Disability Status Scale (DSS; Kurtzke 1961) that only assessed the most rudimentary of cognitive functions in MS. The original DSS over-relied on physical and sensory loss because the zeitgeist of the day conceptualized MS as predominantly a sensory-motor disorder. As reviewed by Butler et al. (2009), neuroimaging improvements in the 1980s and 90s could demonstrate in vivo WM abnormalities outside of motor tracks; this provided the needed independent classifier of underlying brain abnormality to then show presence of impaired neuropsychological performance (see Sepulcre et al. 2009). In other words, once neuroimaging became an established biomarker for the study of MS, acceptance of non-motor cognitive and emotional impairments became straightforward. Butler et al. (2009) discuss how the neuroticizing of MS sequelae influenced by the Freudian zeitgeist of the mid-20th Century meant that any behavior that could not be organically defined was considered as some dimension of a neurosis (Gladstone 2009; Sims 1985; Weighill 1983). Because of these same influences, medicine and psychology also have the distinction of not recognizing the underlying neurological bases of disorders like schizophrenia and autism until the latter half of the 20th Century. It was just 1979 when Malecs (1978) neuropsychological review asked the question whether the patient is brain damaged or schizophrenic? (p. 507). All of this sounds very familiar when considering the effects of mTBI. Absence of a lesion combined with the lack of a cogent medical explanation other than those of somatization and associated psychological/psychiatric sequelae, meant that any bona fide effects from mTBI were to be viewed with skepticism. Now given our ability to use advanced neuroimaging methods to assess mTBI, indisputably these techniques show subgroups with positive neuroimaging and neurocognitive impairments (Van Boven et al. 2009; Matthews et al. 2011; Zhou et al. 2012; Grossman et al. 2012b; Ross et al. 2012; Jorge et al. 2012; Messe et al. 2013; Morey et al. 2012; Nakagawara et al. 2013).
Lastly, it is impossible to calculate what influence forensic neuropsychology has had, but given the amount of forensic activity involving mTBI, it has the potential to influence prevailing thoughts about mTBI outcome. Plainly, there are opposing camps in anything forensic (Bigler and Brooks 2009; Ruff 2009), each with their supporting literature. Litigation involving mTBI is frequent and it is common to see neuropsychological outcome studies utilize cases from forensic sources, which never could be considered unbiased samples.
Integration of Neuroimaging with Neuropsychology Neuropsychologys embrace of neuroimaging began with imagings ability to identify the in vivo lesion (Bigler et al. 1989). Because of the limits of early neuroimaging techniques in the 1970s and 80s only the most fundamental clinical descriptions of brain pathology (i.e., type, size, and location of lesions) were possible during that era. Currently, a vast array of neuroimaging metrics can be applied to image analysis, many of them involving automated image analysis methods (Tate et al. 2012; Wilde et al. 2012; Hunter et al. 2012; Shenton et al. 2012). As Vasterling and Dikmen (2012) point out, there are many clinical and conceptual complexities that need to be attended to in designing neuropsychological outcome studies of mTBI, one of which is how to objectively define any brain pathology. Neuropsychological assessment techniques can be adapted for presentation within a functional neuroimaging environment. Adapting neuropsychological probes in this manner permits some appreciation of regional activation and neural engagement. Similarly electrophysiological methods can be performed off-line from neuroimaging, but then integrated with 3-D imaging so the best of temporal and spatial resolution may be achieved in plotting the activation source. Networks can now be examined using integrative techniques from DTI and resting-state fMRI. As reviewed by Shenton et al. (2012) multi-modality sophisticated neuroimaging methods can be used to identify subtle brain pathology associated with mTBI and should be a part of any neuropsychological outcome study of mTBI. Numerous neuroimaging methods are now available to assess mTBI (Hunter et al. 2012; Duhaime et al. 2012) and the field of neuropsychology should take full advantage of the neuroimaging biomarker approach. By applying multimodality neuroimaging methods as biomarkers for detecting underlying abnormalities associated with mTBI, neuropsychology will have an objective measure to integrate with neurocognitive and neurobehavioral assessment of the mTBI patient. The absence of an objective criterion as to whether some type of neuropathology is independently present or not
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in the mTBI patient is what has led to the confused picture of clinical outcome in the neuropsychology of mTBI. Other biomarkers of TBI are likewise on the horizon (Zetterberg et al. 2013), which also will undoubtedly improve understanding of mTBI outcome. Some of these serum biomarkers may in fact be combined with neuroimaging and likewise; neuroimaging studies are advancing along the lines of direct imaging of pathology like -amyloid and tau proteins, as byproducts of brain injury (Di Battista et al. 2013; Rostami et al. 2012; Jeter et al. 2013).
Limitations The intent of this review was to provide the basis for a sensitive, objective metric to enhance detection of mTBI sequelae which could form the basis for improved and complementary research design for investigations of neuropsychological outcome. This review is selective and focused on neuroimaging studies that identify pathology potentially related to residual impairments in cognitive and/or behavioral functioning post-mTBI in what must be considered the minority of all those who sustain an mTBI. PostmTBI neuropsychological functioning reflects a host of complex factors that includes all pre-morbid genetic and age-dependent influences present at the time of injury including incidental findings (Katzman et al. 1999; Vernooij et al. 2007), biological and emotional resiliency, and vulnerability features associated with the injury itself, as well as a myriad of post-injury factors. Returning to Figs. 5, 6, 13, and 14 where a lesion is clearly visible in these mTBI patients, the state-of-the-art in neuroimaging is that it can still only be inferred how a particular lesion disrupted pre-existing integrity because pre-injury neuroimaging and neurocognitive/neurobehavioral assessments are mostly never available. Furthermore, all of what is presented and discussed herein pertains to correlative findings with neuroimaging variables in cases of mTBI. However, as typically stated, correlation is never synonymous with causation, and given the complexities that attend premorbid and post-injury neuropsychological functioning, more precise relations specific to mTBI must be considered unknown. While this review highlights the worth of potential neuroimaging biomarkers of mTBI, neuroimaging remains an expensive study method. Extensive research studies are underway for blood and other biomarkers of mTBI (Di Battista et al. 2013). These may turn out to be effective and far less expensive than MRI. Regardless of whether neuroimaging and/or blood biomarkers become universally accepted as indicators of neural injury in mTBI, the field needs objectivity. While the price of neuroimaging is a legitimate concern, getting the diagnosis correct is the objective of identifying an effective biomarker.
It may be the case that, within the mildest of TBI the brain could adapt to injury and therefore, positive imaging would possibly reflect an abnormality to which the brain has adapted and re-circuited without apparent ill effecta classic Type 1 error if the neuropsychologist concluded impairment where none existed. Nonetheless, there may be more to the story of so-called recovered mTBI, even in the presence of a lesion. As Eisenberg et al. (2013) demonstrated in their prospective cohort of those who sustain mTBI, a prior concussion distinctly and significantly prolonged symptoms. So, even if cognitive functions return to pre-injury levels, the mere fact of prior brain injury may change the threshold for subsequent injury, therefore indicating residua from the supposed injury from which the mTBI patient had recovered. These are very serious issues for the researcher and clinician to contemplate before they would conclude that no injury had occurred based on neuropsychological findings alone and that there were no untoward effects of mTBI. Because of this it seems evident that the best in technology, including biomarkers of injury, should be brought to bear on this important topic, before there is a blanket conclusion of no lasting effect from mTBI.
Conclusions and Future Directions This review began with a simplified view of concussion but concludes by showing the complexities of what needs to be addressed in neuropsychological outcome research in mTBI. Restoration of neural function is likely the norm following mTBI, but as this review demonstrates, contemporary neuroimaging methods identify residual indicators of neuropathology in subsets of individuals with mTBI. Commenting on the entire TBI field, Chen and D Esposito (2010) state, Unfortunately, most tests of cognitive functioning, including neuropsychological tests and most cognitive neuroscience measures, are not designed to reflect the complexities and low structure of settings in the real world (p.13). Integrating this statement with an editorial in Nature (Editorial 2010) that states as biological insights develop, the crudity of current psychiatric diagnoses will become all too clear (p. 9), means that we have reached a level in the investigation of mTBI sequelae where the entire role of traditional neuropsychological methods in mTBI needs refinement. Neuroimaging provides biomarkers of underlying structural and physiological abnormalities in mTBI, and these pathological changes occur in regions and within neural systems that plausibly give rise to the common types of neurobehavioral and neurocognitive sequelae associated with mTBI. Neuroimaging methods provide objective biomarkers of injury and damage that need to be incorporated into neuropsychological outcome studies.
Neuropsychol Rev (2013) 23:169209 Acknowledgments The assistance of Jo Ann Petrie, Ph.D. in the preparation of this manuscript is gratefully acknowledged as is the assistance of Tracy J. Abildskov in preparation of some of the illustrations.
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Neuropsychol Rev (2013) 23:169209 DOI 10.

Neuroimaging Biomarkers in Mild Traumatic Brain Injury (mTBI)

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

From Chatelinet al. 2011

From Chu et al. 2010

From Metting et al.2013

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

Neuropsychol Rev (2013) 23:169209

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