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Neuropsychol Rev (2013) 23:169209

DOI 10.1007/s11065-013-9237-2


Neuroimaging Biomarkers in Mild Traumatic Brain Injury

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 Keywords Mild Traumatic Brain Injury (mTBI) .
methods that detect abnormalities associated with mild trau- Concussion . Neuropsychology . Neuroimaging .
matic brain injury (mTBI). Despite advances in demonstrating Biomarkers . Neuropathology . Brain damage .
underlying neuropathology in a subset of individuals who Cognitive and neurobehavioral sequelae
sustain mTBI, considerable disagreement persists in neuro-
psychology about mTBI outcome and metrics for evaluation. Abbreviation
This review outlines a thesis for the select use of sensitive
neuroimaging methods as potential biomarkers of brain injury ACR Anterior corona radiata
recognizing that the majority of individuals who sustain an ANAM Automated neurological assessment metrics
mTBI recover without neuroimaging signs or neuropsycho- CC Corpus callosum
logical sequelae detected with methods currently applied. CT Computed tomography
Magnetic resonance imaging (MRI) provides several mea- CTE Chronic traumatic encephalopathy
sures that could serve as mTBI biomarkers including the CVLT California verbal learning test
detection of hemosiderin and white matter abnormalities, as- DAI Diffuse axonal injury
sessment of white matter integrity derived from diffusion DKI Diffusion kurtosis imaging
tensor imaging (DTI), and quantitative measures that directly DMN Default mode network
assess neuroanatomy. Improved prediction of neuropsycho- DOI Day-of-injury
logical outcomes in mTBI may be achieved with the use of DSS Disability status scale
targeted neuroimaging markers. DTI Diffusion tensor imaging
EF Executive function
EN Executive network
FE Finite element
E. D. Bigler (*)
FLAIR Fluid attenuated inversion recovery
Department of Psychology, Brigham Young University, 1001
SWKT, Provo, UT 84602, USA fMRI Functional magnetic resonance imaging
e-mail: GCS Glasgow coma scale
GM Gray matter
E. D. Bigler
Neuroscience Center, Brigham Young University, Provo, UT, USA
GRE Gradient recalled echo
GWI Gulf war illness
E. D. Bigler LDFR Long delay free recall
Magnetic Resonance Imaging Research Facility, Brigham Young LOC Loss of consciousness
University, Provo, UT, USA
M Mean
E. D. Bigler MCI Mild cognitive impairment
Department of Psychiatry, University of Utah, MR Magnetic resonance
Salt Lake City, UT, USA MRI Magnetic resonance imaging
MRS Magnetic resonance spectroscopy
E. D. Bigler
The Brain Institute of Utah, University of Utah, MS Multiple sclerosis
Salt Lake City, UT, USA mTBI Mild traumatic brain injury
170 Neuropsychol Rev (2013) 23:169209

mcTBI Mild complicated traumatic brain injury micronsneuropathologists have still considered the likeli-
OI Orthopedically injured hood of neuronal damage in mTBI (see Blennow et al. 2012).
PCS Post-concussion(al) syndrome The mechanical deformation from stretching, twisting and
PTA Post-traumatic amnesia shearing actions brought on by head impact and
RAS Reticular activating system acceleration/deceleration of the brain during the event that
RAVLT Rey auditory verbal learning test caused the concussion at least transiently alters cellular mor-
RT Reaction time phology and function. For example, Peerless and Rewcastle
SD or s.d. Standard deviation speculated in 1967 that .concussion depends upon varying
SDMT Symbol digit modality test degrees of damage to the axon as well as the neuron. The
SWI Susceptibility weighted imaging current definition of concussionimmediate loss of con-
TBI Traumatic brain injury sciousness with rapid and complete recovery of cerebral func-
TBSS Tract-based spatial statistics tionshould not exclude the fact that a small number of
UF Uncinate fasciculus neurons may have been permanently disconnected or have
WHO World Health Organization perished. (Peerless and Rewcastle 1967, p. 577).
WM White matter It is now the 21st century and although advanced neuroim-
WMHs White matter hyperintensities aging 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 chron-
ically and prospectively, with techniques that more directly
A simplified view of concussionthe mildest form of trau-
examine cerebral microstructure. Moreover, precise biome-
matic brain injury (TBI)is that although it is an acute brain
chanical finite element (FE) studies empirically show where
injury any residuals from a concussion are short-lived physi-
the greatest strains occur in the brain when subjected to head-
ological aberrations without lasting neurological sequelae.
impact or acceleration/deceleration movement, as depicted in
Indeed, the majority of concussions run a benign course with
Fig. 1 from Chatelin et al. (2011). As shown in Fig. 1, these
spontaneous return to baseline level of function without any
regions of greatest axonal elongation, stress and strain occur in
systematic treatment. In the absence of an enduring neurolog-
the very regions where acute magnetic resonance (MR) diffu-
ical deficit, the neuropsychological argument has been made
sion tensor imaging (DTI) changes are well documented in
that any post-concussion cognitive or behavioral change in
mTBI during both the acute and chronic phase (see also Chu
function does not reflect permanent neuropathology. Reasons
et al. 2010; Metting et al. 2013).
behind these assumptions are that indisputably the majority of
Current neuroimaging methods now demonstrate that a
those who experience a mild TBI (mTBI)1 return to pre-injury
subgroup of mTBI patients have more than a transient phys-
baseline and resume typical function, at least based on tradi-
iological disruption in neural function showing identifiable
tional neuropsychological measures (Rohling et al. 2011).
underlying neuropathology (Bigler and Maxwell 2012;
Transient perturbation of neuronal physiology seems a likely
Gonzalez and Walker 2011; Kasahara et al. 2012; Kim et al.
explanation and fits well with the majority of positive out-
2013; Lewine et al. 2007; Lipton et al. 2012; Matthews et al.
comes documented in mTBI research.
2012; Messe et al. 2011; 2012; Niogi and Mukherjee 2010;
Throughout the 1980s and early 1990s, apparent confirma-
Wada et al. 2012).
tion of no identifiable gross neuropathology was the conclu-
This review examines the current status of advanced neu-
sion of the majority of mTBI cases who underwent computed
roimaging findings in neuropsychological outcome research
tomography (CT) or magnetic resonance imaging (MRI) (see
on mTBI. Neuroimaging improvements have resulted in a
Bigler and Snyder 1995). However, given the delicate nature
number of techniques that appear to be sensitive in detecting
of neuronsespecially axons with diameters of just a few
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 analy-
Definition of concussion and mTBI remains controversial and defini- sis techniques, neuroimaging findings may serve a biomarker
tional issues have been discussed by Bigler (2008), but for this review the role for the investigation of cognitive and neurobehavioral
terms concussion and mTBI are used interchangeably. Based on the outcome from mTBI (Kou et al. 2010). Candidate neuroim-
International and Interagency Initiative toward Common Data Elements
aging biomarkers of mTBI are listed in Table 1 and introduced
for Research on Traumatic Brain Injury and Psychological Health TBI is
defined as an alteration in brain function, or other evidence of brain below. This review will only address structural imaging tech-
pathology, caused by an external force (p. 1637, Menon et al. 2010). niques and not functional neuroimaging metrics that also may
Neuropsychol Rev (2013) 23:169209 171

From Chatelinet al. 2011

From Chu et al. 2010 From Metting et al.2013

Fig. 1 (Top) Pictorial description of the neuroimaging steps in develop- mTBI. Note that where these changes occur match the prediction based
ing a finite element (FE) model to map diffusion information demonstrat- on where the greatest axonal elongation strain occurs. From Chu et al.
ing where greatest axonal deformation occurs in the brain as a conse- (2010) used with permission from American Society of Neuroradiology.
quence of trauma. The final image on the right shows the most vulnerable (Bottom Right). During the chronic phase of mTBI the colorized regions
areas to be corpus callosum, deep WM tracts of both cerebral hemispheres depict where group DTI differences are found in mTBI compared with
and the brainstem. From Chatelin et al. (2011) and used with permission non-injured controls used with permission from Metting et al. (2013).
from the Journal of the Mechanical Behavior of Biomedical Materials and Note how the chronic findings are also predicted by the loci of greatest
Elsevier Publishing. (Bottom Left). Red depicts regions of abnormal strain as shown in the FE modeling by Chatelin et al. (2011)
diffusion tensor imaging (DTI) findings within 6 days of sustaining an

have implications for biomarker roles in mTBI (see Candidate Neuroimaging Biomarkers
Bryer et al. 2013; Zhou and Lui 2013); nor will this
review deal with any treatment outcome factors that may Numerous magnetic resonance (MR) techniques currently
come from improved neuroimaging biomarker identifica- identify trauma-related neuropathology (Duhaime et al.
tion of mTBI. 2012; Hunter et al. 2012). The MR imaging (MRI) method
To highlight the various points made in this review, indi- known as diffusion tensor imaging (DTI; Fox et al. 2013) has
vidual cases with mTBI with several types of neuroimaging become the most sensitive and predictive MRI metric in mTBI
abnormalities will be presented. From a clinical neuropsycho- research (Niogi and Mukherjee 2010). DTI is an established
logical perspective, clinical decision making must occur on an neuroimaging procedure used diagnostically and in research
individual basis all-the-while understanding what group data across a variety of neurological diseases and disorders, espe-
analyses may show. Where individual cases are used in this cially those that predominantly influence white matter (WM)
review, they were carefully selected to reflect findings based integrity (Alexander et al. 2007; Chanraud et al. 2010;
on larger studies and not just case studies. 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
Table 1 Potential MRI biomarkers of mTBI
et al. 2011; Voelbel et al. 2012), where damage or disruption
Imaging modality Measures of myelin integrity and oligodendrocytes may characterize
much of the pathology that comes from TBI when chronic
SWI Hypointensities reflective of blood by-products
problems persist (Maxwell 2013). The key element in net-
(i.e. hemosiderin)
works is pathways (Catani and Thiebaut de Schotten 2012),
FLAIR WMHs indicating WM signal abnormality and/or
increased perivascular space and fundamental to all pathways is axon integrity. In regard to
contemporary neuroimaging, DTI provides the best
172 Neuropsychol Rev (2013) 23:169209

visualization and MR metrics of water diffusion that directly (Bazarian et al. 2012; Cubon et al. 2011; Gardner et al. 2012;
assess axon integrity (Mori et al. 2012). Indeed, the research Koerte et al. 2012a; Maugans et al. 2012; Slobounov et al.
and clinical applications of DTI are well established, including 2012; Virji-Babul et al. 2013).
its use in providing in vivo visualization and analysis of WM
integrity in mTBI (see Huston and Field 2013). Other Neuroimaging with Biomarker Potential: Hemosiderin,
White Matter Hyperintensities (WMH), and Regional and
DTI and mTBI In a review specific to DTI and TBI, Hulkower Whole Brain Atrophy Several other candidate measures as
et al. (2013) conclude that, DTI effectively differentiates neuroimaging biomarkers of mTBI, as listed in Table 1, in-
patients with TBI and controls, regardless of the severity and clude detection of hemosiderin (a by-product of blood degra-
timeframe following injury. (in press, e-pub page1). The dation with paramagnetic properties detectable by MRI) as an
Hulkower et al. review was based on the first 100 published indication of shear-force injury, currently best detected using
DTI studies that examined the ability of DTI to detect differ- susceptibility weighted imaging (SWI; Benson et al. 2012).
ences between controls and TBI and included over 30 studies As will be discussed below, cerebral microvasculature is just
that specifically assessed mTBI. As an index of WM integrity as small and delicate as neural tissue and therefore susceptible
DTI metrics may serve as biomarkers of the health of WM to deformation injury where petechial hemorrhage may attend
connections in mTBI (Bigler and Bazarian 2010; Ling et al. mTBI (see Bigler 2004). In individuals with no risk factors for
2012; Niogi and Mukherjee 2010; Kou et al. 2010; Bigler cerebrovascular disease and under 50 years of age, MRI
2013). For neuroimaging findings to serve as biomarkers in detection of hemosiderin is unlikely unless there is injury or
TBI, including mTBI, there must be neuropathological con- disease (Hunter et al. 2012; Kubal 2012; Sharp and Ham
firmation of the relationship between what is observed from 2011). In 52 children with orthopedic injury only, no child
neuroimaging with that viewed histologically (Bigler and had hemosiderin deposition detected whereas in the 41 chil-
Maxwell 2011). Animal studies of TBI with in vivo DTI dren with mTBI, Bigler et al. (2013a) found that 12 children
metrics, compared to histological confirmation, provide the had hemosiderin. As with the detection of hemosiderin, the
necessary neuropathological foundation to infer in the living presence of WM signal abnormalitiesreferred to as WM
human what a particular DTI finding may mean at the histo- hyperintensities (WMHs)are less common in individuals
logical level (see Bennett et al. 2012; Hylin et al. 2013; Budde under 50 years as well (Hopkins et al. 2006), but have been
et al. 2011). Likewise, in cases of epilepsy and cerebral noted to occur with increased frequency in TBI (Bigler et al.
neoplasm, there is pre-surgical and post-surgical confirmation 2013a; Marquez de la Plata et al. 2007). Another imaging
of how DTI changes relate to damaged neural tissue technique that involves WM is diffusion kurtosis imaging
(Abdullah et al. 2013; Liu et al. 2013). Given the status of (DKI; Zhuo et al. 2012); this provides another metric shown
DTI research and clinical findings, DTI is one of several to be affected in mTBI (Grossman et al. 2012a). In this
neuroimaging methods that meet criteria for use as a biomark- technique, because of biological constraints in normal tissue,
er of WM integrity. water diffusion metrics (e.g., kurtosis imaging) should have a
Specific to mTBI, in a study that examined only corpus rather uniform distribution but the shape of the distribution
callosum (CC) DTI findings, Aoki et al. (2012) demonstrated deviates when damage occurs. Small focal contusions occur in
in a meta-analysis of 15 mTBI studies, that DTI consistently mTBI and may result in focal areas of atrophy (Bigler et al.
demonstrated differences between mTBI groups and controls. 2013a). Regions of focal atrophy may be quantified as may
The consistency of these findings across studies allowed Aoki whole brain volumetric changes. Indeed, longitudinal volu-
et al. (2012) to conclude that DTI metrics were sufficient metric studies that provide quantitative metrics show whole
to detect white matter damage in the CC of mTBI patients. (p. brain volume loss over time in mTBI subjects (MacKenzie
870). Aoki et al. focused on the CC because of its vulnerability et al. 2002; Ross et al. 2012; Zhou et al. 2013).
in mTBI to stretch and strain (Bayly et al. 2012; McAllister Neuroimaging biomarkers in mTBI neuropsychological
et al. 2012), but also other studies have shown the vulnerabil- outcome research could be applied in numerous ways. For
ity of other long coursing tracts in the brain like the superior example, Sorg et al. (2013) examined 30 war veterans with a
longitudinal fasciculus and tracts within frontal and temporal history of mTBI (on average more than 2 years post injury)
lobe regions (Shenton et al. 2012). Biomechanics of what with a subgroup of 13 showing impaired neuropsychological
produces an mTBI likely relate to a variety of outcome differ- performancedefined as performance at least one standard
ences (Breedlove et al. 2012), and sports concussion is cer- deviation below the meanon at least one executive function
tainly in a different class from auto-pedestrian head injuries (EF) measure. Figure 2 plots out DTI detected WM differ-
that produce mTBI. Nonetheless, even in sports concussion, ences that related to reduced EF performance in the mTBI
which may produce the mildest of injuries, DTI is capable of group, showing that these regions of reduced EF performance
distinguishing those with significant parenchymal injury and corresponded with reduced WM integrity in the ventral pre-
those without, at least in the acute and early sub-acute stages frontal WM, posterior cingulum bundle, genu, and splenium
Neuropsychol Rev (2013) 23:169209 173

Fig. 2 Atlas-based region of interest (ROI) placement and group com- anisotropy; HC=healthy controls; PIC=posterior internal capsule; Post.
parisons of fractional anisotropy (FA) values depicting where significant Cing. = posterior cingulum bundle; ROI=region of interest; TBSS=tract-
differences occurred in mTBI patients with reduced EF. Placement of the based spatial statistics; VPFWM=ventral prefrontal white matter. Error
tract-based special statistics (TBSS)-derived white matter skeleton re- bars represent standard error of the mean. aP corrected<.10, bP corrected
gions of interest in standard space on a T1 image. Note in each case of <.05. Used with permission from Sorg et al. (2013) and Wolters Kluwer/
reduced EF, FA is also reduced although not always significant. Also, Lippincott Publishers. Note once again the overlap of where significant
most importantly, note that in all comparisons no significant FA differ- DTI differences occur in relation to what was shown in Fig. 1, but now by
ences were observed between controls and those with intact EF. Colors examining neuropsychological outcome specific to white matter (WM)
reflect different ROIs of white matter (WM) tracts. Note: AIC=anterior tracts, a clearer picture emerges as to where pathology affects cognitive
internal capsule; Ant. Cing.=anterior cingulum bundle; DPFWM=dorsal performance
prefrontal white matter; EF = executive functions; FA= fractional
174 Neuropsychol Rev (2013) 23:169209

of the CC. These are all well-known regions that participate in concussive syndrome (PCS) overlap with myriad other neu-
EF networks and likewise, vulnerable to mechanical deforma- rological and neuropsychiatric signs and symptoms and there-
tion during head injury (Chatelin et al. 2011). Relevantly, the fore, their lack of any specificity renders PCS criteria incapa-
Sorg et al. study basically replicates similar observations in ble as effectively serving as a bio-behavioral marker of mTBI.
mTBI research involving these brain regions and EF, as re- If, as is now being shown, neuroimaging methods demon-
ported by others (Jorge et al. 2012; Wada et al. 2012). Taking strate residual neural findings in some who have sustained
this approach the neuroimaging DTI biomarker findings pro- mTBI then the mere classification of mTBI by the event that
vide novel information about brain-behavior relations that produced it will lead to erroneous conclusions.
could never be gleaned from just the neuropsychological data, This review examines the potential role that neuroimaging
since group averaging neuropsychological test findings may biomarkers of brain pathology can play in the next decade of
obscure those with impairment. mTBI outcome research (Kan et al. 2012; Walker and Tesco
As another example, Hellyer et al. (2012) took a different 2013). Much of the confusion over mTBI sequelae is attrib-
approach using DTI and other MR metrics assessed through utable to the absence of reliable biomarkers of brain injury.
machine learning to first segregate TBI patients, the majority Only a brief historical perspective of mTBI will be offered
of whom had mTBI and no visible abnormality on the scan here, as numerous other reviews have covered much of that
from controls. The MRI-based machine learning classifier material in great detail (see Prigatano and Gale 2011; Bigler
extracted just from the CC achieved 86 % correct classifica- 2008; Ruff 2011; Iverson 2005). Likewise, the history of
tion of those with TBI, the majority of whom had mTBI. In neuroimaging in mTBI and contemporary methods, including
turn, these classifiers positively related to impairments in EF underlying MR physics, has been reviewed elsewhere (see
and speed of processing. A different MR biomarker approach Shenton et al. (2012). Most of this review will focus on
from that of Sorg et al. (2013) but with convergence, demon- methods of structural neuroimaging, but there is also a large
strating the added information that neuroimaging provides for body of mTBI research on functional neuroimaging tech-
understanding the neural basis of mTBI effects on cognition. niques, especially functional MRI (fMRI) and MR spectros-
The presence of DTI findings in cases of mTBI has also copy (MRS), which will not be reviewed here but has been by
been used to predict outcome. For example, Rao et al. (2012) Slobounov et al. (2012) and Bryer et al. (2013). At the outset
obtained DTI at 1 month post-injury where frontotemporal of this review, it is categorically stated that the majority of
DTI findings related to clinically significant depression those who sustain an mTBI display and/or experience symp-
assessed at 1 year post injury. Messe et al. (2011; 2012) used toms that are brief and run a benign course, including what
DTI findings in the subacute (821 days) timeframe com- occurred to this author.2 This review is concerned only with
pared to chronic phase (~6 months) where persistence in the minority of mTBI subjects who have sustained an injury
abnormal DTI findings was associated with persistence of which may no longer constitute a simple transient event
post-concussion syndrome (PCS). (Bigler et al. 2013b).
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 Opposing Views of mTBI: Neuroimaging Biomarkers
cognitive sequelae (Bigler et al. 2013c). Further, transient Will Help Resolve Controversies
pathophysiological effects dominate mTBI but are co-
mingled with structural and enduring pathology in a minority To put the Peerless and Rewcastles speculation of axonal
of those injured. Therefore, the fact of having sustained an damage in mTBI into context, their 1967 publication became
mTBI in no way can distinguish the two, and therefore, the the classic paper that established the concept of the WM shear
injury itself when traditionally classified as only an event lesion in TBI; that, in turn, became the foundation for the
that has occurred cannot identify who does or does not have
persistent pathology.
One could argue that there is abundant neuropsychological 2
I sustained a sports-related concussion playing high school football in
literature that supports the transient nature of mTBI with no
1966. I must have displayed significant PTA and confusion on the
lasting effect (Carroll et al. 2004b; Larrabee et al. 2013; sideline because I was taken to the emergency room for evaluation and
Rohling et al. 2011); but all of this prior literature is based subsequently hospitalized overnight for observation. I am amnestic to
almost entirely on the assumption that the eventthe concus- 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
sive injury itselfis a sufficient independent variable that
in the next game on the following Friday. This, of course, was long before
characterizes the injury. Likewise, all of the post-mTBI symp- return-to-play guidelines but for me, post-concussion symptoms were
toms that constitute what has been referred to as the post- minimal and short lived.
Neuropsychol Rev (2013) 23:169209 175

concept of diffuse axonal injury (DAI, see Adams et al. 1982). et al. (2010) found in a prospective longitudinal cohort of 670
The term shear lesion that is now commonplace nomenclature children (aged 018 years) who presented to the emergency
in the neuropsychological literature of TBI began with this room and assessed to have sustained mTBI, that 13.7 % had
Peerless and Rewcastle (1967) publication. Specific to mTBI, persisting symptoms at 3 months or longer post-injury when
and coincidentally in 1967, Taylor also reviewed the topic of compared to a consecutive case-controlled cohort of 197
post-concussional sequelae outlining core clinical features of children who sustained an extra-cranial injury but were not
the post-concussional syndrome (PCS), which nearly three diagnosed with mTBI. Similarly, in a prospective cohort study
decades later would become labeled post-concussional disor- of concussion (all types) and resolution of symptoms that
der by DSM-IV standards (DSM-5 has dropped mention of enrolled 280 patients (1122 years old) over a 12 month
PCS, instead using the major or mild neurocognitive disorder period, Eisenberg et al. (2013) showed that 15 % remained
due to TBI as the qualifier). Taylors opening statement ac- symptomatic at 3 months.
knowledged a 100 year strident debate as to whether PCS was In an adult sample, followed up to 14 years post TBI, that
a residual of brain injury, manifestation of psychogenic prob- contained a substantial number of patients with mTBI,
lems, or something malingered. McMillan et al. (2012) found persistence of disability based
Almost 50 years since that publication the debate continues on the Glasgow Outcome Scale-Extended. In another study,
just as strongly, especially in the field of neuropsychology. Levin et al. (2012) identified 102 mTBI patients at baseline
The debate is not about acute concussive effects, as there is within 4 days of injury and tracked them for 3 months com-
uniform agreement that the acute effects alter brain function. pared to similarly tracked orthopedically injured (OI) con-
Indeed, especially within the realm of sports concussion, well- trols. At 3 months using a conservative cut-point for symptom
designed neuropsychological studies have unequivocally endorsement of PCS, about 10 % of the mTBI sample had
demonstrated consistent acute neurocognitive and neurobe- PCS compared to under 2 % of the OI subjects. At 3 months
havioral effects of a concussion (McCrea 2007), as well as mTBI patients in the Levin et al. study did differ from OI
indisputable evidence of acute electrophysiological aberra- controls on a computer-based measure of processing speed but
tions associated with concussion (Arciniegas 2011; Shaw not on traditional neuropsychological measures.
2002), along with development of reproducible animal models The studies above, and others (see also Dean and Sterr
of concussion and its acute neuropathological effects (Chen 2013; Kumar et al. 2013; Pontifex et al. 2012; Tallus et al.
et al. 2012b; Hylin et al. 2013). Likewise, there is minimal 2013), show that some with mTBI endorse and display
debate about the fact that the majority who sustain mTBI do persisting cognitive and neurobehavioral problems beyond
recover (or, at least return to baseline; see Mott et al. 2012; 3 months. However, are the problems specific to brain injury
Vasterling et al. 2012; Rona 2012). A principal debate centers or related to some other factor? There is abundant literature
on whether mTBI results in residual neuropathological that discusses a host of pre-morbid personality and emotional
changes in some as manifested by persistence of factors that may predispose the individual who sustains an
neurocognitive and neurobehavioral deficits 3 months or lon- mTBI to misattribute residual symptoms to the injury rather
ger after mTBI. than a pre-existing condition (Silver 2012). A fundamental
The camp that views mTBI as a transient physiological problem with this is that misattribution assumes absence of
event with no lasting sequelae is captured by Geiffensteins pathology that could explain the symptom. Without some
statement that mTBI is a self-contained condition that independent biomarker as to potential bona fide neural dam-
resolves quickly without special treatment, a generally accept- age, a true distinction between accurate or misattributed per-
ed conclusion by fair-minded neuropsychologists (see ception in mTBI is impossible.
Carone and Bush 2013, p. xiii). As another example of this Some criticize the mTBI neuropsychological literature be-
perspective, Boone (2013) states, The field [referring to cause of not controlling for depression, litigation and effort,
neuropsychology] as a whole is taking the position that there but Heitger et al. (2009) controlled for all of these factors and
is no long-term cognitive consequence from mTBI (p. 275). observed subtle cognitive deficits associated with mTBI after
The other camp contends that most who experience mTBI 6 months. Hanten et al. (2012) in a well-designed, within
recover and return to pre-injury baseline as measured by subjects longitudinal study of mTBI compared to OI and
traditional neuropsychological assessment methods. non-injured controls that tracked 59 mTBI patients (cognitive
However, as Ponsford et al. (2011) observed in a longitudinal testing at <1 week, 1, and 3 months post-injury), all with no
study involving adults who sustained mTBI, some did exhibit CT abnormalities on the day of injury (DOI) scan, found
ongoing impairment in memory function after 3 months and persisting memory problems to 3 months in some of those
that at least a proportion of these mTBI participants did with mTBI. Konrad et al. (2011) examined 33 mTBI patients
have subtle residual cognitive sequelae 3 months post-injury on average 6 years post-injury, all of whom passed symptom
(p. 945). With some studies estimating 6 % to 35 % occur- validity testing but nonetheless demonstrated persisting,
rences on the incidence of PCS in children after TBI, Barlow chronic cognitive and emotional dysfunction. Dean and Sterr
176 Neuropsychol Rev (2013) 23:169209

(2013) have also controlled for these factors finding residual condition being examined. Once established, hypotheses
subtle cognitive impairments associated with mTBI beyond about how brain impairment or damage that may selectively
3 months post injury. disrupt some components of a cognitive or behavioral system
The Hanten et al. (2012) and Hellyer et al. (2012) studies can then be examined. This is how neuropsychology has
are particularly relevant for this review because they under- demonstrated neurocognitive and neurobehavioral correlates
score the significance of advanced neuroimaging findings in with other major neurological and neuropsychiatric disorders.
mTBI for understanding neuropsychological outcome after To date this approach has not been applied to mTBI because
3 months post injury. The Hanten et al. investigation was there has been no independent marker of brain pathology,
longitudinal, obtained baseline imaging within 96 h, and other than the event of having sustained a mild head injury.
followed up at 1 and 3 months post-injury. The study also Abundant mTBI studies exists on the lack of neuropsycho-
included OI subjects as well as non-injured controls that were logical findings of mTBI, but almost all of those studies have
all imaged with high-field 3-Tesla MRI. Of the 59 (32 %) used the injury itself as the only independent factor to classify
mTBI subjects, 19 had identifiable trauma-related pathology the mTBI condition. If the fact of sustaining an mTBI is
on follow-up MRI, even though none had identifiable DOI CT insufficient to identify a neural condition with potential lasting
abnormalities. Even though MRI findings were based only on sequelae, then the event by itself becomes an inadequate
qualitative ratings by a neuroradiologist, clinically identifiable criterion related to outcomewhat is needed is a biomarker
pathology involving the frontal lobes was associated with that identifies those with neural changes from the mTBI event.
persisting deficit in an EF working memory task in the Therefore, this review turns to the neuropathology of mTBI
mTBI patients (see also the study by Raz et al. 2011 that and first asks a basic question: Are there discernible abnor-
shows MRI correlates with impaired EF performance in malities that can be demonstrated in mTBI using contempo-
mTBI as well as Fig. 2 from Sorg et al. 2013). In the Hellyer rary neuroimaging? If so how should they be characterized as
et al. (2013) investigation the MRI classifier not only dis- independent variables in studying neuropsychological out-
tinguished mTBI subjects, as well as those with more severe come? The current review assumes basic understanding and
injury, from controls but also related to performance on EF background in neuroimaging and neuropathology of TBI,
measures in TBI patients on average almost 3 years post which has been covered in other reviews (Chanraud et al.
injury. These studies support that underlying pathology occurs 2010; Travers et al. 2012; Wilde et al. 2012; Hunter et al.
in some who sustain an mTBI. 2012). It must be emphasized again that this is not a discussion
Unlike what is emerging with contemporary neuroimaging, of all who have sustained an mTBI because the assumption is
past measures that have been used clinically and in research that likely the majority have only experienced a transient event
with mTBI are too coarse to be effective biomarkers. Day-of- and advanced neuroimaging techniques would be negative in
injury (DOI) CT and even traditional markers of injury sever- such individuals. Thus, the assumption that guides this review
ity such as loss of consciousness (LOC) or post-traumatic is that these pathological neuroimaging markers of mTBI will
amnesia (PTA), are poor predictors of outcome when only be found in a subset of individuals with mTBI.
Glasgow Coma Scale (GCS) scores are in the mild 1315
range (Smits et al. 2007). Further, even identifiable abnormal-
ities on a DOI CT scan have limited predictive ability for Neuropathology of mTBI
mTBI, likely because they under detect the number and type
of abnormalities (Smits et al. 2007). Past restrictions in mTBI From a neuropathological standpoint, TBI can be viewed on a
research design (see full discussion of design issues as continuum and as summarized by Graham and Lantos (2002)
reviewed by Bigler et al. 2013c), plus the problems of how shear and tensile strains at the axonal level are the most
mTBI groups should be properly composed (Luoto et al. important single factors contributing to the severity of brain
2012), combined with the absence of a reliable mTBI bio- damage in any patient who sustains a blunt head injury be-
marker, have resulted in major limitations in fully understand- cause it occurs at the moment of injury (p.867). Chatelin et al.
ing mTBI outcomes. (2011), integrating various MRI methods including DTI, de-
As summarized nearly two decades ago by Cipolotti and veloped FE biomechanical models to experimentally examine
Warrington (1995), if neuropsychological assessment is to shear and tensile strains at different injury severity levels.
provide unique information about a condition and its relation- Their results have particular relevance to understanding
ship to underlying neurological impairment, there must be a mTBI because they illustrate, as previously shown in Fig. 1,
method to independently define the pathophysiology or brain where the greatest axonal shear/strain effects occur in TBI
damage of that condition or objectively rule it out. In other corona radiata, corpus callosum, and brainstem. Given that
words, to use neuropsychological measures as dependent information, and turning to acute imaging, as shown by Chu
variables to characterize a disorder, the independent variable et al. (2010), knowing where the shear-strain effects are
reflecting neurological impairment must be specific to the greatest predicts where DTI findings are most likely to acutely
Neuropsychol Rev (2013) 23:169209 177

occur in mTBI (see Fig. 1, lower left panel), as well as where those who sustain an injury full return to baseline is the norm,
abnormalities will be chronically identified, as shown in Fig. 1 lending credence that reversibility of acute mTBI effects oc-
(lower right panel and Metting et al. 2013). curs in the majority (Parkinson 1992). Nonetheless, such a
The study by Tang et al. (2012) demonstrates the continu- physical effect has the potential of initiating complex molec-
um or range of MR diffusion tensor findings in TBI. These ular and metabolic pathologies (Choe et al. 2012), along with
investigators examined TBI patients from mild to severe com- cellular inflammatory reactions (Loov et al. 2013).
pared to a control sample. As shown in Fig. 3, when the TBI Furthermore, there are a host of non-traumatic reversible
subjects were compared to controls, there were significant and encephalopathies that present with acute disturbances in phys-
quite uniformly reduced fractional anisotropy (FA) values iologic functioning only to exhibit complete restoration of
throughout brain WM, but particularly the corpus callosum function as homeostasis returns resulting in no apparent se-
and all areas as identified by Chatelin et al. (2011). However, quelae including neuropsychological (Bavikatte et al. 2010;
basically within these same regions when severity was graded Pula and Eggenberger 2008). The fact that recovery
from mild to severe, the degree of FA changes related specif- meaning return to presumed baselineoccurs in disorders
ically to severity of injury with general conformation to where like reversible encephalopathies lends support to transient
the changes occurred in comparison to the control sample. If and mutable physiological changes associated with mTBI that
one accepts that WM damage can be viewed on a continuum, may not have a permanent effect. Experimentally, in vitro and
studying moderate to severe forms of TBI may provide insight in vivo mTBI models show how physiological disruption may
and understanding of milder forms of TBI. occur on a continuum followed by recovery and restoration
Other biomechanical studies show that the shear-strain (Greer et al. 2012; Johnson et al. 2012b). In this sense resto-
relationship on WM is directly proportional to the severity ration implies a rebuilding where neural repair restores
of injury (Bayly et al. 2012). From this perspective, tensile unimpaired functioning. Regardless of how function is
strain may distort the axon and if this occurs within appropri- returned to its normal state, much of the injury in mTBI may
ate levels of tolerance, only physiological disruption results. result in no lasting neuropathological effect.
This physical effect may be transient or may have subclinical Traumatic axonal injury or TAI can be modeled from
relevance for understanding mTBI, since in the majority of 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 ad-
vanced neuroimaging methods. Both animal and human stud-
ies also demonstrate that neuropathological changes are di-
rectly 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 in-
jury 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
Fig. 3 a Fractional anisotropy (FA) comparisons between control and perspective, understanding more severe TBI provides a frame-
mild to moderate TBI subjects using voxel by voxel TBSS analysis (p <
0.05). Yellow: Control>mild to moderate TBI. Lower FA (yellow) re-
work for understanding the mildest of injuries and how pa-
flects extensive WM abnormalities. b Correlation analysis of FA and thology may be expressed in mTBI.
severity scores using voxel by voxel TBSS results comparing mild to Turning to the seminal neuropathological contributions of
severe TBI subjects (p <0.05). Blue: significant negative correlations Strich (1956) and Peerless and Rewcastle (1967), as neuropa-
between FA and severity. These findings demonstrate that as severity
increases from mild to severe TBI so do DTI differences. Used with
thologists who studied more severe traumatic brain injuries,
permission from Tang et al. (2012) and Springer-Verlag. Note; FA= they viewed the brains microscopic environment and recog-
fractional anisotropy; TBSS=tract-based spatial statistics nized the delicate and vulnerable nature of an axon when
178 Neuropsychol Rev (2013) 23:169209

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),
Fig. 4 A medium power light micrograph of part of a central white
and therefore the definition of concussion or mTBI at that time matter tract from a patient who suffered mTBI with complications and
was dependent upon the clinical description by Oppenheimer. died from respiratory failure as a result of thoracic injuries 18 h after entry
The case study J.M was described as having been struck by to hospital. The field is part of a paraffin section labeled for -amyloid
precursor protein, a marker for axonal injury. The irregular, orange
a motor scooter and stunned yet apparently did not lose
profiles represent axons within which focal loss of fast axonal transport
consciousness, but did have 10 to 15 min of retrograde amne- has resulted in abnormal accumulation of the amyloid protein. The purple
sia and anterograde amnesia of about 20 min (Oppenheimer circles are the nuclei of glial supporting cells and are probably mostly
1968). He had a parietal scalp bruise, but no skull fracture oligodendrocytes. Within this field are a range of types of abnormal axons
which represent different stages in the pathological cascade culminating
and no neurological signs (p. 301). Unfortunately however,
in secondary axotomy. Injured axons form axonal swellings (*) on
he did sustain a chest injury in the accident, including multiple either side of the focus of loss of axonal transport. Axonal swellings
rib fractures that ultimately proved fatal. He also had a continue to increase in diameter as a result of continued anterograde and
longstanding history of being bronchitic, and died of chest retrograde axonal transport and a constriction occurs (black arrows) at
some point within the axonal swelling. The axon undergoes secondary
complications 13 days after the injury (p. 301).
axotomy thereat and separates into fragments. The regions of increased
When J.M.s brain was microscopically examined, the axonal caliber are then at the ends of the fragments and are referred to as
following was observed at autopsy: axonal degeneration bulbs (white arrows). The axonal fragment now
separated from the neuronal cell body then degenerates. From Bigler and
The brain looked entirely normal except for a tiny Maxwell (2012) used with permission from Springer. The inset in the
softening in the lateral sulcus on one side of the mid- lower left shows the classic line drawings from Peerless and Rewcastle
brain. There was no vascular disease, and no sign of (1967) used with permission from the Canadian Medical Association.
The line drawing shows different stages of axonal beading from none in
brain swelling. Histologically, there was some myelin (A) to extensive beading and axonal fragmentation in (D). Note how the
destruction and numerous axonal retraction bulbs in the beading reflective of axonal damage is distinctly observed in the
midbrain lesion. Nine blocks, from various parts of the photomicrograph from the mTBI subject (black arrows)
brain, were stained for microglia. In every block, at least
one microglial cluster was found (Oppenheimer 1968,
heart attack several months post-injury, Bigler (2004) demon-
strated both macrophages and hemosiderin were present in
While Oppenheimer was the first to provide this amount of WMmicro-bleeds likely from trauma with macrophages
neuropathological detail in an mTBI patient, others have indicative of neuroinflammatory processes (Bigler 2013).
confirmed such post-mortem observations as well (see Presence of hemosiderin is a blood by-product from degraded
Bigler 2004; Bigler and Maxwell 2012; Blumbergs et al. blood, in TBI considered a residual from shearing of the
1994; McKee et al. 2010, 2012). Figure 4 shows classic microvasculature or breakdown of the vascular wall from
neuropathology of axonal damage, beading and axon bulb trauma (Benson et al. 2012), and a distinct marker of TAI
formation; indeed the types of pathologies that Peerless and detected by MRI (Scheid et al. 2006).
Rewcastle (1967) observed in more severe TBI was found at Two MR methods are sensitive in detecting edema and
post-mortem in an mTBI patient who succumbed not to TBI microhemorrhages: 1) DTI, for neuroinflammation, and 2)
but to chest-pulmonary injury from the impact (see Bigler and gradient recalled echo (GRE) sequences, in particular sus-
Maxwell 2012). However, the classic pathology of shear ceptibility weighted imaging (SWI), for microhemorrhages.
injury and axon beading and degradation, when it occurs in Certain DTI metrics, like fractional anisotropy (FA), are
mTBI, is only one facet of the potential mTBI pathologies that sensitive to inflammation, because with inflammation a re-
may occur. For example, in an mTBI patient who died from a striction in water dispersion occurs. FA is a DTI metric
Neuropsychol Rev (2013) 23:169209 179

reflective of water diffusion, on a scale of 0.0 to 1.0, with the delicate nature of blood vessels in the brain, and the micro-
normative values typically within a midrange. FA that is too vascular damage that can result from trauma (see also Fujita
low may reflect WM degradation (intracellular water mixes et al. 2012; Sangiorgi et al. 2013). Damage from TBI affects
with extracellar because axon membranes do not effectively both brain parenchyma and blood vessels, which when
constrain water or are absent) and FA too high, may reflect sheared or damaged in ways where blood may leak into the
edema because water diffusion is constrained (Chanraud et al. parenchyma, leave degraded blood by-products in the form of
2010; Shenton et al. 2012). Elevated FA may occur when hemosiderin potentially detectable by MRI. Figure 6 shows
water dispersion is restricted because of regional or more the detection of hemosiderin in the region of the forceps minor
generalized swelling. As already shown in Fig. 1 (lower left in a child with mTBI associated with a high velocity impact
panel), acute inflammation in mTBI occurs in characteristic sports concussion that had normal conventional neuroim-
regions vulnerable to damage (see Chu et al. 2010). With aging in the ED. As with the case presented in Fig. 5, a healthy
regards to detecting microhemorrhages and trauma-related individual without cardiovascular or cerebral vascular risk
vascular pathology, as mentioned, the SWI sequence is par- factors under the age of 30 at the time of injury would not
ticularly sensitive with microhemorrhages and indicators of be expected to have any hemosiderin deposition identified on
hemosiderin deposition occurring within the same regions of imaging. Figure 6 depicts pathology (hemosiderin deposition)
vulnerability (Turtzo et al. 2012; Benson et al. 2012). A most detected after a sports accident where the significance of the
important factor with traumatically induced micro-bleeds is impact dynamics can be less substantial than in motor vehicle
that they may evolve over hours to 12 days post-injury accidents. Here, DTI demonstrates reduced connectivity in the
(Oehmichen et al. 2003). Given CT limitations in detecting frontal region, likely a consequence of the mTBI although no
blood and the fact that in mTBI a CT scan, if done at all, is pre-injury baseline imaging was available for compariosn.
typically the first scan performed, usually within an hour or In addition to the shear/strain effects on blood vessels, TBI
two of coming into the emergency department (ED), and at the moderate-to-severe level of injury severity is a well-
therefore blood or blood byproducts may not be observed known cause of deficits in vascular autoregulation (Yokobori
in the initial imaging as demonstrated in Fig. 5 (also see et al. 2011). Using transcranial Doppler testing of dynamic
Bigler 2008). cerebral autoregulation, Junger et al. (1997) demonstrated in
Graham and Lantos (2002) provide a rationale for viewing mTBI patients 48 h post-injury that eight out of 29 (28 %)
TBI on a continuum, emphasizing the vulnerability of axons, demonstrated poorly functioning or absent cerebral
autoregulation versus none of the controls (p. 425). In pro-
fessional boxers with suspected chronic brain injury from
multiple concussive as well as sub-concussive blows to the
head, impaired cerebral hemodynamics has been demonstrat-
ed (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 dam-
age in mTBI alters vascular compliance adversely influencing
venous drainage. Likewise, Metting et al. (2013) used perfu-
sion 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
Fig. 5 Negative day of injury (DOI) computed tomography (CT) imag-
ing is shown in the two axial images on the top left. Approximately
perivascular nerve network (see Ueda et al. 2006). A variety of
6 weeks post-injury, follow-up MRI demonstrated hemosiderin deposi- abnormal fMRI findings have been reported in mTBI
tion (dark splotches) within the deep right frontal lobe (bottom left (Johnson et al. 2012a; Slobounov et al. 2011b; Chen et al.
coronal image ). These abnormalities persisted 5 years post-injury 2012a), and some form of subtle vascular pathology alone
reflected as white matter hyperintensities (WMHs) on the FLAIR se-
quence in the right frontal region as well as the hemosiderin deposition.
and/or in combination with neuronal pathology may be re-
All axial scans are in radiological orientation where right is on the sponsible for such findings. Regardless, from a structural
viewers left imaging perspective, presence of hemosiderin in the mTBI
180 Neuropsychol Rev (2013) 23:169209

Fig. 6 Hemosiderin deposition (black arrow) detected with susceptibil- anterior frontal region (arrow). Color reflects DTI convention where blue
ity weighted imaging (SWI) in an older child who sustained an mTBI in a reflects vertically oriented tracts, green indicates anterior-posterior orien-
sporting accident. Day-of-injury (DOI) computed tomography (CT) scan tated tracts and warm colors (orange-red) reflect tracts that are laterally
was negative. Diffuse tensor imaging (DTI) tractography (right image) oriented. Axial MR images are not in radiological perspective, because of
shows reduced frontal projection of aggregate tracts within the superior the 3-D image presentation. Right is on the viewers right

patient may not only infer TAI but disrupted vascular integrity all levels of severity, the distribution of these types of lesions
(Scheid et al. 2006). as observed in mTBI is identicallesions at the gray/white
As already indicated traumatic axonal injury or TAI may be margins, deep white matter, and corpus callosum.
the better term to use with regards to understanding all path- In the Bigler et al. (2013a) study that included 41 children
ological effects that relate to axonal damage from trauma (see with mild complicated TBI (mcTBI; defined as some type of
discussion of this point by Bigler and Maxwell 2012), but positive neuroimaging typically on initial CT imaging) all of
regardless of whether the DAI or TAI term is used, in mTBI whom had GCS of 1315 but on CT had evidence of skull
when focal WM abnormalities are visibly present, they are fracture, small contusion or some form of hemorrhage or
best detected in the fluid attenuated inversion recovery edema, 12 (29.3 %) had identifiable hemosiderin deposition
(FLAIR) sequence (Marquez de la Plata et al. 2007; an exam- on follow-up MRI at least 6 months post-injury. Given that
ple of a trauma-related FLAIR signal abnormality is shown in these observations were based on standard GRE sequence and
Fig. 5). The distribution of hyperintense foci on FLAIR im- not SWI, where sensitivity in detecting hemosiderin is 23
aging or the hypointense hemosiderin signal on GRE/SWI in times greater, indicates that this is an under estimate in the
TBI reflecting DAI/TAI pathology is shown in Fig. 7 from number of TAI-type findings in mcTBI (see Benson et al.
Chatelin et al. (2011). While the Fig. 7 illustration is based on 2012). Nonetheless, even with these limitations almost one-

Fig. 7 Chatelin et al. (2011) summarized the location and distribution of visually identifiable abnormalities. Note the frequent occurrence of DAI
diffuse axonal injury (DAI) pathology based on several neuroimaging within the frontal and temporal lobes. Red stars signify abnormalities in
and postmortem studies to show white matter (WM) pathology in deep deep WM regions and black indicates cortical and corpus callosum loci.
tracts within each hemisphere, corpus callosum, and upper brainstem as Used with permission from the Journal of the Mechanical Behavior of
indicated by black stars. Bar graphs represent a simple frequency count of Biomedical Materials and Elsevier publishing
Neuropsychol Rev (2013) 23:169209 181

third of mcTBI patients have a marker of TAI when MRI is Absence of Biomarkers of mTBI Lead to Psychogenic
performed yet there are no systematic large-scale neuropsy- Explanations
chological outcome studies in the literature that specifically
have studied this type of lesion mapping and mTBI. As pointed out by Taylor in 1967, during the chronic phase
Animal models of mTBI can provide a direct comparison after concussion, on conventional neurological testing, there
between neuroimaging and histological confirmation of neu- are no abnormal signs on physical examination (p. 67).
roimaging findings and confirm presence of neuropathology Without any objective marker of neurological impairment,
even at the mild end of TBI severity (Dewitt et al. 2013). The psychological explanations naturally came to the forefront.
shape of the animal brain, especially the rodent brain and skull Indeed, returning to Taylor (1967), he continues:
are very different from the human and therefore the precise
I have yet to read an article on the subject of post
biomechanics of human brain injury cannot exactly be dupli-
concussional sequelae in the British literature which
cated in animal models (Spain et al. 2010). Porcine models
does not contain the words litigation or psychogen-
that more directly mimic the human brain have been devel-
ic in the first dozen lines. Even a critical leading article
oped (Sullivan et al. 2013) and probably hold the greatest
about post-traumatic headache, written in April 1966,
promise for improved understanding of mTBI neuropathology
which concluded that treatment was not easy but was
based on neuroimaging findings integrated with histological
well worthwhile, contained the statement that in at least
confirmation and its effect on cognition and behavior (see
two-thirds of the patients there is a psychogenic ele-
Browne et al. 2011). These animal models provide histopath-
ment. This is certainly an advance on a similar leader
ological confirmation of what may be observed with in vivo
of 1961, which said: Above all, the general physician . .
neuroimaging in the human with TBI, including mTBI (see
. should find it advisable to refer a patient to the psychi-
Budde et al. 2011; Turtzo et al. 2012).
atrist as soon as possible . . . and concluded: In the
Although involving multiple concussive blows to the head,
ultimate analysis it [accident neurosis] is a social disease
ante-mortem imaging in those individuals with suspect chron-
and a function of industrial morale. (p. 67)
ic traumatic encephalopathy (CTE) is providing the neuro-
imaging background for improved understanding of the post- Taylor was referring to Millers classic papers on accident
mortem histopathology of CTE (Baugh et al. 2012; Handratta neurosis (Miller 1961a, b, 1962; Miller and Cartlidge 1972),
et al. 2010). Hart et al. (2013) and Strain et al. (2013) have where at best residual effects from concussion were portrayed
found cognitive deficits and depression in older retired by Miller as a functional disorder characterized by neurosis
National Football League (NFL) players compared to healthy in the title. At worst, residual effects that persisted from
controls, associated with WM-defined DTI findings. concussion were considered by Miller as feigned, malingered
Likewise, Lehman et al. (2012) found three times higher rates impairments associated with secondary gain, especially when
of neurodegenerative mortality in retired NFL players and litigation was involved. For Miller, attribution to cellular
CTE has been established in NFL players (McKee et al. damage as having any part to do with PCS was simply
2010, 2012). There are more unknowns than what is known unsupported speculation (Miller 1961a, p. 992).
about sports-related CTE, but the possibilities of this being a Miller was a neurologist and in the pre-neuroimaging era,
latent phenomenon of mTBI raises sobering questions and objective neurological findings, particularly those pathogno-
means the very best in research design should be applied to monic for damaged neural systems (i.e., an abnormal reflex,
studying mTBI and potential relations with CTE (see hemiplegia) were the only objective findings worthy of
Victoroff 2013) and other forms of neurodegeneration (Lee clinical demonstration of neurological damage or impairment
et al. 2013). Nonetheless, abnormal WM findings have been short of something being observed at the time of neurosurgery
reported in physician-observed concussion from hockey- or autopsy. Understandably, the patient with mTBI and an
related injury as well as soccer players without symptomatic entirely normal clinical neurological examination would
concussion, but with history of head and soccer ball impact not be suspected to have any underlying impairment.
(Koerte et al. 2012b, a; Lipton et al. 2013). The presumed Indeed, one of the classic and influential psychodynamic
relationships with such findings are the history of concussion textbooks at the time of Millers publications, Laughlins
and sub-concussive injuries. While CTE may require multiple (1956) The Neuroses in Clinical Practice, characterized all
concussive and sub-concussive blows to the head, each blow neuroses following trauma, including concussion, as merely
occurs within the realm of mTBI. Taken together, the animal neurotic reactions which have been attributed to or which
and human literature on mTBI provides support for the use of follow a situational traumatic event . (p.633). Specific to
advanced neuroimaging methods, that effectively detect vari- residual effects from concussion, Laughlin writes that
ous common brain pathologies in some who have sustained Evidence could not be found to validate scientifically the
mTBI, and these should become biomarkers for future mTBI theories of an organic basis., rather a large body of data
investigations related to neuropsychological outcome. has been accumulated clearly establishing the basic
182 Neuropsychol Rev (2013) 23:169209

psychologic origins of the symptoms commonly seen in con- potential solution, or at least an improvement in research
nection with these reactions (p.635). design, would be to use neuroimaging as a type of biomarker
Without an independent biomarker of brain injury, the to define mTBI subgroups with common pathology. As al-
natural conclusion is captured by the title of Jacobsons ready shown in Fig. 2, this was the approach taken by Sorg
(1995) review, The post -concussional syndrome : et al. (2013).
Physiogenesis, psychogenesis and malingering: An integra- In addition, this is captured in the study by Niogi et al.
tive model. Macleod (2010); Evans (2010) and Obermann (2008) which examined mTBI patients who underwent DTI as
et al. (2010), all provide updated reviews and perspectives of well as neuropsychological examination. A critical pathway
the functional versus the organic versus the malingering for memory involves the uncinate fasiculus (UF; see Nestor
symptoms that may be associated with mTBI. For example, et al. 2012) and Fig. 8 shows the relation of UF integrity based
as reflected in the article titlePost concussion syndrome: on FA and memory performance. Note in Fig. 8 that the long
The attraction of the psychological by the organic Macleod delay free recall (LDFR) trial of the California Verbal
(2010) makes the case that following concussion the po- Learning Test (CVLT; Delis et al. 2000) positively relates with
tentially malignant influences of psychosocial factors can FA in the UF, but not in the anterior corona radiata (ACR). A
compound the organic state since there is invariably a variety of factors may contribute to reduced memory perfor-
psychological component to any physical disease (p. 1035). mance and UF integrity as the UF is part of language and
Neuropsychological assessment entered the debate in 1974 emotional processing networks and not just memory (Catani
when Gronwall and Wrightson (1974a) demonstrated reduced et al. 2012), but the point is that it was the UF that related to
neuropsychological test performance in a group of individuals memory impairment in mTBI. Furthermore, note that over
with concussion dependent on task complexity and attention half of the mTBI subjects performed well within normative
demands (see also Gronwall and Wrightson 1974b, 1975). ranges of the standardization sample. So, unless the right
Gronwall and Wrightson and countless other investigators pathway is examined in mTBI patients with possible pertur-
have been attempting to characterize PCS symptoms, espe- bation of that pathway related to a particular function, no
cially, inability to carry out normal work, poor concentra- group relationship would be found. No two mTBI patients
tion, fatigue, irritability, and headache (p. 605), since the will ever have identical pathology; therefore, this limits how
original 1974 publications. Gronwall and Wrightson were omnibus whole-brain neuroimaging metrics would be sensi-
immediately criticized (see their commentaries in Gronwall tive in detecting where unique pathology may reside in mTBI
et al. 1990; Wrightson and Gronwall 1999) and the controver- (however, see Kim et al. 2013).
sy continues to this day (see Temme et al. 2013). However, Geary and colleagues (2010, 2011) similarly demonstrated
there would likely not be controversy, or less of it, if objective the importance of the UF in memory in mTBI but also exam-
measures of neural abnormalities could be demonstrated with ined a novel way of assessing list-learning using the CVLT
mTBI. The problem centers on the fact that PCS symptoms (Delis et al. 2000) in an mTBI sample. In 35 controls and 40
are simply not specific to having sustained a concussion; they mTBI subjects, Trial 1 was the only trial that reached signif-
occur from diverse sources and, in the individual with a icance, but the mean (M) and standard deviation (SD) values
history of head injury, are influenced by a host of pre-injury were clinically unimpressive (Control: M =7.63, SD =2.06;
as well as post-injury factors (Silver et al. 2009; Silver 2012). mTBI: M =6.58, SD =1.84); no other CVLT comparisons
Given these ambiguities it is no surprise that neuropsycholog- were significant including no GroupList interaction. In a
ical outcome studies provide such a confusing picture. traditional sense these would be interpreted as potentially
Although memory impairment as a symptom following meaningless and inconsequential clinical findingsthat is,
mTBI is commonplace (Ruff et al. 2009), memory complaints no neuropsychological effect from mTBI. However, the cor-
are ubiquitous symptoms across numerous neurological and relation between UF and CVLT was significant (it should also
neuropsychiatric disorders. Similarly, given the complexity of be noted that the superior longitudinal fasciculus was also
neural systems that underlie memory, diverse structures and significant, likely a reflection of attentional networks in mem-
pathways have the potential to influence memory performance ory), reflecting a distinct relation between reduced verbal
on a neuropsychological task. Indeed, similar arguments can learning and UF integrity.
be made about all symptoms/problems that form PCSnone Another example comes from Little et al. (2010), but this
are unique to having sustained an mTBI and none have a study focused on executive functioning tasks and examined
unique neural underpinning that would be specific to mTBI. DTI metrics of thalamic integrity. Again, only those with
Unless there is some type of biomarker to link the symptom abnormally low FA exhibited reduced neuropsychological
complaint (i.e., problems with memory, fatigue, inability to functioning. In these investigations if neuropsychological tests
concentrate, etc.) to the presenting problem and history, and to were group averaged, irrespective of neuroimaging findings,
which neural system is being affected, it becomes a statistical none or just a few and clinically unimpressive differences
quagmire to find relationships. As argued in this review, one would be observed. Geary et al. (2010) concluded, Most
Neuropsychol Rev (2013) 23:169209 183

Fig. 8 Two cognitive functions are specifically associated with white memory (r =0.057, p =0.725). c The UF FA does not correlate signif-
matter (WM) microstructure in two distinct regions (uncinate fasciculus icantly with attentional control (r =0.133; p =0.41). d Correlation of
[UF] and anterior corona radiata [ACR]) in adults with mild TBI. a attentional control measured by conflict score and the left ACR FA were
Correlation of memory performance and average bilateral UF fractional significant (r =0.47; p =0.001). This shows that cognitive effects from
anisotropy (FA) in both hemispheres (r =0.52, p <0.001). b The ACR FA mTBI may be region and task specific. From Niogi et al. (2008) and used
does not correlate significantly with long delay free recall (LDFR) with permission from Oxford University Press

critically, the finding of diminished recall for Trial 1 was False Distinction of Mild Complicated Traumatic Brain
observed in well-motivated (i.e., as assessed by effort mea- Injury or mcTBI
sures), nonlitigating, nondepressed, and gainfully employed
individuals many years after sustaining a mild TBI (p. 514), Since its introduction as a clinical neuroimaging method, MRI
and that patients with mTBI demonstrated, diminished has proven to be superior in detecting abnormalities associated
verbal learning that is not often interpreted in standard neuro- with any type of TBI (H. S. Levin et al. 1987). However,
psychological assessment. (p. 506). Traditional neuropsy- routine DOI clinical neuroimaging is almost exclusively done
chological methods did not distinguish the groups. with CT because the procedure is quick, clinically sensitive to
Psychogenic interpretations of mTBI effects have been neurosurgically important abnormalities, readily detects skull
dependent upon the absence of neurogenic explanations. fracture and can be done on patients with life support equip-
However, there has been no systematic assessment that has ment or metallic fragments in the head or body (Hunter et al.
pitted the so-called psychogenic versus neurogenic where ad- 2012). Likewise, interpretation is typically based solely on
vanced neuroimaging has been used. Had not advanced neu- clinical judgment of the radiologist, with no quantitative mea-
roimaging techniques been used, the interpretations of the sures applied. As might be expected, presence of DOI CT
memory problems in the mTBI patients described in the stud- abnormality in mTBI has been associated with increased
ies by Niogi et al. (2008), Geary et al. (2010, 2011) and Little levels of neurobehavioral and neurocognitive sequelae (de
et al. (2010), could have been given a psychogenic description. Guise et al. 2010; Kashluba et al. 2008; Mounce et al. 2012;
Without definitive biomarkers of brain injury in mTBI, one Iverson et al. 2000), although this is not always observed in
should be skeptical of its proof and influence on cognition and mTBI samples (Lange et al. 2012; Deepika et al. 2012).
behavior (see M. P. Alexander 1998). However, skepticism Because of the objectivity of DOI CT abnormalities indicating
over mTBI sequelae should form the foundation for critical, presence of parenchymal injury, as noted before, this classifi-
hypothesis driven research using the best in technology, not cation became known as mild complicated TBI or mcTBI.
just the rejection of the existence of the problem, especially This specific classification clearly identifies those mTBI pa-
when the issues of underlying neuropathology have not been tients with a definitive traumatic abnormality on the DOI CT
determined. scan, but the problem with this distinction is that because it is
184 Neuropsychol Rev (2013) 23:169209

only CT based, it substantially underestimates the true pres- volume and a 3.4 % increase in ventricular volume in indi-
ence and type of TBI abnormalities. viduals with mTBI. Both changes were statistically significant
Figure 9 is from a recent study by Yuh et al. (2012) that (p <.05). In the acute phase, quantitative metrics using DTI,
depicts the results from a prospective, multi-center study of like FA may identify differences from controls in more than
mTBI that included 135 patients who received early CT 90 % of mTBI subjects (Wilde et al. 2008). Likewise, several
imaging and MRI within 39 days post-injury. Clinically, mTBI studies have shown that DTI findings over 3 months
CT identified lesions in the form of contusion, hemorrhage, post-injury assist in identifying those with persistent neurobe-
or edema were found in approximately 25 % (numbers con- havioral and neurocognitive sequelae and, in turn, relate to
sistent with other studies as reviewed by Yuh et al. 2012) but those who remain symptomatic (see Ling et al. 2012; Mayer
note, over 40 % were identified with MRI. As reported by et al. 2012a, 2011, 2012b; Messe et al. 2011, 2012).
these investigators, CT was especially poor at identifying When DOI CT is compared with conventional MRI, as
axonal injury. shown in the studies reported above it may detect only half or
As important as Yuh et al. (2012) study is in demonstrating fewer of the abnormalities visibly present with MRI. Further,
how frequently neuroimaging abnormalities are found in with the greater sensitivity of SWI and DTI in detecting
mTBI, a particular limitation of this investigation is that it abnormalities, conservatively within any mTBI sample with
used conventional MRI and only examined T1, T2, T2*GRE reportedly normal CT, somewhere from one-quarter to a
and FLAIR sequences and clinical readings. The SWI se- third of those will have abnormalities detected with MRI.
quence is superior to standard GRE sequences in detecting An example of a normal DOI CT but abnormal MRI appears
hemosiderin, where comparative studies show a two-to- in Fig. 5, demonstrating the importance of follow-up neuro-
threefold increase in detection of abnormalities with SWI over imaging in mTBI even in the absence of any CT findings on
standard GRE (Benson et al. 2012). Yuh et al. did not include the DOI scan. This young adult university student was struck
quantitative analyses at different post-injury time-points, by a car and thrown into the curb. Positive LOC of short
which show a high yield in detecting differences in mTBI duration was independently verified by an observer at the
beyond just clinical findings (see Toth et al. 2013). Notably, scene. Emergency department (ED) assessment indicated a
none of the mTBI patients in the Toth et al. study had abnor- GCS of 13 but a negative CT. She was discharged from the
malities on DOI scanning, and clinical interpretation of the hospital the following day; however, upon returning to her
MRI findings was likewise negative. Only when the neuro- graduate studies she complained of substantial problems
imaging data were subjected to quantitative analyses, were with attention and memory. Follow-up MRI demonstrated
differences detected. It should be noted that Toth et al. at multiple regions of hemosiderin deposition within the fron-
1 month post-injury, in their longitudinal, within subjects tal white matter. Furthermore, these abnormalities remained
design, showed a mean 1 % volume reduction in overall brain essentially unchanged over the next 5 years, demonstrating
their permanency.
All past markers of mTBI such as LOC, DOI CT find-
ings, 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 psy-
chological variables may be at play as sequelae to mTBI
Fig. 9 Incidence of computed tomography (CT) vs. magnetic resonance (McNally et al. 2013). Before psychogenic theories are
imaging (MRI) traumatic brain injury common data element (TBI-CDE) invoked to explain the effects of mTBI, objective and con-
abnormalities in 135 study participants with mTBI. For MRI evidence of
contusion and MRI evidence of hemorrhagic axonal injury, progressively
trolled investigation of potential structural and functional
darker shades of red indicate larger numbers of lesions (gray legend). neuropathologies predictive of outcome is essential (Blaine
Study participants with CT evidence of brain contusion had, in most et al. 2013).
cases, evidence of one or two hemorrhagic contusions, with no CT An example of the potential misapplication of psychogenic
demonstrating more than 3 convincing brain contusions. CT showed
evidence of hemorrhagic axonal injury in 3 of 135 study participants,
interpretations for poorly identified illness comes from mili-
all with 1 to 3 foci of injury. Permission to be reproduced from Yuh et al. tary service men and women who served in the Gulf War in
(2012) and Wiley the early 1990s and developed Gulf War Illness (GWI). When
Neuropsychol Rev (2013) 23:169209 185

first reported GWI was widely touted as a classic psychogenic board, including processing speed with all domains function-
illness within the somatoform category of disorders (Gronseth ing approximately 0.5 to 1.0 SD below control levels.
2005); however, neuroimaging studies using techniques like Figure 10 indicates that the brain was damaged as this TBI
DTI have shown WM pathology in some individuals with cohort exhibited degenerative changes from the sub-acute
GWI that relate to subjective symptoms like fatigue and pain time of initial testing (2 months post-injury) to follow-up
(Rayhan et al. 2013). Such findings call into question (1 year). It is instructive to note that the greatest neuropatho-
umbrella-type psychogenic classifications until potential neu- logical changes occurred in WM, in the areas predicted by
ropathological explanations are ruled out. 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
Limitations in Detecting Neuropsychological Impairment Farbota et al. 2012b from this same group; and Farbota et al.
in TBI 2012a). Concomitant with the neurodegenerative changes
resulting in both gray matter (GM) and WM atrophy (defined
The most common problems from TBI are residual deficits in as volume loss), all domains of cognitive functioning
cognitive speed, visuoconstruction, attention, and memory exhibited improvements over time. However, despite im-
abilities (Millis et al. 2001). The study by Bendlin et al. provements in cognitive functioning with time in a mostly
(2008) provides an ideal example in the demonstration of moderate-to-severe TBI sample, as a group no cognitive func-
residual neuropsychological effects of TBI combined with tion returned to presumed baseline as reflected by the control
the most common areas of damage, in particular WM changes 0.0 z-score.
based on DTI metrics (see Fig. 10). Note how the abnormal- From a psychometric standpoint the extent of cognitive
ities depicted in Fig. 10 overlap with predicted areas of dam- impairment during the chronic phase seems to hover at around
age as shown in Figs. 1 and 7. Inclusion criteria in this inves- 0.5 of a standard deviation difference. Translating this to effect
tigation involved documented positive loss of consciousness, size differences, in TBI, including mcTBI with known gross
positive DOI CT scan and a GCS of at least 13 with initial neuropathological changes, neurocognitive function in most
MRI obtained around 2 months post-injury, with follow up domains would reflect on average medium effect size differ-
around 1 year post-injury. Thus, the Bendlin et al. research ences in comparison to a non-brain injured control sample. If
included mcTBI participants, although the overall sample only medium effect size differences occur in mostly moderate-
would be characterized as a moderate-to-severe TBI group. to-severe TBI with quantifiable brain volume loss from the
The control sample consisted of age and education matched brain injury, what does this mean for those who sustain mTBI,
participants without injury. Figure 11 summarizes the neuro- where pathology may be much more subtle? Does this not
psychological findings. mean that in using traditional neuropsychological measures
Neuropsychological results are presented in z-score format that the expected effect-size differences would be small or
with the 0.0 horizontal line indicating the control reference z- minimal, if present at all (see discussion by Bigler et al.
score. Clearly notable is the distinct influence that sub-acute 2013c)? In some studies involving moderate TBI, neuropsy-
brain injury has on speed of processing when first assessed but chological test findings cannot be differentiated from controls
by 1 year post-injury, improved functioning occurs across the or those with mTBI, even in those with positive neuroimaging

Fig. 10 Neuroimaging findings depicting the extent of gray matter (GM) Patients also showed GM volume decline over time in the cingulum, right
and white matter (WM) damage in the Bendlin et al. (2008) study, post-central gyrus, supplementary motor area, right precentral gyrus, and
showing changes (volume loss) from 2-months post-injury to 12 months. bilateral putamen (areas not shown here). Results are shown in neurolog-
The TBI group showed extensive WM volume decline over time (shown ical orientation (left is left). Color bars reflect t-statistics. Permission to
in hot colors), in addition to a few regions of GM volume decline, reproduce from Elsevier and the authors
including the thalamus and bilateral pallidum (shown in winter colors).
186 Neuropsychol Rev (2013) 23:169209

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 post-
injury reflects the most significant
deficits, which by a year post-
injury 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 CT but positive follow-up MRI with multiple hemosiderin
the neuropsychological technique being used to assess cogni- deposits noted particularly in the frontal area (this case is
tion in mTBI needs to be critiqued? discussed in Bigler 2004). The patient complained of memory
As noted, the CVLT memory task was sensitive to differ- problems but as graphically depicted in Fig. 12, only on Trial
ences on Trial 1, but on average this amounted to less than one 2 of the CVLT-II does this patient perform outside the range of
fewer word retained in the mTBI group on the 16-item word the normative sample, and on that trial only deviates less than
list [Little et al. (2010) and Geary et al. (2010)]. Heitger et al. one word. Without the positive neuroimaging reflecting
(2009) found a significantly lower retention of the distractor abnormalities within known memory/attentional networks,
list on the Rey Auditory Verbal Learning Test (RAVLT; Rey such findings from traditional neuropsychological test re-
1958) in a group of symptomatic mTBI patients but in real sults may simply be overlooked. The memory problems
terms this amounted, on average, to less than one word associated with mTBI may simply not be assessed by these
recalled by the PCS symptomatic mTBI group compared with traditional neuropsychological measures or they may sim-
the symptomatic (again, effort and depression were controlled ply be silent anomalies.
for). Ponsford et al. (2011) examined memory performance at
1 week and 3 months post-mTBI using the ImPACT comput-
erized assessment method (Iverson et al. 2003) and observed a Between Subject Heterogeneity of mTBI Neuropathology:
significant difference at 3 months on a visual composite If No Two TBIs are Ever Identical, How can a Uniform
memory measure; however, the reported effect size difference Neuropsychological Outcome be Expected?
was small at 0.25. Again, from a clinical perspective these are
negligible to minimal differences for the clinical neuropsy- Given the uniqueness of individual brains, combined with the
chologist to detect with traditional neuropsychological mea- unique circumstances and biomechanics of any brain injury
sures in the individual with mTBI. Therefore, not only will the (Watanabe et al. 2012)especially the random nature of
neuropathological substrate of mTBI be subtle for neuroim- injuriesit is unlikely that two brain injuries could ever be
aging techniques to detect, but the neuropsychological effects identical (Rosenbaum and Lipton 2012). Even with the de-
will also be as equally subtle if traditional methods are used. tailed controls and experimental rigor of animal TBI models,
Figure 12 graphically shows this problem in an mTBI case Turtzo et al. (2012) showed using an identical rat strain
of a 17.5 year-old mTBI patient by plotting out CVLT-II mechanically injured in exactly the same fashion with a con-
performance over trials. This individual had initial negative trolled cortical impact methodidentifiable pathology was
Neuropsychol Rev (2013) 23:169209 187

have mcTBI-related focal pathology, but the marked differ-

ences in the distribution of macroscopically identified lesions
are evident. Simple overview of this illustration and the non-
overlapping nature of the lesions would implicate non-
overlapping 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 path-
ways 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 abnor-
malities and aggregate mTBI subjects into similar groups,
why would there be any neuropsychological expectation
that similar deficits in cognitive and neurobehavioral func-
tioning 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 undoubt-
edly 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
Fig. 12 Performance on the California Verbal Learning Test (CVLT) in
an mTBI patient with negative day-of-injury (DOI) computed tomogra- effects that otherwise are present within mTBI subgroups.
phy (CT) but positive magnetic resonance imaging (MRI) with multiple Returning to the Niogi et al. (2008; see Fig. 8) investigation,
hemosiderin deposits within the frontal and temporal lobes. Patient it is only when memory is considered within the context of the
CVLT-II performance (black diamond ) is plotted in comparison to UF integrity, that mTBI related memory impairments become
CVLT-II normative data (gray bars) from the test manual. Note that the
patients performance, while on the low end of the normative distribution apparent, and then only within a subset of those with a history
in each trial, only drops below 1 standard deviation (s.d.) of the compar- of mTBI.
ison sample on Trial 2 in List A Immediate. This case is adapted from
Bigler (2004)
The Concept of Mild Cognitive Impairment
never identical. Similarly, Sullivan et al. (2013) in a porcine and Neuropsychology
model demonstrated that sagittal rotations were most likely to
injure axons, sparing those in other planes. With human FE In terms of injury classification of TBI, mild, moderate and
modeling using individual MRI configured brain anatomy, no severe categorization has been the standard since the origina-
two injuries could be identically simulated (see Bayly et al. tion of the GCS metric in 1974. There is no dispute concus-
2012). sion is a TBI and, provided that no disruption or change in
The mcTBI component of the study by Bigler et al. (2013a) level of consciousness moves the GCS measure below a 13,
found no case where any of the lesions (areas of focal that this level of TBI constitutes the mildest of injuries. If level
encephalomalacia, hemosiderin deposit, or WM signal abnor- of injury is effectively described as ranging from mild to
mality) perfectly overlapped. The major inference of this is severe and if all TBI is on a continuum, as argued in this
reflected in Fig. 13 from four mTBI cases from this study, review, why would the potential for residual cognitive effects
three with a GCS of 15 and one a GCS score of 14. These stop at the moderate range of TBI? As already stated, animal
cases were selected for this illustration as they unequivocally models of TBI may be graded from no discernible
188 Neuropsychol Rev (2013) 23:169209

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)

pathophysiological or neurobehavioral effects, to showing provide objective indicators of underlying neuropathology

increasingly impaired cognitive performance with underlying should assist in better characterization of the neurocognitive
injury severity and neuropathology. With neuroimaging and and neurobehavioral outcomes of mTBI.
electrophysiological studies consistently showing WM pa-
thology and abnormalities in connectivity in mTBI (Morey Subjective Symptoms and the Term Mild Maybe the biggest
et al. 2012; Tallus et al. 2013; Smits et al. 2011; Kirov et al. obstacle with the mild classification within the field of
2013; Messe et al. 2013), combined with animal models and neuropsychology comes with the subjectivity and non-
human studies from multiple concussions showing histologi- descript nature of so many of mTBI symptoms. Much has
cally confirmed brain pathology (McKee et al. 2010, 2012; been written about subjective symptoms in mTBI because of
Wall et al. 2006), why would it not be expected that such their co-occurrence with so many other neurological and
pathology adversely affects cognition and behavior? neuropsychiatric conditions (Chaput et al. 2009; Iverson
Historically, psychological theory of cognitive impairment, et al. 2010; Jakola et al. 2007; Kennedy et al. 2007;
regardless of etiology, consistently has been reported in terms Macleod 2010). This, coupled with issues related to research
of mild, moderate-to-severe impairments in comparison to design of mTBI studies, led the 2004 World Health
some normative sample (Bornstein et al. 1987). This has been Organization (WHO) to label much of the research in mTBI
established for all disorders, be it stroke, degenerative disease, problematic (see Carroll et al. 2004a). Without a definitive
demyelinating disorders, epilepsy, etc., in order to characterize biomarker that differentiates etiology of symptoms from other
neurocognitive effects of the disorder (Beghi et al. 2006; disorders, it should be no surprise that studies that examine
Grau-Olivares and Arboix 2009; Snyder et al. 2011; group outcome in mTBI, mostly endorse biopsychosocial
Waldstein and Wendell 2010). The argument of this review models, some of which minimize or do not discuss any
is that mild neurocognitive and neurobehavioral sequelae do underlying neuropathology (see discussions by Silver 2012;
occur with mTBI and should be characterized as such. And Silver et al. 2009; van Veldhoven et al. 2011; Williams et al.
further, although a rather benign clinical course of full return 2010). On the other hand, expression of a subset of symptoms
of function in mTBI is the norm, neuroimaging methods that associated with mTBI may be psychogenic (Mounce et al.
Neuropsychol Rev (2013) 23:169209 189

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

2012; Macleod 2010); however, a search for underlying neu- neurodegenerative disease. For example, when turning to the
ropathology should be undertaken before the psychogenic literature on aging and dementia, neuroticism was once con-
label is considered. sidered simply a trait not linked in any way with dementia.
While subjective symptoms may be the bane of neuropsy- However, life stressors as well as early-in-life neuroticism and
chology in terms of understanding mTBI (McLean et al. depression have a relationship with the development of de-
2009), understanding the nature of subjective symptoms have mentia, potentially via stress-mediated neuroinflammation
played a key element of what occurs during the prodrome of factors (Wilson et al. 2007).
190 Neuropsychol Rev (2013) 23:169209

Similarly, ill-defined prodromal cognitive complaints in memory impairment and attentional deficits., Duffin
older individuals with subjective memory symptoms do relate et al. (2012) show on average, that stroke patients thought to
to who develops mild cognitive impairment (MCI) and con- have suffered a mild [italics added] cerebrovascular acci-
verts to Alzheimers disease (Jessen et al. 2010; Reisberg et al. dent, exhibited significantly reduced retention on the
2010). Subjective symptoms also appear to be harbingers of RAVLT of approximately one word. Note this is the same
progressive change in other conditions, for example, multiple level of reduced performance that Geary et al. (2010, 2011),
sclerosis (Marrie et al. 2005), Lupus erythematosus (Denburg Little et al. (2010), and Heitger et al. (2009) found in mTBI on
et al. 2003), Parkinsons disease (Bugalho and Oliveira-Maia list retention tasks like the RAVL or CVLT. Although signif-
2012; Skogar et al. 2012). Most relevant to mTBI is that icant, a one or two word less retention on a 15-item word list
recently Lafrance and colleagues (2013) found that history can only be viewed as a subtle, slight difference. Returning to
of TBI was a significant risk factor in development of psy- the Bendlin et al. (2008) study, it shows that effect size
chogenic nonepileptic seizures. It seems intuitive for all neu- differences overall on cognitive performance >12 months
rological and neuropsychiatric disorders that factors heralding post-TBI in mostly moderate-to-severe TBI patients with neu-
vulnerabilities for developing depression and anxiety-based roimaging documented atrophy is only about 0.5. This trans-
disorders provide a backdrop reflecting a different brain at the lates to an expected difference per trial on measures like the
time of sustaining an mTBI than the brain without such CVLT or RAVLT of approximately one less word recalled. If
vulnerabilities. Likewise, any of these pre-existing vulnerabil- those with well documented structural damage exhibit this
ities probably diminishes the resources and resiliencies post- kind of subtleness to their cognitive profile on traditional
injury in coping with the effects of mTBI. In the case of neuropsychological tests, what kind of impairment would be
psychogenic epilepsy, some diminished capacity for emotion- detected in the mTBI patient with mild cognitive problems?
al coping because of the brain injury may be the path for An even more important issue is alluded to by Millis
increased maladaptive emotional adjustment post-injury, (2009) with the following statement: cognitive tests do
resulting in the phenomena of pseudoseizures as found in not directly measure cognition: they measure behavior
the Lafrance et al. (2013) study. Of course, all of the disorders from which we make inferences about cognition
just mentioned (i.e., epilepsy) have their own definitive bio- (p.2410). Neuropsychological measures of cognition only
markers, which then assist in ferreting out how subjective permit inferences to be made about brain function (see
symptoms/complaints may relate to the disorder. Without Lezak et al. 2012). This becomes an even more important
biomarkers for mTBI as offered by advanced neuroimaging issue when attempting to detect subtle deficits, given the
methods, the problems circle back to the imprecision of mea- controlled assessment environment that does not mimic a
suring subjective complaints and no method to tie them to naturalistic setting. The majority of clinically administered
what may be bona fide neuropathology or absence thereof. neuropsychological tests that are performed use highly
Subjective symptoms will remain nondescript and likely regimented standardized presentations of auditory and vi-
not be helpful in discriminating mTBI patients from other sual stimuli, with hand-recording of responses and their
conditions nor useful in predicting who achieves good versus tabulation for scoring and interpreting all done within a
poor recovery. Well-designed neuroimaging studies or studies rigid administration of items, with no extraneous stimuli or
based on other validated biomarkers are needed to address this sound. Likewise, potential differences are as good as are
issue systematically (Zetterberg et al. 2013). For example, the comparative norms and normative samples. This prob-
Chen et al. (2007) demonstrated a relationship between lem is distinctly demonstrated in the mTBI case presented
persisting symptoms and PCS following mTBI and different in Fig. 5.
fMRI activation patterns in prefrontal regions in mTBI sub- The college student previously depicted in Fig. 5 had
jects. Bigler and Bazarian (2010) argue that studying participated in a variety of routine working memory tasks as
persisting symptoms combined with neuroimaging bio- a volunteer participant for fMRI cognitive neuroscience re-
markers must be the next line of research examining the search projects before she was injured. Therefore, pre-injury
effects of mTBI, including emotional outcome and occurrence data were available on not only her cognitive performance but
of non-specific symptoms. her fMRI activation patterns in response to the cognitive
probes (see Wu et al. 2010a; Allen et al. 2011). When re-
The Problem of Measuring What may be Mild in Neuro- assessed more than a year post-injury and having completed
psychological Outcome Using traditional neuropsychological her degree and with full-time employment, although still with
measures, one of the biggest challenges in clinical neuropsy- lingering PCS, cognitively on the paper-and-pencil and com-
chology may be determining what the mild neurocognitive puter based tasks she was able to perform at similar levels as
effects of any disorder are, including mTBI. This problem was pre-injury. However, using an event-related fMRI paradigm
introduced in the discussions involving Figs. 2, 5, 8, and 11. In where performance (response latency) was assessed in milli-
a stroke study that has in its title the detection of subtle seconds, reflective of true neural processing speed, her
Neuropsychol Rev (2013) 23:169209 191

performance level was slower by about ~135 milliseconds. performing basic mental tasks even in the earliest stages of
Accuracy had not changed at all, only slowed processing. recovery, just not as efficiently. But in earlier times from a
Thus, traditional neuropsychological test findings were not survival perspective memory demands would likely have been
tapping underlying neural deficits and what the patient was much more naturalistic than what occurs with the modern
subjectively experiencing. She struggled with attentional pro- challenges of todays technologically sophisticated world,
cesses, speed and working memory, and as can be viewed in and therefore, potentially not as noticeable.
Fig. 5 had distinct frontal pathology (hemosiderin and Anatomically, there is likely a straightforward explanation
WMHs) within known networks associated with attention, for differential evolutionary effects on motor over cognitive
speed of processing and working memory, confirming the recovery. Figure 15 shows the mostly vertically organized
likelihood that her mTBI related complaints were neurogenic. 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 (com-
Evolutionary Influences on Recovery from mTBI pare to Fig. 16) have a common location associated with the
reticular activating system (RAS). One look at the narrow
Survivability from a concussion is true across the animal trajectory, see red arrows in Fig. 16, of these pathways through
kingdom. There are numerous animal models of mTBI this upper midbrain region, see horizontal red lines in Fig. 16,
(Biasca and Maxwell 2007; Cohen et al. 2007; Leker et al. shows the unique confluence of these tracts in relationship to
2002; Shaw 2002; Weber 2007), all demonstrating good re- the large and weighty cerebral hemispheres. Furthermore, the
covery of basic functioning following mTBI in distinct con- upper brainstem remains more rigid being held in position by
trast to moderate-to-severe TBI. In terms of the natural re- the skull base than the cerebral hemispheres, and is tethered to
covery of function, most extensively studied in the athlete, the spinal cord that is tightly held within the spinal column. By
basic motor, sensory and cerebellar functions predictably are definition, any effect at this upper brainstem level must be
the first affected and likewise, the first to come back on-line. minimal in mTBI or otherwise the individual is left with
Evolutionarily, that makes sense because in the brutish fight- longer duration coma and thus a lower GCS than the minimal
flight world of our ancestors, if you were on the losing end of post-resuscitation 13 score required for mTBI classification.
fisticuffs, one would need to sufficiently recover motor ability Any prolonged disruption of the RAS would lead to longer
to flee (see Bigler 2012) or survival was unlikely (Masel and duration coma and persistence of disorders of consciousness
DeWitt 2010). Likewise, in earlier eras to remain part of a (Jellinger 2013). So, by definition these neural systems cannot
human clan, mobility was certainly a key factor as well. From be seriously damaged in order to survive the brain injury and
a cognitive perspective, the concussed individual is capable of remain classified as an mTBI.

Fig. 15 The corticospinal and spinocortical tracts are oriented vertically very different trajectories. Adapted with permission from Catani and
with afferent and efferent pathways coursing through the brainstem. In Thiebaut de Schotten 2008 and Elsevier. See also Catani and Thiebaut
contrast the interhemispheric pathways of the corpus callosum and the de Schotten (2012).
intrahemispheric pathways of the inferior occipitofrontal fasciculus have
192 Neuropsychol Rev (2013) 23:169209

Fig. 16 The left cerebral hemisphere is shown in the upper left as a 3-D T1-weighted image that shows the small midbrain and brainstem in
rendered view from T1-weighted magnetic resonance imaging (MRI). comparison to the large cerebral hemispheres, and then highlighted with
The upper middle panel shows the much smaller brainstem (outlined the middle panel, with the arrows pointing to the region of the cerebral
flesh-tone) with the ventricular system shown in aquamarine for orienta- peduncle and where the corticospinal tracts pass. Lower right panel shows
tion. Notice the smallness of the brainstem in relation to the cerebral a lateral view of the corpus callosum superimposed on the 3-D brain from
hemisphere, as well as the central location of the brainstem in relation to the upper left, showing the orientation of projecting fibers. Colors repre-
the cerebral hemisphere. Mid-sagittal T1-weighted MRI is shown in the sent aggregate tract orientationblue=vertically oriented tracts, green=
upper right panel. Particularly small is the midbrain region, outlined by anteriorly-posteriorly orientated tracts and warm colors (orange-red)=
the horizontal red lines in the upper right image. Lower left is a coronal side-to-side or laterally projecting tracts

However, as shown in Figs. 15 and 16 the long coursing in unarmed combatants, presumed to be present as a reflection
WM inter- and intra-hemispheric pathways are oriented quite of concussion history, and when such findings are within the
differently from the primary motor and somatosensory path- gray-white junction or adjacent to the corpus callosum, the
ways 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), differential-
ly influenced by shear-strain effects and interhemispheric con-
nections. 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.

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 var-
iant and certainly not specific to TBI (see Hopkins et al. 2006; Fig. 17 [View this image in conjunction with Fig. 18]. The FLAIR
Iverson et al. 2011), in an otherwise healthy individual who image in the upper right shows a distinct white matter hyperintensity
(WMHs, red arrow) in the frontal white matter (WM). Plotting the
experiences mTBI, their presence may reflect white matter location of all WMHs (as shown in yellow) in the 3-D DTI surface
damage (Benson et al. 2012; Shenton et al. 2012). WMH may rendered image of the brain (diffusion scan images are fuzzy, and that is
also represent vulnerability indicators since they are associat- why this image represents just a smooth surface outline of the brain), in
ed with disorders like depression (Kempton et al. 2011), the upper left shows the multiple distribution of WMHs. However, using
tract-based spatial statistics (TBSS), differences in WM, compared to a
where pre-existing depression increases the likelihood of normative sample, exhibit a somewhat different distribution of WM
persisting symptoms following mTBI (Silver et al. 2009). findings as shown in red in the 3-D view (ventricular system is shown
Orrison et al. (2009) demonstrated WMH with increased rates in aquamarine for orientation purposes)
Neuropsychol Rev (2013) 23:169209 193

Fig. 18 [View this image in conjunction with Fig. 17]. White matter White=corpus callosum, Purple=arcuate fasciculus, Orange=uncinate
hyperintensities (WMHs, yellow) and tract-based spatial statistics (TBSS) fasciculus, Blue=corticospinal and spinocortical tracts, Dark Green=
white matter (WM) differences (red ) in an mTBI subject are inferior occipito-frontal fasciculus, Light Green=occipito-temporal fas-
superimposed on tubular generated diffuse tensor imaging (DTI) tracts ciculus, Lightest Green=Cingulum Bundle. Different techniques that
for ease in visualizing the tract, showing how depending on which tract is highlight different types of WM findings depend on the imaging sequence
being examined, the WM finding occurs within different tracts. Note: and the method used to identify the difference

likelihood of these signal abnormalities reflecting brain pa- 60 (Pettersen et al. 2008). For example, in a sample of ortho-
thology from trauma is increased (Bigler and Maxwell 2011). pedically injured children with no brain insult, had no evi-
WMHs are best seen on the FLAIR sequence as shown in dence of hemosiderin although two had WMH (Bigler et al.
Fig. 17 (see also Figs. 5 and 13 and previous discussion of T2 2013a). Whether these WMH were trauma-related in any way
and FLAIR identified WMH). is unknown, but likely were just normal variants or incidental
Another method for assessing WM integrity based on DTI findings (Katzman et al. 1999; Vernooij et al. 2007) that pre-
findings is a technique that uses what is referred to as tract- dated the mTBI.
based spatial statistics or TBSS (Grossman et al. 2012b). In If between-subject heterogeneity reflects the unique differ-
comparison with a normative sample, location of statistically ences between subjects in terms of injury biomechanics and
significant deviations in DTI metrics can be identified using dynamics (along with genetic, pre-injury, and complex-post-
TBSS, pathological differences that do not necessarily match injury factors), then the within -subject heterogeneity of
where FLAIR-identified WMHs are located as shown in how and where lesions may influence neural systems, is
Figs. 17 and 18 (see also Dineen et al. 2009). This distinctly just as complex. What becomes evident when these lesions are
demonstrates that these two MRI-derived WM findings plotted is not just whether a lesion is present, but whether the
WMH and DTI tract abnormalitiesin this mTBI patient likely lesion significantly disrupts a network.
represent different aspects of WM anatomy. When WMH were
simultaneously plotted in conjunction with TBSS derived dif-
ferences and overlaid on various white matter fasciculi, the mTBI, Networks, and Resiliency
heterogeneity of how such findings may influence different
neural substrates is immediately evident as shown in Fig. 18. Consistently, the neurocognitive effects of TBI have been
Because abnormalities findings like WMH occur in the shown to result in slower speed of processing and disruptions
normal population, even in children (see Bigler et al. 2013a), in the central EF working memory system (Ciaramelli et al.
their presence alone cannot be considered an unequivocal 2006; Willmott et al. 2009). While a full discussion of atten-
biomarker of injury. However, because TBI is likely to occur tional and working memory networks is beyond the scope of
in an individual under 40 years of age, presence of WMH in this review, what has been referred to as the default mode
younger individuals has a low base rate as do indicators for network (DMN) has become fundamental in understanding
micro-bleeds (see Potchen et al. 2013), although the likeli- the effects of TBI on memory, attention, and processing speed
hood of these findings becomes much more frequent after age (see Arenivas et al. 2012; Bonnelle et al. 2012; Palacios et al.
194 Neuropsychol Rev (2013) 23:169209

2012; Zhou et al. 2012). Of particular relevance to mTBI, the mTBI subjects, have demonstrated that disruptions in the
DMN, in part, relies on patent and efficient pathways between DMN relates to neurocognitive sequelae in TBI (Zhang et al.
parietal and frontal cortices during engagement involving 2012; Johnson et al. 2012a; Sharp et al. 2011; Caeyenberghs
attentional tasks. These are some of the longest et al. 2012; Mayer et al. 2012a). From a cognitive symptom
intrahemispheric pathways, but also require interhemispheric perspective, attention deficits along with disrupted emotional
integration via the corpus callosum. This means that as a regulation are commonplace in mTBI. As shown in the above
consequence of deformation/shear/strain influences that occur mentioned studies WM pathology within the DMN related to
during TBI, the DMN is especially vulnerable to injury, even TBI, especially that which influences both cortical-cortical
at the level of an mTBI. Andrews-Hanna et al. (2010) derived and corticolimbic connections may play a central role in the
a simplified network involving aspects of the DMN as shown evolution of symptoms of memory and emotional dysfunction
in Fig. 19. What is critical about this figure is the interrela- following mTBI.
tionship between key brain structures involving medial tem- The Human Connectome work of Van den Heuvel and
poral lobe memory regions (hippocampus), with intra- and Sporns (2011) has emphasized critical hubs and nodes in
interhemispheric pathways linking the entirety of the memory what they refer to as rich-club connections within ma-
network including the fornix and cingulum bundle. All of jor networks. If damage does not involve a major hub or
these brain regions in the DMN are particularly vulnerable node, then the brain probably has greater resiliency in re -
to the biomechanical and neuropathological effects of TBI networking around the lesion. However, returning to
(Bigler 2007). Fig. 19 from Andrews-Hanna et al., if the anterior medial
In association with the DMN, as partly shown in Fig. 19, prefrontal cortex is damaged, such damage takes out
are key connections, like the cingulum bundle (Wu et al. eight critical links within the network. As Moretti et al.
2010b), which receives input from the hippocampus via the (2012) have shown, disruptions of a hub have far-
mammillary bodies and anterior thalamus. Figure 20, from reaching ipsilateral as well as contralateral adverse in-
Bonnelle et al. (2011) shows that in TBI lower FA, likely fluences. Damage in mTBI outside the rich-club network
reflecting abnormal WM integrity of the cingulum bundle, may have minimal to no effect and permit the brain to
was associated with slower reaction time. In addition to the re-wire. However, any type of lesion disrupting a so-
study by Bonnelle et al., others investigations that included called rich-club network could have widespread influ-
mTBI subjects, some of which exclusively examined only ence, 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
Neuropsychol Rev (2013) 23:169209 195

Fig. 20 Sustained attention as measured by reaction time was found to be cingulum bundle connecting the posterior and anterior parts of the
correlated with cingulum bundle structure in TBI as shown by Bonnelle DMN is shown in green. b Fractional anisotropy (FA) of the cingulum
et al. (2011). Notice how this system involves the default mode network bundle in patients is plotted against the change in reaction time (RT)
and extensive connectiveness of what was previously shown in Fig. 19. a between the first and the last part of the task (N =28). Measures are age
Sagittal view (x =8) of the reference component selected for the function- normalized, i.e., age was regressed out from the measures using a linear
al connectivity analysis. Anterior and posterior midline nodes of the regression, where residuals were saved as standardized values.
default mode network (DMN) are shown in warm colors, and the midline Reproduced with permission from the Society for Neuroscience
node within the executive network (EN) is shown in blue. The right

Are Traditional Neuropsychological Metrics Used this is an absence of any residual neuropsychological effect,
in mTBI Assessment Insensitive to the Cognitive even though structural pathology may be present, or is it the
and Neurobehavioral Effects of the Injury? lack of sensitivity of the test attempting to define a
neurocognitive correlate? All of this implicates an insensitiv-
With the emergence of clinical neuropsychology in the late ity of traditional neuropsychological methods in detecting
1960s, early 1970s neuropsychological methods were consid- subtle abnormal neurological states that may exist in mTBI.
ered the gold standard for diagnosing mTBI (see Boll and Levin et al. (2012) showed in a study that obtained initial
Barth 1983; Barth et al. 1983). The premise was that the post-injury mTBI MRI findings within 24 to 96 h, then at
neurocognitive effects of mTBI were detected when neuro- 1 week, 1 month and 3 months that traditional speed of
psychological test performance deviated below some assumed processing measures like the Symbol Digit Modalities Test
baseline or established norm. However, once factors such as (SDMT; Smith 1992) did not distinguish lasting sequelae,
age, education, time post-injury plus pre-injury psychosocial only computerized reaction time (RT), or Codesub
variables, post-injury variables such as pain, sleep disorder, Reaction Time, the speed of processing task from the
fatigue and emotional functioning were all considered, the Automated Neuropsychological Assessment Metrics
complexity of the problem of mTBI assessment with only (ANAM, Reeves et al. 2002) remained significantly different
neuropsychological tests became evident (Silver 2012; Silver after 3 months. Traditional neuropsychological administration
et al. 2009). of the SDMT is paper-and-pencil with time measured in
Within-subject designed sports concussion studies that seconds. Codesub RT is measured in milliseconds (msecs;
obtained pre-injury measures and then assessed neuropsycho- Cernich et al. 2007).
logical status post-injury, convincingly demonstrated that Millisecond processing speed is more representative of
some traditional neuropsychological methods were sensitive real-time neural processing (Momjian et al. 2003) and po-
in detecting acute effects of mTBI. However, over time these tentially the type of task that best distinguishes between those
standard neuropsychological measures could show a return to with mTBI and controls (Hartikainen et al. 2010). In typical,
baseline, all-the-while electrophysiological and neuroimaging developed, non-injured control subjects cognitive tasks that
findings may not, and subjectively, mTBI patients continue to pit speed versus accuracy show match versus mismatch per-
report PCS (Prichep et al. 2012; Gardner et al. 2012; Henry formance to differ between the 100200 msec range (Ho et al.
et al. 2011; Talavage et al. 2013; Slobounov et al. 2011a, b). 2012). All timed traditional neuropsychological measures as-
At 4 months post-injury using DTI, neuroimaging abnor- sess speed with a manually controlled stopwatch. Stopwatch
malities have been detected in mTBI, yet minimal-to-no neu- accuracy either between trials or between raters for an identi-
ropsychological differences were found on standard clinical cal event is about 100 msec (Vicente-Rodriguez et al. 2011).
measures (Ling et al. 2012). The question reverts to whether Measuring in seconds rather than msecs and the error
196 Neuropsychol Rev (2013) 23:169209

introduced by turning on and off a hand initiated timer would the origin of the deficit. Fortunately, using neuroimaging as a
obscure any subtle differences in true neural processing speed biomarker of thalamic integrity, there are now several studies
potentially induced by mTBI. Combining this error variance of mTBI patients showing abnormal connectivity and resting
with only small-to-medium and often non-significant differ- state activity within the thalamus that relate to cognitive
ences in traditional neuropsychological test performance, even impairment (Grossman et al. 2012b; Nathan et al. 2012;
in moderate-to-severe TBI as demonstrated by Bendlin et al. Yang et al. 2012; Raz et al. 2011; L. Tang et al. 2011;
(2008), suggests that traditional neuropsychological assess- Grossman et al. 2012a; Gosselin et al. 2011; Little et al.
ment methods will be even less sensitive in detecting what 2010). Because of the central role played by the thalamus
may be genuine cognitive, yet subtle differences in those with any small perturbation at this brain level could have potential
mTBI. widespread cortical effects (Izhikevich and Edelman 2008).
Brenner et al. (2010) examined 45 soldiers with well doc- Nonetheless, without neuroimaging or some electrophysio-
umented history of presumed blast-related mTBI divided into logical measure of upper brainstem and/or thalamic integrity,
two groupsone that became asymptomatic and the other neuropsychological techniques are limited in distinguishing
remained symptomatic, yet neuropsychological measures deficits associated with the type of pathology that might be
could not differentiate the groups. Brenner et al. offer the present in these areas without independent confirmation via
following conclusion, standard neuropsychological assess- neuroimaging.
ment may not increase understanding about impairment asso- So, what can it mean in an mTBI patient if neural process-
ciated with mTBI symptoms (p. 160). The longitudinal study ing is disrupted by 50 to 100 msec when engaging attentional
by Heitger et al. (2009) conducted in New Zealand, has been networks, such as the DMN? Mayer et al. (2009) demonstrat-
referred to several times in this review because of the quality ed that an mTBI group, which did not significantly differ from
of the experimental design. It demonstrated the exact same controls on traditional neuropsychological measures of atten-
findings as Brenner et al., matching two groups on injury tion or memory, was significantly slower to disengage and
severity and all aspects of injury demographics where, at reorient to an auditory attention task. As a group, the mTBI
6 months and beyond, one group had recovered and was participants were slower by the 50100 msec range, times
asymptomatic, but the other group remained symptomatic. In below detection with traditional neuropsychological mea-
the symptomatic group, neuropsychological testing identified sures. Given the increased likelihood of WM pathology asso-
deficits in only 5 of the 36 subjects despite all being symp- ciated with mTBI and the subtleness of injury effects, espe-
tomatic from a PCS standpoint. Heitger and colleagues con- cially at a thalamic level, neuropsychology as a field needs to
cluded, This limited ability of neuropsychological testing to rethink the use of traditional neuropsychological methods to
document ongoing impairment in brain function in mCHI study the mildest forms of brain injury. Traditional methods
[mild closed head injury; their term rather than mTBI, as used would not be sensitive in detecting real-world processing
in this review] was also reflected in our results (p. 2865). deficits that could influence processing speed, arousal, and
Abnormalities in eye-movement in the form of slower eye- attention/concentration. For a variety of reasons clinical neu-
tracking did demonstrate consistent differences in the symp- ropsychology has been slow to embrace techniques like com-
tomatic mTBI group, reliably differentiating symptomatic puter and virtual-based methods that may have much greater
from non-symptomatic mTBI subjects. application in detecting subtle impairments, including those
Such findings raise important questions about locus of associated with mTBI (Schultheis et al. 2002; Slobounov et al.
abnormality and whether traditional neuropsychological mea- 2011a; Parsons et al. 2011; Armstrong et al. 2012; Campbell
sures are designed to detect such subtle abnormalities (Grindel et al. 2009).
2006). For example, in the Heitger et al. (2009) study the In addition to the demonstration by Brenner et al. (2010)
deficits in eye-tracking in the symptomatic mTBI group were that traditional neuropsychological measures failed to differ-
considered to be of upper brainstem origin. There are no entiate bona fide cases of mTBI with residual symptoms;
traditional neuropsychological tests that directly assess eye- Geary et al. (2010) acknowledge at the outset of their investi-
movements or upper brainstem function. gation that while mTBI patients often report chronic memory
Of course, the upper brainstem is contiguous with the problems, traditional neuropsychological assessments of-
ventral diencephalon and likewise, in addition to the ten fail to find evidence for such complaints (p. 514). What
ascending RAS that interfaces the brainstem with the some have done within neuropsychology is to conclude
thalamus, there is the diffuse thalamic projection system; that performance in many of these patients, despite their
all of which are important in arousal, attention, and complaints, is within the range of normal or a normative
habituation, and potentially injured in TBI (Lifshitz and sample, and therefore does not represent a deficit or any
Lisembee 2012). Neuropsychological measures may de- type of brain impairment. Instead of considering that the
tect impairments in attention/concentration and working traditional neuropsychometric approach may be insensitive
memory, but such techniques have no ability to localize in detecting deficits and searching for diagnostic solutions,
Neuropsychol Rev (2013) 23:169209 197

neuropsychology as a field has been too quick to dismiss Lastly, it is impossible to calculate what influence forensic
these complaints as merely functional noise that is cog- neuropsychology has had, but given the amount of forensic
nitively inconsequential. activity involving mTBI, it has the potential to influence
prevailing thoughts about mTBI outcome. Plainly, there are
Why has it Been so Challenging to Accept That Some mTBIs opposing camps in anything forensic (Bigler and Brooks
Result in Lasting Sequelae? Butler et al. (2009) provide a 2009; Ruff 2009), each with their supporting literature.
most interesting account in Neuropsychology Review of how Litigation involving mTBI is frequent and it is common to
the conflict in American medicine between the disciplines of see neuropsychological outcome studies utilize cases from
psychiatry and neurology, delayed the recognition of cog- forensic sources, which never could be considered unbiased
nitive dysfunction in multiple sclerosis (MS). In the last samples.
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 Integration of Neuroimaging with Neuropsychology
cognitive impairment was late in being recognized could
be attributed to researchers using an insensitive metric Neuropsychologys embrace of neuroimaging began with im-
the Disability Status Scale (DSS; Kurtzke 1961) that only agings ability to identify the in vivo lesion (Bigler et al.
assessed the most rudimentary of cognitive functions in 1989). Because of the limits of early neuroimaging techniques
MS. The original DSS over-relied on physical and sensory in the 1970s and 80s only the most fundamental clinical
loss because the zeitgeist of the day conceptualized MS as descriptions of brain pathology (i.e., type, size, and location
predominantly a sensory-motor disorder. As reviewed by of lesions) were possible during that era. Currently, a vast
Butler et al. (2009), neuroimaging improvements in the array of neuroimaging metrics can be applied to image anal-
1980s and 90s could demonstrate in vivo WM abnormal- ysis, many of them involving automated image analysis
ities outside of motor tracks; this provided the needed methods (Tate et al. 2012; Wilde et al. 2012; Hunter et al.
independent classifier of underlying brain abnormality 2012; Shenton et al. 2012). As Vasterling and Dikmen (2012)
to then show presence of impaired neuropsychological point out, there are many clinical and conceptual complexities
performance (see Sepulcre et al. 2009). In other words, that need to be attended to in designing neuropsychological
once neuroimaging became an established biomarker for outcome studies of mTBI, one of which is how to objectively
the study of MS, acceptance of non-motor cognitive and define any brain pathology.
emotional impairments became straightforward. Neuropsychological assessment techniques can be adapted
Butler et al. (2009) discuss how the neuroticizing of MS for presentation within a functional neuroimaging environ-
sequelae influenced by the Freudian zeitgeist of the mid-20th ment. Adapting neuropsychological probes in this manner
Century meant that any behavior that could not be organically permits some appreciation of regional activation and neural
defined was considered as some dimension of a neurosis engagement. Similarly electrophysiological methods can be
(Gladstone 2009; Sims 1985; Weighill 1983). Because of performed off-line from neuroimaging, but then integrated
these same influences, medicine and psychology also have with 3-D imaging so the best of temporal and spatial resolu-
the distinction of not recognizing the underlying neurological tion may be achieved in plotting the activation source.
bases of disorders like schizophrenia and autism until the latter Networks can now be examined using integrative techniques
half of the 20th Century. It was just 1979 when Malecs (1978) from DTI and resting-state fMRI. As reviewed by Shenton
neuropsychological review asked the question whether the et al. (2012) multi-modality sophisticated neuroimaging
patient is brain damaged or schizophrenic? (p. 507). methods can be used to identify subtle brain pathology asso-
All of this sounds very familiar when considering the ciated with mTBI and should be a part of any neuropsycho-
effects of mTBI. Absence of a lesion combined with the logical outcome study of mTBI.
lack of a cogent medical explanation other than those of Numerous neuroimaging methods are now available to
somatization and associated psychological/psychiatric sequel- assess mTBI (Hunter et al. 2012; Duhaime et al. 2012) and
ae, meant that any bona fide effects from mTBI were to be the field of neuropsychology should take full advantage of the
viewed with skepticism. Now given our ability to use ad- neuroimaging biomarker approach. By applying multi-
vanced neuroimaging methods to assess mTBI, indisputably modality neuroimaging methods as biomarkers for detecting
these techniques show subgroups with positive neuroimaging underlying abnormalities associated with mTBI, neuropsy-
and neurocognitive impairments (Van Boven et al. 2009; chology will have an objective measure to integrate with
Matthews et al. 2011; Zhou et al. 2012; Grossman et al. neurocognitive and neurobehavioral assessment of the mTBI
2012b; Ross et al. 2012; Jorge et al. 2012; Messe et al. patient. The absence of an objective criterion as to whether
2013; Morey et al. 2012; Nakagawara et al. 2013). some type of neuropathology is independently present or not
198 Neuropsychol Rev (2013) 23:169209

in the mTBI patient is what has led to the confused picture of It may be the case that, within the mildest of TBI the brain
clinical outcome in the neuropsychology of mTBI. Other could adapt to injury and therefore, positive imaging would
biomarkers of TBI are likewise on the horizon (Zetterberg possibly reflect an abnormality to which the brain has adapted
et al. 2013), which also will undoubtedly improve understand- and re-circuited without apparent ill effecta classic Type 1
ing of mTBI outcome. Some of these serum biomarkers may error if the neuropsychologist concluded impairment where
in fact be combined with neuroimaging and likewise; neuro- none existed. Nonetheless, there may be more to the story of
imaging studies are advancing along the lines of direct imag- so-called recovered mTBI, even in the presence of a lesion.
ing of pathology like -amyloid and tau proteins, as by- As Eisenberg et al. (2013) demonstrated in their prospective
products of brain injury (Di Battista et al. 2013; Rostami cohort of those who sustain mTBI, a prior concussion distinct-
et al. 2012; Jeter et al. 2013). ly and significantly prolonged symptoms. So, even if cogni-
tive functions return to pre-injury levels, the mere fact of prior
brain injury may change the threshold for subsequent injury,
Limitations therefore indicating residua from the supposed injury from
which the mTBI patient had recovered. These are very
The intent of this review was to provide the basis for a serious issues for the researcher and clinician to contemplate
sensitive, objective metric to enhance detection of mTBI before they would conclude that no injury had occurred
sequelae which could form the basis for improved and com- based on neuropsychological findings alone and that there
plementary research design for investigations of neuropsycho- were no untoward effects of mTBI. Because of this it seems
logical outcome. This review is selective and focused on evident that the best in technology, including biomarkers of
neuroimaging studies that identify pathology potentially injury, should be brought to bear on this important topic,
related to residual impairments in cognitive and/or behav- before there is a blanket conclusion of no lasting effect from
ioral functioning post-mTBI in what must be considered mTBI.
the minority of all those who sustain an mTBI. Post-
mTBI neuropsychological functioning reflects a host of
complex factors that includes all pre-morbid genetic and
age-dependent influences present at the time of injury Conclusions and Future Directions
including incidental findings (Katzman et al. 1999;
Vernooij et al. 2007), biological and emotional resiliency, This review began with a simplified view of concussion but
and vulnerability features associated with the injury itself, concludes by showing the complexities of what needs to be
as well as a myriad of post-injury factors. Returning to addressed in neuropsychological outcome research in mTBI.
Figs. 5, 6, 13, and 14 where a lesion is clearly visible Restoration of neural function is likely the norm following
in these mTBI patients, the state-of-the-art in neuroimag- mTBI, but as this review demonstrates, contemporary neuro-
ing is that it can still only be inferred how a particular imaging methods identify residual indicators of neuropathol-
lesion disrupted pre-existing integrity because pre-injury ogy in subsets of individuals with mTBI. Commenting on the
neuroimaging and neurocognitive/neurobehavioral assess- entire TBI field, Chen and DEsposito (2010) state,
ments are mostly never available. Furthermore, all of Unfortunately, most tests of cognitive functioning, including
what is presented and discussed herein pertains to correl- neuropsychological tests and most cognitive neuroscience
ative findings with neuroimaging variables in cases of measures, are not designed to reflect the complexities and
mTBI. However, as typically stated, correlation is never low structure of settings in the real world (p.13). Integrating
synonymous with causation, and given the complexities this statement with an editorial in Nature (Editorial 2010) that
that attend premorbid and post-injury neuropsychological states as biological insights develop, the crudity of current
functioning, more precise relations specific to mTBI must psychiatric diagnoses will become all too clear (p. 9), means
be considered unknown. that we have reached a level in the investigation of mTBI
While this review highlights the worth of potential neuro- sequelae where the entire role of traditional neuropsycholog-
imaging biomarkers of mTBI, neuroimaging remains an ex- ical methods in mTBI needs refinement.
pensive study method. Extensive research studies are under- Neuroimaging provides biomarkers of underlying structur-
way for blood and other biomarkers of mTBI (Di Battista et al. al and physiological abnormalities in mTBI, and these patho-
2013). These may turn out to be effective and far less expensive logical changes occur in regions and within neural systems
than MRI. Regardless of whether neuroimaging and/or blood that plausibly give rise to the common types of neurobehav-
biomarkers become universally accepted as indicators of neural ioral and neurocognitive sequelae associated with mTBI.
injury in mTBI, the field needs objectivity. While the price of Neuroimaging methods provide objective biomarkers of inju-
neuroimaging is a legitimate concern, getting the diagnosis ry and damage that need to be incorporated into neuropsycho-
correct is the objective of identifying an effective biomarker. logical outcome studies.
Neuropsychol Rev (2013) 23:169209 199

Acknowledgments The assistance of Jo Ann Petrie, Ph.D. in the prep- syndrome. Journal of Clinical Neuroscience, 17 (7), 924926.
aration of this manuscript is gratefully acknowledged as is the assistance doi:10.1016/j.jocn.2009.11.009.
of Tracy J. Abildskov in preparation of some of the illustrations. Bayly, P. V., Clayton, E. H., & Genin, G. M. (2012). Quantitative imaging
methods for the development and validation of brain biomechanics
models. Annual Review of Biomedical Engineering, 14, 369396.
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