Neuroscience Letters 509 (2012) 1–4

Contents lists available at SciVerse ScienceDirect

Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Commentary

Mild traumatic brain injury: The elusive timing of “recovery”

Erin D. Bigler a,b,c,d,∗
a
Department of Psychology, Brigham Young University, Provo, UT, United States
b
Neuroscience Center, Brigham Young University, Provo, UT, United States
c
Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
d
The Brain Institute of Utah, University of Utah, Salt Lake City, UT, United States

a r t i c l e i n f o

Article history:
Received 5 December 2011
Accepted 6 December 2011

Keywords:
Mild traumatic brain injury
Concussion
Magnetic resonance imaging (MRI)
Magnetic resonance spectroscopy (MRS)
Resting state functional MRI (rs-fMRI)
Recovery
Neuroinflammation
Corpus callosum
Connectivity

Traumatic brain injury (TBI) is typically described by its severity
ranging from mild to severe. Mild TBI (mTBI) is by far the most
common, constituting ∼80–90% of all TBIs [5]. While there is little
disagreement over definition and classification of moderate-to-
severe TBI, classification of mTBI has a lengthy history of ardent
debate, especially over whether any neurocognitive or neuro-
behavioral sequelae may exist beyond the acute phase [14,30].
For example, concussion, a term used since antiquity, most often
implies a transient neurologic condition without lasting sequelae
[13]. However, concussion is a mTBI, likely defining the least severe
mTBI [37]. As such, the terms concussion and mTBI often are used
interchangeably and will be in this commentary. Indisputably, con-
cussion occurs because of acute brain injury; the debate is how to
measure the pathophysiological effects of the injury and whether
such injuries have any lasting effect? In sports concussion how
to determine return to play is assumed to be based on outward
physical and behavioral measures implicating the return of nor-
mal brain function. Fortunately, the majority of those who sustain
a mTBI experience a positive outcome without detectable sequelae,
returning to normal activities including competitive sports without
∗ Correspondence address: Department of Psychology, Brigham Young University,
1001 SWKT, Provo, UT 84602, United States. Tel.: +1 801 422 4287;
fax: +1 801 422 0602.
E-mail address: erin bigler@byu.edu
further problems. However, some do not and therein is the impetus
to better understand mTBI.
Head injury in the concussed athlete is typically a witnessed
event often manifested by well-recognized acute signs and symp-
toms [38]. With athletic trainers, medical personnel and coaches
as witnesses, following some type of collision or impact on the
sports field combined with either an alteration in consciousness
or loss of consciousness (LOC), especially concomitant with motor
manifestation such as tonic posturing and clonic movements, rep-
resent unmistakable, observable indicators of acute brain injury
[7,31]. However, by definition to retain its classification as a mTBI
and not be labeled a more severe brain injury, the above men-
tioned observable symptoms must be short-lived. Even when there
is no LOC, outwardly observable deficits, such as transient coor-
dination and motor instability, eye-tracking abnormalities, and
impaired performance on sideline neuropsychological measures
are most commonly transient. In mTBI objective indicators that a
brain injury has occurred commonly fade after the acute observ-
able presentation as neural function returns to pre-injury baseline;
however, for some as these outward markers fade subjective cogni-
tive, emotional and physical symptoms take their place [38]. Even
the objectively measured motor and eye-tracking as well as bal-
ance instability typically diminish within minutes to hours to days
post-concussion, thereby leaving the concussed individual with no
externally detectable marker of having experienced a brain injury
or indication whether recovery has occurred. In those who do
not recover within the typical acute to early sub-acute timeframe,

0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2011.12.009
2 E.D. Bigler / Neuroscience Letters 509 (2012) 1–4
the more persisting symptoms become vague and ill-defined. For
example, using terminology outlined by the 3rd International Con-
ference on Concussion in Sport [32], the concussed athlete may
complain of “feeling slowed down”, “feeling like ‘in a fog”’, “fatigued
or low energy”, “difficulty concentrating”, etc., often with endur-
ing headache. For the athlete who sustains a concussion and goes
on to develop persisting symptoms, these inherently subjective
complaints of somatic, emotional, and/or neurocognitive symp-
toms overlap with any number of nonspecific neuropsychiatric and
medical conditions. Conventional neuroimaging studies with either
computed tomography (CT) or magnetic resonance (MR) imaging
are most commonly negative, offering not even a macroscopic hint
of a brain injury. Indeed, without any outward, objective indica-
tor of having had a brain injury those with persisting symptoms
are often viewed within the context of neuropsychiatric illness
[49]. Without a biomarker, the study and treatment of mTBI has
led to considerable confusion over how transient or permanent the
effects may be. In competitive sports following a concussion, most
importantly without a biomarker, return to play decisions cannot
be based on any direct index of brain integrity or dysfunction but
only on clinical judgment and decision rules founded on dissolution
of symptoms.
Concussion occurs across all animal species with characteristic
features of brief and transient alterations in consciousness, motor
ability and slowed reaction time common to all [36]. Understanding
why lingering pathophysiological effects of concussion exist may
be aided by viewing concussion from an evolutionary perspective.
Brains evolved to tolerate minor perturbations followed by rapid
restoration of function since the effects of selection would only
occur in those who survive injury [50]. Prior to modern medicine
and emergency care, moderate-to-severe TBI in humans was often
not a survivable event [28]. Likewise, as reviewed by Finger and
Almli [15] the evolutionary record offers little support that “. . . neu-
ral reorganization . . . emerged to ‘heal’ damaged brains (p. 177).”
While true for the severely injured brain, if the typical concussion
produces but a transient event, evolutionary influences may have
molded a hierarchy of restoration effects from quick restitution of
consciousness (if even an alteration in consciousness occurred), to
reestablishing basic reflexes followed by restoration of simple and
complex motor functioning and modes of communication. Quick
restoration of vital conscious processing and sensorimotor function
would promote survival. Possibly the most complex brain func-
tions involving higher-order cognitive processes were not as key in
immediate and basic survival and therefore not as prone to rapid
restoration especially given the complex and intricate neural cir-
cuitry that subserve such processes.
All higher mental abilities require efficient functioning of com-
plex networks, with network complexity proportional to the
cognitive complexity of the task being performed. Higher men-
tal functions involve continuously adapting long-tract intra- and
interhemispheric communication, particularly between frontal and
temporal lobe regions they are particularly vulnerable to injury
[5]. In contrast, basic motor and sensory functions necessary for
survival are not as dependent upon the same level of complexity.
If these assumptions are correct then the outward appearance of
restored basic motor and sensory function in mTBI may occur while
more complex cognitive processes do not [18]. In other words,
a disconnect ensues between outward appearance of “recovery”
in mTBI and what may remain as an underlying pathophysiolog-
ical effect of the injury that only influences the highest levels of
complex cognitive and emotional functioning. From this interpre-
tative perspective, early “recovery” in mTBI may merely be an
external evolutionary guise while the brain continues to restore
function and/or repairs and adapts to more permanent injury that
has affected integrative cerebrocortical systems [4]. If underlying
pathology persists during such outward appearance of “recovery”,
this helps answer why the “recovered” individual with a mTBI
may more readily experience a second concussion, with increased
likelihood for adverse outcome—the so-called “second impact”
syndrome [see 42]. Likewise, this could also explain why subtle
neurocognitive impairments persist in some mTBI patients, typi-
cally in domains that require complex cognitive processes [16,25].
If only subjective symptoms and complaints remain after
mTBI, in the absence of reliable outward indicators that brain
injury/dysfunction may linger in some, how should the pathophys-
iological effects of concussion be detected, if in fact, they even
exist? Conventional clinical CT and MR imaging (MRI) are cer-
tainly not the answer as they are typically uninformative about
any injury. However, MR spectroscopy (MRS), an MRI technique
sensitive in detecting metabolites reflective of neuronal injury
and/or integrity as well as cerebral energy metabolism, may iden-
tify the subtleties of injury [see 1]. Previously, MRS investigations
of TBI have identified abnormalities associated with concussion
[24,20,46,17], confirmed by the Johnson et al. study [22] in this
issue of Neuroscience Letters, but what is so important about the
Johnson et al. [22] study is that these investigators demonstrated
MRS differences in athletes with sports-related concussion who
were medically “cleared” on average at 11 days post-injury since
they passed all physical and neurocognitive screening measures
for beginning aerobic activity as a first step in the return to play
process. Nevertheless, despite this apparent return to pre-injury
ability and no outward signs/symptoms of the ill-effects of con-
cussion, MRS abnormalities were detected, implicating underlying
persistent pathophysiological effects from the mTBI.
The corpus callosum was selected for MRS analysis by Johnson
et al. [22] because biomechanical studies have shown its vulner-
ability to shear/strain action following blunt force trauma and
acceleration/deceleration injury [48]; in addition, the MRS tech-
nique has been shown sensitive in detecting axonal injury from
trauma [2,9]. Furthermore, Johnson et al. [22] combine another MRI
technique, resting state functional MRI (rs-fMRI) which provides an
elegant method for inferring hemispheric connectivity by examin-
ing the synchrony of the fMRI signal in homologous areas of the
brain at rest. Connectivity maps of the brain and their strength
can then be derived. Since projections across the corpus callo-
sum follow predictable pathways with regional specificity [35],
MRS identified abnormalities within the corpus callosum should be
reflected in rs-fMRI findings. Previously, Johnson et al. [see 23] have
already shown a disruption of functional networks in concussion
using rs-fMRI techniques, so the current study not only examined
where MRS abnormalities occurred in the corpus callosum, but how
these MRS findings related to rs-fMRI functional connectivity maps
in concussed athletes cleared to resume training.
In athletes whose medical, cognitive and behavioral indices
had normalized, Johnson et al. [22] show persistent MRS-
identified metabolite imbalance. Interestingly, positive relation-
ships between rs-fMRI indices of frontal and inter-hippocampal
connectivity and MRS findings were only observed in the neuro-
logical normal volunteers and absent in the concussed athletes.
This suggests that the MRS findings of the corpus callosum are
indeed tapping into probable trauma-related disconnection where
compromised metabolic integrity of the corpus callosum persists
despite and ostensible return of ‘baseline’ functioning. Disruption
of frontal and temporolimbic networks has long be thought to
be the basis for neurocognitive and neurobehavioral sequelae of
more severe injury [44,47], with the findings of Johnson et al.
[22] supporting its occurrence in mTBI even in those showing
no overt indicia of the concussion. In other words, the pathology
is only physiologically manifested in abnormal concentrations of
neural cell metabolites spectroscopically detected. Indeed, since
in most cases of concussion conventional neuroimaging is nega-
tive, the neural injury in concussion must be subtle occurring at the
 E.D. Bigler / Neuroscience Letters 509 (2012) 1–4
microscopic level. This means to detect the injury, the biomarker
must be capable of assessing the micro environment of the brain
which MRS can.
Talavage et al. [45] have used fMRI and Barr et al. [3] quanti-
tative EEG measures to examine athletes over time, also showing
persisting abnormalities after athletes purportedly return to base-
line on other measures, including neuropsychological. The work
of Vagnozzi et al. [46] has shown the feasibility of using MRS to
track recovery over time. Yeo et al. [51] have shown the persis-
tence of MRS abnormalities well beyond the sub-acute phase in
non-athletic mTBI. Given the Johnson et al. [22] findings, as well
as other MRS findings in mTBI combined with the straightforward-
ness of performing MRS procedures, it is likely time for large scale
within-subjects, longitudinal investigations of MRS as a biomarker
of mTBI and its role in predicting outcome.
Demonstrating that metabolic perturbations persist beyond
when traditional methods indicate “recovery”, the findings of John-
son et al. [22] point to the elusive nature of how “recovery” from
an mTBI is currently defined by conventional physical, medical,
athletic training and neuropsychological measures. As alluded to
above, that pathophysiological changes remain within a sub-acute
timeframe when an athlete may be cleared to return to competi-
tion could potentially be setting that athlete up for adverse effects
of a second impact injury. Obviously, whether knowing that MRS
abnormalities persist or not and whether this is a key variable in
predicting vulnerability to a second concussion is something that
will require more research. Bazarian et al. [4] using MR diffusion
tensor imaging (DTI) in a prospective cohort study of high school
athletes showed that even in those not clinically experiencing a
diagnosable concussion, but in whom sub-concussive blows were
documented had identifiable changes in white matter particularly
in long tracts within the corona radiata and inferior longitudinal
fasiculus. All of this suggests the vulnerability of white matter to
concussion and that MR neuroimaging methods have reached a
level of sophistication to detect these subtle abnormalities.
If conventional neuroimaging in mTBI does not reveal detectable
abnormalities at the macro level yet MRS, DTI, fMRI and rs-fMRI can
detect them at the micro-metabolic, physiological, and structural
level, what is the pathophysiological basis? Animal studies, includ-
ing mTBI models have shown the vulnerability of white matter to
TBI where a range of changes occur depending on the time post
injury from cellular degradation, demyelination along with reac-
tive changes in astrocytes and neuroinflammation [8,10,26]. Also
in an animal model of TBI, Hayward et al. [19] showed that vascular
pathology accompanies TBI where the microvasculature is proba-
bly just as influenced by cerebral injury as neural cells. Additionally,
mild TBI produces a host of intraparenchymal as well as systemic
inflammatory responses in animal models of mTBI [11,39,21]. In
humans, Metting et al. [34,33] have shown that initial CT brain
perfusion findings predict outcome at six months. Given this back-
ground, what Johnson et al. [22] may be observing in their MRS
findings in mTBI may, in part, be explained by a neuroinflammatory
response [6,27].
Clinicians who assess the mTBI patient and researchers who
study the pathoneurobiology of mTBI are looking for reliable
biomarkers of brain injury to track recovery. MRS provides a non-
invasive, relatively quick in vivo method for quantifying basic
aspects of brain metabolism that holds promise identifying mTBI
biomarkers. As pointed out by Johnson et al. [22] the annual num-
bers of mild TBI cases are enormous and without a biomarker of
whether this type of brain injury has left a pathological effect or
not makes it very challenging to truly advance clinical care of con-
cussion or for researchers to better understand the mechanisms of
injury and pathological consequences to the concussed brain.
As a final discussion point, the Johnson et al. [22] investiga-
tion provides additional support for how mTBI adversely affects
3
the brain by disrupting neural networks where those involved in
basic motor, sensory and language function return to baseline most
rapidly, but those more complex intra- and inter-hemispheric sys-
tems are slower to recover [23,29]. Disruptive effects of mTBI on
networks associated with anterior and posterior aspects of the cor-
pus callosum, as shown by Johnson et al. [22], disturbs complex
networks responsible for integrating executive, emotional as well
as attention/concentration and memory functions [5]. Within these
domains are the common cognitive and neurobehavioral seque-
lae that occur following mTBI. In the past, research searched for
some type of “lesion” and its location that could explain concussion
and its effects. This past viewpoint missed the interdependency of
complex neural systems regulating the highest levels of cortical
functioning where perturbation anywhere within the network may
disrupt the entirety of the network [43]. Efficiencies of large net-
works not only depend on their primary systems but secondary
and tertiary as well. So inefficiency at even a relatively minor level,
but for a complex system may have a substantial effect and this
may be the explanation why small changes detected by the MRS
method point to disrupted neural systems potentially responsi-
ble for underlying symptoms and problems that may result from
mTBI. Understanding how connectivity in the brain is disrupted by
any type of acquired brain injury may be key to understanding the
effects of injury to the brain and its influence on neurobehavioral
outcome [41].
Davenport et al. [12] in a blast injury mTBI study have shown
the heterogeneity of white matter injury using DTI. Given inher-
ent inter-individual differences of each injured person combined
with the almost infinite ways in which a head may be impacted
in sports or civilian injury, no two traumatic events are likely to
be identical. But if the long tracts intra-hemispherically as well
as inter-hemispherically across the corpus callosum are most vul-
nerable in TBI, it would not necessarily matter where the brain is
most injured, but rather which networks are disrupted and to what
degree.
In conclusion, Johnson et al. [22] show that at least in the sub-
acute phase of mTBI by taking a micro-viewpoint assessing brain
metabolism what ostensibly may appear outwardly normal in gross
brain anatomy and even behavior, may have underlying pathol-
ogy demonstrating disrupted brain connectivity [see 29,41]. Thus,
the outward appearances of behavior and gross brain anatomy are
insufficient indicators to infer normal microanatomy, physiology
and biochemistry of the brain in the individual with mTBI. These
outward appearances may be the evolutionary guise that exter-
nally portrays recovery all the while the brain needs additional
time to heal or adapt. How the injured brain handles neuroinflam-
matory responses may be key in understanding mTBI [40] and MRS
and rs-fMRI may provide biomarker findings to study these pro-
cesses. Brain injury is occurring in concussion and neuroimaging
methods have reached a level of technical sophistication and pre-
cision to provide answers to questions about the transient or more
permanent sequelae of mTBI.
References
[1] S. Ashwal, T. Babikian, J. Gardner-Nichols, M.C. Freier, K.A. Tong, B.A. Hol-
shouser, Susceptibility-weighted imaging and proton magnetic resonance
spectroscopy in assessment of outcome after pediatric traumatic brain injury,
Arch. Phys. Med. Rehabil. 87 (2006) S50–S58.
[2] T. Babikian, S.D. Marion, S. Copeland, J.R. Alger, J. O’Neill, F. Cazalis, R. Mink, C.C.
Giza, J.A. Vu, S.M. Hilleary, C.L. Kernan, N. Newman, R.F. Asarnow, Metabolic
levels in the corpus callosum and their structural and behavioral correlates
after moderate to severe pediatric TBI, J. Neurotrauma 27 (2010) 473–481.
[3] W.B. Barr, L.S. Prichep, R. Chabot, M.R. Powell, M. McCrea, Measuring brain
electrical activity to track recovery from sport-related concussion, Brain Inj.
(2011).
[4] J.J. Bazarian, T. Zhu, B. Blyth, A. Borrino, J. Zhong, Subject-specific changes in
brain white matter on diffusion tensor imaging after sports-related concussion,
Magn. Reson. Imaging (2011).
4 E.D. Bigler / Neuroscience Letters 509 (2012) 1–4
[5] E.D. Bigler, W.L. Maxwell, Understanding mild traumatic brain injury: neu-
ropathology and neuroimaging, in: J. Vasterling, R. Bryant, T. Keane (Eds.), PTSD
and Mild Traumatic Brain Injury, Guilford Press, New York, 2012.
[6] W.M. Brooks, S.D. Friedman, C. Gasparovic, Magnetic resonance spectroscopy
in traumatic brain injury, J. Head Trauma Rehabil. 16 (2001) 149–164.
[7] J.J. Bruns, A.S. Jagoda Jr., Mild traumatic brain injury, Mt. Sinai J. Med. 76 (2009)
129–137.
[8] M.D. Budde, L. Janes, E. Gold, L.C. Turtzo, J.A. Frank, The contribution of gliosis to
diffusion tensor anisotropy and tractography following traumatic brain injury:
validation in the rat using Fourier analysis of stained tissue sections, Brain 134
(2011) 2248–2260.
[9] K.M. Cecil, E.C. Hills, M.E. Sandel, D.H. Smith, T.K. McIntosh, L.J. Mannon, G.P.
Sinson, L.J. Bagley, R.I. Grossman, R.E. Lenkinski, Proton magnetic resonance
spectroscopy for detection of axonal injury in the splenium of the corpus cal-
losum of brain-injured patients, J. Neurosurg. 88 (1998) 795–801.
[10] J.A. Creed, A.M. DiLeonardi, D.P. Fox, A.R. Tessler, R. Raghupathi, Concussive
brain trauma in the mouse results in acute cognitive deficits and sustained
impairment of axonal function, J. Neurotrauma 28 (2011) 547–563.
[11] M. Das, C.C. Leonardo, S. Rangooni, K.R. Pennypacker, S. Mohapatra, S.S. Moha-
patra, Lateral fluid percussion injury of the brain induces CCL20 inflammatory
chemokine expression in rats, J. Neuroinflammation 8 (2011) 148.
[12] N.D. Davenport, K.O. Lim, M.T. Armstrong, S.R. Sponheim, Diffuse and
spatially variable white matter disruptions are associated with blast-
related mild traumatic brain injury, Neuroimage (October) (2011) 20,
doi:10.1016/j.neuroimage.2011.1010.1050(Epub ahead of print).
[13] D. Denny-Brown, Cerebral concussion, Physiol. Rev. 25 (1945) 296–325.
[14] R.W. Evans, The postconcussion syndrome: 130 years of controversy, Semin.
Neurol. 14 (1994) 32–39.
[15] S. Finger, C.R. Almli, Brain damage and neuroplasticity: mechanisms of recovery
or development? Brain Res. 357 (1985) 177–186.
[16] E.K. Geary, M.F. Kraus, N.H. Pliskin, D.M. Little, Verbal learning differences
in chronic mild traumatic brain injury, J. Int. Neuropsychol. Soc. 16 (2010)
506–516.
[17] V. Govind, S. Gold, K. Kaliannan, G. Saigal, S. Falcone, K.L. Arheart, L. Harris, J.
Jagid, A.A. Maudsley, Whole-brain proton MR spectroscopic imaging of mild-
to-moderate traumatic brain injury and correlation with neuropsychological
deficits, J. Neurotrauma 27 (2010) 483–496.
[18] C.I. Halterman, J. Langan, A. Drew, E. Rodriguez, L.R. Osternig, L.S. Chou, P.
van Donkelaar, Tracking the recovery of visuospatial attention deficits in mild
traumatic brain injury, Brain 129 (2006) 747–753.
[19] N.M. Hayward, R. Immonen, P.I. Tuunanen, X.E. Ndode-Ekane, O. Grohn, A.
Pitkanen, Association of chronic vascular changes with functional outcome
after traumatic brain injury in rats, J. Neurotrauma 27 (2010) 2203–2219.
[20] L.C. Henry, S. Tremblay, Y. Boulanger, D. Ellemberg, M. Lassonde, Neu-
rometabolic changes in the acute phase after sports concussions correlate with
symptom severity, J. Neurotrauma 27 (2010) 65–76.
[21] R.J. Immonen, I. Kharatishvili, J.P. Niskanen, H. Grohn, A. Pitkanen, O.H. Grohn,
Distinct MRI pattern in lesional and perilesional area after traumatic brain
injury in rat–11 months follow-up, Exp. Neurol. 215 (2009) 29–40.
[22] B. Johnson, K. Zhang, M. Gay, T. Neuberger, S. Horovitz, M. Hallett, W.
Sebastianelli, S. Slobounov, Metabolic alterations in corpus callosum may com-
promise brain functional connectivity in MTBI patients: an (1)H-MRS study,
Neurosci. Lett. (2011).
[23] B. Johnson, K. Zhang, M. Gay, S. Horovitz, M. Hallett, W. Sebastianelli, S.
Slobounov, Alteration of brain default network in subacute phase of injury
in concussed individuals: resting-state fMRI study, Neuroimage 59 (2012)
511–518.
[24] I. Kirov, L. Fleysher, J.S. Babb, J.M. Silver, R.I. Grossman, O. Gonen, Characterizing
‘mild’ in traumatic brain injury with proton MR spectroscopy in the thalamus:
initial findings, Brain Inj. 21 (2007) 1147–1154.
[25] C. Konrad, A.J. Geburek, F. Rist, H. Blumenroth, B. Fischer, I. Husstedt, V. Arolt,
H. Schiffbauer, H. Lohmann, Long-term cognitive and emotional consequences
of mild traumatic brain injury, Psychol. Med. (2010) 1–15.
[26] G. Lotocki, R. Vaccari Jde, O. Alonso, J.S. Molano, R. Nixon, P. Safavi, W.D. Dietrich,
H.M. Bramlett, Oligodendrocyte vulnerability following traumatic brain injury
in rats, Neurosci. Lett. 499 (2011) 143–148.
[27] S. Marino, R. Ciurleo, P. Bramanti, A. Federico, N. De Stefano, 1H-MR spec-
troscopy in traumatic brain injury, Neurocrit. Care 14 (2011) 127–133.
[28] B.E. Masel, D.S. DeWitt, Traumatic brain injury: a disease process, not an event,
J. Neurotrauma 27 (2010) 1529–1540.
[29] A.R. Mayer, M.V. Mannell, J. Ling, C. Gasparovic, R.A. Yeo, Functional connectiv-
ity in mild traumatic brain injury, Hum. Brain Mapp. 32 (2011) 1825–1835.
[30] P. McCrory, When to retire after concussion? Br. J. Sports Med. 35 (2001)
380–382.
[31] P.R. McCrory, S.F. Berkovic, Video analysis of acute motor and convulsive man-
ifestations in sport-related concussion, Neurology 54 (2000) 1488–1491.
[32] P. McCrory, W. Meeuwisse, K. Johnston, J. Dvorak, M. Aubry, M. Molloy, R. Cantu,
Consensus statement on concussion in sport: the 3rd International Conference
on Concussion in Sport held in Zurich, November 2008, J. Athl. Train. 44 (2009)
434–448.
[33] Z. Metting, L.A. Rodiger, R.E. Stewart, M. Oudkerk, J. De Keyser, J. van der
Naalt, Perfusion computed tomography in the acute phase of mild head
injury: regional dysfunction and prognostic value, Ann. Neurol. 66 (2009)
809–816.
[34] Z. Metting, L.A. Rodiger, B.M. de Jong, R.E. Stewart, B.P. Kremer, J. van der
Naalt, Acute cerebral perfusion CT abnormalities associated with posttraumatic
amnesia in mild head injury, J. Neurotrauma 27 (2010) 2183–2189.
[35] K. Pannek, J.L. Mathias, E.D. Bigler, G. Brown, J.D. Taylor, S. Rose, An automated
strategy for the delineation and parcellation of commissural pathways suit-
able for clinical populations utilising high angular resolution diffusion imaging
tractography, Neuroimage 50 (2010) 1044–1053.
[36] D. Parkinson, M. West, T. Pathiraja, Concussion: comparison of humans and
rats, Neurosurgery 3 (1978) 176–180.
[37] G.P. Prigatano, S.D. Gale, The current status of postconcussion syndrome, Curr.
Opin. Psychiatry 24 (2011) 243–250.
[38] M. Putukian, The acute symptoms of sport-related concussion: diagnosis and
on-field management, Clin. Sports Med. 30 (2011) 49–61, viii.
[39] H.R. Ranaivo, S.M. Zunich, N. Choi, J.N. Hodge, M.S. Wainwright, Mild stretch-
induced injury increases susceptibility to interleukin-1beta-induced release
of matrix metalloproteinase-9 from astrocytes, J. Neurotrauma 28 (2011)
1757–1766.
[40] S.R. Schultz, F. Bao, V. Omana, C. Chiu, A. Brown, D.P. Cain, Repeated mild lateral
fluid percussion brain injury in the rat causes cumulative long-term behav-
ioral impairments, neuroinflammation, and cortical loss in an animal model of
repeated concussion, J. Neurotrauma (November) (2011) (Epub ahead of print).
[41] D.J. Sharp, C.F. Beckmann, R. Greenwood, K.M. Kinnunen, V. Bonnelle, X. De
Boissezon, J.H. Powell, S.J. Counsell, M.C. Patel, R. Leech, Default mode network
functional and structural connectivity after traumatic brain injury, Brain 134
(2011) 2233–2247.
[42] S. Signoretti, G. Lazzarino, B. Tavazzi, R. Vagnozzi, The pathophysiology of con-
cussion, PM&R 3 (2011) S359–S368.
[43] O. Sporns, Networks of the Brain, The MIT Press, Cambridge, MA, 2010.
[44] D.T. Stuss, Traumatic brain injury: relation to executive dysfunction and the
frontal lobes, Curr. Opin. Neurol. 24 (2011) 584–589.
[45] T.M. Talavage, E. Nauman, E.L. Breedlove, U. Yoruk, A.E. Dye, K. Morigaki,
H. Feuer, L.J. Leverenz, Functionally-detected cognitive impairment in high
school football players without clinically-diagnosed concussion, J. Neuro-
trauma (2010).
[46] R. Vagnozzi, S. Signoretti, L. Cristofori, F. Alessandrini, R. Floris, E. Isgro, A.
Ria, S. Marziale, G. Zoccatelli, B. Tavazzi, F. Del Bolgia, R. Sorge, S.P. Broglio,
T.K. McIntosh, G. Lazzarino, Assessment of metabolic brain damage and
recovery following mild traumatic brain injury: a multicentre, proton mag-
netic resonance spectroscopic study in concussed patients, Brain 133 (2010)
3232–3242.
[47] T.D. Vannorsdall, N.G. Cascella, V. Rao, G.D. Pearlson, B. Gordon, D.J. Schretlen,
A morphometric analysis of neuroanatomic abnormalities in traumatic brain
injury, J. Neuropsychiatry Clin. Neurosci. 22 (2010) 173–181.
[48] D.C. Viano, I.R. Casson, E.J. Pellman, L. Zhang, A.I. King, K.H. Yang, Concussion
in professional football: brain responses by finite element analysis: Part 9,
Neurosurgery 57 (2005) 891–916, discussion 891–916.
[49] D.G. Weight, Minor head trauma, Psychiatr. Clin. North Am. 21 (1998) 609–624.
[50] Z.M. Weil, G.J. Norman, A.C. DeVries, R.J. Nelson, The injured nervous system:
a Darwinian perspective, Prog. Neurobiol. 86 (2008) 48–59.
[51] R.A. Yeo, C. Gasparovic, F. Merideth, D. Ruhl, D. Doezema, A.R. Mayer, A longi-
tudinal proton magnetic resonance spectroscopy study of mild traumatic brain
injury, J. Neurotrauma 28 (2011) 1–11.