Brain Injury

ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20

Volumetric and morphometric MRI findings in

patients with mild traumatic brain injury

T. Hellstrøm, L. T. Westlye, A. Server, M. Løvstad, C. Brunborg, M. J. Lund, W.

Nordhøy, O. A. Andreassen & N. Andelic

To cite this article: T. Hellstrøm, L. T. Westlye, A. Server, M. Løvstad, C. Brunborg, M. J. Lund, W.

Nordhøy, O. A. Andreassen & N. Andelic (2016): Volumetric and morphometric MRI findings in
patients with mild traumatic brain injury, Brain Injury, DOI: 10.1080/02699052.2016.1199905

To link to this article: http://dx.doi.org/10.1080/02699052.2016.1199905

Published online: 24 Oct 2016.

Submit your article to this journal

Article views: 37

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ibij20

Download by: [Ryerson University Library] Date: 04 November 2016, At: 03:28
 http://tandfonline.com/ibij
ISSN: 0269-9052 (print), 1362-301X (electronic)

Brain Inj, Early Online: 1–9

© 2016 Taylor & Francis Group, LLC. DOI: 10.1080/02699052.2016.1199905

ORIGINAL ARTICLE

Volumetric and morphometric MRI findings in patients with mild

traumatic brain injury
T. Hellstrøm1, L. T. Westlye2,3, A. Server4, M. Løvstad3,5, C. Brunborg6, M. J. Lund2, W. Nordhøy7, O. A. Andreassen2,
& N. Andelic1,8
1
Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway, 2KG Jebsen Centre for Psychosis Research/Norwegian
Centre for Mental Disorder Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, 3Department of
Psychology, University of Oslo, Oslo, Norway, 4Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway, 5Sunnaas
Rehabilitation Hospital, Department of Research, Nesoddtangen, Norway, 6Oslo Centre for Biostatistics and Epidemiology, Research Support Services,
Oslo University Hospital, Oslo, Norway, 7The Intervention Centre, Oslo University Hospital, Oslo, Norway, and 8CHARM Research Centre for Habilitation
and Rehabilitation Models & Services, Institute of Health and Society, University of Oslo, Oslo, Norway

Abstract Keywords
Objective: This study compared cortical and sub-cortical volumes between patients with complicated Mild brain injury, concussion, radiology,
(i.e. presence of intracranial abnormality on the day-of-injury CT) and uncomplicated (i.e. absence of neuroimaging, intracranial injury, cortical
intracranial abnormality) mild traumatic brain injury (MTBI) 4 weeks post-injury. The study hypothe- thickness
sized regionally decreased brain volumes and reduced cortical thickness in patients with complicated
MTBIs compared with uncomplicated MTBI. History
Methods: This study was part of a larger 2 years cohort study on MTBI. Baseline clinical and
magnetic resonance imaging (MRI) data were compared for those with complicated and Received 22 December 2015
uncomplicated MTBI. It identified 168 patients with MTBI (90 uncomplicated and 78 compli- Revised 14 April 2016
cated), aged 16–65 years. 3T MRI-system (Signa HDxt, GE Medical Systems, Milwaukee, WI) and Accepted 6 June 2016
cortical reconstruction and volumetric segmentation by FreeSurfer software have been used. Published online 23 October 2016
Results: No significant differences between uncomplicated and complicated MTBIs were found
in neuroanatomic volumes and cortical thickness after controlling for age, gender and educa-
tion. The complicated MTBI group showed larger ventricles compared with the uncomplicated
group, but this effect diluted when adjusting for potential confounders.
Conclusion: The study findings suggest that the classification of complicated and uncompli-
cated MTBI may be too broad to differentiate volumetric and morphometric effects of injury in
the early post-injury phase.

Introduction (MRI) is more sensitive and might detect intracranial injuries in

Traumatic brain injury (TBI) ranges from severe-to-mild
cases with 80–90% classified as mild TBI (MTBI), which is
defined by a Glasgow Coma Scale (GCS) score of 13–15
[1,2]. The exact incidence of MTBI is difficult to establish
even when applying standardized definitions, due to differ-
ences in healthcare organization including referal practices to
hospitals [3]. Whereas the majority of patients with MTBI
recover without persisting disability, 15–25% report long-
standing cognitive, psychological and behavioural impair-
ments [4–6]. Considering the personal, social and economic
costs associated with these impairments, it is important to
establish a diagnosis of MTBI to determine appropriate treat-
ments for these individuals.
A substantial minority of patients with MTBI (7–40%) exhibits
day-of-injury intracranial abnormalities detected on a computed
tomography (CT) scan [7–13]. Magnetic resonance imaging
Correspondence: T. Hellstrøm, Department of Physical Medicine and
Rehabilitation, Oslo University Hospital, PO Box 4950, Nydalen, Oslo
0407, Norway. E-mail: torgeir.hellstrom@ous-hf.no
10–15% of the patients with negative CT scans [14]. The impor-
tance of distinguishing between MTBI patients with and without
intracranial abnormality was highlighted by Williams et al. [15]
and the terms ‘complicated’ MTBI and ‘uncomplicated’ MTBI
were provided to describe these groups. Complicated MTBI is
characterized by injury severity in the mild range (GCS 13–15,
loss of consciousness (LOC) < 30 minutes, post-traumatic amne-
sia (PTA) < 24 hours), and the presence of a visible intracranial
abnormality or depressed skull fracture on the day-of-injury CT
scan [16]. Uncomplicated MTBI is characterized by the absence
of intracranial abnormalities or depressed skull fracture with all
other severity criteria in the mild range [16]. It is reasonable to
assume that worse functional outcome and increased risk of post-
concussion symptoms would result from complicated vs uncom-
plicated MTBIs, but the results from previous studies are mixed.
Although some studies have indicated that complicated MTBIs
result in worse outcomes compared with uncomplicated MTBIs
[15,17], McCauley et al. [18] reported that CT abnormalities were
not associated with increased risk of post-concussion symptoms
at 3 months post-injury.
2 T. Hellstrøm et al.
Although clinical brain imaging can detect abnormalities
in a limited number of MTBI patients [7–13,19], the persis-
tence of subjective symptoms are often reported [20]. The
lack of objective changes has contributed to MTBI being
referred to as an invisible injury. The insufficient knowledge
of the pathophysiological changes that contribute to the devel-
opment of symptoms is a diagnostic problem and makes it
difficult to provide a more effective treatment for these
patients [21].
Various theories have been proposed to explain the differ-
ent symptoms following MTBI, such as headache, sensory
sensitivity, memory and attention deficits. The proposed
mechanisms include undetected injury-related brain damage
[22], secondary problems such as post-traumatic stress, anxi-
ety and depression [23] or even more often pre-morbid indi-
vidual characteristics [24]. For many patients, however, there
is no clear explanation for their symptoms. One reason for
this lack of explanation is that the brain imaging methods
frequently applied in clinical contexts are not sufficiently
sensitive to subtle brain alterations following MTBI [25,26]
and clinical application of advanced and multimodal neuroi-
maging may improve diagnostic and prognostic validity and
reliability. Indeed, methods such as proton magnetic reso-
nance spectroscopy, diffusion-weighted MRI and functional
MRI (fMRI) have contributed to reveal metabolic, micro-
structural and functional changes in the brain after MTBI
[27–30]. For example, in line with experimental laboratory
studies showing that MTBI causes pronounced synapse
degeneration in the cortical neurons, which contributes to
the development of neurological dysfunction [21], fMRI stu-
dies have shown decreased function in the prefrontal brain
cortex [31] and a recent study has demonstrated structural
brain changes 1 year after a single concussive episode [32].
Investigations that included all severity levels have demon-
strated brain atrophy in areas remote from direct injury
[33–36]. In vivo volumetric MRI analyses have documented
brain atrophy in children after TBI [37], but there is a lack of
studies investigating brain atrophy after MTBI. In cases of
MTBI, the damage may be microscopic and methods that are
sensitive to subtle brain atrophy in patients with no apparent
pathologic findings on clinical MRI scans may provide
important and much-needed objective criteria for MTBI.
TBI-related haemorrhagic lesions are most commonly
observed in frontal and temporal regions and there is reason to
believe that these areas are particularly vulnerable to traumatic
brain injuries in general [37–39]. MTBI was often not included in
previous imaging studies, which calls for caution in extrapolating
findings to mild injuries. However, a primary mechanistic reason
for this selective vulnerability is due to how the concavities of the
scull base cup the frontal and temporal lobes, which creates sur-
face areas of contact among the dura, brain and skull [38]. Zhang
et al. [40] examined primary injury in MTBI by using a computa-
tional model to test the vulnerability of different human brain
tissues and found that the highest shear stress levels in head-to-
head field collisions occurring in professional football games
were localized to the thalamus and midbrain including corpus
callosum. Bigler and Maxwell [41] also noted the frontotemporal
regions, thalamus and midbrain as the areas that are most affected
by MTBI. Importantly, the frontotemporal susceptibility has been
assumed to represent a mechanism by which memory and
Brain Inj, Early Online: 1–9
executive functioning constitute the core cognitive and neurobe-
havioural symptoms of TBI [41].
Using automated whole-brain segmentation, it is possible
to explore the morphometric characteristics of a large number
of neuroanatomic structures. A recent study reviewed long-
itudinal studies of MRI brain volumetry in patients with TBI
[42], where the methods used for TBI diagnosis varied across
studies, and the level of severity ranged from mild-to-severe.
One of the reviewed studies focused on MTBI [43] and found
brain atrophy at 6 months follow-up in patients presenting
with initial MRI abnormalities, but did not compare uncom-
plicated and complicated MTBI.
Using state-of-the-art methods for morphometric and volu-
metric characterization of the human brain, the primary aim
of the current study was to gain insight into global and
regional brain volumetric and morphometric properties 4
weeks after MTBI by comparing cortical and sub-cortical
volumes between groups with uncomplicated and compli-
cated MTBI. This study specifically targeted brain regions
that are known to be vulnerable after TBI. It was hypothe-
sized that complicated MTBIs would display regionally
decreased brain volumes already in the sub-acute phase com-
pared to patients with uncomplicated MTBI. Based on anato-
mical considerations and findings from the extant literature,
preferential volume differences in frontal and temporal brain
areas and in the corpus callosum and thalamus were
hypothesized.
Materials and methods
Design
This study was part of a larger 2 years cohort study on MTBI,
in which baseline clinical and MRI data were compared for
those with complicated and uncomplicated MTBI.
Subjects
The patients were admitted to the university-affiliated Level I
trauma centre (Oslo University Hospital) with MTBI between
September 2011 and September 2013. MTBI was defined
using the criteria from the American Congress of
Rehabilitation Medicine [44] and included patients aged
16–65 years with injury occurring within the preceding 24
hours, hospitalization with ICD-10 diagnosis S06.0-S06.9 and
a GCS between 13–15, loss of consciousness lasting less than
30 minutes and post-traumatic amnesia of less than 24 hours.
The GCS was administered within the first 24 hours following
injury and the lowest GCS score within the first 24 hours is
reported.
This study identified 223 patients with documented MTBI
(see Figure 1 for a flowchart of the recruitment process).
Thirty-six patients did not attend to MRI or withdrew (n =
28), interrupted MRI (n = 5) or had implants that were MRI
incompatible (n = 3), resulting in 187 patients assessed with
MRI. Of these, eight did not show up for clinical appointment
at 6–8 weeks post-injury and for 11 patients the MRI was
discarded due to motion artefact or gross abnormal intracra-
nial findings. Thus, the final sample was 168 patients.
DOI: 10.1080/02699052.2016.1199905 Volumetric findings in mild TBI 3

Identified patients
with MTBI
agreed to participate
16-65 years (n=223)

Excluded (n=36)
• Did not attend to MRI or
withdrew (n=28)
• Interrupted MRI (n=5)
• Implant MRI incompatible
(n=3)

Investigated with
cerebral MRI (n=187)

Did not show for 6-8 weeks

follow-up (n=8)

MRI not useful due to motion

artefact or gross abnormal
intracranial findings (n=11)

Included patients
(n=168)

Figure 1. Flow diagram of MTBI.

The exclusion criteria included current major psychiatric dis-
ease (e.g. psychotic- or bipolar disorder diagnosed by a psychia-
trist or psychologist), a prior brain injury, other diagnosed
neurologic conditions, any known ICD-10 diagnosis of substance
dependence, contraindications for MRI (including pregnancy and
claustrophobia) or non-native Norwegian speakers.
Procedures
The study was approved by the Norwegian Regional Committee
for Medical Research Ethics 2010/1899. All subjects provided
written informed consent.
Demographic variables (age, gender, education, marital
status and pre-injury employment status), injury-related char-
acteristics (cause of injury, GCS, CT scan result, duration of
post-traumatic amnesia (PTA) and loss of consciousness
(LOC)), associated injuries and length of hospital stay
(LOS) were obtained from medical records.
MRI data acquisition and image analysis
contrast. In addition, a T2-weighted sequence and a T2
Susceptibility-Weighted Angiography (SWAN) sequence were
performed to depict haemorrhagic or other lesions. There was no
major scanner upgrade in the study period. All patients’ MRI data
were evaluated for gross pathologies and lesions by a neuroradiol-
ogist (author AS).
Cortical reconstruction and volumetric segmentation was per-
formed with FreeSurfer (http://surfer.nmr.mgh.harvard.edu/). In
short, this processing includes removal of non-brain tissue [45],
automated Talairach transformation, segmentation of the sub-cor-
tical white matter and deep grey matter volumetric structures [46],
intensity normalization, tessellation of the grey/white matter
boundary, topology correction and surface deformation [47,48]
to produce representations of cortical thickness, which are calcu-
lated as the closest distance from the grey/white boundary to the
grey/CSF boundary at each vertex on the surface. The maps are
not restricted to the voxel resolution of the original data and are
capable of detecting submillimeter differences between groups.
For each dataset, the mean cortical thickness and volume was
calculated within surface and volume-based regions of interest
(ROIs) [49] before being submitted to statistical analysis.

MR imaging was performed using a 3T whole-body MRI system

(Signa HDxt, GE Medical Systems, Milwaukee, WI). The proto-
col included a 3D Fast Spoiled Gradient Echo (FSPGR) T1-
weighted sequence used for morphometric assessments (repetition
time (ms)/echo time (ms)/inversion time (ms) = 7,8/2.96/450; flip
angle = 12°; and spatial resolution = 1 × 1 × 1.2 mm). Acquisition
parameters were optimized for increased grey/white matter
Statistical analysis
Cortical and sub-cortical regions of interest included the left
and right frontal and temporal lobe thickness, accumbens area,
caudate, hippocampus, putamen, corpus callosum, left and right
lateral ventricle and thalamus. In additional analyses, in order to
4 T. Hellstrøm et al. Brain Inj, Early Online: 1–9

test and adjust for global measures in the volumetric statistical Table I. Demographics and injury related variables of uncomplicated and
anlyses, intracranial volume, total grey matter volume or total complicated MTBIs.
cortical volume were also included in the models.
Uncomplicated Complicated
Statistical comparisons were performed using SPSS for MTBI MTBI p-
Windows, version 22 (SPSS Inc., Chicago, IL). Sample character- Variables (n = 90) (n = 78) value
istics are presented as the group mean with standard deviation
Age (years), mean (SD) 39.2 (13.2) 40.9 (14.9) 0.43
(SD), medians with 25th and 75th percentiles (25p, 75p) or Gender, n (%) 0.21
proportions. Differences between patients groups on continuous male 54 (60) 54 (69)
variables were tested using Student’s t-test for normally distribu- female 36 (40) 24 (31)
ted data and Mann–Whitney U-test for skewed data. The Chi-
Marital status 0.75
square test for contingency tables was obtained to detect group Married/partnership/live with 57 (63) 50 (64)
differences in categorical variables. All brain volumetric and Unmarried/widowed/divorced 33 (37) 28 (36)
morphometric measures were normally distributed except for Education, n (%) 0.12
left, right, and third ventricle. For these volumes a log transforma- 0–12 years 40 (44) 44 (56)
> 12 years 50 (56) 34 (44)
tion was performed. Employment, n (%) 0.68
One-way analyses of variance (ANOVA) were conducted to Yes 74 (82) 66 (84)
test whether any MRI measures differed between uncomplicated No 16 (18) 12 (16)
and complicated MTBI. To adjust for possible confounders, multi- Mechanism of injury, n (%) 0.07
Traffic accidents 47 (52) 25 (32)
ple linear regression analyses were performed to test for differ- Falls 27 (30) 37 (47)
ences between patients groups, while multi-confounding for age, Violence 8 (9) 9 (11)
gender, sex, education and total intracranial volume. The regres- Other 8 (9) 7 (10)
sion results are presented as β coefficients, standard error of β (SE GCS score, n (%) 0.65
15 63 (70) 59 (76)
(β)), p-values and explained variance (R2). Two tailed p < 0.01 14 24 (27) 16 (20)
was considered significant due to the number of tests performed. 13 3 (3) 3 (4)
Isolated TBI, n (%) 0.64
yes 53 (59) 49 (63)
no 37 (41) 29 (37)
Results LOC, n (%) 0.37
yes (< 5 minutes) 47 (52) 47 (60)
Group comparison in demographic and injury related yes (≥ 5 minutes) 2 (3) 3 (4)
variables no 19 (21) 17 (22)
unknown 22 (24) 11 (14)
Based on the presence of intracranial findings on CT or MRI, the PTA, n (%) 0.14
patients (n = 168) were classified as either uncomplicated no amnesia 6 (6) 11 (14)
< 1 hour 65 (72) 54 (70)
(no CT/MRI findings, n = 90) or complicated MTBI (positive > 1 < 24 hours 0 (0) 1 (1)
CT/MRI findings, n = 78). CT scan at admission was negative in unknown 20 (22) 12 (15)
98 patients, and for six patients a CT scan was not available, Length of acute hospital 1.8 (1.9) 2.9 (3.0) 0.005
whereof five had a negative and one a positive MRI scan. stay (days), mean (SD)
Time to MRI-scan (days), 34.5 (19) 41 (21) 0.04
Thirteen of the patients with negative CT scan (13%) displayed mean (SD), duplication of
injury-related findings on MRI (six diffuse axonal injury, 10 mean (SD)
cerebral contusions and three subdural haemorrhages) and were,
p-values: T-test for continuous variables; Chi-square for categorical
thus, classified as complicated MTBI. variables.
Demographic and injury-related data of the included data-
sets are summarized in Table I. The majority in both groups
were males. There were no significant differences in age,
gender or education. The majority of the injuries were traffic Table III summarizes the results from both the univariate and
injuries (43%). the multiple regression testing of neuroanatomical volumes for
The majority of the patients had GCS 15 (67%) and an effects of group, while covarying for age, gender, sex, level of
isolated TBI (i.e. TBI without associated injuries; 60%). education and intracranial volume. In summary, the univariate
There were no significant differences in GCS, degree of analyses revealed no significant differences between the uncom-
isolated TBI, duration of LOC, duration of PTA or injury plicated and complicated MTBI, neither did the multiple regres-
mechanisms. The duration of hospitalization was longer for sion analyses when controlling for potential cofounders.
the complicated group (mean (SD) = 2.9 (3.0) vs 1.8 (1.9), In addition, regression analyses showed no significant differ-
p = 0.005). MRI was performed at a median time of 34 days ences in overall or regional cortical thickness (see Table IV).
post-injury and the interquartile range (IQR) was 23 days
across MTBI groups. Global measures
Neither the univariate, nor the multiple linear regression analyses
revealed significant differences between the two patient sub-
Regional volumetry and morphometry
groups for total intracranial or cortical volume when adjusting
Table II summarizes the mean (SD) neuroanatomic volumes for intracranial volume (for cortical volume), age, gender, sex and
per ROI. education. The complicated MTBI group showed somewhat
DOI: 10.1080/02699052.2016.1199905 Volumetric findings in mild TBI 5
Table II. The mean values of neuroanatomic measurments per Region Of for potential confounders, it could possibly reflect the devel-
Interest (ROI). opment of atrophy. Atrophy is thought to represent neurode-
generation [52,53] that results from axonal/myelin loss and
Uncomplicated Complicated MTBI
MTBI (n = 90) (n = 78) the lack of cross-sectional difference in this study could
potentially be explained by the short duration of 1 month.
Mean, SD, Mean, SD, It has been reported that patients with complicated MTBI
Structure mm3 mm3 mm3 mm3 p-value
are more likely to show cognitive deficit [15,16,54] and worse
Total ICV 1 593 338 153 750 1 601 861 160 573 0.73 functional outcome after injury [15,17]. Compared to con-
Total gray volume 665 320 67 263 667 731 66 524 0.82 trols, Toth et al. [55] found a significant decrease in cortical
Cortex volume 494 533 54 293 495 623 51 807 0.89 volumes and increase in ventricle volumes 1 month after
L Accumbens area 668 148 660 120 0.73
R Accumbens area 617 126 602 125 0.47 injury in a group of uncomplicated MTBI. Another study
L Amygdala 1 600 200 1 603 195 0.94 [56] also found significantly smaller volumes in several sub-
R Amygdala 1 724 236 1 734 268 0.79 cortical regions in patients exposed to MTBI compared to
Brainstem 21 221 2 474 20 928 2 189 0.42 controls 2 months post-injury. Ross et al. [51] found that
L Caudate 3 836 546 3 776 534 0.47
R Caudate 4 142 534 4 114 599 0.76 patients with MTBI had progressive atrophy in whole brain
CC-posterior 1 004 147 1 012 169 0.72 parenchyma, forebrain parenchyma, cerebral white matter and
CC-mid-posterior 447 91 422 90 0.08 cerebellum in the long-term perspective post-injury compared
CC-central 441 75 428 79 0.30 to controls. Nonetheless, the literature is equivocal, as one
CC-mid-anterior 466 75 448 90 0.16
CC-anterior 922 144 904 141 0.44 study found similar functional and cognitive outcomes
L Hippocampus 4 515 519 4 518 461 0.98 between patients with complicated MTBI and moderate TBI
R Hippocampus 4 534 458 4 489 455 0.52 at discharge and 1 year post-injury [57] and another study
L Pallidum 1 379 213 1 422 243 0.23
found no important differences between those with uncom-
R Pallidum 1 622 225 1 630 240 0.83
L Putamen 5 681 953 5 589 952 0.53 plicated and complicated MTBI [18]. Zhou et al. [32] found
R Putamen 5 655 857 5 648 915 0.96 no differences in brain volumes between uncomplicated
L Thalamus 8 482 1 017 8 595 1 225 0.52 MTBIs and controls 4 weeks post-injury and a recent study
R Thalamus 7 032 888 7 017 1 014 0.92
L lateral Ventricle 10 303 6 306 11 706 6 732 0.16
found no significant differences in morphometry between
Log uncomplicated MTBI and patients with orthopaedic-injuries,
R lateral Ventricle 8 827 5 147 10 734 6 925 0.04 neither acutely nor 3 months after trauma [58]. Ling et al.
Log [50] also found no evidence of cortical or subcortical atrophy
Third Ventricle 1 190 433 1 365 535 0.02
Log
2 weeks and 4 months post-injury in MTBI. Although pre-
Fourth Ventricle 1 864 676 2 060 690 0.06 vious studies with small sample sizes have provided some
evidence that structural MRI may reveal brain pathology in
ICV, Intracranial volume; L, Left; R, Right; CC, Corpus Callosum; Log, patients exposed to MTBI, it is important to establish more
Logarithm.
p-values are from the mean comparisons by the independent T-tests. knowledge on the possible structural changes in the brain in
this patient population. This study used automated and sensi-
tive techniques to compare global and regional brain morpho-
larger lateral ventricles and third ventricle when compared with metry between patients with uncomplicated and complicated
the uncomplicated group, results being not significant according MTBI. Many of the studies published to date are based on
to the regression analysis. small samples, include TBIs of variable severity and have
continued their study inclusion over several years, resulting
in the use of different scanners and MRI protocols, which
Discussion
decreases reliability and sensitivity [33,34,59–62]. All of the
Utilizing sensitive and state-of-the art methods for brain scans obtained in the present study were acquired on the same
volumetry and morphometry, no significant differences were scanner using the same protocol. Furthermore, to reduce
documented in global or regional volumes or thickness clinical heterogeneity, only patients with MTBI were
between uncomplicated and complicated MTBIs ~ 1 month included. To increase the subject sample homogeneity, this
post-injury. The results may suggest that the classification of study also categorized the patients into two groups based on
complicated vs uncomplicated MTBIs is too broad to be the presence of injury-related intracranial findings, as indi-
useful in differentiating volumetric and morphometric effects cated by an experienced neuroradiologist.
of injury in the early post-acute phase. Alternatively, the A previous study found no differences in volumes early post-
results may suggest that neuronal loss occurs at later stages injury between healthy controls and uncomplicated MTBI [32].
of injury [50,51]. To the authors’ knowledge, no previous Some studies with mixed TBI severity have also not found volu-
studies have investigated the difference between uncompli- metric differences early post-injury [61,62]. However, several
cated and complicated MTBIs with brain volumetry and factors complicate a direct comparison with previous studies.
morphometry. In contrast to this hypothesis, the complicated First, there is variability regarding time from injury to MRI scan-
MTBI group did not show significantly smaller regional sub- ning, i.e. the temporal definition of the baseline. In a recently
cortical volumes or thinner frontal or temporal lobe cortical published study that showed no differences between controls and
thickness than uncomplicated MTBI. However, larger lateral uncomplicated MTBI, the MRI scan for MTBI was performed ~ 1
ventricles were found in the complicated MTBI group. month after injury, comparable to this study [32]. Van der Naalt
Although this result did not remain significant when adjusting et al. [17] reported that atrophy can be observed from early post-
6 T. Hellstrøm et al. Brain Inj, Early Online: 1–9

Table III. Neuroanatomic volumes: groups comparison by univariate and multivariate linear regression analyses.

Comparison Groups

Mild uncomplicated vs Mild complicated TBI

Structures Univariate Multivariate*

2
Neuroanatomic volumes B SE p-value R B SE p-value R2

Total ICV 8522 24282 0.726 .001 –4671 20175 0.817 .342
Total gray vol 2410 10352 0.816 .000 4046,9 4389,7 0.358 .830
Cortex volume 1090,3 8222,9 0.895 .000 2457,6 3974,0 0.537 .779
L Accumbens area –7,269 21,121 0.731 .001 –3,464 17,561 0.844 .345
R Accumbens area –14,281 19,494 0.465 .003 –9,698 16,174 0.550 .349
L Amygdala 2,436 30,660 0.937 .000 9,28 26,99 0.731 .265
R Amygdala 10,070 38,968 0.796 .000 7,846 38,02 0.837 .098
Brain Stem –293,419 363,00 0.420 .004 –320,79 270,85 0.238 .474
L Caudate –60,183 83,710 0.473 .003 –51,331 64,216 0.425 .444
R Caudate –28,194 91,509 0.758 .001 –21,197 69,183 0.760 .458
L Hippocampus 2,232 76,345 0.977 .000 18,915 62,067 0.761 .373
R Hippocampus –45,173 70,715 0.524 .002 –29,369 62,355 0.638 .265
L Putamen –92,442 147,49 0.532 .002 –63,299 121,32 0.603 .360
R Putamen –7,661 136,86 0.956 .000 17,281 108,07 0.873 .409
Left Thalamus 112,344 173,09 0.517 .003 112,18 136,24 0.412 .414
Right Thalamus –14,981 146,83 0.919 .000 ,822 111,8 0.994 .450
CC-posterior 8,796 24,454 0.720 .001 7,909 22,673 0.728 .186
CC-mid-poster –24,946 14,033 0.077 .019 –24,444 14,034 0.083 .069
CC-central –12,504 11,990 0.298 .007 –12,678 11,788 0.284 .089
CC-mid-anterior –18,163 12,838 0.159 .012 –15,897 12,022 0.188 .178
CC-anterior –17,711 22,838 0.439 .004 –18,911 20,779 0.364 .218
L Pallidum 42,802 35,299 0.227 .009 43,628 29,822 0.145 .329
R Pallidum 7,543 35,926 0.834 .000 5,738 27,623 0.836 .440
L lateral Ventricle Log 1402,9 1006,6 0.165 .012 949,68 887,3 0.286 .272
R lateral Ventricle Log 1907,1 934 0.043 .024 1490,4 816,3 0.070 .293
Third Ventricle Log 174,98 74,7 0.020 .032 114,32 58,5 0.052 .438
Fourth Ventricle 196,056 105,6 0.065 .020 166,57 101,3 0.102 .145

* multivariate linear regression, adjusted for total intracranial volume, gender, age and education.
Abbreviations: L= left, R = right, CC = Corpus callosum Log = Logarithme

injury, but, in this case, the initial MRI was not performed until
1–3 months post-injury in mild and moderate TBI. Zagorchev
et al. [56] reported atrophy 2 months after injury. Another study
obtained the initial MRI at a median of 1 day post-injury [62] and,
thus, did not expect differences in volume between controls and
patients with TBI, although Warner et al. [62] declare that higher
rates of atrophy may occur during the acute/early sub-acute period
than during the late sub-acute/chronic period. Scanning in the
present study was performed at a mean time of 34 days post-injury
and the lack of findings may potentially be explained by the
relatively short time interval. Indeed, atrophy may occur even
during the early sub-acute period, in some patients injury-induced
neurodegenerative cascade processes may continue and even
accelerate after the initial period, and the rate and anatomical
distribution of any case-control differences may, therefore, depend
on the time elapsed since the injury [63]. Smaller subcortical
volumes and cortical thickness were expected in the complicated
compared with the uncomplicated group. This study, however,
included patients treated at a Level I trauma centre, which could
bias the uncomplicated MTBI towards a more severe outcome,
despite coarse severity indicators being comparable to the com-
plicated MTBI group. It was hypothesized that the more severe
MTBI patients experience more atrophy than those with milder
injuries. This did not seem to be the case, at least not at this
particular time point, although the enlarged ventricles in the
patients with complicated MTBI might represent early indicators
of atrophic processes. In contrast, the results are in line with the
study of Zhou et al. [32], who included patients with single
concussive episodes. As argued above, the present lack of findings
may be possibly explained by the time of scan post-injury, given
that atrophy could be expected first later than after 4 weeks also for
the complicated MTBI group.
The anatomical sites of atrophy in previous studies are, to some
extent, inconsistent. Despite the small number of studies examin-
ing morphometry following MTBI, considerable variability with
respect to the magnetic field strength, time period of scanning
post-injury, brain regions examined, methods of data acquisition
and post processing techniques employed are apparent. The differ-
ences must also be observed in view of the clinical heterogeneity
of MTBI. Although methodological variations could account for
some of the between-study variability, most longitudinal studies
have reported subtle differences over time [32,51,59,62] suggest-
ing that atrophy may occur during the late sub-acute and chronic
phase.
Study limitations
This study has methodological limitations and issues that
require consideration in the interpretation of results. First, it
involves cross-sectional data without a control group which is
recommended in the MTBI research.
DOI: 10.1080/02699052.2016.1199905 Volumetric findings in mild TBI 7
Table IV. Cortical thickness: groups comparison by univariate and multivariate linear regression analyses.

Comparison groups: Mild uncomplicated vs Mild complicated TBI

Structures Univariate Multivariate*

Cortical thickness B SE p-value R2 B SE p-value R2

L hemisphere, mean –0.02 0.02 0.337 0.006 –0.011 0.02 0.447 0.274
R hemisphere, mean –0.01 0.02 0.735 0.001 –0.001 0.02 0.958 0.213
L frontal –0.01 0.02 0.542 0.002 –0.01 0.02 0.693 0.145
R frontal 0.01 0.02 0.622 0.001 0.01 0.02 0.418 0.085
L temporal –0.03 0.02 0.129 0.014 –0.03 0.02 0.135 0.286
R temporal –0.03 0.02 0.148 0.013 –0.02 0.02 0.231 0.241
L parietal –0.02 0.02 0.470 0.003 –0.01 0.02 0.691 0.217
R parietal 0.002 0.02 0.923 0.000 0.01 0.02 0.774 0.194
L cingulate 0.001 0.03 0.984 0.000 0.01 0.02 0.805 0.250
R cingulate 0.04 0.03 0.128 0.014 0.04 0.02 0.064 0.194
L occipital –0.02 0.02 0.281 0.007 –0.02 0.02 0.357 0.158
R occipital –0.03 0.02 0.071 0.019 –0.03 0.02 0.070 0.148
L insula 0.01 0.03 0.831 0.000 0.01 0.02 0.630 0.309
R insula –0.01 0.03 0.820 0.000 –0.002 0.03 0.941 0.214

* Multivariate linear regression, adjusted for gender, age and education.

L, left; R, right.

Second, the MTBI population is by definition heteroge- Conclusion

neous, as reflected in the different injury mechanisms and the
No significant differences in subcortical volumes or fronto-
types of parenchymal injury. However, this study adhered
temporal cortical thickness were found between uncompli-
strictly to American Congress of Rehabilitation Medicine
cated and complicated MTBIs ~ 4 weeks post-injury,
criteria and included only patients with documented injury
although a tendency towards enlarged ventricles potentially
from the emergency department.
marks early atrophic processes in the complicated MTBI.
Third, this study excluded patients with current severe
This does not rule out that macroanatomical changes in
mental illnesses, but did not adjust for milder symptoms
these structures may occur in MTBI, despite normal conven-
related to depression, anxiety or PTSD. Depression has been
tional brain MRI. There is need for longitudinal studies to
linked to brain structural variance in specific regions, includ-
investigate if the sub-classification of MTBI based on con-
ing the limbic system and prefrontal cortex [64–66]. A meta-
ventional brain neuroimaging alone is sensitive with regard to
analysis reported decreased prefrontal, orbitofrontal and hip-
the detection of chronic anatomical effects of injury.
pocampal volumes in MTBI patients with depression [67].
Additionally, this study did not adjust for alcohol/substance
use. Alcohol-dependence has been linked to smaller grey
Acknowledgements
matter volume in the medial frontal cortex, the right lateral
prefrontal cortex and a posterior region surrounding the par- The authors thank all of the patients who took time to parti-
ietal-occipital sulcus [68]. Finally, data were not collected on cipate in the study. We also thank radiograph Anne-Hilde
pre-injury exposure to adverse life events (subjective chronic Farstad for practical MRI assistance and the Department of
stress and cumulative life events), which may influence the Physical Medicine and Rehabilitation, Oslo University
volume in the orbitofrontal cortex, insula and anterior and Hospital for institutional and financial support.
subgenual cingulate regions [69]. Brain morphometric prop-
erties are not biologically specific, i.e. several biological
processes can result in volumetric changes. Further studies Declaration of interest
are needed to disentangle the effects of mild psychiatric
The authors report no conflicts of interest. The authors alone
symptoms, substance use, adverse life events and pure
are responsible for the content and writing of the paper.
MTBI-related variance.
The use of sensitive volumetric and morphometric neuroima-
ging methods in TBI is particularly interesting compared to
References
acquired brain injuries of other aetiologies in that the exact time
of onset of injury is known [42]. For this reason, longitudinal 1. Kay A, Teasdale G. Head injury in the United Kingdom. World
Journal of Surgery 2001;25:1210–1220.
studies of MRI volume in MTBI may be more informative than 2. Andelic N, Sigurdardottir S, Brunborg C, Roe C. Incidence of
cross-sectional analyses when examining structural and functional hospital-treated traumatic brain injury in the Oslo population.
brain processes that accompany MTBI. Future results from this Neuroepidemiology 2008;30:120–128.
project will address longitudinal data to evaluate the long-term 3. Holm L, Cassidy JD, Carroll LJ, Borg J, Neurotrauma Task Force
on Mild Traumatic Brain Injury of the WHOCC. Summary of the
development of brain atrophy and understand its association with WHO Collaborating Centre for Neurotrauma Task Force on Mild
relevant clinical variables. Traumatic Brain Injury. Journal of Rehabilitation Medicine:
8 T. Hellstrøm et al.
Official Journal of the UEMS European Board of Physical and
Rehabilitation Medicine 2005;37:137–141.
4. Ruff RM, Camenzuli L, Mueller J. Miserable minority: emotional
risk factors that influence the outcome of a mild traumatic brain
injury. Brain Injury 1996;10:551–565.
5. Wrightson P, Gronwall D. Time off work and symptoms after
minor head injury. Injury 1981;12:445–454.
6. Bohnen NMDPD, Twijnstra AMDPD, Jolles JPD. Persistence of post-
concussional symptoms in uncomplicated, mildly head-injured patients:
a prospective cohort study. Neuropsychiatry, Neuropsychology, &
Behavioral Neurology 1993;6:193–200.
7. Borg J, Holm L, Cassidy JD, Peloso PM, Carroll LJ, von Holst H,
Ericson K, Injury WHOCCTFoMTB. Diagnostic procedures in mild
traumatic brain injury: results of the WHO Collaborating Centre Task
Force on Mild Traumatic Brain Injury. Journal of Rehabilitation
Medicine: Official Journal of the UEMS European Board of
Physical and Rehabilitation Medicine 2004(Suppl 43):61–75.
8. Iverson GL, Lovell MR, Smith S, Franzen MD. Prevalence of
abnormal CT-scans following mild head injury. Brain Injury
2000;14:1057–1061.
9. Livingston DH, Loder PA, Koziol J, Hunt CD. The use of CT scan-
ning to triage patients requiring admission following minimal head
injury. The Journal of Trauma 1991;31:483–487; discussion 7–9.
10. Tellier A, Della Malva LC, Cwinn A, Grahovac S, Morrish W,
Brennan-Barnes M. Mild head injury: a misnomer. Brain Injury
1999;13:463–475.
11. Thiruppathy SP, Muthukumar N. Mild head injury: revisited. Acta
Neurochirurgica 2004;146:1075–1082; discussion 82–83.
12. Lingsma H, Yue JK, Maas A, Steyerberg EW, Manley GTMDPD,
Cooper SR, Dams-O’Connor K, Menon D, Mukherjee P, Okonkwo
DO, Puccio AM, Schnyer DM, Valadka A, Vassar MJ, Yuh EL.
Outcome prediction after mild and complicated mild traumatic
brain injury: external validation of existing models and identifica-
tion of new predictors using the TRACK-TBI Pilot Study. Journal
of Neurotrauma 2015;32:83–94.
13. Levin HS, Williams DH, Eisenberg HM, High WM Jr., Guinto FC
Jr. Serial MRI and neurobehavioural findings after mild to moder-
ate closed head injury. Journal of Neurology, Neurosurgery and
Psychiatry 1992;55:255–262.
14. Sigurdardottir S, Jerstad T, Andelic N, Roe C, Schanke AK. Olfactory
dysfunction, gambling task performance and intracranial lesions after
traumatic brain injury. Neuropsychology 2010;24:504–513.
15. Williams DH, Levin HS, Eisenberg HM. Mild head injury classi-
fication. Neurosurgery 1990;27:422–428.
16. Iverson GL, Lange RT, Waljas M, Liimatainen S, Dastidar P,
Hartikainen KM, Soimakallio S, Ohman J. Outcome from compli-
cated versus uncomplicated mild traumatic brain injury.
Rehabilitation Research and Practice 2012;2012:415740.
17. van der Naalt J, Hew JM, van Zomeren AH, Sluiter WJ,
Minderhoud JM. Computed tomography and magnetic resonance
imaging in mild to moderate head injury: early and late imaging
related to outcome. Annals of Neurology 1999;46:70–78.
18. McCauley SR, Boake C, Levin HS, Contant CF, Song JX.
Postconcussional disorder following mild to moderate traumatic
brain injury: anxiety, depression, and social support as risk factors
and comorbidities. Journal of Clinical and Experimental
Neuropsychology 2001;23:792–808.
19. Smits M, Hunink MG, van Rijssel DA, Dekker HM, Vos PE, Kool
DR, Nederkoorn PJ, Hofman PA, Twijnstra A, Tanghe HL, Dippel
DW. Outcome after complicated minor head injury. American
Journal of Neuroradiology 2008;29:506–513.
20. Roe C, Sveen U, Alvsaker K, Bautz-Holter E. Post-concussion
symptoms after mild traumatic brain injury: influence of demo-
graphic factors and injury severity in a 1-year cohort study.
Disability and Rehabilitation 2009;31:1235–1243.
21. Gao X, Chen J. Mild traumatic brain injury results in extensive
neuronal degeneration in the cerebral cortex. Journal of
Neuropathology and Experimental Neurology 2011;70:183–191.
22. Ryan LM, Warden DL. Post concussion syndrome. International
Review of Psychiatry (Abingdon, England) 2003;15:310–316.
23. Zatzick DF, Rivara FP, Jurkovich GJ, Hoge CW, Wang J, Fan MY,
Russo J, Trusz SG, Nathens A, Mackenzie EJ. Multisite investiga-
tion of traumatic brain injuries, posttraumatic stress disorder, and
self-reported health and cognitive impairments. Archives of
General Psychiatry 2010;67:1291–1300.
Brain Inj, Early Online: 1–9
24. Stulemeijer M, Vos PE, Bleijenberg G, van der Werf SP. Cognitive
complaints after mild traumatic brain injury: things are not always what
they seem. Journal of Psychosomatic Research 2007;63:637–645.
25. Farkas O, Povlishock JT. Cellular and subcellular change evoked
by diffuse traumatic brain injury: a complex web of change extend-
ing far beyond focal damage. Progress in Brain Research
2007;161:43–59.
26. Povlishock JT, Katz DI. Update of neuropathology and neurologi-
cal recovery after traumatic brain injury. The Journal of Head
Trauma Rehabilitation 2005;20:76–94.
27. Grossman EJ, Ge Y, Jensen JH, Babb JS, Miles L, Reaume J, Silver
JM, Grossman RI, Inglese M. Thalamus and cognitive impairment
in mild traumatic brain injury: a diffusional kurtosis imaging study.
Journal of Neurotrauma 2012;29:2318–2327.
28. Raz E, Jensen JH, Ge Y, Babb JS, Miles L, Reaume J, Grossman
RI, Inglese M. Brain iron quantification in mild traumatic brain
injury: a magnetic field correlation study. AJNR American Journal
of Neuroradiology 2011;32:1851–1856.
29. Tang L, Ge Y, Sodickson DK, Miles L, Zhou Y, Reaume J, Grossman
RI. Thalamic resting-state functional networks: disruption in patients
with mild traumatic brain injury. Radiology 2011;260:831–840.
30. Zhou Y, Milham MP, Lui YW, Miles L, Reaume J, Sodickson DK,
Grossman RI, Ge Y. Default-mode network disruption in mild
traumatic brain injury. Radiology 2012;265:882–892.
31. Witt ST, Lovejoy DW, Pearlson GD, Stevens MC. Decreased pre-
frontal cortex activity in mild traumatic brain injury during perfor-
mance of an auditory oddball task. Brain Imaging and Behavior
2010;4:232–247.
32. Zhou Y, Kierans A, Kenul D, Ge Y, Rath J, Reaume J, Grossman
RI, Lui YW. Mild traumatic brain injury: longitudinal regional
brain volume changes. Radiology 2013;267:880–890.
33. Anderson CV, Wood DM, Bigler ED, Blatter DD. Lesion volume,
injury severity, and thalamic integrity following head injury.
Journal of Neurotrauma 1996;13:59–65.
34. Bigler ED, Blatter DD, Anderson CV, Johnson SC, Gale SD, Hopkins
RO, Burnett B. Hippocampal volume in normal aging and traumatic
brain injury. American Journal Of Neuroradiology 1997;18:11–23.
35. Gale SD, Burr RB, Bigler ED, Blatter D. Fornix degeneration and
memory in traumatic brain injury. Brain Research Bulletin
1993;32:345–349.
36. Yount R, Raschke KA, Biru M, Tate DF, Miller MJ, Abildskov T,
Gandhi P, Ryser D, Hopkins RO, Bigler ED. Traumatic brain injury
and atrophy of the cingulate gyrus. The Journal of Neuropsychiatry
and Clinical Neurosciences 2002;14:416–423.
37. Wilde EA, Hunter JV, Newsome MR, Scheibel RS, Bigler ED, Johnson
JL, Fearing MA, Cleavinger HB, Li X, Swank PR, Pedroza C, Roberson
GS, Bachevalier J, Levin HS. Frontal and temporal morphometric
findings on MRI in children after moderate to severe traumatic brain
injury. Journal of Neurotrauma 2005;22:333–344.
38. Bigler ED. Anterior and middle cranial fossa in traumatic brain
injury: relevant neuroanatomy and neuropathology in the study of
neuropsychological outcome. Neuropsychology 2007;21:515–531.
39. Pierallini A, Pantano P, Fantozzi LM, Bonamini M, Vichi R,
Zylberman R, Pisarri F, Colonnese C, Bozzao L. Correlation
between MRI findings and long-term outcome in patients with
severe brain trauma. Neuroradiology 2000;42:860–867.
40. Zhang L, Yang KH, King AI. A proposed injury threshold for mild
traumatic brain injury. Journal of Biomechanical Engineering
2004;126:226–236.
41. Bigler ED, Maxwell WL. Neuropathology of mild traumatic brain
injury: relationship to neuroimaging findings. Brain Imaging and
Behavior 2012;6:108–136.
42. Ross DE. Review of longitudinal studies of MRI brain volumetry
in patients with traumatic brain injury. Brain Injury 2011;25:1271–
1278.
43. Hofman PA, Stapert SZ, van Kroonenburgh MJ, Jolles J, de Kruijk
J, Wilmink JT. MR imaging, single-photon emission CT, and
neurocognitive performance after mild traumatic brain injury.
American Journal of Neuroradiology 2001;22:441–449.
44. Mild Traumatic Brain Injury Committee, American Congress of
Rehabilitation Medicine, Group HIISI. Definition of mild traumatic
brain injury. Journal of Head Trauma Rehabilitation 1993;8:86–87.
45. Segonne F, Dale AM, Busa E, Glessner M, Salat D, Hahn HK,
Fischl B. A hybrid approach to the skull stripping problem in MRI.
NeuroImage 2004;22:1060–1075.
DOI: 10.1080/02699052.2016.1199905
46. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C,
van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo
A, Makris N, Rosen B, Dale AM. Whole brain segmentation:
automated labeling of neuroanatomical structures in the human
brain. Neuron 2002;33:341–355.
47. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. NeuroImage
1999;9:179–194.
48. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proceedings of the National
Academy of Sciences of the United States of America 2000;97:11050–
11055.
49. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC,
Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT,
Albert MS, Killiany RJ. An automated labeling system for subdi-
viding the human cerebral cortex on MRI scans into gyral based
regions of interest. NeuroImage 2006;31:968–980.
50. Ling JM, Klimaj S, Toulouse T, Mayer AR. A prospective study of gray
matter abnormalities in mild traumatic brain injury. Neurology
2013;81:2121–2127.
51. Ross DE, Ochs AL, Seabaugh JM, Demark MF, Shrader CR,
Marwitz JH, Havranek MD. Progressive brain atrophy in patients
with chronic neuropsychiatric symptoms after mild traumatic brain
injury: a preliminary study. Brain Injury 2012;26:1500–1509.
52. Baugh CM, Stamm JM, Riley DO, Gavett BE, Shenton ME, Lin A,
Nowinski CJ, Cantu RC, McKee AC, Stern RA. Chronic traumatic
encephalopathy: neurodegeneration following repetitive concussive
and subconcussive brain trauma. Brain Imaging and Behavior
2012;6:244–254.
53. Gavett BE, Stern RA, Cantu RC, Nowinski CJ, McKee AC. Mild
traumatic brain injury: a risk factor for neurodegeneration.
Alzheimer’s Research & Therapy 2010;2:18.
54. Borgaro SR, Prigatano GP, Kwasnica C, Rexer JL. Cognitive and
affective sequelae in complicated and uncomplicated mild trau-
matic brain injury. Brain Injury 2003;17:189–198.
55. Toth A, Kovacs N, Perlaki G, Orsi G, Aradi M, Komaromy H, Ezer
E, Bukovics P, Farkas O, Janszky J, Doczi T, Buki A, Schwarcz A.
Multi-modal magnetic resonance imaging in the acute and sub-
acute phase of mild traumatic brain injury: can we see the differ-
ence? Journal of Neurotrauma 2013;30:2–10.
56. Zagorchev L, Meyer C, Stehle T, Wenzel F, Young S, Peters J, Weese J,
Paulsen K, Garlinghouse M, Ford J, Roth R, Flashman L, McAllister T.
Differences in regional brain volumes two months and one year after
mild traumatic brain injury. Journal of Neurotrauma 2015;33:29–34.
57. Kashluba S, Hanks RA, Casey JE, Millis SR. Neuropsychologic and
functional outcome after complicated mild traumatic brain injury.
Archives of Physical Medicine and Rehabilitation 2008;89:904–911.
Volumetric findings in mild TBI 9
58. Narayana PA, Yu X, Hasan KM, Wilde EA, Levin HS, Hunter JV,
Miller ER, Patel VK, Robertson CS, McCarthy JJ. Multi-modal MRI
of mild traumatic brain injury. NeuroImage Clinical 2015;7:87–97.
59. MacKenzie JD, Siddiqi F, Babb JS, Bagley LJ, Mannon LJ, Sinson
GP, Grossman RI. Brain atrophy in mild or moderate traumatic
brain injury: a longitudinal quantitative analysis. American Journal
of Neuroradiology 2002;23:1509–1515.
60. Trivedi MA, Ward MA, Hess TM, Gale SD, Dempsey RJ, Rowley
HA, Johnson SC. Longitudinal changes in global brain volume
between 79 and 409 days after traumatic brain injury: relationship
with duration of coma. Journal of Neurotrauma 2007;24:766–771.
61. Ding K, Marquez de la Plata C, Wang JY, Mumphrey M, Moore C,
Harper C, Madden CJ, McColl R, Whittemore A, Devous MD,
Diaz-Arrastia R. Cerebral atrophy after traumatic white matter
injury: correlation with acute neuroimaging and outcome. Journal
of Neurotrauma 2008;25):1433–1440.
62. Warner MA, Youn TS, Davis T, Chandra A, Marquez de la Plata
C, Moore C, Harper C, Madden CJ, Spence J, McColl R, Devous
M, King RD, Diaz-Arrastia R. Regionally selective atrophy after
traumatic axonal injury. Archives of Neurology 2010;67:1336–
1344.
63. Sidaros A, Skimminge A, Liptrot MG, Sidaros K, Engberg AW,
Herning M, Paulson OB, Jernigan TL, Rostrup E. Long-term
global and regional brain volume changes following severe trau-
matic brain injury: a longitudinal study with clinical correlates.
NeuroImage 2009;44:1–8.
64. Theberge J. Perfusion magnetic resonance imaging in psychiatry.
Topics in Magnetic Resonance Imaging 2008;19:111–130.
65. Kronenberg G, Tebartz van Elst L, Regen F, Deuschle M, Heuser I,
Colla M. Reduced amygdala volume in newly admitted psychiatric
in-patients with unipolar major depression. Journal of Psychiatric
Research 2009;43:1112–1117.
66. Mak AK, Wong MM, Han SH, Lee TM. Gray matter reduction asso-
ciated with emotion regulation in female outpatients with major depres-
sive disorder: a voxel-based morphometry study. Progress in Neuro-
Psychopharmacology & Biological Psychiatry 2009;33:1184–1190.
67. Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol
HE, Kahn RS. Brain volume abnormalities in major depressive
disorder: a meta-analysis of magnetic resonance imaging studies.
Human Brain Mapping 2009;30:3719–3735.
68. Rando K, Hong KI, Bhagwagar Z, Li CS, Bergquist K, Guarnaccia
J, Sinha R. Association of frontal and posterior cortical gray matter
volume with time to alcohol relapse: a prospective study. The
American Journal of Psychiatry 2011;168:183–192.
69. Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R. Cumulative
adversity and smaller gray matter volume in medial prefrontal, anterior
cingulate, and insula regions. Biological Psychiatry 2012;72:57–64.