JOURNAL OF NEUROTRAUMA 25:1343–1345 (November 2008)
© Mary Ann Liebert, Inc.
Diffuse Changes in Cortical Thickness in Pediatric
Moderate-to-Severe Traumatic Brain Injury
Tricia L. Merkley,1Erin D. Bigler,1,2,3Elisabeth A. Wilde,4Stephen R. McCauley,4
Jill V. Hunter,7,8and Harvey S. Levin4,5,6
Generalized whole brain volume loss has been well documented in moderate-to-severe traumatic brain injury
(TBI), as has diffuse cerebral atrophy based on magnetic resonance imaging (MRI) volumetric methods where
white matter may be more selectively affected than gray matter. However, specific regional differences in gray
matter thickness of the cortical mantle have not been previously examined. As such, cortical thickness was as-
sessed using FreeSurfer®software to identify regions of significant gray matter cortical thinning in MRI scans
of 16 young TBI subjects (age range, 9–16 years) compared to 16 demographically matched controls. Signifi-
cant cortical thinning was observed globally in the TBI group compared to the cohort of typically developing
children. Reduced cortical thickness was related to reported deficits in working memory. TBI-induced cortical
thickness reductions are probably due to a combination of focal and diffuse effects and have implications for
the neurobehavioral sequelae of TBI.
Key words: MRI; neural injury; other tools of modern imaging; pediatric brain injury; traumatic brain injury
changes resulting in reduced overall brain volume (Levine
et al., 2008). Given these nonspecific effects, it would be an-
ticipated that TBI would also affect cortical thickness, but
this has not been examined to date. Despite the heterogene-
ity of TBI, including severity and the relative contributions
of focal and diffuse injury, common areas of residual injury
have been observed, suggesting the likelihood that TBI
would result in some characteristic regional changes in cor-
tical thickness, including frontotemporal and limbic regions
(Gale et al., 2005; Levine et al., 2008). Accordingly, in the cur-
rent study, we compared the MRI-derived cortical thickness
of 16 children aged 9–16 years who had sustained moderate-
to-severe TBI to a comparison group of 16 demographically
matched, normally developing children.
Given previous reports of diffuse white matter atrophy
following TBI (Gale et al., 1995a; Levine et al., 2008), we hy-
pothesized that significant differences in cortical thickness
RAUMATIC BRAIN INJURY (TBI) is known to produce both
focal and diffuse damage with generalized atrophic
would also be apparent globally between the TBI and com-
parisons cohorts in our sample, including areas such as the
frontal and temporal cortex, which have been identified pre-
viously using volumetric approaches (Gale et al., 2005; Wilde
et al., 2005; Yount et al., 2002).
The TBI group consisted of 16 children (eight male, eight
female) who had sustained moderate-to-severe injury (initial
Glasgow Coma Scale [GCS] score of 3–12). Mean post-injury
interval was 3.1 ? 2.4 years, and mean age at the time of
scanning was 12.9 ? 2.5 years (Table 1). Sixteen typically de-
veloping children were selected to demographically match
the TBI patients. All subjects underwent magnetic resonance
imaging (MRI) without sedation on 1.5-Tesla Intera scanners
(Philips, Cleveland, OH). A T1-weighted (15 msec TR, 4.6
msec TE, 1.0-mm slices) three-dimensional (3D) sagittal ac-
quisition series with a 256-mm field of view (FOV) was used
for cortical thickness analysis.
Cortical surfaces were reconstructed using FreeSurfer®
v4.0.4 software (Athinoula A. Martinos Center for Biomed-
Departments of 1Psychology and 2Neuroscience, Brigham Young University, Provo, Utah.
3Department of Psychiatry, University of Utah, Salt Lake City, Utah.
Departments of 4Physical Medicine and Rehabilitation, 5Neurosurgery, 6Psychiatry, and 7Radiology, Baylor College of Medicine,
8E.B. Singleton Department of Diagnostic Imaging, Texas Children’s Hospital, Houston, Texas.
ical Imaging, Charlestown, MA; https://surfer.nmr.mgh.har-
vard.edu), which has been described by others (Dale et al.,
1999; Fischl and Dale, 2000; Fischl et al., 1999). Briefly, rep-
resentations of the gray and white matter boundary and the
pial surface were reconstructed for each subject using both
intensity and continuity information from the MRI scan. The
results for each subject were visually inspected and corrected
where necessary (e.g., removal of dura and skull, accurate
delineation of pial and white matter surfaces). Cortical thick-
ness was measured as the distance between these two sur-
faces at each point on the cortical mantle. The procedure has
been shown to be capable of detecting sub-millimeter dif-
ferences between groups (Fischl and Dale, 2000). Surface
smoothing was performed using a 10-mm full-width half-
maximum Gaussian kernel.
The cortical thickness analysis revealed a diffuse pattern of
significant group difference (p ? 0.005 to p ? 0.00001) in corti-
cal thickness (Fig. 1). For reporting group differences by corti-
cal region, we selected a threshold of p ? 0.0008, which corre-
sponds to a threshold of p ? 0.05 Bonferroni-corrected for the
number of multiple comparisons. After adjusting for the ef-
fects of age and gender, highly significant mean cortical loss
was observed in the TBI group as compared to the typically
developing children, including left superior frontal (p ?
0.0002), right pars opercularis (p ? 0.0005), right frontal pole
(p ? 0.0002), rostral middle frontal (left p ? 0.0001, right p ?
0.0004), caudal middle frontal (left p ? 0.0001, right p ? 0.0004),
left precentral (p ? 0.0007), supramarginal (left p ? 0.0001,
right p ? 0.0003), left middle temporal (p ? 0.0001), inferior
temporal (left p ? 0.0006, right p ? 0.0002), left fusiform (p ?
0.0001), postcentral (left p ? 0.0001, right p ? 0.0001), superior
parietal (left p ? 0.0001, right p ? 0.0001), inferior parietal (left
p ? 0.0001, right p ? 0.0001), and precuneus (left p ? 0.0002,
right p ? 0.0003) regions.
MERKLEY ET AL.1344
TABLE 1.DEMOGRAPHIC CHARACTERISTICS OF TRAUMATIC BRAIN INJURY (TBI) AND TYPICALLY DEVELOPING CHILDREN
(n ? 16)
Typically developing children
(n ? 16)
Age at testing (years)
Age at injury (years)
Time post-injury (years)
Gender distribution (M/F)
Mechanism of injury (accident type)
12.9 ? 2.5
9.75 ? 3.0
3.1 ? 2.4
12.8 ? 2.4
N/A 6 auto-pedestrian, 1 bicycle,
6 MVA, 1 motorcycle, 2 RV
5.7 ? 2.8 (range, 3–11) Glasgow Coma Scale scoreN/A
M, male; F, female; MVA, motor vehicle accident; RV, recreation vehicle accident; N/A, not applicable.
children, reflecting adjustments made for age and gender. The p-value color scale indicates group differences ranging from
dark red (p ? 0.005) to yellow (p ? 0.00001). Results are displayed on a customized averaged pediatric subject. (A) Lateral
view (with surfaces inflated to reveal the extent of significant regions) showing group differences bilaterally for temporal
and frontal lobe (p ? 0.005). (B) Lateral view (now shown as pial surfaces) indicating the same significant regions as dis-
played in A. (C) Midsagittal pial surfaces showing significant cortical regional differences.
Regions of significant cortical loss in pediatric traumatic brain injury (TBI) as compared to typically developing
While cortical thickness was not related to the Glasgow Download full-text
Outcome Scale (GOS) (Jennett and Bond, 1975), cortical thick-
ness was highly correlated with the working memory index
of the Behavior Rating Inventory of Executive Function
(BRIEF) (Gioia et al., 2000). Working memory is believed to
be mediated by a distributed network of cortical regions
(Postle, 2006a,b), and working memory impairment is com-
mon subsequent to TBI (Christodoulou et al., 2001). Signifi-
cant correlations with working memory performance were
observed in key regions that have been reported to subserve
working memory function (Postle, 2006a,b), including infe-
rior temporal (left p ? 0.035, right p ? 0.017), left fusiform
(p ? 0.005), superior parietal (left p ? 0.001, right p ? 0.003),
and inferior parietal (left p ? 0.001, right (p ? 0.005).
To our knowledge, this is the first study to specifically in-
vestigate cortical thickness changes in children who have
sustained TBI. While previous studies have implicated
greater white matter vulnerability in TBI (Anderson and
Bigler, 1994; Bigler, 2001; Gale et al., 1995a,b), the current
findings indicate concomitant changes in cortical gray mat-
ter thickness as well. These changes likely result from mul-
tiple etiologies including focal cortical injury from impact
compression and contusion, and deafferentation and def-
ferentation secondary to diffuse axonal injury and Wallerian
degeneration (Bigler, 2007).
Limitations of the study include its small sample size and
cross-sectional design. While the procedure for estimating
cortical thickness has been shown to be highly reliable and
accurate when used with high-quality data (Fischl and Dale,
2000), the nature of traumatic lesions in TBI may cause dis-
tortion in MRI signal characteristics and thus result in ab-
normalities of the parenchymal surface reconstruction. This
could result in some bias because the semi-automated pro-
cedure incorporates atlas-based steps which may not take
into account the degree of deformation in an individual sub-
ject’s brain with focal damage, even though we carefully ex-
amined data from each subject and applied the appropriate
correction as necessary.
Despite these limitations, the results make heuristic sense
and demonstrate global cortical change. The analytic tech-
niques presented in this initial study could be used to ex-
amine the longitudinal effects of TBI on cortical thinning and
its impact on cognition and emotional regulation in children
as they mature.
This research was supported by grants NS-21889 and NIH
R01 HD048946, by the Ira Fulton Foundation, and a grant
from the College of Family, Home and Social Science,
Brigham Young University. The technical assistance of Tracy
J. Abildskov and the editorial assistance of Jo Ann Petrie are
Author Disclosure Statement
No competing financial interests exist.
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Address reprint requests to:
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CORTICAL THINNING IN TRAUMATIC BRAIN INJURY1345