A prospective diffusion tensor imaging study in mild traumatic brain injury.
ABSTRACT Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls.
Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3-5 months after their initial visit.
mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts.
Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.
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ABSTRACT: This article focuses on advancements in neuroimaging techniques, compares the advantages of each of the modalities in the evaluation of mild traumatic brain injury, and discusses their contribution to our understanding of the pathophysiology as it relates to prognosis. Advanced neuroimaging techniques discussed include anatomic/structural imaging techniques, such as diffusion tensor imaging and susceptibility-weighted imaging, and functional imaging techniques, such as functional magnetic resonance imaging, perfusion-weighted imaging, magnetic resonance spectroscopy, and positron emission tomography.Neurologic Clinics 02/2014; 32(1):31-58. · 1.34 Impact Factor
- Seminars in roentgenology 01/2014; 49(1):64-75. · 0.70 Impact Factor
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ABSTRACT: In a subgroup of patients with mild traumatic brain injury (TBI) residual symptoms, interfering with outcome and return to work, are found. With neuropsychological assessment cognitive deficits can be demonstrated although the pathological underpinnings of these cognitive deficits are not fully understood. As the admission computed tomography (CT) often is normal, perfusion CT imaging may be a useful indicator of brain dysfunction in the acute phase after injury in these patients. In the present study, directly after admission perfusion CT imaging was performed in mild TBI patients with follow-up neuropsychological assessment in those with complaints and a normal non-contrast CT. Neuropsychological tests comprised the 15 Words test Immediate Recall, Trailmaking test part B, Zoo Map test and the FEEST, which were dichotomized into normal and abnormal. Perfusion CT results of patients with normal neuropsychological test scores were compared to those with abnormal test scores. In total eighteen patients were included. Those with an abnormal score on the Zoo Map test had a significant lower CBV in the right frontal and the bilateral parieto-temporal white matter. Patients with an abnormal score on the FEEST had a significant higher MTT in the bilateral frontal white matter and a significant decreased CBF in the left parieto-temporal grey matter. No significant relation between the perfusion CT parameters and the 15 Words test and the Trailmaking test part B was present. In conclusion, impairments in executive functioning and emotion perception assessed with neuropsychological tests during follow up were related to differences in cerebral perfusion at admission in mild TBI. The pathophysiological concept of these findings is discussed.Brain and Cognition 01/2014; 86:24–31. · 2.82 Impact Factor
; Prepublished online January 20, 2010; 2010;74;643
A. R. Mayer, J. Ling, M. V. Mannell, et al.
A prospective diffusion tensor imaging study in mild traumatic
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A prospective diffusion tensor imaging
study in mild traumatic brain injury
A.R. Mayer, PhD
J. Ling, BA
M.V. Mannell, BA
C. Gasparovic, PhD
J.P. Phillips, MD
D. Doezema, MD
R. Reichard, MD
R.A. Yeo, PhD
Objectives: Only a handful of studies have investigated the nature, functional significance, and
course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the
semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate
white matter integrity and compared the accuracy of traditional anatomic scans, neuropsycholog-
ical testing, and DTI for objectively classifying mTBI patients from controls.
Methods: Twenty-two patients with semi-acute mTBI (mean ? 12 days postinjury), 21 matched
healthy controls, and a larger sample (n ? 32) of healthy controls were studied with an extensive
imaging and clinical battery. A subset of participants was examined longitudinally 3–5 months
after their initial visit.
Results: mTBI patients did not differ from controls on clinical imaging scans or neuropsychological
performance, although effect sizes were consistent with literature values. In contrast, mTBI pa-
tients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffu-
sivity in the corpus callosum and several left hemisphere tracts. DTI measures were more
accurate than traditional clinical measures in classifying patients from controls. Longitudinal data
provided preliminary evidence of partial normalization of DTI values in several white matter
Conclusions: Current findings of white matter abnormalities suggest that cytotoxic edema may be
present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical dam-
age to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water,
primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may
have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.
ADC ? apparent diffusion coefficient; CC ? corpus callosum; CCI ? cortical impact injury model; CR ? corona radiata; DTI ?
diffusion tensor imaging; EC ? external capsule; FA ? fractional anisotropy; FPI ? fluid percussion injury model; HC ? healthy
controls; IC ? internal capsule; JHU ? Johns Hopkins University; MANCOVA ? multivariate analysis of covariance; mTBI ?
mild traumatic brain injury; RD ? radial diffusivity; ROI ? region of interest; SCR ? superior corona radiata; SLF ? superior
longitudinal fasciculus; UF ? uncinate fasciculus.
Complex cognitive processes such as attention, executive functions, and memory depend on
intact white matter tracts among frontal, parietal, and medial temporal lobes,1which are likely
disrupted following mild traumatic brain injury (mTBI). Histologic evidence of white matter
changes have been observed in both human autopsy2,3and animal4studies of mTBI. Although
traditional neuroimaging sequences (i.e., T1- and T2-weighted imaging) are typically insensi-
tive to these putative white matter changes, diffusion tensor imaging (DTI) is capable of
measuring white matter pathology with histologic correlates in animal models of injury.5
The majority of human mTBI studies have been cross-sectional in nature, examining se-
lected patients (i.e., those with persistent complaints) during the chronic (e.g., after several
e-Pub ahead of print on January 20, 2010, at www.neurology.org.
From The Mind Research Network (A.R.M., J.L., M.V.M., C.G., J.P.P., R.A.Y.), Albuquerque, NM; and Departments of Neurology (A.R.M.,
J.P.P.), Emergency Medicine (D.D.), Psychology (C.G., R.A.Y.), and Pathology (R.R.), University of New Mexico School of Medicine, Albuquerque.
Study funding: Supported by the Department of Energy [DE-FG02-99ER62764 to The Mind Research Network] and the National Institutes of
Health [R24-HD050836 and R21-NS064464-01A1 to A.M.].
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Andrew
Mayer, The Mind Research
Network, Pete & Nancy
Domenici Hall, 1101 Yale Blvd.
NE, Albuquerque, NM 87106
Copyright © 2010 by AAN Enterprises, Inc.
at Stanford University Medical Center on May 22, 2011 www.neurology.org Downloaded from
months or years) injury phase.6-9This can be
problematic as the majority (80%–95%) of
mTBI patients fully recover from their inju-
ries within 6 months.10,11An initial DTI
study on 5 unselected patients (i.e., all eligible
patients) reported reduced fractional anisot-
ropy (FA) in the corpus callosum (CC), inter-
nal capsule (IC), and external capsule (EC)
within 24 hours of injury.12More recent stud-
ies focusing on unselected patients in semi-
acute phase of injury have reported mixed
findings, with 2 adult studies reporting re-
duced FA13,14whereas other adolescent15and
adult16studies have reported increased FA.
Inglese et al.13reported reduced FA in the CC
and IC at approximately 5 years postinjury in
an adult sample, with no significant FA differ-
ences between chronic and semi-acutely in-
jured patients, suggesting limited recovery.
Another study examining mTBI patients lon-
gitudinally (2 out of 5 patients studied) re-
ported evidence of partial FA normalization at
Additionally, few studies have examined po-
tential differences in axial diffusivity or radial
diffusivity (RD) following mTBI in either se-
lected or unselected populations.12,15,17The dis-
tinction between axial diffusivity and RD is
critical given that FA is determined from these
measurements, and each is putatively associated
with different pathologies. Specifically, animal
models of retinal ischemia suggest that axial dif-
fusivity corresponds to axonal pathology
whereas RD measures myelin pathology.18
Mouse models of TBI indicate that axonal pa-
thology (reduced axial diffusivity) is more pro-
nounced in the acute phase of injury, followed
by both pseudonormalization of axial diffusivity
ing processes (RD) and edema.19
The present study examined FA, axial diffu-
sivity, and RD prospectively in an unselected
sample of mTBI patients. Based on previous
clinical studies, we predicted that FA and axial
diffusivity would be reduced in the CC, IC, su-
perior longitudinal fasciculus (SLF), uncinate
fasciculus (UF), and corona radiata (CR) in
mTBI patients compared to controls in the
semi-acute phase of injury (21 days postinjury)
METHODS Participants. Twenty-two patients (recruited
from the University Emergency Department) with mTBI and 21
sex-, age-, and education-matched controls participated in an
ongoing study. DTI data from an independent sample of healthy
controls (HC) were also collected.
All patients experienced a closed head injury resulting in an
alteration in mental status (see table 1) and were evaluated
within 21 days of injury (clinical examination ? 11.75 ? 4.97
days postinjury; imaging examination ? 12.50 ? 5.40 days
postinjury). The majority (85%) of patients completed the imag-
ing and clinical protocols within 3 days of each other. Inclusion
criteria for the mTBI group were based on the American Con-
gress of Rehabilitation Medicine (Glasgow Coma Score of 13–
15, loss of consciousness ?30 minutes, posttraumatic amnesia
?24 hours). mTBI participants and controls were excluded if
there was a positive history of neurologic disease, psychiatric dis-
turbance, additional closed head injuries with more than 5 min-
utes loss of consciousness or any head injury within the last year,
learning disorder, attention deficit hyperactivity disorder, or a
history of substance or alcohol abuse.
Standard protocol approvals, registrations, and patient
consents. Informed consent was obtained from all participants
according to institutional guidelines at the University of New
Clinical assessment. Similar to previous studies,20composite
indices were calculated for attention, working memory, process-
Table 1Mild traumatic brain injury patient information
Male Collision/sports III35
Female MVAII18 13
FemaleFall III15 14
Male Falling objectIII74
Female MVAIII 1919
Male MVA III99
Male FallIII 2019
FemaleMVA III 1416
MaleFallIII 10 10
FemaleAssault II 1111
MaleFalling object III1616
Female MVAIII14 14
Abbreviations: AAN ? American Academy of Neurology; MVA ? motor vehicle accident;
NP ? neuropsychological testing.
February 23, 2010 at Stanford University Medical Center on May 22, 2011www.neurology.org
ing speed, executive function, memory, and emotional status
based on participants’ mean t score in each of the domains (ap-
pendix e-1 on the Neurology®Web site at www.neurology.org).
Somatic and cognitive complaints were also assessed along with
estimates of overall premorbid cognitive functioning and effort
MRI and analyses. T1, T2, and DTI images were collected
on a 3-Tesla Siemens Trio scanner (appendix e-1). The AFNI
software package21was used to process and analyze DTI data
(appendix e-1). Region of interest (ROI) analyses were con-
ducted on the genu, splenium, and body of the CC, as well as the
SLF, the CR, the superior corona radiata (SCR), the UF, and the
IC for both hemispheres based on the Johns Hopkins University
(JHU) white matter atlas.22Scalar means (axial diffusivity, RD,
and FA) were calculated for each ROI, as were measures of inter-
hemispheric variability between homologous left and right ROI
( right ROI ? left ROI )/([right ROI ? left ROI]/2) to investi-
gate increased asymmetry as a marker of injury. Multivariate
analyses were used whenever possible to reduce the number of
multiple comparisons. Effect sizes (Cohen’s d) are also reported
as a measure of clinical significance.23
RESULTS Neuropsychological and clinical measures.
A compilation of all major neuropsychological and
clinical indices is presented in table 2. Results indi-
cated an increase in emotional (t1,38? ?3.11; p ?
0.05; mTBI ? HC), cognitive (t1,38? ?4.20; p ?
0.001), and somatic (t1,38? ?3.62; p ? 0.005)
complaints for mTBI patients compared to controls.
Estimates of premorbid intellectual functioning were
lower in mTBI patients (t1,37? 2.09; p ? 0.05)
despite educational matching.
A multivariate analysis of covariance (MANCOVA)
examining differences in neuropsychological testing
using premorbid intelligence as a covariate was not
significant for group differences. However, effect
sizes (table 2) in the domains of attention, executive
functioning, and memory were of similar magnitude
to those reported in recent meta-analyses on cogni-
tive deficits in mTBI.
Structural imaging data. Anatomicimageswerelimited
to T1- and T2-weighted images. These were found to
be free of pathology for both groups of subjects by a
board-certified neuroradiologist (i.e., all mTBI patients
were classified as being noncomplicated).
ROI analyses. Three MANCOVAs were conducted
to examine group differences (mTBI patients vs
matched controls) in FA values within the corpus
callosum and left and right hemisphere ROI (figure
1A) with estimates of premorbid intellectual func-
tioning as a covariate. Results indicated a multivari-
ate effect of group for both the CC (F3,36? 3.81;
p ? 0.05) and the left (F5,34? 2.70; p ? 0.05) but
not right (p ? 0.10) hemisphere. Follow-up univari-
ate tests indicated that mTBI patients had higher
FA within the genu (F1,38? 7.52; p ? 0.01,
d ? ?0.91), left SCR (F1,38? 5.54; p ? 0.05, d ?
?0.77), left CR (F1,38? 5.47; p ? 0.05, d ?
?0.74), and left UF (F1,38? 6.67; p ? 0.05,
d ? ?0.84). Trends were observed for the left IC
(F1,38? 3.69; p ? 0.062, d ? ?0.62) and the sple-
nium (F1,38? 2.95; p ? 0.094, d ? ?0.53) with
mTBI patients again exhibiting higher FA values
HC were then compared with a larger normative
sample. However, there were no multivariate effects
of group for all multivariate analyses of variance (p ?
0.10), suggesting that our control group was statisti-
cally similar to the larger normative sample in terms
Next, we compared axial diffusivity and RD val-
ues for the 6 ROI that exhibited significant or trend
differences in FA using one-way analyses of covari-
ance (figure 1B). There were no significant differ-
ences between patients and controls in terms of axial
diffusivity. In contrast, RD was lower in mTBI
patients within the genu (F1,38? 5.09; p ? 0.05, d ?
0.74), the left UF (F1,38? 5.67; p ? 0.05, d ?
0.77), and the left CR (F1,38? 4.42; p ? 0.05,
d ? 0.66), with trends present in the left SCR
(F1,38? 3.58; p ? 0.06, d ? 0.59) and left IC (F1,38?
Table 2Demographic and clinical measures for visit 1
brain injuryHealthy controls
p Value Cohen’s da
27.457.39 26.816.680.77 0.09
78.5637.9282.8435.83 0.71 0.12
48.187.05 48.49 7.060.890.04
52.65 8.05 53.63 12.410.770.09
5.704.161.85 2.32 0.0001.33
Abbreviations: EF ? executive function; HQ ? handedness quotient; NBSI-Som ? Neurobe-
havioral Symptom Inventory Somatic complaints (Cog ? cognitive complaints); PS ? pro-
cessing speed; TOMM ? Test of Memory Malingering; WM ? working memory; WTAR ?
Wechsler Test of Adult Reading.
aCohen’s d is an estimate of effect size.
bMeans, standard deviations, and effect sizes for neuropsychological indices reported fol-
lowing correction for WTAR as covariate at 51.03.
cDenotes significant result.
Neurology 74February 23, 2010
at Stanford University Medical Center on May 22, 2011 www.neurology.org Downloaded from
3.99; p ? 0.053, d ? 0.66). Histograms for the nor-
malized RD data are presented in figure e-2.
Finally, a MANCOVA (figure 2) comparing vari-
ability in FA measurements between right and left
hemisphere homologue ROI (SFL, IC, UF, SCR,
and CR) revealed a group effect (F5,34? 4.53; p ?
0.005), with univariate tests indicating increased
variability in patients compared to controls for the
SCR (F1,38? 15.06; p ? 0.001, d ? ?1.21), with
a trend for the UF (F1,38? 3.82, p ? 0.058;
d ? ?0.63).
DTI and clinical measures. Hierarchical multiple re-
gressions were performed on the 6 clinical measures
with the largest effect sizes (attention, memory, exec-
utive functions, cognitive complaints, somatic com-
plaints, and emotional complaints) using FA from
the CC and right and left hemisphere ROI as the
independent variables and premorbid intelligence as
a covariate. Although premorbid intelligence ac-
counted for significant variance in terms of both at-
tentional and executive functioning, only FA levels
in the right hemisphere (F2,18? 6.84; p ? 0.01)
predicted variance in attentional deficits (positive re-
lationship) for the mTBI group.
Next we determined which of our objective mea-
sures of deficits (FA or neuropsychological testing)
would more accurately classify mTBI patients and
HC using binary logistical regression. Estimates of
premorbid intelligence were entered into both mod-
els as it discriminated (Wald ? 4.16; p ? 0.05) be-
Figure 1Fractional anisotropy (FA) values from all regions of interest (ROI)
This figure presents the mean FA values from all ROI for the mild traumatic brain injury patients (mTBI; green bars) and healthy controls (HC; gray bars) for
visit 1 (A) corrected for differences in premorbid intelligence estimates. ROI included the genu (GNU), body (BDY), and splenium (SPL) of the corpus
callosum (CC), the superior corona radiata (SCR), the superior longitudinal fasciculus (SLF), the uncinate fasciculus (UF), the corona radiata (CR), and the
internal capsule (IC). Significant effects are denoted with double asterisks, statistical trends with a single asterisk. (B) Axial diffusivity (AD) and radial
diffusivity (RD) measurements for mTBI patients and HC for regions exhibiting statistical differences in FA. For the y-axis, the units of FA are dimension-
less, whereas axial diffusivity and RD are equivalent to mm2/s.
Figure 2 Variability in mean fractional anisotropy (FA) between right and left
hemisphere regions of interest (ROI)
A measurement of variability in mean FA values between right and left hemisphere homo-
logue ROI for the mild traumatic brain injury patients (mTBI; green bars) and healthy con-
trols (HC; gray bars) corrected for differences in premorbid intelligence estimates. ROI
included the superior longitudinal fasciculus (SLF), the uncinate fasciculus (UF), the corona
isks, statistical trends with a single asterisk.
February 23, 2010 at Stanford University Medical Center on May 22, 2011www.neurology.org