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Contents lists available at ScienceDirect

Brain Multiphysics
journal homepage: www.elsevier.com/locate/brain

In vivo estimates of axonal stretch and 3D brain deformation during mild

head impact
Andrew K Knutsen a,∗, Arnold D. Gomez b, Mihika Gangolli a, Wen-Tung Wang a, Deva Chan c,
Yuan-Chiao Lu d, Eftychios Christoforou e, Jerry L. Prince f, Philip V. Bayly g, John A. Butman h,
Dzung L. Pham a
a
Center for Neuroscience and Regenerative Medicine, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
b
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
c
Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, United States
d
Center for the Developing Brain, Children’s National Hospital, Washington, D.C., United States
e
Department of Mechanical and Manufacturing Engineering, University of Cyprus, Cyprus
f
Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States
g
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, Missouri, United States
h
Clinical Center, National Institutes of Health, Bethesda, Maryland, United States

a r t i c l e i n f o a b s t r a c t

Keywords: The rapid deformation of brain tissue in response to head impact can lead to traumatic brain injury. In vivo
Traumatic brain injury measurements of brain deformation during non-injurious head impacts are necessary to understand the underly-
Tagged MRI ing mechanisms of traumatic brain injury and compare to computational models of brain biomechanics. Using
Brain biomechanics
tagged magnetic resonance imaging (MRI), we obtained measurements of three-dimensional strain tensors that
Axonal strain
resulted from a mild head impact after neck rotation or neck extension. Measurements of maximum principal
strain (MPS) peaked shortly after impact, with maximal values of 0.019–0.053 that correlated strongly with peak
angular velocity. Subject-specific patterns of MPS were spatially heterogeneous and consistent across subjects for
the same motion, though regions of high deformation differed between motions. The largest MPS values were
seen in the cortical gray matter and cerebral white matter for neck rotation and the brainstem and cerebellum
for neck extension. Axonal fiber strain (Ef) was estimated by combining the strain tensor with diffusion tensor
imaging data. As with MPS, patterns of Ef varied spatially within subjects, were similar across subjects within
each motion, and showed group differences between motions. Values were highest and most strongly correlated
with peak angular velocity in the corpus callosum for neck rotation and in the brainstem for neck extension. The
different patterns of brain deformation between head motions highlight potential areas of greater risk of injury
between motions at higher loading conditions. Additionally, these experimental measurements can be directly
compared to predictions of generic or subject-specific computational models of traumatic brain injury.

1. Introduction
Traumatic brain injury (TBI) is a prominent health problem that
affects people across all age groups and throughout the world. In the
United States, approximately 1.7 million emergency department visits,
hospitalizations, and deaths occurred due to TBI in 2010 [1]. The term
TBI encompasses a wide array of injuries of varying severity. Most re-
ported TBIs are classified as mild [2], which is typically defined as a
non-penetrating injury that may lead to loss of consciousness (less than
30 min), post-traumatic amnesia (less than 24 h), confusion, disorienta-
tion, and/or intracranial lesions not requiring surgery [3]. The rate of
mild TBIs per year worldwide is estimated to be 600 per 100,000 people
[4] —or approximately 46 million mild TBIs per year. The rapid defor-
mation of brain tissue and elongation of axonal fibers that occurs due
to head acceleration or impact can lead to injurious shearing of cere-
bral vasculature [5] and focal or diffuse axonal injury [6,7]. Altered
imaging findings have been detected using magnetic resonance imag-
ing (MRI) in specific white matter regions, such as the brainstem and
corpus callosum, post-injury [8-10]. The relationships between the fre-
quency, magnitude, and orientation of head impacts and the resulting
neurodegeneration in the human brain remain largely unknown. The
poor correlations between imaging findings and long-term disability in
mild TBI indicate that injury is occurring that current technology cannot
detect [11].

∗
Corresponding author: Andrew Knutsen, PhD, 10 Center Drive, Building 10, Room B1N264B, MSC 1182, Bethesda, MD 20814-1182
E-mail address: andrew.knutsen.ctr@usuhs.edu (A.K. Knutsen).

https://doi.org/10.1016/j.brain.2020.100015
Received 24 March 2020; Received in revised form 11 June 2020; Accepted 22 June 2020
Available online xxx
2666-5220/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
Please cite this article as: A.K. Knutsen, A.D. Gomez and M. Gangolli et al., In vivo estimates of axonal stretch and 3D brain deformation during
mild head impact, Brain Multiphysics, https://doi.org/10.1016/j.brain.2020.100015
JID: BRAIN
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Computational models of TBI offer a promising approach to predict
how the human brain will deform in response to a wide variety of head
impacts and impact severities; see Madhukar and Ostoja-Starzewski
[12] for a comprehensive review. Computational models can, in prin-
ciple, be used to predict axonal injury [13-16], estimate brain defor-
mation from impacts during sporting events such as American football
[17,18], and to design or evaluate protective equipment such as helmets
[19-21]. Such models must be based on accurate information about the
geometry and structure of the human head and material properties of
relevant brain structures, and should be evaluated by comparison to ex-
perimental measurements of displacement and deformation of the live
human brain in response to known loading conditions.
Experiments to determine how the in vivo human brain deforms dur-
ing injury-level head impacts cannot be performed. To address this lim-
itation, different physical model systems based on surrogates or post-
mortem human specimens have been used to gain insight into human
brain biomechanics and to validate or calibrate computational models.
Physical models of the skull-brain structure, created by filling human
and baboon skulls with silicone gel, have been used to examine the
brain’s response to impact [6,22]. Additionally, experiments using ca-
daveric human specimens have been performed using biplanar x-ray
[23,24] and sonomicrometry [25] to track implanted markers in re-
sponse to head impacts across a wide range of loading conditions. These
data have been analyzed to assess relative displacement of the brain
with respect to the skull [23-26] and strain [26,27], providing impor-
tant measurements of how the brain displaces and deforms at levels at
or near what is reasonably likely to cause injury. However, the material
properties of the postmortem brain differ from the in vivo brain [28],
and they do not provide dense, three-dimensional (3D) measurements
spanning the whole brain.
Measurements of brain motion performed in healthy volunteers un-
der loading that is well below injurious levels provide information that
is complementary to data from studies of physical models and cadav-
eric specimens. Tagged magnetic resonance imaging (MRI) has been
used to estimate the two-dimensional (2D) brain response during ro-
tation within the axial plane [29-31] and sagittal plane [32,33] during
non-injurious impacts. The angular velocities and accelerations in these
studies are quite low—approximately 3 rad/s and 200 rad/s2 for neck
rotation [29] and 2 rad/s and 330 rad/s2 for neck extension[34]. To pro-
vide perspective on the head motion experienced by the participant, this
is approximately 10–15 percent of the angular acceleration experienced
during heading a soccer ball [35]. Additionally, head accelerations up to
31 g and 2888 rad/s2 were measured in 20 healthy volunteers (men and
women age 26–58 years) engaged in non-injurious everyday and more
vigorous activities, such as a soccer ball impact to the forehead, volun-
tary head shaking, plopping down on a chair, and jumping off of a step
[36]. The accelerations in the current study are an order of magnitude
less than those seen commonly in contact sports [36] and are similar
to those experienced during a cough or sneeze [37] or jogging [38].
Thresholds for angular accelerations leading to mild traumatic brain in-
jury were studied in Zhang et al. [39]; the smallest accelerations con-
sidered in that study (approximately 2000 rad/s2 ) were found to have
a very low risk of injury, and even those are much larger than those
experienced during the current study. Even though the loading condi-
tions are very mild in nature, we have previously demonstrated reliable
measurements of in vivo brain deformations using tagged MRI [29-34].
A limitation of the previous MRI studies of in vivo brain motion is
that the computed strain fields were restricted to 2D within the acqui-
sition plane and were provided for a limited number of slices within
the brain [30-33]. However, recent methodological advancements al-
low for estimates of 3D displacement and strain over time from a series
of 2D-tagged MR images acquired in multiple orientations [34,40]. In
this study, we applied this method to acquire tagged MRI data during
either mild neck rotation or neck extension. Strains were then computed
throughout the brain and along white matter tracts identified using dif-
fusion tensor imaging (DTI). To our knowledge, this work represents the
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first measurements of axonal strain during human head acceleration in
vivo.
2. Materials and methods
Twenty MRI data sets were acquired in 19 healthy volunteers during
either neck rotation (N = 10) or neck extension (N = 10), with one sub-
ject scanned using both devices 7 months apart. Eleven subjects were
male and 8 were female; the average age of the volunteers was 31.0 +/-
6.1 years (range of 21–42 years). Subjects provided informed consent
under a protocol approved by the National Institutes of Health CNS In-
stitutional Review Board. All experiments were conducted in the Clinical
Center at the National Institutes of Health.
2.1. Head rotation devices
Two MRI-compatible devices were used to generate repeatable, mild
head rotations in either the axial plane (neck rotation) [29-31,34] or
the sagittal plane (neck extension) [34,41]. The devices allow repeat-
able motion along consistent trajectories, which is needed to accumu-
late a set of tagged MR images that cover the majority of the brain with
adequate spatial resolution. Both the neck rotation device and neck ex-
tension device have been described in detail previously [29,30,32,34],
though we provide a brief description here for completeness.
For neck rotation, the subject lies in the supine position with his/her
head secured to the cradle of the device with side restraint bars and a
strap. The subject voluntarily initiates the motion by manually releasing
a latch. The subject then actively rotates his/her head approximately 32°
toward the left shoulder, at which point the shaft of the device impacts
a padded stop, imparting an accelerative load to the brain. The center
of rotation is located approximately 6.5 cm anterior from the back of
the head and at the midsagittal plane. The head remains in this position
for a few seconds, and then the subject uses a pulley to return the head
back to the original position.
For neck extension, the subject lies in the supine position with
his/her head secured to the device cradle using a strap. The subject vol-
untarily initiates the motion by manually releasing a latch. The cradle
then rotates 5° in the anterior to posterior direction of the head about
an axis located near the base of the neck before reaching a padded stop.
The center of rotation is located approximately 22 cm inferior from the
top of the head and 3 cm anterior from the back of the neck. For this
small angle of rotation, the motion of the head is nearly linear with a
drop of 2.5 cm at the superior extreme. The subject’s head remains in
this position for a few seconds before returning to the original position
using a pulley system. For both devices, an MRI-compatible angular po-
sition encoder (MICRONOR, Camarillo, CA, USA) is rigidly connected
to the device shaft to record angular position, velocity, and acceleration
for each motion.
2.2. MRI acquisition
All MRI scans were acquired using a Siemens 3 T Biograph mMR
(Erlangen, Germany). Anatomical images were acquired using either
a 32-channel or 16-channel receive-only head coil. The acquisition
included a 3D T1-weighted Magnetization-Prepared Rapid Acquisi-
tion Gradient Echo (MPRAGE) with the following parameters: echo
time (TE) = 3.03 ms, repetition time (TR) = 2530 ms, inversion
time (TI) = 1100 ms, field of view (FOV) = 256 × 256 × 176 mm,
matrix = 256 × 256 × 176. A 3D T2-weighted image was also
acquired using the following parameters: TR/TE = 3200/410 ms,
FOV = 250 × 250 × 176 mm, matrix = 256 × 256 × 176. The total
scan time for both the motion and anatomical MRI scans was less than
two hours per imaging session.
For DTI, a total of 40 diffusion weighted image (DWI) volumes were
acquired using a 2D echo planar imaging (EPI) sequence with the fol-
lowing parameters: TR/TE = 16,400/93 ms, FOV = 256 × 256 mm,
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matrix = 128 × 128, 75 slices, slice thickness = 2 mm, 6 DWIs at
b = 0 s/mm2 , 4 non-colinear DWIs at b = 300 s/mm2 , and 30 non-
colinear DWIs at b = 1100s/mm2 . To improve the correction of spatial
distortions introduced by the EPI acquisition, an additional DWI volume
(b = 0 s/mm2 ) was acquired with the same acquisition parameters with
the reverse phase encode direction.
For the tagged MRI portion of the study, one of two MRI-
compatible devices was used to generate a repeatable mild head ac-
celeration—either during neck rotation or neck extension. A combi-
nation of one or two (depending upon slice position) three-channel,
receive-only, spine coils built into the scanner bed and a six-channel,
receive-only, flexible body array coil were used for the acquisition. An
optically gated trigger initiated the application of a 1–1 Spatial Mod-
ulation of Magnetization (SPAMM) tagging pulse followed by a 2D-
segmented cine gradient-echo acquisition with the following param-
eters: TR/TE = 3.01/1.67 ms, tag spacing = 8 mm, segments = 6,
FOV = 240 × 240 mm, matrix = 24 × 160 (reconstructed to 160 × 60),
slice thickness = 8 mm with a 2 mm gap between slices, temporal reso-
lution = 18 ms, number of image frames = 10–12. For the neck rotation
device, the gradient-echo acquisition was triggered by the angular po-
sition sensor when the device shaft rotated through 28.5°. Additionally,
the tag lines were applied at an angle of 30° away from the center line
of k-space so that they were located approximately along the center line
of k-space at the point of impact [30].
To measure deformation over the majority of the brain, multiple
slices were acquired with tag lines oriented along three orthogonal axes
[34]. For the neck rotation, 11–13 axial slices were acquired first with
tag lines along the y-axis and then repeated with tag lines along the x-
axis. Then, six slices were acquired with tag lines along the z-axis; these
slices were orthogonal to the axial plane and oriented every 30°, like
spokes on a wheel, about the approximate brain center. For the neck ex-
tension, 11–14 sagittal slices were acquired first with tag lines along the
y-axis and then repeated with tag lines along the z-axis. An additional
8–13 axial slices were acquired with tag lines along the x-axis. Note
that the x-, y-, and z-axes correspond to right-left, anterior-posterior,
and inferior-superior with the subject at rest in the supine position.
2.3. Image processing
Brain extraction was applied to the MPRAGE and T2-weighted im-
ages using the MONSTR method [42]. Segmentation of the brain-masked
MPRAGE was then performed using the S3DL algorithm [43]. Seg-
mented regions included the cortical gray matter, cerebral white matter,
deep gray matter, cerebellar gray matter, cerebellar white matter, and
brainstem. The DWIs were processed using the TORTOISE3 software
package [44], which included motion and eddy current distortion cor-
rection [45]. EPI-induced geometric distortions were then corrected by
the DRBUDDI module [46] of TORTOISE3 using the DWIs with the re-
versed phase encode gradients and the T2-weighted image. The diffusion
tensor was fitted using a nonlinear least squares robust fitting algorithm
[47] followed by computation of diffusion properties. The corpus callo-
sum was automatically segmented from the estimated diffusion tensor
using the DOTS method [48]. For this study, only fractional anisotropy
[49] and the principal eigenvector of the diffusion tensor were used in
subsequent analyses.
Three-dimensional displacements over time were obtained from the
tagged MRI data using the Harmonic-Phase Analysis with Finite Ele-
ments (HARP-FE) method [34]. The HARP-FE algorithm combines har-
monic phase (HARP) analysis [50] and the finite element method to
compute mechanically regularized measurements of deformation and
displacement from tagged MRI data.
Before HARP-FE, the following pre-processing steps were performed:
For each tagged image slice and tag direction, frames 2 through 10 were
rigidly registered to frame 1 using the command antsRegistration, which
is part of the Advanced Normalization Toolkit V2 [47]. This was done
to remove any potential small differences in how the subjects rotated
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between neighboring slices. The 3 tagged image sets—i.e., the combi-
nation of slices with the same tag line orientation—were then resampled
to a 1.5 mm isotropic grid using cubic b-spline interpolation in Matlab
R2016a (Mathworks, MA, USA). HARP images were created for each tag
orientation and image frame by applying a spherical filter with a radius
of 9 voxels in k-space.
The anatomical and tagged images were acquired using a different
receive coil with the subject’s head in a different position. They therefore
did not intrinsically have any spatial correspondence between them. To
obtain correspondence, the MPRAGE was rigidly registered to an im-
age volume created by summing the three tagged image sets using the
antsRegistration command; the same registration parameters were used
as above, except that a 3D rigid registration was performed instead of
2D. The brain segmentation, T2 -weighted image, and DTI metrics were
transformed to the tagged image space using nearest neighbor or cubic
b-spline interpolation (as appropriate).
2.4. Calculation of strain metrics
HARP-FE was implemented as a plug-in for the FEBio finite element
analysis software [51]. The output from HARP-FE consists of 3D dis-
placement vector field (u) over time. Next, the computed displacement
field was projected from the finite elements to each voxel. Strain fields
were estimated from the displacements using a local fitting approach.
For each frame, displacement (𝑢 = [𝑢 𝑣 𝑤]) was estimated as a function
of space (X, Y, Z) for a given voxel (x0 , y0 , z0 ) using the N voxels within
a radius of 5 voxels and a linear, least-squares fit.
( )
𝑢 𝑥0 , 𝑦0 , 𝑧0 = 𝑎0 + 𝑎1 𝑋1,..,𝑖,..,𝑁 + 𝑎2 𝑌1,..,𝑖,..,𝑁 + 𝑎3 𝑍1,..,𝑖,..,𝑁
( )
𝑣 𝑥0 , 𝑦0 , 𝑧0 = 𝑏0 + 𝑏1 𝑋1,..,𝑖,..,𝑁 + 𝑏2 𝑌1,..,𝑖,..,𝑁 + 𝑏3 𝑍1,..,𝑖,..,𝑁
( )
𝑤 𝑥0 , 𝑦0 , 𝑧0 = 𝑐0 + 𝑐1 𝑋1,..,𝑖,..,𝑁 + 𝑐2 𝑌1,..,𝑖,..,𝑁 + 𝑐3 𝑍1,..,𝑖,..,𝑁 (1)
where ai , bi , and ci are the coefficients to be estimated. Only voxels
labeled as brain tissue by the segmentation were used in the fit. La-
grangian strain tensors were estimated by
1( )
𝑬= 𝛁𝒖 + (𝛁𝒖)𝑇 + 𝛁𝒖 ⋅ (𝛁𝒖)𝑇 (2)
2
where ∇ is the gradient operator. The computed coefficients directly
provide the spatial derivative of displacement. Eigenvalues and eigen-
vectors were computed, and the maximum principal strain (MPS) was
assigned to the first eigenvalue. White matter fiber strain (Ef ) was cal-
culated using the Lagrangian strain tensor and the principal eigenvector
of the diffusion tensor (n) estimated at each voxel:
𝐸𝑓 = 𝒏 ⋅ 𝑬 ⋅ 𝒏 (3)
For fiber strain, only voxels located in either the cerebral white mat-
ter, cerebellar white matter, or brainstem with a fractional anisotropy
value greater than or equal to 0.2 were analyzed. This is a standard cri-
terion for excluding regions of isotropic diffusion, such as gray matter
and cerebrospinal fluid [52].
The volume fraction of strain, which is the percentage of voxels
where the measured strain is above a threshold value, was computed
for thresholds of 0.01, 0.02, 0.03, and 0.04. The 95th percentile value
of the distribution was used (in place of the maximum value) to assess
peak strain values. Pearson’s correlation coefficients were computed to
assess the linear relationship between strain metrics and angular decel-
eration during impact and angular velocity just prior to impact.
3. Results
To acquire a data set with full brain coverage at the desired 18 ms,
the subjects repeated the head motion 112–128 times for neck rotation
data set and 132–156 times for neck extension. The angular position sen-
sor recorded position, velocity, and angular acceleration for each repeti-
tion. In Fig. 1, traces of angular position, velocity, and acceleration ver-
sus time are plotted for each head repetition performed during a single
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A.K. Knutsen, A.D. Gomez and M. Gangolli et al.
Fig. 1. Plots of (a, d) angular position (𝜃), (b, e) angular velocity (𝜔), and (c, f) angular acceleration (𝛼) vs time for each repetition during (a–c) neck rotation and
(d–f) neck extension. The vertical lines indicate the temporal boundaries of the image frames.
neck rotation and neck extension experiment. Additionally, the vertical
gridlines starting at 𝑡 = 0 𝑚𝑠 in Fig. 1 identify the corresponding timing
of the image frames from the tagged MRI acquisition. For each repe-
tition, the largest value was identified and the average was computed
across repetitions for each subject. Note that the largest acceleration is
negative in magnitude, corresponding to a rapid deceleration about the
inferior-superior axis during neck rotation and the left-right axis during
neck extension. For the peak of angular deceleration (𝛼), which occurred
during impact, the mean ± SEM was 212.8 ± 32.1 rad/s2 (range of
156.4–247.1 rad/s2 ) for neck rotation (N = 10) and 282.8 ± 47.4 rad/s2
(range of 213.4–347.5 rad/s2 ) for neck extension (N = 10). For peak
angular velocity (𝜔), which occurred just prior to impact, the mean
was 3.21 ± 0.52 rad/s (range of 2.42–3.73 rad/s) for neck rotation and
1.75 ± 0.16 rad/s (range of 1.53–2.02 rad/s) for neck extension.
Fig. 2 and Supplemental Figures 1 and 2 show axial, coronal, and
sagittal views of voxel-wise estimates of MPS for each image frame for
a single neck rotation and neck extension data set. The spatial patterns
of the MPS are complex and vary over time. The MPS values are plotted
as an overlay on the subject’s MPRAGE image, which allows for visual-
ization of the anatomy. Qualitatively, the MPS values for both head mo-
tions increased to a maximum shortly after impact and then decreased
afterwards, oscillating towards a minimum value. For neck rotation, the
largest MPS values appear in the cortical gray matter and cerebral white
matter. For neck extension, the largest MPS values are seen in the corti-
cal gray matter, though they are mostly limited to the midsagittal plane,
and in the cerebellum and brainstem. Additionally, MPS at peak defor-
mation appears more symmetric for neck extension than neck rotation.
The volume fraction of strain provides an estimate of the volume of
brain tissue with strain above a given threshold. Fig. 3 shows the aver-
age volume fraction (+/- standard error) of MPS and Ef across subjects
for each image frame and both head motions. This shows quantitatively
that the qualitative assessment from Fig. 2 holds across subjects: the
largest MPS and axonal fiber strains occurred in the first frame after the
peak angular acceleration and then generally decreased in subsequent
frames. The neck rotation experiment produced larger volume fractions
than neck extension under the range of loading conditions. MPS is useful
to analyze because it provides a single metric of the maximum deforma-
tion. Additionally, Supplemental Table 1 lists values of MPS, Ef , brain
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Brain Multiphysics xxx (xxxx) xxx
volume, and 𝜔2 for each subject. The Lagrangian strain tensor contains
six unique components, and examination of each is informative. Supple-
mental Figures 3 and 4 show the volume fraction of strain for each strain
component. These figures show the strain components within the plane
of rotation (the axial plane for neck rotation and the sagittal plane for
neck extension) account for the majority of deformation—though some
out-of-plane shearing is observed for both motions.
Fig. 4 shows a plot of the 95th percentile of the MPS distribution
(MPS95) as a function of 𝜔2 for each subject. We focused on the image
frame with the largest amount of deformation—frame 3 for neck rota-
tion and frame 5 for neck extension. Values of MPS95 ranged from 0.026
to 0.053 for neck rotation and 0.019 to 0.029 for neck extension. For
correlation, we chose to use 𝜔2 in place of 𝜔 because it is proportional
to energy at impact. A line was fitted to the data for each head mo-
tion using a linear least squares fitting algorithm (mldivide, Matlab, The
Mathworks, Natick, MA) to illustrate the trend. Pearson’s correlation co-
efficients and p-values were computed and are listed in Table 1. Both
motions showed strong correlation between MPS95 and 𝜔2 : 𝑟 = 0.85 for
neck rotation and 𝑟 = 0.64 for neck extension.
Using each subject’s tissue segmentation, separate distributions of
MPS were computed within the cortical gray matter, cerebral white mat-
ter, deep gray matter, cerebellar gray matter, cerebellar white matter,
and brain stems structures. Analogous to Fig. 4, Fig. 5 plots MPS95 as a
function of 𝜔2 for each of the segmented brain regions. Correlation coef-
ficients and p-values were computed and are listed in Table 1. For neck
rotation, the strongest correlations are seen in the cortical gray matter
(𝑟 = 0.84) and cerebral white matter (𝑟 = 0.85), with a moderate cor-
relation in the cerebellar gray matter (𝑟 = 0.62). For the neck extension
experiment, moderate correlations are seen in the cerebellar gray matter
(𝑟 = 0.68), cerebellar white matter (𝑟 = 0.66), and brainstem (𝑟 = 0.60).
Fig. 6 shows images of positive axonal fiber strain (elongation) from
the image frame with the largest strain values; axonal fiber strains are
mapped onto 3D ellipsoids that indicate the direction of axonal fibers
within the white matter. Axial and sagittal views are shown in three
subjects for each head motion. These images depict a heterogeneous
pattern of axonal fiber strain within the brain, with similar patterns
of deformation between subjects within motion and different area of
high strain between the two motions. The neck rotation data shows a
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Fig. 2. Axial, coronal, and sagittal views of MPS (color) and MPRAGE (grayscale) for each frame/time as measured during (a) one neck rotation experiment and
(b) one neck extension experiment. Impact occurred during the second frame for neck rotation and the fourth frame for neck extension. Peak angular deceleration
occurred during frame 2 for neck rotation and frame 4 for neck extension. The arrows above the MPRAGE on the left-most portion of the figure indicate the direction
of head motion prior to impact. L=left, R=right, A=anterior, P=posterior, I=inferior, S=superior.

Fig. 3. Average (+/- standard error) of volume fraction (VF) of (a, c) max-
imum principal strain (MPS) and (b, d) axonal fiber strain (Ef ) at multiple
thresholds for each acquired image frame during (a–b) neck rotation and
(c–d) neck extension. The temporal resolution between image frames is
18 ms.

contre-coup pattern with high elongation in the left-frontal and right-
posterior white matter, whereas the neck extension data is more sym-
metric with greater elongation of the brainstem. For a more quantita-
tive assessment, we examined the 95th percentile value of the distri-
bution of axonal fiber strains (Ef95) specifically within the brainstem
and corpus callosum. Fig. 7 contains a plot of Ef95 as a function of 𝜔2
for these regions. Correlation coefficients and p-values were computed
and are listed in Table 1. In the corpus callosum, stronger correlation
is seen during neck rotation (𝑟 = 0.65) than neck extension (𝑟 = 0.44).
Conversely, in the brainstem, stronger correlation is observed in neck
extension (𝑟 = 0.79) than neck rotation (𝑟 = 0.25).
4. Discussion
Mild head deceleration during impact produces spatially heteroge-
neous patterns of deformation in the in vivo human brain. The MPS
was presented to provide a single, invariant measure of deformation
throughout the brain, which is more compact than presenting all six
components of the full strain tensor. To further simplify the data for
analysis, both the peak (95th percentile) and volume fractions of strain
were analyzed over the entire brain and in various segmented regions.
Estimates of MPS were largest shortly after impact and then decreased,
though not quite to zero. We attribute this partly to the limited number
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A.K. Knutsen, A.D. Gomez and M. Gangolli et al. Brain Multiphysics xxx (xxxx) xxx

Table 1
Pearson’s correlation coefficients (r) and p-values for the 95th percentile of the distribution of maximum principal
strain (MPS95) or axonal fiber strain (Ef95) compared to peak angular velocity squared (𝜔2 ) across various brain
regions.

Strain Region Neck Rotation (N = 10) Neck Extension (N = 10)

Metric
r p r p

MPS95 Whole Brain 0.85 0.0019 0.64 0.0467

Cortical Gray Matter 0.84 0.0023 0.53 0.1115
Cerebellar Gray Matter 0.62 0.0582 0.68 0.0300
Deep Gray Matter 0.45 0.1916 0.32 0.3597
Cerebral White Matter 0.85 0.0020 0.53 0.1171
Cerebellar White Matter 0.35 0.3255 0.66 0.0383
Brainstem −0.04 0.9181 0.60 0.0696
Ef95 Corpus Callosum 0.65 0.0413 0.44 0.2048
Brainstem 0.25 0.4873 0.79 0.0063

Fig. 4. Relationship between 95th percentile of maximum principal strain
(MPS95) at the time of peak deformation and angular velocity squared (𝜔2 )
during neck rotation and neck extension. Each data point shows the result for a
single subject. The dashed lines show linear fits of the data.
of image frames analyzed—the head has not returned to rest by the last
frame—and partly to decreased signal-to-noise ratio as tag lines fade.
Estimates of viscoelastic time constants vary widely, but some studies,
e.g. [53], suggest that time constants are larger than 1 second, which
implies that viscoelastic relaxation may not be complete at the end of
each data acquisition.
Coefficients of correlation between brain deformation—MPS95 and
Ef95—and 𝜔2 highlighted regional differences that depended on the
type of head motion. For MPS95, higher correlations were seen in the
cortical gray matter and white matter during neck rotation compared to
the cerebellar white matter and brainstem during neck extension. Sim-
ilarly, a regional effect was seen in strains along axonal fibers for both
head motions. Ef95 was more strongly correlated with 𝜔2 in the corpus
callosum during neck rotation and in the brainstem during neck exten-
sion. For both head motions, the largest strain components correspond to
the plane of rotation (Supplemental Figures 3 and 4). The largest defor-
mations occurred in slices with the most brain tissue/mass present, such
as near the mid-sagittal plane (including the cerebellum and brainstem)
for neck extension and axial planes passing through the lateral ventricles

Fig. 5. Relationship between 95th percentile of maximum principal strain (MPS95) at the time of peak deformation and angular velocity squared (𝜔2 ) in the (a)
cortical gray matter, (b) cerebellar gray matter, (c) deep gray matter, (d) cerebral white matter, (e) cerebellar white matter, and (f) brainstem. Each data point shows
the result for the single subject. The dashed lines show a linear fit of the data.
JID: BRAIN
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A.K. Knutsen, A.D. Gomez and M. Gangolli et al.
for neck rotation. The current tagged MRI studies are consistent with ob-
servations from in vivo MRE. Recent MRE studies suggest brain tissue
has an average dynamic shear modulus near 2 kPa under harmonic ex-
citation at 50–60 Hz [54]. Simulations of brain deformation using an
average shear modulus of 2.2 kPa predict strain amplitudes similar to
those in the current study, in response to similar angular accelerations
[55]. Strain levels in the current study are also similar to those seen
in simulations, analyses, and experiments with a gel phantom of shear
modulus 1.7 kPa under similar angular accelerations [56]. MRE can also
uncover spatial variations in tissue properties. In vivo MRE data suggest
decreased shear stiffness in the cerebellum compared to the cerebral
gray and white matter [57]. This could account for the sharper increase
in MPS95 and Ef95 versus 𝜔2 in the cerebellum for neck extension com-
pared to neck rotation. Additionally, it is possible that the bending of
the neck during neck extension could lead directly to greater elonga-
tion of axonal fibers in the brainstem. These results highlight certain
brain regions that might be more likely to be injured due to different
head motions during trauma. Injury to these regions has been highly
implicated in studies of chronic dysfunction following TBI [8-10], with
the brainstem additionally being associated with loss of consciousness
[58,59].
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Brain Multiphysics xxx (xxxx) xxx
Fig. 6. Axial and sagittal views of fiber strain (Ef ) (color)
and MPRAGE (grayscale) during (a–c) neck rotation and
(d–f) neck extension in six subjects at the time of peak de-
formation (frame 3 for neck rotation and frame 5 for neck
extension). Values of Ef were mapped to 3D ellipsoids that
indicate the principal direction and degree of anisotropy
from the diffusion tensors. Arrows above the images in the
top row indicate the direction of head motion prior to im-
pact. L=left, R=right, A=anterior, P=posterior, I=inferior,
S=superior.
Fig. 7. Relationships between the 95th percentile of ax-
onal fiber strain (Ef95) and angular velocity squared (𝜔2 )
in the (a) corpus callosum and (b) brainstem. The dashed
lines show linear fit of the data.
To compute the preferred orientation for axonal fibers at each voxel,
we used a standard model of a single diffusion tensor. The principal
eigenvector of the diffusion tensor provides the preferred direction of
diffusion within that voxel. We then projected the strain tensor onto
the diffusion principal eigenvector, which provides a voxel-wise esti-
mate of axonal strain. This assumes that the fiber orientation approxi-
mately uniform within each voxel. Other studies have applied a model
of fiber dispersion developed for arterial vessels [60] to axonal fibers in
the brain [15,61]. Including fiber dispersion applies an approximately
linear scaling to the axonal fiber strain estimates based on the FA. Under
this model, the estimates provided here would represent the case of FA
equals 1, yielding a maximum estimate of axonal fiber strain within each
voxel. However, interpreting FA as fiber dispersion is a simplification of
actual brain microstructure since it is estimated from a single tensor
model for diffusion that does not account for crossing fiber bundles.
The single tensor diffusion model was used because our DTI acquisi-
tion involves only 30 unique gradient directions with a single diffusion-
weighting parameter (b-value). More advanced diffusion acquisitions
on high performance MRI scanners can be used to acquire data with
increased spatial and angular resolution. For example, the WU-Minn
Human Connectome Project diffusion acquisition protocol specifies 270
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A.K. Knutsen, A.D. Gomez and M. Gangolli et al.
diffusion weighted images with three non-zero b-values [62]. Such data
allows for the use of more complex models of diffusion within each voxel
that can better describe crossing fibers using multi-tensor models or ori-
entation distribution functions. In the future, improved data acquisition
will enable more advanced models of diffusion and axonal strain.
The full 3D strain fields obtained in this study confirm some features
of previously-reported 2D strain fields obtained using tagged MRI. This
is largely because the majority of the deformation occurs within the ax-
ial plane for neck rotation and the sagittal plane for neck extension. For
example, by estimating 2D strains in a single image slice during neck
extension, Bayly et al. [32] observed concentrations of high first prin-
cipal strain in the cortex and cerebellum (e.g., Fig. 6 from Bayly et al.
[32]). That study applied peak linear accelerations of 2–3 g over a 40 ms
period with a different head acceleration device than the one used here.
Despite the lower peak accelerations in the previous 2D study, strain
magnitudes were similar; differences between studies may be partially
explained by the different acceleration profiles produced by different
devices, the limited number of slices and incomplete motion data in
the 2D studies, and subject-to-subject variations in anatomy and phys-
iology. We note that head accelerations in both studies were measured
from sensors on the motion-constraining device; the amount of acceler-
ation experienced by the subject’s head is slightly different (this caveat
also applies to field data from sensors mounted in mouth-guards or hel-
mets). The relationships between brain deformation, impact velocity,
peak acceleration, and the duration of the applied acceleration are crit-
ically important and targets of future research. Chan et al. [29] char-
acterized the 2D deformation response in 34 subjects for neck rotation
using same motion-constraining device used in this study. Strain pat-
terns were similar between the studies (see Figs. 3–5 from Chan et al.
[29]). The largest values of MPS were observed shortly after the time of
peak angular deceleration and occurred in the cortical gray matter.
In general, higher values of MPS were observed during neck rotation
than neck extension. This is likely due largely to an increase in 𝜔 in the
neck rotation experiments. Ideally, we would have observed some over-
lap in 𝜔 between the motions. 𝜔 is primarily determined by the range of
motion of each head motion device and of how each subject accelerates
his/her head prior to impact; head motion prior to impact is an active
process driven by the subject. Given this, varying 𝜔 systematically and
over a larger range is not feasible in healthy volunteers. However, it is
possible to vary the magnitude and duration of the acceleration pulse
for a given 𝜔 by changing the stiffness of the impact pad. This would al-
low us to assess the effectiveness of reducing acceleration, i.e., by using
different types of padding, in reducing in vivo brain deformation.
The data from the current study, comprising 3D dynamic strain fields
together with high-resolution anatomy and white matter fiber orienta-
tion, represent a substantial and valuable resource for the evaluation
of computational models. The primary limitation of this study is that
the applied loading conditions were well below the threshold for injury;
this limitation is necessary for human volunteers to participate in the
study. While a recent study [63] asserted that measurements of brain de-
formation on this order are “not relevant for studying traumatic brain
injury,” we disagree. Both human and cadaver studies have strengths
and limitations. While in vivo measurements of brain deformation oc-
cur in response to loading conditions well below injury thresholds, these
data provide dense, high-resolution measurements of strain over time in
the live, human brain. Conversely, although cadaveric specimens retain
human geometry and anatomical structure, and can be tested under a
larger loading regime, including at thresholds for injury, the measured
displacements are sparse and provide only coarse estimates of strain
[23,24,27]. Additionally, the material properties of cadaveric brain tis-
sue undergo physical changes that can alter the biomechanical response
of the brain [28]. Therefore, computational models should generally
be evaluated by comparison to experimental data over a large range
of loading conditions [64] including mild impacts studied here, partic-
ularly given the increasing interest in the chronic effects of mild and
sub-concussive head impact.
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Similar to cadaveric specimens, animal models can also be used to
measure brain deformation over a range of loading conditions, but un-
like cadavers, the biological response can be studied using histopathol-
ogy. Tagged MRI has previously been used to measure in vivo strain
fields in the rat brain during head impact [65,66], and high-speed video
was used to track marker position and estimate brain deformation for a
hemi-section pig model of injury [7,67,68]. Future work will examine
the use of tagged MRI in an animal model to investigate how brain de-
formation scales over a range of loading conditions, from non-injurious
to injurious. Although tagged MRI allows sampling up to approximately
2.5 ms per image frame, loading conditions should not cause acute in-
jury because the motion must be repeated multiple times to create an
image set.
An additional challenge of using tagged MRI to investigate brain mo-
tion is that the subject must repeat the head rotation multiple times to
acquire each slice of the image volume. The specific number of rep-
etitions is proportional to the spatial and temporal resolution—more
repetitions provide higher spatial and temporal resolution. The strain
resolution is a function of the spatial frequencies included in the band-
pass filter used for HARP, so it is approximately on the order of the
tag spacing [69]. The parameters for this study (4 repetitions per im-
age set, 24 phase encode lines, 18 ms temporal resolution, tag spacing
of 8 mm) were selected based on a previous optimization study [30].
In the prior study, these parameters were shown to provide accurate
estimates of deformation compared to schemes with more repetitions,
and they allowed for the acquisition of a sufficient number of slices to
cover the brain with tag lines along all three axes. Given that the ma-
jority of brain deformation occurs within the plane of rotation, it could
be reasonable to perform some targeted tagged MRI studies in 2D. Two
examples where this could be of interest are to examine specific brain
regions at increased spatiotemporal resolution with a smaller tag spac-
ing and to investigate how changing the acceleration profile for a given
impact energy affects the deformation response of the brain.
In the future, results from these or similar 3D studies may be used to
identify regions of interest for more detailed exploration of higher spa-
tial and/or temporal resolution in a smaller number of 2D slices. While
tagged MRI is best-suited to track motion in tissues, phase contrast MRI
could be used to quantify fluid motion within the brain, e.g. [70]. The
present 3D data could also be analyzed to assess the frequency response
of the brain to impact, a property which has been hypothesized to play
a role in concussion [50]. For developers of computer models, results
from tagged MRI may be supplemented with subject-specific, spatially
varying material properties measured in vivo using magnetic resonance
elastography (MRE) [71,72]. These data together can be used to esti-
mate viscoelastic [73] and anisotropic [74,75] material properties of the
brain and to characterize frequency-dependent interactions between the
scalp, brain, and skull [76].
5. Conclusions
In this study, we used tagged MRI in healthy volunteers to estimate
dense 3D strain fields throughout the brain in response to a mild head
impact during either neck rotation or neck extension. In general, the
amount of brain deformation increased as the severity of the head im-
pact increased, though this varied by brain region and also depended
on the type of head motion. We also show that the majority of the brain
deformation occurred within the plane of rotation and noted the simi-
larity between these 3D strain measurements and previously performed
2D experiments. While obtaining full-field 3D strain fields is critical to
understanding TBI, future tagged MRI experiments of brain deformation
could take advantage of a more rapid 2D acquisition to investigate differ-
ent features or assess varying loading conditions. Finally, this study also
provides the first in vivo estimates of axonal fiber strain due to head ac-
celeration, which were obtained by combining the computed strain ten-
sors with axonal fiber orientations inferred from diffusion tensor imag-
ing. We observed similar patterns of axonal fiber strain across subjects
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A.K. Knutsen, A.D. Gomez and M. Gangolli et al.
within motion that differed between motions. Notably, the brainstem
had larger axonal fiber strains and was more sensitive to increased load-
ing during neck extension than neck rotation. While axonal fiber strains
were larger in the corpus callosum during neck rotation, the sensitivity
to 𝜔 was similar between the motions. The combination of in vivo ex-
perimental measurements of brain deformation under two loading con-
ditions with high resolution neuroimaging data provides an invaluable
resource for development and evaluation of computational models of
TBI.
Declaration of Competing Interest
The authors declare no competing interests.
Acknowledgements
We acknowledge funding from the National Institute of Neurologi-
cal Disorders and Stroke (R01/R56 NS055951 and U01 NS112120), the
Department of Defense in the Center for Neuroscience and Regenerative
Medicine, and the Intramural Research Program of the National Insti-
tutes of the Health. We would like to thank all of the participants in this
study for their time and effort. We also acknowledge the technical exper-
tise of Dr. Snehashis Roy, Mr. Yi-Yu Chou, Ms. Elizabeth McGrath, Ms.
Sarah Yan, Ms. Jennifer Kraszewski, Dr. Ahmed Alshareef, Mr. Aaron
Carass, and Ms. Michelle Albert.
Data availability
Six data sets (3 neck extension, 3 neck rotation) are publicly avail-
able for download at https://www.nitrc.org/projects/bbir/. Additional
data sets are available from the corresponding author upon request.
Author Contributions
AKK, DLP, JAB, JLP, and PVB conceived and designed the study. EC
designed the experimental devices. AKK, ADG, DC, YC, and WTW per-
formed the experiments. AKK and ADG processed and analyzed the data.
AKK drafted the manuscript; all authors critically edited the manuscript
and provided approval for final publication.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.brain.2020.100015.
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