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B2-11
MODELING CHRONIC NEURODEGENERATION FOLLOW-
ING NEUROTRAUMA: A MULTIPLE MODEL EXPERIENCE
Brandon Lucke-Wold
1
, Ryan Turner
1
, Charles Rosen
1
, Anthony
Petraglia
2
1
West Virginia University, Neurosurgery, Morgantown, USA
2
University of Rochester, Neurosurgery, Rochester, USA
Chronic neurodegeneration following neurotrauma is associated with
neuropsychiatric and cognitive symptoms. To enhance understanding
about the underlying pathophysiology linking neurotrauma to neuro-
degeneration, a multi-model pre-clinical approach must be established
and compared to pre-clinical results of tauopathy patterns seen in
post-mortem human samples from athletes. We utilized a scaled and
validated rat blast traumatic brain injury model and a controlled,
closed-head, acceleration-deceleration mouse model. Tau hyperpho-
sphorylation changes were evaluated by western blot and immuno-
histochemistry. Elevated plus maze and Morris water maze were
employed for behavior. Animals exposed to single blast (50PSI re-
flected) had increased AT8 in the contralateral hippocampus at 1
month compared to controls (
q
=
3.962,
p
<
0.05). Animals exposed to
repeat blast (6 blasts over 2 weeks) had increased AT8 (
q
=
8.120,
p
<
0.001) and AT270 (
q
=
4.030,
p
<
0.05) at 1 month post-injury
compared to controls. In the controlled acceleration-deceleration
mouse model, no significant difference in AT8 was seen at 7 days, but
significant difference was reported at 1 month in the ipsilateral hip-
pocampus compared to control (
q
=
4.343,
p
<
0.05). Tau markers
CP-13 (q
=
6.406, p
<
0.001) and PHF (q
=
10.58, p
<
0.001) were
significantly increased in the hippocampi of athletes diagnosed with
Chronic Traumatic Encephalopathy. Elevated plus maze data revealed
rats exposed to single blast (q
=
3.526, p
<
0.05) and repeat blast
(q
=
4.206, p
<
0.05) spent more time impulsively exploring the open
arms compared to controls. Morris water maze testing revealed a
significant difference between groups in acquisition times on days 22–
27. During the probe trial, single blast (t
=
6.437, p
<
0.05) and repeat
blast (t
=
8.002, p
<
0.05) rats spent less time exploring where the
platform had been compared to controls. A multi-model approach
with human sample comparison facilitates investigation into impor-
tant correlates linking neurotrauma to neurodegeneration.
Keywords: Tauopathy, impulsivity, Chronic Traumatic En-
cephalopathy, Multi-model
B3 Poster Session III - Group B: Axonal Injury
B3-01
DYNAMIC SHEARING DEFORMATIONS IN LIVING HU-
MAN BRAIN WITH RELEVANCE TO TRAUMATIC BRAIN
INJURY
Nitin Daphalapurkar
, Shailesh Ganpule
Johns Hopkins University, Mechanical Engineering, Baltimore, USA
Diffuse Axonal Injury (DAI) is a devastating type of Traumatic Brain
Injury (TBI) due to closed-head trauma. It is a debilitating injury that
leads to instantaneous unconsciousness and affects millions of people
every year just in the United States. DAI is a primary type of injury,
meaning the injury to the axons occurs at the time of the accident as
opposed to other secondary factors associated with the injury, which
can be delayed in time (e.g. swelling). DAI is a consequence of an
injury-causing deformation of an axon, leading to its dysfunction. The
exact degree and extent of microscopic injuries are almost impossible
to diagnose
in vivo
using existing imaging modalities, including
Magnetic Resonance Imaging (MRI).
Scientific computations using the Material Point Method (MPM)
were developed to predict dynamic deformations in a person-specific
brain subjected to mild rotational accelerations. Data on the anatomy
of the human head and fiber substructure in the white matter of
the brain was obtained from MRI methods. A simplified form of
Holzapfel-Gasser-Ogden model was used as the constitutive model for
various tissues in the brain. The material model for white matter of the
brain further considered fibrous-substructure and viscoelasticity as-
sociated with the tissue. Constants in the constitutive model were
calibrated based on literature-reported measurements of mechanical
responses. Cerebrospinal fluid was modeled as a non-Newtonian fluid.
The results from computations were validated against deformations
from
in vivo
experiments using the tagged MRI method. Results
suggest: focused shearing strains in the substructures of the brain
might occur when the head is violently accelerated or decelerated. The
dynamics associated with the shear wave propagation can further
amplify the shearing strains in the white matter of the brain. A sim-
ulation of an injury-causing rotation of the head will be used to
demonstrate the ability of the virtual head model to suggest the
likelihood of an injury and the locations of injury.
Keywords: mild rotational accelerations, virtual head model, mul-
tiscale model, 3D deformations in person-specific brain
B3-02
A COMPUTATIONAL MODEL OF WHITE MATTER AXON
FOR QUANTIFYING ACUTE AND DELAYED INJURY SE-
QUELAE, WITH APPLICATION TO REPEATED INJURY
Vladislav Volman
, Laurel Ng, James Stuhmiller
L-3 Communications, Applied Technologies Inc./Simulation, En-
gineering & Testing, San Diego, USA
Background:
The goal of this work was to quantify the neurophys-
iological underpinnings of concussion. Diffusion imaging, post mor-
tem studies, and animal models suggest that concussion is associated
with the damage to white matter axons. Axon stretching affects so-
dium channels and myelin insulation at nodes of Ranvier, potentially
leading to impaired axonal functionality or axonal degeneration.
Methods:
A multi-compartmental approach was adopted to create a
model of white matter axons incorporating key features of axonal orga-
nization. The model incorporated ion channels, ion transport and diffusion
mechanisms, as well as the mechanisms of glial swelling. The geometrical
and neurological parameters for different model components were ex-
tracted from literature to describe white matter axons in human corpus
callosum. The model was programmed in NEURON simulator, which
allows studying detailed multi-compartmental models of neural structures.
Results:
Axonal injury was simulated as coupled left shift (CLS)
of nodal sodium channels properties and/or stretch-induced para-
nodal demyelination. The generic effect of axonal injury was dose-
dependent reduction of axonal signal amplitude and dose-dependent
alteration of axonal signal latency. Paranode demyelination caused
further reduction of axonal signal amplitude and yielded accumulation
of extracellular potassium which facilitated axonal transition to deg-
radation. Glial swelling in response to axonal injury had a protective
effect and reduced the axonal sensitivity to repetitive injury occurring
on the time-scale of several minutes.
Conclusions:
The model results were in a good semi-quantitative
agreement with the existing experimental data. This effort is part of a
larger goal to link a series of models together in an end-to-end fashion
to identify a neurologically based mechanism of concussion. Com-
A-50