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It was initially believed that mTBI resulted in limited behavioral and no
long-term neurological consequences, except for in a small percentage of
patients with pre-existing psychiatric conditions. More recently, a pro-
liferation of neuroimaging studies have reported that neuronal pathology
may be present long after traditional outcome measures (e.g., balance and
neuropsychological testing) have returned to pre-morbid levels of func-
tioning. Animal models suggest that there are several different mecha-
nisms, as well as interactions between mechanisms, through which head
trauma can affect neural functioning. For example, trauma can directly
affect neuronal function (e.g., alterations in synchronous excitatory neu-
ronal activity), cerebral metabolism and the associated coupling with
cerebral blood flow, glutamate levels, the energetic needs of cells fol-
lowing neurotransmission, the structural integrity of white matter matter/
microvasculature, and the intracellular/extracellular matrix. The current
talk will focus on the use of magnetic resonance imaging (MRI) tech-
niques to investigate some of these neuropathologies across the spectrum
of mTBI disorders. Specifically, the talk will include a review of recent
MRI findings in single-episode and repetitive mTBI, a discussion of how
trauma may affect underlying signals of interest, as well as several
methodological challenges associated with the analyses of mTBI patients.
We conclude that the heterogeneity inherently associated with mTBI
research demonstrates the need for well-powered clinical studies in ho-
mogeneous samples (time post-injury, injury severity, single versus re-
petitive mTBI, chronically symptomatic versus asymptomatic, etc.) and
novel analytical techniques. Studies that incorporate multiple MRI mo-
dalities are critically needed to truly understand the underlying patho-
physiology and natural course of recovery in mTBI.
Keywords: mild, traumatic brain injury, magnetic resonance im-
aging, connectivity, neurobehavioral symptoms
S03-02
MRI OF EXPERIMENTAL TRAUMATIC BRAIN INJURY
Timothy Duong
U of Texas Health Science Ctr San Antonio, Research Imaging In-
stitute, San Antonio, USA
Traumatic brain injury (TBI) is a leading cause of death and disability.
The initial physical impact of TBI causes direct mechanical damage
and is followed by progressive secondary responses, including dis-
ruptions of cerebral blood flow (CBF) and vascular reactivity (VR),
which could lead to metabolic stress, vascular dysfunction, neural
dysfunction, and ischemia. In rat models of mild to moderate TBI, we
observed dynamic and widespread abnormalities of CBF and VR in
and around the impact area 1–3 hours after injury. Importantly, many
brain regions with disrupted CBF and VR were not yet abnormal on
anatomical and diffusion MRI at this time point. These observations
suggest that CBF and VR are more sensitive to acute TBI and may
have predictive value.
In addition, calcium dysfunction is involved in secondary traumatic
brain injury (TBI). Manganese-enhanced MRI (MEMRI), in which
the manganese ion acts as a calcium analog and a MRI contrast agent,
was used to study rats subjected to a controlled cortical impact.
Comparisons were made with conventional T
2
MRI, sensorimotor
behavior, and immunohistology. We concluded that MEMRI detected
early excitotoxic injury in the hyperacute phase, preceding vasogenic
edema. In the subacute phase, MEMRI detected contrast consistent
with tissue cavitation and reactive gliosis. MEMRI offers novel
contrasts of biological processes that complement conventional MRI
in TBI.
http://ric.uthscsa.edu/duong/index.htmKeywords: MRI, cerebral blood flow, diffusion tensor imaging,
manganese enhanced MRI, control cortical impact, animal model of
TBI
S03-03
CLINICAL PHENOTYPE OF TRAUMATIC VASCULAR IN-
JURY AND POSSIBLE THERAPEUTIC IMPLICATIONS
Ramon Diaz-Arrastia
Center for Neuroscience and Regenerative Medicine, Department of
Neurology, Rockville, USA
Traumatic Vascular Injury (TVI) is a well-established but relatively un-
derstudied endophenotype of TBI. Studies in humans with moderate to
severe TBI, as well as from athletes and military Veterans exposed to
repetitive mild TBIs, demonstrate prominent microvascular pathology.
TVI is an attractive target for therapeutic intervention, as there are multiple
well established pharmacologic and non-pharmacologic therapies which
target vascular health. Pharmacologic therapies targeted at improving ce-
rebrovascular function such HMG-CoA reductase inhibitors, phosphodi-
esterase 5 (PDE5) inhibitors, HDLmimetics, and PPAR-g agonists, among
others, have been studied in TBI models and many are approved for human
use in other diseases. Non-pharmacologic therapies targeted at improving
vascular function, including aerobic exercise, dietary interventions, and
nutraceuticals such as omega-3 fatty acids, also show promise for limiting
neural injury and promoting plasticity and repair after TBI. Early-phase
clinical trials of TVI-directed therapies will require well-validated bio-
markers which can be used to document target engagement and to provide
evidence of biological efficacy. MRI is a promising tool to measure ce-
rebrovascular reactivity non-invasively, as well as to assess disruption of
the blood-brain barrier. Near InfraRed Spectroscopy (NIRS) also shows
promise as an inexpensive and widely available biomarker of TVI. We
have used MRI and NIRS with a hypercapnia challenge to demonstrate
that CVR is commonly depressed after TBI. Further, CVR shows promise
as a pharmacodynamic biomarker for TVI-directed therapies.
Keywords: cerebrovascular reactivity, PDE5 inhibitors, arterial spin
labelling, dynamic contrast enhancement
S04 Progenitor Cell Therapy for Adult TBI: Preclinical
Findings and Clinical Outcomes
S04-01
CELLULAR THERAPIES FOR TBI: TARGETS AND AP-
PROACH
Charles Cox
1
, Pramod Dash
2
, Jennifer Juranek
3
, Linda Ewing-Cobbs
4
1
UTHealth, Pediatric Surgery, Houston, USA
2
UTHealth, Anatomy and Neuroscience, Houston, USA
3
UTHealth, Pediatrics, Houston, USA
4
UTHealth, Oedatrics, Houston, USA
Currently there are no approved small molecule or biological therapeutic
to mitigate the secondary neuroinflammatory response that ensues after
severe traumatic brain injury. Our group has focused on the use of pro-
genitor cell therapeutics to mitigate the inflammation and subsequent
edema associated with TBI. Pre-clinical data using autologous bone
marrow derived mononuclear cells suggest that the observed functional
improvements noted in rodent models is related to the polarization of
microglia and macrophages to a M2 phenotype vs. a M1 phenotype.
Phase 1 and Phase 2 clinical trials in adults and children have focused on
the anti-inflammatory effects and associated structural preservation that
can be quantified using DT-MRI volumetrics and tractography. Im-
portantly, these imaging data can be correlated with functional outcomes
when examining discrete regions of interest. The data to be presented will
review our early phase clinical trials and the results that correlate imaging
findings and outcomes associated with cellular therapies for severe TBI.
Keywords: Cell Therapy
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