NNS 2015 Program & Abstract Book

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

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.htm

Keywords: 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

, Pramod Dash

, Jennifer Juranek

, Linda Ewing-Cobbs

UTHealth, Pediatric Surgery, Houston, USA

UTHealth, Anatomy and Neuroscience, Houston, USA

UTHealth, Pediatrics, Houston, USA

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

A-138