Vascular endothelial growth factor (VEGF) may play a role in neuroprotection after traumatic brain injury (TBI) in addition to being a regulator of angiogenesis. Gene therapy using an adenovirus carrying an engineered zinc-finger protein (Adv-ZFP) and transcription factor construct targeted to the VEGF gene, has been shown to upregulate genomic expression of VEGF-A isoforms in skeletal muscle. Our objective was to use this gene therapy to explore cell survival in TBI. Rats were subjected to a unilateral fluid percussion injury (FPI) in the cortex. Groups consisted of control, injured and injured-treated animals. Adv-ZFP-VEGF was injected into the cortex and hippocampus. Engineered ZFP-VEGF increases VEGF-A protein levels and correlates with increased CA2 hippocampal cell survival and reduction in apoptotic cell death following TBI. NF200 expression in TBI+VEGF animals was comparable to levels in naive animals. This study suggests a therapeutic strategy to treat delayed cell death in a model of TBI.

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Post-mortem human surrogate (PMHS) head specimens were subjected to two different angular speed pulses. Each pulse was approximately a half-sine with either a peak angular speed of either 40 or 20 rad/s and duration of either 30 or 60 milliseconds. High-speed biplane x-ray was used to record the motion of the brain and skull via radio-opaque markers implanted at specified locations in the brain, and lead markers on the skull. Specimens were perfused to physiologic conditions throughout preparation and testing to maintain the integrity of the brain tissue and ensure coupling of the brain and skull. Intracranial pressure was measured anteriorly and posteriorly. The test event was controlled by a cam-follower-flywheel mechanism, which facilitated control of pulse parameters and provided a form of "infinite energy" so that the device and therefore the test input would not be influenced by the characteristics of the object under test. This approach kept the independent and dependent variables separated. The brain targets were also deployed in a prescribed manner with two methodologies that were scalable to different specimens. The repeatable input and target deployment schemes helped reduce experimental variation (between tests and subjects) to produce consistent response data. Displacement of the brain was calculated with respect to a body-fixed basis on the skull. The relative motion of the brain with respect to the skull was shown to be dependent on the location of the target in the brain. The major deformation axis of each target followed the contour of the skull or bony landmark to which it was closest. Intracranial pressure was relatively low because the changes were due to inertial effects in the absence of impact. Tests with lower speeds and longer durations produced less deformation, lower intracranial pressures, and longer pressure durations than the tests that were high-speed, short-duration. The response of the brain to rotation of the head was quantified at two test levels and on two PMHS specimens. / Master of Science / Motor-vehicle collisions (MVCs) are the second leading cause of traumatic brain injury (TBI) in the United States and the leading cause of TBI-related death [1a]. Regulations are in place for vehicle design to reduce the occurrence and severity of head injuries during MVCs. The metric used is based on the resultant linear acceleration at the center of gravity of the occupant’s head. However, TBI are still occurring despite the current regulations. This suggests the importance of using additional injury metrics to predict TBI in MVCs. In automotive impact biomechanics, a combination of real world, experimental, and simulation data is used to determine how the human body responds during MVCs. While computer (finite element) simulations can provide extensive information about the kinematic and kinetic response of the human body, these models require experimental data to validate and evaluate their responses. This study focuses on determining the response of the human cadaver brain to angular speed loading without contact of the head. High-speed biplane x-ray and radiopaque markers were used to quantify the displacement of the brain with respect to the skull throughout rotational events. Two angular speed profiles with different peak angular speeds and durations were used. The methods were determined to reduce experimental variation to obtain data that is useful for finite element model validation. The average peak angular speed for the high-speed tests was 41.8 rad/s and the average peak angular speed for the low-speed tests was 22.0 rad/s. The peak angular speed only varied by 10% between similar tests. The motion of the brain lagged behind that of the skull, producing a relative displacement of the brain with respect to the skull. The magnitude and primary direction of the relative displacement was dependent on the location at which it was measured. The location of the radiopaque target with respect the anatomical coordinate system and bony landmarks of the skull are both important in determining the characteristics of the relative displacement profiles. The high-speed tests produced an average displacement of +/-5 mm, while the low-speed tests had an average displacement of +/-2.5 mm in the X-direction. Intracranial pressure (ICP) was also measured at two points in the cranial cavity, and showed the delayed response of the brain to the rotational loading of the head.

abstract: Traumatic brain injury (TBI) is a leading cause of disability worldwide with 1.7 million TBIs reported annually in the United States. Broadly, TBI can be classified into focal injury, associated with cerebral contusion, and diffuse injury, a widespread injury pathology. TBI results in a host of pathological alterations and may lead to a transient blood-brain-barrier (BBB) breakdown. Although the BBB dysfunction after TBI may provide a window for therapeutic delivery, the current drug delivery approaches remains largely inefficient due to rapid clearance, inactivation and degradation. One potential strategy to address the current therapeutic limitations is to employ nanoparticle (NP)-based technology to archive greater efficacy and reduced clearance compared to standard drug administration. However, NP application for TBI is challenging not only due to the transient temporal resolution of the BBB breakdown, but also due to the heterogeneous (focal/diffuse) aspect of the disease itself. Furthermore, recent literature suggests sex of the animal influences neuroinflammation/outcome after TBI; yet, the influence of sex on BBB integrity following TBI and subsequent NP delivery has not been previously investigated. The overarching hypothesis for this thesis is that TBI-induced compromised BBB and leaky vasculature will enable delivery of systemically injected NPs to the injury penumbra. This study specifically explored the feasibility and the temporal accumulation of NPs in preclinical mouse models of focal and diffuse TBI. Key findings from these studies include the following. (1) After focal TBI, NPs ranging from 20-500nm exhibited peak accumulation within the injury penumbra acutely (1h) post-injury. (2) A smaller delayed peak of NP accumulation (40nm) was observed sub-acutely (3d) after focal brain injury. (3) Mild diffuse TBI simulated with a mild closed head injury model did not display any measurable NP accumulation after 1h post-injury. (4) In contrast, a moderate diffuse model (fluid percussion injury) demonstrated peak accumulation at 3h post-injury with up to 500 nm size NPs accumulating in cortical tissue. (5) Robust NP accumulation (40nm) was found in female mice compared to the males at 24h and 3d following focal brain injury. Taken together, these results demonstrate the potential for NP delivery at acute and sub-acute time points after TBI by exploiting the compromised BBB. Results also reveal a potential sex dependent component of BBB disruption leading to altered NP accumulation. The applications of this research are far-reaching ranging from theranostic delivery to personalized NP delivery for effective therapeutic outcome. / Dissertation/Thesis / Doctoral Dissertation Biomedical Engineering 2018

INTRODUCTION: Traumatic brain injury (TBI) is a major public health problem, causing approximately 52,000 deaths from 1.7 million injuries in the United States annually, with a combined direct and indirect economic cost estimated at $60-75 billion per year. Traumatic subarachnoid hemorrhage (tSAH), a subtype of closed head injury, has a high prevalence within TBI—evident in up to two-thirds of moderately and severely brain injured patients. tSAH is also associated with poor clinical outcomes; some research suggests mortality and unfavorable outcome rates are two-to-three times higher in patients with tSAH, based on brain imaging, compared to those without. To date, no pharmacological treatment has been conclusively shown to improve outcomes in humans for either moderate or severe TBI or for specific tSAH injury. The aim of this study was to assess whether the effect of PROG was substantially different in study TBI patients with evidence of tSAH on initial brain imaging compared to those that did not have evidence of tSAH. METHODS: ProTECT III clinical trial data was used for an exploratory, post hoc subgroup analysis to determine the effect of the hormone progesterone (PROG) on outcome. Study subjects with any abnormality on baseline brain imaging were included in the analysis and two subgroups, tSAH positive (+tSAH) and tSAH negative (–tSAH), were selected. The primary outcome evaluated was a favorable/unfavorable dichotomy derived from the 6-months post-injury Extended Glasgow Outcome Scale (GOSE) assessment, which evaluates both mortality and functional outcomes. Risk ratios (RRs) were calculated for the total sample and each of the two subgroups and used as statistical evidence for interaction between PROG and tSAH. RESULTS: All subjects from the original ProTECT III trial cohort (N=882) with no abnormalities found on baseline computed tomography (CT) image (n=125) or missing image (n=1) were excluded from this analysis. Subjects with one or more abnormalities noted on CT (+CT, n=756) were then divided into subgroups based on presence (n=582) or absence (n=174) of tSAH. Subjects with +tSAH were more severely injured than –tSAH (mean Rotterdam CT score 3.3 vs. 2.2; 3.1 overall) and had a lesser proportion of favorable outcomes (47.4% vs. 74.3%; 53.6% overall). Compared to placebo, patients treated with progesterone had marginally better likelihood of favorable outcomes (risk ratio among +tSAH 1.06, 95% confidence interval [CI], 0.89 to 1.26; and RR among –tSAH 1.02, 95% CI 0.85 to 1.22). A multivariable model, adjusted for baseline differences in treatment group covariates did not yield substantially different results for the effect of progesterone on favorable outcomes (+tSAH 1.07; 95% confidence interval [CI], 0.84 to 1.36, –tSAH 1.08; 95% CI 0.75 to 1.56, +CT 1.06; 95% CI 0.87 to 1.29). CONCLUSION: Our study demonstrated that progesterone did not result in different effects in patients with or without tSAH than those without based on initial brain imaging. This investigation supports previous research findings; tSAH is correlated with more severe injury and worsened outcomes. Concomitant injuries found in +tSAH group are likely worsening the outcomes over –tSAH, but this was not evaluated here. More complex statistical modeling should be used on this data to determine if it provides evidence that tSAH is an independent prognosticator of unfavorable outcome or merely associated with more severely injured patients.

The purpose of the current study was to determine if the Nova Multilingual Neuropsychological Battery (NMNB) can detect neurological deficits in the traumatic brained injured (TBI) Hispanic sample by comparing subtest mean scores to the normal group mean scores. The NMNB is comprised of 39 subtests and was developed to account for language and cultural factors thought to influence neuropsychological test results. It was hypothesized that significant differences would be found in NMNB measures sensitive to brain damage. A sample size of 100 English-Spanish speaking bilinguals (50 TBI and 50 cognitively intact participants) was tested in Spanish in order to compare cognitive performance across the various NMNB measures. Due to the number of comparisons, the alpha level for this study was set to .01 to reduce Type I error. Results of the ANCOVA's partially supported the hypothesis after controlling for age and education. Findings show that the NMNB measures were able to successfully detect the TBI Spanish group from the normal Spanish group. Significant differences were displayed in the tests measuring nonverbal abilities, memory and learning, visual spatial skills, and executive functioning. More specifically, no significant differences were displayed in the tests measuring crystallized premorbid abilities, while tests measuring more fluid abilities detected problems with abstract thinking and information processing in the TBI sample. A similar deficit pattern was displayed across all measures of higher functioning systems. Deficits were detected in the nonverbal measures that involved complex attention (selective, divided, and alternating forms of attention) and concentration for visuospatial tasks, pattern synthesis and manipulation, but not for simple visuospatial attentional activities. Significant differences were found in motor speed, but not in the number of errors. These findings support previous research indicating that Hispanics tend to favor accuracy over speed. Additionally, results reveal significant differences across all memory measures. Using Cohen's d, large effect sizes were displayed between the groups ranging from 1.5 to 2.3 in the verbal and visual memory measures. Similar effect sizes were also displayed in tests of executive functioning. Preliminary data of this study suggests that the NMNB may be a sound assessment tool for detecting neurological impairments in TBIs. Collectively, the NMNB displayed significant differences in motor and processing speed, memory, visuospatial tasks, and executive functioning commonly documented in non-Hispanic TBIs. This study concluded that culturally sensitive neuropsychological tests that also control for demographic variables such as age and education can provide accurate results for Hispanics with TBI. However, these results should be interpreted with caution as this study was limited to a small sample size with an unequal proportion of TBI severity levels and educational experiences beyond educational levels. Future studies should focus on obtaining larger samples with varying TBI severity levels. Samples should also include bilingual Hispanics tested in English as well as monolingual Spanish speakers in order to develop profiles that may be useful in differential diagnosis.

Traumatic brain injury (TBI) is the leading cause of disability in individuals under 45 years of age, with mild TBI (mTBI) accounting for the majority of cases. The juvenile brain is in a period of robust synaptic reorganization and myelination, making adolescence a particularly vulnerable time to incur a TBI. Learning and memory deficits that involve the hippocampal formation are often observed following mTBI in adults. To examine this issue in the juvenile brain, we assessed changes in hippocampal synaptic plasticity following closed-head mTBI in male and female Long-Evans rats (25-28 days of age). Synaptic plasticity of field excitatory post-synaptic potentials (fEPSPs) was assessed using in vitro electrophysiology at either one hour, one day, seven days, or 28 days following mTBI in the dentate gyrus (DG) and the cornu ammonis area 1 (CA1) regions of the hippocampus. In female rats, the CA1 region ipsilateral to the impact showed a significant reduction in long-term potentiation (LTP) as early as one hour following mTBI. Similar LTP deficits were apparent at one day in the DG, and persisted to 28 days following injury. In male rats, a deficit in both DG- and CA1-LTP was maximal in the ipsilateral hemisphere by seven days following injury, but these deficits did not persist to 28 days post-injury. These data suggest that the juvenile brain is susceptible to mTBI-induced impairments in plasticity, and sex and regional differences are apparent in the expression and recovery of synaptic plasticity following mTBI. / Graduate

Traumatic brain injury (TBI) constitutes a major health problem and is a leading cause of long-term disability and death. Patients with severe traumatic brain injury, S-TBI, comprise a heterogeneous group with varying complexity and prognosis. The primary aim of this thesis was to increase knowledge about clinical course and outcome with regard to prognostic factors. Papers I, II and III were based on data from a prospective multicentre observational study from six neurotrauma centers (NCs) in Sweden and Iceland of patients (n=103-114), 18-65 years with S-TBI requiring neurosurgical intensive care or collaborative care with a neurosurgeon (the “PROBRAIN” study).  Paper IV and V were performed on a regional subset (n=37). In Paper I, patients with posttraumatic disorders of consciousness (DOC) were assessed as regards relationship between conscious state at 3 weeks and outcomes at 1 year. The number of patients who emerged from minimally conscious state (EMCS) 1 year after injury according to status at 3 weeks were: coma (0/6), unresponsive wakeful syndrome (UWS) (9/17), minimally conscious state (MCS) (13/13), anaesthetized (9/11). Outcome at 1 year was good (Glasgow Outcome Scale Extended (GOSE>4) in half of the patients in MCS (or anaesthetized) at 3 weeks, but not for any of the patients in coma or UWS.    In Paper II, the relationships between clinical care descriptors and outcome at 1 year were assessed. A longer length of stay in intensive care, and longer time between discharge from intensive care and admission to inpatient rehabilitation, were both associated with a worse outcome on the GOSE. The number of intervening care units between intensive care and rehabilitation, was not significantly associated with outcome at 1 year.  In Paper III, the clinical course of cognitive and emotional impairments as reflected in the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) and the Hospital Anxiety and Depression Scale (HADS) were assessed from 3 weeks to 1 year together with associations with outcomes GOSE and Rancho Los Amigos Cognitive Scale-Revised (RLAS-R) at 1 year. Cognition improved over time and appeared to be stable from 3 months to 1 year.  In Paper IV, clinical parameters, the clinical pathways from injury to 3 months after discharge from the NC in relation to outcomes 3 months post-injury. Ratings on the RLAS-R improved significantly over time. Eight patients had both “superior cognitive functioning” on the RLAS-R and “favourable outcome” on the GOSE. Acute transfers to the one regional NC was direct and swift, transfers for postacute rehabilitation scattered patients to many hospitals/hospital departments, not seldom by several transitional stages.  In Paper V, an initial computerized tomography of the brain (CTi) and a further posttraumatic brain CT after 24 hours (CT24) were evaluated according to protocols for standardized assessment, the Marshall and Rotterdam classifications. The CT scores only correlated with clinical outcome measures (GOSE and RLAS-R) at 3 months, but failed to yield prognostic information regarding outcome at 1 year. A prognostic model was also implemented, based on acute data (CRASH model). This model predicted unfavourable outcomes for 81% of patients with bad outcome and for 85% of patients with favourable outcome according to GOSE at 1 year. When assessing outcomes per se, both GOSE and RLAS-R improved significantly from 3 months to 1 year.  The papers in this study point both to the generally favourable outcomes that result from active and aggressive management of S-TBI, while also underscore our current lack of reliable instruments for outcome prediction. In the absence of an ability to select patients based on prognostication, the overall favourable prognosis lends support for providing active rehabilitation to all patients with S-TBI. The results of these studies should be considered in conjunction with the prognosis of long-term outcomes and the planning of rehabilitation and care pathways. The results demonstrate the importance of a combination of active, acute neurotrauma care and intensive specialized neurorehabilitation with follow-up for these severely injured patients.

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