Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury

Biomechanical analysis of open-skull high-rate traumatic brain injury using finite element mouse brain model

To better understand traumatic brain injury (TBI), it is necessary to correlate with injuries, which are observed from in vivo laboratory experiments, to brain mechanical responses, which can so far be best predicted by finite element (FE) models. Firstly, a previously validated FE model was improved to investigate the effect of repeated impacts and lateral movements on brain responses to ensure the accuracy and reproducibility of controlled cortical impact (CCI) across different labs. Then, a new FE mouse brain model with the detailed three-dimensional (3D), non-linear vasculature was developed to study how the vasculature affected brain response in CCI and predicted vasculature responses. Lastly, the correlation between brain mechanical strains and microvessel injury induced by CCI was investigated. In summary, the biomechanics of CCI was further characterized and a new mouse brain model with detailed vasculature was developed to understand brain mechanics and microvessel damage

Microfabrication Approaches for Understanding the Role of Vascular Mechanics in Progressive Diseases

University of Minnesota Ph.D. dissertation. August 2016. Major: Biomedical Engineering. Advisor: Patrick Alford. 1 computer file (PDF); xi, 118 pages.Vascular disease is a common cause of death that typically results from long-term alteration of vessel structure and function. The underlying mechanisms that lead to pathologic changes in the vasculature are largely unclear, especially in progressive diseases of the cerebral vessels. With the growing prevelance of blast traumatic brain injury in modern warfare, never before has investigation of cerebral vascular disease been more pertinent. Here, we focus on the development of microfabrication experimental approaches for probing the critical mechanical and biochemical pathways involved in progression of diseases, such as cerebral vasospasm, subarachnoid hemorrhage, and Alzheimer’s disease, that often result from TBI. First, we develop a microfluidic patterned deposition technique for studying functional mechanics in chronic vascular disease at the tissue scale. We modify substrate surfaces with genipin, a natural crosslinker, to extend culture times of in vitro vascular tissues that mimic native tissue structure and function. We successfully validate our technique, showing maintenance of patterned structural alignment and mechanical function over the course of two weeks. Lastly, we investigate the relationship between vascular disease and Alzheimer’s disease. Amyloid beta is a key precursor in the development of Alzheimer’s disease that accumulates in neuronal and cerebrovascular tissue and can result in neurodegeneration. During the development of cerebral amyloid angiopathy (CAA), which is present in over 80% of Alzheimer's disease cases, amyloid beta plaques form in the cerebral vessel walls and lead to severe attenuation of physiologic vasodilation. We measured the effect of amyloid beta treatment on vascular smooth muscle cell functional contractility using a single-cell traction force microscopy technique and developed a thin-walled arterial model for growth and remodeling response to mechanical perturbations. We found that amyloid beta induces a reduction in vascular smooth muscle cell mechanical output. We implemented this loss of function into a constrained mixture arterial model that suggests vessel growth and remodeling, in response to amyloid beta-mediated alteration of smooth muscle function, can lead to an inability of cerebral vessels to vasodilate. Our findings provide a possible explanation for the vascular injury and malfunction often associated with the development of neurodegeneration in Alzheimer’s disease

Impacts of exercise intervention on various diseases in rats.

BackgroundExercise is considered as an important intervention for treatment and prevention of several diseases, such as osteoarthritis, obesity, hypertension, and Alzheimer's disease. This review summarizes decadal exercise intervention studies with various rat models across 6 major systems to provide a better understanding of the mechanisms behind the effects that exercise brought.MethodsPubMed was utilized as the data source. To collect research articles, we used the following terms to create the search: (exercise [Title] OR physical activity [Title] OR training [Title]) AND (rats [Title/Abstract] OR rat [Title/Abstract] OR rattus [Title/Abstract]). To best cover targeted studies, publication dates were limited to "within 11 years." The exercise intervention methods used for different diseases were sorted according to the mode, frequency, and intensity of exercise.ResultsThe collected articles were categorized into studies related to 6 systems or disease types: motor system (17 articles), metabolic system (110 articles), cardiocerebral vascular system (171 articles), nervous system (71 articles), urinary system (2 articles), and cancer (21 articles). Our review found that, for different diseases, exercise intervention mostly had a positive effect. However, the most powerful effect was achieved by using a specific mode of exercise that addressed the characteristics of the disease.ConclusionAs a model animal, rats not only provide a convenient resource for studying human diseases but also provide the possibility for exploring the molecular mechanisms of exercise intervention on diseases. This review also aims to provide exercise intervention frameworks and optimal exercise dose recommendations for further human exercise intervention research

Tissue-engineered microvessel models of the human blood-brain barrier

The vasculature in the brain is formed by brain microvascular endothelial cells (BMECs) surrounded by pericytes and astrocytic endfeet. Together these cellular components constitute the blood-brain barrier (BBB) and regulate transport into and out of the brain. BMECs possess intrinsic barrier properties to regulate transport, including enriched expression of tight junctions (TJs) which block paracellular transport, efflux pumps which limit transcellular transport, and nutrient transporter systems which increase substrate transcellular transport. In healthy individuals, these properties limit the passage of ~98% of small molecules into the brain, representing a major hurdle for brain disease treatment. However, during some brain diseases the BBB displays structural and functional alterations which can directly contribute to disease progression. In this work, tissue-engineered three-dimensional (3D) brain microvessels are developed to enable studies of the BBB during health and disease. Key advantages of 3D microvessels compared to two-dimensional assays (i.e., transwells) are established, including recapitulation of critical microenvironmental cues present within the native BBB (i.e., cylindrical geometry, cell-matrix interactions, and shear flow), physiological permeability, and high spatiotemporal resolution. Chapter 1 provides an overview of brain microvascular plasticity; this overview highlights processes that are later studied within our 3D microvessel models. Chapter 2 describes the tissue-engineering approach to form 3D microvessels by seeding induced pluripotent stem cell (iPSC)-derived BMECs into ~150 μm diameter channels patterned within type I collagen. This model is used to study: (1) brain specificity of barrier function, (2) efflux inhibition, (3) cytokine response, and (4) the influence of neurodegenerative mutations. Chapter 3 describes a study on the mechanisms of enhanced drug delivery using hyperosmotic BBB opening. The hyperosmotic agent mannitol results in dose-dependent and spatially heterogeneous increases in paracellular permeability through the formation of transient focal leaks; additionally, the susceptibility to opening and subsequent repair is modulated by growth factor treatment. Chapter 4 describes a bead assay and tissue-engineered microvessel model of brain angiogenesis used to study the influence of chemical and physical factors on angiogenic phenotype. Together these works show that tissue-engineered BBB microvessels can provide insight into the mechanisms of drug delivery and various brain disease states

Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases

Oxygen is vital to maintain the normal functions of almost all the organs, especially for brain which is one of the heaviest oxygen consumers in the body. The important roles of oxygen on the brain are not only reflected in the development, but also showed in the pathological processes of many cerebral diseases. In the current review, we summarized the oxygen levels in brain tissues tested by real-time measurements during the embryonic and adult neurogenesis, the cerebral diseases, or in the hyperbaric/hypobaric oxygen environment. Oxygen concentration is low in fetal brain (0.076–7.6 mmHg) and in adult brain (11.4–53.2 mmHg), decreased during stroke, and increased in hyperbaric oxygen environment. In addition, we reviewed the effects of oxygen tensions on the behaviors of neural stem cells (NSCs) in vitro cultures at different oxygen concentration (15.2–152 mmHg) and in vivo niche during different pathological states and in hyperbaric/hypobaric oxygen environment. Moderate hypoxia (22.8–76 mmHg) can promote the proliferation of NSCs and enhance the differentiation of NSCs into the TH-positive neurons. Next, we briefly presented the oxygen-sensitive molecular mechanisms regulating NSCs proliferation and differentiation recently found including the Notch, Bone morphogenetic protein and Wnt pathways. Finally, the future perspectives about the roles of oxygen on brain and NSCs were given

Clinical Recovery from CNS Damage

After decades of focusing on how to alleviate and prevent recurrence of acute CNS injuries, the emphasis has finally shifted towards repairing such devastating events and rehabilitation. This development has been made possible by substantial progress in understanding the scientific underpinnings of recovery as well as by novel diagnostic tools, and most importantly, by emerging therapies awaiting clinical trials. In this publication, several international experts introduce novel areas of neurological reorganization and repair following CNS damage. Principles and methods to monitor and augment neuroplasticity are explored in depth and supplemented by a critical appraisal of neurological repair mechanisms and possibilities to curtail disability using computer or robotic interfaces. Rather than providing a textbook approach of CNS restoration, the editors selected topics where progress is most imminent in this labyrinthine domain of medicine

Doctor of Philosophy

dissertationThe cerebrovasculature is vital in maintaining health in the brain, but can be damaged by traumatic brain injury (TBI). Even in cases without hemorrhage, vessels are deformed with the surrounding tissue. Subfailure deformation could result in altered mechanical properties and dysfunction of these vessels. This dissertation aims to provide a better understanding of the biaxial mechanical properties of cerebral arteries, as well as determine mechanical stretch thresholds which produce ultimate failure and subfailure alteration of mechanical properties or vessel function. Three in vitro studies were undertaken. Passive biaxial mechanical properties under physiological loading, as well as failure properties of rat middle cerebral arteries (MCAs), were measured and compared to those of human pial arteries. Best fit parameters for a Fung type strain energy function are provided for the biaxial mechanical properties. Rat MCAs are stiffer in the axial direction than the circumferential, but less stiff in both directions than human arteries. Rat MCAs also exhibit a lower ultimate failure stress but higher failure stretch. The effect of subfailure axial overstretch on the contractile behavior of smooth muscle cells (SMCs) in rat MCAs was investigated. Potassium dose response tests were conducted before and after a single axial overstretch, with varying magnitude and strain rate. Overstretches beyond a threshold of both magnitude and strain rate significantly reduced SMC contraction relative to time-matched controls, mirrored by an increase in potassium concentration required to evoke the half maximal contraction. The effect of subfailure axial overstretch on passive mechanical properties in sheep MCAs was investigated. Axial response was measured before and after a single quasi-static overstretch of various magnitudes. Post-overstretch, samples showed persistent softening (lower stress values at a given level of stretch). Softening was only observed above an overstretch threshold, and then increased with overstretch severity until a second threshold was reached, above which softening did not increase until failure. This dissertation provides improved understanding of cerebrovascular mechanics and relationships between such data acquired from animals and humans. It also provides insight into the potential role of subfailure cerebrovascular damage in disease states associated with TBI, such as second impact syndrome and strok

Low-intensity blast-induced mild traumatic brain injury : linking blast physics to biological outcomes

Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast (LIB) mediated pathophysiology upon later neurobehavioral disorders has been controversial. Our prior considerations of blast physics predicted ultrastructural injuries at nanoscale levels. Here, we provide quantitative data using a LIB injury murine model exposed to open-field detonation of 350 g of high-energy explosive C4. The use of an open-field experimental blast generated a primary blast wave with a peak overpressure of 6.76 pounds per square inch (PSI) (46.6 kPa) at a 3-meter (m) distance from the center of the explosion, with no apparent impact / acceleration in exposed animals. We first characterized neuropathological and behavioral changes. Using transmission electron microscopy (TEM), we further identified multifocal neuronal damages, myelin sheath defects, mitochondrial abnormalities, and synaptic dysregulation after LIB injury. Next, we used quantitative proteomics, bioinformatics analysis, biochemical investigations to seek insights into the molecular mechanisms underlying the ultrastructural pathology. Results illustrated the alterations of mitochondrial, axonal, synaptic proteins in related signaling pathways. These observations uncover unique ultrastructural brain abnormalities, biochemical correlates, and associated behavioral changes due to LIB injury. Insights on the early pathogenesis of LIB-induced brain damages provide a template for further characterization of its chronic effects, identification of potential biomarkers and targets for intervention.Includes bibliographical reference

Jejum intermitente profilático promove adaptações mitocondriais influenciando a conectividade metabólica cerebral após um traumatismo cranioencefálico grave

Introdução: O traumatismo cranioencefálico (TCE) está associado a um metabolismo cerebral e conectividade metabólica prejudicados, culminando na neurodegeneração através de vários mecanismos associados à mitocôndria. O jejum intermitente (IF) é uma abordagem dietética reconhecida por causar reprogramação metabólica cerebral, melhorando assim a função cognitiva. Objetivos: Acessar o potencial profilático de uma estratégia de IF em camundongos para restringir os déficits neuroenergéticos e cognitivos que se seguem ao TCE grave. Métodos: Camundongos C57BL / 6J foram submetidos à dieta ad libitum (ALD) ou protocolo de IF em dias alternados durante 20 dias. Após 48 horas, os camundongos foram submetidos ao impacto cortical controlado (CCI) grave, resultando em três grupos experimentais: SHAM e CCI (ALD) ou IF (IF anterior mais CCI). Resultados: Cinco dias após a lesão, o CCI apresentou comprometimento da captação de glicose e conectividade metabólica, efeito que foi prevenido pelo IF. Além disso, o IF preveniu a disfunção mitocondrial, o inchamento mitocondrial pelo cálcio e alterações no potencial da membrana mitocondrial induzida pelo CCI. Além disso, a produção aumentada de H2O2 mitocondrial induzida por CCI foi atenuada por IF, culminando em viabilidade celular preservada. Esses defeitos metabólicos foram refletidos no comprometimento da memória espacial induzido pelo CCI que foi prevenido pelo IF. Conclusão: O IF modulou vários mecanismos subjacentes associados à progressão da lesão após TCE grave, prevenindo o comprometimento mitocondrial e cognitivo, e melhorando a conectividade metabólica. Esses resultados expandem a literatura e fornecem novas evidências funcionais e moleculares fortalecendo os efeitos benéficos atribuídos do IF à saúde geral do cérebro e seus benefícios profiláticos ao TCE.Introduction: Traumatic Brain Injury (TBI) is associated with impaired brain metabolism and metabolic connectivity, culminating in neurodegeneration through several mitochondria –associated mechanisms. Intermittent Fasting (IF) is a recognized dietary approach, which causes brain metabolic reprograming, thereby improving brain metabolism and cognitive function. Objectives: Access the prophylactic potential of a IF strategy in mice to restrain the neuroenergetic and cognitive deficits that follows severe TBI. Methods: C57BL/6J mice underwent ad-libitum diet (ALD) or intermitent (alternating day) fasting protocol during 20 days. After 48-hours, mice were assigned to sham or severe controlled cortical impact (CCI) resulting in three experimental groups: SHAM and CCI (ALD) or IF (previous IF plus CCI). Results: Five days after injury, CCI presented impaired glucose uptake and metabolic conectivity, an effect prevented by IF. Additionally, IF prevented mitochondrial dysfunction, impaired calcium metabolism and mitochondrial membrane potential dynamics induced by CCI. Also, increased CCI-induced mitochondrial H2O2 production was attenuated by IF, culminating in preserved cell viability. These metabolic effects were reflected in CCI-induced impairment in spatial memory, which was prevented by IF. Conclusion: In conclusion, IF modulated several underlying mechanisms associated with injury progression following severe TBI, preventing both metabolic and cognitive impairment. These results expand the literature and provide functional and molecular pieces of evidence strengthening the attributed beneficial effects of IF to overall brain health and its prophylactic benefits to TBI