Stem Cell Studies in Traumatic Brain Injury

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rates after TBI, there is no effective treatment to improve the neural structural repair and functional recovery of patients. Neural regeneration through neural stem cells, either by stimulating endogenous neural stem cells or by stem cell transplantation, has gained increasing attention as a potential strategy to repair and regenerate the injured brain. This chapter summarizes strategies that have been explored to enhance endogenous neural stem cells-mediated regeneration and recent developments in cell transplantation studies for post-TBI brain repair with varying types of cell sources.

Military-Relevant Rodent Models of Blast-Induced Traumatic Brain Injuries

Explosive weaponry is the main cause of injuries in current military actions and terrorist attacks. Blast injuries and blast-induced neurotrauma (BINT) are caused by blast waves generated during an explosion. In both civilian and military environments, exposure to a blast may cause instant death, injuries with immediate manifestation of symptoms, and latent injuries that are initiated at the time of exposure and may manifest over a period of hours, months, or even years. Chronic health impairments due to blast often remain un- or underdiagnosed and represent significant challenges for treatment and rehabilitation. We need to advance our understanding of the mechanisms of these injuries to develop better preventive, diagnostic and treatment approaches. This could be achieved through research using clinically and militarily relevant and scientifically reliable models. This chapter provides an overview on rodent BINT models and discusses the generalizable and blast-specific factors that every rodent BINT model should fulfill.

The Role of Inflammation in Traumatic Brain Injury

Inflammation occurring following brain trauma represents a significant constituent of complex secondary responses that dictate patients’ outcome. Although a few decades have passed since its discovery, new aspects of this intriguing phenomenon are still being uncovered, ranging from the multiple roles of mediators regulating the inception, progression, and resolution of neuroinflammation, to the development of antiinflammatory therapies. This review provides a summary of the vast research on traumatic brain injury inflammation. The authors describe the fundamental aspects of cytokine and immune cell functions, the orchestrated collaboration of chemokines and leukocytes, the phenotypic distinction of macrophage populations, and the contribution of glial cells. Among the beneficial properties of neuroinflammation, they briefly discuss cytokines’ impact on neurogenesis; the chapter concludes by touching on the implications of antiinflammatory therapies.

Blast Traumatic Brain Injury Mechanisms

Blast traumatic brain injury (bTBI) is a leading cause of head injury in soldiers returning from the battlefield. Primary blast brain injury remains controversial with little evidence to support a primary mechanism of injury. The four main theories described herein include blast wave transmission through skull orifices, direct cranial transmission, thoracic surge, and skull flexure dynamics. It is possible that these mechanisms do not occur exclusively from each other, but rather that several of them lead to primary blast brain injury. Biomechanical investigation with in-vivo, cadaver, and finite element models would greatly increase our understanding of bTBI mechanisms.

Therapeutic Hypothermia and Targeted Temperature Management in the Treatment of Traumatic Brain and Spinal Cord Injury

Traumatic brain and spinal cord injury are devastating conditions that affect thousands of people each year within the United States. Despite significant research efforts, few successful treatments are available, reflecting the highly complex pathophysiology of neurotrauma. Treatment modalities that target multiple injury pathways may be required to provide robust and long-term improvements in functional recovery. The successful use of therapeutic hypothermia in various patient populations has a rich history, either applied selectively to the nervous tissues or administered systemically. Some recent clinical trials in brain and spinal cord injury have reported benefits with therapeutic hypothermia and targeted temperature management, whereas others have not shown dramatic improvements. This field remains controversial in terms of how and when to use temperature-related therapeutic interventions to maximize protection and repair. This chapter summarizes current knowledge on this evolving field and discusses future directions for research and clinical care.

Why Do We Not Have a Drug to Treat Acute Spinal Cord Injury?

More than 100 years ago, Alfred Reginald Allen developed the weight-drop model of graded, reproducible contusion injury to the dorsal spinal cord. Allen also introduced the concept of secondary injury mechanisms, hypothesizing that hemorrhage and elevated intraspinal pressure contribute to the destruction of the spinal cord and functional deficits. Our understanding of the secondary injury cascade has advanced tremendously over the past 100 years, with numerous therapeutic targets identified. Yet we lack an effective drug treatment for acute spinal cord injury. Reasons for the failure to translate promising preclinical findings to successful clinical trials include concerns regarding the quality of preclinical studies, including possible bias and inappropriate statistical analysis; questions regarding the suitability of animal models; and the complexity of secondary mechanisms following spinal cord injury. Perhaps, however, we have overlooked the targets identified by Allen, namely the intraspinal hemorrhage and elevations in intraspinal pressure.

Animal Models of Spinal Cord Injury

The annual incidence of spinal cord injury (SCI) is approximately 17,000 new cases per year, with an estimated 282,000 persons living with SCI in the United States. Animal models of SCI remain instrumental in elucidating pathological mechanisms and in the discovery of novel therapeutic interventions. Indeed, 50% of the most cited SCI research utilizes animal models. Classification of SCI based on pathological features serves as a primary framework for the development of animal models. Additionally, the spinal location of the SCI in the animal model is a critical consideration. Both large and small animal models are critical to advancing discovery.

Bioengineering in Brain Trauma Research

The study of traumatic brain injury (TBI) encompasses research spanning from injury prevention to clinical interventions, all of which have been influenced by bioengineering. Bioengineering uses quantitative analyses and problem-solving skills to approach the complexity of many areas of neurotrauma research including injury biomechanics, imaging, biomarkers, and data analytics. This chapter presents basic bioengineering concepts, highlights significant contributions to neurotrauma research, and discusses opportunities in the field that may lend themselves to bioengineering solutions. The intention of the author is to promote an appreciation of engineering and to catalyze problem-solving among readers, engineers and non-engineers alike.

The Link Between Traumatic Brain Injury and Neurodegenerative Diseases

Traumatic brain injury (TBI) is a physical impact to the head usually in the form of a single or repetitive closed head injury. TBI is classified as mild, moderate, and severe based on neurological assessment which may include neuroimaging. TBI is a heterogeneous injury, with most cases being mild and difficult to diagnose. TBI can be separated into a primary injury and secondary injury. Primary injury is a result of the physical head impact, whereas secondary injury can occur as long as months to years later and is the result of pathophysiological changes in the central nervous system. TBI is considered a risk factor for chronic neurodegenerative diseases (Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, chronic traumatic encephalopathy) in spite of each disease having unique clinical symptoms, pathologies, and specific discriminating proteins. To date, little is known about the pathological changes responsible for linking TBI to neurodegenerative diseases.

Return to Play, School, or Work After Concussion

Improvements have been made in the management of concussions, and this includes the methods for advising concussed patients about the processes to be followed for return to play (RTP) in sports, return to learn (RTL) in schools, and return to work (RTW) on the job. The aim of management is to facilitate return by a graduated process of steps during which an individual’s thresholds for exacerbation of symptoms are used as a guide, with advice given not to exceed these thresholds. There are no available objective biomarkers to guide these processes and so advice and monitoring are based on clinical findings.