**Meet the editors**

Dr. Nikolai V. Gorbunov received his PhD degree in Biology from the Russian Academy of Sciences. He received an award from the NRC NAS (http://sites. nationalacademies.org/pga/rap/) and the Department of Energy in pursuing postdoctoral training in translational science at the University of Pittsburgh and the Pacific Northwest National Laboratory (https://www.

emsl.pnl.gov/emslweb, Washington, USA). His translational research area has encompassed (i) molecular pathology of blast-induced polytrauma and countermeasures against brain radiation injury that he explored at the Walter Reed Army Institute of Research (http://wrair-www.army.mil) and the Uniformed Services University of the Health Sciences (https://www. usuhs.edu). In this framework, his interest focuses on the interplay of the etiological factors leading to injury and the mechanisms driving resilience, defense, and morphogenic responses in organelles, cells, and tissues arranging biological barriers. The research objectives are (i) to define the key structural components and pathways, which regulate and sustain intrinsic resistance, recovery, or remodeling of cells and systems following harmful exposures and damage and (ii) to employ the acquired knowledge for further development of new injury-specific treatment models.

Dr. Joseph B. Long is the chief of the Blast-Induced Neurotrauma Branch of the Center for Military Psychiatry and Neuroscience at the Walter Reed Army Institute of Research in Silver Spring, MD. In this capacity, he heads a research team using animal models and biofidelic surrogates to validate and characterize scaled experimental blast exposure conditions and assessments

of outcomes relevant to blast-injured warfighters. Their research targets definition of the biomechanical and neurobiological underpinnings of blast TBI, determination of the contributions of operational, environmental, and psychological stressors and nutritional deficiencies to mTBI severity, and establishment of effective countermeasures to improve return to duty and readiness. He received his BSc degree in Biology from the Bucknell University in 1977 and PhD degree in Pharmacology from the University of North Carolina at Chapel Hill School of Medicine in 1982. Prior to becoming a civilian researcher at the Walter Reed Army Institute of Research, he served 7 years of active duty in the US Army.

Contents

**Preface VII**

Chapter 2 **Head Injury Mechanisms 13**

**Brain Injury 21**

E. Kaloostian

Theus

Mahmood Momeny

Chapter 1 **Introduction: Biomedical Challenges and Socioeconomic Burden 3**

Nikolai V. Gorbunov and Joseph B. Long

**Pathogenesis and Biomarkers 11**

Chapter 3 **Age-Dependent Responses Following Traumatic**

Chapter 4 **Explosive Blast Mild Traumatic Brain Injury 39** John Magnuson and Geoffrey Ling

**Neurorestorative Processes 49**

Chapter 6 **Diffuse Axonal Injury: A Devastating Pathology 85**

**Section 2 Traumatic Head and Brain Injury: Epidemiology, Etiology,**

Esmaeil Fakharian, Saeed Banaee, Hamed Yazdanpanah and

Thomas Brickler, Paul D. Morton, Amanda Hazy and Michelle H.

Chapter 5 **Traumatic Penumbra: Opportunities for Neuroprotective and**

Andrea Regner, Lindolfo da Silva Meirelles and Daniel Simon

Christ Ordookhanian, Katherine Tsai, Sean W. Kaloostian and Paul

**Section 1 Introduction 1**

## Contents



Christ Ordookhanian, Katherine Tsai, Sean W. Kaloostian and Paul E. Kaloostian

Chapter 7 **Role of Fibrinogen in Vascular Cognitive Impairment in Traumatic Brain Injury 105**

Nino Muradashvili, Suresh C. Tyagi and David Lominadze

Preface

assess, and predict the outcomes.

tion of long-term outcomes.

This book is a collective effort of a dozen authors with expertise in neurotrauma, neurovas‐ cular injury, neurobiology, radiological diagnostics, and supportive care. Thus, the compila‐ tion features an up-to-date overview of crucial aspects of etiology, classifications, pathogenesis, clinical managements, and epidemiology of traumatic brain injury (TBI) and emphasizes a crucial role of fundamental research in biology of TBI for development and implementation of new regimens and modalities to cure the TBI-related diseases and resto‐

Trauma to the head with brain injury has emerged as a serious health concern worldwide due to the severity of outcomes and growing socioeconomic impacts of the diseases, e.g., long-term medical care, partial and life disability, and so on. Etiology of TBI is multidimen‐ sional. TBI can result from sharp gear impingement with the head and the resultant pene‐ trating head wound. It can also occur on coupling of an external (applied) mechanical force with the head (e.g., due to body collision, fall, or blast exposure) and subsequent dissipation of the applied energy in the skull or by generation of an inertial force and energetic stress waves in the brain tissue that can produce either open head wound or blunt head wound characterized by coup-contrecoup and shear types of brain injury. The blunt head wound is of particular concern on neurosurgery admission because it is often difficult to diagnose,

TBI affects the human populations of all ages, regardless of social or ethnic background—in urban or rural areas, in sport arenas or war zones, whether a pedestrian or driving in traffic, and hunting or fighting on a battlefield. Thus, the multifactorial etiology and diverse patho‐ physiology create the significant obstacles for unified TBI management. In this respect, early implementation of effective clinical diagnostics is essential for emergency care and mitiga‐

Over the past decade, a great deal of work was done to clarify the pathogenesis and the molecu‐ lar and cellular mechanisms underlying the TBI disease(s). These efforts have promoted the development of advanced diagnostic techniques and new modalities for assessing and manag‐ ing the intracranial hemorrhage, edema, and intracranial pressure; for mitigating the neuroin‐ flammation; and for sustaining the metabolic and circulatory homeostasis. With this effort, particular attention has been paid to the implementation of new procedures for neuronal and vascular regeneration and rehabilitative care. Tremendous progress has also been achieved in the development of contrast-enhanced computed tomography imaging; in in silico modeling and prevention of the injury, as well as in discovery of specific biomarkers of brain trauma; and

in the development of new models for risk analysis and prediction of TBI outcomes.

ration of postinjury neurogenesis, cognitive function, and mental health.


## Preface

Chapter 7 **Role of Fibrinogen in Vascular Cognitive Impairment in**

**Section 3 Traumatic Brain Injury: Advanced Diagnostics, Acute Management and Supportive Care 121**

Chapter 9 **Traumatic Axonal Injury in Patients with Mild Traumatic**

Chapter 10 **Metabolic Responses and Profiling of Bioorganic Phosphates**

Chapter 8 **Perfusion Computed Tomography in Traumatic**

Nino Muradashvili, Suresh C. Tyagi and David Lominadze

Cino Bendinelli, Shannon Cooper, Christian Abel, Andrew Bivard

**and Phosphate Metabolites in Traumatic Brain Injury 155** Noam Naphatali Tal, Tesla Yudhistira, Woo Hyun Lee, Youngsam

Christ Ordookhanian, Meena Nagappan, Dina Elias and Paul E.

Sombat Muengtaweepongsa and Pornchai Yodwisithsak

Ching-Chih Chen, Yu-Chiang Hung and Wen-Long Hu

Chapter 13 **Complementary Traditional Chinese Medicine Therapy for**

**Traumatic Brain Injury 105**

**Brain Injury 123**

**VI** Contents

and Zsolt J. Balogh

**Brain Injury 137** Sung Ho Jang

**Brain Injury 177**

**Brain Injury 197**

Kaloostian

Kim and David G. Churchill

Chapter 11 **Management of Intracranial Pressure in Traumatic**

Chapter 12 **Targeted Temperature Management in Traumatic**

**Traumatic Brain Injury 217**

This book is a collective effort of a dozen authors with expertise in neurotrauma, neurovas‐ cular injury, neurobiology, radiological diagnostics, and supportive care. Thus, the compila‐ tion features an up-to-date overview of crucial aspects of etiology, classifications, pathogenesis, clinical managements, and epidemiology of traumatic brain injury (TBI) and emphasizes a crucial role of fundamental research in biology of TBI for development and implementation of new regimens and modalities to cure the TBI-related diseases and resto‐ ration of postinjury neurogenesis, cognitive function, and mental health.

Trauma to the head with brain injury has emerged as a serious health concern worldwide due to the severity of outcomes and growing socioeconomic impacts of the diseases, e.g., long-term medical care, partial and life disability, and so on. Etiology of TBI is multidimen‐ sional. TBI can result from sharp gear impingement with the head and the resultant pene‐ trating head wound. It can also occur on coupling of an external (applied) mechanical force with the head (e.g., due to body collision, fall, or blast exposure) and subsequent dissipation of the applied energy in the skull or by generation of an inertial force and energetic stress waves in the brain tissue that can produce either open head wound or blunt head wound characterized by coup-contrecoup and shear types of brain injury. The blunt head wound is of particular concern on neurosurgery admission because it is often difficult to diagnose, assess, and predict the outcomes.

TBI affects the human populations of all ages, regardless of social or ethnic background—in urban or rural areas, in sport arenas or war zones, whether a pedestrian or driving in traffic, and hunting or fighting on a battlefield. Thus, the multifactorial etiology and diverse patho‐ physiology create the significant obstacles for unified TBI management. In this respect, early implementation of effective clinical diagnostics is essential for emergency care and mitiga‐ tion of long-term outcomes.

Over the past decade, a great deal of work was done to clarify the pathogenesis and the molecu‐ lar and cellular mechanisms underlying the TBI disease(s). These efforts have promoted the development of advanced diagnostic techniques and new modalities for assessing and manag‐ ing the intracranial hemorrhage, edema, and intracranial pressure; for mitigating the neuroin‐ flammation; and for sustaining the metabolic and circulatory homeostasis. With this effort, particular attention has been paid to the implementation of new procedures for neuronal and vascular regeneration and rehabilitative care. Tremendous progress has also been achieved in the development of contrast-enhanced computed tomography imaging; in in silico modeling and prevention of the injury, as well as in discovery of specific biomarkers of brain trauma; and in the development of new models for risk analysis and prediction of TBI outcomes.

In conjunction with the advances summarized above, scientific reviews and research reports presented in this book are dedicated to recent concepts on postimpact events and mechanisms implicated in TBI pathogenesis such as (i) pathomorphological responses to trauma and trau‐ matic hemorrhage and development of traumatic penumbra; (ii) impairment of blood-brain barrier functions; (iii) cerebral edema and impairment of brain perfusion; (iv) neuro-immune responses and neurovascular inflammation; and (v) alterations in metabolic homeostasis, with a focus on mitigation of traumatic sequelae and development of countermeasures and treatments of neurodegeneration and neurological disorders. Specific features of the book are implemented in (i) diffusion tensor tractography (MRI) for imaging of the neural tracts in mild and severe diffuse traumatic axonal injury and (ii) brain mapping with perfusion CT (i.e., contrast-enhanced CT) for the assessment of size of cerebral contusions, development of penumbra, and autoregulation of intracerebral vascular flow and brain tissue perfusion.

The selected topics encompass personal experience and visions of the chapter contributors and editors as well as a broad analysis of the literature on etiology, pathogenesis, diagnosis, and management of traumatic brain injury.

Giving a wide-angle perspective on biology and clinical management of TBI, we addressed this book to a broad audience of readers from students to practicing clinicians. For reader's conven‐ ience, the book chapters are arranged in two parts: Part I—*Traumatic Head and Brain Injury: Epidemiology, Etiology, Pathogenesis, and Biomarkers* and Part II—*Traumatic Brain Injury: Advance‐ ments in Diagnostic, Clinical Management, and Supportive Care*. Each chapter is supplemented with sufficient lists of references that include sources of the original data and concepts.

> **Nikolai V. Gorbunov** Uniformed Services University of the Health Sciences Bethesda, Maryland, USA

> > **Joseph B. Long** Dpt. of Traumatic Brain Injury The Walter Reed Army Institute, USA

**Introduction**

**Section 1**

**Section 1**

## **Introduction**

In conjunction with the advances summarized above, scientific reviews and research reports presented in this book are dedicated to recent concepts on postimpact events and mechanisms implicated in TBI pathogenesis such as (i) pathomorphological responses to trauma and trau‐ matic hemorrhage and development of traumatic penumbra; (ii) impairment of blood-brain barrier functions; (iii) cerebral edema and impairment of brain perfusion; (iv) neuro-immune responses and neurovascular inflammation; and (v) alterations in metabolic homeostasis, with a focus on mitigation of traumatic sequelae and development of countermeasures and treatments of neurodegeneration and neurological disorders. Specific features of the book are implemented in (i) diffusion tensor tractography (MRI) for imaging of the neural tracts in mild and severe diffuse traumatic axonal injury and (ii) brain mapping with perfusion CT (i.e., contrast-enhanced CT) for the assessment of size of cerebral contusions, development of penumbra, and autoregulation of intracerebral vascular flow and brain tissue perfusion.

The selected topics encompass personal experience and visions of the chapter contributors and editors as well as a broad analysis of the literature on etiology, pathogenesis, diagnosis,

Giving a wide-angle perspective on biology and clinical management of TBI, we addressed this book to a broad audience of readers from students to practicing clinicians. For reader's conven‐ ience, the book chapters are arranged in two parts: Part I—*Traumatic Head and Brain Injury: Epidemiology, Etiology, Pathogenesis, and Biomarkers* and Part II—*Traumatic Brain Injury: Advance‐ ments in Diagnostic, Clinical Management, and Supportive Care*. Each chapter is supplemented

**Nikolai V. Gorbunov**

**Joseph B. Long**

Bethesda, Maryland, USA

Dpt. of Traumatic Brain Injury

The Walter Reed Army Institute, USA

Uniformed Services University of the Health Sciences

with sufficient lists of references that include sources of the original data and concepts.

and management of traumatic brain injury.

VIII Preface

**Chapter 1**

**Provisional chapter**

**Introduction: Biomedical Challenges and**

**Introduction: Biomedical Challenges and** 

DOI: 10.5772/intechopen.75743

Modern socioeconomic developments have generally resulted in a greatly improved quality of life for most, but these advances have been accompanied by the introduction of numerous health challenges arising from new diseases and casualties associated with environmental, industrial, and economical disasters, social and armed military clashes, occupational exposures, daily high-speed traffic accidents, and so on. Among the diseases of growing public and military health concern is traumatic brain injury (TBI), which has been recently recognized as a "silent epidemic" emerging globally at the transition of the twentieth and twenty-

Traumatic brain injury (TBI) can be defined as alteration in brain functions due to head collision with a stationary or a moving object (e.g., a projectile) or upon coupling of an external mechanical force (e.g., g-force, blast shock wave (SW)) with the head [9–12]. The traumatic effects of these insults emerge as either open or closed head wounds yielding penetrating or closed TBI [11–14]. Clinical classification of TBI severity is widely achieved using the *Glasgow Coma Scale* (*GCS*)—a neurological scale designed to tally medical conditions of individuals in the disease sequelae. The severity of TBI can be classified as mild, moderate, severe, as well as vegetative state and brain death—estimated upon clinical presentation of a patient's neurologic signs and symptoms varying from case to case. Translational and clinical observations indicate that many symptoms resolve completely upon recovery, while others, especially

**2. Traumatic brain injury (TBI): definition, assessment and** 

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Socioeconomic Burden**

**Socioeconomic Burden**

http://dx.doi.org/10.5772/intechopen.75743

**1. Introduction**

first centuries [1–8].

**classification**

Nikolai V. Gorbunov and Joseph B. Long

Nikolai V. Gorbunov and Joseph B. Long

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Introduction: Biomedical Challenges and Socioeconomic Burden Introduction: Biomedical Challenges and Socioeconomic Burden**

DOI: 10.5772/intechopen.75743

Nikolai V. Gorbunov and Joseph B. Long Nikolai V. Gorbunov and Joseph B. Long

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75743

**1. Introduction**

Modern socioeconomic developments have generally resulted in a greatly improved quality of life for most, but these advances have been accompanied by the introduction of numerous health challenges arising from new diseases and casualties associated with environmental, industrial, and economical disasters, social and armed military clashes, occupational exposures, daily high-speed traffic accidents, and so on. Among the diseases of growing public and military health concern is traumatic brain injury (TBI), which has been recently recognized as a "silent epidemic" emerging globally at the transition of the twentieth and twentyfirst centuries [1–8].

### **2. Traumatic brain injury (TBI): definition, assessment and classification**

Traumatic brain injury (TBI) can be defined as alteration in brain functions due to head collision with a stationary or a moving object (e.g., a projectile) or upon coupling of an external mechanical force (e.g., g-force, blast shock wave (SW)) with the head [9–12]. The traumatic effects of these insults emerge as either open or closed head wounds yielding penetrating or closed TBI [11–14]. Clinical classification of TBI severity is widely achieved using the *Glasgow Coma Scale* (*GCS*)—a neurological scale designed to tally medical conditions of individuals in the disease sequelae. The severity of TBI can be classified as mild, moderate, severe, as well as vegetative state and brain death—estimated upon clinical presentation of a patient's neurologic signs and symptoms varying from case to case. Translational and clinical observations indicate that many symptoms resolve completely upon recovery, while others, especially

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

those resulting from "secondary injury" due to neurological complications and reactive traumatic responses to "primary trauma," can persist as chronic illnesses resulting in partial or permanent disability [2, 3, 13, 15–18]. Consequently, TBI should not be regarded as a single clinical entity with a defined outcome but rather represents "a spectrum of brain injuries," where each TBI subtype can lead to a distinct clinical condition which requires case-specific medical treatment [3]. From these considerations efficient personalized therapy would need implementation of advanced diagnostic techniques (such as contrast-enhanced computed tomography, diffusion tensor MRI, TBI biomarkers) for assessment of injury and monitoring of recovery (discussed in Chapters 1.5, 2.1, 2.2 of this book).

cerebral air embolism. A combination of DAI, meningitis, brain edema, ischemia, and neurocognitive disorders accompanied by systemic organ system complications are the described

Introduction: Biomedical Challenges and Socioeconomic Burden

http://dx.doi.org/10.5772/intechopen.75743

5

The pathogenesis and recoveries from these varieties of TBI are age- and phenotype-dependent, greatly adding to the complexities and challenges for the development of therapies [29–31]. A recent focus in translational research has been the roles of genetic and epigenetic polymorphism in TBI disease, giving new perspectives on TBI management and identification of potential targets for rehabilitation [30–32]. This translational research has been primarily driven by animal models that have been developed over the past decades to mimic the clinical sequelae of human TBI. As noted earlier, since human TBI is very heterogeneous, no single animal model suffices, and researchers have relied upon the use of distinct yet complementary models to capture the characteristic features of human TBI documented through clinical and postmortem examination. As extensively reviewed [23 34–36], although imperfect, these in vivo and in vitro models together have provided valuable insights into posttraumatic sequelae which can be targeted for therapeutic intervention. Nevertheless, the failure to date to successfully translate a neuroprotective drug through phase 2 and 3 clinical trials highlights the compelling need to improve models to achieve an ecological validity and a greater

features of blast TBI and reflect the multifactorial nature of SW effects [12, 21, 23, 28].

**4. Epidemiology and social impact of TBI-related diseases**

making diagnosis, management, and prognosis extremely difficult.

The epidemiology of TBI is overwhelming worldwide. According to the U.S. Department of Health and Human Services, in the United States, the overall incidence of TBI (either as an isolated injury or in combination with other injuries (i.e., polytrauma)) in 2010 was estimated to be 823.7 per 100,000 population, and the cost for direct TBI medical care in U.S. was estimated at more than \$50 billion per year [4]. A lower TBI rate was reported in Europe (235 per 100,000) in 2006 [5]. It should be noted that the above numbers in U.S. did not account for those persons who received care at the U.S. military or Veterans Affairs hospitals [6]. According to the U.S. Department of Defense report of 2013, the cohort of servicemen diagnosed with a TBI from 2000 through 2011 represented 235,046 persons (or 4.2% of the 5,603,720 who served in the Army, Air Force, Navy, and Marine Corps) (http://dvbic.dcoe.mil/dod-worldwidenumbers-tbi) [7, 11, 33]. Overall, among TBI casualties, almost 100% of persons with severe head injury and over 50% of those with moderate head injury acquire permanent disability and will not return to their premorbid level of function, which creates a major socioeconomic burden [4, 5, 9, 33]. In addition, dramatic psychological changes can occur among the TBI survivors who experience "the invisible injuries" of brain trauma (e.g., posttraumatic stress disorder (PTSD)). These occult injuries are particularly challenging, since the changes occur in the absence of any outward manifestation of injury and alterations in patient appearance,

In the global perspective, the recent continuous expansion of military conflicts in the Middle East, Afghanistan, and North Africa occurs with the implementation of enormous amounts of weaponized conventional explosives which when deployed and detonated inevitably affect

translational value.

#### **3. TBI: Etiology, pathobiology and translational research**

Statistically, the vast majority of TBI is associated with vehicle collisions, damaging assaults, falls, collision/contact sports, and combat operations [4–11, 13]. These events initiate the primary mechanisms of blunt, ballistic, and blast-associated neurotrauma that may or may not be accompanied by skull fracture. Penetrating TBI is readily apparent and generates damage localized along the projectile path through the brain that includes a site of fractured or perforated skull, ruptured meninges, and lesions of the brain tissue [13, 19]. The absence of such conspicuous hallmarks in closed TBI can result in an initial underestimation of injury severity, particularly when a TBI score is "mild" [12]. In situations producing blunt closed TBI, the damaging forces to the head induce an intracranial inertial force due to linear acceleration/deceleration or rotational momentum to the brain, so it collides inside with the skull resulting in focal "coup or contrecoup or rotational shearing injuries" [12, 20, 21]. Moreover, the same external forces to the skull can generate an array of tensor stress forces (e.g., normal and shear, tensile) through the brain tissue that cause cell compression/stretching, disorder axonal trafficking (i.e., axoplasmic transport of mitochondria, synaptic vesicles, proteins, etc., from neuron's body through the axoplasm), and yet shear and fraction neuronal fibers and disrupt the microvasculature and meningeal structures, thus leading to different forms of intracranial hemorrhage [13, 18, 20, 22–28]. The disruption and dismantling of brain circuitry by these mechanical forces are the principal effectors of injury [20, 25]. Primary brain contusions can elicit concussions, diffuse axonal injury (DAI) and encephalopathy, dysregulation of intracranial pressure and the flow of cerebrospinal fluid (CSF), and the impairment of visceral organs and systems complicated by a variety of neurochemical and metabolic effects [12, 20, 21, 26, 27]. From an etiological perspective, the secondary injury factors can feature brain ischemia and hypoxia, hypercapnia, neuroinflammation, impairment of blood-brain barrier, cerebral edema, meningitis, seizures, and so on [12–17, 21, 25].

A devastating form of TBI is produced by shock waves generated by detonation of explosive devices [7, 11, 12]. At the center of the explosion, gaseous products instantaneously expand from a small volume at a very high-pressure state through the surrounding ambient pressure environment. The compressed gases expand outwards at a supersonic speed in a form of air shock wave (SW). When encountering the head, the SW can impart energy to skull bones, dura and arachnoid mater, CSF, and neuronal tissue through which energy is delivered and dissipated via different mechanisms, namely inertia, spalling, shearing, compression, and cerebral air embolism. A combination of DAI, meningitis, brain edema, ischemia, and neurocognitive disorders accompanied by systemic organ system complications are the described features of blast TBI and reflect the multifactorial nature of SW effects [12, 21, 23, 28].

those resulting from "secondary injury" due to neurological complications and reactive traumatic responses to "primary trauma," can persist as chronic illnesses resulting in partial or permanent disability [2, 3, 13, 15–18]. Consequently, TBI should not be regarded as a single clinical entity with a defined outcome but rather represents "a spectrum of brain injuries," where each TBI subtype can lead to a distinct clinical condition which requires case-specific medical treatment [3]. From these considerations efficient personalized therapy would need implementation of advanced diagnostic techniques (such as contrast-enhanced computed tomography, diffusion tensor MRI, TBI biomarkers) for assessment of injury and monitoring

Statistically, the vast majority of TBI is associated with vehicle collisions, damaging assaults, falls, collision/contact sports, and combat operations [4–11, 13]. These events initiate the primary mechanisms of blunt, ballistic, and blast-associated neurotrauma that may or may not be accompanied by skull fracture. Penetrating TBI is readily apparent and generates damage localized along the projectile path through the brain that includes a site of fractured or perforated skull, ruptured meninges, and lesions of the brain tissue [13, 19]. The absence of such conspicuous hallmarks in closed TBI can result in an initial underestimation of injury severity, particularly when a TBI score is "mild" [12]. In situations producing blunt closed TBI, the damaging forces to the head induce an intracranial inertial force due to linear acceleration/deceleration or rotational momentum to the brain, so it collides inside with the skull resulting in focal "coup or contrecoup or rotational shearing injuries" [12, 20, 21]. Moreover, the same external forces to the skull can generate an array of tensor stress forces (e.g., normal and shear, tensile) through the brain tissue that cause cell compression/stretching, disorder axonal trafficking (i.e., axoplasmic transport of mitochondria, synaptic vesicles, proteins, etc., from neuron's body through the axoplasm), and yet shear and fraction neuronal fibers and disrupt the microvasculature and meningeal structures, thus leading to different forms of intracranial hemorrhage [13, 18, 20, 22–28]. The disruption and dismantling of brain circuitry by these mechanical forces are the principal effectors of injury [20, 25]. Primary brain contusions can elicit concussions, diffuse axonal injury (DAI) and encephalopathy, dysregulation of intracranial pressure and the flow of cerebrospinal fluid (CSF), and the impairment of visceral organs and systems complicated by a variety of neurochemical and metabolic effects [12, 20, 21, 26, 27]. From an etiological perspective, the secondary injury factors can feature brain ischemia and hypoxia, hypercapnia, neuroinflammation, impairment of blood-brain barrier,

A devastating form of TBI is produced by shock waves generated by detonation of explosive devices [7, 11, 12]. At the center of the explosion, gaseous products instantaneously expand from a small volume at a very high-pressure state through the surrounding ambient pressure environment. The compressed gases expand outwards at a supersonic speed in a form of air shock wave (SW). When encountering the head, the SW can impart energy to skull bones, dura and arachnoid mater, CSF, and neuronal tissue through which energy is delivered and dissipated via different mechanisms, namely inertia, spalling, shearing, compression, and

of recovery (discussed in Chapters 1.5, 2.1, 2.2 of this book).

4 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

cerebral edema, meningitis, seizures, and so on [12–17, 21, 25].

**3. TBI: Etiology, pathobiology and translational research**

The pathogenesis and recoveries from these varieties of TBI are age- and phenotype-dependent, greatly adding to the complexities and challenges for the development of therapies [29–31]. A recent focus in translational research has been the roles of genetic and epigenetic polymorphism in TBI disease, giving new perspectives on TBI management and identification of potential targets for rehabilitation [30–32]. This translational research has been primarily driven by animal models that have been developed over the past decades to mimic the clinical sequelae of human TBI. As noted earlier, since human TBI is very heterogeneous, no single animal model suffices, and researchers have relied upon the use of distinct yet complementary models to capture the characteristic features of human TBI documented through clinical and postmortem examination. As extensively reviewed [23 34–36], although imperfect, these in vivo and in vitro models together have provided valuable insights into posttraumatic sequelae which can be targeted for therapeutic intervention. Nevertheless, the failure to date to successfully translate a neuroprotective drug through phase 2 and 3 clinical trials highlights the compelling need to improve models to achieve an ecological validity and a greater translational value.

#### **4. Epidemiology and social impact of TBI-related diseases**

The epidemiology of TBI is overwhelming worldwide. According to the U.S. Department of Health and Human Services, in the United States, the overall incidence of TBI (either as an isolated injury or in combination with other injuries (i.e., polytrauma)) in 2010 was estimated to be 823.7 per 100,000 population, and the cost for direct TBI medical care in U.S. was estimated at more than \$50 billion per year [4]. A lower TBI rate was reported in Europe (235 per 100,000) in 2006 [5]. It should be noted that the above numbers in U.S. did not account for those persons who received care at the U.S. military or Veterans Affairs hospitals [6]. According to the U.S. Department of Defense report of 2013, the cohort of servicemen diagnosed with a TBI from 2000 through 2011 represented 235,046 persons (or 4.2% of the 5,603,720 who served in the Army, Air Force, Navy, and Marine Corps) (http://dvbic.dcoe.mil/dod-worldwidenumbers-tbi) [7, 11, 33]. Overall, among TBI casualties, almost 100% of persons with severe head injury and over 50% of those with moderate head injury acquire permanent disability and will not return to their premorbid level of function, which creates a major socioeconomic burden [4, 5, 9, 33]. In addition, dramatic psychological changes can occur among the TBI survivors who experience "the invisible injuries" of brain trauma (e.g., posttraumatic stress disorder (PTSD)). These occult injuries are particularly challenging, since the changes occur in the absence of any outward manifestation of injury and alterations in patient appearance, making diagnosis, management, and prognosis extremely difficult.

In the global perspective, the recent continuous expansion of military conflicts in the Middle East, Afghanistan, and North Africa occurs with the implementation of enormous amounts of weaponized conventional explosives which when deployed and detonated inevitably affect civilian populations in the conflict zones. The bTBI civilian casualties due to these proxy wars are poorly determined [8]. Considering massive migration of civilian populations driven by these disasters to Europe, the bTBI epidemiology in these groups requires a particular attention, since their social care is becoming a burden of host countries.

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Introduction: Biomedical Challenges and Socioeconomic Burden

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[2] Rusnak M. Traumatic brain injury: Giving voice to a silent epidemic. Nature Reviews.

[3] Malpass K. Read all about it! Why TBI is big news. Nature Reviews. Neurology. 2013;**9**(4):

[4] Frieden TR, Houry D, Baldwiin G. Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. Atlanta, GA: Centers for Disease Control and Prevention. National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention; 2015. https://www.cdc.gov/traumaticbraininjury/pdf/

[5] Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, Maas A. Epidemiology of traumatic brain injuries in Europe: A cross-sectional analysis. Lancet Public

[6] Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths 2002-2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and

[7] CDC, NIH, DOD, and VA Leadership Panel. Report to Congress on Traumatic Brain Injury in the United States: Understanding the Public Health Problem among Current and Former Military Personnel. Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the Department of Defense (DOD), and the Department of Veterans Affairs (VA); 2013. https://www.cdc.gov/traumaticbraininjury/

[8] Hagopian A, Flaxman AD, Takaro TK, Esa Al Shatari SA, Rajaratnam J, Becker S, Levin-Rector A, Galway L, Hadi Al-Yasseri BJ, Weiss WM, Murray CJ, Burnham G. Mortality in Iraq associated with the 2003-2011 war and occupation: Findings from a national cluster sample survey by the university collaborative Iraq Mortality Study. PLoS Medicine.

[9] Ainsworth CR, Brown GS. Head Trauma: Background, Epidemiology, Etiology. 2015.

[10] Menon DK, Schwab K, Wright DW, Maas AI. Demographics and Clinical Assessment Working Group of the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health. Position statement: Definition of traumatic brain injury. Archives of Physical Medicine and Reha

Neurology. 2013;**9**(4):186-187. DOI: 10.1038/nrneurol.2013.38

Health. 2016;**1**(2):e76-e83. DOI: 10.1016/S2468-2667(16)30017-2

pdf/report\_to\_congress\_on\_traumatic\_brain\_injury\_2013-a.pdf

2013;**10**(10):e1001533. DOI: 10.1371/journal.pmed.1001533

http://emedicine.medscape.com/article/433855-overview

bilitation. 2010;**91**:1637-1640

179. DOI: 10.1038/nrneurol.2013.55

tbi\_report\_to\_congress\_epi\_and\_rehab-a.pdf

#### **5. Conclusion**

TBI disease remains a continually growing public health concern both domestically and globally and has taken on a heightened urgency with the recent recognition of a growing number of chronic traumatic encephalopathy victims among athletes and Warfighters exposed to repetitive sub-concussive insults [37–39]. Although a daunting problem, considerable progress has been made over the past decade with characterizations of TBI etiology, epidemiology, and advances in definitions of age- and genotype-specific pathobiology/pathophysiology, diagnostics, acute medical-surgical treatments (e.g., prevention of secondary injuries and maintenance of brain physiology), as well as on the development of new modalities for long-term targeted therapy, rehabilitative care, and TBI prevention (see Chapters 1.1–2.5 of this book). Despite significantly reduced TBI mortality rates at surgical emergency and acute treatments, improvements in long-term outcomes remain a great challenge, largely because as noted earlier, the disease does not represent one pathological entity but is rather a syndrome represented by a wide range of lesions that can require different patient-specific therapies in order to sustain neurological and physiological recovery. Further resolution of these problems requires a mutual effort of clinicians/surgeons, biomedical scientists, biotechnologists, pharmacologists, and biomedical engineers.

#### **Disclaimer**

The contents, opinions and assertions contained herein are private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense. The authors report no conflict of interest.

#### **Author details**

Nikolai V. Gorbunov<sup>1</sup> \* and Joseph B. Long<sup>2</sup>

\*Address all correspondence to: gorbunov.nikolaiv@gmail.com

1 Uniformed Services University of the Health Sciences, Bethesda, MD, USA

2 Blast-Induced Neurotrauma Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA

#### **References**

civilian populations in the conflict zones. The bTBI civilian casualties due to these proxy wars are poorly determined [8]. Considering massive migration of civilian populations driven by these disasters to Europe, the bTBI epidemiology in these groups requires a particular atten-

TBI disease remains a continually growing public health concern both domestically and globally and has taken on a heightened urgency with the recent recognition of a growing number of chronic traumatic encephalopathy victims among athletes and Warfighters exposed to repetitive sub-concussive insults [37–39]. Although a daunting problem, considerable progress has been made over the past decade with characterizations of TBI etiology, epidemiology, and advances in definitions of age- and genotype-specific pathobiology/pathophysiology, diagnostics, acute medical-surgical treatments (e.g., prevention of secondary injuries and maintenance of brain physiology), as well as on the development of new modalities for long-term targeted therapy, rehabilitative care, and TBI prevention (see Chapters 1.1–2.5 of this book). Despite significantly reduced TBI mortality rates at surgical emergency and acute treatments, improvements in long-term outcomes remain a great challenge, largely because as noted earlier, the disease does not represent one pathological entity but is rather a syndrome represented by a wide range of lesions that can require different patient-specific therapies in order to sustain neurological and physiological recovery. Further resolution of these problems requires a mutual effort of clinicians/surgeons, biomedical scientists, biotechnologists, pharmacologists, and bio-

The contents, opinions and assertions contained herein are private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the

Department of Defense. The authors report no conflict of interest.

\* and Joseph B. Long<sup>2</sup> \*Address all correspondence to: gorbunov.nikolaiv@gmail.com

1 Uniformed Services University of the Health Sciences, Bethesda, MD, USA

2 Blast-Induced Neurotrauma Branch, Walter Reed Army Institute of Research,

tion, since their social care is becoming a burden of host countries.

6 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

**5. Conclusion**

medical engineers.

**Disclaimer**

**Author details**

Nikolai V. Gorbunov<sup>1</sup>

Silver Spring, MD, USA


[11] Marshall SA, Bell R, Armonda RA, Ling GSF. Traumatic Brain Injury. Chapter 8. In: Lenhart MK, Savitsky E, Eastridge B. Combat Casualty Care: Lessons Learned from OEF and OIF. Fort Detrick, MD: Office of The Surgeon General Borden Institute; 2012. pp. 343-391. http://www.cs.amedd.army.mil/borden/book/ccc/uclafrontmatter.pdf; https://archive.org/stream/CombatCasualtyCare/CCCFull\_djvu.txt

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[23] Sosa MA, De Gasperi R, Paulino AJ, Pricop PE, Shaughness MC, Maudlin-Jeronimo E, Hall AA, Janssen WG, Yuk FJ, Dorr NP, Dickstein DL, McCarron RM, Chavko M, Hof PR, Ahlers ST, Elder GA. Blast overpressure induces shear-related injuries in the brain of rats exposed to a mild traumatic brain injury. Acta Neuropathologica Communications. 2013;**1**(1):51. DOI: 10.1186/2051-5960-1-51

[11] Marshall SA, Bell R, Armonda RA, Ling GSF. Traumatic Brain Injury. Chapter 8. In: Lenhart MK, Savitsky E, Eastridge B. Combat Casualty Care: Lessons Learned from OEF and OIF. Fort Detrick, MD: Office of The Surgeon General Borden Institute; 2012. pp. 343-391. http://www.cs.amedd.army.mil/borden/book/ccc/uclafrontmatter.pdf;

[12] Ling G, Bandak F, Grant G, Armonda R, Ecklund J. Neurotrauma from Explosive Blast. In: Elsayed, Atkins, editors. Explosion and Blast Related Injuries. Amsterdam: Elsevier;

[13] Black KL, Hanks RA, Wood DL, Zafonte RD, Cullen N, Cifu DX, Englander J, Francisco GE. Blunt versus penetrating violent traumatic brain injury: Frequency and factors associated with secondary conditions and complications. The Journal of Head Trauma Reha-

[14] Kazim SF, Shamim MS, Tahir MZ, Enam SA, Waheed S. Management of penetrating brain injury. Journal of Emergencies, Trauma, and Shock. 2011;**4**(3):395-402. DOI: 10.

[15] Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Frontiers in Neurology. 2013;**4**:30.

[16] Webster KM, Sun M, Crack P, O'Brien TJ, Shultz SR, Semple BD. Inflammation in epileptogenesis after traumatic brain injury. Journal of Neuroinflammation. 2017;**14**(1):10.

[17] Bae DH, Choi KS, Yi HJ, Chun HJ, Ko Y, Bak KH. Cerebral infarction after traumatic brain injury: Incidence and risk factors. Korean Journal of Neurotrauma. 2014;**10**(2):

[18] Hegde A, Prasad GL, Kini P. Neurogenic pulmonary oedema complicating traumatic posterior fossa extradural haematoma: Case report and review. Brain Injury. 2017;**31**(1):

[19] Hegde MN. A Coursebook on Aphasia and Other Neurogenic Language Disorders. 3rd

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[21] Chandra N, Sundaramurthy A. Acute pathophysiology of blast injury—From biomechanics to experiments and computations: Implications on head and polytrauma. Chapter 18. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. ISBN-13:

[22] Strich SJ. Shearing of nerve fibres as a cause of brain damage due to head injury. Lancet

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2008. pp. 91-104. ISBN: 978-0-12-369514-7

4103/0974-2700.83871. PMCID: PMC3162712

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[36] Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap? Neuroscience. 2005;**136**(4):971-989. Epub 2005 Oct 20. Review

**Section 2**

**Traumatic Head and Brain Injury: Epidemiology,**

**Etiology, Pathogenesis and Biomarkers**


**Traumatic Head and Brain Injury: Epidemiology, Etiology, Pathogenesis and Biomarkers**

[36] Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap?

[37] Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse

[38] Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA, Kubilus CA, Martin BM, Murphy L, Baugh CM, Montenigro PH, Chaisson CE, Tripodis Y, Kowall NW, Weuve J, McClean MD, Cantu RC, Goldstein LE, Katz DI, Stern RA, Stein TD, McKee AC. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. Journal of the American Medical Association. 2017;**318**(4):360-370.

[39] Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, Fritts NG, Stamm JM, Robbins CA, McHale L, Simkin I, Stein TD, Alvarez VE, Goldstein LE, Budson AE, Kowall NW, Nowinski CJ, Cantu RC, McKee AC. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;**81**(13):1122-1129. DOI: 10.1212/

Neuroscience. 2005;**136**(4):971-989. Epub 2005 Oct 20. Review

10 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

model. Brain. 2018;**141**(2):422-458. DOI: 10.1093/brain/awx350

DOI: 10.1001/jama.2017.8334

WNL.0b013e3182a55f7f. Epub 2013 Aug 21

**Chapter 2**

**Provisional chapter**

**Head Injury Mechanisms**

**Head Injury Mechanisms**

Esmaeil Fakharian, Saeed Banaee,

Esmaeil Fakharian, Saeed Banaee,

http://dx.doi.org/10.5772/intechopen.75454

**Abstract**

nial traumatic lesions.

**1. Introduction**

Hamed Yazdanpanah and Mahmood Momeny

Hamed Yazdanpanah and Mahmood Momeny

DOI: 10.5772/intechopen.75454

Head injury is a major cause of death and disability in young, active population. It may introduce energy through the skin to the deepest structures of the brain. The entered energy may cause direct or primary injury, or result in other, secondary, events to the tissues. These are mechanical loads and are classified as static when the duration of loading is more than 200 ms and dynamic when less than this. The dynamic loads are further classified as impact if the injurious agent has contact with the head or impulsive when the load exerted to other body part/s results in damage to the brain by the change in speed of the head motion. Impact loads can either exert their effect with direct contact to the tissue or may cause inertial loads. The direct contact can cause deformation of the skull or induce energy stress waves to the head and brain. All of these events will result in tissue strain due to compression, tension, or shear. The strain will culminate in injury, which may be a scalp abrasion, laceration, skull fracture, or different kinds of intracra-

**Keywords:** TBI, biomechanics, acceleration, primary events, secondary events

Trauma defined as a physical harm from an external source is probably one of the earliest experiences of the man on the earth. The first evidence of head injury in human was found in Tanzania. It is due to a crocodile bite about 2,000,000–1,800,000 years BC [1]. On the base of Holy Quran and Genesis, the first death is that of Abel happened by a heavy object struck on head by his brother Cain [2]. Along the history these lesions have included all kinds of blunt and penetrating

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Chapter 2 Provisional chapter**

#### **Head Injury Mechanisms Head Injury Mechanisms**

Esmaeil Fakharian, Saeed Banaee, Hamed Yazdanpanah and Mahmood Momeny Esmaeil Fakharian, Saeed Banaee, Hamed Yazdanpanah and Mahmood Momeny

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75454

#### **Abstract**

Head injury is a major cause of death and disability in young, active population. It may introduce energy through the skin to the deepest structures of the brain. The entered energy may cause direct or primary injury, or result in other, secondary, events to the tissues. These are mechanical loads and are classified as static when the duration of loading is more than 200 ms and dynamic when less than this. The dynamic loads are further classified as impact if the injurious agent has contact with the head or impulsive when the load exerted to other body part/s results in damage to the brain by the change in speed of the head motion. Impact loads can either exert their effect with direct contact to the tissue or may cause inertial loads. The direct contact can cause deformation of the skull or induce energy stress waves to the head and brain. All of these events will result in tissue strain due to compression, tension, or shear. The strain will culminate in injury, which may be a scalp abrasion, laceration, skull fracture, or different kinds of intracranial traumatic lesions.

DOI: 10.5772/intechopen.75454

**Keywords:** TBI, biomechanics, acceleration, primary events, secondary events

#### **1. Introduction**

Trauma defined as a physical harm from an external source is probably one of the earliest experiences of the man on the earth. The first evidence of head injury in human was found in Tanzania. It is due to a crocodile bite about 2,000,000–1,800,000 years BC [1]. On the base of Holy Quran and Genesis, the first death is that of Abel happened by a heavy object struck on head by his brother Cain [2]. Along the history these lesions have included all kinds of blunt and penetrating

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

injuries to the head, more commonly in occupational activities such as those reported in Edwin-Smith papyrus in workers of the Egyptian pyramids [1, 3] or conflicts and quarrels as in Goliath and David confrontation or those gladiators managed by Galen [4]. By the development of the human society and increasing speeds particularly in transportation after industrial revolution, new injurious events appeared so that gradually traffic accidents became one of the most important causes of morbidity and mortality in all parts of the world [2].

(as either of acceleration or deceleration) which are known as impulsive loads. Impulsive loading occurs when the head is not directly struck, but set into motion as a result of a force applied to another part of the body [16]. In such instances, usually, there is no direct and gross evidence of injury to head, i.e., the injury is produced by the inertial changes of the head. In the next group, which is known as impact loads, the offending object when strikes the head may result in injury to tissues from the skin level downwardly depending to the surface area, density, size, and speed of object, directly. On the other hand, it may change the speed of the head and cause its acceleration or deceleration. So, there are inertial changes in the head, and

Head Injury Mechanisms

15

http://dx.doi.org/10.5772/intechopen.75454

The inertial loads produced by either impulsions or impactions are exerted by different kinds of acceleration/deceleration. These include translational, rotational, and angular ones, which are defined on the base of the changes on the center of gravity of the skull, the pineal gland. In translation, the changes should be along one of the X, Y, or Z planes. In rotation, the process should be around the axes. These two kinds of acceleration/decelerations are not very common due to the articulation of the skull to the spine; however, the former when happened usually is not associated with severe events, while the latter is highly injurious. The most common kind of event is the angular change, which may be a combination of the abovementioned

The impaction of an object to the head can result in change in the configuration of the tissue, either the skin, bone, or deep structures. If this change is above the elasticity of the tissue, it

the final result may include those produced by the impulsions.

**Figure 1.** A diagram of head injury mechanisms (from Ommaya and Gennarlli [14]).

accelerations.

Management of head injury has significantly changed in the past few decades with better understanding of the mechanisms of load transfer to the tissues and biophysical, biochemical, and physiological consequences which result in many different clinical presentations from a simple scalp laceration to brief periods of loss of consciousness and extending to persistent vegetative state [5–11].

Considering the mechanisms of load transfer to the head, different kinds of traumatic pathologies, including skull fracture; epidural, subdural, intracerebral, and intraventricular hematoma; as well as different kinds of contusion and finally diffuse brain injuries, could be identified and their behavior and injurious effects on the brain and clinical consequences defined [10].

In this chapter, we are going to discuss about different kinds of head trauma, their classification, and some aspects of biomechanics of these events.

#### **2. Head injury biomechanics**

The consequences of trauma as an energy transmitted to the head is dependent on physical characters of the invading substance, including the density of the invading substance, its size, speed, and duration of loading [12].

By the entrance of a damaging energy load or mechanical input to the head, the first delineating factor for the evolving injury will be the duration of the energy loading [13]. This time interval has defined in a range of 50 to 200 ms. Those lasting more than 200 ms are labeled as static loads, and those less than this, and most frequently less than 50 ms, are considered as dynamic loads [14, 15].

The static causes of injury are very rare and are usually seen when the head is entrapped between hard objects, e.g., the ground and the ruined elements of a building in an earthquake. These heavy loads may cause deformation of the skin or bone and their damage (usually a focal injury).

#### **3. Dynamic injuries**

The dynamic causes of injury include a wide variety of mechanisms. The first of these is produced by the transmission of energy to the brain tissue through the changes in speed (as either of acceleration or deceleration) which are known as impulsive loads. Impulsive loading occurs when the head is not directly struck, but set into motion as a result of a force applied to another part of the body [16]. In such instances, usually, there is no direct and gross evidence of injury to head, i.e., the injury is produced by the inertial changes of the head. In the next group, which is known as impact loads, the offending object when strikes the head may result in injury to tissues from the skin level downwardly depending to the surface area, density, size, and speed of object, directly. On the other hand, it may change the speed of the head and cause its acceleration or deceleration. So, there are inertial changes in the head, and the final result may include those produced by the impulsions.

injuries to the head, more commonly in occupational activities such as those reported in Edwin-Smith papyrus in workers of the Egyptian pyramids [1, 3] or conflicts and quarrels as in Goliath and David confrontation or those gladiators managed by Galen [4]. By the development of the human society and increasing speeds particularly in transportation after industrial revolution, new injurious events appeared so that gradually traffic accidents became one of the most impor-

Management of head injury has significantly changed in the past few decades with better understanding of the mechanisms of load transfer to the tissues and biophysical, biochemical, and physiological consequences which result in many different clinical presentations from a simple scalp laceration to brief periods of loss of consciousness and extending to persistent

Considering the mechanisms of load transfer to the head, different kinds of traumatic pathologies, including skull fracture; epidural, subdural, intracerebral, and intraventricular hematoma; as well as different kinds of contusion and finally diffuse brain injuries, could be identified and their behavior and injurious effects on the brain and clinical consequences

In this chapter, we are going to discuss about different kinds of head trauma, their classifica-

The consequences of trauma as an energy transmitted to the head is dependent on physical characters of the invading substance, including the density of the invading substance, its size,

By the entrance of a damaging energy load or mechanical input to the head, the first delineating factor for the evolving injury will be the duration of the energy loading [13]. This time interval has defined in a range of 50 to 200 ms. Those lasting more than 200 ms are labeled as static loads, and those less than this, and most frequently less than 50 ms, are considered as

The static causes of injury are very rare and are usually seen when the head is entrapped between hard objects, e.g., the ground and the ruined elements of a building in an earthquake. These heavy loads may cause deformation of the skin or bone and their damage (usually a

The dynamic causes of injury include a wide variety of mechanisms. The first of these is produced by the transmission of energy to the brain tissue through the changes in speed

tant causes of morbidity and mortality in all parts of the world [2].

14 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

tion, and some aspects of biomechanics of these events.

**2. Head injury biomechanics**

speed, and duration of loading [12].

dynamic loads [14, 15].

**3. Dynamic injuries**

focal injury).

vegetative state [5–11].

defined [10].

The inertial loads produced by either impulsions or impactions are exerted by different kinds of acceleration/deceleration. These include translational, rotational, and angular ones, which are defined on the base of the changes on the center of gravity of the skull, the pineal gland. In translation, the changes should be along one of the X, Y, or Z planes. In rotation, the process should be around the axes. These two kinds of acceleration/decelerations are not very common due to the articulation of the skull to the spine; however, the former when happened usually is not associated with severe events, while the latter is highly injurious. The most common kind of event is the angular change, which may be a combination of the abovementioned accelerations.

The impaction of an object to the head can result in change in the configuration of the tissue, either the skin, bone, or deep structures. If this change is above the elasticity of the tissue, it

**Figure 1.** A diagram of head injury mechanisms (from Ommaya and Gennarlli [14]).

will result in its permanent deformity, laceration of the skin, or fracture in the bone. With the greater loads, the offending agent may cause depression of the bone into the intracranial space, namely, depressed skull fracture and laceration of deeper tissues, i.e., dura, brain, and vessels, causing epidural hematoma (EDH), subdural hematoma (SDH), contusion, and intracerebral hematoma (ICH). In more severe cases, especially when the speed is high and the size of the agent is small, perforation and penetration may also happen, e.g., in gunshot wounds. Instead, the impaction may be associated with the passage of a load of energy through the skull and the brain. This energy load causes deformation of the brain and its friction to the surrounding structures including skull base and dural membranes or distortion of the cerebral fiber tracts around each other and finally contusion of the brain tissue (**Figure 1**) [17, 18].

imbalance due to kidney problems, different kinds of heart disturbances, liver insufficiency,

Head Injury Mechanisms

17

http://dx.doi.org/10.5772/intechopen.75454

Considering the abovementioned components in production of an injury to the head, different kinds of the clinical cases can be identified. It can be started with the injury to the bone. In a static loading, the long duration of the time of the entered load results in change in the normal configuration of the skull. When this is above the elasticity of the bone for toleration of the entering energy which is usually a compression at the entrance point (outer table of the skull) and tension in either just below the load inner table or the periphery of the entered load, it will result in tissue failure as fracture of the skull. The severity of fracture is dependent on the amount of load and timing. If it is not so big and lasts for brief periods, there will be no further damage to the deeper structures, and usually the victim will be conscious with a single line or stellate pattern of fracture. On occasions with a great load, the whole skull is severely broken into fragments and the brain tissue disrupted, so that it may ooze from the lacerated scalp or nose and ear canals. In such instances, the victim is in deep coma with severe impairment of

Skull fracture may result from impaction of the head by an object and its contact resulting in change in configuration of the skull. The consequence of this contact if the surface area of the object is more than five square centimeters may be fracture in the skull. If the surface area is smaller, the object denser with a higher speed, it may penetrate the skull or even perforate it and pass through the brain tissue, as mentioned previously. If the event is in an eloquent region, there may be neurological deficit dependent on the brain function. These are the direct or primary sequel of the injury. There are other events which may appear as a complication of the mentioned events, secondary traumatic effects. Different kinds of intracranial hematomas, including EDH, SDH, ICH, and even intraventricular hematoma (IVH), as well as contusion of the brain tissue (admixture of vascular and brain tissue injury), may result from injury to the vessels in the related places. These lesions may result in mass effect in intracranial space, increase in intracranial pressure, and herniation of the brain. Brain laceration as a primary lesion may predispose the patient to convulsion and epilepsy. Another important complication of this kind of injury is infection of the bone and intracranial content, if the overlying skin is lacerated and prepares access for the microorganisms to the deeper structures. These latter events are other examples of secondary effects, although except EDH, which is always a complication of skull deformation (with or without fracture) and always a secondary phe-

nomenon; all other events may happen as a primary event, as discussed in Section 3.

An important point regarding static and impact contact loads to the head is that they usually cause focal lesions in the brain, and these kinds of lesions are not accompanied by change in level of consciousness, primarily. This can be used as a hallmark for those injuries which are not produced by the inertial loads to the brain. It should be reiterated that changing level of consciousness in the above discussed lesions may happen as a complication of either enlargement of the produced hematoma or contusion or the mass effect produced by other secondary effects of injury like edema around the lesions. However, the mechanism of disturbed consciousness in these lesions, usually, is not injury to the brain as the main source of consciousness, because

and so on, which are not under the scope of this section.

the brain and brain stem function, resulting in death.

#### **4. Tissue strain and tissue injury**

All of these elements, tissue deformation, shock wave, and acceleration/deceleration, will exert energy to the tissue and result in tissue strain as compression, tension, or shear. These may result in injury to the tissues, which in the skull are either neural components, vessels, or bone. It must be reiterated that tissue injury will appear when the load entered to the tissue is above the tolerance and elasticity of the tissue so that the changes appeared on that result in an irreversible event. The tolerance of tissues is dependent on their physical characteristics, the amount of energy, duration of energy loading, and the size of the load, and so it is different for different tissues and even different ages for the same tissue. Most of our experiences in usual daily activity are within the physiological tolerance of our tissues and so are harmless, while more aggressive activities such as some of the professional sports, although still within the range, are at the upper limit of physiologic tolerance and if happened repeatedly will result in gradual or even acute appearance of brain dysfunction. What is happening in different accidents, either vehicles or falling from heights, is above the physical tolerance of the tissues and results in different sequels depending on the involved component.

#### **5. Primary and secondary injuries**

These are the mechanisms involved in the condition known as primary injury [19, 20], i.e., the direct result of the entered energy to the head. They may in themselves result in other consequences with further injurious effects either as complications of the first phenomenon or exaggerating it. These are known as secondary injuries, the most common of which are hypoxia and hypotension. Secondary injury may also involve mitochondrial dysfunction, excitotoxicity, free radical production, activation of injurious intracellular enzymes, and other mechanisms within the injured nervous tissues which may result in further dysfunctions of the system [13, 20]. Some of the secondary events are similar to the primary phenomenon which will be dealt here, soon. There are also tertiary injuries, which are usually later effects of the energy loading of the head resulting in other system dysfunctions such as electrolyte imbalance due to kidney problems, different kinds of heart disturbances, liver insufficiency, and so on, which are not under the scope of this section.

will result in its permanent deformity, laceration of the skin, or fracture in the bone. With the greater loads, the offending agent may cause depression of the bone into the intracranial space, namely, depressed skull fracture and laceration of deeper tissues, i.e., dura, brain, and vessels, causing epidural hematoma (EDH), subdural hematoma (SDH), contusion, and intracerebral hematoma (ICH). In more severe cases, especially when the speed is high and the size of the agent is small, perforation and penetration may also happen, e.g., in gunshot wounds. Instead, the impaction may be associated with the passage of a load of energy through the skull and the brain. This energy load causes deformation of the brain and its friction to the surrounding structures including skull base and dural membranes or distortion of the cerebral fiber tracts around each other and finally contusion of the brain tissue (**Figure 1**) [17, 18].

16 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

All of these elements, tissue deformation, shock wave, and acceleration/deceleration, will exert energy to the tissue and result in tissue strain as compression, tension, or shear. These may result in injury to the tissues, which in the skull are either neural components, vessels, or bone. It must be reiterated that tissue injury will appear when the load entered to the tissue is above the tolerance and elasticity of the tissue so that the changes appeared on that result in an irreversible event. The tolerance of tissues is dependent on their physical characteristics, the amount of energy, duration of energy loading, and the size of the load, and so it is different for different tissues and even different ages for the same tissue. Most of our experiences in usual daily activity are within the physiological tolerance of our tissues and so are harmless, while more aggressive activities such as some of the professional sports, although still within the range, are at the upper limit of physiologic tolerance and if happened repeatedly will result in gradual or even acute appearance of brain dysfunction. What is happening in different accidents, either vehicles or falling from heights, is above the physical tolerance of

the tissues and results in different sequels depending on the involved component.

These are the mechanisms involved in the condition known as primary injury [19, 20], i.e., the direct result of the entered energy to the head. They may in themselves result in other consequences with further injurious effects either as complications of the first phenomenon or exaggerating it. These are known as secondary injuries, the most common of which are hypoxia and hypotension. Secondary injury may also involve mitochondrial dysfunction, excitotoxicity, free radical production, activation of injurious intracellular enzymes, and other mechanisms within the injured nervous tissues which may result in further dysfunctions of the system [13, 20]. Some of the secondary events are similar to the primary phenomenon which will be dealt here, soon. There are also tertiary injuries, which are usually later effects of the energy loading of the head resulting in other system dysfunctions such as electrolyte

**4. Tissue strain and tissue injury**

**5. Primary and secondary injuries**

Considering the abovementioned components in production of an injury to the head, different kinds of the clinical cases can be identified. It can be started with the injury to the bone. In a static loading, the long duration of the time of the entered load results in change in the normal configuration of the skull. When this is above the elasticity of the bone for toleration of the entering energy which is usually a compression at the entrance point (outer table of the skull) and tension in either just below the load inner table or the periphery of the entered load, it will result in tissue failure as fracture of the skull. The severity of fracture is dependent on the amount of load and timing. If it is not so big and lasts for brief periods, there will be no further damage to the deeper structures, and usually the victim will be conscious with a single line or stellate pattern of fracture. On occasions with a great load, the whole skull is severely broken into fragments and the brain tissue disrupted, so that it may ooze from the lacerated scalp or nose and ear canals. In such instances, the victim is in deep coma with severe impairment of the brain and brain stem function, resulting in death.

Skull fracture may result from impaction of the head by an object and its contact resulting in change in configuration of the skull. The consequence of this contact if the surface area of the object is more than five square centimeters may be fracture in the skull. If the surface area is smaller, the object denser with a higher speed, it may penetrate the skull or even perforate it and pass through the brain tissue, as mentioned previously. If the event is in an eloquent region, there may be neurological deficit dependent on the brain function. These are the direct or primary sequel of the injury. There are other events which may appear as a complication of the mentioned events, secondary traumatic effects. Different kinds of intracranial hematomas, including EDH, SDH, ICH, and even intraventricular hematoma (IVH), as well as contusion of the brain tissue (admixture of vascular and brain tissue injury), may result from injury to the vessels in the related places. These lesions may result in mass effect in intracranial space, increase in intracranial pressure, and herniation of the brain. Brain laceration as a primary lesion may predispose the patient to convulsion and epilepsy. Another important complication of this kind of injury is infection of the bone and intracranial content, if the overlying skin is lacerated and prepares access for the microorganisms to the deeper structures. These latter events are other examples of secondary effects, although except EDH, which is always a complication of skull deformation (with or without fracture) and always a secondary phenomenon; all other events may happen as a primary event, as discussed in Section 3.

An important point regarding static and impact contact loads to the head is that they usually cause focal lesions in the brain, and these kinds of lesions are not accompanied by change in level of consciousness, primarily. This can be used as a hallmark for those injuries which are not produced by the inertial loads to the brain. It should be reiterated that changing level of consciousness in the above discussed lesions may happen as a complication of either enlargement of the produced hematoma or contusion or the mass effect produced by other secondary effects of injury like edema around the lesions. However, the mechanism of disturbed consciousness in these lesions, usually, is not injury to the brain as the main source of consciousness, because it is a wholistic function and focal damages cannot produce it, but it is mainly produced by the displacement of the brain tissue from its connecting hiatuses and compression/ischemia of the brain stem sources of the condition. These are well known as cerebral herniations, as another example of secondary injury.

with all of the events in reality. While managing head injury patients, one of these pitfalls is the definition of dynamic and static loadings of the brain on the base of duration of the event which is a small fraction of a second for both. This means that it is always possible to have a spectrum of different mechanisms and lesions due to both of the mechanisms. The algorithm should be used for better prediction, understanding, and explanation of the events on the base

, Hamed Yazdanpanah<sup>1</sup>

1 Department of Neurosurgery, Kashan University of Medical Sciences (KAUMS), Kashan,

[1] Bertullo G.History of traumatic brain injury (TBI). African Journal of Business Management.

[2] Fakharian E. Trauma research and its importance. Archives of Trauma Research. 2012;**1**

[3] Ghannaee Arani M, Fakharian E, Sarbandi F. Ancient legacy of cranial surgery. Archives

[4] Ghannaee Arani M, Fakharian E, Ardjmand A, Mohammadian H, Mohammadzadeh M, Sarbandi F. Ibn Sina's (Avicenna) contributions in the treatment of traumatic injuries.

[5] Cloots RJH, Gervaise HMT, van Dommelen JAW, Geers MGD. Biomechanics of traumatic brain injury: Influences of the morphologic heterogeneities of the cerebral cortex. Annals of Biomedical Engineering. 2008;**36**(7):1203-1215. DOI: 10.1007/s10439-008-9510-3

[6] Gaetz M. The neurophysiology of brain injury. Clinical Neurophysiology. 2004;**115**:4-18

[7] Cloots RJH, van Dommelen JAW, Kleiven S, Geers MGD. Multi-scale mechanics of traumatic brain injury: Predicting axonal strains from head loads. Biomechanics and

[8] Greve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mount Sinai Journal of

Modeling in Mechanobiology. 2013;**12**:137-150. DOI: 10.1007/s10237-012-0387-6

and Mahmood Momeny1

Head Injury Mechanisms

19

http://dx.doi.org/10.5772/intechopen.75454

of detailed clinical evaluation and not as a restrict rule.

\*Address all correspondence to: efakharian@gmail.com

2 Trauma Research Center, KAUMS, Kashan, IR Iran

2015;**3**(7):381-409. DOI: 10.18081/2333-5106/015-07/381-409

of Trauma Research. 2012;**1**(2):72-74. DOI: 10.5812/atr.6556

Medicine. 2009;**76**:97-104. DOI: 10.1002/msj.20104

Trauma Monthly. 2012;**17**(2):301-304. DOI: 10.5812/traumamon.4695

**Author details**

IR Iran

**References**

Esmaeil Fakharian1,2\*, Saeed Banaee1

(1):1-2. DOI: 10.5812/atr.5287

Concussion, diffuse axonal injury (DAI), SDH, ICH, and IVH as primary lesions should be discussed with the mechanism of change in speed of movement of tissues in the head or inertial loads [21]. These can be viewed as a wide spectrum of injuries with very mild cases as brief period of confusion and memory disturbance to short interval of loss of consciousness or concussion [16], to long-standing deep coma or persistent vegetative state (PVS) due to diffuse injury to neurons and axons of the brain or DAI. In normal circumstances, axons are compliant and readily return to their original length after loading. However, with rapid application of tissue strain, such as at the time of head impact, with the anisotropic and complex arrangement, axons behave differently, essentially becoming brittle and vulnerable to injury [22].

In between there are injury to vascular components either in the surface of the brain (SDH), due to the difference in the elasticity and ability of the brain movement and the bridging veins connecting the brain to the venous sinuses placed in the dural layers, or in deeper parts from the cortex and subcortical layers (ICH) to the ventricle (IVH). As was stated previously, the common presentation of all of these events is loss of consciousness (LOC) of the patient from the time of event. The duration of LOC is dependent on the energy load, its effect on the specific parts of the brain, and severity of the injury in the brain.

A key clinical point is that when these lesions are produced by non-inertial loads, as discussed in previous paragraphs, and cause disturbance of level of consciousness due to their secondary effects, appropriate and in time decompression may result in recovery of the consciousness, while in those with inertial loads, decompression may not be followed by recovery of consciousness just after operation or even in longer durations. So, restrict consideration on the clinical course of the patient at the time of admission and focusing on the possible unconsciousness will help the surgeon to predict probable surgical findings and the early post-op outcome.

#### **6. Conclusion**

We suggest that application of the discussed algorithm for assessment of the injured patients may help clinicians for predictions of the sequelae outcomes. If used appropriately it even can be used for clinical evaluation of the injured patients and decision-making for a rational paraclinical study. Although increasing availability of computed tomographic (CT) scanners in most hospitals has supplanted the need for skull X-ray study as one of the primary steps in patients with head injury, however whenever inertial loads are considered as the main mechanism of trauma, even in the absence of CT scanners, the use of skull X-ray will not be helpful for the diagnosis of the probable injuries.

Finally, it must be kept in mind that classifications and delineations are used for better understanding of the events on the base of current knowledge and so may occasionally not comply with all of the events in reality. While managing head injury patients, one of these pitfalls is the definition of dynamic and static loadings of the brain on the base of duration of the event which is a small fraction of a second for both. This means that it is always possible to have a spectrum of different mechanisms and lesions due to both of the mechanisms. The algorithm should be used for better prediction, understanding, and explanation of the events on the base of detailed clinical evaluation and not as a restrict rule.

#### **Author details**

it is a wholistic function and focal damages cannot produce it, but it is mainly produced by the displacement of the brain tissue from its connecting hiatuses and compression/ischemia of the brain stem sources of the condition. These are well known as cerebral herniations, as another

Concussion, diffuse axonal injury (DAI), SDH, ICH, and IVH as primary lesions should be discussed with the mechanism of change in speed of movement of tissues in the head or inertial loads [21]. These can be viewed as a wide spectrum of injuries with very mild cases as brief period of confusion and memory disturbance to short interval of loss of consciousness or concussion [16], to long-standing deep coma or persistent vegetative state (PVS) due to diffuse injury to neurons and axons of the brain or DAI. In normal circumstances, axons are compliant and readily return to their original length after loading. However, with rapid application of tissue strain, such as at the time of head impact, with the anisotropic and complex arrangement, axons behave differently, essentially becoming brittle and vulnerable to injury [22].

In between there are injury to vascular components either in the surface of the brain (SDH), due to the difference in the elasticity and ability of the brain movement and the bridging veins connecting the brain to the venous sinuses placed in the dural layers, or in deeper parts from the cortex and subcortical layers (ICH) to the ventricle (IVH). As was stated previously, the common presentation of all of these events is loss of consciousness (LOC) of the patient from the time of event. The duration of LOC is dependent on the energy load, its effect on the spe-

A key clinical point is that when these lesions are produced by non-inertial loads, as discussed in previous paragraphs, and cause disturbance of level of consciousness due to their secondary effects, appropriate and in time decompression may result in recovery of the consciousness, while in those with inertial loads, decompression may not be followed by recovery of consciousness just after operation or even in longer durations. So, restrict consideration on the clinical course of the patient at the time of admission and focusing on the possible unconsciousness will help the surgeon to predict probable surgical findings and the early post-op outcome.

We suggest that application of the discussed algorithm for assessment of the injured patients may help clinicians for predictions of the sequelae outcomes. If used appropriately it even can be used for clinical evaluation of the injured patients and decision-making for a rational paraclinical study. Although increasing availability of computed tomographic (CT) scanners in most hospitals has supplanted the need for skull X-ray study as one of the primary steps in patients with head injury, however whenever inertial loads are considered as the main mechanism of trauma, even in the absence of CT scanners, the use of skull X-ray will not be

Finally, it must be kept in mind that classifications and delineations are used for better understanding of the events on the base of current knowledge and so may occasionally not comply

cific parts of the brain, and severity of the injury in the brain.

18 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

helpful for the diagnosis of the probable injuries.

example of secondary injury.

**6. Conclusion**

Esmaeil Fakharian1,2\*, Saeed Banaee1 , Hamed Yazdanpanah<sup>1</sup> and Mahmood Momeny1

\*Address all correspondence to: efakharian@gmail.com

1 Department of Neurosurgery, Kashan University of Medical Sciences (KAUMS), Kashan, IR Iran

2 Trauma Research Center, KAUMS, Kashan, IR Iran

#### **References**


[9] Post A et al. The dynamic response characteristics of traumatic brain injury. Accident Analysis and Prevention. 2015;**79**:33-40. DOI: 10.1016/j.aap.2015.03.017

**Chapter 3**

**Provisional chapter**

**Age-Dependent Responses Following Traumatic Brain**

Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several preclinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood-brain barrier (BBB) that exacerbates secondary injuries. A better understanding of age-related mechanism(s) underlying brain injury will aid in establishing more effective treatment strategies aimed at improving restoration and preventing further neuronal loss. This review looks at studies that focus on modeling the adolescent population and highlights the importance of individualized aged therapeutics to TBI. **Keywords:** childhood, juvenile, traumatic brain injury, brain development, functional

**Age-Dependent Responses Following Traumatic Brain** 

DOI: 10.5772/intechopen.71344

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Traumatic brain injury (TBI) is a leading cause of long-term disability among all age groups with the adolescent population having a higher incidence of TBI [1]. Males sustain TBI at a much higher rate compared to females [1], and functional outcomes vary across patient's age and severity of injury [2, 3]. Studies have shown that younger patients are more likely to demonstrate continued improvements, while older patients are more likely to decline [2, 4].

Thomas Brickler, Paul D. Morton, Amanda Hazy and

Thomas Brickler, Paul D. Morton, Amanda Hazy and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71344

outcome, age dependence

**1. Introduction**

**Injury**

**Injury**

Michelle H. Theus

**Abstract**

Michelle H. Theus


**Provisional chapter**

#### **Age-Dependent Responses Following Traumatic Brain Injury Injury**

**Age-Dependent Responses Following Traumatic Brain** 

DOI: 10.5772/intechopen.71344

Thomas Brickler, Paul D. Morton, Amanda Hazy and Michelle H. Theus Michelle H. Theus Additional information is available at the end of the chapter

Thomas Brickler, Paul D. Morton, Amanda Hazy and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71344

#### **Abstract**

[9] Post A et al. The dynamic response characteristics of traumatic brain injury. Accident

[10] Saatman KE et al. Classification of traumatic brain injury for targeted therapies. Journal

[11] Stein SC. Patrick G, Meghan S, Mizra K, Seema SS. 150 years of treating severe traumatic brain injury: A systematic review of progress in mortality. Journal of Neurotrauma.

[12] McLean AJ, Anderson RWG: Biomechanics of closed head injury. In: Reilly P, Bullock R,

[13] Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA. Current concepts: Diffuse axonal injury-associated traumatic brain injury. Archives of Physical Medicine and

[14] Ommaya AK, Gennarelli TA. Cerebral concussion and traumatic unconsciousness. Brain.

[15] Smith DH, Meaney DF, Shull WH. Diffuse axonal injury in head trauma. The Journal of

[16] Poirier MP. Concussions: Assessment, management, and recommendations for return to activity. Clinical Pediatric Emergency Medicine. 2003;**4**:179-185. DOI: 10.1016/S1522-8401

[17] Bayly PV, Cohen TS, Leister EP, Ajo D, Leuthardt EC, GM: Deformation of the human brain induced by mild acceleration. Journal of Neurotrauma. 2005;**22**(8):845-856. DOI:

[18] Feng Y, Abney TM, Okamoto RJ, Pless RB, Genin GM, Bayly PV. Relative brain displacement and deformation during constrained mild frontal head impact. Journal of The

[19] Hawryluk GWJ, Manley GT. Classification of traumatic brain injury: past, present, and future. In: Grafman J, Salazar AM, editors. Handbook of Clinical Neurology. Vol. 127 (3rd series). Traumatic Brain Injury, Part I. Waltham, USA: Elsevier B.V.; 2015. pp. 15-21

[20] Werner C, Engelhard K. Pathophysiology of traumatic brain injury. British Journal of

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1974;**97**:633-654

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Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several preclinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood-brain barrier (BBB) that exacerbates secondary injuries. A better understanding of age-related mechanism(s) underlying brain injury will aid in establishing more effective treatment strategies aimed at improving restoration and preventing further neuronal loss. This review looks at studies that focus on modeling the adolescent population and highlights the importance of individualized aged therapeutics to TBI.

**Keywords:** childhood, juvenile, traumatic brain injury, brain development, functional outcome, age dependence

#### **1. Introduction**

Traumatic brain injury (TBI) is a leading cause of long-term disability among all age groups with the adolescent population having a higher incidence of TBI [1]. Males sustain TBI at a much higher rate compared to females [1], and functional outcomes vary across patient's age and severity of injury [2, 3]. Studies have shown that younger patients are more likely to demonstrate continued improvements, while older patients are more likely to decline [2, 4].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

On the other hand, childhood TBI (<6 years of age) presents poorer recovery of function compared to early adolescent or adolescent-aged patients [5, 6], with severe TBI in early childhood resulting in long-term impairment. Although better neuroplasticity or adaptation to brain injury in children has once been attributed to better recovery, the effect of age on outcome depends upon the function under study and the stage of development at the time of injury. In fact, the effects of childhood TBI may take years to "grow into deficit" as the developing brain hits milestones of maturation [7, 8]. Multiple regression analyses has also identified that age-at-injury onset is a major contributor to post-injury IQ [6]. While there are distinct periods of vulnerability in the developing brain, evidence from animal models also show that metabolic and physiological alterations specific to the juvenile or early adolescent brain may induce acute protection compared to adults [9–11]. These potentially distinct age-related responses are currently understudied and require a more accurate correlation of disease outcome with the maturation stage of the brain. Moreover, both small and large animal models need to be interpreted with caution since developmental milestones are distinct between swine, mice, and rat species as well as across different strains during the postnatal stages of growth. These differences make age comparisons to human infancy, childhood, early adolescence, adolescence, and adulthood challenging. To that end, correlating age-specific TBI outcomes from rodent to human thus requires consideration of key neurobiological maturation events, rather than chronological age, to predict differential responses to TBI which may eventually help guide effective diagnostic and treatment strategies. Here, we will review key events that accompany brain development in both humans and rodents to identify temporal "benchmarks" that may positively or negatively influence age-at-injury outcome. We will also provide an overview of research findings from clinical and preclinical age-related TBI studies.

because it is highly composed of myelin [14], a specialized membrane, densely enriched with

Age-Dependent Responses Following Traumatic Brain Injury

http://dx.doi.org/10.5772/intechopen.71344

23

Human brain development commences during the third week of gestation and continues through adolescence [15]. Within the first year of life, the brain doubles in volume and will grow another 15% over the following year [16]. By the age of 6, the brain will have increased in size by fourfold which is roughly 90% of the size achieved in adulthood [15]. At the beginning of the fetal period of development, the brain is smooth, and later becomes convoluted with folds and ridges. This drastic increase in cortical volume is primarily through an increase in surface area, as opposed to an increase in thickness, which is how the cortex constitutes up to 80% of the total brain mass [17]. Higher-order cognitive function requires precise connections and communication throughout the brain. For example, cortical neurons can form connections with neighboring and distant cells to enable communication and integration of sensory, cognitive, and motor modalities. The corpus callosum is the largest white matter tract in the brain and serves as a major highway of axons connecting the left and right cerebral hemispheres. These axons are wrapped in myelin to foster rapid interhemispheric communication of information. Myelination is a process that begins around the middle of the second trimester, is most appreciably robust up to the second year of life, and continues throughout adolescence, though to a much lesser degree during adulthood [18, 19]. White matter development in the human brain is an asynchronous process, commencing earlier and more rapidly in sensory than motor pathways, and is later highly prominent in the frontal and temporal lobes at 6–8 months of age [19]. The left and right cerebral hemispheres serve different functions and do not develop in a completely symmetric manner [19]. One explanation for such spatial and temporal asymmetries is a hierarchy of connections formed in an experience-dependent order, such that brain regions involved with lower-level processes need to be established earlier in life before higher-order integrative regions are required. For example, the somatosensory cortex—important for tactile information—matures earlier in development than the prefrontal cortex which is involved in higher-level executive functions such as planning [20]. Our knowledge of human brain development has primarily been gathered from noninvasive neuroimaging measurements and their functional correlates to neurological outcomes, in addition to cellular associations with histopathology. It has become increasingly clear that the brain is extremely vulnerable during key developmental epochs. During these sensitive maturation-dependent time windows, childhood TBI may increase the risk of brain dysmaturation and atypical development depending on the severity and location of the injury [21–23]. For example, generalized (frontal/extrafrontal) or extrafrontal lesion severity but not frontal lesion alone was predictive of poor performance in children who sustained a moderate to severe TBI at ages 1–9 years of age [23]. Mechanistic insights into the etiologies of the neurological deficits and age-specific regions of vulnerability are vital to the understanding and treatment of pediatric TBI. However, rodent models of childhood and adolescent TBI in the postnatal growth stage may be difficult to translate into chronological age in humans. A better understanding of the major developmental processes in the brain across species and strains at the time of injury may be more instrumental for interpreting key findings. A few of these

lipids, which can accelerate neuronal communication throughout the brain.

major milestones in neurodevelopment are noted below in **Table 1**.

#### **1.1. Human brain structure and development**

The human brain is a remarkably complex organ which we still do not fully understand. Representing 2% of the entire body weight in adulthood, the brain requires 20% of the body's oxygen supply to accommodate its extreme metabolic demands. Human brain development is a highly dynamic process which can be broken down into orchestrated cellular and molecular epochs. The neocortex is the newest and arguably most sophisticated structure in the human brain and accounts for most of the brain size. By adulthood, the neocortex will have amassed approximately 20 billion neurons each capable of forming an average of 7000 connections with other neurons [12, 13]. The brain is considered to be immune privileged as it is isolated from the bloodstream by the blood-brain barrier (BBB). Cerebral spinal fluid (CSF) flows through the ventricles located in the center of the brain also provides a cushion. The cerebrum is described as having four lobes: frontal, parietal, temporal, and occipital. The frontal lobe is involved in higher-order executive functions such as planning, reasoning, abstract thinking, decision-making, attention, and personality. Gray and white matters represent the two broad components of the brain. Gray matter is heavily populated with neuronal cell bodies which are essential for transmitting/communicating information throughout the brain. White matter accounts for 50% of the human brain volume and is white in appearance because it is highly composed of myelin [14], a specialized membrane, densely enriched with lipids, which can accelerate neuronal communication throughout the brain.

On the other hand, childhood TBI (<6 years of age) presents poorer recovery of function compared to early adolescent or adolescent-aged patients [5, 6], with severe TBI in early childhood resulting in long-term impairment. Although better neuroplasticity or adaptation to brain injury in children has once been attributed to better recovery, the effect of age on outcome depends upon the function under study and the stage of development at the time of injury. In fact, the effects of childhood TBI may take years to "grow into deficit" as the developing brain hits milestones of maturation [7, 8]. Multiple regression analyses has also identified that age-at-injury onset is a major contributor to post-injury IQ [6]. While there are distinct periods of vulnerability in the developing brain, evidence from animal models also show that metabolic and physiological alterations specific to the juvenile or early adolescent brain may induce acute protection compared to adults [9–11]. These potentially distinct age-related responses are currently understudied and require a more accurate correlation of disease outcome with the maturation stage of the brain. Moreover, both small and large animal models need to be interpreted with caution since developmental milestones are distinct between swine, mice, and rat species as well as across different strains during the postnatal stages of growth. These differences make age comparisons to human infancy, childhood, early adolescence, adolescence, and adulthood challenging. To that end, correlating age-specific TBI outcomes from rodent to human thus requires consideration of key neurobiological maturation events, rather than chronological age, to predict differential responses to TBI which may eventually help guide effective diagnostic and treatment strategies. Here, we will review key events that accompany brain development in both humans and rodents to identify temporal "benchmarks" that may positively or negatively influence age-at-injury outcome. We will also provide an overview of research findings from clinical and preclinical

22 Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

The human brain is a remarkably complex organ which we still do not fully understand. Representing 2% of the entire body weight in adulthood, the brain requires 20% of the body's oxygen supply to accommodate its extreme metabolic demands. Human brain development is a highly dynamic process which can be broken down into orchestrated cellular and molecular epochs. The neocortex is the newest and arguably most sophisticated structure in the human brain and accounts for most of the brain size. By adulthood, the neocortex will have amassed approximately 20 billion neurons each capable of forming an average of 7000 connections with other neurons [12, 13]. The brain is considered to be immune privileged as it is isolated from the bloodstream by the blood-brain barrier (BBB). Cerebral spinal fluid (CSF) flows through the ventricles located in the center of the brain also provides a cushion. The cerebrum is described as having four lobes: frontal, parietal, temporal, and occipital. The frontal lobe is involved in higher-order executive functions such as planning, reasoning, abstract thinking, decision-making, attention, and personality. Gray and white matters represent the two broad components of the brain. Gray matter is heavily populated with neuronal cell bodies which are essential for transmitting/communicating information throughout the brain. White matter accounts for 50% of the human brain volume and is white in appearance

age-related TBI studies.

**1.1. Human brain structure and development**

Human brain development commences during the third week of gestation and continues through adolescence [15]. Within the first year of life, the brain doubles in volume and will grow another 15% over the following year [16]. By the age of 6, the brain will have increased in size by fourfold which is roughly 90% of the size achieved in adulthood [15]. At the beginning of the fetal period of development, the brain is smooth, and later becomes convoluted with folds and ridges. This drastic increase in cortical volume is primarily through an increase in surface area, as opposed to an increase in thickness, which is how the cortex constitutes up to 80% of the total brain mass [17]. Higher-order cognitive function requires precise connections and communication throughout the brain. For example, cortical neurons can form connections with neighboring and distant cells to enable communication and integration of sensory, cognitive, and motor modalities. The corpus callosum is the largest white matter tract in the brain and serves as a major highway of axons connecting the left and right cerebral hemispheres. These axons are wrapped in myelin to foster rapid interhemispheric communication of information. Myelination is a process that begins around the middle of the second trimester, is most appreciably robust up to the second year of life, and continues throughout adolescence, though to a much lesser degree during adulthood [18, 19]. White matter development in the human brain is an asynchronous process, commencing earlier and more rapidly in sensory than motor pathways, and is later highly prominent in the frontal and temporal lobes at 6–8 months of age [19]. The left and right cerebral hemispheres serve different functions and do not develop in a completely symmetric manner [19]. One explanation for such spatial and temporal asymmetries is a hierarchy of connections formed in an experience-dependent order, such that brain regions involved with lower-level processes need to be established earlier in life before higher-order integrative regions are required. For example, the somatosensory cortex—important for tactile information—matures earlier in development than the prefrontal cortex which is involved in higher-level executive functions such as planning [20].

Our knowledge of human brain development has primarily been gathered from noninvasive neuroimaging measurements and their functional correlates to neurological outcomes, in addition to cellular associations with histopathology. It has become increasingly clear that the brain is extremely vulnerable during key developmental epochs. During these sensitive maturation-dependent time windows, childhood TBI may increase the risk of brain dysmaturation and atypical development depending on the severity and location of the injury [21–23]. For example, generalized (frontal/extrafrontal) or extrafrontal lesion severity but not frontal lesion alone was predictive of poor performance in children who sustained a moderate to severe TBI at ages 1–9 years of age [23]. Mechanistic insights into the etiologies of the neurological deficits and age-specific regions of vulnerability are vital to the understanding and treatment of pediatric TBI. However, rodent models of childhood and adolescent TBI in the postnatal growth stage may be difficult to translate into chronological age in humans. A better understanding of the major developmental processes in the brain across species and strains at the time of injury may be more instrumental for interpreting key findings. A few of these major milestones in neurodevelopment are noted below in **Table 1**.


Therefore, given the lengthy developmental course of myelination and synaptogenesis, TBI may disrupt the maturation of functions that support higher-order cognitive outcomes later in life [39, 44, 45]. The expression of glutamate receptors NMDA and AMPA greatly changes during development [46, 47]. Typically, there is an imbalance between excitatory and inhibitory neurotransmission in the developing brain, which could heighten the sensitivity of the young brain to glutamatergic excitotoxicity after trauma that may not be amplified in a mature brain [48]. Interestingly, the younger brain has less antioxidant capacity compared to the more matured brain, which during TBI increases the amount of reactive oxygen species (ROS) that could exacerbate the injury in the younger brain [49]. Inflammation also plays a critical role in brain tissue recovery after TBI [50]. In early childhood TBI, microglial cells that have infiltrated the brain may become overactive exacerbating secondary tissue damage [51]. Taken together, improving our understanding of developmentally related differences will be vital for predicting differential, age-specific outcomes and treatment responses to TBI .

Age-Dependent Responses Following Traumatic Brain Injury

http://dx.doi.org/10.5772/intechopen.71344

25

Since the adolescent population sees a disproportionate percentage of hospitalizations and deaths compared to other age groups, this population should have its own outcome category tailoring research findings and treatment outcomes [52]. While adolescents fall between the childhood and adult age groups, how to appropriately treat these patients has been particularly challenging in the hospital setting [53]. Over a 13-year study, Gross and colleagues analyzed the adolescent TBI population (15–17 years of age) treated at pediatric or adult trauma centers. Although this study found no significant differences in outcomes between the centers, it raised an important question regarding how to treat adolescent brain injury, where differences in developmental vulnerability may exist compared to early childhood [53]. While early childhood TBI is associated with deficits in memory [54, 55], attention [56], intellectual functioning [57], and language acquisition [58], few studies have compared the outcomes of adolescent aged or young adults to older adults. A multiple regression model has demonstrated that increased age negatively influences outcome, as measured by the Disability Rating Scale (DRS) [4]. This study found a greater decline in older patients (≥40 years) over 5 years post-TBI but also demonstrated that the greatest amount of improvement in disability in young adults (16–26 years) compared to adults (27–39 years) and aged (≥40 years) patients. The mechanism(s) underlying this age-specific difference may be due, in part, to a reduction in the capacity to recover or decreased synaptic plasticity and cortical volume as we age or yet undetermined protective factors present during the late adolescence. Although TBI incidence has a bimodal age distribution peaking in adolescence and again in the elderly, few agerelated studies have compared acute and chronic effects across the spectrum of age ranges including early childhood, adolescence, adulthood, and elderly. One prospective study of 330 severe TBI patients showed that younger patients (0–19 years of age) had a significantly higher percentage of good outcomes, lower mortality rates, and a reduced incidence of surgical mass lesions compared to adults (20–80 years of age) [11]. Although poorer recovery of function is known to exist in early childhood compared to adolescent-aged TBI patients, it should be noted that the mean age for the abovementioned study was 15–19 years and 39 years, respectively. Taken together, these findings suggest that the greatest vulnerability in age-specific responses lies in early childhood and advanced ages. Interestingly, there may be a narrow time window during which adolescence may confer protection, the mechanism(s) of

which may be fully elucidated using animal models of brain injury, discussed below.

\* Estimates determined across species with www.translatingtime.net, based on Workman et al. [28].

† Estimate based off of neurogenesis completion in rat by postnatal day 15 [8]. F, female; M, male; P, postnatal days; Y, years; M, months; E, embryonic days; na, not applicable.
