TRAUMATIC BRAIN INJURY (TBI) MODELS Tamar V. Jeffery, MD Research Fellow I Cerebral Resuscitation Laboratory

TRAUMATIC BRAIN INJURY (TBI) MODELS

Tamar V. Jeffery, MD

Research Fellow I

Cerebral Resuscitation Laboratory

INTRODUCTION• Epidemiology and Impact

• Pathophysiology– Mechanisms of Injury– Phases of Injury– Tissue Level Processes– Cellular Level Processes– Functional Processes

• Experimental Models of TBI

• Summary and Discussion

EPIDEMIOLOGY AND IMPACT• Epidemiology

– Military vs. Civilian

• Mechanisms

• Classification Schemes

EPIDEMIOLOGY AND IMPACT• EPIDEMIOLOGY

– According to the CDC• Approximately 1.5 million in the U.S.

suffer from a TBI annually• 50,000 die from TBI each year• Approximately 200,000 annually require

hospitalization• More than 5.3 million live with

disabilities caused by TBI• 85,000 suffer long term disabilities• Includes admissions to a hospital • Excludes emergency room or office visits


– National Health Interview Survey• Mild TBI 131 cases per 100,000

• Mod TBI 15 cases per 100,000

• Severe TBI 21 cases per 100,000

– Joint Theater Registry/US Army Institute of Surgical Research

• 20-30% of combat casualties (IEDs)

• 44% mild TBI

• 56% mod-severe TBI

EPIDEMIOLOGY AND IMPACT• IMPACT

– Approximately $4 billion plus annually• Potential loss wages• Acute care• Hospitalization• Rehabilitation


– Meaningful recovery is functional (as opposed to tissue) recovery

– Symptoms may be acute or delayed – Decreased incidence in the civilian

population and increasing in the military population (blast injury)

EPIDEMIOLOGY AND IMPACT• MECHANISMS

– MVCs– Falls– Firearms– Work-related– Impact loading– Impulsive loading– Static

EPIDEMIOLOGY AND IMPACT• CLASSIFICATION SCHEMES • MILD

– Loss of consciousness and/or confusion, disorientation < 30 min

– Amnesia to events <1hr– MRI and CAT scans normal– Cognitive problems

• headache, difficulty thinking, memory problems, attention deficits, mood swings and frustration

EPIDEMIOLOGY AND IMPACT• CLASSIFICATION SCHEMES

• MODERATE– Loss of consciousness 1-24 hour– Amnesia to events 1-2 days– Radiologic findings


• SEVERE– Loss of consciousness > 30 min

• Military >24 hr

– Amnesia to events > 24 hrs• Military > 1 wk

– Impairment of higher level cognitive functions – Limited function of extremities, abnormal

speech/language, emotional problems– Variable range of injuries and recovery


– Open Head Injury(penetrating)• Bullet wounds, etc. • Largely focal damage • Effects can be just as serious as closed

brain injury– Closed Head Injury(blunt)

• Falls, motor vehicle crashes, etc• Direct, indirect, rotational, deceleration• Focal and diffuse damage • Effects tend to be broad (diffuse) • Non penetration injury including fracture


• Focal• Hypoxic-ischemic injury

• Cerebral edema

• Intracranial hemorrhage

• Subdural hemorrhage

• Epidural hemorrhage

• Axonal injury

• Contusion

• Laceration

EPIDEMIOLOGY AND IMPACT• Diffuse

• Hypoxic-ischemic damage• Cerebral edema• Axonal injury (DAI)• Vascular injury (DVI)

PATHOPHYSIOLOGY

• PHASES OF TBI– Primary, Primary Evolution, Secondary,

Regeneration

• TISSUE-LEVEL

• CELLULAR-LEVEL

• FUNCTIONAL

PATHOPHYSIOLOGY

• PHASES OF TBI– PRIMARY

• Direct contusion, shearing and stretching, vascular response

• Cessation of blood flow and metabolism• Rupture of cellular and vascular membranes • Release of intracellular contents• Location and magnitude of damage reflect

the characteristics injury• Preventative measures

PATHOPHYSIOLOGY

• PHASES OF TBI– EVOLUTION OF PRIMARY INJURY

• Skull fracture hematoma, hemorrhage, ICP damage to CNs

• Ex: injury temporal region –auditory-vestibular dysfunction

• Initiation of secondary injury

PATHOPHYSIOLOGY

• PHASES OF TBI– SECONDARY INJURY

• Delayed process-hours to days• Progressive deterioration• Interplay between ischemic, inflammatory,

and cytotoxic processes promoting necrosis and apoptosis

• Significantly contributes to post-traumatic neurological disability

PATHOPHYSIOLOGY

• PHASES OF TBI– REGENERATION

• Influenced by primary and secondary injury responses

• Repair events– Phagocytic removal of cellular debris– Glial scar formation– Changes to neuronal networks

PATHOPHYSIOLOGY

• TISSUE-LEVEL PROCESSES– DIRECT TISSUE INJURY

• BRAIN LACERATION• AXONAL INJURY

– HEMMORRHAGE– EDEMA– VASOSPASM– ISCHEMIA

PATHOPHYSIOLOGY

• TISSUE-LEVEL PROCESSES– Chemical / Toxic

• Metabolic disorders • Chemicals damage the neurons • Insecticides, solvents, carbon monoxide

poisoning, lead poisoning

PATHOPHYSIOLOGY

• TISSUE-LEVEL PROCESSES• Hypoxia/Anoxia

• Irreversible injury• Heart attacks, respiratory failure, hypotension

and low oxygen states • Severe cognitive and memory deficits

• Tumors• invading the spaces causing direct damage

• Infections• breach in blood-brain protective system

PATHOPHYSIOLOGY

• CELLULAR LEVEL– Apoptosis and necrotic cell death– Excitatory amino acid neurotransmitters

• Glutamate and aspartate• Glutamate receptor activation

– Influx of Ca 2+ (intracellular and extracellular)– Activation of intracellular proteases

• Calpains, phospholipases, endonucleases

– Free radicals • Superoxides, hydrogen peroxide, hydroxyl radicals,

nitric oxide, peroxynitrite

Zhang et a l. Critical Care 2005 Simplified schematic representation of the initiation and regulation of neuronal apoptosis after traumatic brain injury

PATHOPHYSIOLOGY

• CELLULAR LEVEL• Biochemical Markers of TBI

– Excitatory amino acid neurotransmitters– Ionic influx (Ca 2+, K+, Mg2+)– Free radicals– Intracellular proteases– Glucose metabolism– Endonucleases– Phospholipases– Protein kinases– LDH– MAP-2– Tau protein

PATHOPHYSIOLOGY

• CELLULAR LEVEL• Biochemical Markers of TBI

– Apoptotic and necrosis pathway– Autophagy pathway– Growth factors– Inflammatory pathway

• growth factors • catecholamines• neurokines• cytokines• chemokines

– Genetics

PATHOPHYSIOLOGY

• CELLULAR LEVEL• Ideal Biochemical Marker of TBI

– Easily detectable substances derived from neurons and glia

– Quickly measurable– Measureable in serum– Highly brain specific and sensitive

PATHOPHYSIOLOGY

• CELLULAR LEVEL

• Biochemical Markers of Interest– Neuron Specific Enolase NSE– S100B– Glial Fibrillary Acidic Protein GFAP

PATHOPHYSIOLOGY

• CELLULAR LEVEL• Assay

– Same as ischemic injury

– ELISA

– NeuN

– H&E

– Western Blot

– TUNEL

– High Performance Liquid Chromatography HPLC

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL– Physical– Cognitive– Emotional– Behavioral

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL– Physical

• Movement disorders– Tremor– Ataxia– Myoclonus– Parkinson’s disease

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL– Cognitive

• Coma• Brain death• Persistent vegetative state• Minimally conscious state• Memory loss• Language and communication• Vision, smell, hearing

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL– Emotional and Behavioral

• Impaired attention• Disruption of insight, judgment, and

thought processing• Distractibility• Deficits in abstract reasoning, planning,

problem solving, multitasking• Depression

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL– Post-traumatic seizures

• Increase risk of reoccurrence if within the 1st week post trauma

– Post Concussive Syndrome• Lingering symptoms after mild TBI• Physical, cognitive, behavioral

– Headaches, vertigo, difficulty concentration, depression

PATHOPHYSIOLOGY

• FUNCTIONAL LEVEL• Morris Water Maze• Beam-balance• Roto-rad test• Postural reflex test

EXPERIMENTAL MODELS OF TBI• WHAT MAKES A GOOD MODEL?

• TBI MODELS– WEIGHT DROP– CONTROLLED CORTICAL IMPACT

CCI– FLUID PERCUSSION FPI

• WHAT MODEL IS BEST FOR US?

EXPERIMENTAL MODELS OF TBI• WHAT MAKES A GOOD MODEL?

• 1) Mechanical force to induce injury is controlled, reproducible, and quantifiable

• 2) Inflicted injury is reproducible, quantifiable, and mimics components of human conditions

• 3) Injury outcome measured by morphological, physiological, biochemical, or behavioral parameters, is related to the mechanical force causing the injury

• 4) Intensity of the mechanical force should predict the outcome severity

EXPERIMENTAL MODELS OF TBI• TBI MODELS

– WEIGHT DROP• Variables-weight and height• Biochemical events accompanying

contusion/concussion• Series of weights dropped through a

Plexiglas tube from known heights onto exposed skull of the rat which is protected by a steel helmet


– WEIGHT DROP• Helmet absorbs the impact force and spreads

it evenly over the skull to prevent skull fracture

• The animal rests on a foam cushion which provides a translational acceleration and deceleration component to the injury

• After initial impact, the weight recoils up the injury tube and the foam bed is pushed away to prevent a second impact or mechanism in place to prevent second impact

Marmarou/Weight-Drop Injury/Impact Acceleration Model


– WEIGHT DROP• Advantages

– Inexpensive– Simple – Diffuse injury– Reproduces secondary injury observed

clinically» Edema, contusion


– WEIGHT DROP• Disadvantages

– Potential skull fracture despite helmet– Rebound injury even with cushioning– Severity of injury not well controlled– Velocity of weight biphasic

» Air resistance in tube» Heights <3cm increased velocity» Heights >3cm degree of injury not linearly

proportional to height» Impact and duration of impact not controlled


– Controlled/Closed Cortical Impact (CCI)

• General Motors research lab• Quantifiable parameters in relation to injury

– Force, velocity, depth of impact, magnitude of damage

– Biomechanical events



• Stroke constrained pneumatic impactor• Accurate and reliable due to control of

parameters by operator• Reproduces grades of injury-mostly severe

Controlled Cortical Impact Model



• Advantages– Controllable parameters of injury– Controlled severity of injury– Decreased risk of rebound injury



• Disadvantages– Lack of brain stem deformation– Duration of pressure pulse not controlled


– FLUID PERCUSSION FPI• Quantifiable parameters in relation to injury

– Force, velocity, depth of impact, magnitude of damage, pressure pulse,

• Graded levels of injury associated with predictable neurologic, histologic, and physiologic outcomes comparable to those observed in humans


– FLUID PERCUSSION FPI• Pendulum hammer that hits end of a

plunger within a saline filled tube• Pressure pulse to intact dura through a

craniotomy inducing brief ICP and deformation of cerebral tissue

Fluid Percussion Injury(FPI)


– FLUID PERCUSSION FPI• Advantages

– Behavioral outcomes comparable to humans– Spinal cord injury– Biochemical processes


– FLUID PERCUSSION FPI• Disadvantages

– Air in chamber can decreased the magnitude of pressure

EXPERIMENTAL MODELS OF TBI• OTHER TBI MODELS

– PENETRATING– BLAST INJURY

EXPERIMENTAL MODELS OF TBI• WHAT MODEL IS BEST FOR US?

• Replicate pathological components or phases of clinical trauma aiming to address pathology and/or treatment

• Design and choice should emulate the goal of the research

• Reproducibility• FLUID PERCUSSION MODEL

SUMMARY AND DISCUSSION• Summary

– Common injury, large economical and social impact

– Recognition of the therapeutic window– Progressive cascade of events for

research– The Model of Choice=Fluid Percussion

SUMMARY AND DISCUSSION• The Department of Defense Post-Traumatic Stress

Disorder • Traumatic Brain Injury Research Program of the Office of

Congressionally Directed Medical Research Programs recently

• Awarded the Mission Connect Mild TBI Translational Research Consortium a five year grant totaling approximately $35 million

• Consortium includes teams from The University of Texas Health Science Center at Houston, The University of Texas Medical Branch at Galveston (UTMB), Baylor College of Medicine, Rice University and the Transitional Learning Center in Galveston

SUMMARY AND DISCUSSION• QUESTIONS

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TRAUMATIC BRAIN INJURY (TBI) MODELS Tamar V. Jeffery, MD Research Fellow I Cerebral Resuscitation Laboratory