Transcript TBI Models

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
EPIDEMIOLOGY AND
IMPACT
• EPIDEMIOLOGY
– 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
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Potential loss wages
Acute care
Hospitalization
Rehabilitation
EPIDEMIOLOGY AND
IMPACT
• EPIDEMIOLOGY
– 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
EPIDEMIOLOGY AND
IMPACT
• CLASSIFICATION SCHEMES
• 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
EPIDEMIOLOGY AND
IMPACT
• CLASSIFICATION SCHEMES
– Open Head Injury(penetrating)
• Bullet wounds, etc.
• Largely focal damage
• Effects can be just as serious as closed
brain injury
– Closed Head Injury(blunt)
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Falls, motor vehicle crashes, etc
Direct, indirect, rotational, deceleration
Focal and diffuse damage
Effects tend to be broad (diffuse)
Non penetration injury including fracture
EPIDEMIOLOGY AND
IMPACT
• CLASSIFICATION SCHEMES
• Focal
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Hypoxic-ischemic injury
Cerebral edema
Intracranial hemorrhage
Subdural hemorrhage
Epidural hemorrhage
Axonal injury
Contusion
Laceration
EPIDEMIOLOGY AND
IMPACT
• Diffuse
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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 –auditoryvestibular 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
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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
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Apoptotic and necrosis pathway
Autophagy pathway
Growth factors
Inflammatory pathway
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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
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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
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Tremor
Ataxia
Myoclonus
Parkinson’s disease
PATHOPHYSIOLOGY
• FUNCTIONAL LEVEL
– Cognitive
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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
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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
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– 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
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– WEIGHT DROP
• Advantages
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Inexpensive
Simple
Diffuse injury
Reproduces secondary injury observed
clinically
» Edema, contusion
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– WEIGHT DROP
• Disadvantages
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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
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– 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
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– Controlled/Closed Cortical Impact
(CCI)
• Stroke constrained pneumatic impactor
• Accurate and reliable due to control of
parameters by operator
• Reproduces grades of injury-mostly severe
Controlled Cortical
Impact Model
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– Controlled/Closed Cortical Impact
(CCI)
• Advantages
– Controllable parameters of injury
– Controlled severity of injury
– Decreased risk of rebound injury
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– Controlled/Closed Cortical Impact
(CCI)
• Disadvantages
– Lack of brain stem deformation
– Duration of pressure pulse not controlled
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– 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
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– 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)
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– FLUID PERCUSSION FPI
• Advantages
– Behavioral outcomes comparable to humans
– Spinal cord injury
– Biochemical processes
EXPERIMENTAL
MODELS OF TBI
• TBI MODELS
– 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