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Traumatic Brain Injury

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Alicia Meconi

on 7 June 2016

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Transcript of Traumatic Brain Injury

Characterising behaviouiral and neuropathological changes produced by multiple mild traumatic brain injury in juvenile rats
Journal Club Presentation, March 26, 2014
Presented by: Alicia Meconi, MSc Candidate
Supervisor: Dr. Brian Christie
TBI

mTBI
80%
mTBI 1
it appears that i need to type ten words in English in order for prezi to detect language
Experimental Approach: Timeline
Prior mTBI is major risk factor for subsequent mTBI
Characterise tissue damage produced by multiple mTBI in juvenile male and female rats
Objective

Novel Object Recognition Task
Morris Water Maze
Experimental Models for TBI
- transition metals catalyze production of reactive radicals. metallothioneins are among a number of proteins that alleviate reox activity of transition metals; hence, they have an antioxidant role. Metallothionein I and II are not as highly expressed in the developing brain relative to the adult brain, making the immature brain more vulnerable to transition metal-induced oxidative stress. 14 in bayar et al 2006
Activated microglia are enhanced superoxide produccers (25 in bayar et al 2006)
Phol et al 85 have shown that in the developing rat brin excitotoxic cell death peaks at 4h and subsides by 24h, but apoptotic cell death peaks at 24h in more distal areas. - 99
also found that nmda antagonists recovered excitotoxic injury but exacerbated secondary aptototic damage.
this is markedly enhanced in the immature brain

AOx enzymes are different in infants (P25)
Catalayse is about 150% adult
GPXis about 90%

overwhelming ox stress can lead to necrotic or apoptotic cell death
Traumatic Brain Injury (TBI)
Classifying Traumatic Brain Injury
No universal classification system
Can be classified based on
Type of injury
Severity of symptoms
REFERENCES
Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Atlanta: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2004.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974; 81-84
Severe: 3-8
Moderate: 9-12
Mild: 13-15
Traumatic Brain Injury (TBI)
Leading cause of death and disability in individuals under 45
Mild Traumatic Brain Injury (mTBI)
80% of total TBI incidence
100-300/100 000 reported
600/100 000 total
Children:
Highest incidence
Increased risk for persistent symptoms
Weight Drop Model
Weight Drop Model
Behavour - Focus on L & M
Other interesting questions
Neurodegeneration
Evans Blue
Experimental Approach: Behaviour
Neuropathology Underlying mTBI
excitotoxicity
nmda involvement
mitochondria
ox stress
impact -> pathophysiological processes such as (Bla, bla, bla, ox stress, bla) -> ???? -->functional and behavioural deficits
Immmunohistochemistry
Ox Stress
Assault
Confusion
Dizziness
Headache
Nausea
Sleep disturbance
Motor deficits
Irritability


Edema -increased fluid intake into intracellular or extracellular space
Increased ICP will reduce bloodflow into brain and add iscemic damage
Elovic E, Baerga E, Cuccurullo S. Mechanism and Recovery of Head Injury. In: Cuccurullo S, editor. Physical Medicine and Rehabilitation Board Review. New York: Demos Medical Publishing; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK27256/
Score of 3-15 based on:
Eye response
Verbal response
Motor response
(Langlois et al, 2004)
Primary Injury
Direct result of impact
Complex pathophysiological response to
that elicits a change in neurological function
Secondary Injury
Indirect result of impact (12-24h)

Surface contusion/laceration
Skull fracture
Diffuse axonal injury
Diffuse vascular injury
Redox imbalance
Edema/ Swelling
Increased intracranial pressure
Excitotoxicity
Complex pathophysiological response
to a
that elicits
Common Causes
Common Symptoms
Falls
Motor vehicle accidents
Struck by/against object
Memory deficits
Learning deficits
forceful impact or head movement
a change in neurological function
edema is part of inflammatory response
metabolic dysfunction - anabolic and catabolic pathways regulating availablility of important substrates like glucose become dysregulated
mitochondrial dysfunction as well - dysfunctional ETC (due to redox damage and metabolic demand) loss of membrane potential-->loss of pmf--> uncoupling of oxidative phosphorylation

excitotoxicity - mTBI elicits astrogliosis (reactive astrocytes) which is an icnrease in the proliferation of astrocytes
Injury severity depends on
(Elovic et al, 2004)
2 Cassidy, J. D. et al. Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004;36:28-60.
Glasgow Coma Scale
Eye Opening




Verbal Response





Best Motor Response
Spontaneous
To loud voice
To pain
None
Oriented
Disoriented
Inappropriate words
Incomprehensible sounds
None

Obeys
Localizes
Withdraws (flexion)
Exension
None
4
3
2
1
5
4
3
2
1
5
4
3
2
1
Glasgow Coma Scale
(Teasdale, 1974)
Return to Play
1. No Activity, Mental and Physical Rest until symptom free

2. Light Aerobic Activity like walking or stationary cycling

3. Sport Specific Activity like skating or running

5. Training Drills without Body Contact

5. Training Drills with Body Contact – only once cleared by a physician

6. Game Play

Each step in the return to play process must take a minimum of 1 day. If symptoms return during this process, either with activity or later in the day, stop the activity and return to rest until symptoms resolve before trying any activity again. A physician should be consulted if symptoms persist.

PCS

In the USA
1.1 million treated
235, 000 hospitalized
50, 000 die
80, 000 - 90,000 sustain long-term disability
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 Control; 2010.

Wood, Rodger L. "Post concussional syndrome: all in the minds eye!." Journal of Neurology, Neurosurgery & Psychiatry 78.6 (2007): 552-552.
(Faul et al 2010)
Loss of consciousness <30 minutes
Disorientation <24 hours

Usually resolve within 2-14 days (really 7)
(Iverson, 2005)
Treated
Admitted
Death
Long-term disability
Estimated Average Annual Number of Traumatic Brain Injury-Related Emergency Department Visits,
Hospitalizations, and Deaths, United States, 2002–2006
TBI-related ED visits in the USA, 2002-2006
Populations of Interest

Males:
Highest incidence
Females:
Increased risk for persistent symptoms
5 Bazarian JJ, Blyth B, Mookerjee S, He H, McDermott MP. Sex differences in outcome after mild traumatic brain injury. J Neurotrauma.2006

Thameem Dheen, S., Charanjit Kaur, and Eng-Ang Ling. "Microglial activation and its implications in the brain diseases." Current medicinal chemistry 14.11 (2007): 1189-1197.
(faul et al 2010)
(Barlow, 2010)
(Faul et al, 2010)
(Faul et al, 2010)
(Bazarian et al, 2010)
TBI
20%
(Adapted from Faul et al., 2010)
mTBI = mild traumatic brain injury
Mild Traumatic Brain Injury (mTBI)
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 Control; 2010.
Fluid Percussion
Controlled Cortcal Impact
Bregma
Parietal Bone
Injury
Lambda
Disadvantages
Variability due to
Advantages
Non-stereotaxic
Closed-head injury
Minimizes complications
Juvenile rats (postnatal day 25-28)
Experimental: two mTBIs 24 hours apart
Control: two sham surgeries 24 hours apart
Multiple mTBI will produce learning and memory deficits accompanied by neural degeneration and reactive gliosis
Deficits and pathology will differ between males and females
latent axonal damage - injury alters permeability of axonal membrane and disrupts cytoskeletal elements (especially axonal neurofilaments that provide structural support to the axon)- this can cause axonal distortion, impaired axoplasmic transport, and eventually separation of proximal and distal portion.
Disafferentation can occur - where structural changes and occasionally neruonal death occur due to loss of input can follow
In a cat model this has been seen to evolve over 12-24h after injury and is seen in the absence of structural damage to neighbouring supportive/vascular tissue
200g weight
Impactor
Foam platform
Reliably produces mTBI in rodents
Anesthetize subject
Small incision down midline
Position impactor tip on skull
Place gauze pad under impactor
Drop weight 10cm
Close incision
(Reviewed by Albert-Weisenberger and Siren, 2010)
Head hold
Gause pad
mTBI 2
-1d 0 1h 1d 7d
Collect Data
Time points - symptoms
Acknowledgments
Summary of Objectives and Expectations
Objective
Assess changes in learning and memory function following multiple mTBI in juvenile male and female rats
Learning and memory impairments are a common symptom of mTBI
Suggest damage to hippocampus
Spatial and episodic learning
Not directly impacted
Bonus: Motor assessment?
Measure distance and time to platform
Determine swim speed
Hypothesis
Juvenile rats will experience learning and memory deficits at 1h and 1d following multiple mTBI
Time points
1 hour (h)
1 day (d)
7 d
Characterisation of injury
Behaviour
Histology

Dr. Brian Christie
Dr. Bob Chow
Dr. Leigh Anne Swayne
Emily White
Jennifer Graham
Crystal Bostrom
Thank you!
Traumatic Brain Injury (TBI)

Males:
Highest incidence
Females:
Increased risk for persistent symptoms
Complex pathophysiological response
to a forceful impact or head movement that elicits a change in neurological function
forceful impact or
head movement
(Prins et al, 2010)
(Guskiewicz et al, 2003)
Multiple mTBI:
(Baugh et al, 2012)
Hilights need for improved diagnostic tools
Associated with development of neurological disorders
Increased risk for long-term deficits
Increased risk for more severe damage
Populations of Interest
(Faul et al, 2010)
Familiarization Habituation Recognition
Assesses object recognition memory
Hippocampus-dependant
Subject must differentiate novel object from previously encountered object
Spatial learning and memory
Hippocampus-dependent
Subject must recall location of submerged platform
Visually distinctive
surroundings
Pool
Platform

Multiple mTBI will produce inflammation, astrogliosis, and neurodegeneration in male and female juvenile rats
Retrieved from Chen, C. C., Hung, T. H., Wang, Y. H., Lin, C. W., Wang, P. Y., Lee, C. Y., & Chen, S. F. (2012). Wogonin Improves Histological and Functional Outcomes, and Reduces Activation of TLR4/NF-κB Signaling after Experimental Traumatic Brain Injury. PloS one, 7(1), e30294.
Chicago

Significant following moderate-severe mTBI
(Prins et al, 2010)
(Chen et al, 2012)
Assess using Fluoro Jade C
Labels degenerating neurons
Mechanism unknown
May not be associated with single or multiple mTBI
Combine with Fluoro Jade C staining
Glial fibrillary acidic protein (GFAP)
Labels reactive astrocytes
Astrogliosis associated with mTBI
(Schultz et al, 2011)
Ionized calcium adapter molecule 1 (IBA1)
Labels activated microglia
Isaksson, J., Hillered, L., & Olsson, Y. (2001). Cognitive and histopathological outcome after weight-drop brain injury in the rat: influence of systemic administration of monoclonal antibodies to ICAM-1. Acta neuropathologica, 102(3), 246-256.
Chicago

Increased expression following mTBI
(Issakson, 2005)
CNS immune cells
Phagocytose degenerating neruons
Overactivity may have toxic effects
Inflammatory molecules
Pro-oxidant molecules
Activated microglia
(Retrieved from: Liaury et al. Journal of Neuroinflammation 2012 9:56)
(Ren, Z., Iliff, J. J., Yang, L., Yang, J., Chen, X., Chen, M. J., ... & Nedergaard, M. (2013). ‘Hit & Run’model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. Journal of Cerebral Blood Flow & Metabolism, 33(6), 834-845.
Immmunohistochemistry
Reactive Astrocytes
Enlarged
Increased proliferation
Release ATP
Release glutamate
May be protective and detrimental following mTBI
Characterise cognitive and neuropathological changes resulting from multiple mTBI in juvenile male and female rats
Multiple mTBI will produce learning and memory deficits accompanied by neural degeneration and reactive gliosis in male and female juvenile rats
Deficits and pathologies will differ between female and male subjects

Characterise cognitive and neuropathological changes resulting from multiple mTBI in juvenile male and female rats
Hicks, R. R., Smith, D. H., Lowenstein, D. H., MARIE, R. S., & McIntosh, T. K. (1993). Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. Journal of neurotrauma, 10(4), 405-414.
mTBI is associated with cell loss in the hippocampus
(Hicks et al, 1993)
1.4 million annual emergency department visits
15% suffer post-concussive syndrome (PCS)
Deficits persist > 3 months
(Wood, 2007)
Hypothesis
Hypothesis
Objective
Combine with Fluoro Jade C staining
Summary of Objectives
Hypothesis
Full transcript