Glial responses to TBI
 Gliosis (change in glial cells) common after
injury - esp. astrocytes form glial scar that reestablishes physical and chemical integrity of
CNS.
 Whereas adult neurogenesis is focal/limited,
glial responses widespread/robust.
 Astrocytes react to TBI, with response graded
by injury severity. Both beneficial and
detrimental consequences
 Glial response detrimental: numerous studies
(e.g. Rodgers et al., 2013) find that antiinflammatory (that reduce glial response) help
recovery.
 Glial response beneficial: Myer (2006) in mice
with moderate TBI, selective ablation of the
reactive astrocytes increased neuronal
degeneration by 60%
Astrocytes react to injury
Ren et al. (2013)
Concussions and permanent injury
 Some suggest the mildest TBIs cause no permanent injury:
– American Association of Neurological Surgeons: “experts emphasize
that although some concussions are less serious than others, there
is no such thing as a ‘minor concussion’. In most cases, a single
concussion should not cause permanent damage”
– On the other hand, even if symptoms typically ~7 days, unclear if
there is not subtle permanent injury.
 If no lasting injury, what is the mechanism for transient
cognitive dysfunction?
– Can this explain vulnerability for 2nd injury?
– Popular models suggest all TBIs cause chemical
cascade, this can either resolve or lead to permanent 2nd
injury.
Lifestyle: Football and dementia
 Savica et al. (2012) no
significant difference
between high school
football (‘46-’56) and band
Football
(438)
Lehman et al. (2012)
3439 NFL players from
‘59-’88. AD/ALS x4
expected, esp. Speed.
Band
(140)
Speed
(173)
NonSpeed
(152)
Dementia 3.0%
1.4%
Dementia 3.4%
0.6%
Parkinson's 2.3%
3.6%
Parkinson's 3.4%
0.6%
ALS
0.7%
ALS
0.6%
0.5%
1.1%
Vanacore (2013): not necessarily due to TBI: perhaps intense physical activity, use of drugs, exposure to neurotoxins
Biochemical changes in TBI
Concussion (mTBI) lead to behavioral changes
that typically resolve ~7 days (discussed last
week)
Understanding mechanism is important
– Biomarkers for return to play
– Are all concussions permanent TBI, or are some
simply transient biochemical imbalances?
– Might help treatment (prevent 2nd injury)
Neuron Chemistry
 Neurons firing via electro-chemical signals. Requires energy
gradient to work.
 Potassium/Sodium pumps expel two sodium and intake two
calcium ions.
 Net result, neuron rests at -70mV
 70% of the energy is used to maintain the Na+, K+
membrane potentials.
 Pumps work continuously to keep gradients, firing causes
rapid, large brief expense of energy.
 When cell fires:
 sodium channels briefly open: sodium rushes in:
neuron briefly has positive voltage (+30mV)
 next, potassium channels briefly open, potassium
rushes out, voltage restored
 Refractory period
 Absolute: Neuron can not re-fire while sodium channels
open
 Relative: Low sensitivity while potassium channels
open
K+
K+
Na+
Na+
Na+
Cellular Respiration

Fueling neurons (can not use free fatty acids)

Create pyruvate
–
Anaerobic Glycolysis (Primary)
 Convert glucose to pyruvate and 2 ATP
 Occurs in Cytoplasm
–

Ketone bodies (starvation, worst-case)
Use Pyruvate
–
Aerobic (‘Conversion’, sustained, primary):
 Where: Mitochondria
 Efficient (36 ATP)
 Requires: O2
 Waste: CO2, free radicals (specifically, reactive oxygen species
[ROS])
 Anti-oxidant enzymes to counteract free radicals
–
Anaerobic (‘Fermentation’, burst, backup)
 Where: Cytoplasm
 Inefficient (2 ATP)
 Waste: Lactic Acid (marker for fermentation)
Metabolism
 Human Brain about 2% of body weight, 20% of energy.
– Brain: glucose is principal fuel, ketone is emergency backup.
– Rest of body: glucose or fatty acids.
– Humans have relatively large brain/body (high energy demands) with
large energy reserves (fat).
– Other animals: ~5% energy at rest
 When fasting (or extremely low carb diet):
– <0.25 days: glycogen reserves
– 0.25..3 days: fat converted to free fatty acids and glucose
– >3 days: liver converts fatty acids to ketones (@4 days, 70% of brain
metabolism is from ketones). Even so, not enough glucose comes
from fat breakdown, so additional glucose must come from
breakdown of proteins (e.g. muscle).
– Other mammals: Fat breakdown typically provides sufficient amount
of glucose. No need to produce ketones or break down proteins.
– Ketogenic diet controls pediatric epilepsy, potentially because calorie
restriction, fewer free radicals, acidic (blocks ion channels), less
glucose, more inhibitory GABA.
Understanding 2nd Injury
 Barone & Feuerstein (1999) [for ischemic stroke]
Necrosis: cell death - contusion and border, hippocampus
Apoptosis: cell suicide - not due to membrane failure, glutamate
mediated, minimal immune response
Neurometabolic Cascade
 Giza & Hovda (2001) Sequence of
biochemical changes after TBI.
– Initial (minutes)
K+ increase
Glutamate release
Lactate increase
– Sustained (days)
Blood flow (CBF) decrease
Ca+ increase
– Biphasic
cerebral metabolic rate (CMR)
of glucose initially increased,
then decreased
Why is glucose usage reduced?
Clear evidence TBI leads to chemical changes
Mechanism debated. Two (not mutually
exclusive) options:
– Decreased need for glucose metabolism. E.G.
Pappius (1995) suggest noradrenergic and
serotonergic reductions.
However, these effects appear short lived (hours),
whereas CBF disturbed for days.
– Metabolic dysfunction, e.g. Giza & Hovda’s
neurometabolic cascade
Neurometabolic Cascade
 Giza & Hovda (2001) Model to explain
sequence of Neurometabolic Cascade.
– Initial injury: membranes injured,
glutamate and K+ leak into extracellular
space.
– Ionic pumps work overtime K+,
exhausting ATP.
– Glutamate causes influx of calcium.
– Glucose uptake initially increases, but
Calcium overload makes aerobic
conversion inefficient.
– Claim: mTBI is primarily cellular
dysfunction and little cell death, where in
more severe TBI calcium leads to
apoptosis.
Neurometabolic Cascade
 Giza & Hovda (2001); Barkhoudarian,
Hovda, Giza. (2011)
1. Cell membrane deformed/leaky: Glutamate
released, Ca+ influx
2. Glutamate activates post-synaptic NMDA,
Releasing K+, Intake Ca+
3. Ionic pumps attempt to restore gradient
(pump in K+, pump out Na+). This requires
ATP
4. ~30 minutes: Hyperglycosis to create ATP
5. ATP demands lead to Lactate accumulation
and Ca+ influx of mitochondria.
6. 30min-5days, mitochondria function
inefficient: decreased glucose metabolism
(50%) decreased aerobic activity, increased
free radicals.
Neurometabolic Cascade
 Barkhoudarian et al. (2011)
– hyperglycolysis and oxidative dysfunction ~30 min post injury.
 Anaerobic glycolysis is the transformation of glucose to
pyruvate when limited amounts of oxygen (O2) are
available
Inefficient anaerobic function designed for short bursts limited reserves.
– ~6hrs post injury: glucose hypometabolism (approximately
50%). Lasts ~5days (mild) ~months (severe)
– Tissue vulnerable to subsequent injury during this period
– In mild cases cells eventually return to normal function, in
severe cases apoptosis.
Human evidence for metabolic cascade
 Vespa et al. (2005) Often small
primary injury includes widespread
dysfunction as observed by decreased
oxidative metabolism (CMRO2) and
altered glucose metabolism.
 Little Post-traumatic ischemia
 Ongoing metabolic crisis (elevated
lactate/pyruvate ratio, LPR)
 Found LPR (anaerobic) negatively
correlated with CMRO2 (aerobic)
Human evidence
– Stein et al. (2012) evaluated 72 individuals with
controlled ICP during initial 72h of severe TBI.
76% Low glucose
93% elevated lactate/pyruvate ratio (LPR) >25
• Lactate produced by pyruvate only under anaerobic conditions
74% metabolic crisis (both low glucose and high LPR)
Metabolic crisis predicted poor 6 month outcome
Cascade Implications
 Cascade model suggests glucose conversion
transiently disrupted.
 Switching to ketones when glucose use is disrupted
may be beneficial.
 Recent studies suggest ketone neuroprotective
(Prins, 2008) and post-injury (Prins et al., 2005;
Deng-Bryant et al., 2011) in younger rats.
 Perhaps fasting/ketogenic diet useful for mTBI
Cascade Summary
 Barkhoudarian et al. (2011) Implications
– Return to play: "concussion-induced pathophysiologic
conditions, as manifested by metabolic perturbations,
altered blood flow, axonal injury, and abnormal neural
activation, reduce cerebral performance and make the
brain more susceptible to cellular injury”
– Appears to suggest that some mTBI may be transient
biochemical imbalance rather than permanent injury.
Vulnerable window
 Prins et al. (2013) Glucose
metabolism altered in rats for
~7 days (differs with age and
injury).
 2nd injury in this timeframe
will have severe
consequences
 Why? Perhaps poor auto
regulation since CBF and
metabolism uncoupled.
Evidence for vulnerable period
 Humans: initially vulnerable to
2nd TBI
– Is this biochemical or psychological
(poor awareness)?
 Recent animal studies suggest
~7day window of vulnerability for
2nd injury.
– Mice: Longhi et al (2005)
– Rats: Vagnozzi et al. (2007)
Tavazzi et al. (2007)
– This data proves biochemical
involvement
Axon disconnection
 Park et al. (2008): In addition to damage to gray matter, specific
secondary effects influence axonal disconnection
1. Impaired microcirculation due to stenosis and
2. astrocyte foot swelling
3. Proliferation of glial cells
4. Excess glutamate
5. Calcium Influx
6. Excitotoxicity
7. Ca accumulation
8. Disconnection
Pause
Break
Predictors of TBI prognosis
 Considerations
– Severity/Mechanism
– Pre-injury function
– Age
– Health
– Gender
– Genetics (APoE e4)
 Resources
– http://mitbitraining.org
– http://www.nctbitraining.org/main.aspx
TBI Classification
Mechanism
– Closed vs. Open
Open: Penetrating vs. Perforating
Pathology
– General: Primary vs. Secondary Injury
– Blast: Primary : Secondary : Tertiary : Quaternary
Morphology
– Focal vs. Diffuse
Severity
– Mild vs. Moderate vs. Severe
Causes of TBI
Civilian TBI causes varies with age
Initial severity and outcome
 Dikmen et al. (1995) Relative to general trauma
controls, TBI associated with poor cognitive
performance
– In particular: attention, memory, processing
speed
– At 1 year post injury, those with less than 1
hr TFC performed similar to controls, 1-24hrs
impaired in attention and memory, longer
had more global impairments.
 Zatick et al. (2011) also showed worse injuries
associated with worse outcome and better
recovery for milder deficits.
 Roozenbeek (2012): 39274 patients: age, GCS
motor score, and pupillary reactivity strongly
predict 6mos outcome.
Predictors of good outcome
 More education is correlated with good prognosis
(Kreutzer et al., 1993) and premorbid cognitive
function (Hanks et al., 1999).
– Perhaps due to cognitive reserve (Satz et al., 1993; Stern et
al., 2006)
 Generally, severe symptoms predict poor outcome
– Low GCS, long PTA and LOC, brain imaging findings, dural
penetration, pupillary abnormalities, hypoxia, systemic
complications
– Acute neuropsychological results is a better predictor than
neurological severity (Hanks et al., 2008)
Recovery from mild TBI
Numerous studies suggest mild TBI typically
resolves <3 months without treatment (Dikmen
et al., 1986; Dikmen et al., 2001; Levin et al.,
1987; Barth et al., 1989; Macciocchi et al.,
1996; McCrea et al. 2003)
– 90% spontaneous recovery
– 10% persistent symptoms, include dizziness,
headaches, pain, fatigue, depression, return to
work. If complicated mTBI, ‘post concussive
syndrome’.
Recovery from Moderate/Severe TBI
 Millis et al. (2001) tracked 182 individuals 5 years post injury
– 22% improved, 63% unchanged, 15% declined
– Improvement in processing speed, visuoconstruction, verbal memory
 Dikmen et al. (1995) 1yr post injury, more severe TBI were 25
percentile points lower than trauma controls.
 Salmond et al. (2005) more severe TBI impaired in attention,
verbal learning & reaction time, but spared spatial working
memory.
 Not all cognitive deficits are organic: medication, depression
and premorbid factors contribute.
Gender
 TBI more frequent in men then women
 Iverson et al. (2011) study of 11951 men and 654 women with
TBI from Afghanistan/Iraq
– PTSD most common, women relatively less
– Depression common, women x2 more
– Anxiety disorders, women x1.3 more
– Type of TBI (e.g. blast) might explain some of these
differences
Genetics
 APoE 4 associated with Alzheimers Disease (independent of
TBI).
 APoE 4 and recurrent TBI have cognitive and dementia risks
(see sports literature: Jordan et al., 1997; Kutner et al., 2000).
 Impact on single TBI remains controversial
– Teasdale (2005). Large study (1094 patients, 513 with
mTBI) showed no difference at 6 mos. However, potential
interaction such that pediatric TBI with APoE 4 had worse
outcome
Pediatric TBI
 Giza (2006) review notes differences
– Pediatric skull thinner, more pliable
– Larger head relative to body, less developed neck muscles
– Different causes (pediatric falls)
– Higher blood flow, higher metabolism
– Higher incidence of post traumatic epilepsy
– Interfere with developmental potential
– Calcium influx more diffuse in children (see cascade slides)
– Young brain more vulnerable to excitotoxic injury
 Treatment: education of caregivers (parents,
teachers); continuous assessment (skills may
not have yet developed).
Elderly TBI
 Roe et al. (2013) examined severe Norwegian TBI in adults vs
elderly.
– Elderly more likely to have suffered falls
– Hematoma more common
Dura sticks to skull, anticoagulants common
– 25% of adults and 66% of elderly died within 3 mos.
– Adults more likely to be inpatients and go to rehab units.
– No difference in functional outcome at 3 mos.
Clinically: Work rehab not as important, since
there is less recovery, educate caregivers.
Pause
Break
Military Traumatic Brain Injury
– Brain related problems major issue for military
Incidence and Financial Costs
Reasons for high incidence
Blast Induced Neuro Trauma
Gunshot wounds
– Resources
http://www.dvbic.org/resources
http://www.gvsu.edu/veteranstbi/ ($)
War related injuries
 In Vietnam, wounded: killed was 2.6:1
 In Iraq/Afghanistan the ratio is 16:1
– Radically improved acute care
Embedded medics
New training and medical equipment
• decompressive craniotomy common for evacuation (ICP)
New body armor
Different type of injury (in Iraq/Afghanistan, typically blast)
Low rate of injury means ability to provide maximal acute
care (e.g. no triage)
– Clear long-term obligations for care
US Health Care Costs
US spends disproportionate
amount on health care.
Yet, 48m US citizens do not
have health care
Rising cost of military medicine
 DoD health care costs rose from $19bn in 2001 to $49.4bn in 2014.
 VA 2014 Budget rose from $48.7bn in 2001 to $152.7 billion in 2014
VA Budget
Mental Disorders in US Military
Mental disorders
largest and fastest
growing military
hospitalization
Not only TBI: 20%
from Iraq/Afghanistan
report
PTSD/depression.
Military TBI
Higher incidence (better awareness?)
Incidence by severity
Increase appears to be in mild TBI
– Better identification?
– Are ‘mild’ blast TBIs
similar to other
mild TBIs?
Military TBI
 approximately 80% of service members TBIs occur in a nondeployed setting.
 Common causes of TBI include vehicle crashes, falls, sports and
recreation activities, and military training.
 77% mild TBI
3.2%
Civilian vs Military TBI
Blast TBI signature
injury from current
wars.
Civilian Causes Vary With Age
68% injured in
combat have blast
injuries
TBI in the military
TBI incidence for 1.6m deployed to
Afghanistan/Iraq
– ~1800 penetrating wounds.
– 66% of all wounded soldiers that do not return
immediately to service have TBIs.
Total combat TBI rates vary between sources
– ~10,000 blast injuries (assuming 85% have closed
head injuries)
– ~30% of troops who have been at the front for >4
months at risk from blast injury.
Blast Induced Neuro Trauma
Blast leading cause of
injury/death in Iraq
– 69.4% of wounded caused
by explosion
– 62% of blast injuries result
in TBI
– 85% of TBIs are closed
head
Blast Injury : Multiple types of TBI
Blast Injury
 Primary Blast Injury: blast pressure wave[s]
 Secondary Blast Injury: Sharpnel stiking victim
– e.g. penetrating injury
 Tertiary Blast Injury: Victim hitting objects
– Closed or open head injury
 Quaternary Blast Injury: Other
– Include flash burns, crush and respiratory injuries,
psychological consequences
 NB: Primary, Secondary and Tertiary Blast Injuries
can each cause primary or secondary brian injuries.
BINT Consequences
Cernak and Noble-Haeusslein (2010): Despite
similar secondary injury cascades, BINT has
characteristics not seen in other types of brain
injury
– weight loss
– hormone imbalance
– chronic fatigue
– headache
– problems in memory, speech and balance
Blast injuries
MacDonald et al. (2011)
examined 21 controls and
63 soldiers with blast
related mTBI (no injury
detected with CT), DTI
within 90 days of injury. (47
followed up 6-12 months
later)
– Reduced white matter near
Cerebellum, Cingulate,
Orbitofrontal cortex.
Blast Induced Neurotrauma (BINT)
 BINT signature injury of recent wars
 Overpressure has dramatic effects on gascontaining organs (lungs, ears).
 Brain mostly liquid/solid and not compressible
(Monro-Kellie doctrine).
– Both initial pressure wave and reflections can cause
injury.
 Scott et al. (2006): Military blast associated with
Hearing loss (42%), eye injuries (26%), brain
injuries (66%), abdominal injuries (22%) and
stress syndromes.
Blast injury
Lu et al. (2012) exposed monkeys to blast
injuries. Histology at 3 days or 1 mos post
injury
– Behaviorally: working memory and motor
impairments
– Purkinje neurons in the cerebellum and pyramidal
neurons in the hippocampus
– White matter injury to myelinated axons. Apoptosis
of astrocytes.
Return to duty
Scherer et al. (2013) describe current and
suggested guidelines for ‘tactical athletes’
based largely from knowledge of sports
– Classic concussion “duty restrictions for at least 24
hours, longer if symptoms persist”.
– Recently, once asymptomatic, exercise to target
heart rate and then conduct cognitive task
(Exertion to 65%-85% of predicted heart rate
maximum).
– Take into account symptoms, comorbidities, history
(previous exposure).
Posttraumatic epilepsy
TBI-related epilepsy accounts for 20% of
symptomatic (cause known) epilepsy, 5% of all
epilepsy (mostly idiopathic [cause unknown],
often with genetic component).
Garga and Lowenstein 2006 review suggests
2-25% incidence depending on TBI severity
Salazar et al. (1985) found 53% incidence of
epilepsy in 421 Vietnam vets with penetrating
brain wounds.
Seizures often months to years after injury.
Ballistic Trauma (Gunshot wounds)
 GSW often cause widespread white matter shearing.