Glial responses to TBI

Gliosis (change in glial cells) common after injury - esp. astrocytes form glial scar that re-establishes 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 anti-inflammatory (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 injuryRen 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)

Band(140)

Dementia 3.0% 1.4%

Parkinson's 2.3% 3.6%

ALS 0.5% 0.7%

Lehman et al. (2012)3439 NFL players from ‘59-’88. AD/ALS x4 expected, esp. Speed.

Speed(173)

NonSpeed (152)

Dementia 3.4% 0.6%

Parkinson's 3.4% 0.6%

ALS 1.1% 0.6%

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

Na+

Na+

Na+

K+K+

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+ increaseGlutamate releaseLactate increase

– Sustained (days)

Blood flow (CBF) decreaseCa+ increase

– Biphasic

cerebral metabolic rate (CMR) of glucose initially increased, then decreased

Why is glucose usage reduced?

Clear evidence TBI leads to chemical changesMechanism 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 ischemiaOngoing 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 glucose93% 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 disconnection1. 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 militaryIncidence and Financial CostsReasons for high incidenceBlast Induced Neuro TraumaGunshot wounds

– Resourceshttp://www.dvbic.org/resourceshttp://www.gvsu.edu/veteranstbi/ ($)

War related injuries

In Vietnam, wounded: killed was 2.6:1In Iraq/Afghanistan the ratio is 16:1

– Radically improved acute careEmbedded medicsNew training and medical equipment

• decompressive craniotomy common for evacuation (ICP)

New body armorDifferent 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 non-deployed 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 warsOverpressure has dramatic effects on gas-

containing 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.