KPE368 Final Exam

What are the 3 phases of recovery?

* acute
* subacute
* persistent

Describe the acute phase

* 24-48 hours
* decrease in but overtime resolves
* principles within acute phase: rest, avoid high risk sport, avoid stimuli/stressors and provide education

Describe the subacute phase

* after 72 hours
* people have different understandings of persistent symptoms

How is concussion multifactorial?

* centre of it is neurometabolic cascade disruption
* co-morbidities: things that contribute to it (neck injury)
* pre-morbidities: what the patient brings in (previous concussion, sleep disorders, etc.) and can increase recovery time

What are examples of co-morbidities?

* neck injury
* msk injury
* sleep issues
* anxiety
* pressure in head

What are examples of pre-morbidities?

* personality
* previous concussion

How does the DSM define persistent symptoms?

1. cognitive deficits in attention and memory
2. at least 3 or more symptoms including HA, dizziness, fatigue, irritability, apathy, personality change, or sleep or affective disturbances


1. present for 3 months of greater

How does WHO define persistent symptoms?

presence of 3 or more symptoms that must be present in the first month of injury: HA, dizziness, fatigue, irritability, insomnia, and concentration or memory difficulties

What are the differences between how WHO and DSM define persistent symtoms?

* DSM symptoms have to be present for 3 months or greater
* WHO 3 or more symptoms have to be present in the first month of injury

What are the problems with how persistent symptoms are defined by WHO and DSM?

* doesnt tell you timeline
* one is more short term the other is long term
* cant have new symptoms
* e.g. have dizziness in 2nd month

Why has the diagnosis of PCS disorder been controversial?

* symptoms have been associated with other conditions (e.g. depression, migraines, etc.)
* athletes can begin to experience aerobic deconditioning 1-2 weeks of inactivity
* what cant be debated it persistent symptoms result in **substantial functional disability**

What was the previous name ‘persistent symptoms’ was referred to? How did it help?

* change from Post-Concussion Syndrome (PCS) to persistent symptoms
* change in name added no value

How does CISG define persistent symptoms?

persistent symptoms > 2 weeks of symptoms in adults

How was risk reduced in patients with PCS?

Moser et al. showed that 61.5% of adolescents with persistent symptoms after concussion improved after receiving education and reassurance and engaging in 1 week of prescribed exercise

* dark room, avoid stimulus
* considered gold standard

Why is the efficacy of rest being challenged?

* taking away benefits of PA
* dysregulation of day to day
* changing up stimulus is important
* psychological component (used to moving, helps with getting energy out, helps with sleep, lifestyle)
* social (social interaction, self esteem, lack of togetherness,

What are the symptom clusters?

* somatic/physical
* cognitive
* cervicogenic
* vestibuloocular
* headache
* mood/affect
* sleep-related

What is the BCTT used for? Who developed it?

* Buffalo Concussion Treadmill Test (BCTT)
* used as rehab intervention for those with persistent symptoms
* university of buffalo
* barry willer & john leddy

Describe how the BCTT works

* patients walk on a treadmill at a speed of 3.0 - 3.3 mph at 0% grade
* the grade is increased by 1% after 1 minute
* the grade is continuously increased by 1%/min during first 15 mins
* after 15 mins, speed increased by 0.2 - 0.4 mph/min
* test terminated after symptoms at >3 change in symptoms or 25 mins
* stop and take their HR, take 80% of that and prescribe it as exercise level

What is the pathophysiology of physiological concussion disorder?

persistent alterations in cellular metabolism, cerebrovascular physiology “metabolic mismatch”

what are the symptoms of a physiological concussion?

* mild mod HA “pounding” at rest
* dizziness, nausea, fatigue, and sensitivities
* sx made worse by PA and CE

what are the treadmill results for someone with a physiological concussion?

early symptom limited threshold (5-15 mins)

what is the physical exam for a physiological concussion?

normal physical exam

may have elevates resting HR

what is the treatment for a physiological concussion?

* submaximal aerobic exercise prescription
* treatment of co-existing dysfunctions

what is the pathophysiology of a vestibulo-ocular concussion?

isolated dysfunction of central and peripheral components of vestibulo-ocular neurological subsystem

what are the symptoms of a vestibulo-ocular concussion?

* mild mod HA
* eye strain typically absent at rest but CE exacerbates
* intermittent blurred vision, dizziness, or focusing

what are the treadmill results for a vestibulo-ocular concussion?

able ot exercise for 15-25 mins

what is the physical exam of a vestibulo-ocular concussion?

* impaired convergence, accommodation, saccades, and VOR
* positive Dix-Hallpike Maneuver

what is the treatment for vestibulo-ocular concussion?

* submaximal aerobic exercise prescription
* targeted vestibular and vision therapy

what is the pathophysiology of a cervicogenic concussion disorder?

isolated mechanoreceptive or proprioceptive dysfunction within cervical spine neurological sub-system

what are the symptoms of a cervicogenic concussion?

* mild mod HA “dull”, occipital HA elicited by PA
* neck pain or stiffness, decreased ROM, postural imbalance

what are the treadmill results for cervicogenic concussion?

able to exercise for 15-25 mins

what is the physical exam for cervicogenic concussion?

* decreased ROM
* sub-occipital and paraspinal neck tenderness
* impaired cervical spine proprioception

what is the treatment for cervicogenic concussion?

* cervical spine manual therapy
* gaze and postural stabalization
* submaximal aerobic exercise prescription

what is the submaximal exercise prescription?

* advised exercise protocol
* 80-90% of the HR achieved during treadmill testing
* 20 mins of exercise, 5-6 days/week
* follow up advised 1-3 weeks, and repeat treadmill testing
* superivised initially or intermittent

What were the results of the study to see if aerobic exercise resolved symptoms?

* stationary bike 3 days after injury
* 60% of max HR
* 2 days on, 1 day off
* resolution of symptoms faster in people that were given exercise protocol

What are mechanisms behind why exercise helps concussion recovery?

* neutrophins → BDNF
* improvements to ANS/normalization of cerebral blood flow
* neuroendocrine

What is BDNF? How does it help improve concussion?

* Brain Derived Neurotrophic Factor (BDNF) increases
* involved in neuroplasticity, neuroprotection, growth and differentiation, during developing and in adult brain
* direct administration increases cell proliferation in hippocampus and blocking BDNF reduces cell proliferation
* important for memory

What were the effects of studies testing BDNF?

* greatest effect of exercise occurs on regions not directly related to motor system (hippocampus)
* BDNF levels higher post aerobic exercise intervention
* resistance training doesnt increase resting BDNF levels post intervention
* no signficant differences observed between males and females, nor in serum vs plasma

Describe the ANS mechanism for exercise and concussion symptoms

* primary ANS control - hypothalamus damaged in concussion
* proposed mechanism is uncoupling of connections between central ANS, arterial baroreceptors and the heart
* affects CBF and cardiac rhythm
* Affects cardiac function at and in exercise
* elevated HR and altered HRV - interpreted to reflect altered balance of sympathetic and parasympathic input
* physical deconditioning of cardiovascular system as a result of rest

How does exercise training help concussion with the ANS mechanism?

* improves CBF control and cerebral vasoreactivity (ability to maintain a steady supply of oxygenated blood)

Describe the neuroendocrine mechanism for exercise improving concussion symptoms

* central components of stress system located in hypothalamus and brainstem


* paraventricular nuclei (PVN) of hypothalamus → corticotropin-releasing hormone (CRH)
* locus coeruleus (LC) → catecholamines: norepinephrine; and epinephrine


* physical exercise reduces urine epinephrine as a result of attenuation of sympathetic nervous tension
* similar findings with cortisol

how does serotonin act as a mechanism for exercise improving concussion symptoms?

* serotonin may have structural effects on brain during development and adulthood
* effects mood
* a small molecule that functions as both neurotransmitter in the CNS and a hormone in the periphery
* exercise interventions increase serotonin
* chronic stress → decrease in serotonin
* acute stress → increase serotonin

Describe the mood/affect cluster and what are treatment options?

* anxiety and depression levels 2x higher
* non pharmagological: CBT
* pharmacological: selective serotonin reuptake inhibitor (SSRI) e.g. celexa, prozac, zoloft
* target different clusters

Describe the headache cluster and what are treatment options?

* various types


* migraine vs tension-type
* location: unilateral or bilateral, front or back
* type: stabbing vs dull; frequent vs infrequent


* treatment options:
* non pharmacological
* lifestyle strategies (stimulus, control use of caffeine/tobacco/alcohol, manual therapy)
* manual therapy (for cervicogenic)
* pharmacological
* OTC pain meds/analgesics (acetaminophen, ibuprofen)
* migraine specific medications
* peri-neural injection

Describe the sleep-wake cluster and what are treatment options?

* >50% of patients report sleep disturbances following mTBI
* insomnia
* poor sleep maintenance
* early awakening/delayed sleep onset
* alterations in circadian cycle
* treatment:
* non pharmacological
* no phone in bed, caffine, etc.
* melatonin
* magnesium and zinc supplementation
* acupunture and mindfulness-based stress reduction therapy
* pharmacological
* modafinil and armodafinil

Why are balance issues complicated?

* multiple things contributing to balance
* eyes (visual system)
* ears (vestibular system)
* body’s sense of where it is in space (proprioception)

What are the 2 pathways visual info is conveyed by?

* magnocellular stream
* parvocellular stream
* involved in different components

Explain the parvocellular process (Central/focal vision)

* seeing fine details, identification of what we are seeing
* conscious vision

Explain the magnocellular process (peripheral/ambient/spatial)

* info about our surroundings, where we are in space, where objects are relative to us, and how we would like to move through space
* motion processing system
* peripheral range versus peripheral awareness
* established by an interplay between vision, proprioception, posture and vestibular systems. this is **pre conscious and anticipatory**)

What are rehabilitation exercises for vision related interventions?

* visual perception
* convergence/divergence/accommodation
* saccades and smooth pursuits
* gaze stability
* visual acuity
* spatial awareness

What are optical interventions for vision related interventions?

* lenses
* prism
* able to deviate the direction in which light rays are travelling
* can walk more normal
* can be kind of expensive
* tints
* filters the most problematic wavelengths
* blue lights tints (on computer)
* selective occlusion
* can help with visual motion sensitivity, balance, and scrolling on a screen

How is musculature in cervical spine effected in concussion?

* activation of deep musculature in neck is important for stability and strength of cervical musculature
* “load sharing” is optimized with appropriate contribution of deep musculature - dynamically and statically
* it is frequently noted in literature, those who suffer from chronic or mechanical neck pain have weaker neck muscles
* deep cervical flexors - hard to train, risk factors for concussion when those muscles are weak you have poor postural issues
* when damaged → exacerbate issues
* want to train in rehab

What are the differences between males and females in neck muscles?

* study with uni students
* attached weight to their head, counter load balancing, released it to see how they would react
* females weaker neck muscles

What are the 3 stages in building deep cervical flexors?

* pre rehab
* isometric and dynamic stabilization
* immediate
* isometric neutral posture stabilization
* avoid (excessive) movements/manipulations
* later
* movements, manual therapies, stabilization

how is vestibular system effected in concussion?

* ear has different canals contributing to how your body is aware in space
* fluid movement in canals
* when this is blocked, positional vertigo
* little manual movement tilting, recalibrating the canals and making sure there is proper movement into those
* easily corrected potential solution

what is rehab for vestibular system?

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* **multi modal programs** adresses all aspects (sensory inputs, controller, motor outputs) of the balance control system
* visual tracking/convergence exercises
* gradual progression of head movements
* standing balance exercises (eyes open, closed)
* includes lots of components and hoping one sticks

what are characteristics of “punch drunk”

* in 1928, dr martland noticed clinical condition in boxers
* they developed:
* unsteady gate
* mental confusion
* slowed muscular response
* hesitant speech
* tremors
* dragging of leg or foot when ambulating
* facial characteristics similar to parkinsos

what did they believe “punch drunk” was caused by

* single or repeated blows to head or jaw, which caused hemorrhages in deeper portions of brain
* condition more common in second rate fighters
* association between exposure to boxing and likelihood of developing these features
* irreversible
* progressive even after retirement

Parker in 1934

* reporting 3 cases of TE
* high prevalence of exposure
* clinical picture complex
* suggestion of diffuse and scattered lesions of brain affecting different systems at one and the same time
* assume difficulties resulted from repeated injuries to brain during pugilistic careers
* exact pathological mechanism not known

Roberts study in 1969

* clinical + pathological features
* clinical
* 3 stages:
* affective disturbances and psychotic symptoms
* social instability, psychiatric symptoms, memory loss, development of parkinsons
* general cognitive dysfunction
* pathology
* in 37 (17%) lesions of nervous system detected by:
* neuropsychological assessment
* radiological techniques of that era, such as pneumoencephalography “air study”

Corsellis et al. 1973

* 15 retired boxers studied post mortem
* neuropathological findings of dementia pugilistica
* specifically:
* cerebral atrophy
* atrophy of the mammillary bodies
* thinning of hypothalamic floor
* enlargement of lateral and third ventricles, cavum septum pellucidum (cavum septi pellicidi)

Corsellis et al. 1973 additional key features

* increase in astrocytes
* type of glial cell → metabolic support, regulation of ion concentration in extracellular space, nervous system repair
* presence of neuro-fibrillary tangles
* tau - hyperphosphorylated - insoluble
* unlike with AD, tangles were seen in absence of senile plaques

What is tau?

* tubulin associated unit
* ties that hold microtubule rails together - come undone, the neurons’ internal transportation networks fail, often resulting in death of neuron as well
* tau phosphorylation plays both physiological and pathological roles in cell
* in pathological conditions in which there is an imbalance in phosphorylation/dephosphorylation of tau, aberrant tau phosphorylation

what is amyloid?

* general term for protein fragments that the body porduces normally
* **beta amyloid** is protein fragment snipped from an amyloid precursor protein
* not clear of actual role, but in healthy brain protein fragments are broken down and eliminated (esp. in sleep)
* become problematic when they lose their structure and normal physiological function → deposits as plaques → disrupt healthy surrounding tissues

what are the differences between senile (amyloid) plaques and nfts?

* senile (amyloid) plaques
* protein fragments and accumulate to form hard, insoluble plaques
* **found between neurons**
* neurofibrillary tangles
* tangles consist primarily of tau, forms part of a structure called a microtubule
* tau protein is abnormal (hyperphosphorylation) the microtubule structures collapse
* **found within neurons**

Late 1980’s/early 90’s Roberts et al.

* reexamined brain
* more sensitive and modern immunochemistry techniques
* discovered large numbers of **diffuse b-amyloid plaques** (comparable to those seen in AD)
* this is important because prior to 90s it was assumed “senile plaques” were not present in dementia pugilistica

When was the first use of CTE?

* 1940 bowman and blau

Omalu’s 2005 neurosurgery case study

* first documented case of long-term neurodegenerative changes in a retired professional NFL player consistent with CTE
* complete autopsy
* key finding: coricol amyloid plaques and NFTs were unacommpanied by tangles in medical temporal and hippocampus
* typical changes of AD

what was the backlash to omalu et al 2005?

* by NFL
* misinterpretation of their neuropathological findings in relation to characteristics of chronic CTE
* failure to provide adequate clinical history
* no proof of significant injury so cant state it is “traumatic”
* offensive linemen have low incidence of MTBI compared with other position players

When did correlation between concussion history, MCI and depression happen?

2005 and 2007

Guskieweicz et al

what did mckee establish?

* 2009
* further characterize CTE pathologic findings in ewview of 48 autopsy confirmed cases

McKee et al. 2009

* review of 48 cases of CTE recorded in literature and document detailed findings of cte in athletes
* behaviour:
* memory and behaviour disturbances
* parkinsonism, speech difficulties, gait abnormalities
* neuropathologically:
* atrophy of cerebral hemispheres, medial temporal lobe, thalamus & mamillary bodies
* dilation of lateral ventricles / septi pellucidi
* tau-positive neurofibrillary tangles & astrocytic tangles
* **b-amyloid inconsistent feature**

McKee et al. 2013

* post mortem brains of 85 histories with repetitive MTBIS
* 68 subjects CTE
* stage correlated with increased duration of football play
* CTE sole diagnosis in 43 cases (63%), 8 motor neuron disease (12%), 7 alzheimers disease (11%)

Differences between AD and CTE

* more brown/rust then AD
* NFTS more concentrated at depths of sulci
* NFT cluster and around vasculature (perivascular)
* NFTS distributed preferentially to superficial layers
* astrocytic tanlges or NFTS in mamillary body

what are clinical features of CTE?

* can only be diagnosed post mortem
* progressive cognitive, motor, and mood decline
* early symptoms:
* memory problems, confusion, headaches
* depressive symptoms and suicide ideation
* poor impulse control and short temper
* some patients develop signs of parkinsons
* not considered linear progression from concussion
* history of repetitive brain trauma

CTE hypothesis #1

* 1928 article, Martland proposed
* brain injury due to single or repeated blows on head or jaw which cause multiple concussion hemorrhaes in deeper part of cerebrum. these hemorhages are then replaced by a gliosis or degenerative progressive lesion in areas involved

CTE hypothesis #2

shear trauma to axons resulting = increased membrane permeability and ion shifts

leads to calcium influx and subsequent release… triggering tau and phosphorylation and aggregation

CTE hypothesis #3

immune excitotoxicity

* proinflammatory and anti-inflammatory cytokines and chemokines
* additional head trauma occurs / frequent trauma microglia remain in a proinflammatory, exitotoxic mode
* leads to progressive neurodegeneration and the deposition of hyperphosphorylated tau protein, resulting in neurofibrillary tangle formation

CTE hypothesis #4

* McKee et al propose that concussive impacts result in fluid waves within lateral ventricles that place a shear stress on the septum pellucidum
* resulting in an enlarged cavum septum and septal fenestrations
* ischemia also plays note
* noting that tau pathology occurs at depths of sulci
* they proporse damage to blood brain barrier and release of neurotoxins contributes to perivascular nests of tau-immunoreactive neurofibrillary tangles

Other variables associated with disease burden of CTE

* genetics
* style of play
* manner in which previous concussions managed
* psychiatric and other mental disorders
* alcohol and drug use
* obesity
* age related changes to brain, coexisting dementing illnesses

agreed on consensus criteria for neuropathology of CTE

* accumulation of hyperphosphorylated (p-tau) in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at depths of cortical sulci

CTE and football

* very common in football
* only in american findings though - not canada

CTE and other neurodegenerative diseases (comorbidites)

* nearly all those with CTE had AD, frontotemporal dementia, lewy body disease, or ALS

Prevalence of CTE in general population

* 98.3% history of traumatic brain injury
* participation in sports - 34%
* military veterans - 19%
* women - 40.6%

Other causes of abnormal tau protein other than head injury?

* ageing
* natural consequence
* drug use

what is a biomarker?

* characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmalogic responses to a therapeutic intervention

what are cons of using CT, fMRI, CSF as biomarker for concussion?

* costly
* radiation
* CSF: infection, leakage, back pain, nausea

what are neuroinjury markers?

* concussion causes markers to be released from neuronal cell into surrounding environment
* once released - called Damage Associated Molecular Patterns (DAMPs)
* cross BBB which is more permeable now
* body recognizes them - activates immune system

how is concussion and immune response tied?

* DAMPS released - microglial cells recognize and initiate
* cytokines released
* inflammatory response can cause injury to BBB, increasing permeability
* DAMPS and cytokines make their way to blood activating peripheral immune system
* immune cells in periphery enter brain to help

how do peripheral tissues react to concussion?

* neural circuitry disrupted in autonomic centres of brain due to concussion
* activate peripheral tissues (e.g. adrenal, endothelium, liver)
* molecules released from these tissues (hormones, cytokines)
* biomarkers but not from brain

examples of biomarkers of brain injury?

* neuroinjury
* s100b
* NSE
* GFAP
* UCH-L1
* tau
* inflammation
* IL6
* TNFa
* neuroendocrine
* GH
* cortisol
* prolactin
* TSH

which 2 biomarkers are approved for clinical use? are they useful?

* GFAP
* UCH-L1
* reduce unnecesary CTs
* save money and exposure to radiation
* not improving existing clinical measures (CT head rules)
* concussion is symptom+mechanism (dont have straightforward mechanism - doctor has to make call)

what have we learned by using biomarkers to study concussion pathophysiology?

* males and females have different inflammatory responses to concussion
* inflammation looks different in concussion
* PRDX-6 and tau elevate after injury
* PRDX-6: protect membrane and mitochondria
* tau: axonal injury
* neuroendocrine hormones uniqely correlated with specific symptoms
* concussion history mediates inflammatory response

confounds of biomarkers?

* participation in collision sports strongly correlated with tau
* molecules typically have more than 1 function in body
* other things beyond concussion effect biomarker levels (stress, exercise) (UCH-L1 increase after exercise)

what do we know about concussion cell level changes? (neuroimaging)

* microstructural damage
* impaired cell function
* impaired communication
* ionic + glutamate release
* impaired cell function
* metabolic dysfunction (mismatch)
* autoregulatory changes
* ischemia/oxidative stress
* altered blood flow
* sterile info
* cellular swelling
* altered blood flow

what are the 4 modalities of case studies in concussion MRI?

1. effects at early injury


1. ASL: blood flow
2. highly variable blood flow response at early injury
2. symptom severity


1. BOLD: brain function
2. shows functional networks related to symptom severity
3. brain recovery at medical clearance


1. DTI: white matter microstructure
2. lingering white matter abnormalities at medical clearance
4. long-term brain changes


1. T1: grey matter morphology
2. shows long term declines in frontal grey matter

Incidence Rates for Youth

* excess of 600 per 100,000 children
* around the world - 33 million concussions each year
* youth sport - 12% of youth
* females increasing a lot
* most in fall and winter
* not just from sports - motor vehicle
* highest for children under 5

why are we seeing increases in concussion? do you think kids are being less safe?

* more education around concussion
* people getting care after
* more trainers/athletic therapists

what are 3 ways to identify a suspected concussion?

1. self reported signs and symptoms
2. observed signs & symptoms from coaches, teachers, and/or parents
3. peer-reported signs & symptoms from child/youth

* youth report more than just self report

whats important to remember when youth are experiencing concussion symptoms?

* effects other parts of their life (social, school)
* function - needs and what they love to do