TBI Flashcards
(253 cards)
1
Q
What defines a traumatic brain injury (TBI)?
A
Direct injury to the head (e.g., fall, blow, concussive accident)
Can occur with or without a skull fracture
Can result in structural and/or functional damage to the brain
2
Q
What was the approximate number of UK hospital admissions for head injury in 2011–2012?
A
Around 213,000 cases
Includes a broad range of head injuries (sports, motor accidents, etc.)
Some patients died upon hospital arrival
3
Q
What is the annual incidence of severe TBI cases in the UK?
A
Estimated 10,000–20,000 cases per year
Refers to severe impairment (e.g., inability to walk, use limbs, speak)
Does not include fatalities
4
Q
Which demographics are most at risk of sustaining a TBI?
A
Males (twice as likely as females) due to increased risk-taking behavior
Age groups 15–24 and over 80
Young adults: due to high-risk activities
Elderly: due to increased fall susceptibility
5
Q
What are common causes of TBI?
A
Motor vehicle and cycling accidents
Falls, sports injuries (e.g., rugby, American football, boxing)
Violence (e.g., pub fights, blunt force trauma)
6
Q
How effective are cycle helmets in reducing TBI risk?
A
Can reduce risk by over 80%
Significantly decrease injury severity
Strongly advocated in clinical and public health messaging
7
Q
What are the potential neurological consequences of TBI?
A
Personality changes (e.g., Phineas Gage)
Motor or sensory deficits
Cognitive impairments (e.g., memory, attention, executive function)
Depends on injury location and severity
8
Q
What is the Glasgow Coma Scale (GCS) and what does it assess?
A
Standardised tool to evaluate TBI severity
Assesses:
Motor response
Verbal response
Eye opening
Higher score = milder injury; lower score = more severe injury
Early GCS score (within 24 hours) can predict recovery outcomes
9
Q
What are the three main types of primary brain injuries?
A
Open (penetrating): skull breached (e.g., Phineas Gage)
Closed: brain shaken without skull fracture
Crush: skull compressed without penetration
10
Q
What are coup and contrecoup injuries?
A
Coup: brain impacts skull at site of blow (primary injury)
Contrecoup: brain rebounds to opposite side (secondary injury)
Both can cause significant damage due to skull rigidity
11
Q
What is visible in post-mortem brains with severe TBI?
A
Necrotic (blackened) tissue indicating cell death
Blood accumulation forming haematomas
Damage typically visible on ventral surfaces (e.g., temporal/frontal lobes)
12
Q
Why are closed head injuries rarely isolated?
A
Brain rebounds inside the skull → coup and contrecoup injuries
Can also involve rotational forces causing axonal shearing
Common in motor vehicle accidents and violent impacts
13
Q
What additional injury is often associated with TBI in vehicle accidents?
A
Whiplash: rapid hyperextension followed by hyperflexion of the neck
Can occur even if the head does not strike an object
Often damages both brain and cervical spinal cord
14
Q
What is a contusion in the context of brain injury?
A
Bruised brain tissue
Typically involves swelling and ruptured blood vessels
Often coexists with haematomas
15
Q
What is a haematoma and how does it form?
A
Collection of blood outside blood vessels within the brain
Caused by ruptured vessels due to trauma
Increases intracranial pressure and can compress brain tissue
16
Q
How does increased intracranial pressure (ICP) affect the brain?
A
Compresses brain tissue, reducing function
May cause headaches, swelling, hydrocephalus
Can be life-threatening if untreated
17
Q
What is the Monroe-Kellie Doctrine?
A
The skull has a fixed volume made up of:
Brain tissue (~80%)
Blood (~10%)
Cerebrospinal fluid (CSF) (~10%)
An increase in one component must be offset by a decrease in others, or ICP will rise
18
Q
What is the normal range for intracranial pressure (ICP)?
A
7–15 mmHg in a healthy adult
> 20 mmHg is elevated and may require medical intervention
Severe swelling can raise it to dangerous levels (>30 mmHg)
19
Q
What are the main treatments for raised intracranial pressure?
A
Craniotomy: removal of part of skull to relieve pressure
Shunt insertion: drains excess CSF, often to abdominal cavity
Induced coma: reduces brain activity and pressure
Diuretics: temporarily reduce fluid via blood–brain barrier
20
Q
What is neurochemical injury in TBI?
A
Secondary injury phase involving:
ROS (reactive oxygen species) → oxidative damage
Excitotoxicity from glutamate overload
Glucose metabolism disruption
Neuroinflammation
21
Q
What are the key features of neuroinflammation after TBI?
A
Astrocytes become reactive and form glial scars
Microglia release cytokines: IL-1β, IL-6, TNF-α
Activation triggered by DAMPs (damage-associated molecular patterns)
Creates a hostile environment that may spread injury
22
Q
What role do macrophages play in TBI?
A
Normally excluded from the CNS by the blood-brain barrier
Can infiltrate following BBB disruption
Help clear debris, but may also worsen inflammation
23
Q
How does TBI appear on MRI imaging?
A
Reduced brain tissue volume in injured regions
Enlarged ventricles due to brain atrophy
Loss of grey and white matter in severe cases (e.g., corpus callosum)
24
Q
What is diffuse axonal injury (DAI)?
A
Widespread damage to axons caused by shearing forces
Interrupts transport of signals and materials
Axonal swellings and disconnection often observed
Accumulation of β-amyloid precursor protein at injury sites
25
What are the consequences of diffuse axonal injury?
Signal transmission failure
Degeneration of white matter tracts
Long-term disability or persistent vegetative states in severe cases
26
What is Chronic Traumatic Encephalopathy (CTE)?
Progressive neurodegenerative disease linked to repeated head trauma
Common in athletes (boxing, football, rugby)
Characterised by cognitive decline, aggression, and suicidal tendencies
27
What are the histopathological features of CTE?
Atrophy of both grey and white matter
Persistent glial activation (astrocytes and microglia)
Abnormal protein aggregates: tau and TDP-43
Enlarged ventricles due to loss of brain tissue
28
What is the link between CTE and tau pathology?
Abnormal tau phosphorylation and aggregation
Similar to Alzheimer's disease, but with different distribution and context
Tau pathology is central to CTE progression
29
What is the function of glial scars formed by astrocytes after TBI?
Isolate the damaged area to prevent spread
Secrete protective and inhibitory molecules
May also block axonal regeneration in the long term
30
Why don’t woodpeckers get traumatic brain injury despite repetitive impact?
Specialised anatomy:
Shock-absorbing tongue structure
Smaller brain (less momentum)
Skull adaptations to distribute force
Possibly controversial, still under research
31
What neurochemical injuries occur shortly after TBI?
Excessive ROS (reactive oxygen species)
Glutamate excitotoxicity
Impaired glucose metabolism
Neuroinflammation from activated glial cells
32
What is glutamate excitotoxicity in TBI?
Excess glutamate release overactivates receptors
Causes calcium influx and cellular damage
Leads to neuronal death and worsens secondary injury
33
What are the main causes of reduced oxygen delivery in TBI?
Disrupted blood flow due to vessel damage
Increased intracranial pressure reducing perfusion
Can result in ischaemia and cell death
34
What types of atrophy occur after TBI?
Axonal atrophy (white matter loss)
Neuronal/cerebral atrophy (grey matter loss)
Can be progressive and irreversible
35
What is hydrocephalus and how is it related to TBI?
Excess CSF accumulation in brain ventricles
Caused by impaired flow or absorption
Leads to increased intracranial pressure and brain swelling
36
What is the long-term significance of glial activation in TBI?
Chronic inflammation
Inhibits repair and promotes neurodegeneration
Associated with diseases like CTE and Alzheimer’s
37
What are DAMPs and their role in TBI?
Damage-Associated Molecular Patterns
Released from injured cells
Trigger microglial and astrocyte activation
Promote inflammatory cascades
38
What is the impact of blood-brain barrier breakdown in TBI?
Allows infiltration of peripheral immune cells (e.g., macrophages)
Increases local inflammation
Compromises CNS immune privilege
39
What cellular responses occur at the injury site after TBI?
Astrocyte proliferation and scar formation
Microglial activation and cytokine release
Axonal degeneration and myelin disruption
Neuronal apoptosis/necrosis
40
How is axonal transport disrupted by TBI?
Physical damage to axons impairs signal and protein transport
Leads to axon swelling, beading, and β-APP accumulation
Reduces communication between brain regions
41
What is β-amyloid precursor protein (β-APP) and why is it significant in TBI?
A protein that accumulates in damaged axons
Marker of diffuse axonal injury
Normally transported down axons, but transport halts after trauma
42
What brain region is particularly affected in severe white matter degeneration?
Corpus callosum
Connects left and right hemispheres
Can be severely reduced in size post-TBI
43
What is Chronic Traumatic Encephalopathy (CTE)?
A progressive neurodegenerative disease
Linked to repeated head trauma, especially in athletes
Leads to cognitive, emotional, and motor deficits
44
What are common symptoms of CTE?
Aggression, confusion, memory loss
Parkinsonism-like symptoms (e.g., tremors)
Increased suicide risk
45
What proteinopathies are associated with CTE?
Hyperphosphorylated tau
TDP-43 protein inclusions
Similar pathology to Alzheimer’s but distinct progression
46
What structural changes are observed in CTE brains?
Enlarged ventricles
Grey and white matter atrophy
Persistent glial activation and chronic inflammation
47
How is CTE staged histopathologically?
Staged I–IV based on severity and spread
Involves tau accumulation and progressive brain tissue loss
Staging used to classify post-mortem diagnosis
48
Why don’t woodpeckers suffer TBI despite repeated head impact?
Specialized anatomy: spring-like tongue supports brain
Tightly packed brain reduces bounce
Possible role of brain size and cushioning structures
49
What is the role of astrocytic scars post-TBI?
Prevent spread of damage
Secrete protective and inhibitory molecules
Create a barrier but may also inhibit regeneration
50
How does TBI increase the risk of neurodegenerative diseases?
Chronic inflammation
Protein misfolding (tau, TDP-43)
Long-term neuronal loss and brain atrophy
51
What is the approximate annual incidence of spinal cord injuries in the UK and US?
UK: 1,000–2,000 cases/year
US: ~12,000–25,000 cases/year
52
Why is spinal cord injury research often underfunded compared to conditions like cancer or stroke?
Low incidence numbers compared to other conditions
Harder to justify funding based on number of affected individuals
53
Why do spinal cord injury numbers accumulate over time despite low yearly incidence?
Injured individuals often survive with near-normal lifespans
Injuries are chronic, with limited cure options
Population of affected individuals grows each year
54
Which two age groups are most affected by spinal cord injury and why?
Young adults (15–24): risk-taking behavior
Elderly (65+): increased risk of falls
55
Why are pneumonia and septicaemia common causes of death in spinal cord injury patients?
Patients may develop infections (e.g. from bedsores)
Immobility increases risk
Respiratory complications in higher-level injuries
55
What is the gender distribution of spinal cord injuries?
~80% of cases occur in males
56
What are the most common causes of spinal cord injury?
Motor vehicle accidents (most common)
Falls
Sports injuries
Violence
57
Where does the spinal cord end anatomically within the vertebral column?
At the level of lumbar vertebra 1 (L1)
Below L1: cauda equina (nerve roots only)
58
Why is the lumbar region safe for procedures like lumbar puncture?
No spinal cord tissue below L1
Only nerve roots (cauda equina), reducing risk of damage
59
What does the H-shaped (butterfly) region in a spinal cord cross-section represent?
Grey matter: neuronal cell bodies
59
What are the main regions of the spinal cord and their general locations?
Cervical: neck
Thoracic: chest/ribcage
Lumbar: lower back
Sacral: pelvic area
Coccygeal: tailbone (smallest, often not depicted)
60
What surrounds the grey matter in the spinal cord and what does it contain?
White matter: axons in ascending (sensory) and descending (motor) tracts
61
Which sensory modalities are carried in the dorsal (posterior) columns of the spinal cord?
Fine touch
Vibration
Proprioception
62
Where are pain and temperature sensations processed in the spinal cord?
Anterior/lateral columns (spinothalamic tract)
63
What is the primary motor tract in the spinal cord and where is it located?
Corticospinal tract
Located in lateral white matter
64
What determines the symptoms a spinal cord injury patient will experience?
Location and severity of the injury
Specific tracts and functions affected at that level
65
What spinal cord level must be affected to result in quadriplegia?
Cervical region (typically above C6)
66
What functions are lost in quadriplegia?
Loss of motor and sensory function from the neck/chest down
Often includes impaired or absent arm/hand movement
May require ventilator if injury is above C3
67
What functions are lost in paraplegia?
Loss of motor/sensory function in lower limbs
May also affect abdominal and pelvic regions
68
What spinal levels are typically affected in paraplegia?
Thoracic, lumbar, or sacral spinal cord
69
In quadriplegics, which function do patients most often prioritise recovering?
Arm and hand function (more than walking)
Enables independence for feeding, dressing, etc.
70
What function is most commonly prioritised by paraplegic patients?
Sexual function
Followed by bladder/bowel and overall mobility
71
Why is walking function often ranked lower than expected in spinal cord injury patients?
Patients adapt to wheelchair use
Regaining independence (e.g., hand use or bladder control) often becomes more important
72
What does the ASIA scale assess?
Severity of spinal cord injury
Ranges from ASIA A (complete) to ASIA E (normal)
73
What does an ASIA A classification indicate?
Complete spinal cord injury
No sensory or motor function preserved below the injury level
74
What does an ASIA E classification indicate?
Normal motor and sensory function post-injury
75
Why do pain and temperature loss occur contralaterally in Brown-Séquard syndrome?
Spinothalamic tracts decussate (cross) at the level of spinal entry
76
What is Brown-Séquard syndrome?
Hemisection of the spinal cord (rare)
Ipsilateral motor and fine touch loss
Contralateral pain and temperature loss
77
What is Central Cord Syndrome?
Damage to central grey/white matter, often cervical
Commonly caused by tumours or hyperextension
Affects upper limbs more than lower limbs
78
Why does Central Cord Syndrome often impair upper limbs more?
Cervical region is disproportionately affected
Upper limb motor neurons are more centrally located in the spinal cord
79
What is spinal shock?
Temporary loss of all neurological activity below the lesion
Characterised by flaccid paralysis and loss of reflexes
May resolve partially or fully after hours to days
80
What is flaccid paralysis during spinal shock?
Complete loss of voluntary movement and reflex activity
No muscle tone or electrical activity
81
What typically follows flaccid paralysis in spinal shock?
Spastic paralysis
Involuntary muscle spasms due to dysregulated reflex arcs
82
Why does blood pressure decrease during spinal shock?
Loss of sympathetic nervous system output
Leads to vasodilation and hypotension
83
Why are sphincter reflexes and tone absent in spinal shock?
Disruption of autonomic control below the lesion
Loss of bladder and bowel regulation
84
What happens to blood vessels during spinal cord injury?
Risk of haemorrhage, haematoma formation, and oedema
Breakdown of the blood-spinal cord barrier
85
What is glutamate excitotoxicity in spinal cord injury?
Excessive glutamate release causes overactivation of receptors
Leads to calcium overload, oxidative stress, and neuronal death
86
What is hyperthermia in the context of spinal cord injury?
Local increase in tissue temperature due to inflammation
Can exacerbate cellular damage and oedema
86
What is axonal injury more severe in spinal cord injury than TBI?
Direct impact to dense white matter tracts in the cord
Loss of long-distance communication pathways
87
What is the difference between local and global loss of function post-injury?
Local: loss specific to affected segment
Global: widespread dysfunction during spinal shock or severe inflammation
88
How does a spinal cord injury evolve over time?
Starts with acute damage and a lesion epicentre
Spreads over weeks to months due to inflammation, cell death, and tissue degeneration
Forms a cystic cavity or fibrotic scar
89
What forms the glial scar after spinal cord injury?
Reactive astrocytes that become hypertrophic
Secrete chondroitin sulfate proteoglycans (CSPGs) that inhibit axon growth
90
What are chondroitin sulfate proteoglycans (CSPGs) and their role?
Molecules secreted by astrocytes post-injury
Inhibit axon growth and regeneration across the lesion site
91
What is GFAP and its significance in spinal cord injury?
Glial fibrillary acidic protein
Upregulated in reactive astrocytes, marks glial scarring
92
What is the role of myelin debris after spinal cord injury?
Remains uncleared in CNS
Contains inhibitory molecules that prevent axon regrowth
93
Why does the glial scar prevent axonal regeneration?
Physical and chemical barrier
CSPGs and compact astrocytes block axon extension and sprouting
94
What additional cells contribute to the inhibitory post-injury environment?
Oligodendrocyte debris
Microglia releasing pro-inflammatory cytokines
Infiltrating fibroblasts (if BBB is compromised)
95
Is there any axonal sprouting near the lesion site?
Yes, limited sprouting may occur at lesion margins
Often insufficient to re-establish functional connections
96
What are the two main environmental inhibitors of axon regeneration in the CNS?
Glial scar (astrocyte-mediated, CSPG-rich)
Myelin debris (inhibitory molecules, uncleared)
97
Why does the glial scar form a “dead zone” for axon regrowth?
Scar tissue blocks physical entry
CSPGs and debris inhibit neurite outgrowth
Inflammatory environment is neurotoxic
98
Why does axon regeneration succeed in the PNS but fail in the CNS?
PNS: Schwann cells support growth, clear debris, and form Bands of Büngner
CNS: Astrocytes and oligodendrocytes create inhibitory environment (glial scar, myelin debris)
99
What role do Schwann cells play in PNS axon regeneration?
Clear myelin debris
Secrete growth-promoting factors
Form guidance structures (Bands of Büngner)
100
What is the typical axon regrowth rate in the PNS?
Approximately 1 mm per day under optimal conditions
101
What facilitates debris clearance in the PNS?
Schwann cells and infiltrating macrophages from systemic circulation
102
What is Wallerian degeneration?
Degeneration of the axon distal to the injury site
Occurs in both PNS and CNS
PNS clears debris efficiently, CNS does not
103
Why is CNS axon regeneration inefficient despite sprouting?
Growth cones encounter inhibitory molecules and retract
Macrophages fail to clear debris
Inflammatory environment persists
104
What is chromatolysis (chromatoptosis) in neurones?
Dispersal of Nissl substance from the cell body after injury
Indicates impaired protein synthesis and stress response
Precedes apoptosis or degeneration
105
What histological feature signifies chromatolysis?
Loss or peripheralisation of rough endoplasmic reticulum and ribosomes
Pale, swollen neuronal cell body with displaced nucleus
106
Does chromatolysis always lead to neuronal death?
Not always; PNS neurones may recover
In CNS, often a sign of eventual apoptosis or atrophy
107
How do CNS neurones survive after axon injury without regeneration?
May persist in a dysfunctional state without axonal connections
Remain alive but non-functional without synaptic targets
108
What is the outcome of successful axonal regeneration in the PNS?
Restoration of connection to target
Normal or near-normal function
Myelination resumes (though often thinner)
Protein synthesis returns to baseline
109
How does remyelination in regenerated PNS axons compare to the original state?
Newly formed myelin is typically thinner than original
Still sufficient for functional conduction
110
What does a dystrophic end bulb indicate in the CNS?
Axonal regeneration attempt failed
Growth cone collapsed
Axon has retracted or died back
111
Can CNS neurones survive long-term with degenerated axons?
Yes
May persist without targets
Remain alive but non-functional
112
What is the role of macrophages in PNS vs CNS injury?
PNS: Efficient clearance of debris, support regeneration
CNS: Poor clearance, limited supportive function
113
What is the difference in inflammatory response between CNS and PNS after injury?
CNS: Prolonged, damaging inflammation (cytokines, ROS, glial scarring)
PNS: Transient inflammation, supports repair
114
What are Bands of Büngner and their function?
Structures formed by Schwann cells after injury
Guide regrowing axons to their distal targets
Critical for PNS regeneration
115
Why is the glial scar a barrier to CNS regeneration?
Astrocytes secrete CSPGs (chondroitin sulfate proteoglycans)
Physically and chemically block axon growth
116
What determines if a CNS neurone dies or survives post-injury?
Extent of injury
Presence of inhibitory factors
Ability to sustain protein synthesis
Severity of inflammation
117
What does the persistence of a neurone with no axon suggest?
The neurone has survived injury
No functional output or synaptic transmission
May remain quiescent indefinitely
118
What can enhance axon regeneration speed in the PNS?
Electrical stimulation
Possibly growth factors (not deeply discussed here)
119
Why doesn’t CNS regeneration mirror PNS regeneration?
Astrocytes form inhibitory glial scar
Myelin debris not effectively cleared
Presence of CSPGs and persistent inflammation
Oligodendrocytes remain inactive or inhibitory
120
What is chromatolysis and how does it relate to regeneration?
Cellular response to axon injury in neurones
Dispersal of Nissl substance (rough ER)
Indicates protein synthesis shut down
Precedes either recovery or cell death
121
Can chromatolysis be reversible?
Yes in the PNS (e.g. temporary reaction before regeneration)
Often irreversible in the CNS, leading to degeneration or apoptosis
122
What does persistent chromatolysis indicate in CNS neurones?
Likely failure to recover
Precursor to neuronal death
Or long-term non-functional state
123
What happens if a CNS neurone survives injury but its axon is degenerated?
It may remain alive but functionally silent
Unable to regenerate or re-establish synaptic connections
124
What is the difference between functional regeneration in PNS and CNS?
PNS: Functional recovery possible
CNS: Axon sprouting may occur, but rarely re-establishes proper targets
125
What prevents axonal sprouting in the CNS from restoring function?
Encounter with inhibitory environment (glial scar, CSPGs)
Lack of guidance cues like those in PNS (Bands of Büngner)
126
Why is CNS regeneration considered inefficient despite the presence of sprouting?
Environmental factors are hostile to growth
Axons retract or form dystrophic end bulbs
Neurones remain disconnected from targets
127
Why is regeneration limited in the CNS following injury?
Limited macrophage access → poor debris clearance
Upregulation of inhibitory factors (e.g., glial scar, CSPGs)
Presence of myelin-associated inhibitors
Absence of supportive cells like Schwann cells
128
What are the key environmental differences between the PNS and CNS that affect regeneration?
PNS:
- Macrophages clear debris efficiently
- No astrocytes/glial scar
- Schwann cells guide axons via Bands of Büngner
- Supportive ECM and fibroblasts
CNS:
- Poor clearance
- Inhibitory environment with glial scar and myelin
- Lacks Schwann cells
129
What factors contribute to successful peripheral nerve regeneration?
Schwann cells: debris clearance, Bands of Büngner
Fibroblasts: ECM production
Vascularisation: nutrient/oxygen delivery
Proximity of distal and proximal stumps
Intact extracellular matrix
130
Why is nerve crush injury more conducive to regeneration than nerve transection?
ECM and vasculature remain mostly intact
Distal stump is retained → easier axonal guidance
Schwann cell channels remain aligned
131
What is the typical rate of peripheral nerve regeneration in humans?
~1 mm/day
Full functional recovery (e.g. shoulder to hand) may take over a year
132
What happens to Schwann cells in chronically denervated distal stumps?
Without axons to myelinate, they begin to die off within 2–3 months
133
Why is muscle atrophy a concern in peripheral nerve injuries?
Loss of neuromuscular junction activity → muscle degeneration due to denervation
134
Q: What are common clinical interventions for traumatic brain injury (TBI)?
Surgical: Skull resection to relieve intracranial pressure
Medical: Diuretics to reduce swelling
Rehabilitation: Physical therapy to regain motor function
Assistive devices: Wheelchairs, tools for daily living
Pharmacological: Anticoagulants, anti-seizure drugs
Experimental: Steroids (e.g., methylprednisolone in the US), hypothermia, hyperbaric oxygen therapy
135
What is hyperbaric oxygen therapy and its goal in TBI?
Involves placing the patient in a pressurised chamber with 100% oxygen
Aims to restore oxygen to ischaemic or at-risk neurons
Intended to prevent atrophy or necrosis
Still in clinical trials with limited proven efficacy
136
What is the purpose of hypothermia treatment in CNS injury?
Reduces inflammatory temperature spike
Potentially limits lesion spread
Still considered experimental with subtle effects
137
What is spinal decompression surgery and why is timing important?
Removal of bone compressing the spinal cord
Most effective when performed within 24 hours
Can result in 1–3 grade improvements on the ASIA scale
138
What are the controversies surrounding methylprednisolone in spinal cord injury?
Historically used for neuroprotection in the US
Side effects now often outweigh benefits
Still standard in the US due to medicolegal issues, but discouraged elsewhere
138
How does rehabilitation vary between patients after spinal cord injury?
All patients receive some baseline rehab
Quality/intensity depends on insurance and healthcare access
Tailored to motor recovery potential and ASIA score
139
Why is CNS regeneration more limited than PNS regeneration?
CNS environment is inhibitory (glial scar, CSPGs, myelin debris)
Lacks growth-promoting factors (e.g., Schwann cells, supportive ECM)
Poor vascularisation and debris clearance
Low plasticity in mature neurons
140
What did experiments on lampreys reveal about CNS regeneration?
Lampreys can regenerate their spinal cords after transection
Full functional recovery occurs within ~11 weeks
Even re-transection leads to re-regeneration
Their CNS environment is growth-permissiv
140
What did Aguayo’s 1980s sciatic nerve graft experiment show?
CNS axons (from spinal cord) grow into a peripheral (sciatic) nerve graft
Axons prefer the PNS environment over CNS
No re-entry into CNS once axons are in the graft
Demonstrates CNS axons can grow if given a permissive environment
141
What was the key finding from Richardson & Issa (1984) on DRG neurons?
Central axon regeneration improves if peripheral axon is also injured
Suggests that a peripheral lesion “primes” the neuron
Leads to central axon regeneration that otherwise wouldn’t occur
142
What are regeneration-associated genes (RAGs) and how are they induced?
Genes upregulated to support axon growth
Examples: GAP-43 and CAP-23
Induced by peripheral injury or pharmacological cyclic AMP application
Limited to sensory neurons (e.g., DRG, retinal ganglion cells)
143
What is the 'conditioning lesion' effect in CNS sensory systems?
Peripheral lesion (or inflammation) primes CNS axon regeneration
Works in DRG and retinal ganglion cells
Motor neurons do not show this effect
144
What are the basic requirements for CNS repair?
Neuron survival (neuroprotection)
Axon extension toward target
Axon guidance (via scaffolds or cues)
Synapse formation and integration into functional circuits
145
Q: What molecular events occur in axonal repair after injury in Aplysia (sea snail)?
Membrane damage leads to calcium influx
Depolarisation activates voltage-gated calcium channels
Proteases like calpains degrade damaged components
Actin and microtubules are repolymerised
Membrane resealing occurs, leading to growth cone formation
145
Why is calcium essential for axonal regeneration in regenerative species?
Triggers membrane resealing
Stimulates cytoskeletal reorganisation
Absence of calcium = failed growth cone formation
High calcium promotes regeneration via actin/microtubule assembly
146
What cellular components are required for successful axon regeneration?
Calcium signalling
Cytoskeletal proteins (actin, tubulin)
Vesicle transport systems
In regenerative animals: local mRNA translation in axons
Nutrient/membrane uptake from extracellular environment
147
Is long-distance axon regrowth always necessary for functional recovery?
Not always
Plasticity may compensate by rerouting nearby undamaged neurons
Especially effective in immature CNS during the critical period
148
What is plasticity and when is it most effective?
Rewiring of intact neurons to take over lost functions
High in early development (critical period)
Reduced in adults due to extracellular matrix rigidity
Can be experimentally enhanced in animals
149
What are perineuronal nets and their role in CNS plasticity?
Extracellular matrix structures around mature neurons
Composed of CSPGs (chondroitin sulfate proteoglycans)
Inhibit synaptic remodelling and axonal sprouting
Knockout increases plasticity in adult CNS
150
What is the effect of perineuronal net removal?
Increases plasticity and regenerative capacity
Shown in animal models to enhance repair
Not yet practical or safe for humans
151
Why is myelin debris a problem after CNS injury?
Myelin debris is not cleared efficiently
Inhibits axon regeneration
Contains inhibitory molecules like Nogo-A
Astrocyte activity and lack of macrophage access contribute to persistence
152
How was the inhibitory effect of CNS myelin discovered?
Goldfish retinal axons grew well on goldfish oligodendrocytes (growth-permissive)
Mammalian cells showed reduced growth on CNS myelin
Martin Schwab’s 1988 study: CNS myelin inhibits even non-neuronal cells
Primary neurons showed clear growth inhibition on CNS myelin
153
What evidence shows goldfish CNS myelin is growth-permissive?
Retinal axons grew freely among goldfish oligodendrocytes
Time-lapse studies showed uninterrupted extension
Contrasts sharply with inhibitory mammalian CNS myelin
154
What did Schwab’s 1988 experiment demonstrate about CNS myelin?
Fibroblasts grew poorly on mammalian CNS myelin
Compared to PNS myelin and poly-lysine (growth-promoting control)
Highlighted CNS-specific inhibitory nature
155
How do primary neurons behave when cultured on CNS vs PNS myelin?
No growth on rat CNS myelin
Good growth on PNS myelin or goldfish CNS myelin
Confirms CNS myelin inhibition is mammal-specific
156
What did the 1981 study using laminin and CNS myelin streaks show?
Goldfish retinal axons grew along laminin stripes
Avoided rat CNS myelin streaks (no growth observed)
Growth was uninhibited on goldfish CNS myelin
Confirmed that mammalian CNS myelin is inhibitory while goldfish CNS myelin is not
157
Why is goldfish CNS myelin considered growth-permissive?
Does not inhibit axon extension
Allows retinal axons to grow even in CNS environments
Contrasts with mammalian CNS myelin that repels axons
158
What is the significance of CNS myelin inhibition in mammals?
One of the main reasons CNS regeneration fails
Axons encounter a hostile environment post-injury
Inhibitory molecules and lack of clearance halt regrowth
158
Which cell types contribute to myelin in the CNS and PNS?
CNS: Oligodendrocytes
PNS: Schwann cells
Only CNS-derived myelin is inhibitory to regeneration
159
What happened when primary SCG neurons were cultured with rat CNS myelin?
Axons avoided CNS myelin regions
Preferential growth on poly-L-lysine or PNS/goldfish CNS myelin
Demonstrated specific inhibition by mammalian CNS myelin
159
How do inhibitory and permissive myelin types impact regeneration research?
Mammalian CNS myelin is a major barrier to axon repair
Regenerative therapies aim to neutralise these inhibitors
Studying species like goldfish helps identify supportive factors
160
What does poly-L-lysine serve as in axonal growth studies?
A neutral or growth-promoting control substrate
Used to benchmark growth responses against CNS and PNS myelin
161
What conclusion can be drawn from the comparison of mammalian and goldfish CNS myelin?
Mammalian CNS myelin contains inhibitory molecules
Goldfish CNS myelin lacks these inhibitors and supports regeneration
Species-specific differences impact regenerative capacity
162
Why is studying species like goldfish and lamprey valuable in CNS regeneration research?
They offer natural models of successful CNS regeneration
Can help identify genes and pathways absent or inactive in mammals
Provide targets for enhancing human CNS repair
163
What experiment demonstrated axon growth inhibition by CNS myelin using retinal axons?
Retinal axons from goldfish were plated over streaks of CNS rat myelin
Growth avoided CNS myelin streaks
Growth continued over laminin or goldfish CNS myelin
Demonstrated mammalian CNS myelin is a physical barrier to regeneration
164
What role does laminin play in axonal growth assays?
Laminin is a known growth-promoting substrate
Serves as a positive control to confirm axonal growth potential
Helps contrast the inhibitory effect of CNS myelin
165
What did time-lapse imaging reveal about goldfish retinal axon growth on goldfish CNS oligodendrocytes?
Axons grew freely and made turns around oligodendrocytes
No sign of growth inhibition
Indicates growth-permissive nature of goldfish CNS myelin
165
What are the broader implications of myelin-based inhibition for CNS injury in mammals?
CNS myelin debris poses a barrier to axon regeneration
Clearance of myelin is poor in the CNS
Identifying myelin-associated inhibitors is critical for developing therapies
166
Which types of cells produce myelin in the CNS and PNS respectively?
CNS: Oligodendrocytes
PNS: Schwann cells
167
What did Santiago Ramón y Cajal observe in injured mammalian CNS tissue?
Hypertrophic and atrophic neurons appeared post-injury
Disruption of cortical tissue architecture was evident
Axons curled back with degenerating end bulbs
Supported his conclusion that mature CNS lacks regenerative potentia
168
What key insight did Cajal propose about CNS regeneration?
“In the adult CNS, nothing may be regenerated”
Observations of limited or absent axonal regrowth in mature animals
This pessimistic view remains largely accurate even after 100 years
169
Why is the lamprey used as a model for studying CNS regeneration?
Capable of full spinal cord regeneration after transection
Functional recovery (e.g., swimming) occurs within 11 weeks
Regeneration occurs even after repeat injury (re-transection)
Demonstrates natural CNS regrowth capacity not present in mammals
170
What was the result of repeat spinal cord transection in lampreys?
Regenerated spinal cords after 11 weeks could regenerate again
Functional recovery (e.g., locomotion) resumed
Suggests persistent regenerative machinery in lamprey CNS
171
What prevented CNS axons from re-entering the CNS in Aguayo’s graft experiment?
Axons grew readily into the peripheral (sciatic nerve) graft
Growth ceased at CNS re-entry point due to inhibitory environment
Demonstrated CNS axons’ intrinsic ability to grow in permissive settings
Highlighted boundary as the key barrier, not the neurons themselves
171
What anatomical layout did Richardson & Issa exploit in their 1984 experiment?
Dorsal root ganglion (DRG) neurons with bifurcated axons:
- One central branch (to CNS)
- One peripheral branch (to PNS)
Injured both branches to observe enhanced central regrowth
172
What experimental result demonstrated that central axon regeneration can be “primed”?
Injury to peripheral branch → upregulation of regenerative state
Concurrent central injury → allowed normally non-regenerative axon to grow
Showed neuron-intrinsic change induced by peripheral damage
173
How can pharmacological agents mimic a conditioning lesion in DRG neurons?
Cyclic AMP application to DRG neurons mimics peripheral injury
Induces RAGs like GAP-43 without needing physical damage
Demonstrates molecular “priming” independent of actual lesion
174
Why is the conditioning lesion effect limited to sensory neurons?
Observed in DRG neurons and retinal ganglion cells
Motor neurons do not upregulate RAGs with peripheral injury or cAMP
Suggests distinct intrinsic molecular pathways between neuron types
174
What molecule is used to stimulate regeneration in retinal ganglion cells?
Zymosan (an inflammatory stimulator)
Induces RAGs in optic nerve by mimicking peripheral inflammation
Activates regeneration in CNS sensory neurons (e.g., retina)
175
Why is neuron survival critical before attempting CNS repair?
CNS lacks a pool of regenerative or stem cells
Dead neurons cannot be replaced easily
Neuroprotection must precede regeneration attempts
176
What is the role of a growth cone in axon regeneration?
Forms after membrane resealing and cytoskeletal reorganisation
Directs axonal extension toward targets
Characterised by actin filaments and membrane turnover
177
Why does the adult CNS show low plasticity compared to early development?
Mature extracellular matrix (e.g., perineuronal nets) inhibits remodelling
Functional connections become rigid to preserve stability
Sensory and motor systems less flexible than during the critical period
178
What did visual cortex experiments reveal about the critical period?
Occlusion of one eye in children <5 years led to cortical remapping
The non-occluded eye took over visual cortex areas
Same manipulation in adults had no effect — no remapping occurred
178
What is the critical period in CNS development?
Early postnatal phase of heightened synaptic plasticity
Connections are pruned and refined
Neural circuits are highly modifiable before solidifying in adulthood
179
What are perineuronal nets composed of and what is their function?
Made of chondroitin sulfate proteoglycans (CSPGs)
Surround mature neurons, especially dendrites
Inhibit synaptic remodelling and limit plasticity in adult CNS
180
Why is myelin debris a major barrier to CNS regeneration?
Not cleared efficiently due to poor macrophage access
Persists in lesion sites and inhibits axon regrowth
Contains molecules like Nogo-A that actively block regeneration
180
What happens when perineuronal nets are experimentally removed?
Plasticity increases in the adult CNS
Regeneration and functional recovery improve in animal models
Achieved via genetic or enzymatic degradation of net components
181
How was the inhibitory effect of CNS myelin first discovered?
1991 goldfish experiment: retinal axons grew normally on goldfish oligodendrocytes
1988 Schwab study: mammalian CNS myelin inhibited cell growth
Confirmed CNS-specific inhibition even in non-neuronal cells
182
How do goldfish retinal axons behave on goldfish oligodendrocytes?
Axons grew freely and navigated around glial cells
No signs of growth inhibition
Demonstrates growth-permissive nature of goldfish CNS myelin
183
What was Martin Schwab’s 1988 finding on CNS myelin?
Fibroblasts and neurons grew poorly on mammalian CNS myelin
Growth was normal on PNS myelin and poly-lysine control
Proved mammalian CNS myelin contains growth inhibitors
183
What did SCG neuron cultures show about CNS myelin?
Axons avoided rat CNS myelin-coated regions
Grew well on PNS myelin and goldfish CNS myelin
Confirmed species- and region-specific inhibition
184
What did the 1981 laminin/CNS myelin stripe assay reveal?
Goldfish retinal axons grew along laminin stripes
Avoided rat CNS myelin streaks (no axonal extension)
Grew well over goldfish CNS myelin → species-specific permissiveness
185
What conclusion can be drawn from comparing mammalian and goldfish CNS myelin?
Mammalian CNS myelin inhibits regeneration
Goldfish CNS myelin supports axon growth
Highlights species-specific molecular environment differences
186
What is the purpose of poly-L-lysine in axonal growth assays?
A positively charged, growth-promoting control surface
Serves as a benchmark to assess inhibitory or permissive effects of myelin
Enables clear comparison in co-culture studies
187
Why is studying species like goldfish and lamprey valuable for CNS regeneration research?
Natural models of successful CNS repair
Help identify genes and pathways absent or inactive in mammals
Provide therapeutic targets to enhance human CNS regeneration
188
What experimental setup showed physical inhibition by CNS myelin using retinal axons?
Goldfish retinal axons plated over streaks of rat CNS myelin
Axons avoided CNS myelin and grew over laminin/goldfish myelin
Demonstrated CNS myelin acts as a physical growth barrier
188
What role does laminin play in regeneration experiments?
A growth-promoting extracellular matrix protein
Used as a positive control to confirm axonal growth capacity
Helps contrast with inhibitory substrates like CNS myelin
189
What did time-lapse imaging show about axon growth on goldfish CNS oligodendrocytes?
Axons grew continuously and turned around glial cells
No pausing or retraction observed
Confirmed absence of inhibitory signals in goldfish CNS myelin
190
What are the broader implications of CNS myelin inhibition in mammals?
Major reason why CNS regeneration fails after injury
Persistent debris and inhibitory molecules halt axon regrowth
Therapies aim to neutralise these inhibitory signals
191
How does understanding permissive vs. inhibitory myelin aid regeneration research?
Highlights molecular targets for therapeutic intervention
Guides development of treatments to neutralise CNS inhibitors
Comparative species studies inform human therapy design
192
What did SCG neuron experiments with myelin substrates demonstrate?
Axons grew on poly-L-lysine, PNS myelin, and goldfish CNS myelin
Avoided mammalian CNS myelin regions
Reinforced role of CNS myelin as an active inhibitor
192
What are the three main myelin-associated inhibitors (MAIs) identified in CNS myelin?
- Nogo-A
- MAG (Myelin-associated glycoprotein)
- OMgp (Oligodendrocyte-myelin glycoprotein)
193
Where are the MAIs (Nogo-A, MAG, OMgp) expressed and what is their function?
- Expressed in oligodendrocytes
- Inhibit regenerative growth at various
194
Which neuronal receptors mediate growth inhibition by MAIs?
Nogo receptor (NgR)
p75 receptor
195
What is the role of MAG in the mature CNS?
Localised to mature myelin
Helps stabilise neural networks
Permissive during embryonic development
196
Through which pathways does Nogo-A exert its inhibitory effects?
Acts via p75 and NgR
Disrupts calcium influx essential for neurite growth
197
What kind of protein is OMgp and where is it involved?
GPI-anchored protein
Functions in cell-cell interactions around nodes of Ranvier
198
What was the result of anti-Nogo-A antibody application in a rodent spinal cord injury model?
Axonal growth occurred several millimetres beyond the lesion site
Antibodies 11C7 and 7B12 were effective
198
What therapeutic was developed to neutralise Nogo-A and when?
Anti-Nogo-A antibody
Development published around 2005
199
What did non-human primate studies show with anti-Nogo-A treatment?
Hemi-section lesions at C7–8 level
Treated animals showed more robust axonal arbor growth than controls
199
What is the current clinical status of anti-Nogo-A antibody?
Reportedly in Phase III trials
Being tested for both spinal cord injury and multiple sclerosis
200
What was the result of triple knockout mice lacking Nogo-A, MAG, and OMgp?
Slightly more axonal growth
No improvement in behavioural recovery
Myelin integrity compromised
200
Why is genetically knocking out MAIs not a viable treatment strategy?
Compromises the structure and function of myelin
Leads to worse neurological outcomes
201
What glial cells are present in the normal CNS?
Microglia
Astrocytes
Oligodendrocyte precursor cells (OPCs)
Oligodendrocytes
202
What are the baseline roles of astrocytes and OPCs in the healthy CNS?
Astrocytes: support neurons, maintain homeostasis, secrete growth factors
OPCs: precursor cells for oligodendrocytes, cycle through CNS
203
What cellular changes occur in glial cells after CNS injury?
Astrocytes and OPCs become hypertrophic and proliferate
Increased cytokine and CSPG secretion
Microglia become activated, proliferate, and secrete inflammatory factors
203
Why are CSPGs inhibitory to axon regeneration?
Contain glycosaminoglycan (GAG) side chains
Cause steric hindrance, preventing axonal growth through scar tissue
204
What enzyme can reduce CSPG-mediated inhibition and how?
Chondroitinase ABC (ChABC)
Digests GAG side chains from CSPGs, making them growth-permissive
204
What was the key finding of Liz Bradbury's 2002 study using ChABC?
Enabled axonal growth beyond lesion site in rat spinal cord injury model
205
How did Garcia-Alias (2009) expand on ChABC studies?
Combined ChABC with rehabilitation
Compared general vs. specific rehabilitation in rats
205
What is the role of specific rehabilitation in enhancing recovery?
Significantly improves function when tailored to the task (e.g., grasping)
Outperformed general rehabilitation
206
What was shown by combining anti-Nogo-A antibody with ChABC treatment?
Synergistic effect
Greatest axonal growth and functional recovery compared to single treatments
206
What behavioural task was used to test functional recovery in Garcia-Alias’ study?
Staircase task with sugar pellets
Specific rehabilitation group had highest accuracy
207
What happens if the astrocytic component of the glial scar is genetically removed?
Worse outcomes
Increased lesion spread
Impaired recovery
208
What conclusion was drawn about the glial scar in CNS injury?
Glial scar (especially astrocytic) plays a protective and regenerative role
Better to modulate than eliminate
209
What are the main goals and functions of cell transplantation in CNS repair?
Bridge cystic cavities
Provide a growth-permissive substrate
Replace specific lost cell types
Secrete growth factors
Possibly remyelinate axons
210
Which cell type has remyelination potential after CNS injury?
Oligodendrocyte precursor cells (OPCs)
211
Why is remyelination less critical in spinal cord injury than in multiple sclerosis?
MS involves widespread demyelination
SCI mainly requires axonal bridging and growth across lesions
212
What are olfactory ensheathing cells (OECs) and why are they considered for CNS repair?
Glial cells from the nasal cavity
Do not myelinate, but ensheath axons
Support regenerative olfactory neurons in vivo
213
What makes Schwann cells promising for CNS transplantation?
Provide ideal substrate for axon growth
Secrete beneficial growth factors
Promote regeneration despite being PNS-derived
214
What are the three main types of stem cells used in CNS repair research?
Induced pluripotent stem cells (iPSCs)
Embryonic stem cells
Multipotent progenitor cells (e.g., from bone marrow)
215
How have embryonic stem cells been used in Parkinson’s disease models?
Transplanted into basal ganglia regions like caudate
Showed some functional restoration
Required immunosuppression
216
What are the limitations of using embryonic stem cells in clinical practice?
Ethical concerns
Risk of immune rejection
Challenges in maintenance and long-term viability
217
Why haven’t Schwann cells progressed to clinical trials yet?
Still undergoing testing in larger animals like pigs
Issues with integration into CNS due to being PNS-derived
218
What halted early enthusiasm for OECs in clinical use?
Clinics falsely advertised OEC transplants
Patients paid for treatments that weren’t genuine
Damaged global trust in OEC therapies
219
What advantages do OECs offer over Schwann cells?
Better integration into CNS tissue
Capable of bridging cystic cavities
Endogenous to a CNS environment (olfactory system)
220
What evidence supports the effectiveness of stem cells in spinal cord injury?
Robust axonal regrowth
Integrated into host tissue
Restored electrophysiological and motor function
220
What was the purpose of re-transection in stem cell studies?
Confirmed regrown axons were responsible for recovered function
221
What roles can biomaterials play in CNS repair?
Provide scaffold for axon growth
Deliver cells or drugs (e.g., ChABC)
Serve as a substrate or controlled-release system
221
What is epidural stimulation and how does it support recovery?
Electrical stimulation of the dura above the spinal cord
Activates surviving local circuits to enable rhythmic movement
222
What is a central pattern generator (CPG)?
Neural circuit producing rhythmic motor patterns without brain input
222
Are central pattern generators clearly established in humans?
Controversial; established in quadrupeds but debated in humans
223
Where are CPGs primarily located and how do they function?
Located in lumbar spinal cord
Function via propriospinal neurons linking forelimbs and hindlimbs
224
What are propriospinal neurons and what is their role?
Interneurons connecting cervical and lumbar enlargements
Coordinate rhythmic locomotor activities like walking
225
What clinical outcomes have been observed with epidural stimulation in SCI patients?
Enabled walking with assistance (e.g., walker, harness)
No permanent effect—stimulation must be continuous
226
What factors influence the success of CNS recovery therapies?
Acute vs. chronic phase of injury
Extent and location of damage
Patient motivation and rehabilitation
Plasticity vs. full regeneration
227
What is the overarching conclusion for future spinal cord repair strategies?
Combined therapies (e.g., cells, drugs, stimulation, scaffolds) are essential for functional recovery
