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Spinal Cord Injury Flashcards

1
Q

Where are motor neurons located?

A

Ventral Horn (lamina 9)

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2
Q

Features of motor neurons

A

Large (propagation of big APs)

Lumbar cervical enlargements permit fine control

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3
Q

Where are sensory neurons located?

A

Dorsal Horn

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4
Q

Function of the intermediate horn (lamina 7)?

A

IML Column

Contains sympathetic preganglionic neurons

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5
Q

What are the lateral pathways, and what is their function?

A

Corticospinal and Rubrospinal tracts

Control distal musculature via direct cortical input

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6
Q

What are the medial pathways, and what is their function?

A

Reticulospinal and vestibulospinal tracts

Control of posture and locomotion via the brainstem

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7
Q

What is the ‘Triple influence’ of motor control?

A

Sensory inputs from muscle
Spinal Interneurones (CPGs)
Descending tracts

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8
Q

What are the levels of processing in motor control?

A

High- strategic control (neocortex)

Mid- tactical control (motor cortex, cerebellum)

Low- execution (brainstem, SC)

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9
Q

What do the functional impairments in CST injury depend upon?

A

The extent of damage

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10
Q

Investigating extent of CST damage

Anderson 2005

A

Complete unilateral hemisection of rodent spinal cord
- Dorsolateral CST involved (deduced by BDA tracing)

Impaired food pellet retrieval, grip strength, horizontal rope walking- dependent on lesion

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11
Q

Compensation by sprouting following CST injury

What happened 4 weeks post-injury?

(Ghosh 2009)

A

C3/4 Hemisection- induced an ipsilateral forelimb paralysis and hindlimb spasticity

4 weeks post-injury:

  • Delayed activation of the ipsilateral cortex on VSD imaging with hindlimb stimulation
  • Anterograde tracer: increased midline CST crossings
  • Retrograde tracer: ipsilesional cortex labelling
  • BOLD-fMRI/VSD: increased reliance on the unimpaired forelimb and cortical representation
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12
Q

Effect of stimulating spared CST fibres

Ghosh 2009 contd.

A

Improved locomotor function in impaired limbs (decreased movement errors)

Increased sprouting

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13
Q

Role of Rubrospinal tract in compensation

A

RST removal after CST injury

  • Massive loss of function in skilled tasks
  • Simultaneous removal not as severe
  • ? loss of plasticity in system
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14
Q

Role of Ventromedial tract in compensation

A

Recovery of dexterous movements in macaque monkeys may be due to VMT

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15
Q

Role of Reticulospinal tract in compensation

chABC treatments

A

ChABC treatment improves reaching/grasping vs. Penicillinase-treated animals

Density of reticulospinal processes is improved

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16
Q

Function of CPGs

A

Generate rhythmic activity at the spinal level to flexor/extensor groups

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17
Q

Autonomic effects of SCI

A

Control from medulla (of rVLM- blood pressure, SNA; and Raphe- chemoreception, thermoregulation)

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18
Q

Barringtons nucleus function

A

Autonomic input to the bladder/colon

-PRV labelling

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19
Q

Why do children wet the bed?

A

Supraspinal pathways do not develop until later childood, lack of reflex central control

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20
Q

Aetiology of SCI?

A

80% patients male
Bimodal age distribution
Caused by vehicle accidents, sports, falls

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21
Q

Quadriplegia

A 
Cervical Lesion (C1 to T1)
Upper and lower limbs affected
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22
Q

Paraplegia

A

Thoraco-lumbar Lesion

Lower limbs affected

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23
Q

Why is regenerative potential reduced in older patients?

A

Changes in myelination and inflammation pathways

PTEN KO in animals (negative mTOR pathway regulator) reduces regeneration speed

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24
Q

Immediate consequences of SCI- neurogenic shock

A

Areflexia/hyporeflexia, flaccid paralysis

Hypotension and bradyarrhythmias due to unopposed PS outflow

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25
Intermediate consequences of SCI
Hyperreflexia Segmental reflexes return Autonomic dysreflexia
26
Later consequences of SCI
Spastic paralysis | Clonus
27
Complications of SCI
``` Pressure sores Respiratory secretions accumulation Osteoporosis/ fractures DVTs Allodynia Loss of thermoregulation CVD ```
28
Primary injury of SCI
Axonal damage/trauma
29
Secondary injury
Limited neurogenesis Inflammation (lymphocyte and macrophage invasion) Cyst and glial scar formation Demyelination Oligodendrocyte death and demyelination (glutamate-mediated excitotoxicity)
30
Issues with research in SCI for patients
Research does not match priorities of patients
31
Cardiac dysfunction following SCI
T1-4 (cardiac sympathetic impulses) Loss of orthostatic BP control- injury at T3-4 -Reduced SNA, plasma ADR/NA levels
32
Bowel/bladder dysfunction following SCI
Detrusor overactivity, filling sensations, increased frequency and residual volume Patients more likely to use anticholinergic and alpha inhibitors
33
Autonomic Dysreflexia features
Patients with lesions above T6 (splanchnic sympathetic outflow) - Precipitated by physiological stimuli (bladder distension, pressure, faecal impaction) - Vasodilation above, vasoconstriction below lesion level
34
Symptoms of Autonomic Dysreflexia
Facial flushing, headaches, hypertension Immunosuppression - High level SCI (above T3) more susceptible to infection/splenic atrophy
35
AD and 5-HT fibre loss
Clip-induced SCI model - Colonic distension associated with increased BP changes - Decreased 5-HT immunofluorescence vs. ChAT control
36
5-HT regeneration capability | Cornide-Petronio 2011
Previous rat studies: Raphe transplantation may improve motor function Sea lamprey model: large reticulospinal axons - Descending 5-HT from the rhombencephalon capable of regenerating caudal to lesion site- immunostaining - 5-HT fibres may have better sprouting capabilities than other types
37
Novel SCI therapies
Macrophage treatments (depletion/therapy Therapeutic Hypothermia Myelin-Associated Growth Factors Reducing Excitotoxicity (Na Channel blockers)
38
Macrophage depletion therapies
Popovich 1999: Depletion of macrophages with Clodronate in a contusion SCI model - Reduced ED1+ macrophage staining - Behavioural recovery was associated with white matter sparing but NO motor improvements (BBB score) - Neutrophil attenuation prior to depletion
39
Macrophage depletion and fibroblast recruitment
- Clodronate in a contusion model - Reduced association of CD11b+ macrophages with fibroblasts - Increased axonal growth - No testing of behavioural effects (ISSUE)
40
Reducing the inflammatory response (Reparixin)
- Inhibits Cytokine-Induced Neutrophil Chemoattractant 1 (CINC-1) receptors - Clip compression SCI model- Reparixin reduces lesion area, BBB score, AD - Lower TNF alpha, CINC-1, Death receptor (Fas, p75) expression: reduced oligodendrocyte death
41
Reducing the inflammatory response (Alpha4/Beta1 Abs)
A4/B1 Integrin Antibodies - Important in macrophage activation and migration - Reduced AD and increased sparing of 5-HT axons
42
Macrophage Therapy | Rapalino 1998
T8/9 transected rats treated with haematogenous macrophages pre-exposed to peripheral nerve ± acidic FGF - Higher partial recovery of motor function (BBB score and electrophysiological recovery) - Anterograde Labelling (Rhodamine Dextran)- regrowth across the lesion in WM and GM
43
Macrophage Therapy Lammertse Clinical Trial
Phase 2b RCT Received treatment 7 weeks post-injury 2:1 treatment:control randomisation; no sham procedure Serious AEs in 2 pts (atelectasis, spinal instability) Macrophage injection is a confounding variable- may damage tissue
44
Macrophage depletion vs therapy Evidence for this
- Macrophage benefits may be more subacute - Presence of other inflammatory cells may be relevant - M1 macrophages pro-inflammatory, expression rapidly induced following injury - M2 macrophages anti-inflammatory- reduces lesion area, locomotor footfall errors in rats Cortical DRG neurons cultured in M2 had increased survival vs. M1; increased sprouting of long projection axons -Synergistic action with chABC
45
Therapeutic Hypothermia
4h treatment at 33 deg. in cervical displacement SCI after administration 5 minutes after SCI (NEEDS to be applied early) Improved grip strength and reduced lesion size 43% patients had an improved ASIA grade after 10 months
46
Targetting Myelin-Associated Inhibitory Factors
MAIFs are downstream effectors of growth cones and cause collapse of growth cones -e.g. RhoA inhibition- improved motor recovery in open field motor score
47
MAIFs- Trials Thailmar 1999 Cethrin treatments
IN-1 Antibody treatment in CST injury -IN-1 active against NI-35 and NI-250 Treatment induced a bilateral corticobulbar projection, improvement in grasping and rope-climbing function Cethrin- Intrathecal injection improves ASIA score
48
Growth Factor treatments
BDNF and CBD injection (single intrathecal dose) increased neurofilament and BBB score
49
Sodium Channel Blockers
Phenytoin, Riluzole, Mexiletine administered immediately after SCI -Improved motor function, reduced neuronal/oligodendrocyte death (histology) Riluzole within 12h of SCI in humans -Improved motor score- most significant in ASIA-B patients
50
Combination therapies
``` Epidural Stimulation + 5-HT + Treadmill Anti Nogo (MAIF Ab) + Treadmill ```
51
Harnessing CPGs/Spared fibres
5-HT agonists e.g. Quipazine improves walking rhythm in a cat model Treadmill training- increases active CPGs (FOS+ nuceli increased)
52
Typical SCI Animal Model Features and Issues
Rat most common species - Anatomical differences Thoracic injuries are most common - Cervical injury 50% of human cases - Thoracic models more reproducible - Cervical models higher mortality- respiratory compromise - Other structural differences (vascularisation, WM/GM composition, spacing) Mostly Biological/ Behavioural measures measured - BBB score- hindlimb function only, doesnt assess co-ordinated movement Mostly dorsal injuries - Human injuries normally anterior
53
Contusion Injury Model
Most commonly used + Best represents pathophysiology in humans +Simulates canal occlusion, cyst/cavity formation +Assess levels of loss over time -Reproducibility
54
Transection Injury Model
+Assessing Regeneration, Degeneration, effects of neurotrophic factors + Animals act as their own controls in hemisections - Compensation ^ (CST sprouting) - Not representative of clinical pathology
55
Other SCI models
Ischaemia re-perfusion model Inflammatory SCI model Photochemically-induced Ischaemic SCI
56
Future approaches to SCI model development
Intermediate model between rodents and humans
57
What is Spinal Muscular Atrophy
Loss of BS/Spinal Cord LMNs - Due to changes in the SMN gene (axonal/dendritic development) - SMN1 deletion is the cause, severity is determined by SMN2 cnv
58
Neural Stem Cells grafts for SCI Boido 2009- NPs vs MSCs
Boido 2009 Neural Precursors and MSCs injected into thoracic hemisected mice 2 weeks post injury- Both improved grip strength, improved survival, increased 5-HT staining Only NPs expressed NeuN, and had better migration across the lesion MSCs may promote recovery via a neurotrophic role
59
Neural Stem Cells grafts for SCI Hou 2013- Autonomic function
NSCs grafted 2 weeks after lesion Restored MAP and HR, reduced AD -Retransection abolished recovery NSCs filled the lesion site, produced extensive axons - Co-localised with NeuN, differentiated into catecholaminergic/ 5-HT nuerons -Projected to the IML and innervated SPNs
60
Issues with NSC transplants
Causes further trauma Allodynia Withdrawal/cold threshold reduced
61
Potential of endogenous NSCs
CCZ cells proliferate in response to EGF and bFGF in vitro CCZ cells co-localise with BrdU and Ki67 in Macaque monkey model Ependymcal cells can only differentiate into astrocytes and oligodendrocytes in response to injury? - Increased nestin expression (marker or progenitor response) following injury Sabelstrom 2013: eliminating NSC populations affect glial scar formation - Increased atrophy in adjacent segments - Attenuated upregulation of mRNA for key neurotrophic factors
62
Manipulating Endogenous NSCs
Imamura-- NSC OPCs, astrocyte survival, STAT3 pathway Corns pape- ACh modulates electrophysiological response - vs. control and antagonists -Our work- Donepezil and PNU, no increase in astrogliosis
63
Harnessing Central Pattern Generators
Epidural stimulation - Produced alternating rhythmic muscle group movement in 4/10 patients - Rest had simultaneous muscle group activation - Human CPGs may be harnessed but input from brainstem important (maintaining posture- bipedal) 5-HT administration - 5HT but not NMDA induced rhythmic activity in spinalised rats and in slices
64
Autonomic Dysreflexia with Noxious/ Innocuous stimuli
Noxious stimuli: HR, MAP increase over time with noxious stimuli, compared to innocuous

Neuroscience (17 decks)

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