Spinal Cord Injury Flashcards
Where are motor neurons located?
Ventral Horn (lamina 9)
Features of motor neurons
Large (propagation of big APs)
Lumbar cervical enlargements permit fine control
Where are sensory neurons located?
Dorsal Horn
Function of the intermediate horn (lamina 7)?
IML Column
Contains sympathetic preganglionic neurons
What are the lateral pathways, and what is their function?
Corticospinal and Rubrospinal tracts
Control distal musculature via direct cortical input
What are the medial pathways, and what is their function?
Reticulospinal and vestibulospinal tracts
Control of posture and locomotion via the brainstem
What is the ‘Triple influence’ of motor control?
Sensory inputs from muscle
Spinal Interneurones (CPGs)
Descending tracts
What are the levels of processing in motor control?
High- strategic control (neocortex)
Mid- tactical control (motor cortex, cerebellum)
Low- execution (brainstem, SC)
What do the functional impairments in CST injury depend upon?
The extent of damage
Investigating extent of CST damage
Anderson 2005
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
Compensation by sprouting following CST injury
What happened 4 weeks post-injury?
(Ghosh 2009)
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
Effect of stimulating spared CST fibres
Ghosh 2009 contd.
Improved locomotor function in impaired limbs (decreased movement errors)
Increased sprouting
Role of Rubrospinal tract in compensation
RST removal after CST injury
- Massive loss of function in skilled tasks
- Simultaneous removal not as severe
- ? loss of plasticity in system
Role of Ventromedial tract in compensation
Recovery of dexterous movements in macaque monkeys may be due to VMT
Role of Reticulospinal tract in compensation
chABC treatments
ChABC treatment improves reaching/grasping vs. Penicillinase-treated animals
Density of reticulospinal processes is improved
Function of CPGs
Generate rhythmic activity at the spinal level to flexor/extensor groups
Autonomic effects of SCI
Control from medulla (of rVLM- blood pressure, SNA; and Raphe- chemoreception, thermoregulation)
Barringtons nucleus function
Autonomic input to the bladder/colon
-PRV labelling
Why do children wet the bed?
Supraspinal pathways do not develop until later childood, lack of reflex central control
Aetiology of SCI?
80% patients male
Bimodal age distribution
Caused by vehicle accidents, sports, falls
Quadriplegia
Cervical Lesion (C1 to T1) Upper and lower limbs affected
Paraplegia
Thoraco-lumbar Lesion
Lower limbs affected
Why is regenerative potential reduced in older patients?
Changes in myelination and inflammation pathways
PTEN KO in animals (negative mTOR pathway regulator) reduces regeneration speed
Immediate consequences of SCI- neurogenic shock
Areflexia/hyporeflexia, flaccid paralysis
Hypotension and bradyarrhythmias due to unopposed PS outflow
Intermediate consequences of SCI
Hyperreflexia
Segmental reflexes return
Autonomic dysreflexia
Later consequences of SCI
Spastic paralysis
Clonus
Complications of SCI
Pressure sores Respiratory secretions accumulation Osteoporosis/ fractures DVTs Allodynia Loss of thermoregulation CVD
Primary injury of SCI
Axonal damage/trauma
Secondary injury
Limited neurogenesis
Inflammation (lymphocyte and macrophage invasion)
Cyst and glial scar formation
Demyelination
Oligodendrocyte death and demyelination (glutamate-mediated excitotoxicity)
Issues with research in SCI for patients
Research does not match priorities of patients
Cardiac dysfunction following SCI
T1-4 (cardiac sympathetic impulses)
Loss of orthostatic BP control- injury at T3-4
-Reduced SNA, plasma ADR/NA levels
Bowel/bladder dysfunction following SCI
Detrusor overactivity, filling sensations, increased frequency and residual volume
Patients more likely to use anticholinergic and alpha inhibitors
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
Symptoms of Autonomic Dysreflexia
Facial flushing, headaches, hypertension
Immunosuppression
- High level SCI (above T3) more susceptible to infection/splenic atrophy
AD and 5-HT fibre loss
Clip-induced SCI model
- Colonic distension associated with increased BP changes
- Decreased 5-HT immunofluorescence vs. ChAT control
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
Novel SCI therapies
Macrophage treatments (depletion/therapy
Therapeutic Hypothermia
Myelin-Associated Growth Factors
Reducing Excitotoxicity (Na Channel blockers)
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
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)
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
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
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
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
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
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
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
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
Growth Factor treatments
BDNF and CBD injection (single intrathecal dose) increased neurofilament and BBB score
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
Combination therapies
Epidural Stimulation + 5-HT + Treadmill Anti Nogo (MAIF Ab) + Treadmill
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)
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
Contusion Injury Model
Most commonly used
+ Best represents pathophysiology in humans
+Simulates canal occlusion, cyst/cavity formation
+Assess levels of loss over time
-Reproducibility
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
Other SCI models
Ischaemia re-perfusion model
Inflammatory SCI model
Photochemically-induced Ischaemic SCI
Future approaches to SCI model development
Intermediate model between rodents and humans
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
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
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
Issues with NSC transplants
Causes further trauma
Allodynia
Withdrawal/cold threshold reduced
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
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
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
Autonomic Dysreflexia with Noxious/ Innocuous stimuli
Noxious stimuli: HR, MAP increase over time with noxious stimuli, compared to innocuous
