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Neuroscience > Spinal Cord Injury > Flashcards

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
Q

Intermediate consequences of SCI

A

Hyperreflexia
Segmental reflexes return
Autonomic dysreflexia

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26
Q

Later consequences of SCI

A

Spastic paralysis

Clonus

27
Q

Complications of SCI

A 
Pressure sores
Respiratory secretions accumulation
Osteoporosis/ fractures
DVTs
Allodynia
Loss of thermoregulation
CVD
28
Q

Primary injury of SCI

A

Axonal damage/trauma

29
Q

Secondary injury

A

Limited neurogenesis
Inflammation (lymphocyte and macrophage invasion)
Cyst and glial scar formation
Demyelination
Oligodendrocyte death and demyelination (glutamate-mediated excitotoxicity)

30
Q

Issues with research in SCI for patients

A

Research does not match priorities of patients

31
Q

Cardiac dysfunction following SCI

A

T1-4 (cardiac sympathetic impulses)
Loss of orthostatic BP control- injury at T3-4
-Reduced SNA, plasma ADR/NA levels

32
Q

Bowel/bladder dysfunction following SCI

A

Detrusor overactivity, filling sensations, increased frequency and residual volume
Patients more likely to use anticholinergic and alpha inhibitors

33
Q

Autonomic Dysreflexia features

A

Patients with lesions above T6 (splanchnic sympathetic outflow)

  • Precipitated by physiological stimuli (bladder distension, pressure, faecal impaction)
  • Vasodilation above, vasoconstriction below lesion level
34
Q

Symptoms of Autonomic Dysreflexia

A

Facial flushing, headaches, hypertension
Immunosuppression
- High level SCI (above T3) more susceptible to infection/splenic atrophy

35
Q

AD and 5-HT fibre loss

A

Clip-induced SCI model

  • Colonic distension associated with increased BP changes
  • Decreased 5-HT immunofluorescence vs. ChAT control
36
Q

5-HT regeneration capability

Cornide-Petronio 2011

A

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
Q

Novel SCI therapies

A

Macrophage treatments (depletion/therapy
Therapeutic Hypothermia
Myelin-Associated Growth Factors
Reducing Excitotoxicity (Na Channel blockers)

38
Q

Macrophage depletion therapies

A

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
Q

Macrophage depletion and fibroblast recruitment

A
  • Clodronate in a contusion model
  • Reduced association of CD11b+ macrophages with fibroblasts
  • Increased axonal growth
  • No testing of behavioural effects (ISSUE)
40
Q

Reducing the inflammatory response (Reparixin)

A
  • 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
Q

Reducing the inflammatory response (Alpha4/Beta1 Abs)

A

A4/B1 Integrin Antibodies

  • Important in macrophage activation and migration
  • Reduced AD and increased sparing of 5-HT axons
42
Q

Macrophage Therapy

Rapalino 1998

A

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
Q

Macrophage Therapy

Lammertse Clinical Trial

A

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
Q

Macrophage depletion vs therapy

Evidence for this

A
  • 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
Q

Therapeutic Hypothermia

A

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
Q

Targetting Myelin-Associated Inhibitory Factors

A

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
Q

MAIFs- Trials

Thailmar 1999

Cethrin treatments

A

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
Q

Growth Factor treatments

A

BDNF and CBD injection (single intrathecal dose) increased neurofilament and BBB score

49
Q

Sodium Channel Blockers

A

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
Q

Combination therapies

A 
Epidural Stimulation + 5-HT + Treadmill
Anti Nogo (MAIF Ab) + Treadmill
51
Q

Harnessing CPGs/Spared fibres

A

5-HT agonists e.g. Quipazine improves walking rhythm in a cat model
Treadmill training- increases active CPGs (FOS+ nuceli increased)

52
Q

Typical SCI Animal Model Features and Issues

A

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
Q

Contusion Injury Model

A

Most commonly used
+ Best represents pathophysiology in humans
+Simulates canal occlusion, cyst/cavity formation
+Assess levels of loss over time
-Reproducibility

54
Q

Transection Injury Model

A

+Assessing Regeneration, Degeneration, effects of neurotrophic factors
+ Animals act as their own controls in hemisections
- Compensation ^ (CST sprouting)
- Not representative of clinical pathology

55
Q

Other SCI models

A

Ischaemia re-perfusion model
Inflammatory SCI model
Photochemically-induced Ischaemic SCI

56
Q

Future approaches to SCI model development

A

Intermediate model between rodents and humans

57
Q

What is Spinal Muscular Atrophy

A

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
Q

Neural Stem Cells grafts for SCI

Boido 2009- NPs vs MSCs

A

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
Q

Neural Stem Cells grafts for SCI

Hou 2013- Autonomic function

A

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
Q

Issues with NSC transplants

A

Causes further trauma
Allodynia
Withdrawal/cold threshold reduced

61
Q

Potential of endogenous NSCs

A

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
Q

Manipulating Endogenous NSCs

A

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
Q

Harnessing Central Pattern Generators

A

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
Q

Autonomic Dysreflexia with Noxious/ Innocuous stimuli

A

Noxious stimuli: HR, MAP increase over time with noxious stimuli, compared to innocuous

Neuroscience (17 decks)

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