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Title: Improving mobility after corticospinal tract injury
Author: Kathe, Claudia
ISNI:       0000 0004 5991 1706
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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The corticospinal tract is one of the major motor tracts in the spinal cord. Traumatic injury to it through spinal cord injury or stroke results in loss of dexterity, coordinated locomotion and fine motor function. With time the spinal circuitry adapts, which may result in spasticity. This thesis is a characterisation of a corticospinal tract injury in a rodent model and evaluates three different treatments, which aim to improve functional recovery post-injury. The first result chapter describes the unilateral pyramidotomy surgery, which lesions the corticospinal tract at medullary level in the brainstem. I performed different behavioural tests assessing motor and sensory function, which revealed sustained deficits. Furthermore, I developed 3 different neurophysiology protocols, which assess functional neurophysiological recovery following sprouting of the uninjured corticospinal tract. I found direct cortical stimulation in combination with EMG recordings from a forelimb muscle (the extensor carpii radialis) is most suitable for longitudinal neurophysiological monitoring of corticospinal tract plasticity. Two of the result chapters evaluate two different gene therapies, which modulate intrinsic neuronal properties. In each, we transduced the motor cortex with a regeneration-associated gene. First, we overexpressed protein tyrosine phosphatase, non-receptor type 2, which also may act as a transcription factor. I performed a unilateral pyramidotomy lesion and treated the unaffected corticospinal tract to increase sprouting. The second gene therapy we tested was with ribonuclease inhibitor 1, which inhibits ribonucleases that are degrading RNA. I performed a cervical lateral hemisection and treated the lesioned corticospinal tract to increase regeneration. To assess if these treatments were effective, I performed behavioural testing, neurophysiology and immunohistochemistry. Both treatments, with Ptpn2 and RNH1, improved functional recovery, neurophysiological outcomes and increased plasticity. In the last result chapter, I performed a bilateral corticospinal tract lesion/pyramidotomy, which causes spasticity through spinal circuitry maladaptations. First, I characterised spasticity behaviourally by developing a new open-field scoring system, neurophysiologically with two different preparations assessing reflex pathways and anatomically by looking at excitatory and inhibitory spinal networks. Next, I treated these rats with intramuscular neurotrophin-3, which is developmentally important for patterning of spinal reflex pathways. Rats had reduced spasticity and improved functional locomotor recovery. In conclusion, I have evaluated three different treatments after corticospinal tract injury, which all improved functional, neurophysiological and anatomical outcomes.
Supervisor: Moon, Lawrence David ; McMahon, Stephen Brendan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available