Abstract
Spinal cord injury (SCI) results in debilitating permanent deficits in motor, sensory and autonomic function for which, to date, there is no adequate treatment. Thus, there is a pressing need for the development of novel treatment interventions. Restoring upper limb function after SCI is among the highest priorities for tetraplegic patients. Therefore, in this thesis, we aim to assess the ability of a novel combination of therapies aimed at restoring upper limb and hand function in a clinically relevant cervical contusion injury model in adult rats. Here, we proposed a novel neurorehabilitation paradigm, using a combination of three different treatment interventions. We investigated the effects of these treatments on functional improvements after a clinically relevant contusion SCI. Contused animals received different combinations of the following treatment approaches: intraspinal injections of the neuroplasticity-promoting agent Chondroitinase ABC (ChABC), daily physical rehabilitation on upper limb-specific tasks and daily cortical epidural electrical stimulation.We first established a novel chronic experimental methodology for assessing muscle function over time after SCI in awake freely moving animals using electromyography (EMG) recordings, a tool commonly used for assessing recovery of function in patients. Thereby, providing a novel and physiologically sensitive outcome measure of assessing muscle activity. We then utilized this methodology to investigate the effects of the combinational treatments on restoring evoked and voluntary muscle activity after SCI. Our results demonstrated that the full combination of the treatments administered (ChABC plus rehabilitation plus stimulation) was more effective than single treatments alone and was associated with increased evoked and voluntary muscle activity, significant forelimb task specific functional improvements and increased synaptic density below the injury site. Furthermore, we examined the effects of long term and short term cortical epidural electrical stimulation paradigms as part of the full combination of treatments. Similar effects were observed, with both paradigms leading to increased evoked muscle activity and functional improvements. Finally, we investigated the effects of the full combination of treatments on eliciting reorganization of the cortical motor map by observing changes in stimulation-induced movements under anaesthesia. Our results demonstrated some spontaneous injury-induced cortical reorganization, evident by changes in the observed movement patterns. However, the group that received the full combination of treatments showed enhanced cortical reorganisation that was associated with significantly increased upper limbspecific movements.
We therefore propose a novel combinatorial treatment paradigm for treating spinal cord injury. We hypothesise that the observed recovery is due to the ChABC-induced permissive environment together with cortical epidural electrical stimulation-induced neuroplasticity and axonal sprouting, along with the use of physical rehabilitation to guide newly formed connections and increase specific and targeted neuroplasticity, thereby leading to useful functional recovery. Furthermore, by longitudinally monitoring both voluntary and evoked muscle activity we reveal that the combination treatment led to significantly increased muscle activity, which also translated to marked improvements in tasks specific for assessing upper limb dexterity. Thus, we provide a robust methodology for obtaining longitudinal assessments of muscle function which correlate with skilled reach and grasp performance and provide sensitive measurements for determining improved functional outcome after SCI and therapeutic intervention along with a novel neurorehabilitation paradigm which led to significant recovery of upper limb and hand functions.
| Date of Award | 1 Jul 2019 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Elizabeth Bradbury (Supervisor) & Stephen McMahon (Supervisor) |