Download files
Abstract
This thesis examined the physiological mechanisms of neuroplasticity in ischemic stroke, and specifically, its relationship to functional and motor recovery. Novel electrophysiological techniques comprising of threshold-tracking paired-pulse transcranial magnetic stimulation (TMS) and peripheral nerve excitability studies were utilized to assess the mechanisms of plasticity involving the central and peripheral nervous system in stroke patients, and whether electrophysiological biomarkers of such neuroplastic processes may be developed to assist in neurorehabilitative strategies to facilitate stroke recovery.
Initial peripheral nerve excitability studies were undertaken in a cohort of normal control participants to assess the reproducibility of study parameters. This study demonstrated that peripheral nerve excitability results showed minimal change over time in normal controls. The study also investigated changes in peripheral axonal properties in a patient with limb ischemia to enable later comparison to peripheral axonal changes in studies of patients with ischemic strokes. Results demonstrated relative axonal depolarization in the ischemic limb that significantly improved following reperfusion.
Central and peripheral studies were undertaken in acute stroke patients immediately after the event and assessed over the subacute period in the first 3 months. TMS studies demonstrated significant reductions in intracortical inhibition in both lesioned and contralesional hemispheres in the immediate phase of stroke that persisted at follow-up in association with clinical improvements, suggesting that bihemispheric intracortical excitability may be biomarkers of an adaptive plastic process after stroke. Furthermore, peripheral studies demonstrated complex changes in axonal biophysical parameters that suggest a down-stream (transynaptic) plastic process that may reflect changes occurring in the central nervous system.
To explore the changes in cortical excitability and potential maladaptive forms of neuroplasticity, chronic stroke patients with disabling spasticity were studied prior to and following the administration of peripheral intramuscular botulinum toxin. Results revealed significant intracortical disinhibition over the contralesional motor cortex that normalized after treatment with botulinum toxin. This was associated with clinical improvements in spasticity indicating a maladaptive process in the contralesional motor cortex of chronic stroke patients that may be contributing to the development of spasticity, and that this abnormality can be modulated with treatment.
Studies undertaken in acute cerebellar stroke patients followed over a period of 12 months, also demonstrated persistent motor cortex disinhibition bilaterally that correlated with the degree of impairment, again suggesting an adaptive plastic process occurring in the motor cortices following cerebellar infarction. The study also illustrated that stroke recovery involved widespread reorganization on a neural network level in the brain and provides insight into the complex pathophysiological mechanisms of recovery following stroke.
To further explore and clarify the cortical excitability changes that occur over the contralesional motor cortex, longitudinal studies were undertaken in stroke patients from the time of ictus and followed up to a period of 18 months. The study demonstrated that in well recovered stroke patients, intracortical disinhibition was maintained over the ipsilesional hemisphere over this period, whilst contralesional intracortical hyperexcitability remained a feature in those patient groups with more severe baseline functional impairment and cortical location of stroke. The results suggest that ongoing cortical network recruitment in the contralesional hemisphere may be required in those patients with significant disruption to the integrity of ipsilesional motor pathways.
In conclusion, threshold-tracking electrophysiological studies and in particular, paired-pulse transcranial magnetic stimulation, have enhanced our understanding of the physiological mechanisms associated with neuroplasticity in stroke recovery. These techniques may be used to further explore the mechanisms underlying novel neuromodulatory therapies as well as to improve the way in which these interventions are delivered. Furthermore, threshold-tracking transcranial magnetic stimulation may provide a means of developing neurophysiological biomarkers that can be incorporated into future clinical trials in stroke rehabilitation.