- Title
- Investigating deep brain stimulation as a tool to prevent secondary neurodegeneration following stroke
- Creator
- Welsh, John
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- A stroke occurs every nine minutes in Australia and is a leading cause of death and disability worldwide. Approximately fifteen million people around the world suffer from a stroke each year, of which five million die from initial trauma and a further five million suffer from ongoing disability. Not only does it leave patients with permanent damage caused by the initial blocked or ruptured blood vessel, it is also known to cause regions that are connected to the infarction1 to die over time. This secondary neurodegeneration (SND) may be linked to accelerated cognitive decline, dementia and other neurological disorders. A key contributor to SND is a process called excitotoxicity, where an imbalance of excitatory signalling in regions connected to the lesion can lead to cell death by an array of biochemical pathways. One of the secondary regions susceptible to SND after cortical stroke is the thalamus, which will form the focus of this thesis. An in-silico model of the thalamocortical network was developed to capture the dynamics of excitatory inputs to the sensory thalamus. The model strongly supports the role of corticothalamic neurons as modulatory inputs and sensory inputs as drivers. We found two key scenarios, whereby stroke can lead to the generation of aberrant signalling in the thalamus: (1) the loss of corticothalamic excitation switches neurons from a tonic mode of firing to bursting and (2) significant over-excitation from spilled extracellular glutamate generates both increased responses to stimulation and spontaneous firing. The latter of these two observations is strongly linked to the hypothesis of excitotoxicity. In-vivo electrophysiological recordings in an anaesthetised mouse model of stroke, confirms that a cortical lesion impacts activity throughout the thalamocortical network. The loss of cortical activity lead to a decrease in thalamic activity and also a loss of feedback from the cortex in the somatosensory response. The recordings did not find support for the hypothesis of over-excitation or hyperexcitability and did not show evidence of cell loss caused by SND. The somatosensory evoked response in the VPL is the first to be recorded in a mouse model, and the waveform shows similarities to those recorded from other rodent species in the literature. The neuronal sources of each peak in the evoked potential were explored to suggest likely contributions from pre-synaptic, thalamo-reticular and corticothalamic neurons, which was supported in computational simulations. A new method is proposed to extract spike times and firing rates from electrophysiological recordings. The algorithm constructs a global spike waveform dictionary which is used in conjunction with a sparse optimisation approach to discriminate overlapping spikes in a sliding time window. This proposed method was found to be effective in both real and simulated, low SNR, multi-unit recordings. A simple, signed-refractory policy was shown to significantly improve the performance of a number of conventional spike detection algorithms. Finally, a method was developed to chronically implant electrodes in the mouse thalamus for freely-moving recording and deep brain stimulation (DBS). A safe and effective set of stimulation parameters was determined to maximally stimulate the thalamocortical pathway. A pilot study of DBS to rescue thalamocortical neurons showed some minor, but not statistically significant, improvements that warrant further investigation with a larger animal cohort.
- Subject
- deep brain stimulation; secondary neurodegeneration; neurodegeneration; stroke
- Identifier
- http://hdl.handle.net/1959.13/1442914
- Identifier
- uon:41832
- Rights
- Copyright 2021 John Welsh
- Language
- eng
- Full Text
- Hits: 792
- Visitors: 957
- Downloads: 198
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 19 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 275 KB | Adobe Acrobat PDF | View Details Download |