Damage precipitating cognitive decline in Alzheimer's disease (AD) begins long before behavioural alterations become clinically apparent. At this prodromal stage, communication between networks of neurons connecting different brain regions starts to break down; setting in motion a chain of events leading to clinical AD. A significant challenge facing Alzheimer's researchers today is finding a cheap, easy-to-perform test capable of detecting prodromal AD. Such a test would afford significant benefits to patients, including a chance of early intervention. Perhaps, more importantly, it would also aid development and testing of novel therapies aimed at combating AD before it causes irreversible damage. Since oscillations in electrical field activity are important for facilitating connectivity across the brain and have been seen to alter in AD, this work studied how oscillations and regional connectivity are affected in the AD brain. Specifically, local field oscillations were recorded from the hippocampus and prelimbic cortex (regions implicated in memory formation and maintenance) in a double transgenic AD model - the TASTPM mouse. Here, periods of predominant theta activity were assessed both spontaneously, under urethane anaesthesia and following electrical induction through dorsal periaqueductal gray (dPAG) stimulation. From these recordings, spectral power and connectivity between regions was assessed using both a traditional measure of functional connectivity (inter-region correlation) and through a novel information theoretic approach measuring effective connectivity (transfer entropy).Perhaps the most prominent finding from this study was the observation that young TASTPM mice, at an age prior to overt cognitive decline or plaque deposition, showed significant alterations in measures of both functional and effective connectivity. This suggests that such measures may be used as biomarkers predictive of prodromal AD and, as such, may be used to aid development of drugs targeted towards treatment of prodromal AD.This study also uncovered a number of interesting observations concerning hippocampal/prelimbic connectivity. Firstly, although spectral power and inter-regional correlation peaked at ∼ 3Hz, information flow between these structures was strongest at ∼6Hz. This suggests that low and high-band theta activity may fulfil separate functions. Secondly, at theta frequencies, information flowed predominantly from the prelimbic cortex to the hippocampus. However, during lower frequency activity, information flowed predominantly in the opposite direction. Suggesting that separate frequency bands may be important for routing information flow between these structures. Finally, the strength of information transfer was seen to oscillate at approximately double the frequency of its carrier signal, perhaps suggesting locking of information transfer to certain phases of an underlying oscillation. Therefore, oscillations may structure information transfer by temporal windowing and frequency-locked routing; processes which can be studied using measures of effective connectivity such as transfer entropy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:764309 |
| Date | January 2014 |
| Creators | Fox, Sarah |
| Contributors | Gigg, John |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/oscillations-memory-and-alzheimers-disease(bbacb2f0-74f3-4071-b02f-19c0c5570227).html |
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