Volumetric analysis (VA) in magnetic resonance imaging (MRI) has provided great comprehension of the neuroanatomical changes associated to normal cognition and progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), the most common form of dementia. However, the use of VA has primarily focused in gray matter changes; the emergence of diffusion tensor imaging (DTI) has allowed a better understanding of the microstructural changes in both white and gray matters in MCI and AD patients, with numerous studies showing DTI to be more sensitive than VA in discriminating between MCI to AD. Diffusion kurtosis imaging (DKI), an extension of DTI, is speculated to be more sensitive in detecting changes due to differences in mathematical modeling, as it accounts for non-Gaussian diffusion in the brain. Studies using DKI suggested kurtosis parameters—axial, radial, and mean kurtoses—are able to provide further microstructural details in additional information to tensor and diffusion parameters, namely axial, radial, and mean diffusivities, and fractional anisotropy. In this study, DKI is compared to DTI and VA in an attempt to evaluate the sensitivities of each technique. DKI of all four cerebral lobes and VA of the hippocampus were performed in 30 patients, 18 diagnosed with AD and 12 with MCI. Mann-Whitney U test was performed to determine differences between MCI and AD, and correlations between diffusion parameters and hippocampal volume to mini-mental state examination (MMSE) scores as a biomarker of cognitive function were tested using Pearson’s R correlation test. MMSE scores were statistically different between sexes (p = 0.025) and between MCI and AD groups (p = 0.048), as well as positively correlated with age (p = 0.004). A marginal trend was observed in the hippocampal volume between MCI and AD (p = 0.077), and did not significantly correlate with MMSE. Several diffusivity and kurtosis parameters were significantly different between MCI and AD groups in the white and gray matters of the parietal and occipital lobes. Only tensor parameters had significant negative correlations with MMSE scores in within-group analyses of the two lobes. Correlational tests of white and gray matters of all four lobes to MMSE scores revealed more significant correlations between tensor parameters than kurtosis parameters. Findings from the present study provide further evidence that diffusion MRI is a more sensitive technique than VA in the discrimination between MCI and AD. Results from this study also corroborate with another DKI study exploring diffusivity in neuroanatomical regions predominately composed of white matter in AD progression. While DKI provides additional information on the microstructural changes of white matter and gray matter during disease progression in the brain, whether DKI is superior to DTI requires further research. Diffusion MRI appears to be more advantageous when comparing cognitive function on a continuum like MMSE scores than segregated groups. / published_or_final_version / Diagnostic Radiology / Master / Master of Medical Sciences

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Current concepts of hippocampal circuitry assume a large population of excitatory principal neurones whose activity is largely governed by a network of local-circuit GABAergic interneurones. The diversity of hippocampal local-circuit neurones and their synaptic control over principal cell activity was investigated in vitro, in order to define their synaptic connections and functional roles. Single and dual intracellular recordings were made from local-circuit neurones and pyramidal cells in area CA1 of the rat hippocampal slice. Interneurones were tentatively distinguished from pyramidal cells based on their firing as well as their membrane properties. Intracellular labelling of recorded cells with the marker biocytin revealed a diversity of cell types based on differential dendritic and axonal morphology and synaptic connections. The physiological data revealed that all types of interneurone tested evoked inhibitory postsynaptic potentials (IPSPs) in simultaneously recorded pyramidal cells. The IPSPs had fast rise and decay kinetics and the ones tested pharmacologically, were mediated by GABA_A receptors. Similarly, individual interneurones were also shown to innervate other local-circuit interneurones in addition to pyramidal cells, the evoked effects being qualitatively similar in both types of postsynaptic targets. The postsynaptic effect and functional role of one type of hippocampal interneurone, the basket cell, was investigated in greater detail. Basket cell-evoked IPSPs were reliable, but showed some frequency-dependent attenuation. Moreover, basket cell IPSPs were found to interact with intrinsic pyramidal cell conductances to elicit rebound depolarisations and facilitate action potential generation. More detailed investigation showed that basket and axo-axonic cells were particularly effective in entraining pyramidal cell firing and sub-threshold membrane potential oscillations. Through these powerfully tuned mechanisms, sub-types of local-circuit interneurone provide a powerful mechanism to synchronise the activity of pyramidal cells. These results demonstrate a remarkable diversity of GABAergic local-circuit neurones in the hippocampal CA1 area and suggest that specific subtypes of cell mediate different functions.

Memory of some forms requires the hippocampus, a brain structure in the medial temporal lobe that reveals remarkable synaptic plasticity. Most synapses in the hippocampus require NMDA-receptors for the induction of this plasticity. Memories that require the hippocampus may also require NMDA-receptor mediated plasticity. This thesis tested the involvement of NMDA receptor activity in memory for a non-spatial, social learning task that requires the hippocampus: the social transmission of food preference, NMDA receptor antagonist (CPP) injected systemically 55 minutes prior to training impaired performance 72 hours later, but not 48 hours, 24 hours, or 15 minutes later. NMDA receptor antagonist (AP-5) injected into the dorsal hippocampus 30 minutes prior to training also impaired performance at the 72-hour delay. Injections of CPP at 10 minutes or 24 hours post-training had no effect on performance. These results suggest that hippocampal NMDA receptor activity is necessary for stable learning of the non-spatial social transmission of food preference.

Thesis (M.S.)--Brigham Young University. Dept. of Physiology and Developmental Biology, 2006. / Includes bibliographical references (p. 47-50).

Thesis (Ph.D.) -- McMaster University, 1999. / Includes bibliographical references (leaves 130-151). Also available via World Wide Web.

Thesis (Ph. D.)--Michigan State University. Dept. of Psychology, 2006. / Title from PDF t.p. (viewed on Nov. 20, 2008) Includes bibliographical references (p. 175-190). Also issued in print.

Thesis (Ph. D.)--Carleton University, 2004. / Includes bibliographical references (p. 118-146). Also available in electronic format on the Internet.

Thesis (Ph. D.)--University of Hong Kong, 2008.