In recent years there has been an increased interest in working with piece-wise linear caricatures of nonlinear models. Such models are often preferred over more detailed conductance based models for their small number of parameters and low computational overhead. Moreover, their piece-wise linear (PWL) form, allow the construction of action potential shapes in closed form as well as the calculation of phase response curves (PRC). With the inclusion of PWL adaptive currents they can also support bursting behaviour, though remain amenable to mathematical analysis at both the single neuron and network level. In fact, PWL models caricaturing conductance based models such as that of Morris-Lecar or McKean have also been studied for some time now and are known to be mathematically tractable at the network level. In this work we proceed to analyse PWL neuron models of conductance type. In particular we focus on PWL models of the FitzHugh-Nagumo type and describe in detail the mechanism for a canard explosion. This model is further explored at the network level in the presence of gap junction coupling. The study moves to a different area where excitable cells (pancreatic beta-cells) are used to explain insulin secretion phenomena. Here, Ca2+ signals obtained from pancreatic beta-cells of mice are extracted from image data and analysed using signal processing techniques. Both synchrony and functional connectivity analyses are performed. As regards to PWL bursting models we focus on a variant of the adaptive absolute IF model that can support bursting. We investigate the bursting electrical activity of such models with an emphasis on pancreatic beta-cells.

This project focused on understanding the mechanisms involved in CNS integration. The anatomy and physiology of mammalian olfactory system was investigated in order to develop an organotypic in vitro sensory system to increase our understanding of sensory processing at a neural network level. The olfactory network cultures grown on multielectrode arrays (MEAs) were found to only rarely exhibit electrical activity and it was decided this was an unsuitable preparation for the purposes of this study. The spinal cord was chosen as a secondary sensory system, initially in co-culture with dorsal root ganglia and then alone, with special interest in gap junction function. Gap junctions have received increasing attention as contributors to pattern generation in neuronal ensembles, including the generation or modification of highly coordinated, intense bursting states. The main result section of this study explored the effects of four gap junction blockers (carbenoxolone (CBX), halothane, I-octanol and oleamide) on the spontaneous activity of mouse and rat frontal cortex and spinal cord cultures grown on microelectrode arrays (MEAs). It was our hypothesis that the characteristic coordinated bursting seen in most frontal cortex and in some higher density spinal cord cultures would be influenced via gap junction communication. The four compounds tested generated interesting, and in one case paradoxical effects. Frontal cortex cultures were all inhibited in a dose-dependent manner, which included total cessation of activity by halothane, CBX, I-octanol, or oleamide (at concentrations 250 muM, 100 muM, 20 muM, 20 muM, respectively). All cultures showed spontaneous recovery at lower concentrations and reversibility after culture medium changes at higher concentrations. In addition, measurements of network burst rates and coefficients of variation of burst period indicate that burst coordination among channels was reduced by these compounds. These responses were generally mirrored in the spinal cord, except for CBX, which produced a paradoxical transient intense increase in network spike and burst production. The results of this study show the effect of the gap junction blockers to be not only tissue specific, but also to differ from species to species. It is still unclear whether these differences seen really are through the blockade of gap junctions, or due to the secondary effects of the blockers used. Further studies showed that strychnine (1 muM) prevented this transient activity increase in spinal cord networks, implying that CBX may temporarily block glycine inhibition. Blocking intracellular calcium mobility with thapsigargin (up to 5 muM) did not affect the effects of gap junction blockers used.

Transcranial magnetic stimulation (TMS) is a non-invasive technique used to reversibly modulate the activity of cortical neurons using time-varying magnetic fields. Recently TMS has been used to demonstrate the functional necessity of human cortical areas to visual tasks. For example, it has been shown that delivering TMS over human visual area V5/MT selectively disrupts global motion perception. The temporal resolution of TMS is considered to be one of its main advantages as each pulse has a duration of less than 1 ms. Despite this impressive temporal resolution, however, the critical period(s) during which TMS of area V5/MT disrupts performance on motion-based tasks is still far from clear. To resolve this issue, the influence of TMS on direction discrimination was measured for translational global motion stimuli and components of optic flow (rotational and radial global motion). The results of these experiments provide evidence that there are two critical periods during which delivery of TMS over V5/MT disrupts performance on global motion tasks: an early temporal window centred at 64 ms prior to and a late temporal window centred at 146 ms post global motion onset. Importantly, the early period cannot be explained by a TMS-induced muscular artefact. The onset of the late temporal window was contrast-dependent, consistent with longer neural activation latencies associated with lower contrasts. The theoretical relevance of the two epochs is discussed in relation to feedforward and feedback pathways known to exist in the human visual system, and the first quantitative model of the effects of TMS on global motion processing is presented. A second issue is that the precise mechanism behind TMS disruption of visual perception is largely unknown. For example, one view is that the “virtual lesion” paradigm reduces the effective signal strength, which can be likened to a reduction in perceived target visibility. Alternatively, other evidence suggests that TMS induces neural noise, thereby reducing the signal-to-noise ratio, which results in an overall increase in threshold. TMS was delivered over the primary visual cortex (area V1) to determine whether its influence on orientation discrimination could be characterised as a reduction in the visual signal strength, or an increase in TMS-induced noise. It was found that TMS produced a uniform reduction in perceived stimulus visibility for all observers. In addition, an overall increase in threshold (JND) was also observed for some observers, but this effect disappeared when TMS intensity was reduced. Importantly, susceptibility to TMS, defined as an overall increase in JND, was not dependent on observers’ phosphene thresholds. It is concluded that single-pulse TMS can both reduce signal strength (perceived visibility) and induce task-specific noise, but these effects are separable, dependent on TMS intensity and individual susceptibility.

This thesis aimed to further investigate the effects of movements on modulations of visual and somatosensory perception. The first experiment (Chapter 2) investigated spatial mislocalisation of visual stimuli presented before saccade using a pointing paradigm and found that a predictive remapping of visual space occurred before saccade and the post-saccadic remapping employed spatially as well as temporally accurate memory of pre-saccadic visual stimuli. The second experiment (Chapter 3) examined relevance of saccadic chronostasis to remapping of visual space using a target displacement paradigm and found that it did not serve as a mechanism that fills in a perceptual gap during saccadic suppression. The third (Chapter 4) and fourth (Chapter 5) experiments adopted a target blanking paradigm and found that the pre-saccadic stimuli predictively remapped before saccade were anchored to the location of the pre-saccadic target remapped using a precise efference copy and neither saccade landing sites nor remembered locations of pre-saccadic targets were used in this process. Behavioural (Chapter 6) and fMRI (Chapter 7) studies were conducted to investigate modulations of tactile perception by manual movements and found that the tactile attention induced by the cued index finger facilitated processing of tactile stimuli presented to the responded hand. The somatosensory ROIs mainly showed a bias towards contralateral tactile stimulation in comparison with ipsilateral tactile stimulation. The right primary motor cortex (right M1), the left precuneus (left PreC) and the left middle frontal gyrus (left MFG) showed significant modulations of somatosensory processing by the Moving condition compared to the Non Moving condition. The final chapter included summaries and conclusions of each chapter and proposals for future investigations.

The auditory nerve conveys fine-grained temporal information that reflects individual cycles of the basilar membrane vibration. The current project is concerned with how this temporal fine-structure information is processed in the human auditory system. Integration of fine-structure temporal information across the ears (binaural processing) plays a crucial role in sound localisation and signal detection in noise. However, in monaural processing, the role of temporal fine-structure information remains uncertain, because spectral information is usually also available. The first study in this project used behavioural methods, along with model simulations, to show that the binaural system exploits phase differences between disparate frequency channels for processing fine-structure interaural temporal differences (ITDs). The second study explored the neural representation of ITDs by using electroencephalography (EEG) to measure the transient brain response to a change in ITD in an otherwise continuous sound. The results suggest that fine-structure ITDs are coded by a non-topographic opponent-channel mechanism, based on the overall activity levels in two broadly tuned hemispheric channels. The third study used rapid event-related functional magnetic resonance imaging (fMRI) to investigate the topography of the transient ITD change response measured in the second study. The ITD change response was compared with the transient response to the onset of pitch in an otherwise continuous sound. It was found that the topographies of the transient ITD and pitch responses were very similar to the topographies of the corresponding sustained responses measured in previous epoch-related fMRI studies. The last two studies examined whether temporal fine-structure information is used for frequency coding in monaural processing. The fourth study aimed to eliminate temporal fine-structure cues from the neural representation of low-frequency pure tones by presenting the tones in conditions of binaural unmasking, because a previous study had shown that temporal envelope cues to pitch are inaccessible in such masking conditions. However, frequency discrimination performance for pure tones was found to be similar in monaural and binaural masking conditions. The fifth study suggests that this was because frequency discrimination of low-frequency pure tones relies on spectral rather than temporal cues. In this study, frequency discrimination performance was measured for partially masked pure tones and was found to reflect the level-dependent changes in the shape of the pure-tone excitation pattern.

OBJECTIVE This thesis examines sex differences in the structural properties of the corpus callosum (CC) during adolescence and investigates the possible role of sex hormones in the development of these sex differences, as well as hormonal effects on the inter-individual variations in the structure of the CC in young women. DESIGN This thesis is conducted on three separate study samples: 1) the Saguenay Youth Study (SYS) sample (n=737); 2) the IMAGEN Study sample (n=1,979); and 3) the Cycle Study sample (n=26). The SYS and IMAGEN studies are large-scale studies carried out with magnetic resonance imaging (MRI) in typically developing adolescents from Canada (12 to 18 years) and Europe (13 to 15 years), respectively. In these studies, the “sex hormone-CC” relationship is explored by examining the association between the CC and: testosterone level, duration of sex hormone exposure (since menarche), puberty stage and contraceptive use. The Cycle study examines the CC of 13 freely cycling and 13 oral contraceptives (OCP) using young women (18 to 30 years) scanned using MRI across four separate phases of their menstrual cycle. Freesurfer-based computational anatomy is used to estimate the volume of the total corpus callosum and its segments in all three studies. Magnetization transfer imaging (MTI) is used to assess microstructural properties of the corpus callosum in the Cycle study. RESULTS The relative volume of the corpus callosum is seen to be sexually dimorphic in both the SYS and IMAGEN adolescents with a female versus male advantage that is particularly significant for the anterior, central and posterior segment of the corpus callosum; the mid-anterior segment is larger in males versus females. Pubertal stage of adolescent boys (SYS) demonstrates a negative correlation with the relative volume of the anterior CC and a positive correlation with the relative volume of the mid-anterior CC. These associations are consistent with the sex differences observed (anterior: F>M; mid-anterior: M>F), thus suggesting that male sex hormones that are responsible for inducing pubertal development of boys may play a role in generating the sexually dimorphic volume of the corpus callosum in a region-specific manner. Contraceptive use in adolescent girls (SYS and IMAGEN) is negatively associated with the relative volume of the corpus callosum. In addition, the Cycle study demonstrates a trend for lower MTR values in women using contraceptives versus freely cycling women, thus suggesting that the natural sex steroids suppressed by use of oral contraceptives may exert a positive effect on the volume of the CC, possibly by increasing the degree of myelination. The Cycle study demonstrates an increase in the relative volume of the total corpus callosum of freely cycling women from the ovulatory to the luteal phase with corresponding decreases in the MTR value of the total CC. This finding suggests that increased production of progesterone during the luteal phase may cause an increase in the relative volume of the CC, possibly by increasing the axonal calibre. CONCLUSION Sex steroids influence the structure (relative volume and MTR) of the corpus callosum.

Functional magnetic resonance imaging (fMRI) has become a ubiquitous tool in cognitive neuroscience. The technique allows the non-invasive measurements of cortical responses, but only on the millimeter scale. Recently, two methods aimed at studying the selectivity of neuronal populations on a subvoxel scale. The first technique, fMRI adaptation, relies on the observation that the fMRI response in a given voxel is reduced after prolonged presentation of a stimulus, and that this reduction is selective to the characteristics of the repeated stimuli. The second technique, multi-variate pattern analysis (MVPA), makes use of multi-variate statistics to recover small biases in individual voxels. This thesis compared the two techniques with the aim of studying early- and mid-level processing in the visual cortex. Chapter 3 investigated whether adaptation and MVPA provide consistent results about the properties of the cortical areas under study. To address this question, this thesis compared the two methods for their ability to detect the well documented orientation selectivity in early visual cortex. Using optimised experimental designs for each, this thesis found that the MVPA approach was more sensitive to small differences in stimulus orientation than the adaptation paradigm. Estimates of orientation selectivity obtained with the two methods were, however, very highly correlated across visual areas. Chapters 4 and 5 used both techniques to investigate how local orientation signals are combined and detected in intermediate levels of visual processing. In both chapters the MVPA was more efficient in detecting differences between stimulus categories. In particular, chapter 4 used plaid stimuli, made of the linear sum of two sinusoidal gratings. We obtained weak but consistent evidence, pointing to the direction that V2 might play a role in Fourier component integration. Chapter 5 used contour stimuli constructed from two luminance modulated sinusoidal gratings, with different orientations. Whereas, adaptation failed to reveal contour selectivity, MVPA accuracy was high in most areas tested. However, the experiment did not reveal a significant difference between the test and control conditions. Chapter 6 investigated the encoding of spatial phase in the cortex. Phase is a fundamental aspect of spatial vision, crucial both for the extraction of local features and overall scene perception. This thesis showed that several visual areas, including the primary visual cortex, were sensitive to relative phase combinations. However, phase coherence was optimally encoded in extrastriate areas as predicted by the physiological properties of higher regions.

This thesis concerns the investigation of metabolic changes in 1H metabolite levels in the human visual cortex due to visual stimulation using proton magnetic resonance spectroscopy (1H-MRS) at 7T. The work described in this thesis has been undertaken by the author and collaborators at the Sir Peter Mansfield Magnetic Resonance Centre at the University of Nottingham. Detection of functional changes in 1H metabolites may enable a greater understanding of neurotransmitter activity and metabolic pathways used for energy synthesis during activation of brain tissue. Previous 1H MRS studies of the activated human brain mainly focused on observing lactate (Lac) changes. More recent studies by Mangia et al, taking advantage of the increased signal and spectral resolution at 7T, have investigated the change in the level of Lac, glutamate (Glu), Aspartate (Asp) and Glucose (Glc) during activation. However, Mangia, did not measure significant change in the level of gamma aminobutyric acid (GABA) and Glutamine (Gln), which might be expected to change due to increased neurotransmitter cycling rates during activation. Given that the metabolite changes observed due to visual stimulation were relatively small. We used a long, intense visual stimulus, designed to retain attention, to confirm and quantify the changes in the levels of Glu, GABA, and Gln, and to further investigate the Lac and Asp response to visual stimulation. Our present results using a moving stimulus of full-screen flickering contrast-defined wedges, have demonstrated many more metabolic changes throughout two different time scales of stimulation. Small (2~11%) but significant stimulation induced increases in Lac, Glu and glutathione (GSH) were observed along with decreases in Asp, GIn and glycine (Gly). In addition, decreases in (intracellular) Glc and increases in GABA were seen but did not reach significance. The opposite changes in Glu and Asp are indicative of increased activity of the malate-aspartate shuttle, which taken together with the opposite changes in Glc and Lac reflect the expected increase in brain energy metabolism. The increases in Glu and GABA coupled with the decrease in GIn can be interpreted in terms of increased activity of the Glu/Gln and Gln/Glu/GABA neurotransmitter cycles. An entirely new observation is the increase of GSH during prolonged visual stimulation. The similarity of its time course to that of Glu suggests that it may be a response to the increased release of Glu or to the increased production of reactive oxygen species. Gly is also a precursor of GSH and a decrease on activation is consistent with increased GSH synthesis. Together these observations constitute the most detailed analysis to date of functional changes in human brain metabolites. Interestingly, the Lac response was confined to the first visual stimulus. It is possible that processes triggered during the first period of visual stimulation, could continue for a while after stimulation has ended. If this is an important mechanism of the activity-stimulated brain Lac response, shortening the duration of the first stimulus might lead to an increase in Lac response during the second period of stimulation. With this in mind, we designed a repeated visual stimulation paradigm, varying the duration of the first stimulation (shorter than 9.9-min, based on our previous results), to see the effect on the Lac response during the second visual stimulation period. A gradual increase in Lac under the prolonged stimulation, following the first brief stimulation (1s, 16s and 48s, respectively), was observed and maintained until the end of these periods. Lac responses during the second stimulation period looked similar whether the first stimulation was 1s or 16s. With the increase of first visual stimulus duration (48s), the Lac response under the second stimulation period was slightly diminished. No significant Lac accumulation can be evident to the second stimulation, when the initial stimulation was 288s. The averaged Lac level was considerably below baseline after cessation of the first 288s stimulus. It is possible that the increased glycolytic flux, triggered during the initial longer stimulation, would still continue for a while during recovery, accounting for the decreased brain Lac level during resting periods from stimulation. Further experiments are ongoing, varying the duration of the second resting periods, to see the effect on the Lac response to the second stimulation.

Recognition memory is a part of declarative memory; defined as the ability to discriminate previously presented stimuli from novel stimuli (Squire, Wixted & Clark, 2007). This thesis reports eight experiments that investigated factors that modulate recognition memory using a recognition memory paradigm that reflects the space learning effect (Greene, 1989) and repetition. Results from chapter two varied the space between stimuli repetition across two presentations and found that stimuli that is repeated following a short delay, and then repeated again following a longer delay led to poorer recognition memory compared to other variations. Additionally, results showed impaired recognition for older adults compared to younger adults for first repetition, but not for the second repetition, where no age effects were found (Experiment 1). Electroencephalography (EEG) technique (Experiment 2) examined the old/new effects (higher mean amplitude for old items compared to new items) pertaining to familiarity, recollection and post-retrieval monitoring through the three signatures commonly found in recognition memory, i.e. FN400, late positive component (LPC) and the late frontal effect (LFE) respectively to understand the underlying processes that supports repetition. Contrary to prior research, results showed an absence of the FN400 and LPC effect. However, with respect to the LFE, there was a reverse old/new effect in the left anterior superior (LAS) region for stimuli repeated for the first time which can be attributed to decision making, memory evaluation, and confidence in line with past literature (Allan et al, 1998; Ally & Budson, 2007; Ally et al. 2008; Dobbins & Han, 2006; Fleck, Daselaar, Dobbins & Cabeza, 2006). Chapter 3 investigated the effects of uni-modal (auditory or visual presented alone) and multi-modal stimuli, i.e. auditory and visual modality presented together (cross-modal), on recognition memory. The results show that unlike visual and cross-modal memory retrieval, repetition does not facilitate auditory recognition memory. The results also show that participants have higher d’ scores in the cross-modal stimuli compared to uni-modal stimuli (experiment 3). Although older participants show benefits with cross-modal stimuli, and with repetition, they still performed poorer compared to their younger counterparts (experiment 4). Chapter four investigated semantic congruency of multi-modal pairs in recognition memory. The results show that this effect only lasts for the first repetition and is absent for subsequent repetitions, for both older and younger adults (experiment 5). ERP results showed the presence of the FN400 old/new effect for trials repeated for the second time in the LAS region indicating recognition may be supported by familiarity for items repeated for the second time. In contraction to past research, there was no LPC or the LFE effects seen (experiment 6). Lastly, chapter five focuses on recognition memory in relation to modality mismatch. Modality mismatch is a situation that arises when information is encountered in a different modality compared to when it was initially presented (Mulligan & Osborn, 2009). The results from chapter five shows that auditory modality impairs recognition when it is either presented initially, or after a short delay. However, auditory presentations with a semantically associated pair (visual), either at initial presentation, or only if its pair was encountered after a short delay, there was no significant effect of modality mismatch at long delay (experiment 7). Results showed an absence of the FN400 effect indicating that FN400 effect is sensitive to perceptual match in line with Tsivilis et. al (2001). Lastly, experiment 8 showed that in the presence of modality mismatch, ERP results suggest that participants may rely on recollection to guide recognition process as seen by the presence of the LPC effect. Furthermore, the LPC also seems to index the amount of information to be retrieved consistent to past research (Fjell, Walhovd & Reinvang, 2005; Vilberg, Moosavi & Rugg, 2006), whereby larger amplitude were seen when the trial was in the cross-modal format compared to uni-modal format. As for the LFE component, the presence of the larger mean amplitude in the superior regions for uni-modal trials repeated for the second time suggests further post-retrieval monitoring associated with retrieval of additional information presented initially. Overall findings of this thesis have explored the factors that affect recognition memory, namely repetition, modality and age, and attempted to determine the underlying processes supporting recognition memory when items are repeated, or pairs of stimuli are semantically associated or modality is mismatched during encoding. This is particularly implicated in learning environments, providing further understanding in how repetition can enhance memory and its effects in environments where incongruent information is received, or repeated information encountered in a different modality.

Background: The brain is the most commonly affected organ during Toxoplasma gondii infection but the mechanisms utilized by this protozoan parasite for disrupting the brain's endothelial cells lining the blood–brain barrier (BBB) and moving to invade the brain are not yet understood. In the present study, we investigated the cellular pathogenicity of T. gondii infection in human brain microvascular endothelial cells (HBMECs), a fundamental component of the BBB. Methods: Intracellular development of T. gondii tachyzoites within HBMECs was characterized by using Acridine Orange (AO) staining. The integrity of HBMECs moolayer and tight junction permeability during T. gondii infection were assessed using transendothelial electrical resistance (TEER). Morphological changes associated with infection was assessed by scanning electron microscopy (SEM) and transmission electron microscope (TEM). Cell viability and metabolic changes associated with infection were identified using alamar blue and nuclear magnetic resonance (1H NMR). The changes in lipid content and fatty acid composition of the total phospholipids were evaluated using LipidTox staining and gas chromatography (GC). The changes in the content of trace elements in response to T. gondii infection was assessed using inductively coupled plasma mass spectrometry (ICP-MS). Results and Discussion: The invasion, growth, and replication of T. gondii tachyzoites within HBMECs are possible, with disruption of the integrity and viability of the host cell through the course of infection. AO staining of T. gondii tachyzoites infecting HBMECs showed a marked increase in the surface area of tachyzoites during infection, indicating that tachyzoites invade their host cell and form their own compartments (PV) in which tachyzoites proliferate with a generation time of 24 h, eventually leading to cell rupture and exit of the parasites. A decrease was noted in the TEER of infected cells compared to uninfected controls, indicating that the invasion of the HBMECs by T. gondii had detectable effects on the integrity HBMECs monolayer by increased tight junction permeability. Morphological analysis revealed that the intracellular development of the tachyzoites disruption of tight junctions HBMECs monolayer and reorganization of some organelles of the host cell, such as the mitochondria, endoplasmic reticulum, and Golgi apparatus around the Parasitophorous vacuole membrane (PVM) and remained stable throughout the growth of the tachyzoites. The tight association between the PVM and host organelles may provide lipids and other macromolecules for parasite survival, proliferation, membrane biogenesis, and energy requirement. A marked decrease was noted in cell viability of infected cells at 48 h PI, compared to uninfected controls by alamar blue assay, indicating that growth of the parasites that cause a metabolic burden on the host cells. Metabolite analysis of HBMECs infected with T. gondii revealed a drastic increase in lactate and glutamine levels, as well as a reduction in choline and myo-inositol levels with infection. A drastic increase in lactate and glutamine levels may be attributed to the fact that T. gondii requires energy from the host, primarily via glycolysis and glutaminolysis. It is believed that increased lactate and glutamine levels result in increased paracellular permeability. A drastic reduction in choline and myo-inositol levels suggests the use of host lipid fractions for increased membrane maintenance or parasite lipid anabolism. It is believed that increased phosphatidylcholine levels result in altered monolayer permeability. Fatty acid analysis of HBMECs infected with T. gondii revealed a significant increase in C18:0 and C18:1n9c. It is believed that increased monounsaturated and polyunsaturated fatty acids result in increased tight junction permeability via modulated occludin and ZO-1 localization. Trace element analysis of HBMECs infected with T. gondii revealed a significant increase in Zn, Fe, Mg, and Cd levels, as well as a reduction in Co levels in growth medium obtained from the infected cells compared to non-infected controls. It is possible that altered trace elements levels, whether a parasite-induced or host-cell response, is important for protection against cellular oxidative stress and DNA damage during infection, and for suppressing cell apoptosis. In conclusion, the results obtained show that HBMECs permit the invasion, growth and proliferation of T. gondii tachyzoites and that infection can disrupt tight junction permeability and cause multiple morphological changes in the relocation of the host cell organelles around the PV and changes in the levels of host cell metabolites and trace elements. These findings provide a more in depth understanding of how T. gondii replicate within the HBMECs during infection, which may lead to novel ways to prevent or treat this disease.