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Functional magnetic resonance imaging (fMRI) offers a number of opportunities to non-invasively study the properties of the human visual system. Advances in scanner technology, particularly the development of high-field scanners, allow improvements in fMRI such as higher resolution and higher signal to noise ratio (SNR). We aimed to examine what these advances in scanner technology, combined with novel analysis techniques, can tell us about the processing of motion stimuli in the human visual cortex. In Chapter 3 we investigated whether high-resolution fMRI allows us to directly study motion-selective responses in MT+. We used event-related and adaptation methods to examine selectivity for coherent motion and selectivity for direction of motion, and examined the potential limitations of these techniques. One particular analysis technique that has been developed in recent years uses multivariate methods to classify patterns of activity from visual cortex. In Chapter 4 we investigated these methods for classifying direction of motion, particularly whether successful classification responses are based on fine-scale information such as the arrangement of direction-selective columns, or a global signal at a coarser scale. In Chapter 5 we investigated multivariate classification of non-translational motion (e.g. rotation) to see how this compared to the classification of translational motion. The processing of such stimuli have been suggested to be free from the large-scale signals that may be involved in other stimuli, and therefore a more powerful tool for studying the neural architecture of visual cortex. Chapter 6 investigated the processing of plaid motion stimuli, specifically ’pattern’ motion selectivity in MT+ as opposed to ’component’ motion selectivity. These experiments highlight the usefulness of multivariate methods even if the scale of the signal is unknown.

Calcium ions play an important role in many signalling pathways involved in normal cell metabolism. Pertrebations of normal Ca++ signalling may also play a pivotal role in the initiation of cell death. In these studies I have examined the influx of 45Ca++ into the extensor tibiae muscle of the locust (Schistocerca gregaria ). 45Ca++ entry could be stimulated by the addition of glutamate receptor-agonists or by activation of voltage activated calcium channels. L-glutamate, L-quisqualate and NMDA stimulated the influx of 45Ca++ while L-aspartate had only a small effect. DL-ibotenate, kainate, AMPA and glycine had no effect on 45Ca++ uptake (all agonists were tested at concentrations up to (100μM). Glycine (1μM) enhanced the 45Ca++ entry induced by NMDA and L-glutamate. Only the glycine potentiation of L-glu-stimulated responses was abolished in the presence of Mg++ (2mM) or AP5 (10μM) whereas the NMDA-stimulated response was completely abolished by these agents. These finding suggests that in the presence of glycine, L-glutamate may activate NMDA receptors and that in the absence of glycine L-glu-stimulated 45Ca++ entry occurs via activation of the qGluR. Depolarisation of the extensor tibiae muscles (50mM KCl) stimulated 45Ca++ influx by activation of voltage-sensitive calcium channels. Philanthotoxin-343 (0.1μM) had no effect on depolarisation activated calcium entry, however, nifedipine (1μM) an L-type calcium channel antagonist inhibited this Ca++ influx. Nifedipine did not inhibit L-glu-stimulated Ca++ entry suggesting that in these muscles L-type Ca++ channels are not involved in the Ca++ influx pathway following G1uR activation. Philanthotoxin-433 (PhTX-433) and many of its synthetic analogues are potent inhibitors of locust GluR. In the future these analogues may prove as useful potential neuroprotective agents or as novel pesticides. Over 100 analogues of PhTX-433 have been synthesized with changes made in the four regions of the structure, the thermospermine moiety, the tyrosyl moiety, the butyryl moiety and the terminal amino moiety. The effects of different concentrations (10-4M to 10-14M) of synthetic analogues of PhTX-433 (PhTX-343, PhTX-343-Arg, PhTX-4) were investigated in the 45Ca++ influx assay using locust extensor tibiae muscle. PhTX-343-Arg was more potent (IC50= - 7x10-9) than PhTX- 343 (IC50= - 10-8M) or PhTX-4 in blocking 45Ca H uptake. These findings were further supported by electrophysiological studies. The interaction of these synthetic analogues of philanthotoxin with GluR of locust muscle were further investigated by examining the effect of these compounds on evoked excitatory post synaptic potentials. In recent years control of ticks have been very important issue because of the social and economical damage they cause. Neuromuscular transmission is a main target site for the chemical control of many pests. Philanthotoxin and its analogues block the glutamate receptors which are involved in arthropod neuromuscular transmission and thus may prove useful as novel pesticides. The action of synthetic analogues of philanthotoxin (C7PhTX-343, DNP12-, PhTX-343 and PhTX-343) were examined on evoked excitatory postsynaptic potential in tick coxal muscle. These compounds all antagonized the evoked EPSP. C7PhTX-343 and DNP12-PhTX-343 exhibited same potency (IC50 = 10-8M) and both were more potent than PhTX-343 (IC50 ='2X10-5M). In recent years Xenopus oocyte has taken over a new role as a test tube for the study of the biogenesis, functional architecture and modulation of plasma membrane protein. Attempts were made to express mRNA from embryonic tissue of tick and locust leg muscle in to Xenopus oocyte for pharmacological studies. Xenopus oocytes failed to translate RNA faithfully and efficiently from these sources. Rat brain RNA injected oocytes used as control, expressed routinely.

A ubiquitous feature of neural responses is their dependence on stimulus context. One prominent contextual effect is the reduction in neural response size with stimulus repetition, known as “adaptation”. As adaptation is often stimulus-specific, it has been used in visual neuroimaging studies to probe mechanisms of stimulus representation that would otherwise be hidden due to the limited spatial resolution of the available measurement techniques. However, work on the visual system has suggested that stimulus-specific adaptation may not only reflect stimulus representations, but may itself also modify representational information. The four studies described in this report examined the effects of stimulus context on auditory cortical responses using electroencephalography (EEG). The first study used adaptation to examine the neural representation of musical pitch in auditory cortex. Whilst pitch is often treated as a single dimension, namely, the repetition rate of the stimulus waveform, in music, pitch actually has two dimensions: pitch height (the octave in which a note resides) and pitch chroma (the position of the note within an octave). The current study provided evidence for an explicit representation of pitch chroma in an anterolateral region of non-primary auditory cortex. The second, third and fourth studies examined the auditory “mismatch response” (MMR). The MMR refers to the increase in response size to a stimulus when it is presented infrequently (as a “deviant”) compared to when it is presented frequently (as a “standard”). The second study found that the MMR could not be fully accounted for by a passive release from adaptation. Instead, the MMR seemed to reflect a sharpening of the neural representation of the adaptor stimulus with repeated presentation. This suggests that the MMR may be involved in perceptual learning. The third study examined the time courses of the contextual effects on neural responses. Both short- and longer-term effects were observed, with the effects differing between the different components of the auditory evoked response. Notably, the N1 component was influenced by complex effects that seemed to partially reflect the longer-term probabilities of certain short segments of the stimulus sequence, whereas the P2 was influenced by a strong suppressive effect with a remarkably short time course. The fourth study examined whether the contextual effects on auditory-evoked transient and sustained responses are sensitive to the absolute, or the relative, stimulus probabilities. For the transient N1 response, the most striking finding was that adaptation was broadly tuned for deviant stimuli, but sharply tuned for stimuli that were, in terms of their relative probabilities, standards. In contrast, the sustained response appeared to be influenced by a different effect, which facilitated responses to deviant stimuli. The current results suggest that contextual effects differ vastly between different deflections of the auditory-evoked responses, that they include effects that are both complex and long-lasting (of the order of ten seconds or longer), and that they involve not only suppressive, but also facilitatory effects.

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.