Biophysical simulations of memory must choose which aspects of known neurophysiology and neuroanatomy to model. Relevant aspects were constrained by functional requirements determined for on-line acquisition in context dependent memory, memory that is retrieved by contextual cues. In an on-line task, the protocol of data presentation and the tunes at which encoding or retrieval in memory is needed are not predetermined. A sequence of neuronal spike patterns representing items may be presented only once. Yet, episodic memory of the sequence immediately encodes the temporal context of familiar items, a process known to depend on hippocampal function. For this, interference caused by overlapping spike patterns must be avoided, a requirement that suggested the relevance of coincidental spiking. Overlap in the input to the hippocampus was reduced by recruiting such spikes in a model of encoding in dentate gyrus. Durable encoding is required in the hippocampus, since hippocampal damage can cause retrograde amnesia in context dependent memory that spans years. Long-lasting synaptic changes involved modeling relevant neurophysiology concerning protein production elicited by the spaced reactivation of spike patterns. The likelihood of reactivation was increased by the well-known process of long-term potentiation of synaptic transmission. Such potentiation is elicited when a presynaptic spike precedes a postsynaptic spike within a specific time window repeatedly. The intervals in a sequence of spike patterns must be compressed and the sequence repeated, requirements that were achieved with a model of short-term memory based on persistent spiking. Retrieval may be concurrent with these encoding processes due to effects of different phases of a brain rhythm at theta frequency (3-12 Hz) that modulate transmission and plasticity. A model of short-term memory by Lisman and Idiart (Science 267:1512-15), extended by Jensen et al. (Learning and Memory 3:243

Studies investigating human information processing have provided evidence that in some cases, movements can be prepared in advance. Although evidence for motor preparation has been shown at cortical and spinal levels, motor preparation at a subcortical level is not well described. One line of inquiry has involved the use of a startling acoustic stimulus (115-124 dB) that can act as an early trigger for pre-programmed actions in reaction time (RT) tasks. In light of this new research paradigm, the startle reflex may be used as a tool to investigate motor preparation. Here, six experiments were conducted that work towards the goals of understanding the mechanism of RT shortening due to startle, and motor preparation at a subcortical level. The first section (2 experiments) of this dissertation provides evidence that when a motor action can be prepared in advance, it is pre-programmed and stored subcortically awaiting the normal cortical “go” signal. A startle appears to activate structures directly that are involved with the voluntary response channel leading to early triggering of the pre-programmed response, and dramatically reduced RT. In the current dissertation we investigated alternative mechanisms to explain startle RT facilitation, including the stimulus intensity effect, and a fast transcortical route, with results supporting the original subcortical storage hypothesis. The second section (4 experiments) presents data which together provide insight into motor programming processes, and the circumstances under which a response is pre-programmed. For example, when the possibility of not having to make the response existed, a known response was not pre-programmed. Similarly, no pre-programming occurred when certainty existed regarding when to respond. However, while a previous experiment showed that having to make a choice between several response alternatives precluded pre-programming, this dissertation shows that if possible response alternatives are not in conflict with one another, multiple responses can be prepared in parallel. Finally, the complexity of a response such as one involving multiple sequenced sub-components may limit the ability to pre-program in a simple RT task. Taken together, these results suggest that pre-programming is dependent on the task characteristics and appears to involve implementation of strategies to increase programming efficiency.

Glycine is the third most abundant of the amino acids released by muscle. Perfused rat hind-limb and sheep diaphragm preparations were employed to study the origin of glycine produced by non-ruminant and ruminant muscle. Neither the degradation of muscle and erythrocyte glutathione nor the 'leaching out' of the intracellular glycine pool contributed to the glycine released by either muscle. When the perfusions were carried out with the medium free of amino acids, the proteolysis accounted for 57% of the total glycine release by the rat hind-limb and 38% by the sheep diaphragm. Minimum de novo synthesis of glycine was 12.3 umol/3 h/30 g in the rat muscle and 10.3 umol/3 h/30 g in the sheep muscle. Addition of serine to the perfusion medium stimulated significantly both the rate of glycine efflux and total glycine production in the rat hind-limb. Similar results were obtained with the sheep diaphragm; however, the increases were not statistically significant. Addition of 5-formyl tetrahydrofolate, a specific inhibitor of serine hydroxymethyltransferase, SHMT (EC 2.1.2.1) significantly decreased the rate of glycine efflux from both the muscles. The observations using cold serine were confirmed with the experiments employing radioisotopes. Up to 40% of total glycine produced by the rat hind-limb was derived from serine, whereas in the sheep diaphragm it was only 4%. In both the muscles synthesis of glycine from serine was by SHMT and not glycine synthase (EC 2.1.2.10). Synthesis of glycine from threonine was negligible in both the muscles. SHMT activity increased in liver, diaphragm and hind-limb muscle of female rats treated with trenbolone acetate or testosterone, anabolic agents. Both the muscles incorporated 14C from (U-14C) serine and (3-14C) serine to methionine, cystine, alanine, aspartate and glutamate + glutamine. The label from (U-14C) glucose was recovered in serine and glycine in the rat hind-limb but not in the sheep diaphragm. A 'serine-glycine' cycle involving kidney and muscle is proposed. The possible significance of glycine released by muscle is discussed. Development of a system for the perfusion of sheep diaphragm with erythrocyte-free medium, and a method for the determination of radioactivity in C-2 of glycine also form a part of the thesis.

This thesis aimed to investigate the role of posterior parietal cortex (PPC) in relation to saccade planning and more specifically the spatial remapping processes essential to this behaviour. These experiments begin through the use of transcranial magnetic stimulation (TMS) on a version of the classic double-step saccade paradigm (Chapter 2). TMS was not found to disrupt spatial remapping on this task and a potential explanation for this in terms of task specifications was proposed. In Chapter 4 this theme was explored further through a series of variations on the double-step saccade task, in which the order of target presentation was manipulated; these led to the conclusion that both target encoding and spatial remapping are influenced by such task-related factors. In Chapter 3, a second set of TMS experiments is discussed, which investigated the updating of saccade plans in response to a change in target location, rather than eye position. Finally in Chapters 5 and 6 neuroimaging studies that aimed to evaluate the cortical areas involved in these processes are discussed. The first of these (Chapter 5) was an extension of the behavioural studies previously conducted in Chapter 4. The second employed a novel saccade paradigm to investigate the effect of intervening saccades made between the time of target encoding and execution (Chapter 6). The findings from these experiments supported the idea that the PPC is important for representing saccade goals and updating these following a change in the spatial relationship between the centre of gaze and the target location for a future saccade. In Chapter 7 the findings from the aforementioned studies were discussed in relation to current debate within this area of research, concerning in particular the functional significance of saccade-related neuronal activity in PPC, as were suggestions for future studies that might help provide further insight into these issues.

The aim of this thesis was to investigate the role of the perirhinal cortex in visual discrimination learning in the rat. Experiment one measured postoperative reacquisition of two sets of concurrent visual discriminations acquired at different time intervals prior to surgery. Perirhinal ablation did not result in a temporally graded retention deficit, but a deficit limited to immediate postoperative performance. Experiment two measured postoperative acquisition of a new set of concurrent visual discriminations, with a stimuli set of 15 pairs, thereby increasing demands on stimuli identification. It was found that perirhinal ablation did not affect postoperative acquisition. Experiment 3a measured postoperative acquisition of a two choice visual discrimination and generalisations to it. Perirhinal ablation led to an impairment in performing the visual discrimination when presented in the generalisation task. Experiment 3b measured the effects of perirhinal ablation on postoperative performance in generalisation to a visual discrimination learnt prior to surgery. It was found that perirhinal ablation led to a deficit in generalising to transformations in stimuli form, but not to transformations in stimuli size. Experiment four measured acquisition of a titrating visual generalization task that increased demands on stimuli identification. Perirhinal ablation impaired acquisition of this task. Experiment five was designed to measure the effects of perirhinal ablation on acquisition of a generalization task with complex visual stimuli. However, neither the sham or perirhinal animals succeeded in learning the task. The final experiment measured postoperative acquisition of a simple visual discrimination and its partial reversal and acquisition of a biconditional visual discrimination task. Perirhinal ablation impaired acquisition of the biconditional discrimination, whereas acquisition of the simple discrimination and its reversal remained intact. Therefore, perirhinal ablation in the rat leads to selective impairments in the acquisition and retention of visual discrimination learning. These findings suggest that the perirhinal cortex may contribute to discrimination learning tasks that require the identification of complex visual stimuli.

A new framework is described for managing uncertainty and for dealing with artefact corruption to introduce objectivity in the interpretation of the electroencephalogram (EEG). Conventionally, EEG interpretation is time consuming and subjective, and is known to show significant inter- and intra-personnel variation. A need thus exists to automate the interpretation of the EEG to provide a more consistent and efficient assessment. However, automated analysis of EEGs by computers is complicated by two major factors. The difficulty of adequately capturing in machine form, the skills and subjective expertise of the experienced electroencephalbgrapher, and the lack of a reliable means of dealing with the range of EEG artefacts (signal contamination). In this thesis, a new framework is described which introduces objectivity in two important outcomes of clinical evaluation of the EEG, namely, the clinical factual report and the clinical 'conclusion', by capturing the subjective expertise of the electroencephalographer and dealing with the problem of artefact corruption. The framework is separated into two stages .to assist piecewise optimisation and to cater for different requirements. The first stage, 'quantitative analysis', relies on novel digital signal processing algorithms and cluster analysis techniques to reduce data and identify and describe background activities in the EEG. To deal with artefact corruption, an artefact removal strategy, based on new reUable techniques for artefact identification is used to ensure that artefact-free activities only are used in the analysis. The outcome is a quantitative analysis, which efficiently describes the background activity in the record, and can support future clinical investigations in neurophysiology. In clinical practice, many of the EEG features are described by the clinicians in natural language terms, such as very high, extremely irregular, somewhat abnormal etc. The second stage of the framework, 'qualitative analysis', captures the subjectivity and linguistic uncertainty expressed.by the clinical experts, using novel, intelligent models, based on fuzzy logic, to provide an analysis closely comparable to the clinical interpretation made in practice. The outcome of this stage is an EEG report with qualitative descriptions to complement the quantitative analysis. The system was evaluated using EEG records from 1 patient with Alzheimer's disease and 2 age-matched normal controls for the factual report, and 3 patients with Alzheimer's disease and 7 age-matched nonnal controls for the 'conclusion'. Good agreement was found between factual reports produced by the system and factual reports produced by qualified clinicians. Further, the 'conclusion' produced by the system achieved 100% discrimination between the two subject groups. After a thorough evaluation, the system should significantly aid the process of EEG interpretation and diagnosis.

A conceptual model of visual perception has been developed using a multidisciplinary approach which combines both top-down and bottom-up descriptions of vision. Top-down psychological theories of visual perception have been investigated resulting in the development of a theory of perception which combines the best of existing accounts. Perception is defined in terms of a combination of "data driven" and "concept driven" explanations. Bottom-up neurophysiological descriptions have also been investigated to provide possible descriptions of structure and function for the development of a conceptual model based upon the theory. An attempt is made to provide a "complete" account of visual perception through the development of both the theory and conceptual model. Further it is envisaged that the development of such a model will provide new insight into the development of artificial vision systems and new algorithms for perceptual function in such systems.

The role of the FEF/FPA and SEF in oculomotor prediction was investigated using psychophysics, functional MRI (fMRI) and TMS. The separate contribution of advance knowledge of target direction and target timing to predictive saccades, and neural activity in frontal oculomotor structures was first investigated. The greatest proportion of predictive saccades were elicited when subjects had advance knowledge of both target direction and target timing; advance knowledge of target direction increased the proportion of predictive saccades, while advance knowledge of target timing decreased saccade latencies without increasing predictive saccades. Activity was greater in the FEF for all saccade tasks with a predictable component than reflexive saccades. Activity in the FEF was higher in tasks for which saccade latencies were lower. These data suggest that target direction and target timing independently reduce saccade latencies, and that this information converges in the FEF to allow the generation of predictive saccades. In the SEF, activity was greater only in the condition when both target direction and target timing were predictable. This finding may reflect a role of the SEF in oculomotor sequencing rather than in prediction per se. / In order to assess whether the FEF play a general role in oculomotor prediction, and not just in saccades, the role of the FPA in predictive pursuit was evaluated by applying TMS to the FPA and SEF during sinusoidal pursuit. TMS of the FPA modulated eye velocity both at peak target velocity and at the target turnaround. The induced changes in eye velocity occurred with a short latency, that is, before visual signals could travel from the retina to brainstem. This would suggest that TMS of the FPA likely increased the gain of the transformation of predictive signals, rather than visual signals, to motor commands. Stimulation of the SEF increased eye velocity only when applied at the target turnaround. Previous studies have demonstrated that stimulation of SEF increases eye velocity during pursuit initiation. Our finding that this facilitation also occurs at the target turnaround may berelated to similarities between pursuit initiation and the turnaround, including the necessity to rapidly increase eye velocity from zero.

The work presented in this thesis concerns neurophysiology and pharmacology of the oesophageal afferent pathways involved in oesophago-pharyngeal reflexes and oesophageal nociception. Disturbances of reflexes governing contractile and relaxation responses of the upper oesophageal sphincter (DOS) are likely to be implicated in the pathophysiology of conditions involving excessive oesophago-pharyngeal regurgitation, impaired oesophageal clearance, and an abnormal belch reflex. Visceral hypersensitivity, a heightened perception of gastrointestinal sensation is frequently observed in functional gastrointestinal disorders and provides compelling evidence that it plays an important role in the pathogenesis of functional heartburn and non-erosive reflux disease. The work in this thesis explores the neurophysiology, pharmacology and pathophysiology of oesophago-DOS reflexes in humans by experimentally inducing DOS relaxations in healthy controls and patients with reflux laryngitis, and by recording DOS motor responses during spontaneous oesophago-pharyngeal regurgitation. Nociception was assessed by measuring oesophageal sensitivity to electrical stimulation and oesophageal acid perfusion in healthy controls, which was then compared with several heartburn populations (functional heartburn, erosive and non-erosive reflux disease). Additional studies were performed to evaluate the potential role of intraluminal impedance in defining antegrade bolus flow through the pharyngo-oesophageal segment during swallowing as a prelude to the adaptation of the technique to find a more accurate method for the detection of oesophago-pharyngeal regurgitation. The main findings from this work are as follows. 1) Mucosal lignocaine-sensitive afferents mediate the distension-induced oesophago-DOS relaxation reflex and lignocaine insensitive, presumably muscular mechanoceptors, mediate the distension-induced oesophago-DOS contractile reflex. The latter reflex is also upregulated by oesophageal acidification indicative of a possible protective mechanism. 2) Prolonged studies in patients with proven oesophago-pharyngeal regurgitation demonstrated that the most common mechanism of oesophago-pharyngeal regurgitation is a transient, non-swallow related, relaxation of the DOS. 3) Experimental evaluation of the oesophago-DOS relaxation reflex revealed that it is upregulated in patients with reflux laryngitis, suggesting that the aberrant afferent signalling in the oesophagus may be a contributory factor mediating oesophago-pharyngeal regurgitation. 4) Measurement of oesophageal sensory thresholds in response to electrical stimulation and acid perfusion revealed that all patients, irrespective of the presence or absence of mucosal injury, exhibit acid-induced hypersensitisation. 5) The viscro-somatic referral pattern of acid- and electrically-induced chest pain is increased in patients with functional heartburn and non-erosive reflux disease. These findings support the hypothesis that central sensitisation of nociceptive pathways may contribute to symptom reporting in these heartburn populations.

Thesis (Ph.D.) -- McMaster University, 2001. / Includes bibliographical references (leaves 192-218). Also available via World Wide Web.