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Chapter 1 introduces the notions of multisensory integration (the binding of information coming from different modalities into a unitary percept) and multisensory response enhancement (the improvement of the response to multisensory stimuli, relative to the response to the most efficient unisensory stimulus), as well as the general goal of the present thesis, which is to investigate different aspects of the multisensory integration of auditory and visual stimuli in manual and saccadic responses. The subsequent chapters report experimental evidence of different factors affecting the multisensory response: spatial discrepancy, stimulus salience, congruency between cross-modal attributes, and the inhibitory influence of concurring distractors. Chapter 2 reports three experiments on the role of the superior colliculus (SC) in multisensory integration. In order to achieve this, the absence of S-cone input to the SC has been exploited, following the method introduced by Sumner, Adamjee, and Mollon (2002). I found evidence that the spatial rule of multisensory integration (Meredith & Stein, 1983) applies only to SC-effective (luminance-channel) stimuli, and does not apply to SC-ineffective (S-cone) stimuli. The same results were obtained with an alternative method for the creation of S-cone stimuli: the tritanopic technique (Cavanagh, MacLeod, & Anstis, 1987; Stiles, 1959; Wald, 1966). In both cases significant multisensory response enhancements were obtained using a focused attention paradigm, in which the participants had to focus their attention on the visual modality and to inhibit responses to auditory stimuli. Chapter 3 reports two experiments showing the influence of shape congruency between auditory and visual stimuli on multisensory integration; i.e. the correspondence between structural aspects of visual and auditory stimuli (e.g., spiky shape and “spiky” sounds). Detection of audio-visual events was faster for congruent than incongruent pairs, and this congruency effect occurred also in a focused attention task, where participants were required to respond only to visual targets and could ignore irrelevant auditory stimuli. This particular type of cross-modal congruency was been evaluated in relation to the inverse effectiveness rule of multisensory integration (Meredith & Stein, 1983). In Chapter 4, the locus of the cross-modal shape congruency was evaluated applying the race model analysis (Miller, 1982). The results showed that the violation of the model is stronger for some congruent pairings in comparison to incongruent pairings. Evidence of multisensory depression was found for some pairs of incongruent stimuli. These data imply a perceptual locus for the cross-modal shape congruency effect. Moreover, it is evident that multisensoriality does not always induce an enhancement, and in some cases, when the attributes of the stimuli are particularly incompatible, a unisensory response may be more effective that the multisensory one. Chapter 5 reports experiments centred on saccadic generation mechanisms. Specifically, the multisensoriality of the saccadic inhibition (SI; Reingold&Stampe, 2002) phenomenon is investigated. Saccadic inhibition refers to a characteristic inhibitory dip in saccadic frequency beginning 60-70 ms after onset of a distractor. The very short latency of SI suggests that the distractor interferes directly with subcortical target selection processes in the SC. The impact of multisensory stimulation on SI was studied in four experiments. In Experiments 7 and 8, a visual target was presented with a concurrent audio, visual or audio-visual distractor. Multisensory audio-visual distractors induced stronger SI than did unisensory distractors, but there was no evidence of multisensory integration (as assessed by a race model analysis). In Experiments 9 and 10, visual, auditory or audio-visual targets were accompanied by a visual distractor. When there was no distractor, multisensory integration was observed for multisensory targets. However, this multisensory integration effect disappeared in the presence of a visual distractor. As a general conclusion, the results from Chapter 5 results indicate that multisensory integration occurs for target stimuli, but not for distracting stimuli, and that the process of audio-visual integration is itself sensitive to disruption by distractors.

Mutations in the RAS-RAF-MEK-ERK (MAPK) pathway give rise to a range of developmental disorders collectively referred to as the RASopathies. De novo germline mutations in patients suffering from these syndromes promote similar phenotypes, which include heart abnormalities, characteristic facial features, cutaneous malformations, gastrointestinal malfunctions, failure to thrive and a spectrum of mental retardation. Although many RASopathies patients show a propensity to develop early-onset benign and malignant tumours, Cardio-faciocutaneous (CFC) syndrome patients do not seem to share this predisposition, with the exception of an increased number of naevi. CFC syndrome is caused by mutations in BRAF, MEK1 or MEK2, with the majority of patients harbouring BRAF mutations. Intriguingly, both kinase-activating and kinase-impaired mutations have been identified in CFC patients. Here, I use the zebrafish system to address the activity of the CFC syndrome alleles and the MAPK pathway in a developmental context and test the potential of small molecule inhibitors to restore normal development. I established an assay for the activity of CFC, melanoma and engineered BRAF and MEK human mutated alleles in vivo. Using zebrafish as an animal model organism, a panel of 31 mutant and wild-type BRAF, MEK1 and MEK2 alleles were expressed in early zebrafish embryos to assess their role in development. Irrespective of the predicted kinase activity, all embryos expressing BRAF and MEK mutant alleles reproducibly manifested the cell movement phenotype during gastrulation. Consistent with aberrant fibroblast growth factor (FGF) signalling and defective gastrulation, in situ hybridisation against convergence-extension markers showed misregulated convergence-extension movement patterns in CFC zebrafish embryos. Finally, I performed whole embryo RNA expression microarrays to identify genes regulated downstream of the CFC mutations, and I discuss the potential for a possible link to some of the phenotypes associated with a CFC zebrafish model. I established that the CFC, BRAF and MEK mutant embryos are sensitive to inhibition of MEK signalling by small molecules. Importantly, a time-window of treatment was identified which was sufficient to restore normal gastrulation movements and to prevent the developmental side effects promoted by the inhibitors at later stages of development. In order to begin considering the therapeutic potential of small molecules in developmental disorders (at least in our model system), the effect of low concentrations of the inhibitors in the normal formation of diverse tissues was thoroughly examined during zebrafish development. From these studies, I identified a concentration of MEK inhibitor that could be administered in a continuous fashion to prevent CFC-associated cell movement defects during gastrulation, without additional later developmental defects. Finally, I addressed the role of MEK-ERK signalling in a specific behavioural phenotype in zebrafish. Many RASopathies patients suffer from mental retardation and experience learning and attention difficulties. Research in our laboratory has identified a novel zebrafish behaviour induced by enhanced cAMP signalling, where the zebrafish seek shaded areas in their environment and exhibit frequent defensive shoaling behaviour. I used western blotting to establish that enhanced cAMP signalling activates the MAPK signalling pathway and, in collaboration with members our laboratory, that this phenotype can be suppressed by administration of the PD325901 MEK inhibitor. While we do not yet know the effect of CFC syndrome mutations on this behaviour, we suggest that altered MEK-ERK signalling may underlie important features of vertebrate behaviour.

Selective attention is a filtering system that focuses on relevant information in our environment while irrelevant information is suppressed. The two well-known components of selective attention, facilitation and inhibition, work hand in hand to aid the processing of relevant information. The main theme of the present thesis was to study the inhibitory component of visual selective attention using stimuli such as motion and shape in a rapid serial visual presentation. Therefore, the first three experimental chapters investigated how relevant motion and shape information are processed and perceived in the presence of similar irrelevant information. The findings showed that first order visual motion detection is impaired in the presence of distracters and this inhibition of distracters is generated in a bottom-up manner. The findings were, however, not straightforward. The findings from Experiments 6-10 showed that distracter information (shape) influences shape target detection only when distracters are made salient and the perceptual load of the task is moderately difficult. Collectively, the findings in this present thesis suggest that there may be more than one kind of inhibition generated for different kinds of stimuli.

Following recent research linking executive functioning to children 's skills, this thesis explores the relationship between children's inhibition effciency and mathematical ability. This relationship was initially explored using six Stroop task variants containing verbal, numerical or pictorial stimuli. The results indicated that, in the numerical variants only, children of lower mathematical abilty possess less effcient inhibition mechanisms, compared to children of higher mathematical ability. Thus, it is proposed that low-abilty mathematicians may possess a domain-specifc problem with the inhibition of numerical information. The increased interference scores of the lowability mathematicians, however, were only evident under those conditions which also required a degree of switching between temporary strategies. A series of experiments also examined children's ability to inhibit prepotent responses and switch between strategies whilst performing mental arithmetic. The aim of these experiments was to provide a more naturalistic and appropriate exploration of the hypothesized relationship between mathematical abilty and inhibition effciency. These results also indicated that low-ability mathematicians possess fewer executive resources to cope with increased inhibition demands. A further systematic manipulation of switching and inhibition demands revealed that the low-abilty mathematicians experienced a particular difculty when both types of inhibitory demands (i.e. inhibiting a prepotent response and inhibiting an established strategy)were present. This suggests that their reduction in inhibition effciency stems from the amount of demands, rather than the type of demands placed on the executive system. Furthermore, the results indicated that inhibition effciency may be a specifc element of mathematical ability rather than an element of intellectual ability in general. The final study involved a group of low-abilty mathematicians and examined the disturbing impact of irrelevant information on their arithmetic word problem solving abilty. This study revealed that irrelevant numerical (IN) information has a more detrimental impact on performance than irrelevant verbal (IV) information. It is proposed that it is more difcult to inhibit IN information, as it appears more relevant to intentions, and thus, enters WM with a higher level of activations. In sum, the results indicate that low-abilty mathematicians have a reduced domainspecific working memory capacity, characterized by ineffcient inhibition mechanisms.