Synaesthesia is a cognitive trait in which stimuli of one sensory modality are automatically and consistently experienced in conjunction with perceptions in a separate modality or processing stream. Investigations of synaesthesia may help determine the neural processing required in the generation of a conscious experience. In order to gain the most complete understanding of synaesthesia, we have applied an integrated neurophenomenological approach. In Chapter 2 we present an extended case study of spatial-form synaesthesia (SFS) phenomenology. This investigation goes significantly beyond the rudimentary accounts of provided elsewhere, and provides novel observations on inducer-concurrent relationships, suggesting that guided introspection techniques can provide neurobehaviourally relevant information. In Chapters 3-5 we investigate neural activity in grapheme-colour synaesthesia (GCS). In Chapter 3 we demonstrate that activation in colour selective areas during synaesthetic colour processing is dependent on individual differences in phenomenology, thereby reconciling previous attempts to replicate this key finding in the GCS literature. In Chapter 4 we find no evidence for trait level differences in context specific functional connectivity in GCS, however, we demonstrate that localisation of the synaesthetic concurrents modulate connectivity between colour and low-level visual areas. In 5 we replicate findings of trait level differences in resting state fronto-parietal networks, suggesting that the RFPN may be a significant network in aspects of the synaesthetic experience common to all participants. We demonstrate that localisation of concurrents also modulates resting state visual networks, whilst automaticity of concurrents modulates parietal networks. Both Chapters 4 and 5 support a model of synaesthesia in which localisation of concurrents is modulated by bottom-up connectivity, between colour and early visual areas. This thesis demonstrates that individual differences in synaesthetic phenomenology significantly impact neural activity. We propose that future investigations place emphasis on the phenomenological experience of the participant in the interpretation of neural effects.

Epileptic seizures, characterised by paroxysmal disturbance of brain electrical activity, are recognisable by temporary change in clinical state (for example motor signs, behavioural modification or altered conscious level), temporally associated with the cerebral discharge. While analysis of such clinical seizure signs (“semiology”) formed the main basis of epilepsy study from the late 19th century onwards, understanding of the neural basis of semiological expression has advanced relatively little, in comparison to other aspects of epilepsy research. Analysis of ictal clinical signs is today considered essential for diagnosis of epilepsy, offering clues to underlying anatomical localisation and pathophysiology; however, paradoxically, the cerebral substrate of semiological signs remains incompletely understood in many cases and its localising value is therefore debated. Characterising the anatomo-pathophysiological basis of seizure semiology is especially important in the context of epilepsy pre-surgical evaluation, even more so when no radiologically visible lesion is present, since semiological analysis, if validated for a given seizure type, offers crucial localising information. For pharmacoresistant focal epilepsies in which surgical treatment might be possible, a number of cases require intracranial EEG recording. The method of stereoelectroencephalography (SEEG) is particularly useful as this allows simultaneous exploration of multiple, distant brain structures using stereotaxically placed multi-lead electrodes with concurrent video recording. The data thus acquired help form a three dimensional view of spatio-temporal seizure dynamics. Using SEEG it is therefore possible to undertake detailed analysis of semiological patterns and to study their temporal relation to the abnormal electrical cerebral activity occurring in brain networks during seizures. Epileptic seizures characterised clinically by transient cognitive dysfunction, behavioral change and complex motor signs are particularly challenging to analyse and categorise semiologically; indeed any paroxysmal behavioral disturbance must also be analysed with regards to whether it is actually caused by an epileptic discharge or not, since other forms of pathology, particularly psychogenic nonepileptic seizures (PNES), may be difficult to distinguish from epileptic seizures on a purely clinical basis, and require video-EEG recording for confirmation. This issue is particularly pertinent for prefrontal and parietal lobe seizures, which pose specific challenges for electroclinical analysis. PNES have a different and as yet poorly defined neurobiological basis compared to epileptic seizures. However growing understanding of the brain networks underlying emotional dysfunction, complex motor behaviour and altered consciousness, in particular data derived from intracranial studies of epileptic seizures, can help to further knowledge of how altered activity within these neural networks might interact with psychological and other factors in the pathophysiology of PNES. Through detailed observation of multiple epileptic seizures across a large population of patients, it can be appreciated that similarities exist in both clinical pattern and anatomical organisation of seizures. The existence of semiological patterns is in favour of the hypothesis that specific neural circuits underlie some forms of behavioural expression, and thus reinforces the validity of pursuing this line of investigation in epileptic seizures.

Objective: Cognitive Estimation Tests (CETs) are used to assess decision-making. Previous versions include culturally- biased questions likely to disadvantage certain sections of the population. This study aimed to develop a new culture fair questionnaire and assess its reliability and validity. Method: A 30-item questionnaire was developed and assessed for culture fairness. A normative range of answers was gathered, and a scale developed to define level of deviation from typical responses. Performance in a group of people with brain injury was compared to a matched group of healthy controls. Those with brain injury deemed able to make significant life decisions were compared with a group considered to lack this capacity, to determine whether this test may be useful when assessing decision-making capacity. Correlational analyses were conducted to determine whether there was a relationship between the test and performance on the Dysexecutive Questionnaire (DEX), a measure of everyday executive functioning. Test-retest reliability was examined with 30 of the normative sample. Results: Results confirm previous literature showing that those with brain injury perform significantly worse than healthy controls. The test did not discriminate between patients with and without capacity to make important decisions, did not significantly correlate with the total score on the DEX and demonstrated relatively poor consistency. Conclusions: Based on these results, CETs do not appear to be reliable or valid enough for use in clinical assessments. A sub-set of the most sensitive items may prove useful, but further work is required to examine the reliability and validity of this item subset in new samples.

Psychotic disorders such as schizophrenia and bipolar disorder have a strong genetic component. The aetiology of psychoses is known to be complex, including additive effects from multiple susceptibility genes, interactions between genes, environmental risk factors, and gene by environment interactions. With the development of new technologies such as genome-wide association studies and imputation of ungenotyped variants, the amount of genomic data has increased dramatically leading to the necessary use of Machine Learning techniques. Random Forest has been widely used to study the underlying genetic factors of psychiatric disorders such as epistasis and gene-gene interactions. Several authors have investigated the ability of this algorithm in finding single and interaction effects, but have reported contradictory results. Therefore, in order to examine Random Forest ability of detecting single and interaction effects based on different variable importance measures, I conducted a simulation study assessing whether the algorithm was able to detect single and interaction models under different correlation conditions. The results suggest that the optimal Variable Importance Measures to use in real situations under correlation is the unconditional unscaled permutation variable importance measure. Several studies have shown bias in one of the most popular variable importance measures, the Gini importance. Hence, in a second simulation study I study whether the Gini variable importance is influenced by the variability of predictors, the precision of measuring them, and the variability of the error. Evidence of other biases in this variable importance was found. The results from the first simulation study were used to study whether genes related to 29 molecular biomarkers, which have been associated with schizophrenia, influence risk for schizophrenia in a case-control study of 26476 cases and 31804 controls from 39 different European ancestry cohorts. Single effects from ACAT2 and TNC genes were detected to contribute risk for schizophrenia. ACAT2 is a gene in the chromosome 6 which is related to energy metabolism. Transcriptional differences have been shown in schizophrenia brain tissue studies. TNC is expressed in the brain where is involved in the migration of the neurons and axons. In addition, we also used the simulation results to examine whether interactions between genes associated with abnormal emotion/affect behaviour influence risk for psychosis and cognition in humans, in a case-control study of 2049 cases and 1794 controls. Before correcting for multiple testing, significant interactions between CRHR1 and ESR1, and between MAPT and ESR1, and among CRHR1, ESR1 and TOM1L2, and among MAPT, ESR1 and TOM1L2 were observed in abnormal fear/anxiety-related behaviour pathway. There was no evidence for epistasis after Bonferroni correction.

Cysteine Dioxygenase is an enzyme that catalyses the reaction of cysteine to cysteinesulfinic acid and is thought to regulate the intracellular concentrations of its substrate. The enzyme may also be involved in the oxidation of exposed sulfidrils of protein and by implication, involved in cell signalling or regulation. Substrate and products of cysteine dioxygenase are known to be disrupted in a number of neurodegenerative diseases making the protein an important target for medical research. To date, the structure of the protein has not been solved. An understanding of its structure and reaction mechanism will further the understanding of the aetiology of a number of different pathologies. Its structure may also further the development of novel pharmacological drugs.

Mental retardation is the most common brain disease. One of the first genes identified in X-linked mental retardation (XLMR) was the OPHN-1 gene. Mutation of this gene has been described in patients with moderate to severe cognitive impairments. MR is characterized by reduced cognitive function with or without other clinical features, thus providing a direct approach to study the neurobiology of cognition and pathogenesis of MR. I propose in this thesis to clarify the underlying mechanisms responsible for the learning impairments. My first approach was to investigate the functioning of a neuronal population using extracellular recording of fast oscillations which are thought to underlie higher cognitive performance. I showed that \(Ophn-1\) null mice displayed weaker gamma oscillations. Thereafter, Investigation of the synaptic properties of CA3 pyramidal neurons using the patch-clamp technique has been undertaken. I have shown reduced inputs of excitatory and inhibitory neurotransmission to CA3 pyramidal neurons accompanied with reduced frequency dependent facilitation of the inhibitory neurotransmission at 33Hz. Finally, a reduction in readily releasable pool size in inhibitory synapses of CA3 area was unravelled. This defect explained the reduction of frequency of sIPSCs and consequently the reduction in gamma oscillations power in Ophn-1\(^{-/y}\) slices.

Mestrado em Psiquiatria e Saúde Mental / Master Degree Course in Psychiatry and Mental Health

Mestrado em Psiquiatria e Saúde Mental / Master Degree Course in Psychiatry and Mental Health

Mestrado em Psiquiatria e Saúde Mental / Master Degree Course in Psychiatry and Mental Health

Mestrado em Psiquiatria e Saúde Mental / Master Degree Course in Psychiatry and Mental Health