The aim of the thesis was to conduct a detailed examination of the evidence pertaining to the cerebral lateralisation of musical function. Theoretical models from the neuropsychological and cognitive psychology fields were employed, with emphasis placed on the way the models interrelate to gain a more coherent account of music cognition and its relationship to cerebral lateralisation. (For complete abstract open document.)

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Not embargoed. Vita. Bibliography: 207-220.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 100-106).

Thesis (D.Phil (Social Work and Criminology))--University of Pretoria, 2005. / Includes abstract in English and Afrikaans. Bibliography.

The aim of this thesis is to examine the underlying cognitive and neural processes at play during retrieval of temporal and contextual source information. This was assessed across three experimental chapters. In the first experimental chapter, Chapter 2, the neural loci of context associations were assessed. Rats trained on an odour-context association task were given lesions to either the Lateral Entorhinal Cortex (LEC) or sham lesions. After surgery, performance on the odour-context task was assessed. It was hypothesised that memory for previously learned odour-context associations would be impaired following LEC lesions but not sham lesions. The results supported this hypothesis, demonstrating impaired memory for the previously learned odour-context associations in the LEC lesion group compared to the Sham lesion. In Chapter 3, the underlying retrieval processes used to retrieve time and context in human memory was assessed across three experiments. It was hypothesised that time would be remembered accurately using both recollection and familiarity, while correct context memory should rely on recollection alone. Two out of the three experiments supported this hypothesis, demonstrating that temporal information can be retrieved using familiarity in certain instances. The final experimental Chapter 4 used fMRI to extend Chapter 3 and examine whether neural activity would be greater in regions associated with recollection during memory for context, while activity in familiarity-related regions would be higher during memory for time. Results revealed no support for these predictions with no regions linked to recollection showing greater context-related activity, and no regions previously linked to familiarity exhibiting increased activation as temporal information was retrieved. The results are discussed in relation to established recollection and familiarity frameworks and previous work examining the neural substrates supporting memory for time and context.

Introdução: O Padrão Alternante Cíclico (“CAP”, do inglês - Cyclic Alternating Pattern) é um ritmo fisiológico do sono NREM, que corresponde aos períodos de ativação cíclica expressos por eventos fásicos do sono. O aumento na expressão de taxa do CAP tem sido considerado uma medida de instabilidade e fragmentação do sono. O CAP representa uma condição favorável para a ocorrência de descargas interictais e/ou ictais. A modulação do CAP em pacientes com Epilepsia do Lobo Temporal (ELT) não está bem definida. Objetivos: Analisar a expressão do CAP em pacientes com ELT e comparar com o grupo de controle. Selecionar o grupo de pacientes sem distúrbios do sono que possam influenciar a organização do sono. Métodos: Foi realizado estudo transversal com grupo de controle de comparação. A seleção foi pareada em sexo e idade entre pacientes com ELT e o grupo de controle, obedecendo aos critérios de inclusão e exclusão. Os parâmetros do sono e CAP foram analisados em 13 pacientes com ELT (6 do sexo masculino e 7 do sexo feminino; idade média: 33,8 ± 8,5 anos) e 13 indivíduos sadios (8 do sexo masculino e 5 do sexo feminino; idade média: 26,1 ± 9,2 anos), os quais não apresentaram distúrbios do sono. A comparação dos dois grupos foi realizada através do “teste t” de Student e confirmada pelo “teste U” de Mann-Whitney. Resultados: Os pacientes com ELT apresentaram aumento na taxa de CAP (44,02 ± 5,23 % versus 31,83 ± 3 %; p<0,001) e maior duração do tempo de CAP (133,77 ± 15,56 min. versus 99,38 ± 9,6 min.; p<0,001) em relação aos indivíduos sadios. Não houve diferença na média da duração da fase A (9,27 ± 1,15 seg. versus 8,7 ± 0,61 seg.; p<0,131), e a média da duração da fase B não atingiu diferença significativa (22,92 ± 1,71 seg. versus 21,54 ± 1,78 seg.; p<0,054) entre os dois grupos. A comparação dos parâmetros de sono e de CAP dentro de cada grupo, mostrou não haver diferença entre os gêneros. A análise estatística dos parâmetros do sono em pacientes com ELT evidenciou uma diferença significativa das seguintes variáveis: menor latência ao sono (5,8 ± 2,4 min. versus 14,2 ± 7,6 min.; p=0,002); aumento do número da troca de estágios com média de 91,1 ± 25,7 versus 68,2 ± 12,8; p=0,008; menor duração de estágio IV (30,8 ± 14,8 min. versus 51,4 ± 12,5 min.; p=0,001); maior percentual do estágio III (7,7 ± 2,8% versus 5,7 ± 1,7%; p=0,035); menor percentual do estágio IV (7,9 ± 4% versus 12,9 ± 3,3%; p=0,002) em pacientes com ELT, comparando com o grupo de controle. A análise dos despertares breves demonstrou em pacientes com ELT: maior número de despertares breves em sono (66,5 ± 20 versus 41,8 ± 9; p=0,001); maior número de despertares breves em sono NREM (52,9 ± 19,6 versus 31 ± 9,5; p=0,002); maior duração total de despertares breves em sono (549,1 ± 170,3 seg. versus 357,2 ± 88,5 seg.; p=0,002); maior duração total de despertares breves em sono NREM (436,8 ± 165,7 seg. versus 271,9 ± 95,2 seg.; p=0,006); aumento do índice de despertar breve em sono (10,2 ± 2,9 versus 6,3 ± 1,7; p=0,001); aumento do índice de despertar breve em sono NREM (10,3 ± 3,4 versus 6 ± 2; p=0,001). Não houve diferença significativa de número (13,6 ± 5,6 versus 10,8 ± 3,7; p=0,149), duração total (112,3 ± 48,3 seg. versus 85,3 ± 25,2 seg.; p=0,091) e índice de despertar breve (9,7 ± 3,8 versus 7,4 ± 2,4; p=0,075) em sono REM entre os dois grupos. Todos os pacientes comELT tiveram uma eficiência do sono normal e similar ao grupo de controle (90,4 ± 2,9 % versus 90,6 ± 2,9 %). Conclusões: Os pacientes com ELT apresentam aumento da taxa de CAP e da duração de tempo de CAP em relação ao grupo controle, demonstrando um aumento na instabilidade e fragmentação do sono. O aumento na expressão da taxa de CAP, alterações nos parâmetros de fragmentação e descontinuidade do sono, expressos pelo aumento de número, duração e índice de despertares breves em sono NREM e o número de mudanças de estágios, associados à eficiência normal do sono em nosso grupo de pacientes com ELT, podem sugerir que o CAP tem um papel na modulação do sono. A fragmentação e a instabilidade do sono em pacientes com ELT, provavelmente, ocorrem devido à própria epilepsia e podem refletir a interação do foco epiléptico com os sistemas responsáveis pela manutenção e estabilidade de sono. / Introduction: Cyclic Alternating Pattern (“CAP”) is a NREM sleep physiological rhythm corresponding to periods of cyclical activation expressed by phasic events of sleep. The increase in the CAP rate expression has been considered a measure for sleep instability and fragmentation. CAP offers a favorable condition for interictal and/or ictal discharges. The CAP modulation in patients with Temporal Lobe Epilepsy (TLE) is not well defined. Objectives: Analyze the CAP expression in patients with TLE comparing it with a control group. Select the group of patients without sleep disorders which may interfere with sleep organization. Methods: A transversal study was conducted with a comparing control group. The selection was paired on gender and age between patients with TLE and the control group, in accordance with inclusion and exclusion criteria. The sleep parameters and CAP were analyzed in 13 patients (6 males and 7 females; mean age: 33,8 ± 8,5 years) and 13 healthy individuals (8 males and 5 females; mean age: 26,1 ± 9,2 years) who did not present sleep disorders. The comparison of the two groups was made through Student’s t-test and was confirmed by the Mann-Whitney U test. Results: Patients with TLE showed an increase in the CAP rate (44,02 ± 5,23% versus 31,83 ± 3%; p<0,001) and CAP time was longer (133,77 ± 15,56 min. versus 99,38 ± 9,6 min.; p<0,001) as compared to healthy individuals. There was no difference in the duration average of stage A (9,27 ± 1,15 sec. versus 8,7 ± 0,61 sec.; p<0,131), and the duration average of stage B did not show a significant difference (22,92 ± 1,71 sec. versus 21,54 ± 1,78 sec.; p<0,054) between both groups. The comparison of sleep parameters and CAP within the group showed that there is no difference between the genders. The statistical analysis of sleep parameters in patients with TLE showed a significant difference in the following variables: lower sleep latency (5,8 ± 2,4 min. versus 14,2 ± 7,6 min.; p=0,002); increase in the number of stage shifts with an average of (91,1 ± 25,7 versus 68,2 ± 12,8; p=0,008); lower duration of the stage IV (30,8 ± 14,8 min. versus 51,4 ± 12,5 min.; p=0,001); higher percentage of the stage III (7,7 ± 2,8% versus 5,7 ± 1,7%; p=0,035); lower percentage of the stage IV (7,9 ± 4% versus 12,9 ± 3,3%; p=0,002) in patients with TLE as compared to the control group. The analysis of arousals in patients with TLE showed: a higher number of arousals during sleep (66,5 ± 20 versus 41,8 ± 9; p=0,001); a higher number of arousals during NREM sleep (52,9 ± 19,6 versus 31 ± 9,5; p=0,002); a longer total duration of arousals during sleep (549,1 ± 170,3 sec. versus 357,2 ± 88,5 sec.; p=0,002); a longer total duration of arousals during NREM sleep (436,8 ± 165,7 sec. versus 271,9 ± 95,2 sec.; p=0,006); an increase of arousal index during sleep (10,2 ± 2,9 versus 6,3 ± 1,7; p=0,001); an increase of arousal index during NREM sleep (10,3 ± 3,4 versus 6 ± 2; p=0,001). There was not a significant difference in number (13,6 ± 5,6 versus 10,8 ± 3,7; p=0,149), total duration (112,3 ± 48,3 sec. versus 85,3 ± 25,2 sec.; p=0,091) and arousal index (9,7 ± 3,8 versus 7,4 ± 2,4; p=0,075) during REM sleep between the two groups. All patients with TLE showed a sleep efficiency that is normal and similar to the control group (90,4 ± 2,9% versus 90,6 ± 2,9%).Conclusions: Patients with TLE showed an increase in CAP rate and a longer CAP duration in relation to the control group, demonstrating an increase in the instability and fragmentation of sleep. The increase in the CAP rate expression, alterations in the parameters of sleep fragmentation and discontinuity that as expressed by increase in the number, duration, arousal index during NREM sleep and number of stage shifts, associated with normal sleep efficiency in our group of patients with TLE may suggest that CAP may have influence in the modulation of sleep. Sleep fragmentation and instability in patients with TLE may occur probably due to epilepsy itself, reflecting the interaction of the epileptic foci with the systems responsible for the maintenance and stability of sleep.

Introdução: A recorrência de crises epiléticas pós cirurgia para tratamento da epilepsia do lobo temporal tem sido classificada como precoce ou tardia dependendo do tempo da primeira crise depois do procedimento. Contudo, este tempo de recorrência é variado, sendo arbitrariamente definido nos artigos científicos. Objetivos: Nós desenvolvemos um modelo matemático que pode identificar pacientes com chance de recorrência de crises pós-operatórias precoces ou tardias. Após, analisamos os dois grupos para identificar as diferenças clínicas, eletrofisiológicas e de neuroimagem entre estes pacientes. Métodos: Uma coorte histórica com 247 pacientes tratados com cirurgia para epilepsia do lobo temporal foi estudada. Dentre os paciente onde as crises epiléticas retornaram, utilizamos o tempo de recorrência em uma curva ROC para avaliar com maior acurácia o melhor período para predizer o prognóstico cirúrgico a longo prazo. Com isto, dividimos os pacientes em dois grupos: os de recorrência precoce e os de recorrência tardia. Após, nós analisamos as diferenças clínicas e radiológicas entre estes pacientes. Resultados: As crises epiléticas retornaram em 107 (48.9%) pacientes. A curva ROC mostrou que 6 meses era o tempo onde o prognóstico a longo prazo poderia ser determinado com maior acurácia (AUC = 0.761; sensibilidade = 78.8%; especificidade = 72.1%). Nós observamos que nos pacientes onde a recorrência ocorreu nos primeiros 6 meses após a cirurgia, a epilepsia começou mais precocemente (OR: 6.034; CI95%: 1.056–11.013; p=0.018), estes pacientes possuíam um pior prognóstico (6.849;2.538–18.518;p=0.001), necessitaram de maior número de medicação anti-epilética após o procedimento (2.07;1.162–9.345;p=0.013) e mais freqüentemente foram submetidos a uma nova cirurgia para controle de crises (9.592;1.181–77.877;p=0.021). Nos pacientes com recorrência tardia, as crises epiléticas eram mais comumente associadas a fatores desencadeantes (9.615;3.521–26.315;p<001). Conclusão: Pacientes com recorrências de crises epiléticas precoces ou tardias possuem diferentes características que podem estar relacionadas a diferenças entre os tipos de zonas epileptogênicas, eficácia dos procedimentos cirúrgicos ou mesmo à própria epileptogenicidade. A existência de tais disparidades podem ajudar a explicar os diferentes padrões de recorrência de crises pós cirurgia para epilepsia, auxiliando no planejamento do tratamento destes pacientes a longo prazo. / Background: Recurrence of seizures after surgery for epilepsy has been generally classified as either early or late depending on the time between surgery and seizure recurrence. However, the time of seizure recurrence is variable and it has been arbitrarily defined in the literatures. Objective: Here we establish a statistical-based model for discriminating patients with early or late seizure recurrence and examine the clinical, electrophysiological, and neuroimaging differences between these two groups of patients. Methods: A historical cohort of 247 patients treated surgically for temporal lobe epilepsy was identified. In those patients who recurred, the post-operative time until seizure recurrence was examined using an ROC curve to discriminate with greater accuracy the best period for predicting the long-term prognosis of patients. This approach divided patients in two groups, those with early and those with late seizure recurrence. Following this division, we compared differences between these groups in terms of a number of clinical and radiological variables. Results: Seizures recurred in 107 (48.9%) patients. The ROC curve showed that 6 months was the time when long-term surgical outcome could be determined with best accuracy, (AUC = 0.761; sensitivity = 78.8%; specificity = 72.1%). We observed that patients with seizure recurrence during first 6 months after surgery started seizing at younger age (OR: 6.034; CI95%: 1.056–11.013; p=0.018), had a worse outcome (6.849;2.538–18.518;p=0.001), needed a higher number of antiepileptic medications after surgery (2.07;1.162–9.345;p=0.013) and were more frequently submitted to reoperations (9.592;1.181–77.877;p=0.021). Patients with late relapse more frequently had seizures associated with trigger events (9.615;3.521–26.315;p<001). Conclusion: Patients with early or late recurrence of seizures have different characteristics that might reflect diversity in the epileptogenic zone and epileptogenicity itself. These disparities might help to explain variable patterns of seizures recurrence after epilepsy surgery.

Introdução: Dois grandes estudos de genoma humano ENIGMA e CHARGE identificaram uma variante genética comum da tescalcina (TESCrs7294919) envolvida no volume hipocampal em indivíduos saudáveis. Sabe-se que o gene TESC é altamente expresso na embriogênese e no hipocampo adulto e pode ter papel chave em doenças que afetam o hipocampo, entre estas, a epilepsia do lobo temporal. Neste estudo será investigado o impacto do polimorfismo rs7294919 em pacientes com epilepsia do lobo temporal. Métodos: Estudo de associação de 162 pacientes com epilepsia do lobo temporal e 100 controles sem epilepsia. Foram comparadas as frequências das variantes rs7294919 entre pacientes com epilepsia e controles e avaliados os impactos das diferenças alélicas nas principais características de epilepsia. Resultados: Não houve diferenças significativas entre os polimorfismos rs7294919 entre pacientes e controles (Tabela 1). No entanto, o genótipo CT foi mais comum no sexo masculino do que do sexo feminino (Tabela 2, Tabela 3 e Figura 1). Não foram observadas outras diferenças em relação à média de idade de início da epilepsia, história familiar de epilepsia, presença de aura, controle das crises, anormalidades de EEG interictal e achados de neuroimagem. Depois de controle de variáveis confusionais, o alelo C esteve significativamente aumentado em pacientes do sexo masculino(OR = 2,57; IC = 1.26-5.24 ; p = 0,009). Conclusão:Aobservação de uma maior frequência do alelo do alelo C em homens pode sugerir um efeito dependente da tescalcina através do seu gene TESCsobre o desenvolvimento da epilepsia do lobo temporal. Tanto quanto sabemos, este é o primeiro estudo da tescalcina no desenvolvimento de epilepsia. / Rationale: Two independent large genome-wide association studies identified a common genetic variant of tescalcin polymorphism (TESC rs7294919), that is significantly associated with hippocampal volume in healthy subjects. It is known that the TESC gene is highly expressed in embryogenesis and in adult hippocampus and might play a role in characteristics of diseases that affect hippocampus, among them temporal lobe epilepsy. In this study we investigate the impact of rs7294919 variants in temporal lobe epilepsy. Methods: This is an association study of 162 patients with temporal lobe epilepsy and 100 controls without epilepsy. We compared frequencies of rs7294919 variant between patients with epilepsy and controls and evaluate the impact of allelic difference in main characteristics of epilepsy. Results: There were no significant differences between TESC gene polymorphisms of patients and controls (Table 1). However, genotype CT was more frequent in male than females (Table 2, Table 3 and Figure 1). No other differences were observed regarding mean age of epilepsy onset, family history of epilepsy, presence of aura, seizure control, EEG interictal abnormalities and neuroimaging findings. After controlling for confounding variables, C allele was increased in male patients (O.R. = 2.57; CI = 1.26-5.24; p=0.009. Conclusions: Our finding might suggest a gender dependent effect of tescalcin polymorphism (TESC rs7294919) on development of epilepsy. As far as we are aware, this is the first study of tescalcin polymorphism on development of epilepsy. In our view, other studies in this venue are necessary to confirm our findings and explore other possible effects of tescalcina polymorphisms on development and characteristics of epilepsy.

Orientador: Prof. Dr. Alexandre Hiroaki Kihara / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Neurociência e Cognição, 2016. / Status epilepticus (SE) is a clinical emergency that can lead to the development of temporal lobe epilepsy (TLE). The term epileptogenesis refers to the transformation of physiological neuronal networks into a dysfunctional state. In most patients presenting TLE, the development and maintenance of spontaneous seizures are linked with calcium (Ca+2)-dependent processes like neuronal loss, reactive gliosis and pathological neuronal plasticity. It has been shown that SE produces an increase in ryanodine receptor-dependent intracellular Ca+2 levels in hippocampal neurons, which remain elevated during the progression of the disease. In this context, the aim of this work was to investigate the effects of ryanodine receptors (RyRs) inhibition on the expression of important synaptic and plasticity-related proteins during the latent period of the pilocarpine model of TLE. First, we performed western blot and immunolabeling analyses in order to evaluate the pattern of distribution of the activity-regulated cytoskeleton-associated protein (ARC) in the rat hippocampus during the latent period. We observed decrease of the total protein levels 48 hours after SE, together with downregulation of its nuclear immunolabeling in granular cells of the dentate gyrus (DG). In addition, we observed the appearance of intense ARC immunoreactive neurons (IAINs) colocalizing mainly with excitatory neurons in CA1, CA3 and hilus. Intrahippocampal injections of the RyRs blocker dantrolene increased the total protein levels of the presynaptic protein synapsin I (SYN I) 48 hours after SE. We also observed up-regulation of SYN I and synaptophysin (SYP) in hippocampal regions known to receive important synaptic inputs. Finally, dantrolene showed neuroprotective effects by decreasing neuronal loss in CA1 and CA3 of experimental hippocampi. Our results suggest that ARC might be participating in the overall hippocampal reorganization and increase of excitability observed during epileptogenesis. In addition, RyRs may contribute to trigger the hippocampal neurodegeneration and synaptic alterations that lead to the development of acquired epilepsy.