The current set of three proposed experiments focused on integrating neurological and behavioral levels of analysis in the context of pathological gambling. A thoroughgoing analysis on previous gambling research was explored and discussed in the first four chapters. Specifically, this analysis outlines: similarities between pathological gambling and other substance addictions, new technological advances (i.e. functional magnetic resonance imaging), verbal behavior in general and its role in pathological gambling specifically, and treatment assessments and interventions. Three experiments were then developed and designed based on the outcomes suggested by the literature review. Experiment I determined the effectiveness of the Gambling Functional Assessment (GFA; Dixon & Johnson, 2007) as a clinically relevant gambling assessment tool. Experiment II also investigated neurological differences between pathological gamblers. Similar to other behavioral and substance addictions, limbic and cortical brain systems are activated during gambling related tasks and activities. However, as gambling pathology increases, brain activation in these regions have been reported to decrease, and it is unclear how pathological gamblers brain activation patterns differ across function maintaining gambling (i.e. attention, escape, sensory, and tangible maintaining functions). Therefore, Experiment II built upon the findings of Experiment I by contrasting brain activation images from the two highest maintaining functions of play, as indicated by the GFA. Concomitantly, Experiment III assessed function based assessment and treatment of pathological gamblers, by comparing brief 30 min exposure to function based or non- function based Acceptance and Commitment Therapy for gamblers. Results from both studies suggested differences in brain activation patterns, yet similarities across subjective closeness to win ratings of the slot machine. Furthermore, brain activation patterns did not change following function based therapy, while subjective ratings in the function based treatment group decreased. Implications for brain-behavior relationships both in a gambling context and in relation to behavior therapy will be discussed.

The human brain is a complex and powerful organ, directing every aspect of life from somatosensory and motor function to visceral responses to higher order cognition. Neurological and psychiatric disorders often disrupt normal functioning. While the clinical symptoms of such disorders are known, their biological underpinnings are not as clearly characterized. Structural neuroimaging is a powerful, non-invasive tool that can play a critical role in finding biomarkers of these illnesses. Currently, variations in pre-processing techniques yield inconsistent and conflicting results. As neuroimaging is a nascent branch of medical research, gold standards in imaging methodologies have not yet been established. Quantitatively validating and optimizing the way these images are preprocessed is the first step towards standardization. Voxel-based morphometry (VBM) is one technique that is commonly used to compare whole-brain structural differences between groups. Statistical tests are used to compare intensities of voxels throughout all brain scans in each group. In order to ensure that comparable voxels are being tested, the images must be fitted into a common space, which is done through image preprocessing. Spatial normalization to templates is an early pre-processing step that is executed unreliably as many options for both templates and normalization algorithms exist. To determine the effect variations in template usage may cause, we utilized a VBM approach to detect simulated lesions. Template performance was analyzed by comparing the accuracy with which the lesion was detected.

The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease (AD) while the ε2 allele confers a reduced risk compared with the most common ε3 allele. Neuroimaging studies using magnetic resonance imaging (MRI) have shown that APOE genotype affects brain structure and function. The aims of the research presented in this DPhil thesis were twofold: 1) to investigate the effect of APOE genotype on brain function in healthy adults using magnetoencephalography (MEG), which is a direct measure of neuronal activity and 2) to explore interactions between the AD risk factors APOE ε4 allele, age and female gender and their effects on brain structure and function using resting-state functional MRI and diffusion tensor imaging. MEG revealed similar neuronal activity at rest for APOE ε2 and ε4 carriers, i.e. those with opposite AD risk, indicating a more general effect on the functional architecture of the brain that is not directly linked to AD risk. However, differences between APOE ε2 and ε4 carriers became apparent when reactivity to stimuli was explored using the excellent temporal resolution of MEG. APOE ε4 carriers showed faster sensory pro- cessing and APOE genotype effects were found for functional networks associated with attention. In the second part of this project, female APOE ε4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus and a significant age-related decrease in connectivity of these regions. Increased vulnerability of this connection might be one reason for increased AD risk and interventions targeting hippocampal connectivity might be especially effective in at-risk populations. The research presented in this DPhil thesis showed a complex pattern of APOE genotype effects on brain structure and function. While global APOE genotype effects on functional and structural connectivity do not follow patterns of AD risk, more specific measures of connectivity and task-related brain function could be of use in the development of preclinical markers for AD development.

To understand how the brain functions, we must investigate the transient interactions that underpin communication between cortical regions. EEG possesses the optimal temporal resolution to capture functional connectivity, but it lacks the spatial resolution to identify the cortical locations responsible. To circumvent this problem electrophysiological connectivity should be investigated at the source level. There are many quantifiers of connectivity applied to EEG data, but some are not sensitive to the direct, or indirect, influence of one region over another, and others require the specification of a priori models so are unsuitable for exploratory analyses. Transfer Entropy (TE) can be used to infer the direction of linear and non-linear information exchange between signals over a range of time-delays within EEG data. This thesis explores the creation of a new method of mapping dynamic brain connectivity using a trial-based TE analysis of EEG source data, and the application of this technique to the investigation of semantic and number processing within the brain. The first paper (Chapter 2) documents the analyses of a semantic category and number magnitude judgement task using traditional ERP techniques. As predicted, the well-known semantic N400 component was found, and localised to left ATL and inferior frontal cortex. An N365 component related to number magnitude judgement was localised to right superior parietal regions including the IPS. These results offer support for the hub-and-spoke model of semantics, and the triple parietal model of number processing. The second paper (Chapter 3) documents an analysis of the same data with the new trial-based TE analysis. Word and number data were analysed at 0-200ms, 200-400ms, and 400-600ms following stimulus presentation. In the earliest window, information exchange was occurring predominately between occipital sources, but by the latest window it had become spread out across the brain. Task-dependent differences of regional information exchange revealed that temporal sources were sending more information to occipital sources following words at 0-200ms. Furthermore, the direction and timing of information movement within a front-temporal-parietal network was identified during 0-400ms of the number magnitude judgment. The final paper (Chapter 4), documents an attempt to track the influence of TMS through the brain using the TE analysis. TMS was applied to bilateral ATL and IPS because they are both important hubs in the brain networks that support semantic and number processing respectively. Left ATL TMS influenced sources located primarily in wide-spread left temporal lobe, and inferior frontal and inferior occipital cortices. The anatomical connectivity profile of the temporal lobe suggests that these are all plausible locations, and they exhibited excellent spatial similarities to the results of neuroimaging experiments that probed semantic knowledge. The analysis of right ATL TMS obtained a mirror image of the left. Left parietal stimulation resulted in a bilateral parietal, superior occipital, and superior prefrontal influence, which extended slightly further in the ipsilateral hemisphere to stimulation site. A result made possible by the short association and callosal fibres that connect these areas. Again, the results at the contralateral site were a virtual mirror image. The thesis concludes with a review of the experimental findings, and a discussion of methodological issues still to be resolved, ideas for extensions to the method, and the broader implications of the method on connectivity research.

Recent functional neuroimaging research has highlighted the role of the posterior parietal cortex (PPC) during episodic memory retrieval (Vilberg & Rugg, 2007; Vincent et al., 2006; Wagner et al., 2005; Wheeler & Buckner, 2003; Yonelinas et al., 2005). It has been shown that the PPC is active during the retrieval of old information, when subjects incorrectly believe that new information has been encountered before (false alarms), and when retrieval is accompanied by recollection (Wagner et al., 2005). A preliminary positron emission tomography (PET) study suggests that the PPC is also active when retrieval occurs unintentionally or incidentally, prompted by the presence of an old stimulus item. Collectively these studies suggest that activity in the PPC may be driven by familiarity, irrespective of task demands and independent of its veracity. The main goal of this thesis was to explore, with functional magnetic resonance imaging (fMRI), the conditions under which activity in the PPC may be modulated by the familiarity of veridical and perceived memories. Subjects were presented with scene/word pairs that were repeated 1, 3, or 7 times on Day 1. On Day 2, while MRI scans were recorded, subjects studied either, new items, old pairs (same-form) one additional time (2nd,, 4th, or 8th presentation), or pairs in which the word associated with each picture was changed (different-form) one additional time (2nd,, 4th, or 8th presentation). Same form pairs activated bilateral inferior parietal lobule compared to novel pairs replicating the findings from the PET study on incidental retrieval. Same and different form pairs did not differ on amount of parietal activity. Additionally, same form pairs that were repeated 8 times displayed more PPC activity than same form pairs repeated two and four times while there was no difference across different form repetitions. Together these results indicate that items that are old and that those that are new but are perceived as old activate the inferior parietal lobule.

Amputation induces substantial reorganization of the body part somatotopy in primary sensory cortex (S1), and these effects of deafferentation increase with time. Determining whether these changes are reversible is critical for understanding the potential to recover from deafferenting injuries. Here, we report evidence that the representation of a transplanted hand and digits can actually recapture the pre-amputation S1 hand territory in two transplant patients. With limited sensation 4 months post operation, one of the patient's (D.S.) palmar tactile stimulation evoked contralateral S1 responses that were indistinguishable in location and amplitude from those detected in healthy matched controls. The other patient (M.S.) demonstrated not only much improved sensation but also recovered ability to localize tactile stimuli 120+ months after the operation. The results described suggest that even decades after complete deafferentation, restoring afferent input to S1 leads to re-establishment of the gross hand and digits representations within their original territory. Stimulation of the deafferented cortical maps may play an important role in maintaining their viability until the afferent input is restored. Motor imagery and creation of virtual visual feedback of the absent hand with a mirror have been proposed as stimuli. We used fMRI to record neural activity while 11 unilateral hand amputees and matched controls performed aurally-paced thumb-finger sequencing movements with their intact hand (matching hand in case of controls) under visual guidance during four conditions: 1) intact hand (ME), 2) ME with motor imagery of the amputated hand, 3) ME with virtual visual feedback of the amputated hand, and 4) ME with motor imagery and the virtual visual feedback of the amputated hand. In contrast to controls, amputees showed increases in activity during all four conditions within the former functionally-defined sensorimotor hand territory. Movements of the intact hand likely increase activity in the former hand territory as a result of decreased interhemispheric inhibition. This stimulation may maintain deafferented hand representations that can recover soon after the afferent input is restored by hand transplantation.

No neuroimaging investigation to date has considered the effects of social context on self-referential processing, despite the fact that the hypothesis that people engage different selves in different contexts has been with psychology for more than a century. To address this gap in the empirical record, a suite of three functional magnetic resonance imaging (fMRI) experiments was conducted in order to assess patterns of neural activity associated with self-referential (compared to non-self-referential) processes (Experiment 1), computational models of reinforcement-learning processes (Experiment 2), and social context modulation of personally relevant cognition (Experiment 3). I demonstrate that distinct patterns of neural activity in cortical midline structures and the mesial ventral striatum are associated with thinking about the self privately, sharing information about the self with a parent, and sharing with a friend. These differentiated disclosure responses (Experiment 3) are evident at the whole brain level and in regions of interest defined by functional activity in independent tasks of self (Experiment 1) and reward (Experiment 2). In addition to providing empirical evidence for contextually differentiated self-representations in the brain, this dissertation validates the use of fMRI paradigms designed to functionally localize self-referential and reward-related activity either independently or in conjunction, as well as distinguish components of ventral striatal activity unique to each task. Finally, I consider strategies for approaching future investigations of self and social cognition in terms of reinforcement learning.

Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T22:33:32Z (GMT). No. of bitstreams: 1 Fernandes_DanielaAlves_M.pdf: 5738934 bytes, checksum: 206ca01256f59acd22d595142eadef05 (MD5) Previous issue date: 2012 / Resumo: A epilepsia é a segunda patologia neurológica que mais afeta a população mundial e a epilepsia do lobo temporal é a mais comum das epilepsias focais com maior frequência, associada à refratariedade e a distúrbios de memória. A lesão epileptogênica pode ser estudada através de imagens de ressonância magnética (RM), EEG entre outros exames, facilitando a indicação da cirurgia que tem como objetivo reduzir as crises, entretanto a função cognitiva pode ser afetada. Nosso propósito foi avaliar a eficácia da cirurgia quanto ao controle das crises, desempenho de memória nos pacientes e comparar os resultados de avaliações neuropsicológicas pré e pós-operatórias quanto à frequência de crises, abordagem cirúrgica e volumetria da estrutura e lacuna. Foram analisados 55 pacientes submetidos à cirurgia de epilepsia e 29 indivíduos controles saudáveis. Todos foram submetidos à aquisição de imagens em um aparelho de RM 2T em dois tempos com intervalos médios de 4,4±2,8 anos. A volumetria do hipocampo e lacuna cirúrgica foi realizada com o software Display, utilizando o protocolo de Bonilha et at., 2004. Os pacientes foram avaliados de acordo com a classificação pós-operatória de Engel Jr., 1997 e testes de avaliações neuropsicológicas que incluiu subtestes: da Wechsler Memory Scale-Revised; Wechsler Adult Intelligence Scale-Revised e Rey Auditory Verbal Learning Test, realizados com um intervalo médio de 8,5 anos após a cirurgia. Para análise dos dados pré/pós-operatórios foi utilizado o teste T de Student, de Wilcoxon ou Man-Whitney, correlação de Pearson e Spearman de acordo com as características das variáveis. Observamos diferença significativa nas avaliações neuropsicológicas, quando comparadas entre os próprios indivíduos nos grupos pré e pós-operatório e nos grupos de acordo com a Escala de Engel e lado da cirurgia, com piora no desempenho cognitivo no período pós-operatório. Mostraram melhora no desempenho de memória os que foram classificados em Engel IA quando comparados aos indivíduos que continuaram com crises. Os grupos submetidos à amigdalohipocampectomia seletiva e ressecção cortical associada à amigdalohipocampectomia não apresentaram diferenças significativas quanto ao desempenho de memória. O grau de escolaridade influenciou negativamente no resultado das avaliações. Nossos resultados mostraram que 80% foram classificados em Engel I, 18,2% em Engel II e 1,8% em Engel III. A volumetria dos hipocampos direito e esquerdo ipsilaterais à cirurgia apresentaram valores menores que dos controles. Os hipocampos esquerdos e direitos pré/pósoperatórios contralaterais à atrofia não apresentaram resultado significativo quando comparado as volumetrias dos controles e nem quando comparados entre si. Os dados de volumetria associados à memória apresentaram grau razoável e moderado de correlação. Nossos resultados mostraram que após a ressecção cirúrgica existe um declínio no desempenho de memória, porém a frequência de crises desses pacientes diminui significativamente e que o tipo de abordagem cirúrgica não interfere no desempenho de memória, mesmo com o maior volume da ressecção de pacientes submetidos à lobectomia temporal anterior / Abstract: Epilepsy is the second most frequent neurological disease and temporal lobe epilepsy is the most common form of focal epilepsy and is more frequently associated to refractoriness and memory decline. The epileptogenic lesion can be studied through magnetic resonance imaging, EEG and other tests, facilitating the indication of surgery that aims to reduce seizure frequencies, however cognitive function may be affected. We proposed to evaluate the effectiveness of surgery on the management of seizures, memory performance and compare the results of neuropsychological assessments pre/post-operative and the frequency of seizures, surgical approach and volume of hippocampi and amount of resection. We analyzed 55 patients who underwent epilepsy surgery and 29 healthy control subjects. All patients underwent imaging in a 2T MR scanner in two steps with intervals of 4.4 ± 2.8 years. The volumetry of the hippocampus and surgery gap was done with the software display, using the protocol described by Bonilha et al, 2004. Patients were evaluated according to the postoperative classification of Engel Jr., 1997 and neuropsychological evaluation that included the subtests, Wechsler Memory Scale-Revised, Wechsler Adult Intelligence Scale-Revised and Rey Auditory Verbal Learning Test, performed with an average interval 8.2 years after surgery. For data analysis, pre/post-operative we used the Student t test, Wilcoxon or Man-Whitney, Pearson and Spearman correlation test according to the characteristics of variables. We observed significant differences in neuropsychological evaluations, when we compared the groups pre/post-operative and the groups according to the Engel Scale and side of surgery, with worsening of cognitive performance in the postoperative period. There was a relative improvement in memory performance in those who were classified as Engel IA compared to individuals who continued to have seizures. The comparisons between the groups of selective amygdalohippocampectomy and anterior temporal lobe resection showed no significant differences in memory performance. The level of education had a negative influence on the outcome of neuropsychological evaluations. Our results showed that 80% were classified as Engel I, 18.2% in Engel II and 1.8% in Engel III. The volumetry of the left and right hippocampi ipsilateral to the surgery showed lower values than controls. The left and right hippocampus pre/post-operative contralateral to the side of surgery did not show significant differences when compared to controls. There was a correlation between hipocampal volumes and memory performance. Our results showed that after surgical resection there is a decline in memory performance, but the frequency of seizures in these patients decreased significantly and that the types of surgical approaches do not differ in terms of post-operative nor the total volume of the surgical lacunae / Mestrado / Neurociencias / Mestre em Ciências

Orientador: Fernando Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T23:40:05Z (GMT). No. of bitstreams: 1 Fernandes_DanielaAlves_D.pdf: 7319654 bytes, checksum: db061970bef101957f53339b302dc1a9 (MD5) Previous issue date: 2015 / Resumo: A quantificação da atrofia das estruturas temporais mesiais pelas imagens de RM em pacientes com ELTM permite a identificação "in vivo" das alterações anatômicas associadas à esta patologia e sua correlação com dados neuropsicológicos, permitem a definição de um bom diagnóstico. Apesar da comprovação da eficácia do tratamento cirúrgico para o controle das crises, ainda não são claros os efeitos da ressecção de estruturas mesiais do lobo temporal na performance cognitiva, a longo prazo. O objetivo deste trabalho foi realizar um estudo prospectivo de uma série de pacientes com ELTM submetidos ao tratamento cirúrgico, comparando os resultados pré/pós-cirúrgicos obtidos a partir da análise de dados de avaliação neuropsicológica (ANP) e imagens de RM. No estudo avaliamos 119 indivíduos, 88 pacientes e 31 controles saudáveis. Os pacientes foram classificados de acordo com a escala proposta por Engel para controle de crises após a cirurgia. Avaliamos o coeficiente de inteligência estimado (QIe), as memórias verbal e não verbal com testes utilizados na rotina de investigação pré-operatória do nosso serviço. Utilizamos análises longitudinais específicas realizadas com o software SPSS®22. Consideramos p?0,05. Quanto à classificação de Engel observamos que 73,7% dos pacientes foram classificados em Engel I; 17,1% foram classificados em Engel II; 8,0% foram classificados em Engel III e 1,1% classificado em Engel IV com tempo médio de seguimento de 8,8 anos após a cirurgia. Para as ANP pré/pós-operatória observamos um declínio de memória para esses pacientes relacionado ao controle de crises e lado da cirurgia (p<0,0001). Para as ANP pós-operatórias realizadas em dois tempos diferentes e separadas em grupos quanto ao controle de crises e lado da cirurgia, não observamos diferença significativa, entretanto todos os testes indicaram uma tendência de melhora no desempenho de memória e QIe. Observamos maior volume hipocampal para os controles (média=3706±842), volume reduzido do hipocampo contralateral para pacientes livre de crises (média=3602±711) e menor ainda para os pacientes com presença de crises (média=3284±521). Para a análise de intensidade de sinal no lobo temporal contralateral dos pacientes, observamos uma diferença significativa (p=0,005) entre controles e pacientes com média menor para os controles. Também observamos alterações com diferença significativa para os tratos analisados em imagens de DTI, no lado ipsilateral à cirurgia comparados aos controles. Nossos resultados mostram bom controle de crises após a cirurgia, mesmo após um longo período. Entretanto observamos que após a cirurgia existe um declínio na performance dos testes neuropsicológicos para muitos pacientes, independente do lado operado. Porém, a análise a longo prazo mostra que existe uma recuperação parcial desse declínio, que pode estar associada a interação entre fatores de aprendizado e plasticidade cerebral; ou seja, podemos inferir que de alguma forma a melhora no controle das crises permite uma "recuperação" da eficiência cognitiva a longo prazo / Abstract: The quantification of the atrophy of the mesial temporal structures by MR images in patients with TLE allows identification "in vivo" of the anatomical changes associated with this disease and its correlation with neuropsychological data, allowing for the establishment of a proper diagnosis. Despite the evidence of the effectiveness of surgical treatment for seizure control, it is not yet clear the effects of resection of the mesial temporal lobe structures in cognitive performance in the long-term follow up. The aim of this study was to evaluate prospectively of a series of patients with TLE undergoing epilepsy surgery, comparing pre/post-surgical results obtained from neuropsychological assessment (NPA). We included 119 subjects, 88 patients and 31 healthy controls. Of the 113 patients, 88 had two NPA and 60 underwent two MRIs after surgery. Patients were classified according to Engel¿s scale. We evaluated the estimated intelligence coefficient (eIQ), the verbal and non-verbal memories with tests used in preoperative routine. We use specific longitudinal analyzes with SPSS®22 software. We observed that 73.7% of patients were classified as Engel I; 17.1% were classified as Engel II; 8.0% were classified as Engel III and 1.1% classified as Engel IV after surgery with a mean follow up of 8.8 years. The NPA pre/postoperative showed a memory decline for these patients related to seizures control and side of surgery (p<0.0001). We found no significant difference between the postoperative NPAs carried out in two different times and separated in groups regarding seizure control and side of surgery; however, all tests indicated a trend towards improvement trend in memory performance and eIQ. We observed a larger hippocampal volume for the controls (mean=3706±842), in comparison with seizure free patients (mean=3602±711) and smaller hippocampal contralateral volumes for patients with persistent seizures after surgery (mean=3284±521). We observed a significant difference (p=0.005) in T2 signal between patients and controls (increase in patients). We also observed changes with a significant difference to the white matter tracts analyzed with diffusion tensor images, in the ipsilateral side of surgery compared to controls. Our results show good seizure control after surgery, even after a long period of follow up. However, our results showed that after surgery there is a decline in the performance on neuropsychological tests for most patients, regardless of the side of surgery. However, the long-term repeated analysis showed that there is partial recovery that may be associated with the interaction between learning effect and brain plasticity. We can hypothesize that the improvement in seizure control after surgery allows "recovery" of the long-term cognitive efficiency / Doutorado / Fisiopatologia Médica / Doutora em Ciências

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