Introdução: Embora alterações estruturais cerebrais na esquizofrenia venham sendo repetidamente demonstradas em estudos de ressonância magnética (RM), ainda permanece incerto se tais alterações são estáticas ou progressivas. Enquanto estudos longitudinais são tradicionalmente utilizados na avaliação da questão da progressão, estudos transversais de neuroimagem comparando diretamente pacientes com esquizofrenia crônica e de primeiro episódio a controles saudáveis têm sido bastante raros até o presente. Com o recente interesse em meganálises combinando dados multicêntricos de RM visando-se a maior poder estatístico, o presente estudo multicêntrico de morfometria baseada no voxel (VBM) foi realizado para avaliar os padrões de alterações estruturais cerebrais segundo os diferentes estágios da doença, bem como para avaliar quais (se alguma) dessas alterações se correlacionariam especificamente a moderadores clínicos potenciais, tais como exposição cumulativa a antipsicóticos, tempo de doença e gravidade da doença. Métodos: Selecionou-se uma ampla amostra de pacientes com esquizofrenia (161, sendo 99 crônicos e 62 de primeiro episódio) e controles (151) a partir de quatro estudos prévios de RM (1,5T) realizados na mesma região do Brasil. O processamento e análise das imagens foi realizado usando-se o software Statistical Parametric Mapping (SPM8) com emprego do algoritmo DARTEL (diffeomorphic anatomical registration through exponentiated Lie algebra). Os efeitos de grupo sobre os volumes regionais de substância cinzenta (SC) foram analisados através de comparações voxel-a-voxel por análises de covariância em modelos lineares gerais, inserindo-se, em todas as análises, o volume total de SC, protocolo do scanner, idade e sexo como variáveis de confusão. Por fim, foram realizadas análises de correlação entre os aludidos moderadores clínicos potenciais e os volumes cerebrais globais e regionais. Resultados: Os pacientes com esquizofrenia de primeiro episódio apresentaram reduções volumétricas sutis em comparação aos controles, em um circuito neural circunscrito e identificável apenas em análises SVC (small volume correction) [p < 0.05, com correção family-wise error (FWE)], incluindo a ínsula, estruturas têmporo-límbicas e corpo estriado. Os pacientes crônicos, por outro lado, apresentaram um padrão de alterações extensas comparativamente aos controles, envolvendo os córtices frontais orbitais, superiores e inferiores bilateralmente, córtex frontal médio direito, ambos os córtices cingulados anteriores, ambas as ínsulas, e os córtices temporais superior e médio direitos (p < 0.05, análises whole-brain com correção FWE). Foram encontradas correlações negativas significantes entre exposição cumulativa a antipsicóticos e volumes globais de SC e substância branca nos pacientes com esquizofrenia, embora as correlações com reduções regionais não tenham sido significantes. Detectaram-se, ainda, correlações negativas significantes entre tempo de doença e volumes regionais relativos da ínsula esquerda, córtex cingulado anterior direito e córtices pré-frontais dorsolaterais nas análises SVC para os grupos conjuntos (esquizofrenia crônica e de primeiro episódio). Conclusão: Os achados supracitados indicam que: a) as alterações estruturais associadas com o diagnóstico de esquizofrenia são mais disseminadas na forma crônica em comparação à de primeiro episódio; b) reduções volumétricas regionais em áreas específicas do cérebro podem variar em função do tempo de doença; c) a exposição cumulativa a antipsicóticos associou-se a alterações volumétricas globais, e não regionais / Introduction: Although structural brain changes in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression, cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls have been very scarce to date. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, illness duration and overall illness severity. Methods: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses ]p < 0.05, family-wise error (FWE)-corrected], including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). Significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. There were also significant negative correlations between duration of illness and relative GM volumes of the left insula, and right anterior cingulate and dorsolateral prefrontal cortices on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. Conclusion: The above data indicate that: a) brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients; b) relative GM volume deficits in specific brain regions may vary as a function of duration of illness; c) cumulative doses of antipsychotics usage were associated with brain volumes globally rather than regionally

Introdução: Os glicocorticoides (GCs) estão envolvidos na regulação e adaptação da resposta ao estresse, exercendo seus efeitos através de seus receptores. Variações polimórficas no gene do receptor de glicocorticoide (GR) têm sido caracterizadas funcionalmente. O polimorfismo A3669G do gene do GR está relacionado a modificações na sensibilidade aos GCs e mudanças no perfil metabólico. Concentrações fisiológicas de GCs estimulam a ingestão calórica e, na presença de insulina, modificam a preferência alimentar. A variante A3669G do gene do GR parece levar a um menor risco para diabetes, em pacientes com Síndrome de Cushing, e para o tabagismo, quando associado a um polimorfismo do gene do receptor de mineralocorticoide, sugerindo uma modulação na via de recompensa. O objetivo deste trabalho é avaliar a associação de variantes do polimorfismo A3669G do gene do GR com o comportamento alimentar e parâmetros metabólicos em uma amostra de estudantes, correlacionando com dados de neuroimagem funcional. Métodos: A amostra provém de alunos de 6 escolas de Porto Alegre, avaliados em 2008 e em 2013. Em 2008, 131 indivíduos apresentavam o protocolo completo de avaliação e, destes, 74 retornaram em 2013. A avaliação incluiu genotipagem, antropometria, exames laboratoriais, comportamento alimentar e um paradigma avaliando a ativação cerebral em resposta a visualização de imagens de alimentos palatáveis, não palatáveis e de objetos neutros. A análise da associação com os fenótipos foi realizada através do teste t de Student e Chi quadrado; os dados do estudo longitudinal foram analisados por meio de Equações de Estimatição Generalizada. Resultados: A variante G do polimorfismo A3669G do gene do GR foi encontrado em 17,6% em 2008 e em 14,9% da amostra em 2013. Não houve diferença entre os grupos de carreadores do alelo G e não carreadores quanto a diferentes confundidores; a comparação entre as médias dos dois grupos sobre o consumo calórico proveniente de proteínas, carboidratos e gorduras em 2008 não revelou diferenças significativas; nesta etapa, as análises evidenciaram maior consumo de açúcares e de calorias totais no grupo não carreador do alelo G. Em 2013, estes indivíduos não carreadores do alelo G do polimorfismo A3669G apresentaram maior insulinemia e além de aumento no índice de resistência à insulina, sem diferenças no consumo alimentar. Os dados de neuroimagem funcional indicaram que a visualização de imagens de alimentos palatáveis pelo grupo não carreador do alelo G ativou o giro occipital médio, uma região implicada no processamento visual, mostrando menor ativação em giro pré central e nas áreas de Brodmann 4 e 6, relacionadas ao planejamento motor e sensibilidade ao sabor. Conclusão: Os resultados mostram que os indivíduos não carreadores da variante G do polimorfismo A3669G do gene do GR apresentaram menor sensibilidade à insulina, precedidos pela modulação na preferência alimentar. Os achados em neuroimagem funcional indicam maior saliência de incentivo aos alimentos palatáveis e predisposição à impulsividade no grupo não carreador do alelo G. Sugere-se que a redução na sensibilidade em nível celular aos GCs relacionada à presença do alelo G, afete a ingestão alimentar, reduzindo o consumo de alimentos palatáveis, diminuindo o risco para doenças metabólicas. / Introduction: Glucocorticoids are involved in regulation and adaptation of the stress response, exerting effects through its receptors. Variations on the glucocorticoid receptors genes have been characterized functionally. The A3669G polymorphism of the glucocorticoid receptor gene is related to a change in the tissue sensitivity to glucocorticoids and altered metabolic profile. Physiological concentrations of glucocorticoids stimulate food intake and in the presence of insulin affect food preferences. The G variant of the A3669G polymorphism appears to lead to a lower risk for diabetes, in patients with Cushing's syndrome, and smoking, when associated with a polymorphism of the mineralocorticoid receptor gene, suggesting a modulation in reward pathways. The objective of this study is to evaluate the association of A3669G polymorphism variants with feeding behavior and metabolic parameters in a sample of students correlating with functional neuroimaging data. Methods: The sample includes students of 6 schools in Porto Alegre, evaluated at two occasions 2008 and in 2013. In 2008, 131 individuals had complete protocol assessment and, from these, 74 returned in for re- evaluation in 2013. The evaluation included genotyping, anthropometry, laboratory tests, feeding behavior and a functional MRI paradigm to verify brain activation in response to the visualization of palatable, non- palatable foods and neutral items. The association with phenotypes was performed using Student's t test and Chi-square; longitudinal study data were evaluated using Generalized Estimating Equations. Results: The variant of the A3669G polymorphism was found in 17.6% of the students in 2008 and 14.9% of the sample in 2013. There was no difference between groups in the sample composition; the comparison between groups of the mean caloric intake originating from proteins, carbohydrates and fats in 2008 revealed no significant differences; at this time, analysis showed lower consumption of sugars and total calories in the G carrier group. In 2013, these individuals showed a reduction in insulin level and resistance, with no differences in food intake. The fMRI data indicated that viewing a food palatable image by the wild-type allele carrier group activated a region involved in visual processing (middle occipital gyrus) and deactivated an area related to motor planning and sensitivity to taste (pre central gyrus). Conclusion: The results showed that G carriers of the A3669G polymorphism of glucocorticoid receptor gene had lower insulin resistance levels, preceded by modulation of their food preference. The findings in functional neuroimaging showed increased incentive salience on viewing palatable food images and a predisposition for impulsivity in noncarriers. Data suggest that reduction in glucocorticoids sensitivity at a cellular level affects food intake, by reducing consumption of palatable foods, possibly decreasing the risk for metabolic diseases.

Submitted by Fernanda Furlanetto Bellentani null (fernandafbelle@gmail.com) on 2017-03-07T01:02:32Z No. of bitstreams: 1 Tese Bellentani FF.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-03-10T16:53:16Z (GMT) No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Made available in DSpace on 2017-03-10T16:53:16Z (GMT). No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) Previous issue date: 2017-02-17 / A conectividade funcional é anormal na epilepsia do lobo temporal mesial (ELTm). O objetivo deste estudo foi investigar os efeitos de fármacos antiepilépticos (FAES) na conectividade funcional de pacientes com ELTm. Para isso, 31 pacientes com ELTm (16 à direita e 15 à esquerda) e 36 controles foram investigados. Sequências 3D volumétricas T1 e imagens funcionais a partir de sinal BOLD foram adquiridas em um equipamento 3T. Os dados da ressonância magnética funcional (RMf) em repouso foram processados e analisados utilizando o programa CONN. Para cada sujeito, duas formas de análise foram realizadas: uma de correlação entre as várias regiões de interesse e outra de região interesse para todos os voxels. A análise de grupos foi feita utilizando um modelo linear geral com nível de significância de p < 0,05 corrigido para múltiplas comparações. Foram realizadas comparações entre pacientes com ELTm (direita ou esquerda) e controles, seguidas de comparações de acordo com a carga de FAEs. A partir dessas análises, foi constatado uma redução de conectividade com volume total de 9092 mm3 (p<0,0001), em pacientes com ELTm esquerda e 5234 mm3 (p<0,0001), em pacientes com ELTm direita . Quando considerada a carga de medicação, pacientes com ELTm esquerda, recebendo doses altas, apresentaram redução de conectividade nas regiões temporais. Nos pacientes que recebiam doses baixas, essa redução atingiu uma área total mais extensa, no córtex frontal medial, na região posterior do cíngulo e pré-cúneo. Para o lado direito, em pacientes recebendo doses altas, a redução de conectividade foi observada apenas na área do cótex frontal medial. Nos que receberam doses baixas, 2 áreas com redução foram observadas (córtex frontal medial e região posterior do cíngulo) e com uma extensão maior. A análise de correlação envolvendo regiões de interesse mostrou, para ambos os lados, que o circuito amígdalo-hipocampal e a rede de modo padrão apresentaram maior conectividade quando utilizadas maiores doses de FAEs. Com base nesses resultados, foram confirmadas áreas de conectividade funcional anormal em pacientes com ELTm e que se apresentam mais difusas em pacientes com ELTm esquerda. Conclui-se também que as doses de medicamentos podem influenciar nestas observações, uma vez que o aumento de dose tende a normalizar a conectividade funcional cerebral. / The functional connectivity is abnormal in mesial temporal lobe epilepsy (MTLE). The objective of this study was to investigate the effects of antiepileptic drugs (AED) laterality and medication effect in the functional connectivity of MTLE. For this, 31 patients with MTLE (16 right and 15 left) and 36 controls were investigated. 3D volumetric sequences T1 and functional images from BOLD signal were acquired in a 3T equipment. Functional magnetic resonance imaging (fMRI) data were processed and analyzed using the CONN program. Two forms of analysis were performed for each patient: one of correlation between the various regions of interest and other of region of interest for all the voxels. The group analyzes was done following a general linear model with a level of significance of p < 0,05 corrected for the multiple comparisons. Comparisons were made between patients with MTLE (right or left) and controls, following of comparisons according to the AED. From these analysis, it was observed that in patients with left MTLE, there was a reduction in connectivity with total volume of 9092 mm³ (p<0,0001) and in patients with right MTLE, the areas of decreased connectivity totaled 5234 mm³ (p<0,0001). When considering the medication load, patients with left MTLE receiving high doses presented reduced connectivity in the temporal regions and in patients receiving low doses, this reduction reached a more extensive total area, in the medial frontal cortex, in the posterior region of the cingulate and pre-cuneous. To the right side, in patients receiving high doses, a reduced connectivity was observed only in the area of the medial frontal cortex, whereas in those receiving low doses, 2 areas with reduction were observed (medial frontal cortex and posterior cingulate region). The analysis of correlation involving regions of interest showed, to both sides that the amygdalo-hippocampal circuit and the network pattern mode presented greater connectivity when higher doses of AED. Based on these results were confirmed areas of abnormal functional connectivity in patients with MTLE and are more difuse in patients with left MTLE. It was also concluded that drug doses can influence these observations, once the doses increase tends to normalize functional brain connectivity.

This lecture takes a dual-targeted approach in: 1) acquainting the audience with newer neuroimaging techniques applied to the consequences of vestibular dysregulation following noise or blast-induced mild traumatic brain injury (mTBI); and 2) considers treatment and rehabilitation modalities of vestibular and balance dysfunction in order to help veteran’s resume normal activities-of-daily-living. Relevant examples from each targeted lecture will be provided. Intended Audience: Professionals interested in the area of vestibular and balance assessment, neuroimaging, and rehabilitation.

<p>Social phobia is a disabling anxiety disorder characterized by an excessive fear of negative evaluation in social situations. The present thesis explored the epidemiology and neurobiology of the disorder. By means of a mailed questionnaire, the point prevalence of social phobia in the Swedish general population was estimated at 15.6%. However, prevalence rates varied between 1.9 and 20.4% across the different levels of distress and impairment used to define cases. Thus, although social anxiety is widespread within the community, the precise diagnostic boundaries for social phobia are difficult to determine. Social phobia was associated with female gender, low educational attainment, psychoactive medication use, and lack of social support. A cluster analysis revealed that subtypes of social phobia mainly differed dimensionally on a mild-moderate-severe continuum, with number of cases declining with increasing severity. Public speaking was the most common social fear in all groups of social phobics and in the population at large.</p><p>In the neurobiological studies, positron emission tomography was used to examine brain serotonin metabolism and changes in the regional cerebral blood flow (rCBF) response to public speaking stress following treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral group therapy. Social phobics exhibited lowered serotonin turnover, relative to non-phobics, mainly in the medial temporal cortex including the bilateral rhinal and periamygdaloid regions. Symptom improvement with cognitive-behavioral- as well as SSRI-treatment was accompanied by a reduced rCBF-response to public speaking in the amygdala, hippocampus and adjacent temporal cortex, i.e. regions that serve important functions in anxiety. Thorough suppression of rCBF in limbic brain regions was associated with favorable long-term treatment outcome. These results provide neuroimaging evidence for a presynaptic serotonergic dysfunction in social phobia and for a common neural mechanism whereby psychological and pharmacological anti-anxiety treatments act.</p>

Social phobia is a disabling anxiety disorder characterized by an excessive fear of negative evaluation in social situations. The present thesis explored the epidemiology and neurobiology of the disorder. By means of a mailed questionnaire, the point prevalence of social phobia in the Swedish general population was estimated at 15.6%. However, prevalence rates varied between 1.9 and 20.4% across the different levels of distress and impairment used to define cases. Thus, although social anxiety is widespread within the community, the precise diagnostic boundaries for social phobia are difficult to determine. Social phobia was associated with female gender, low educational attainment, psychoactive medication use, and lack of social support. A cluster analysis revealed that subtypes of social phobia mainly differed dimensionally on a mild-moderate-severe continuum, with number of cases declining with increasing severity. Public speaking was the most common social fear in all groups of social phobics and in the population at large. In the neurobiological studies, positron emission tomography was used to examine brain serotonin metabolism and changes in the regional cerebral blood flow (rCBF) response to public speaking stress following treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral group therapy. Social phobics exhibited lowered serotonin turnover, relative to non-phobics, mainly in the medial temporal cortex including the bilateral rhinal and periamygdaloid regions. Symptom improvement with cognitive-behavioral- as well as SSRI-treatment was accompanied by a reduced rCBF-response to public speaking in the amygdala, hippocampus and adjacent temporal cortex, i.e. regions that serve important functions in anxiety. Thorough suppression of rCBF in limbic brain regions was associated with favorable long-term treatment outcome. These results provide neuroimaging evidence for a presynaptic serotonergic dysfunction in social phobia and for a common neural mechanism whereby psychological and pharmacological anti-anxiety treatments act.

Functional neuroimaging techniques such as near-infrared spectroscopy (NIRS) have been studied in brain-computer interface (BCI) development. Previous research has suggested that the addition of a second brain-monitoring modality may improve the accuracy of a NIRS-BCI. The objective of this study was to determine whether the classification accuracies achievable by a multimodal BCI, which combines NIRS and transcranial Doppler ultrasonography (TCD) signals, can exceed those attainable using a unimodal NIRS-BCI or TCD-BCI. Nine able-bodied subjects participated in the study. Simultaneous measurements were made with NIRS and TCD instruments while participants were prompted to perform a verbal fluency task or to remain at rest, within the context of a block-stimulus paradigm. In five of nine (55.6%) participants, classification accuracies with the NIRS-TCD system were significantly higher (p<0.05) than with NIRS or TCD systems alone. Our results suggest that multimodal neuroimaging may be a promising approach towards improving the accuracy of future BCIs.

Background: Functional imaging studies have examined the neural circuitry of subjects with obsessive compulsive disorder (OCD), and the changes associated with oral treatment. However, the effect of intravenous (IV) serotonin reuptake inhibitors (SRIs) on neuronal activation has not been investigated in OCD subjects, even though IV SRIs have been shown to be more effective than oral pharmacotherapy. Methods: Six OCD and 6 control subjects underwent functional magnetic resonance imaging while receiving infusions of citalopram and placebo, in a randomized, crossover design. Results: Compared to controls, OCD subjects exhibited hyperactivation of the orbitofrontal cortex and anterior cingulate cortex while looking at symptom provoking pictures at baseline. However, after the citalopram infusion, patients displayed attenuations of these regions, which correlated with reductions in subjective anxiety ratings. Conclusion: The effects observed after the IV citalopram infusion are similar to modulations observed after prolonged oral pharmacotherapy trials, illustrating the benefits of IV SRIs.

Functional neuroimaging techniques such as near-infrared spectroscopy (NIRS) have been studied in brain-computer interface (BCI) development. Previous research has suggested that the addition of a second brain-monitoring modality may improve the accuracy of a NIRS-BCI. The objective of this study was to determine whether the classification accuracies achievable by a multimodal BCI, which combines NIRS and transcranial Doppler ultrasonography (TCD) signals, can exceed those attainable using a unimodal NIRS-BCI or TCD-BCI. Nine able-bodied subjects participated in the study. Simultaneous measurements were made with NIRS and TCD instruments while participants were prompted to perform a verbal fluency task or to remain at rest, within the context of a block-stimulus paradigm. In five of nine (55.6%) participants, classification accuracies with the NIRS-TCD system were significantly higher (p<0.05) than with NIRS or TCD systems alone. Our results suggest that multimodal neuroimaging may be a promising approach towards improving the accuracy of future BCIs.

Background: Functional imaging studies have examined the neural circuitry of subjects with obsessive compulsive disorder (OCD), and the changes associated with oral treatment. However, the effect of intravenous (IV) serotonin reuptake inhibitors (SRIs) on neuronal activation has not been investigated in OCD subjects, even though IV SRIs have been shown to be more effective than oral pharmacotherapy. Methods: Six OCD and 6 control subjects underwent functional magnetic resonance imaging while receiving infusions of citalopram and placebo, in a randomized, crossover design. Results: Compared to controls, OCD subjects exhibited hyperactivation of the orbitofrontal cortex and anterior cingulate cortex while looking at symptom provoking pictures at baseline. However, after the citalopram infusion, patients displayed attenuations of these regions, which correlated with reductions in subjective anxiety ratings. Conclusion: The effects observed after the IV citalopram infusion are similar to modulations observed after prolonged oral pharmacotherapy trials, illustrating the benefits of IV SRIs.