Background Obesity and associated metabolic dysregulation are linked to impaired cognitive function and alterations in brain structure, which increases the risk of age-related dementia. Increased glucocorticoid (GC) exposure may be a potential mediator of these negative effects on the brain. Methods and results In paper 1, we tested the relationship between cortisol levels, brain morphology and cognitive function in 200 women and men. Salivary cortisol levels were negatively related to cortical surface areas in prefrontal brain regions in both sexes. In participants with type 2 diabetes, high salivary cortisol levels were associated with lower memory performance. In paper 2, we tested in 70 overweight women the effects on tissue-specific GC metabolism of a Paleolithic diet or a diet following the Nordic nutrition recommendations. The 24-month interventions led to decreased expression of the GC-activating enzyme 11βHSD1 in adipose tissue, interpreted as a normalization of an obesity-related disturbance in GC metabolism. Furthermore, GC metabolism by 5α-reductase increased substantially after 2 years, an unexpected and novel result. The outcomes did not differ by diet. In paper 3, 20 women included in paper 2 were examined with functional magnetic resonance imaging (fMRI) while performing a memory task at baseline and after 6 months. Memory performance improved and functional brain responses increased in the hippocampus. Once again, the results were similar in both diet groups. In paper 4, 24 overweight participants with type 2 diabetes were examined with fMRI, using the same memory test as in paper 3, at baseline and after 12 weeks of intervention with a Paleolithic diet with or without exercise training. Functional brain response increased in the hippocampus, but memory was not improved. The addition of physical exercise did not alter the results. Conclusion Cortisol levels are linked to prefrontal brain structure and, at least in type 2 diabetes, lower memory performance. Furthermore, the dysregulated GC metabolism in obesity can be reversed by long-term diet- induced weight loss. Finally, dietary interventions with associated metabolic improvements alter functional brain responses during memory testing, including increased activation of the hippocampus. Whether these changes are linked to alterations in GC exposure and mediate improved cognition requires further study.

<p>Neuronal current MRI (ncMRI) is a field of study to directly map electrical activity in the brain using MRI, which has many benefits over functional MRI. One potential ncMRI method, Lorentz effect imaging (LEI), has shown promise but needs a better theoretical understanding to improve its use.</p><p>We develop three computational models to simulate the LEI experiments of an electrolyte filled phantom subject to a current dipole based on: ion flow, particle drift, and electromagnetohydrodynamics (EMHD). With comparative experimental results, we use the EMHD model to better understand the Lorentz effect over a range of current strengths. We also quantify the LEI experimental images and assess ways to measure the underlying current strength, which would greatly benefit comparative brain mapping.</p><p>EMHD is a good predictor of LEI signal loss. We can measure the underlying current strength and polarity in the phantom using LEI images. We can also use trends from the EMHD model results to predict the required current density for signal detection in future LEI experiments. We can also infer the electric field strength, flow velocity, displacement, and pressure from the predicted current magnitude in an LEI experiment.</p><p>The EMHD model provides information that greatly improves the utility and understanding of LEI. Future study with our EMHD model should be performed using shorter dipole lengths, higher density and lower strength of current sources, and varying current source frequencies to understand LEI in the setting of mapping brain activity.</p> / Dissertation

Background: Despite our distinct impression to the contrary, we are only conscious of a fraction of all the neural activity underlying our thoughts and behavior. Most neural processes occur non-consciously, and in parallel with our conscious experience. However, it is still unclear what the limits of non-conscious processes are in terms of higher cognitive functions. Many recent studies have shown that increasingly more advanced functions can operate non-consciously, but non-conscious information is still thought to be fleeting and undetectable within 500 milliseconds. Here we used various techniques to render information non-conscious, together with functional magnetic resonance imaging (fMRI), to investigate if non-consciously presented information can be retained for several seconds, what the neural substrates of such retention are, and if it is consistent with working memory maintenance. Results: In Study I we used an attentional blink paradigm to render stimuli (single letters) non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that non-conscious memory performance was above chance after all delay durations, and showed no signs of decline over time. Univariate fMRI analysis showed that the durable retention was associated with sustained BOLD signal change in the prefrontal cortex and cerebellum during the delay period. In Study II we used continuous flash suppression (CFS) to render stimuli (faces and tools) non-conscious, and a variable delay period (5 or 15 s) prior to memory test. The durable retention of up to 15 s was replicated, and it was found that stimuli identity and spatial position was retained until prospective use. In Study III we used CFS to render tools non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that memory performance was not better than chance. However, by using multi-voxel pattern analysis it was nonetheless possible to detect the presence vs. absence of non-conscious stimuli in the frontal cortex,and their spatial position (left vs. right) in the occipital cortex during the delay. Conclusions: Overall these findings suggest that non-consciously presented information (identity and/or position) can be retained for several seconds,and is associated with BOLD signal in frontal and posterior regions. These findings are consistent with working memory maintenance of non-consciously presented information, and thereby constrain models of working memory and theories of consciousness.

Behaviour is guided by accumulated experience, valuation and comparison. While many aspects associated with these functions are mediated by the frontal lobes, the precise contribution from particular regions remains debated. This thesis will deal with how an organism comes to select an option and will specifically focus on the role of the orbitofrontal cortex (OFC) in two mechanisms in this process: learning of outcome specificities and selecting between multiple options based on their expected values. Despite evidence emphasizing anatomical and connective heterogeneity within this structure, the OFC is often regarded as a uniform region. This thesis aims to resolve some of this uncertainty by assuming that the medial and lateral regions of the OFC contribute differentially to learning and decision-making. Two distinct methodologies were used in these investigations. First, the contribution of the medial OFC to social and emotional processing was examined. The findings from this study disprove previously held beliefs that the medial regions of the OFC guide social and emotional behaviours, but indicted a role for this region in value-guided decision-making. The second study examined functional differences between the lateral and medial OFC by making circumscribed lesions to either region in macaque monkeys. The animals performed a number of 3-armed bandit tasks which were designed to investigate different aspects of value assignment and comparison. The results show that while lateral OFC was required for "credit assignment" – the correct assignment of values to visual cues – medial OFC was critical for comparison of the cues' values during decision-making. In unchanging probabilistic environments, mOFC lesions induced decision-making impairments when value comparison was difficult without affecting credit assignment and associative learning. By contrast, lateral OFC lesions caused the opposite pattern of impairment. The final study used human-neuroimaging techniques to investigate the differential representation of outcome-specific contingency learning and found not only that the expectation of a unique outcome facilitated learning and memory recall but that this was supported by a neural network which included the lateral regions of the OFC and the anterior cingulate cortex. Activity in the mOFC did not correlate with outcome-specific contingency learning but instead reflected both the value associated with the receipt and expectation of a reward. Taken together, the results from this thesis suggest that specific parts of the OFC make markedly different contributions to these very different cognitive functions.

Balance of motor network activity between the two brain hemispheres after stroke is crucial for functional recovery. Several studies have extensively studied the role of the affected brain hemisphere to better understand changes in motor network activity following stroke. Very few studies have examined the role of the unaffected brain hemisphere and confirmed the testretest reliability of connectivity measures on unaffected hemisphere. We recorded blood oxygenation level dependent functional magnetic resonance imaging (fMRI) signals from nine stroke survivors with hemiparesis of the left or right hand. Participants performed a motor execution task with affected hand, unaffected hand, and both hands simultaneously. Participants returned for a repeat fMRI scan 1 week later. Using dynamic causal modeling (DCM), we evaluated effective connectivity among three motor areas: the primary motor area (M1), the premotor cortex (PMC) and the supplementary motor area for the affected and unaffected hemispheres separately. Five participants manual motor ability was assessed by Fugl-Meyer Motor Assessment scores and root-mean square error of participants tracking ability during a robot-assisted game. We found (i) that the task performance with the affected hand resulted in strengthening of the connectivity pattern for unaffected hemisphere, (ii) an identical network of the unaffected hemisphere when participants performed the task with their unaffected hand, and (iii) the pattern of directional connectivity observed in the affected hemisphere was identical for tasks using the affected hand only or both hands. Furthermore, paired t-test comparison found no significant differences in connectivity strength for any path when compared with one-week follow-up. Brain-behavior linear correlation analysis showed that the connectivity patterns in the unaffected hemisphere more accurately reflected the behavioral conditions than the connectivity patterns in the affected hemisphere. Above findings enrich our knowledge of unaffected brain hemisphere following stroke, which further strengthens our neurobiological understanding of stroke-affected brain and can help to effectively identify and apply stroke-treatments.

O dito popular afirma que quando uma pessoa perde um dos sentidos há uma compensação por parte dos outros sentidos para suprir a perda. Através de três experimentos psicofísicos baseados no modelo de Posner (Inibição de Retorno) e técnicas de Ressonância Magnética Funcional, surdos congênitos foram comparados a pessoas ouvintes com o objetivo de verificar se os surdos possuem processos atencionais diferentes dos ouvintes, e se as mesmas áreas corticais como a área de Wernicke, Broca e Córtex auditivo - eram ativadas em ambos os grupos. A tarefa consistia em pressionar um botão todas as vezes que os sujeitos detectassem a presença de um quadrado maior (alvo) apresentado em uma tela, enquanto também eram apresentados quadrados menores (pista) ora do mesmo lado, ora do lado oposto ao alvo. Através do Experimento I se pôde verificar que ambos os grupos apresentaram os fenômenos clássicos do Paradigma de Posner: Facilitação ou Inibição de Retorno, o que denotou a possibilidade de mecanismos atencionais semelhantes para ambos os grupos. Foi observado, porém, que os ouvintes eram mais rápidos que os surdos para responder à tarefa quando o intervalo temporal entre pista e alvo era longo (800ms), comparado ao tempo que levavam para responder quando o intervalo entre pista e alvo era curto (100 ms). O Experimento I suscitou a hipótese de que os surdos possivelmente apresentassem uma diferença de processamento temporal. No Experimento I todas as condições eram apresentadas de forma randômica. O Experimento II foi elaborado com o objetivo de por em evidência a 22 diferença dos TRM para intervalos curtos e longos, portanto os intervalos entre pista e alvo passaram a ser apresentados de forma fixa. Ao comparar os resultados do Experimento I com os do Experimento II (Intervalos Temporais Fixos), se pode verificar que os ouvintes apresentaram Tempos de Reação Manual mais lentos, enquanto os surdos apresentaram as mesmas médias a despeito da vantagem temporal, o que levou a sugerir a hipótese de que os surdos apresentem um déficit no processamento temporal. O experimento III consistiu na utilização do Paradigma de Posner enquanto os sujeitos eram submetidos ao exame de Ressonância Magnética Funcional com o objetivo de investigar se as regiões corticais ativadas poderiam ser semelhantes nos dois grupos. As imagens por Ressonância Magnética Funcional (RMF) demonstraram ativações nas áreas de Wernickie, Broca, e córtex auditivo em ambos os grupos enquanto executavam a tarefa, que embora não possuísse nenhum contexto semântico explícito, possuía o tempo como o principal parâmetro físico no qual os sujeitos pudessem se basear para melhorar o desempenho na tarefa. O tempo é um dos parâmetros físicos primários da língua oral, diferente da língua de sinais que possui o parâmetro visual e espacial como primário. Os resultados sugerem que as ativações corticais nos centros de audição e fala podem indicar uma plasticidade cruzada no grupo de surdos. Ainda, a participação do córtex auditivo no processamento da elaboração de estratégias para responder a uma tarefa que não contenha um contexto semântico explicito possivelmente indica sua participação no processamento de linguagem. / It is popularly said that when a person loses one sense, there is a compensation by the other remaining senses to suppress the loss. Throughout three Phsycophysic Experiments based on Inhibition of Return Posners Paradigm and Functional Magnetic Resonance (fMRI) Techniques, congenital deaf people were compared to normal hearing people in order to check if deaf people possess different attentional pattern compared to normal hearing people, and if the same cortical areas Wernicke and Brocas area and Hearing Cortex were activated in both groups. Experiment I consisted on pressing a button every time the presence of a big square (target) was detected by subjects while non-predictive small squares (cue) were also presented at the same or opposite side of the target. At Experiment I it was observed that both groups presented Posners Paradigm classical phenomena: Facilitation or Inhibition of Return, what suggested the possibility that attentional pattern may be similar to both groups. Therefore, it was observed that normal hearing people were faster than deaf people to respond to the task when time interval between cue and target was long (800 ms) when compared to the time they spent to respond when time interval between cue and target as short (100 ms). 24 Experiment I raised the hypotheses that possibly deaf people may present a temporal processing difference. At Experiment I every condition was randomly presented. Experiment II was elaborated to highlight MRT differences between short and long time intervals, so every time interval was presented on a fixed order. Comparison of Experiment I and II (Fixed Time Intervals) showed that normal hearing people presented shorter Manual Reaction Times (MRT), while deaf people kept the same averages despite the temporal advantage, what suggested that deaf people may present a deficit on temporal processing. Experiment III used Posners Paradigm while subjects were submitted to fMRI scanning in order to check if activated cortical regions could be similar in both groups. fMRI images demonstrate Wernicke and Brocas area and hearing cortex activations in both groups while executing the task, which, although did not have any explicit semantic content, had time as the main physical parameter on which subjects could be based to increase performance to respond to the task. Time is one of the oral language primary physical parameter, different of signed language which has visual and spatial parameters as primaries. Results suggest that cortical audition center activations may indicate a cross-modal plasticity at the deaf group. Yet, participation of hearing cortex on strategy elaboration to respond to a task which does not have any explicit semantic content possibly indicates the participation of hearing cortex on language processing.

BACKGROUND: Social cognitive ability is a significant determinant of functional outcome and deficits in social cognition are a disabling symptom of psychotic disorders. The neurobiological underpinnings of social cognition are not well understood, hampering our ability to ameliorate these deficits. Using ‘resting-state’ fMRI (functional magnetic resonance imaging) and a trans-diagnostic, data-driven analytic strategy, we sought to identify the brain network basis of emotional intelligence, a key domain of social cognition. METHODS: Subjects included 60 participants with a diagnosis of schizophrenia or schizoaffective disorder and 46 healthy comparison participants from three different sites: Beth Israel Deaconess Medical Center, Boston, MA, McLean Hospital, Belmont, MA, and University of Pittsburgh, Pittsburgh, PA. All participants underwent a structural T1/MPRAGE and resting-state fMRI scan. Emotional Intelligence was measured using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). A connectome-wide analysis of brain connectivity examined how each individual brain voxel’s connectivity correlated with emotional intelligence using multivariate distance matrix regression (MDMR). RESULTS: We identified a region in the left superior parietal lobule (SPL) where individual network topology predicted emotional intelligence. Specifically, the association of this region with the Default Mode Network (DMN) predicted higher emotional intelligence (r = 0.424, p < 0.001) and association with the Dorsal Attention Network (DAN) predicted lower emotional intelligence (r = -0.504, p < 0.001). This correlation was observed in both schizophrenia and healthy comparison participants. These results held true despite corrections for sex, age, race, medication dosage (chlorpromazine equivalents), and full scale IQ (FSIQ), and was replicable per site. Post-hoc analyses showed that membership of the left SPL was entirely within the DMN in high scorers and within the DAN in low scorers. This relationship was also shown to be specific to the identified left SPL region when compared to adjacent regions. Sulcal depth analysis of the left SPL revealed a correlation to emotional intelligence (r = 0.269, p = 0.0075). CONCLUSIONS: Previous studies have demonstrated individual variance in brain network topology but the cognitive or behavioral relevance of these differences was undetermined. We observe that the left SPL, a region of high individual variance at the cytoarchitectonic level, also demonstrates individual variance in its association with large scale brain networks and that network topology predicts emotional intelligence. This is the first demonstration of a clinical phenotype in individual brain network topology. / 2019-07-03T00:00:00Z

Esta dissertação apresenta os principais métodos estatísticos para analisar as séries temporais de fMRI com o objetivo de detectar regiões ativadas e caracterizar o erro envolvido nessa decisão. Na análise de imagens funcionais, devido à baixa razão sinal-ruído, torna-se necessário o uso de técnicas elaboradas de processamento. O resultado da aplicação de técnicas estatísticas sobre as séries temporais obtidas da imagem de fMRI, é um mapa estatístico paramétrico, (Statistical Parametric Map), (SPM), uma imagem 3-D que permite determinar o estado do voxel, ativado ou não ativado, e a significância estatística do resultado. Propomos um novo método baseado na Difusão Anisotrópica Robusta, (Robust Anisotropic Diffusion), (RAD), que explora uma característica fundamental da imagem funcional, a correlação espacial das regiões ativadas do cérebro humano. O método proposto permite obter mapas estatísticos que melhoram a determinação das áreas ativadas a partir de dados fMRI ruidosos. Os novos mapas estatísticos paramétricos, baseados na correlação espacial da imagem fMRI, reduzem os erros do processo de classificação dos voxels, melhorando assim o mapeamento das regiões ativadas no cérebro. Aplicamos a técnica proposta em dados gerados artificialmente, simulando ruído e sinal, e avaliamos o novo método proposto e um método clássico de processamento de fMRI. Apresentamos resultados comparativos entre um método clássico, o método de correlação e o novo método. Calculamos os erros envolvidos e apresentamos a curvas características de operação de um receptor, (Receiver Operating Characteristics), (ROC), para ambos métodos, comparando os parâmetros mais importantes. Também avaliamos o novo método em dados reais de fMRI de um experimento em blocos com estímulo visual. / This dissertation presents the main statistical methods to analyse fMRI temporal series to detect activated regions and to characterise the error involved in this decision. Due to low signal to noise ratio, elaborate processing techniques are necessary to analyse functional images. Statistical techniques are usually applied on the temporal series obtained from fMRI, resulting in a Statistical Parametric Map (SPM), a 3-D image that makes it possible to determine the state of a voxel, as activated or not activated, and the statistical significance of the result. We proposed a new, simple an elegant method based on Robust Anisotropic Diffusion (RAD) to exploit the spatial correlation of activated regions of the human brain. The new method, named Robust Anisotropic Diffusion of Statistical Parametric Maps (RADSPM), allows one to obtain statistical maps that improve the determination of activated areas from noisy fMRI data. The new parametric statistical maps, based on the voxel spatial correlation of the fMRI image, reduce the classification error thus improving the significance of the results. We have tested the new technique in both simulated and real fMRI, obtaining sharp and noiseless SPMs with increased statistical significance. We compare results of the new RADSPM method with those of a classic method, the conventional correlation method. We calculate the involved errors and we present Receiver Operating Characteristics (ROC) curves for both methods, comparing the most important parameters for simulated fMRI data. We also evaluate the new method on real data of a visual fMRI experiment.

L'une des capacités humaines fondamentales est la capacité d'interpréter des symboles. Malgré plusieurs décennies de travaux en neuropsychologique et neuroimagerie sur le substrat cognitif et neuronal des représentations sémantiques, de nombreuses questions restent sans réponse. Les présents travaux de thèse tentent de démêler l'un de ces mystères: les substrats neuronaux des différentes composantes du mot sont-ils dissociables? Ce travail comporte deux composantes principales : l'une théorique et l'autre empirique. Dans la première partie, nous passons en revue les différentes positions théoriques concernant les corrélats cognitifs et neuraux des représentations sémantiques. De plus, nous proposons une distinction opérationnelle entre les dimensions moto-perceptives (c'est-à-dire les attributs des objets auxquels les mots se réfèrent perçus par les sens) et conceptuelles (c'est-à-dire l'information construite par l'intégration des multiples caractéristiques perceptives). Dans la deuxième partie, nous présentons les résultats des études menées afin d'étudier l'automaticité de la récupération, l'organisation topographique et la dynamique temporelle des dimensions moto-perceptives et conceptuelles de la signification des mots. Tout en contribuant à notre compréhension de la manière dont le sens des mots est codé dans le cerveau, les travaux présentés dans cette thèse ont des implications méthodologiques et théoriques importantes. En particulier, ils soulignent l'importance d'une intégration fructueuse entre les théories cognitives et les méthodes statistiques avancées afin d'éclairer les mystères entourant les représentations sémantiques. / One of the core human abilities is that of interpreting symbols. Notwithstanding decades of neuropsychological and neuroimaging work on the cognitive and neural substrate of semantic representations, many questions are left unanswered. The research in this dissertation attempts to unravel one of them: are the neural substrates of different components of concrete word meaning dissociated? In the first part, I review the different theoretical positions and empirical findings on the cognitive and neural correlates of semantic representations. Crucially, I propose an operational distinction between motor-perceptual dimensions (i.e., those attributes of the objects referred to by the words that are perceived through the senses) and conceptual ones (i.e., the information that is built via a complex integration of multiple perceptual features). In the second part, I present the results of the studies I conducted in order to investigate the automaticity of retrieval, topographical organization, and temporal dynamics of motor-perceptual and conceptual dimensions of word meaning. The results suggest that the neural substrates of different components of symbol meaning can be dissociated in terms of localization and of the feature of the signal encoding them, while sharing a similar temporal evolution.

Esta dissertação apresenta os principais métodos estatísticos para analisar as séries temporais de fMRI com o objetivo de detectar regiões ativadas e caracterizar o erro envolvido nessa decisão. Na análise de imagens funcionais, devido à baixa razão sinal-ruído, torna-se necessário o uso de técnicas elaboradas de processamento. O resultado da aplicação de técnicas estatísticas sobre as séries temporais obtidas da imagem de fMRI, é um mapa estatístico paramétrico, (Statistical Parametric Map), (SPM), uma imagem 3-D que permite determinar o estado do voxel, ativado ou não ativado, e a significância estatística do resultado. Propomos um novo método baseado na Difusão Anisotrópica Robusta, (Robust Anisotropic Diffusion), (RAD), que explora uma característica fundamental da imagem funcional, a correlação espacial das regiões ativadas do cérebro humano. O método proposto permite obter mapas estatísticos que melhoram a determinação das áreas ativadas a partir de dados fMRI ruidosos. Os novos mapas estatísticos paramétricos, baseados na correlação espacial da imagem fMRI, reduzem os erros do processo de classificação dos voxels, melhorando assim o mapeamento das regiões ativadas no cérebro. Aplicamos a técnica proposta em dados gerados artificialmente, simulando ruído e sinal, e avaliamos o novo método proposto e um método clássico de processamento de fMRI. Apresentamos resultados comparativos entre um método clássico, o método de correlação e o novo método. Calculamos os erros envolvidos e apresentamos a curvas características de operação de um receptor, (Receiver Operating Characteristics), (ROC), para ambos métodos, comparando os parâmetros mais importantes. Também avaliamos o novo método em dados reais de fMRI de um experimento em blocos com estímulo visual. / This dissertation presents the main statistical methods to analyse fMRI temporal series to detect activated regions and to characterise the error involved in this decision. Due to low signal to noise ratio, elaborate processing techniques are necessary to analyse functional images. Statistical techniques are usually applied on the temporal series obtained from fMRI, resulting in a Statistical Parametric Map (SPM), a 3-D image that makes it possible to determine the state of a voxel, as activated or not activated, and the statistical significance of the result. We proposed a new, simple an elegant method based on Robust Anisotropic Diffusion (RAD) to exploit the spatial correlation of activated regions of the human brain. The new method, named Robust Anisotropic Diffusion of Statistical Parametric Maps (RADSPM), allows one to obtain statistical maps that improve the determination of activated areas from noisy fMRI data. The new parametric statistical maps, based on the voxel spatial correlation of the fMRI image, reduce the classification error thus improving the significance of the results. We have tested the new technique in both simulated and real fMRI, obtaining sharp and noiseless SPMs with increased statistical significance. We compare results of the new RADSPM method with those of a classic method, the conventional correlation method. We calculate the involved errors and we present Receiver Operating Characteristics (ROC) curves for both methods, comparing the most important parameters for simulated fMRI data. We also evaluate the new method on real data of a visual fMRI experiment.