Real world decision-making requires simultaneously determining what we are observing in our environment (perceptual decision-making; PDM) and what the stimuli and actions are worth (reward-based decision-making; RDM). There is evidence of a bi-directional relationship between reward and perceptual information in guiding choice, with some studies suggesting that individuals optimally combine the two. Uncertainty in both reward expectations and perception have been shown to alter choice behavior, however few studies have manipulated both variables simultaneously. Given the distinct theoretical and computational foundations of PDM and RDM, it has also been assumed that the underlying behavioral and neural substrates of perceptual and reward-based choice are separable. However, there is evidence that task structure and subjective value/uncertainty more generally contribute to activity in large-scale networks of the brain, rather than domain specific features (perceptual salience/reward). Variability in task structures and methods of manipulating and modeling sensory and reward uncertainty, make it hard to draw definitive conclusions across these perspectives with currently available data. The current study used behavioral and fMRI techniques to investigate the neurobehavioral substrates of decision-making under simultaneous perceptual and reward uncertainty in a sample of healthy adult volunteers. The primary objectives of this project were to test: a) how simultaneous manipulations in sensory and reward uncertainty influence choice, b) whether task structure alters the influence of sensory and reward information on choice behavior, and c) whether activity in underlying neural substrates reflect domain-specific or domain-general processes. Results showed that choices were best predicted by a combined model of perceptual salience and reward, with an overall bias towards perceptual salience information. Choice percentage was not impacted by task structure, however choices were better predicted by individual features (salience and reward) when they were manipulated stably, than dynamically. Activity in the brain showed greater overlap between dynamic task conditions when compared to both salience and reward conditions. There was also greater overlap between stable task conditions when compared to reward but not salience conditions. Preliminary evidence suggests that activity in decision-relevant regions of the brain varied by uncertainty and value rather than salience and reward per se. / Doctor of Philosophy / Real world decision-making requires knowing what things in our environment are and knowing what they are worth. Uncertainty about what different options are, can affect the actions we take and the outcomes we expect. Uncertainty about the outcome of our choices or actions can also influence how attend to or consider certain options when making choices. We also know that context can affect our behavior. For example, when our environment changes frequently, choices that might have been good in the past, may not necessarily be the best course of action in the future. This can add further confusion about what to do. Across several mental health conditions, we see that problems arise when individuals need to take actions based on incomplete, uncertain, or frequently changing information. Real world decision-making requires knowing what things in our environment are and knowing what they are worth. Uncertainty about what different options are, can affect the actions we take and the outcomes we expect. Uncertainty about the outcome of our choices or actions can also influence how we attend to or consider options when making choices. We also know that context can affect our behavior. For example, when our environment changes frequently, choices that might have been good in the past, may not necessarily be the best course of action in the future. This can add further confusion about what to do. Across several mental health conditions, we see that problems arise when individuals need to take actions based on incomplete, uncertain, or frequently changing information. The first goal of this study was to better understand what healthy individuals do when they are faced with different levels of uncertainty around about what different options are (through changes in visual clarity), and what they are worth (through changes in probability of reward). A second goal was to see whether how the frequency at which choice clarity and outcomes change, effects the kinds of choices people make. Third, the study used a measure of brain activity, to determine what the brain is doing which participants make these complex decisions. Results showed that people's choices were best predicted by considering both clarity of the options and their outcome. Having certainty about the identity of the choices was more important than the value of those choices. Also, information about clarity and value of options were more likely to be considered when they were stable, versus when they were changing frequently. Decision-relevant regions of the brain seemed to respond most to overall information about uncertainty and stability of options rather than their clarity or outcome value per se. Future research should test these findings in a larger sample, further explore individual differences in how people respond to various types of uncertainty and determine how knowledge of these individual differences can inform personalized treatment for individuals with related mental health challenges.

Posttraumatic stress disorder (PTSD) is accompanied by marked alterations in cognition and behavior, particularly when negative, high-value information is present (Aupperle, Melrose, Stein, & Paulus, 2012; Hayes, Vanelzakker, & Shin, 2012) . However, the underlying processes are unclear; such alterations could result from differences in how this high value information is updated or in its effects on processing future information. To untangle the effects of different aspects of behavior, we used a computational psychiatry approach to disambiguate the roles of increased learning from previously surprising outcomes (i.e. associability; Li, Schiller, Schoenbaum, Phelps, & Daw, 2011) and from large value differences (i.e. prediction error; Montague, 1996; Schultz, Dayan, & Montague, 1997) in PTSD. Combat-deployed military veterans with varying levels of PTSD symptoms completed a learning task while undergoing fMRI; behavioral choices and neural activation were modeled using reinforcement learning. We found that associability-based loss learning at a neural and behavioral level increased with PTSD severity, particularly with hyperarousal symptoms, and that the interaction of PTSD severity and neural markers of associability based learning predicted behavior. In contrast, PTSD severity did not modulate prediction error neural signal or behavioral learning rate. These results suggest that increased associability-based learning underlies neurobehavioral alterations in PTSD. / Master of Science

Successful episodic recollection occurs when an event properly binds with its context. Source misattribution demonstrates incorrect binding of a memory with its contextual information. By contrast, false memories are memories of events that did not occur. Although theoretically they should not be bound with contextual information, often, false memories are accompanied by contextual information. This phenomenon is known as content borrowing. This thesis project examined the differences between the two contextual memory errors. The DRM paradigm was used to induce both source misattributions and content borrowing. This allowed the neural differences between the two to be directly tested. No differences were found between source misattribution and content borrowing. However, false memories with content borrowing showed different neural activations from true memory with correct source, true memory with incorrect source, and correct rejection. This suggests that false memories and source misattributions may represent similar errors in memory that rely on gist memory traces. / Master of Science

Cocaine use has contributed to 5 million individuals falling into the cycle of addiction. Prior research in cocaine dependence mainly focused on rewards. Losses also play a critical role in cocaine dependence as dependent individuals fail to avoid social, health, and economic losses even when they acknowledge them. However, dependent individuals are extremely adept at escaping negative states like withdrawal. To further understand whether cocaine use may contribute to dysfunctions in aversive learning, this paper uses fMRI and an aversive learning task to examine cocaine dependent individuals abstinent from cocaine use (C-) and using as usual (C+). Specifically of interest is the neural signal representing actual loss compared to the expected loss, better known as prediction error (δ), which individuals use to update future expectations. When abstinent (C-), dependent individuals exhibited higher positive prediction error (δ+) signal in their striatum than when they were using as usual. Furthermore, their striatal δ+ signal enhancements from drug abstinence were predicted by higher positive learning rate (α+) enhancements. However, no relationships were found between drug abstinence enhancements to negative learning rates (α±-) and negative prediction error (δ-) striatal signals. Abstinent (C-) individuals' striatal δ+ signal was predicted by longer drug use history, signifying possible relief learning adaptations with time. Lastly, craving measures, especially the desire to use cocaine and positive effects of cocaine, also positively correlated with C- individuals' striatal δ+ signal. This suggests possible relief learning adaptations in response to higher craving and withdrawal symptoms. Taken together, enhanced striatal δ+ signal when abstinent and adaptations in relief learning provide evidence in supporting dependent individuals' lack of aversive learning ability while using as usual and enhanced relief learning ability for the purpose of avoiding negative situations such as withdrawal, suggesting a neurocomputational mechanism that pushes the dependent individual to maintains dependence. / Master of Science

The capacity to estimate the number of objects (numerosity) in the environment is ontogenetically precocious and phylogenetically ancient. In animals, this ability holds significant adaptive advantages, directly influencing survival and reproductive success. In humans, it may serve an additional purpose by providing a start-up kit for the acquisition of symbolic numbers, thus making it a potential focus for mathematics education and intervention strategies. Behavioral, neurophysiological, and neuroimaging findings suggest that numerosity information is directly extracted from the environment. However, numerosity is inherently linked with other visual characteristics of sets (such as larger sets often occupy more space or are more densely spaced), making it challenging to determine the extent to which the observed response to numerosity is distinct from the response to other visual attributes. In my PhD research I provide experimental evidence through neuroimaging and computational modeling techniques elucidating where, when, and how numerical information is encoded in the human brain. This work therefore provides a threefold contribution. First, I show that numerosity is represented over and above nonnumeric visual features in a widespread network of areas starting from early visual areas and further amplified in associative areas along the dorsal but also notably the ventral stream, and that the neural representational geometries of regions across the two steams are substantially identical. Second, I showed that numerosity is represented at an early stage and seemingly in parallel across of a set of regions including early visual, parietal, and temporal, preceding the emergence of non-numeric features that could indirectly contribute to numerosity computation. Finally, by comparing the fMRI data with a convolutional neural network (CNN) to explore similarities and differences between the model and human brain data, I discovered that although the CNN can perform approximate numerosity comparisons and the structure of their representation in their hidden layers captures well numerosity representation in early visual areas of humans, it falls short of fully simulating the way in which associative brain regions represent numerosity. Taken together, the findings of this thesis provide experimental evidence supporting the notion that number is a primary visual feature, encoded independent from other visual features quickly and widely across the human brain. Furthermore, they emphasize the need for additional investigation to unravel the computational mechanisms underlying numerosity in the human brain.

Yes / Two subdivisions of human V5/MT+; one located posteriorly (MT/TO-1), the other more anteriorly (MST/TO-2), were identified in human participants using functional magnetic resonance imaging (fMRI) on the basis of their representations of the ipsi- versus contra-lateral visual field. These subdivisions were then targeted for disruption by the application of repetitive transcranial magnetic stimulation (rTMS). rTMS was delivered to cortical areas whilst participants performed direction discrimination tasks involving three different types of moving stimuli defined by the translational, radial or rotational motion of dot patterns. For translational motion, performance was significantly reduced relative to baseline when rTMS was applied to both MT/TO-1 and MST/TO-2. For radial motion there was a differential effect between MT/TO-1 and MST/TO-2, with only disruption of the latter area affecting performance. rTMS failed to reveal a complete dissociation between MT/TO-1 and MST/TO-2 in terms of their contribution to the perception of rotational motion. On the basis of these results MT/TO-1 and MST/TO-2 appear to be functionally distinct subdivisions of hMT/V5+. Whilst both areas appear to be implicated in the processing of translational motion, only the anterior region (MST/TO-2) makes a causal contribution to the perception of radial motion. / BBSRC

Visual perception theory distinguishes between two distinct levels of object processing: holistic, based on global shape, and configural, based on local features and/or component parts. Empirical evidence suggests that different cortical regions may support these levels; holistic processing correlates with activation in the lateral occipital-temporal cortex (LOC), whereas configural processes correspond to activation in the parietal lobe, particularly the intraparietal sulcus (IPS). This study combined theories of visual part structure with neuroimaging methods to investigate the relative contribution of holistic and configural processing in an ecologically valid object recognition task. Rather than rely on stimuli specifically designed to evoke holistic or configural processing, this study used photographs of objects selected without a priori assumptions concerning physical part structure. Twenty participants viewed objects at fixation while undergoing fMRI, followed by a behavioral object identification task involving the same objects presented in peripheral vision. Behavioral data were analyzed according to theories of visual crowding to yield an objective estimate of the number of parts perceived within each object. Neuroimaging results revealed increased activation for holistic objects containing fewer parts in the right parietal lobe and superior temporal gyrus and bilaterally in the fusiform gyrus, suggesting a relation between holistic processing areas and object perception. Configural objects with many parts elicited increased activation in the left angular gyrus. This study, to our knowledge, is the first to investigate the cortical visual regions involved when observers engage in holistic and configural processing as a natural part of visual recognition. / Master of Science

Apesar das evidências a favor da automaticidade no processamento de estímulos aversivos, especialmente na amígdala, a sua resposta parece ser dependente da disponibilidade de re- cursos atentivos. Dessa forma, a atenção pode atuar como um mecanismo de regulação emocional, importante para a compreensão de uma série de distúrbios psiquiátricos em que este mecanismo está prejudicado. Nesse estudo, investigamos o processo do regulação e- mocional pela atenção sob uma condição de grande demanda atentiva e com estímulos altamente aversivos. Imagens funcionais por ressonância magnética foram adquiridas de 22 voluntários saudáveis enquanto figuras emocionais (IAPS - International Afective Picture System), neutras e aversivas (corpos mutilados) eram apresentadas enquanto eles realiza- vam três tarefas diferentes, em que a atenção era manipulada. As imagens foram apresenta- das no centro do campo visual, enquanto apareciam duas barras, uma de cada lado da figu- ra. As três tarefas atentivas correspondiam a reconhecer: (1) a valência emocional da figura, (2) a semelhança na orientação das duas barras com diferenças de 0º ou 90º (tarefa fácil) e (3) a semelhança das mesmas com diferença de 0º ou apenas 6º (tarefa muito difícil). Nas análises de regiões de interesse (ROIs) observamos um padrão de regulação emocional, com dimuição da amplitude do sinal BOLD estimado, nas regiões da amígdala, ínsula ante- rior, cíngulo posterior e córtex pré-frontal medial, ventrolateral e orbitofrontal na tarefa fácil. Já na tarefa difícil, esse comportamento se manteve, com excessão do sinal da ínsula e do orbitofrontal, que voltou a subir, talvez, por um efeito de estresse. Verificamos uma maior amplitude do sinal BOLD na região dos córtices pré-frontal dorsolateral, parietal superior e área motora suplementar quando a atenção foi alocada para as tarefas de barras, supostamente, por um efeito da demanda maior de atenção. Nestes resultados, todo um conjunto de estruturas envolvidas no processamento emocional foi regulado pela manipu- lação da atenção nas tarefas. Também observamos uma correlação entre o traço de afeto positivo dos sujeitos e a estimativa do sinal BOLD da amígdala sob a regulação emocional. Estas evidências indicam que, mesmo para estímulos extremamente negativos, a disponibi- lidade de recursos de atenção e, talvez, mecanismos inibitório de controle cognitivos sobre a amígdala sejam fatores condicionantes da resposta emocional. / Because of the biological significance of motional stimuli, their processing is considered largely automatic. However, there are also evidences that processing of emotional stimuli requires some level of attention. Higher attention demands in a task may limit emotional processing which can be interpreted as an emotion regulation strategy. Our experiments utilized highly demanding attention task while also highly aversive and arousing visual stimuli comprising mutilated bodies is presented. The experiment employed a single task, which consisted of determining whether two peripheral bars were like oriented or not, such to evaluate further brain mechanisms involved in emotion regulation by functional mag- netic resonance imaging (fMRI). Our results revealed that task-irrelevant unpleasant images slowed reaction time during the performance of the main easy task, but not at highly de- manding one which is suggesting of emotion suppression. Such modulatory effect was also revealed by ROI analysis showing that many brain regions, including regions of amygdala, anterior insula, posterior cingulate, and medial, ventrolateral and orbitofrontal prefrontal cortex have their processing of emotional visual stimuli reduced by attentional manipula- tions while there were BOLD signal increases in dorsolateral prefrontal and superior parie- tal cortex respective to attention demand. These results suggest that attentional manipula- tions that more fully consume attentional resources in order to demonstrate that the proc- essing of emotional stimuli is limited.

O tecido cerebral é altamente dependente de uma complexa rede vascular e um suprimento adequado de oxigênio, uma vez que o metabolismo oxidativo é a principal via de produção de ATP. Entretanto, durante o aumento da atividade neuronal existe uma relação não linear entre fluxo sanguíneo cerebral e consumo de oxigênio, verificado por tomografia de emissão de pósitrons e posteriormente por técnicas quantitativas de ressonância magnética nuclear. O aumento mais pronunciado do fluxo sanguíneo em comparação com o consumo de oxigênio levanta questões sobre a possibilidade de o oxigênio atuar como um fator limitante. Apesar dos efeitos devastadores da privação completa de oxigênio ao tecido cerebral dentro de minutos, a redução da disponibilidade de oxigênio por curtos períodos de tempo é comum em pacientes com apneia do sono e está associada como fator de risco à hipertensão e acidentes vasculares. Acreditamos que a obtenção de novas informações sobre o efeito da disponibilidade de oxigênio na regulação da resposta vascular e do metabolismo energético no cérebro humano in vivo é crucial para um melhor entendimento de aspectos básicos do metabolismo energético cerebral e sua relação com o sistema neurovascular. Nesta tese foi avaliado o impacto da redução da disponibilidade de oxigênio no acoplamento neurovascular e metabólico do cérebro humano saudável. Dois estudos foram realizados na presença de hipóxia moderada, com saturação sanguínea entre 80 a 85%, e normóxia como condição de controle. O primeiro utilizou técnicas quantitativas de ressonância magnética funcional (fMRI) em 3T para caracterizar a resposta vascular evocada de 9 sujeitos saudáveis perante a estimulação visual. O segundo visou caracterizar as concentrações metabólicas em repouso e também as alterações induzidas pela estimulação visual em 11 sujeitos, utilizando a técnica de espectroscopia de ressonância magnética funcional (fMRS) em 7T. Os dados de fMRI mostraram reduções significativas das áreas corticais recrutadas durante a hipóxia moderada, embora as áreas comuns às três técnicas que continuaram ativas demonstraram respostas com amplitude de fluxo e volume sanguíneos similares a normoxia. Além disto, a variação de consumo de oxigênio devido à estimulação visual foi menor durante a hipóxia. Tais achados potencialmente poderiam indicar diminuição da extensão do recrutamento neuronal, porém um novo desacoplamento entre atividade neuronal e a resposta vascular, ou seja, aumento da atividade neuronal sem uma mesma resposta vascular durante a hipóxia moderada não poderia ser descartado. O estudo de fMRS demonstrou alterações metabólicas (glutamato e lactato) induzidas pela estimulação similares em ambas as condições gasosas. Entretanto, alterações significativas nas concentrações de aspartato, glutamato e glutamina foram observadas entre as condições no repouso. A combinação dos achados de ambos os estudos aqui apresentados sugere que a hipóxia moderada não resulta na diminuição do recrutamento neuronal, pois variações similares de glutamato e lactato, considerados fortes marcadores do aumento de atividade neuronal, foram observadas durante hipóxia moderada. Entretanto, há evidências de que a disponibilidade reduzida de oxigênio leva a alterações no mecanismo do acoplamento vascular e também no metabolismo basal. Análises futuras serão necessárias para verificar se existe um mecanismo fisiológico que explica as alterações vasculares e metabólicas aqui observadas. / The cerebral tissue is highly dependent on a complex vascular network and a tight regulated supply of oxygen, since oxidative metabolism is the primary source of ATP synthesis. Increased neuronal activity leads to a well-established mismatch between CBF and CMRO2, measured by PET and nuclear magnetic resonance techniques. The much larger CBF evoked response as compared to CMRO2 response raises questions about the role played by oxygen as a potential limiting factor. Despite the devastating effects of intense hypoxia to cerebral tissue, moderate oxygen deprivation through short periods of time is frequent in chronic disorders such as obstructive sleep apnea and has been suggested to be a risk factor for morbidities such as hypertension and stroke. Identifying the impact of mild hypoxia on functional brain metabolism in the healthy human brain is a crucial step for understanding basics aspects of cerebral bioenergetics and its relationship with the neurovascular system. In this thesis we evaluate the impact of reduced oxygen availability in the neurovascular and metabolic coupling of the healthy human brain. Two studies were performed in the presence of mild hypoxia, with 80 to 85% arterial blood oxygen saturation, and normoxia as the control condition. The first study utilized functional Magnetic Resonance Imaging techniques (fMRI) at 3T to characterize the vascular response to visual stimulation in 9 subjects. The second study aimed at characterizing the neurochemical profile of the human brain and quantifying the stimulus-induced metabolic changes as measured by fMRS at 7T in 11 subjects. The fMRI data showed significant reductions in the recruited cortical areas during mild hypoxia, although activated areas in all three imaging modalities showed responses with similar amplitude of blood flow and volume from normoxia. In addition, the variation of oxygen consumption due to stimulation was smaller during mild hypoxia. These findings could potentially suggest decreased neuronal recruitment, although a new decoupling between neuronal activity and vascular response (i.e. similar neuronal recruitment with different vascular response) could not be discarded. The fMRS study showed similar stimulus-induced glutamate and lactate changes during both gas conditions. However, significant concentration differences were observed in aspartate, glutamate and glutamine during rest conditions. Finally, the combination of the data from the two studies herein presented suggests that mild hypoxia does not result in reduced neuronal recruitment despite the altered vascular response, as shown by the similar glutamate and lactate stimulus-induced responses, known to be strong markers of increased neuronal activity. However, there are evidences that support altered neurovascular coupling and metabolic concentrations during reduced oxygen availability at rest. Further analysis will be necessary to elucidate how the new steady state concentrations of aspartate, glutamate and glutamine could be linked to physiological mechanism that potentially alters the neurovascular response.

A avaliação da variabilidade inter-individual da atividade funcional é de grande importância na utilização da ressonância magnética funcional (fMRI) no contexto clínico. O objetivo principal desse estudo é analisar a variabilidade da ativação cerebral dos sistemas vestibular e oculomotor, através da fMRI em resposta à estimulação optocinética horizontal e aos movimentos de rastreio e sacade dos olhos. Para isso, imagens por ressonância magnética foram obtidas de vinte e três voluntários assintomáticos (treze para o estudo optocinético e dez para os estudos rastreio e sacade) em um scanner de 1.5 T Siemens (Magneton Vision) com seqüências do tipo EPI-BOLD. Os mapas estatísticos foram obtidos no programa Brain Voyager, utilizando o método Modelo Geral Linear. Encontramos ativação significante no córtex visual primário, ao longo do giro occipital médio e inferior, no giro temporal médio, superior e inferior, no giro pós- e pré-central, ao longo do giro frontal inferior, superior e médio, no giro supramarginal, no lobo parietal superior e inferior, na ínsula e no cíngulo anterior e posterior. Grupos de atividade também foram encontrados em estruturas subcorticais (putamen, globo pálido, corpo caloso e tálamo), além do cerebelo. A análise da freqüência de ativação revelou uma alta variabilidade entre voluntários. Contudo, as regiões com maior freqüência de ativação foram as áreas frontais e a área que compreende o giro temporal médio e médio superior. Utilizamos dois métodos para a análise dos índices de lateralização, o primeiro admite um valor estatístico fixo e o segundo leva em consideração a dependência do limiar estatístico com o número de pixels ativados, o segundo método mostrou-se mais confiável. Os índices mostraram uma dominância do hemisfério direito para o estudo optocinético. Já, para os estudos rastreio e sacade, não verificamos essa dominância. Esse estudo permitiu a caracterização das mais freqüentemente áreas envolvidas nas tarefas de estimulação optocinética e dos movimentos de rastreio e sacade dos olhos. A combinação dessas tarefas constitui uma grande ferramenta para determinar a lateralização dessas funções e mapear as maiores áreas envolvidas nos sistemas oculomotor e vestibular. / Assessing inter-variability of functional activations is of practical importance in the use of functional magnetic resonance imaging (fMRI) in clinical context. The main objective of this study is to analyze the variability of cerebral activation of the vestibular and oculomotor systems through an optokinetic horizontal, a pursuit and saccadic eye movement stimulations by means of fMRI. For this, images of magnetic resonance were acquired of twenty and three asymptomatic volunteers (thirteen for the optokinetic study and ten for the pursuit and saccade stimulations) in scanner of 1.5 T Siemens (Magneton Vision) with EPI-BOLD fMRI sequences. The statistical maps were analyzed in Brain Voyager software, using the method General Linear Model. We find significant activation in primary visual cortex, in middle and inferior occipital gyrus, in middle, superior and inferior temporal gyrus, in postcentral and precentral gyrus, in middle, inferior and superior frontal gyrus, in supramarginal gyrus, in superior and inferior parietal lobule, in insula and in anterior and posterior cingulate gyrus. Groups of activity had been also found in subcorticals structures (putamen, globus pallidus, corpus callosum and thalamus), beyond the cerebellum. The analysis of the activation frequency displays a high variability between volunteers. However, the most frequently activation regions were localized in areas frontals and in regions comprehending the middle and medial superior temporal gyrus. We use two methods for the analysis of the laterality index, the first admits a fixed statistical value and the second takes in consideration the dependence of the statistical threshold within the activated number of pixels, the second method revealed more reliability. The indices had shown a right hemisphere dominance for the optokinetic study but, for the pursuit and saccade stimulations, we do not verify this dominance. Our study allowed the characterization of the most frequently involved foci in tasks of optokinetic and pursuit and saccade eye movement stimulations. The combination of these tasks constitutes a suitable tool for determine the lateralization of these functions and for mapping major areas involved in the oculomotor and vestibular systems.