Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Made available in DSpace on 2016-03-15T19:39:42Z (GMT). No. of bitstreams: 1 Ricardo Rafael de Araujo.pdf: 639007 bytes, checksum: 913741be473f0be64fda69ad9172445d (MD5) Previous issue date: 2011-02-25 / Fundo Mackenzie de Pesquisa / Attention can be understood as a set of neural mechanisms that enhance the processing of relevant information, thoughts or actions while ignoring irrelevant or scattered stimuli. Thus, attention allows the organism to interact in a proper way with the environment. Among the brain structures associated with the control of attention, the Dorsolateral Prefrontal Cortex (DLPFC) has a remarkable role in current literature as a region associated with behavioral control. Transcranial Direct Current Stimulation (TDCS) is based on the application of a low intensity electric current through electrodes placed in the scalp, aimed at modulating the activity of different brain areas. This technique has been used to study brain functions. This study has the objective of verifying how attention can be modulated through the application of bilateral tDCS on DLPFC using measures of reaction time (RT) in tasks of temporal and spatial orientation. To accomplish that, two experiments were planned and executed. In the first one, which focused on the voluntary orienting of spatial attention, each participant had to orient attention to the position indicated by an arrow; in the second, on voluntary orienting of temporal attention, each participant had to orient attention to the most frequent time interval of visual targets. In both cases, participants had to respond as fast as possible when the target was displayed by pressing a joystick key. RTs were registered. The sample was composed of 18 undergraduate students, age range 19-25 years old (12 for the first experiment and 6 more for the second). In each experiment, subjects were submitted to three tDCS conditions (anodal, cathodal and sham) on the DLPFC during the undertaking of tests. Analyses of variance were made, in order to compare the involved factors. For the experiment of spatial orientation, the anodal condition produced lower RTs, when compared to sham. For the temporal orienting experiment it was observed that, in the anodal modulation, RTs were increased for the less frequent interval (500 ms), indicating that the anodal tDCS can have influenced in a more effective way attentional orienting to the most frequent intervals. Therefore it is possible to postulate the existence of a facilitating effect of anodal tDCS in the modulation of DLPFC, which generated an impact in attentional orienting, lowering RTs to the valid condition (spatial) when compared to sham tDCS. / A atenção pode ser compreendida como um conjunto de mecanismos neurais que facilitam o processamento de informações, pensamentos ou ações relevantes enquanto ignoram outros irrelevantes ou dispersos. Deste modo a atenção permite que o organismo interaja de maneira adequada com o ambiente. Dentre as estruturas cerebrais associados ao controle da atenção, o Córtex Prefrontal Dorsolateral (CPFDL) tem tomado papel de destaque na literatura atual como uma região associada ao controle comportamental. A Estimulação Transcraniana por Corrente Contínua (ETCC) se baseia na aplicação de corrente elétrica de baixa intensidade por meio de eletrodos posicionados no escalpe com o objetivo de modular a atividade de diferentes regiões cerebrais e tem sido utilizada como modo de estudo da função cerebral. Esse trabalho tem como objetivo verificar como a atenção pode ser modulada a partir da aplicação ETCC bilateral sobre o CPFDL, utilizando medidas de tempo de reação (TR) em tarefas de orientação temporal e espacial. Para Tanto foram planejados e executados dois experimentos. No primeiro experimento, relativo à orientação voluntária da atenção espacial, cada participante deveria orientar a atenção para a posição do espaço indicada por uma seta. O segundo experimento, relativo à orientação voluntária da atenção temporal, cada participante deveria orientar a atenção para o intervalo temporal de maior recorrência. Em ambos os casos os participantes deveriam responder o mais rapidamente possível ao aparecimento do alvo pressionado uma tecla de joystick registrando-se assim o seu TR. Participaram desse estudo 18 alunos de graduação (12 no primeiro desenho experimental, e para o segundo desenho experimental foram adicionados mais 6 colaboradores) na faixa etária de 19 à 25 anos. A cada sessão os colaboradores deveriam responder a ambos os experimento enquanto eram submetidos a diferentes polaridades de ETCC (anódica, catódica e placebo) sobre o CPFDL. Foram feitas análises de variância para comparar os fatores estudados. No experimento de orientação espacial a condição anódica produziu TR menores em comparação à condição placebo. No caso do experimento de orientação temporal foi observado que na modulação anódica houve um aumento nos TR no intervalo menos recorrente de 500 ms, indicando que a ETCC anódica pode ter influenciado de modo mais efetivo o direcionamento atencional aos intervalos mais freqüentes. Neste sentido é possível sugerir a existência de um efeito facilitatório da ETCC anódica na moducalçao do CPFDL, o que gerou um impacto no direcionamento atencional, diminuindo os TR para a condição valida (orientação espacial) quando comparados a ETCC placebo.

As teorias mais influentes acerca do funcionamento do córtex pré-frontal (PFC) tomam essa estrutura como um córtex de associação e de integração de informações oriundas de outras estruturas nervosas. Isso implicaria na participação direta do PFC nos processos de memória operacional e em processo atencionais. Estudos hodológicos e neurofisiológicos sugerem, que o córtex orbitofrontal (OFC) seria responsável pela integração de informações de caráter sensorial, motivacional e afetivo, enquanto o córtex pré-frontal ventromedial (vmPFC) seria diretamente ligado ao OFC, tendo um papel crucial na codificação de estímulos emocionais oriundos da amígdala. Nesse contexto, é aceito que a integração das informações feita por essas estruturas seja essencial para o processo de tomada de decisões, uma vez que esse comportamento necessita de uma avaliação do ambiente em termos de comparações de situações novas a experiências prévias armazenadas na memória, assim como um balanço entre custos, benefícios e cálculo de possíveis valores da recompensa. Para testar essas hipóteses, ratos com danos seletivos no vmPFC foram submetidos testes de avaliação de ansiedade e medo condicionado no paradigma de teste e reteste no labirinto em cruz elevado (LCE), assim como a testes de memória de referência espacial e memória operacional no labirinto aquático de Morris. Outro grupo de animais teve matrizes de multi-eletrodos implantadas no OFC para a avaliação da atividade neuronal dessa estrutura em um teste envolvendo tomada de decisões, no qual devem escolher entre ganhar 1 pellet de chocolate imediatamente ou 4 pellets envolvendo atrasos variados. No teste no LCE, animais com lesão no vmPFC diferem dos animais controle por apresentarem uma diminuição do tempo de avaliação de risco sem apresentar alterações nos parâmetros que aferem memória, atividade locomotora e ansiedade. No teste de memória de referência espacial após treinamento extensivo de busca pela plataforma em um mesmo local no labirinto aquático, animais com lesão persistem no local quando se retira a plataforma (probe test). Já no teste de memória operacional, no qual a localização da plataforma é alterada diariamente, esses animais não diferem do grupo controle. Na tarefa envolvendo tomada de decisões, observou-se uma atividade eletrofisiológica de neurônios do OFC relacionada ao momento crítico no qual o animal deve realizar uma escolha. Em conjunto, esses resultados mostram que o vmPFC está relacionado à flexibilidade comportamental e tomada de decisões, possivelmente em conjunto com o OFC, cuja atividade neuronal sugere uma participação nos processos de tomada de decisões e de elaboração de estratégias / The most influential theories on the function of the prefrontal cortex (PFC) suggest that this structure is an association cortex, responsible for integration of information received from other parts of the brain. This would implicate in direct participation of the PFC in working memory and attentional processes. Given this context, hodological and neurophysiological studies suggest that the orbitofrontal cortex (OFC) would be responsible for the integration of sensory, motivational and affective aspects, while the ventromedial prefrontal cortex (vmPFC), which is directly connected to the OFC, would have a key role in encoding emotional stimuli from the amygdala. It is well accepted that the processing of these aspects of information is crucial for decision-making processes, given the fact that this expression of behavior requires an evaluation of the environment in terms of comparing novel situation to previous experiences, as well as processing the balance between costs, outcomes and reward values. In order to test these hypotheses, rats with selective lesions to the vmPFC were subjected to the elevated plus maze (EPM) to evaluate anxiety and conditioned fear in the test retest paradigm. Animal were also tested in a spatial reference memory and a working memory tasks in the Morris water maze. Another group of rats had multi-electrode arrays chronically implanted in the OFC for the evaluation of the neuronal activity during a decision-making task, in which the animals had to choose between a small reward of one chocolate pellet immediately and a large reward of four chocolate pellets after varying delays. The results of the EPM show that animals with lesion to the vmPFC differ from control animals by showing diminished time evaluating risk in the second exposure to the EPM, without damage to locomotor activity, memory and anxiety levels. In the reference spatial memory task in the water maze, after extensive training searching for the hidden platform in the same location, lesioned animals persisted searching for the platform in that particular location after it was removed (probe test). However, in the working memory task, in which the platform is presented in a different location each day, lesioned animals did not differ from control animals. In the decision-making task, differential electrophysiological activity in OFC neurons was observed, particularly in the moment of the task in which the animal was required to perform the choice between rewards. Together, these results suggest that the vmPFC is related to behavioral flexibility and decision-making, possibly acting together with the OFC, which neuronal activity suggests participation in decision-making processes

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that affects roughly 1 in 3500 individuals. In addition to physical features (e.g., neurofibromas), developmental disorders are also common that can affect cognition, learning, attention and social function. The NF1 gene encodes neurofibromin, a GTPase activating protein (GAP)-like protein that negatively regulates Ras GTPase activation. Mutation at the NF1 locus increases the output of MAPK and PI3K signal transduction from the cellular membrane to the nucleus. Similar to humans, Nf1+/- mice show spatial learning abnormalities that are potentially correlated with increases in GABA-mediated inhibition and deficits in long-term potentiation in the hippocampus. Here, we demonstrate for the first time that Nf1+/- mice exhibit a selective loss of long-term social learning / memory and increased GABAergic inhibition in the basolateral amygdala, a critical brain region for regulating social behaviors. Next, utilizing a genetic intercross, we show that the co-deletion of p21-activated kinase type 1 (Pak1-/-), which positively regulates MAPK activation, restores Nf1+/--dependent MAPK hyperactivation in neurons cultured from the frontal cortex. We found that the co-deletion of Pak1 in Nf1+/- mice (Nf1+/- / Pak1-/-) also restores the deficits in long-term social learning / memory seen in Nf1+/- mice and normalizes the increases in GABA-mediated inhibition in the BLA, as compared to Nf1+/- mice. Together, these findings establish a role for Nf1 and Pak1 genes in the regulation of social learning in Nf1-deficient mice. Furthermore, proteomic studies identify dysregulation of F-actin and microtubule dynamics in the prefrontal cortex, and implicate proteins associated with vesicular release as well as neurite formation and outgrowth (e.g., LSAMP, STXBP1, DREB). In the BLA, disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) was identified, and ADAM22 may play a role in the regulation of AMPA receptors. Finally, due to the increased co-occurrence of NF1 and autism, these findings may also have important implications for the pathology and treatment of NF1-related social deficits and some forms of autism.

No description available.

Convergent evidence suggests that the dorsal medial prefrontal cortex (dmPFC) makes an important contribution to goal-directed action selection. The dmPFC is also part of a network of brain regions that becomes compromised in old age. It was hypothesized that during decision-making, some process of comparison takes place in the dmPFC between the representation of available actions and associated values, and that this process is changed with aging. These hypotheses were tested in aged and young adult rats performing a novel 3-choice, 2-cue decision task. Neuron and local field potential activity revealed that the dmPFC experienced different states during decision and outcome phases of the task, with increased local inhibition and oscillatory (gamma and theta) activity during cue presentation, and increased excitatory neuron activity (among regular firing neurons) at goal zones. Although excitatory and inhibitory activity appeared anti-correlated over phases of the decision task, cross-correlations and the prominent gamma oscillation revealed that excitation and inhibition were highly correlated on the millisecond scale. This "micro-scale" coupling between excitation and inhibition was altered in aged rats and the observed changes were correlated with changes in decision and movement speeds of the aged animals, suggesting a putative mechanism for age-related behavioral slowing. With respect to decision-making, both aged and young adult rats learned over multiple days to follow the rewarded cue in the 3-choice, 2-cue task. Support for the hypothesis that the dmPFC simultaneously represents alternative actions was not found; however, neuron activity selective for particular goal zones was observed. Interestingly, goal-selective neural activity during the decision period was more likely to take place on error trials, particularly on high-performing sessions and when rats exhibited a preference for a particular feeder. A possible interpretation of these patterns is that goal representations in the dmPFC might have sometimes overruled learned habits, which are likely to be involved in following the correct cue and which are known to be supported by other brain regions. These results describe fundamental properties of network dynamics and neural coding in the dmPFC, and have important implications for the neural basis of processing speed and goal-directed action.

Behavioral data in individuals with Down syndrome (DS) and mouse models of the syndrome suggest impaired object processing. In this study we examined the component processes that may contribute to object memory deficits. A neuropsychological test battery was administered to individuals with DS (n=28), including tests targeting perirhinal cortex (PRC) and prefrontal cortex (PFC) function, tests of perception (i.e., convexity based figure ground perception), and tests of memory (object recognition and object-in-place learning). To compare to individuals with DS, the same number of typically developing chronological age (CA, n=28) and mental age-matched (MA, n=28) controls were recruited. We observed object memory deficits in DS (p<0.001). In contrast, the DS group showed relatively intact use of convexity when making figure-ground judgments and spared PRC-dependent function, as compared to MA control. In addition, measures of PFC function seemed to be related to performance on object recognition tasks. These findings suggest that the inputs into the MTL from low and high level perceptual processing streams may be intact in DS. The object memory deficits we observed might reflect impaired PFC function.

The present study compared lateralization of cortical activation patterns in the prefrontal cortex (PFC) of adults who stutter (AWS) and typical speakers (TS) as measured with functional near infrared spectroscopy (fNIRS) in habitual and fluency-enhanced speaking conditions. Participants were AWS (n = 11) and gender- and age-matched TS (n = 11) who completed speaking tasks in three condition blocks: (1) habitual speech using no speaking strategy (2) prolonged speech after receiving short-term training in fluency-shaping strategy-use (3) syllable-timed speech after being trained to speak in rhythm with a metronome at 92 beats per minute. The three primary dependent variables were mean change in HbO (oxygenation) relative to resting baseline in the right and left PFC hemispheres and a Laterality Index (L-R)/(L+R) calculated from these values. Two primary hypotheses were tested: (1) AWS will present with greater right-hemisphere PFC oxygenation relative to TS in a habitual or everyday speaking task (2) AWS will present with reduced right-hemisphere PFC activation (leftward shift in laterality more similar to TS) during fluency-enhanced speech strategy tasks relative to a habitual speech task. Real-time stuttered speech measures using fNIRS indicated greater effortfulness of speech production in AWS when speaking fluently and disfluently as measured by greater bilateral change in PFC HbO relative to TS. AWS laterality did not differ from TS during everyday conversation and did not significantly change when using fluency-enhancing strategies, which was counter to the hypotheses. The TS group presented with significantly greater leftward PFC HbO in the metronome condition compared to AWS. Prolonged speech and metronome-timed speech seem to be associated with different activation patterns in the PFC for AWS and for TS. Results suggest an alternative explanation for compensatory activation in AWS during speech production, such that AWS present with greater overall activation in both PFC hemispheres relative to TS which results in greater right-sided laterality than TS. Future long-term studies on adults receiving prolonged speech treatment and examination of similar measures in young children who stutter may reveal more about the compensatory versus causal nature of stuttering.

The role of the primate frontopolar cortex (FPC) has been investigated using human neuroimaging, lesion and disruption techniques. The results of these investigations have led to a variety of theories regarding the function of this region. It has been linked to the formation of task sets, the performance of multiple tasks, reasoning, context-specific memory (including episodic memory, prospective memory and source memory), attention to internally or externally generated information, mentalising and decision-making. It has not previously been possible to study this area using animal lesion techniques. Here, behavioural experiments conducted using non-human primates (rhesus macaque monkeys) who have received lesions to the frontal pole investigate the contribution of this region to context-specific memory, decision-making and social cognition. Functional magnetic resonance imaging (fMRI) is used to investigate changes in functional network connectivity which occur after lesions to this region. A long-lasting impairment is observed in contextual memory judgements (specifically, how recently a stimulus was encountered) after lesions to the frontal pole. An analysis of the influence of the outcomes of previous choices on behaviour on an analogue to the Wisconsin Card Sorting Test (WCST) indicate that monkeys with lesions to area 10 may be less influenced by the outcomes of an extended history of rewards than control animals. Long-lasting widespread disruption to functional networks after lesions to this region indicate that indirect anatomical connections from this region to posterior areas play a crucial role in the normal functioning of posterior networks.

Le modèle cognitif dualiste du jugement moral fondé sur l'opposition raison-émotion et dans lequel la raison contrôlerait les émotions est encore très largement dominant (Greene, Sommerville et al. 2001). Pourtant, l'idée de ce contrôle raisonné des émotions, en particulier lors de la résolution de dilemmes sociaux a été remise en cause (Knoch, Pascual-Leone et al. 2006). Comme l'a suggéré Jorge Moll, en proposant une approche beaucoup plus intégrée, la prise de décision dans un contexte moral pourrait ne pas se limiter à cette opposition entre processus affectifs et raisonnés (Moll, Zahn et al. 2005). Par ailleurs, lors de la résolution de dilemmes moraux, ce qui est appelé le jugement semble être dissocié du choix de l'action, mais à ce jour, la plupart des études publiées confondent les deux. Dans ce travail nous nous efforçons d'apporter les arguments théoriques et expérimentaux démontrant que les processus qui conduisent au jugement et ceux conduisant au choix moral sont dissociés. Et que de plus, le jugement repose sur la génération d'émotions secondaires par des processus cognitifs complexes (raisonnés) et le choix sur des émotions plus automatiques. Pour pouvoir l'expliquer nous proposons un modèle plus général de l'évaluation et de la décision morale reposant non plus sur deux, mais trois types de processus. / The cognitive dualistic model of moral judgment based on the opposition reason-emotion and in which the reason would control the emotions is still largely dominant (Greene, Sommerville et al. 2001). However, the idea of rational control of emotions, especially when solving social dilemmas, has been questioned (Knoch, Pascual-Leone et al. 2006). As suggested by Jorge Moll, offering a much more integrated approach, the decision in a moral context may not be limited to the contrast between emotional and rationnal process (Moll, Zahn et al. 2005). Moreover, when resolving moral dilemmas, what is called the judgment seems to be dissociated from the choice of action, but to date, most published studies confuse the two. In this work, we strive to provide the theoretical and experimental evidences that the processes that lead to the judgment and to the moral choice are dissociated. And moreover, the judgment is based on the generation of secondary emotions by complex cognitive processes (rational) and the choice based on more automatic emotions. To explain this we propose a more general model of evaluation and moral decision based not on two, but three types of processes.