Goal-directed behavior is based on representations of contingencies between a certain situation (S), a certain (re)action (R) and a certain outcome (O). These S-R-O representations enable flexible response selection in different situations according to the currently pursued goal. Importantly however, the successful formation of such representations is a necessary but not sufficient precondition for goal-directed behavior which additionally requires the actual usage of the contingency information for action control. The present fMRI study aimed at identifying the neural basis of each of these two aspects: representing vs. explicitly using experienced S-R-O contingencies. To this end, we created three experimental conditions: S-R-O contingency present and used for outcome-based response selection, S-R-O contingency present but not used, and S-R-O contingency absent. The comparison between conditions with and without S-R-O contingency revealed that the angular gyrus is relevant for representing S-R-O contingencies. The explicit usage of learnt S-R-O representations in turn was associated with increased functional coupling between angular gyrus and several subcortical (hippocampus, caudate head), prefrontal (lateral orbitofrontal cortex (OFC), rostrolateral prefrontal cortex (RLPFC)) and cerebellar areas, which we suggest represent different explicit and implicit processes of goal-directed action control. Hence, we ascribe a central role to the angular gyrus in associating actions to their sensory outcomes which is used to guide behavior through coupling of the angular gyrus with multiple areas related to different aspects of action control.

Although research has highlighted the importance of decisions when learning and performing motor actions, few studies have focused on individuals’ ability to choose between potential motor actions. To help bridge this gap, this thesis presents a series of studies that investigate the behaviour of able-bodied individuals when attempting to choose movements based on a speed-accuracy tradeoff. In the first study, a two-alternative forced-choice task was used to determine whether people are consistent with Fitts’s law when choosing the movement they perceive to require the least movement duration. Participants performed almost perfectly when clear visual cues were available—when one of the targets was closer, wider, or both. Contrary to Fitts’s law, however, participants showed a preference for closer targets when visual cues were not informative—when one of the targets was closer and narrower. This study demonstrates that motor decisions are not always optimal, especially when participants are naïve at the task. To determine the basis of individuals’ preference for closer targets, a pair of studies explored the relation between motor decisions, imagined movements, and visual perception. Participants showed a similar deviation from Fitts’s law when imagining movements—believing that movement duration increased with distance within the same index of difficulty. Participants did not behave similarly, however, in a perceptual version of the decision task. These results suggest that imagined movements and motor decisions are linked, but they are not always based on veridical representations of actual movement. To further probe the origin of individuals’ erroneous belief about movement duration, the final study of this thesis measured movement duration for movements made at speeds other than ‘as fast as possible’. Movements made at more natural movement speeds shared important similarities with decisions and imagined movements. This study suggests that the biases seen in naïve motor decisions might originate from participants considering movements for which they have more experience, such as target-directed movements made at a naturally-selected pace. Together, the findings presented in this thesis may help to identify the ways that motor decisions can deviate from optimal, suggesting how those decisions must change with practice to better accomplish a task.

The brain displays moment-to-moment activity fluctuations that reflect various levels of engagement with the outside world. Processing external stimuli is not only associated with increased brain metabolism but also with prominent deactivation in specific structures, collectively known as the default-mode network (DMN). The role of the DMN remains enigmatic partly because its electrophysiological correlates and temporal dynamics are still poorly understood. Using unprecedented wide-spread depth recordings in epileptic patients, undergoing intracranial EEG during pre-surgical evaluation, we reveal that DMN neural populations display task-related suppressions of gamma (60-140 Hz) power and, critically, we show how millisecond temporal profile and amplitude of gamma deactivation tightly correlate with task demands and subject performance. The results show also that during an attentional task, sustained activations in the gamma band power are presented across large cortical networks, while transient activations are mostly specific to occipital and temporal regions. Our findings reveal a pivotal role for broadband gamma modulations in the interplay between activation and deactivation networks mediating efficient goal-directed behavior

Although research has highlighted the importance of decisions when learning and performing motor actions, few studies have focused on individuals’ ability to choose between potential motor actions. To help bridge this gap, this thesis presents a series of studies that investigate the behaviour of able-bodied individuals when attempting to choose movements based on a speed-accuracy tradeoff. In the first study, a two-alternative forced-choice task was used to determine whether people are consistent with Fitts’s law when choosing the movement they perceive to require the least movement duration. Participants performed almost perfectly when clear visual cues were available—when one of the targets was closer, wider, or both. Contrary to Fitts’s law, however, participants showed a preference for closer targets when visual cues were not informative—when one of the targets was closer and narrower. This study demonstrates that motor decisions are not always optimal, especially when participants are naïve at the task. To determine the basis of individuals’ preference for closer targets, a pair of studies explored the relation between motor decisions, imagined movements, and visual perception. Participants showed a similar deviation from Fitts’s law when imagining movements—believing that movement duration increased with distance within the same index of difficulty. Participants did not behave similarly, however, in a perceptual version of the decision task. These results suggest that imagined movements and motor decisions are linked, but they are not always based on veridical representations of actual movement. To further probe the origin of individuals’ erroneous belief about movement duration, the final study of this thesis measured movement duration for movements made at speeds other than ‘as fast as possible’. Movements made at more natural movement speeds shared important similarities with decisions and imagined movements. This study suggests that the biases seen in naïve motor decisions might originate from participants considering movements for which they have more experience, such as target-directed movements made at a naturally-selected pace. Together, the findings presented in this thesis may help to identify the ways that motor decisions can deviate from optimal, suggesting how those decisions must change with practice to better accomplish a task.

Introdução: A terapia hemodinâmica perioperatória baseada em metas modificou a evolução dos pacientes pediátricos cirúrgicos de alto risco, demonstrando ser eficaz na redução de complicações. O objetivo deste estudo foi avaliar o efeito de um protocolo perioperatório guiado por metas baseado na adequação da saturação venosa central mensurada de forma contínua na perfusão tecidual e nas complicações pós-operatórias de pacientes pediátricos submetidos a cirurgia cardíaca. Métodos: Estudo prospectivo, randomizado, e controlado, realizado no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina de Universidade de São Paulo(Incor-HCFMUSP). Pacientes pediátricos submetidos a cirurgia cardíaca eletiva foram randomizados para grupo terapia hemodinâmica baseado na monitorização da saturação venosa contínua pelo cateter PediaSat (grupo intervenção) ou para grupo padrão. O grupo intervenção foi tratado no intraoperatório e nas primeiras 24 horas de pós-operatório de acordo com um protocolo guiado por metas, baseado na adequação da saturação venosa central (SvcO2 >= 65% nas cardiopatias acianóticas e >= 55% nas cardiopatias cianóticas). O desfecho primário foi a depuração do lactato nas primeiras 24 horas de pós-operatório. Os desfechos secundários foram a ocorrência de complicações pós-operatórias durante a internação hospitalar (insuficiência renal, vasoplegia, baixo débito cardíaco, arritmia, infecção, sangramento e reoperação), tempo de ventilação mecânica, tempo de uso de inotrópicos e de vasopressores e tempo de internação na unidade de terapia intensiva e no hospital e mortalidade operatória. Também foram analisados dados hemodinâmicos e variáveis de perfusão tecidual dos pacientes no período perioperatório. Resultados: No período de julho de 2014 a março de 2016, 65 pacientes foram incluídos no estudo. O número de pacientes que apresentou depuração dos níveis de lactato maior que 30% foi semelhante nos dois grupos (60% no grupo padrão e 59,4% no grupo intervenção, P=0,919). Não houve diferenças em relação a quantidade de dobutamina ou de transfusão de hemácias entre os grupos durante o protocolo. Em relação aos desfechos secundários, o grupo intervenção apresentou menor tempo de ventilação mecânica em comparação como grupo padrão (24,59 h ± 19,69 vs. 85,63 h ± 86,54, P < 0.001), menor tempo de uso de vasopressor [0 h (0-0) vs. 0 h (0-54), P = 0,021], e menor tempo de internação na unidade de terapia intensiva [6 dias (4-10) vs. 8 dias (6-21), p = 0,030 ]. Não houve diferenças entre os grupos em relação aos outros desfechos. Conclusões: Em crianças submetidas a cirurgia cardíaca, uma estratégia de terapia hemodinâmica guiada tendo como alvo a adequação da saturação venosa central de oxigênio não teve impacto na depuração dos níveis de lactato em 24 horas. Entretanto, a estratégia de terapia hemodinâmica guiada foi associada a redução do tempo de ventilação mecânica, da necessidade de vasopressores e do tempo de internação na unidade de terapia intensiva / Introduction: Perioperative hemodynamic therapy through defined goals improves outcomes in high surgical risk patients. The aim of this study was to evaluate whether the use of a perioperative hemodynamic protocol based on the optimisation of the continuous oxygen central venous saturation reduces complications in children undergoing cardiac surgery. Methods: This was a randomized clinical study, performed at the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina de Universidade de São Paulo. Pediatric patients undergoing cardiac surgery were randomized to hemodynamic therapy based on continous monitorization of central venous saturation of oxgen through the PediaSat catheter (intervention group) or to usual care group. The intervention group during the intraoperative and in the first 24 hours of postoperative were submitted to a hemodynamic protocol of care based on the optimization of central venous saturation (SvcO2 >= 65% in acyanotic disorders and >= 55% in cyanotic disorders). The primary outcome was lactate clearance in 24 hours of postoperative. Secondary outcomes were postoperative complications during hospital stay (acute kidney injury, vasoplegic shock, low cardiac output syndrome, arrhythmia, infection, bleeding and reoperation), duration of mechanical ventilation, duration of inotropes and vasopressors, length of intensive care unit and hospital stay) and death. We also evaluated hemodynamic data and perfusion tissue markers in patients during perioperative care. Results: In the period of July 2014 to March 2016, 65 patients were included in the study. The number of patients presenting lactate clearance higher than 30% in 24 hours was not different between groups (60.6% in the usual care group and 59.4% in the intervention group, P=0.919). There was no difference between groups in the use of dobutamine and in the number of transfused red blood cells units during the protocol. The intervention group had a lower duration of mechanical ventilation when compared to usual care group (24.59 h ± 19.69 s. 85.63 h ± 86.54, P < 0.001). The intervention group had also lower duration of vasopressor therapy [0 h (0-0) vs. 0 h (0-54), P = 0,021], and reduced length of intensive care unit stay [6 days (4-10) vs. 8 days (6-21), p = 0,030].There was no differences between groups in other outcomes. Conclusions: In pediatric patients undergoing cardiac surgery, a strategy of hemodynamic optimization aiming to adequate central venous saturation of oxygen had no influence in lactate clearance. However, hemodynamic therapy was associated with a lower duration of mechanical ventilation, less needing of vasopressors and shorter length of intensive care unit stay

Introdução: O objetivo do estudo foi avaliar os efeitos da terapia guiada por metas (TGM) sobre desfechos em pacientes de alto risco submetidos à cirurgia cardíaca. Métodos: Estudo prospectivo randomizado que avaliou 126 pacientes submetidos às cirurgias de revascularização do miocárdio ou valvar internados na Unidade de Terapia Intensiva Cirúrgica (UTI) do Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram randomizados para um algoritmo de terapia guiada por metas (grupo TGM, n=62) ou grupo controle (n=64). No grupo TGM, um índice cardíaco superior a 3 L/min/m2 foi utilizado como alvo através de fluidos, inotrópicos e transfusão de concentrado de hemácias, com início após desmame da circulação extracorpórea e com término após 8 horas de admissão na UTI. Resultados: O desfecho primário foi um composto de mortalidade e complicações maiores em 30 dias. Os pacientes do grupo TGM receberam maior volume (mediana e intervalo interquartílico) de fluidos em relação ao grupo controle [1000 (625 - 1500) vs. 500 (500 - 1000) mL (P < 0,001)], e não houve diferença na administração de inotrópicos ou hemotransfusão. A incidência do desfecho primário foi menor no grupo TGM (27,4 vs. 45,3%, p=0,037). O grupo TGM apresentou menor incidência de infecção (12,9 vs. 29,7%, P=0,002) síndrome do baixo débito cardíaco (6,5 vs. 26,6%, P=0.002). Foram também observados menor dose acumulada de dobutamina (12 vs. 19 mg/Kg, P=0,003), menor tempo de internação na UTI (3 [3-4] vs. 5 [4-7] dias; P < 0,001) e no hospital (9 [8-16] vs. 12 [9-22] dias, P=0,049) no grupo TGM comparado ao grupo controle. Não houve diferença nas taxas de mortalidade em 30 dias. (4,8% vs. 9,4%, respectivamente; P = 0,492). Conclusão: A estratégia de terapia guiada por metas através de fluidos, inotrópicos e transfusão sanguínea reduziu a incidência de complicações maiores em 30 dias em pacientes de alto risco submetidos a cirurgia cardíaca / Introduction: The objective of the study was to evaluate the effects of goal-directed therapy on outcomes in high-risk patients undergoing cardiac surgery. Methods: A prospective randomized controlled trial that evaluated 126 patients undergoing coronary artery bypass or valve repair in a Surgical Intensive Care Unit (ICU) of the Heart Institute/Faculty of Medicine of University of Sao Paulo. Patients were randomized to a cardiac output-guided hemodynamic therapy algorithm (GDT group, n=62) or to usual care (n=64). In the GDT arm, a cardiac index of greater than 3 L/min/m2 was targeted with intravenous fluids, inotropes and red blood cell transfusion starting from cardiopulmonary bypass and ending eight hours after arrival to the ICU. Results: The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. Patients from the GDT group received a greater median (interquartile range) volume of intra-venous fluids than the usual care group [1000 (625 - 1500) vs. 500 (500 - 1000) mL (P<0.001)], with no differences in the administration of either inotropes or red blood cell transfusions. The primary outcome was reduced in the GDT group (27.4 vs. 45.3%, p=0.037). The GDT group had a lower incidence of infection (12.9 vs. 29.7%, P=0.002) and low cardiac output syndrome (6.5 vs. 26.6%, P=0.002). We also observed lower ICU cumulative dosage of dobutamine (12 vs. 19 mg/Kg, P=0.003) and a shorter ICU (3 [3-4] vs. 5 [4-7] days; P < 0.001) and hospital length of stay (9 [8-16] vs. 12 [9-22] days, P=0.049) in the GDT compared to the usual care group. There were no differences in 30-day mortality rates (4.8% vs. 9.4%, respectively; P = 0.492). Conclusions: Goal directed therapy using fluids, inotropes and blood transfusion reduced 30-day major complications in high-risk patients undergoing cardiac surgery

: Mon travail de thèse a porté sur l’étude neurocomportementale des actions et des habitudes chez le Rat. En effet, lors d’un apprentissage opérant la réponse peut être acquise selon deux systèmes associatifs. Le premier dépend d’une représentation des conséquences de la réponse, le second d’une association plus « simple » entre le stimulus et la réponse. Un premier axe de recherche a consisté à étudier plusieurs paramètres du conditionnement, afin de déterminer leur influence sur le contrôle de la réponse instrumentale par un système plutôt que l’autre. Le deuxième axe de recherche a porté sur l’étude des substrats neuronaux impliqués dans l’acquisition et l’expression d’une action, par l’intermédiaire de techniques d’inactivation cérébrale et d’étude immuno-histochimique de l’expression génique de la protéine Fos. / Previous research has established that instrumental conditioning, in both primates and rats, is mediated by two concurrent associative systems. In early stages of training, instrumental response is thought to be mediated by an association between the action and the outcome (A-O). While training proceeds however, as the response becomes less sensible to the outcome value, it is conceived as being mediated by an association between thestimulus and the response (S-R). Recent evidences suggest that the both systems operate in tandem and/or competition from the beginning of training. This work aimed at studying the mechanisms that coordinate the control of the instrumental response by the goal-directedsystem or the habit system. A first batch of results indicates no effect of the amount of training sessions on the goal-directed nature of the conditioned instrumental response. Indeed,the outcome devaluations by CTA or selective satiety reduced the instrumental performances,independently of the training procedure applied. The instrumental responses resulting from our 3 training procedures depend of an actualized representation of their outcomes. A secondbatch of results indicates that information about the context of instrumental conditioning isincluded in the incentive representation of the outcome. Indeed, we observed no sensitivity tooutcome devaluation when devaluation occurred outside the training context. These results offer new original hypotheses about context encoding and the nature of instrumental responding. A third batch of experiments investigates the role of the prelimbic cortex in acquisition vs. expression of goal-directed instrumental behaviour, using reversible neuronal inactivation. The results show that the prelimbic cortex plays a transient but crucial role in theacquisition of goal-directed responding and that the A-O and S-R systems can operate in a competitive fashion early in training. Using ex-vivo imaging, a last batch of experiments aimed to study the temporal cerebral activation throughout instrumental training with a focuson prefrontal and striatal regions. Results show levels of Fos expression that vary with regions. At the beginning of conditioning, the density of Fos positive nuclei is high in the prefrontal regions. It decreases with training. Labelling is denser in the dorsomedial striatumthan in the dorsolateral striatum. The weak activation in the dorsolateral striatum appears consistent with the absence of habit. These data are in accordance with data of the literature concerning dynamics of activation in cortico-striatal circuits. Furthermore, they are in agreement with the suggestion that activity in the prelimbic cortex could promote the acquisition of goal-directed action by the induction of neuronal plasticity in the dorsal striatum.

Orientador: Francisco José Teixeira Neto / Resumo: Objetivo: Comparar a acurácia diagnóstica da variação da pressão de pulso (VPP), variação do volume sistólico mensurada através do análise de contorno de pulso (VVSACP), índice de variabilidade pletismográfica (IVP), pressão venosa central (PVC) e índice do volume diastólico final global mensurado pela técnica de termodiluição transpulmonar (GEDVITDTP) para predizer a fluido-responsividade em cães. Animais: Quarenta cadelas saudáveis (13,8–26,8 kg) submetidas a ovário-salpingo-histerectomia. Métodos: A anestesia foi mantida com isoflurano sob ventilação mecânica com volume controlado (volume corrente 12 mL/kg, pausa inspiratória 40%, relação inspiração/expiração: 1:1,5). O débito cardíaco e o volume sistólico foram obtidos pela técnica de termodiluição transpulmonar através de um cateter inserido na artéria femoral. A fluido-responsividade (FR) foi avaliada por uma prova de carga (solução de Ringer com lactato, 20 mL/kg durante 15 minutos), administrada uma vez (n = 21) ou duas vezes (n = 18) antes da cirurgia. Respondedores a volume foram definidos como indivíduos onde o VS mensurado pela técnica de termodiluição transpulmonar, elevou-se acima de 15% após a última prova de carga. Resultados: Dos 39 animais incluídos no estudo, 21 cães foram classificados como respondedores e 18 não respondedores ao último desafio volêmico. As áreas sob as curvas de características de operação do receptor (AUROC) foram de 0,976, 0,906, 0,868 e 0,821 para VPP, IVP, PVC e VVSACP, respectivament... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: To compare the diagnostic accuracy of pulse pressure variation (PPV), stroke volume variation from pulse contour analysis (SVVPCA), plethysmographic variability index (PVI), central venous pressure (CVP) and global end-diastolic volume index measured by transpulmonary thermodilution (GEDVITPTD) to predict fluid responsiveness (FR) in dogs. Animals: A group of 40 bitches (13.8–26.8 kg) undergoing ovariohysterectomy. Methods: Anesthesia was maintained with isoflurane under volume-controlled ventilation (tidal volume 12 mL/kg; inspiratory pause during 40% of inspiratory time; inspiration: expiration ratio 1:1.5). Transpulmonary thermodilution cardiac output was recorded through a femoral artery catheter. FR was evaluated by a fluid challenge (lactated Ringer's, 20 mL kg over 15 minutes) administered once (n = 21) or twice (n = 18) before surgery. Individuals were responders if stroke volume index measured by transpulmonary thermodilution increased >15% after the last fluid challenge. Results: Of the 39 animals studied, 21 were responders and 18 were nonresponders. Area under the receiver operating characteristics curve (AUROC) was 0.976, 0.906, 0.868 and 0.821 for PPV, PVI, CVP and SVVPCA, respectively (p < 0.0001 from AUROC = 0.5). GEDVITPTD failed to predict FR (AUROC: 0.660, p = 0.078). Best cut-off thresholds discriminating responders and nonresponders, with respective zones of diagnostic uncertainty (gray zones) were: PPV >16% (15–16%), PVI >11% (10–13%), SVVPCA ... (Complete abstract click electronic access below) / Doutor

The motivational value of food is lower during satiety compared to fasting. Dynamic changes in motivational value promote food seeking or meal cessation. In obesity this mechanism might be compromised since obese subjects ingest energy beyond homeostatic needs. Thus, lower adaptation of eating behaviour with respect to changes in motivational value might cause food overconsumption in obesity. To test this hypothesis, we implemented a selective satiation procedure to investigate the relationship between obesity and the size of the behavioural devaluation effect in humans. Lean to obese men (mean age 25.9, range 19–30 years; mean BMI 29.1, range 19.2–45.1 kg/m2) were trained on a free operant paradigm and learned to associate cues with the possibility to win different food rewards by pressing a button. After the initial training phase, one of the rewards was devalued by consumption. Response rates for and wanting of the different rewards were measured pre and post devaluation. Behavioural sensitivity to reward devaluation, measured as the magnitude of difference between pre and post responses, was regressed against BMI. Results indicate that (1) higher BMI compared to lower BMI in men led to an attenuated behavioural adjustment to reward devaluation, and (2) the decrease in motivational value was associated with the decrease in response rate between pre and post. Change in explicitly reported motivational value, however, was not affected by BMI. Thus, we conclude that high BMI in men is associated with lower behavioural adaptation with respect to changes in motivational value of food, possibly resulting in automatic overeating patterns that are hard to control in daily life.

Behavior is considered goal-directed when the actor integrates information about the subsequent outcome of an action (Balleine & O'Doherty, 2010; Dickinson & Balleine, 1994; Kiesel & Koch, 2012), potentially enabling the anticipation of consequences of an action. Thus, it requires prior acquisition of knowledge about the current contingencies between behavioral responses and their outcomes under certain stimulus conditions (J. Hoffmann & Engelkamp, 2013). This association chain enables events lying in the future to be mentally represented and assessed in terms of value and achievability. However, while neural correlates of instructed goal-directed action integration processes have already been examined in a functional magnetic resonance imaging (fMRI) study using this paradigm (Ruge & Wolfensteller, 2015), there has been no information if those processes are also reflected in Electroencephalography (EEG) and if so which specific EEG parameters are modulated by them. This dissertation set out to investigate neurocognitive mechanisms of instructed outcome response learning utilizing two different imaging methods, namely EEG and fMRI. Study 1 was an exploratory study to answer the question what kinds of learning-related EEG correlates were to expect. The O-R outcome integration specific EEG correlates identified in Study 1 served as regressors in a unified general linear model (EEG-informed fMRI analysis) in the co-registered EEG-fMRI study (Study 2). One of the key questions in this study was if the EEG signal could help to differentiate between BOLD pre-response activation associated with processes related to response preparation or initiation and activation associated with post-response outcome integration processes. The foundation to both studies of this work was an experimental paradigm of instructed S-R-O learning, which included a learning and a test phase. Stimuli were four abstract visual patterns that differed in each block. Each visual stimulus required a distinct manual response and was predictably followed by a distinct auditory outcome. Instructions were delivered via a “guided implementation” procedure in which the instruction was embedded within the first three successful behavioral implementation trials. In these first three trials, the visual stimulus was followed by an imperative stimulus highlighting the correct response. The guided implementation phase was followed by an unguided implementation phase where the correct response now had to be retrieved from memory. Behaviorally, the strength of acquired O-R associations can be analyzed via O-R compatibility effects measured in a subsequent outcome-priming test phase (Greenwald, 1970). In this test phase a previously learned outcome becomes an imperative stimulus that requires either the response, which produced that outcome in the preceding learning phase (O-R compatible), or a response, which produced a different outcome (O-R incompatible). The experimental design was embedded into an EEG recording setup in study 1 while study 2 comprised a simultaneous EEG-fMRI recording setup in which EEG scalp potentials were continuously recorded during the experimental session inside the MR scanner bore. Study 1 revealed various ERP markers correlated with outcome response learning. An ERP post-response anterior negativity following auditory outcomes was increasingly attenuated as a function of the acquired association strength. This suggests that previously reported action-induced sensory attenuation effects under extensively trained free choice conditions can be established within few repetitions of specific R-O pairings under forced choice conditions. Furthermore, an even more rapid development of a post-response but pre-outcome fronto-central positivity, which was reduced for high R-O learners, might indicate the rapid deployment of preparatory attention towards predictable outcomes. Finally, the study identified a learning-related stimulus-locked activity modulation within the visual P1-N1 latency range, which was thought to reflect the multi-sensory integration of the perceived antecedent visual stimulus with the anticipated auditory outcome. In general, study 2 was only partially able to replicate the EEG activity dynamics related to the formation of bidirectional R-O associations that were observed in study 1. Primarily, it was able to confirm the modulation in EEG negativity in the visual P1-N1 latency range over the learning course. The EEG-informed analysis revealed that learning-related modulations of the P1-N1 complex are functionally coupled to activation in the orbitofrontal cortex (OFC). More specifically, growing attenuation of the EEG negativity increase from early to late SRO repetition levels in high R-O learners was associated with an increase in activation in the OFC. An additional exploratory EEG analysis identified a recurring post outcome effect at central electrode sites expressed in a stronger negativity in late compared to early learning stages. This effect was present in both studies and showed no correlation with any of the behavioral markers of learning. The EEG-informed fMRI analysis resulted in a pattern of distinct functional couplings of this parameter with different brain regions, each correlated with different behavioral markers of S-R-O learning. First of all, increased coupling between the late EEG negativity and activation in the supplementary motor area (SMA) was positively correlated with the O-R compatibility effect. Thus, high R-O learners exhibited a stronger coupling than low R-O learners. Secondly, increased couplings between the late EEG negativity and activation in the somatosensory cortex as well as the dorsal caudate, on the other hand, were positively correlated with individual reaction time differences between early and late stages of learning. Regarding activation patterns prior to the behavioral response the results indicate that the OFC could serve as a (multimodal) hub for integrating stimulus information and information about its associated outcome in an early pre-stage of action selection and initiation. Learnt S-O contingencies would facilitate initiating the motor program of the action of choice. Hence, the earlier an outcome is anticipated (based on stimulus outcome associations), the better it will be associated with its response, eventually leading to stronger O-R compatibility effects later on. Thus, one could speculate that increased activation in response to S-R-O mappings possibly embodies a marker for the ongoing transition from mere stimulus-based behavior to a goal-directed behavior throughout the learning course. Post-response brain activation revealed a seemingly two-fold feedback integration stream of O-R contingencies. On one hand the SMA seems to be engaged in bidirectional encoding processes of O-R associations. The results promote the general idea that the SMA is involved in the acquisition of goal-directed behavior (Elsner et al., 2002; Melcher, Weidema, Eenshuistra, Hommel, & Gruber, 2008; Melcher et al., 2013). Together with prior research (Frimmel, Wolfensteller, Mohr, & Ruge, 2016) this notion can be generalized not only to extensive learning phases but also to learning tasks in which goal-directed behavior is acquired in only few practice trials. However, there is an ongoing debate on whether SMA activation can be clearly linked to sub-processes prior or subsequent to an agent’s action (Nachev, Kennard, & Husain, 2008). The results of this work provide additional evidence favoring an involvement of the SMA only following a performed action in response to an imperative stimulus and even more, subsequent to the perception of its ensuing effect. This may give rise to the interpretation that the SMA is associated with linking the motor program of the performed action to the sensory program of the perceived effect, hence establishing and strengthening O-R contingencies. Furthermore, the analysis identified an increased coupling of a late negativity in the EEG signal and activation in the dorsal parts of the caudate as well as the somatosensory cortex. The dorsal caudate has not particularly been brought into connection with O-R learning so far. I speculate that the coupling effect in this part of the caudate reflects an ongoing process of an early automatization of the acquired behavior. It has already be shown in a similar paradigm that behavior can be automatized within only few repetitions of novel instructed S-R mappings (Mohr et al., 2016).:Table of contents Table of contents II List of Figures IV List of Tables VI List of Abbreviations VII 1 Summary 1 1.1 Introduction 1 1.2 Study Objectives 2 1.3 Methods 3 1.4 Results 4 1.5 Discussion 4 2 Theoretical Background 7 2.1 Introduction 7 2.2 Theories of acquiring goal-directed behavior 9 2.2.1 Instrumental learning 9 2.2.1.1 Behavioral aspects 9 2.2.1.2 Neurophysiological correlates 14 2.2.2 Acquisition of goal-directed behavior according to ideomotor theory 16 2.2.2.1 Behavioral aspects 16 2.2.2.2 Neurophysiological correlates 22 2.3 Summary 25 2.4 Methodological background 26 2.4.1 Electroencephalography (EEG) 26 2.4.2 Functional magnetic resonance imaging (fMRI) 28 2.4.3 Co-registered EEG-fMRI 29 3 General objectives and research questions 34 4 Study 1 – Learning-related brain-electrical activity dynamics associated with the subsequent impact of learnt action-outcome associations 36 4.1 Introduction 36 4.2 Methods 39 4.3 Results 47 4.4 Discussion 60 5 Study 2 - Within trial distinction of O-R learning-related BOLD activity with the means of co-registered EEG information 64 5.1 Introduction 64 5.2 Methods 66 5.3 Results 86 5.4 Discussion 101 6 Concluding general discussion 109 6.1 Brief assessment of study objectives 109 6.2 Novel insights into rapid instruction based S-R-O learning? 109 6.2.1 Early stimulus outcome information retrieval indicates the transition from stimulus based behavior to goal-directed action 110 6.2.2 Post-response encoding and consolidation of O-R contingencies enables goal-directedness of behavior 112 6.3 Critical reflection of the methodology and outlook 116 6.3.1 Strengths and limitations of this work 116 6.3.2 Data quality assessment 117 6.3.3 A common neural foundation for EEG and fMRI? 119 6.3.4 How can co-registered EEG-fMRI contribute to a better understanding of the human brain? 121 6.4 General Conclusion 123 7 References 124 Danksagung Erklärung