Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

A model of reversal learning and working memory in medicated and unmedicated patients with Parkinsons disease

Wepresent a neural network model of cognition in medicated and unmedicated patients with Parkinson’s disease (PD) in various learning and memory tasks. The model extends our prior models of the basal ganglia and PD with further modeling of the role of prefrontal cortex (PFC) dopamine in stimulus–response learning, reversal, and working memory. In our model, PD is associated with decreased dopamine levels in the basal ganglia and PFC, whereas dopamine medications increase dopamine levels in both brain structures. Simulation results suggest that dopamine medications impair stimulus–response learning in agreement with experimental data (Breitenstein et al., 2006; Gotham, Brown, & Marsden, 1988). Weshow how decreased dopamine levels in the PFC in unmedicated PD patients are associated with impaired working memory performance, as seen experimentally (Costa et al., 2003; Lange et al., 1992; Moustafa, Sherman, & Frank, 2008; Owen, Sahakian, Hodges, Summers, & Polkey, 1995). Further, our model simulations illustrate how increases in tonic dopamine levels in the PFC due to dopamine medications will enhance working memory, in accord with previous modeling and experimental results (Cohen, Braver, & Brown, 2002; Durstewitz, Seamans, & Sejnowski, 2000; Wang, Vijayraghavan, & Goldman-Rakic, 2004). The model is also consistent with data reported in Cools, Barker, Sahakian, and Robbins (2001), who showed that dopamine medications impair reversal learning. In addition, our model shows that extended training of the reversal phase leads to enhanced reversal performance in medicated PD patients, which is a new, and as yet untested, prediction of the model. Overall, our model provides a unified account for performance in various behavioral tasks using common computational principles.Research reported in this publication was supported by National Institutes of Health Award 1 P50 NS 071675-02 from the National Institute of Neurological Disorders and Stroke and by a 2013 internal UWS Research Grant Scheme award P00021210 to A.A.M

Computational models of basal-ganglia pathway functions: focus on functional neuroanatomy

Over the past 15 years, computational models have had a considerable impact on basal-ganglia research. Most of these models implement multiple distinct basal-ganglia pathways and assume them to fulfill different functions. As there is now a multitude of different models, it has become complex to keep track of their various, sometimes just marginally different assumptions on pathway functions. Moreover, it has become a challenge to oversee to what extent individual assumptions are corroborated or challenged by empirical data. Focusing on computational, but also considering non-computational models, we review influential concepts of pathway functions and show to what extent they are compatible with or contradict each other. Moreover, we outline how empirical evidence favors or challenges specific model assumptions and propose experiments that allow testing assumptions against each other

Propuesta de un programa de rehabilitación neuropsicológica de las funciones ejecutivas en población mayor con enfermedad de Parkinson

Trabajo Fin de Master Curso 2015/2016[EN] Parkinson's disease (PD) is a progressive neurodegenerative process characterized by motor symptoms such as tremor, stiffness and bradykinesia, as well as emotional and cognitive changes. Considering the health and technology advances, life expectancy is increasing, which implies an increase in the population with diseases of this type. On the other hand, the executive functions are of great importance to manage the rest of cognitive functions and daily activities, which are affected in these cases. Considering the lack of evidence on PD from a neuropsychological approach, the present work proposes a program of neuropsychological rehabilitation of executive functions for this type of patients, in cognitive related areas, seeking autonomy in their natural environment. Specifically, this program is intended to patients diagnosed with PD between 50 and 65 years and in the absence of primary progressive dementia due to Alzheimer's Disease. The rehabilitation program counts on the creation of specific tasks for this case, with a duration of twelve months, in which previous, during, after and long term evaluations are performed to check if the intervention is effective or must be adapted to meet the objectives. The results obtained from the Neuropsychological tests for cognitive functions in general, executives in particular and skills in everyday activities can check for maintenance and improvement as well as progression over time. Thus, this project could be used as a starting point for future works in which clinical practice guidelines and protocols can be created for health professionals working with this type of patients. [ES] La Enfermedad de Parkinson (EP) se trata de un proceso neurodegenerativo progresivo caracterizado por síntomas motores como temblor, rigidez y bradicinesia, así como por alteraciones emocionales y cognitivas. Considerando los avances sanitarios y tecnológicos, la esperanza de vida cada vez es mayor, lo que implica un aumento de población con enfermedades de este tipo. Por otra parte, las funciones ejecutivas resultan ser de gran importancia para gestionar el resto de funciones cognitivas y actividades cotidianas, las cuales resultan comúnmente afectadas en estos casos. Considerando la falta de evidencia sobre la EP desde un enfoque neuropsicológico, en el presente trabajo se propone un programa de rehabilitación neuropsicológica de las funciones ejecutivas para este tipo de pacientes, pretendiendo obtener un mantenimiento o mejora en dichas funciones, esperando igualmente algún grado de generalización en áreas cognitivas relacionadas, procurando la autonomía en su entorno natural. Concretamente, dicho programa está destinado a pacientes diagnosticados de EP entre 50 y 65 años y en ausencia de demencia progresiva primaria consecuencia de la Enfermedad de Alzheimer. El programa de rehabilitación cuenta con la creación de tareas específicas para este caso, con una duración de doce meses, en los cuales se realizarán evaluaciones previas, durante, posteriormente y a largo plazo para comprobar si la intervención es efectiva o debe adaptarse para cumplir con los objetivos. Los resultados obtenidos de las pruebas neuropsicológicas de las funciones cognitivas en general, ejecutivas en particular y de habilidades en las actividades de la vida diaria permitirán comprobar si existe mantenimiento o mejora así como su progresión a lo largo del tiempo. Así, este proyecto podría utilizarse como punto de partida para futuros trabajos en los que crear guías de práctica clínica y protocolos para los profesionales sanitarios que trabajen con este tipo de pacientes

A neurocomputational model of dopamine and prefrontal-striatal interactions during multicue category learning by Parkinson patients

Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates performance in multicue category learning, such as the "weather prediction" task. The model addresses how PD and dopamine medications affect stimulus selection processes, which mediate reinforcement learning. In this model, PFC dopamine is key for attentional learning, whereas basal ganglia dopamine, consistent with other models, is key for reinforcement and motor learning. The model assumes that competitive dynamics among PFC neurons is the neural mechanism underlying stimulus selection with limited attentional resources, whereas competitive dynamics among striatal neurons is the neural mechanism underlying action selection. According to our model, PD is associated with decreased phasic and tonic dopamine levels in both PFC and basal ganglia. We assume that dopamine medications increase dopamine levels in both the basal ganglia and PFC, which, in turn, increase tonic dopamine levels but decrease the magnitude of phasic dopamine signaling in these brain structures. Increase of tonic dopamine levels in the simulated PFC enhances attentional shifting performance. The model provides a mechanistic account for several phenomena, including (a) medicated PD patients are more impaired at multicue probabilistic category learning than unmedicated patients and (b) medicated PD patients opt out of reversal when there are alternative and redundant cue dimensions

Mathematics anxiety and cognition : a computational modelling study

Anxiety about performing numerical calculations is becoming an increasingly important issue. Termed mathematics anxiety, this condition negatively impacts performance in numerical tasks which can affect education outcomes and future employment prospects. The disruption account proposes this poor performance is from the anxiety and its worrying thoughts disrupting the limited resources of working memory (specifically the attentional and inhibitory functions) leaving less cognitive resources available for the current task. There are many behavioural studies on mathematics anxiety. However, its underlying cognitive and neural mechanisms remain unclear. This thesis examines the relationship between mathematics anxiety and attentional control using neural network modelling, there are no neural network models simulating mathematics anxiety. The numerical Stroop task and the symbolic number comparison task were modelled with a single neural network model architecture examining the effect of modifications to both tasks. Different model modifications were used to simulate high and low math-anxious conditions by modifying attentional processes and learning. The model simulations suggest that mathematics anxiety is associated with reduced attention to numerical stimuli. These results are consistent with attentional control theory where anxiety decreases the influence of the goal-directed attentional system and increases the influence of the stimulus-driven attentional system. Notably, when simulating the numerical Stroop task, the high math-anxious model with reduced attention to numerical stimuli experienced less neural activation in the response layer for the inhibitory condition than the low math-anxious model, suggesting an under activation of working memory resources when experiencing conflict. Furthermore, the model was able to account for several other cognitive conditions, including reduced learning, the physical Stroop task across learning, and the speed-accuracy trade-off

Fronto-striatal contributions to cognition and behaviour: Investigations in neurodegeneration

Alterations to fronto-striatal neural circuitry are the hallmark of many neurodegenerative conditions, giving rise to significant cognitive and behavioural symptoms. This thesis explores fronto-striatal atrophic change in two such conditions, Parkinson’s disease (PD) and behavioural variant frontotemporal dementia (bvFTD). This is a critical area of interest in PD where the role of atrophy in non-motor symptoms, as opposed to dopamine-mediated functional changes, is only beginning to be uncovered. In contrast, cognitive and behavioural decline in bvFTD has long been associated with cortical atrophy, but the contribution of striatal atrophic change is less established. Fronto-striatal atrophy in the conditions is investigated for its role in an array of cognitive and behavioural symptoms. In each study reported, patients have undergone either caregiver questionnaires, neuropsychological testing or novel experimental tasks, to assess 1) neuropsychiatric symptoms (Chapter 2, Publications I and II); 2) learning deficits (Chapter 3, Publication III); and 3) social decision-making (Chapter 4, Publication IV). Behavioural measures are related to fronto-striatal atrophy via voxel-based morphometry, a technique for neuroimaging analysis that enables quantification of local grey matter volume. This analysis was approached firstly at the group level to determine the extent of fronto-striatal grey matter loss in patients with respect to age-matched controls, before being correlated with specific cognitive/behavioural scores. Broadly, the results show that either distinct, or combined, regional fronto-striatal atrophy was related to cognition and behaviour in PD and bvFTD. More specially, these findings highlight a role for fronto-striatal atrophy in both the cognitive and everyday manifestations of neuropsychiatric dysfunction in PD, and in specific learning deficits. These findings have important implications for understanding the pathophysiology of those symptoms in PD, and represent a critical consideration in the future development of therapeutic interventions. In bvFTD these novel findings reveal a role for the striatum in complex cognition and behaviour, emphasising this as an important region for characterising symptoms in the disease, which may assist in diagnosis. Together, the findings provide important insights into the cognitive and behavioural symptoms in neurodegenerative disease, which at present remain incompletely understood and difficult to treat

Cognitive anatomy of the temporal lobe: Effect of personality in population with mild cognitive impairment & Functional specialization for memory systems in healthy individuals.

Résumé: L'impact de la maladie d'Alzheimer (MA) est dévastateur pour la vie quotidienne de la personne affectée, avec perte progressive de la mémoire et d'autres facultés cognitives jusqu'à la démence. Il n'existe toujours pas de traitement contre cette maladie et il y a aussi une grande incertitude sur le diagnostic des premiers stades de la MA. La signature anatomique de la MA, en particulier l'atrophie du lobe temporal moyen (LTM) mesurée avec la neuroimagerie, peut être utilisée comme un biomarqueur précoce, in vivo, des premiers stades de la MA. Toutefois, malgré le rôle évident du LMT dans les processus de la mémoire, nous savons que les modèles anatomiques prédictifs de la MA basés seulement sur des mesures d'atrophie du LTM n'expliquent pas tous les cas cliniques. Au cours de ma thèse, j'ai conduit trois projets pour comprendre l'anatomie et le fonctionnement du LMT dans (1) les processus de la maladie et dans (2) les processus de mémoire ainsi que (3) ceux de l'apprentissage. Je me suis intéressée à une population avec déficit cognitif léger (« Mild Cognitive Impairment », MCI), à risque pour la MA. Le but du premier projet était de tester l'hypothèse que des facteurs, autres que ceux cognitifs, tels que les traits de personnalité peuvent expliquer les différences interindividuelles dans le LTM. De plus, la diversité phénotypique des manifestations précliniques de la MA provient aussi d'une connaissance limitée des processus de mémoire et d'apprentissage dans le cerveau sain. L'objectif du deuxième projet porte sur l'investigation des sous-régions du LTM, et plus particulièrement de leur contribution dans différentes composantes de la mémoire de reconnaissance chez le sujet sain. Pour étudier cela, j'ai utilisé une nouvelle méthode multivariée ainsi que l'IRM à haute résolution pour tester la contribution de ces sous-régions dans les processus de familiarité (« ou Know ») et de remémoration (ou « Recollection »). Finalement, l'objectif du troisième projet était de tester la contribution du LTM en tant que système de mémoire dans l'apprentissage et l'interaction dynamique entre différents systèmes de mémoire durant l'apprentissage. Les résultats du premier projet montrent que, en plus du déficit cognitif observé dans une population avec MCI, les traits de personnalité peuvent expliquer les différences interindividuelles du LTM ; notamment avec une plus grande contribution du neuroticisme liée à une vulnérabilité au stress et à la dépression. Mon étude a permis d'identifier un pattern d'anormalité anatomique dans le LTM associé à la personnalité avec des mesures de volume et de diffusion moyenne du tissu. Ce pattern est caractérisé par une asymétrie droite-gauche du LTM et un gradient antéro-postérieur dans le LTM. J'ai interprété ce résultat par des propriétés tissulaires et neurochimiques différemment sensibles au stress. Les résultats de mon deuxième projet ont contribué au débat actuel sur la contribution des sous-régions du LTM dans les processus de familiarité et de remémoration. Utilisant une nouvelle méthode multivariée, les résultats supportent premièrement une dissociation des sous-régions associées aux différentes composantes de la mémoire. L'hippocampe est le plus associé à la mémoire de type remémoration et le cortex parahippocampique, à la mémoire de type familiarité. Deuxièmement, l'activation correspondant à la trace mnésique pour chaque type de mémoire est caractérisée par une distribution spatiale distincte. La représentation neuronale spécifique, « sparse-distributed», associée à la mémoire de remémoration dans l'hippocampe serait la meilleure manière d'encoder rapidement des souvenirs détaillés sans interférer les souvenirs précédemment stockés. Dans mon troisième projet, j'ai mis en place une tâche d'apprentissage en IRM fonctionnelle pour étudier les processus d'apprentissage d'associations probabilistes basé sur le feedback/récompense. Cette étude m'a permis de mettre en évidence le rôle du LTM dans l'apprentissage et l'interaction entre différents systèmes de mémoire comme la mémoire procédurale, perceptuelle ou d'amorçage et la mémoire de travail. Nous avons trouvé des activations dans le LTM correspondant à un processus de mémoire épisodique; les ganglions de la base (GB), à la mémoire procédurale et la récompense; le cortex occipito-temporal (OT), à la mémoire de représentation perceptive ou l'amorçage et le cortex préfrontal, à la mémoire de travail. Nous avons également observé que ces régions peuvent interagir; le type de relation entre le LTM et les GB a été interprété comme une compétition, ce qui a déjà été reporté dans des études récentes. De plus, avec un modèle dynamique causal, j'ai démontré l'existence d'une connectivité effective entre des régions. Elle se caractérise par une influence causale de type « top-down » venant de régions corticales associées avec des processus de plus haut niveau venant du cortex préfrontal sur des régions corticales plus primaires comme le OT cortex. Cette influence diminue au cours du de l'apprentissage; cela pourrait correspondre à un mécanisme de diminution de l'erreur de prédiction. Mon interprétation est que cela est à l'origine de la connaissance sémantique. J'ai également montré que les choix du sujet et l'activation cérébrale associée sont influencés par les traits de personnalité et des états affectifs négatifs. Les résultats de cette thèse m'ont amenée à proposer (1) un modèle expliquant les mécanismes possibles liés à l'influence de la personnalité sur le LTM dans une population avec MCI, (2) une dissociation des sous-régions du LTM dans différents types de mémoire et une représentation neuronale spécifique à ces régions. Cela pourrait être une piste pour résoudre les débats actuels sur la mémoire de reconnaissance. Finalement, (3) le LTM est aussi un système de mémoire impliqué dans l'apprentissage et qui peut interagir avec les GB par une compétition. Nous avons aussi mis en évidence une interaction dynamique de type « top -down » et « bottom-up » entre le cortex préfrontal et le cortex OT. En conclusion, les résultats peuvent donner des indices afin de mieux comprendre certains dysfonctionnements de la mémoire liés à l'âge et la maladie d'Alzheimer ainsi qu'à améliorer le développement de traitement. Abstract: The impact of Alzheimer's disease is devastating for the daily life of the affected patients, with progressive loss of memory and other cognitive skills until dementia. We still lack disease modifying treatment and there is also a great amount of uncertainty regarding the accuracy of diagnostic classification in the early stages of AD. The anatomical signature of AD, in particular the medial temporal lobe (MTL) atrophy measured with neuroimaging, can be used as an early in vivo biomarker in early stages of AD. However, despite the evident role of MTL in memory, we know that the derived predictive anatomical model based only on measures of brain atrophy in MTL does not explain all clinical cases. Throughout my thesis, I have conducted three projects to understand the anatomy and the functioning of MTL on (1) disease's progression, (2) memory process and (3) learning process. I was interested in a population with mild cognitive impairment (MCI), at risk for AD. The objective of the first project was to test the hypothesis that factors, other than the cognitive ones, such as the personality traits, can explain inter-individual differences in the MTL. Moreover, the phenotypic diversity in the manifestations of preclinical AD arises also from the limited knowledge of memory and learning processes in healthy brain. The objective of the second project concerns the investigation of sub-regions of the MTL, and more particularly their contributions in the different components of recognition memory in healthy subjects. To study that, I have used a new multivariate method as well as MRI at high resolution to test the contribution of those sub-regions in the processes of familiarity and recollection. Finally, the objective of the third project was to test the contribution of the MTL as a memory system in learning and the dynamic interaction between memory systems during learning. The results of the first project show that, beyond cognitive state of impairment observed in the population with MCI, the personality traits can explain the inter-individual differences in the MTL; notably with a higher contribution of neuroticism linked to proneness to stress and depression. My study has allowed identifying a pattern of anatomical abnormality in the MTL related to personality with measures of volume and mean diffusion of the tissue. That pattern is characterized by right-left asymmetry in MTL and an anterior to posterior gradient within MTL. I have interpreted that result by tissue and neurochemical properties differently sensitive to stress. Results of my second project have contributed to the actual debate on the contribution of MTL sub-regions in the processes of familiarity and recollection. Using a new multivariate method, the results support firstly a dissociation of the subregions associated with different memory components. The hippocampus was mostly associated with recollection and the surrounding parahippocampal cortex, with familiarity type of memory. Secondly, the activation corresponding to the mensic trace for each type of memory is characterized by a distinct spatial distribution. The specific neuronal representation, "sparse-distributed", associated with recollection in the hippocampus would be the best way to rapidly encode detailed memories without overwriting previously stored memories. In the third project, I have created a learning task with functional MRI to sudy the processes of learning of probabilistic associations based on feedback/reward. That study allowed me to highlight the role of the MTL in learning and the interaction between different memory systems such as the procedural memory, the perceptual memory or priming and the working memory. We have found activations in the MTL corresponding to a process of episodic memory; the basal ganglia (BG), to a procedural memory and reward; the occipito-temporal (OT) cortex, to a perceptive memory or priming and the prefrontal cortex, to working memory. We have also observed that those regions can interact; the relation type between the MTL and the BG has been interpreted as a competition. In addition, with a dynamic causal model, I have demonstrated a "top-down" influence from cortical regions associated with high level cortical area such as the prefrontal cortex on lower level cortical regions such as the OT cortex. That influence decreases during learning; that could correspond to a mechanism linked to a diminution of prediction error. My interpretation is that this is at the origin of the semantic knowledge. I have also shown that the subject's choice and the associated brain activation are influenced by personality traits and negative affects. Overall results of this thesis have brought me to propose (1) a model explaining the possible mechanism linked to the influence of personality on the MTL in a population with MCI, (2) a dissociation of MTL sub-regions in different memory types and a neuronal representation specific to each region. This could be a cue to resolve the actual debates on recognition memory. Finally, (3) the MTL is also a system involved in learning and that can interact with the BG by a competition. We have also shown a dynamic interaction of « top -down » and « bottom-up » types between the pre-frontal cortex and the OT cortex. In conclusion, the results could give cues to better understand some memory dysfunctions in aging and Alzheimer's disease and to improve development of treatment