Time representation in reinforcement learning models of the basal ganglia

Reinforcement learning (RL) models have been influential in understanding many aspects of basal ganglia function, from reward prediction to action selection. Time plays an important role in these models, but there is still no theoretical consensus about what kind of time representation is used by the basal ganglia. We review several theoretical accounts and their supporting evidence. We then discuss the relationship between RL models and the timing mechanisms that have been attributed to the basal ganglia. We hypothesize that a single computational system may underlie both RL and interval timing—the perception of duration in the range of seconds to hours. This hypothesis, which extends earlier models by incorporating a time-sensitive action selection mechanism, may have important implications for understanding disorders like Parkinson's disease in which both decision making and timing are impaired

A Phylogenetic Perspective on Distributed Decision-Making Mechanisms

This paper challenges a common assumption about decision- making mechanisms in humans: decision-making is a distinctively high-level cognitive activity implemented by mechanisms concentrated in the higher-level areas of the cortex. We argue instead that human behavior is controlled by a multiplicity of highly distributed, heterarchically organized decision-making mechanisms. We frame it in terms of control mechanisms that procure and evaluate information to select activities of controlled mechanisms and adopt a phylogenetic perspective, showing how decision-making is realized in control mechanisms in a variety of species. We end by discussing this picture's implication for high-level cognitive decision-making

A Phylogenetic Perspective on Distributed Decision-Making Mechanisms

This paper challenges a common assumption about decision- making mechanisms in humans: decision-making is a distinctively high-level cognitive activity implemented by mechanisms concentrated in the higher-level areas of the cortex. We argue instead that human behavior is controlled by a multiplicity of highly distributed, heterarchically organized decision-making mechanisms. We frame it in terms of control mechanisms that procure and evaluate information to select activities of controlled mechanisms and adopt a phylogenetic perspective, showing how decision-making is realized in control mechanisms in a variety of species. We end by discussing this picture's implication for high-level cognitive decision-making

Modulation of the 5-HT3 Receptor as a Novel Anti-Dyskinetic Target in Parkinson’s Disease

La L-3,4-dihydroxyphénylalanine (L-DOPA) est le traitement le plus efficace de la maladie de Parkinson. Cependant, avec une administration chronique de L-DOPA, les patients développent des complications motrices telles que les dyskinésies. Des études antérieures ont montré que le blocage des récepteurs type 3 de la sérotonine (5-HT3) réduit les niveaux de dopamine dans les ganglions de la base, suggérant qu'il pourrait atténuer la libération de dopamine qui caractérise l'état dyskinétique. Ici, nous avons étudié les effets de l’ondansétron, un antagoniste hautement sélectif du récepteur 5-HT3 à diminuer et à prévenir le développement des dyskinésies induites par L-DOPA chez le rat lésé a la 6-hydroxydopamine. Dans la première expérience, les rats sensibilisés avec L-DOPA pour induire des mouvements involontaires anormaux (AIMs), ont reçu L-DOPA en combinaison avec l'ondansétron ou un véhicule. Dans la seconde expérience, les doses efficaces d'ondansétron ont été administrées simultanément avec L-DOPA pendant 22 jours, et la sévérité des dyskinésies a été évaluée. Après 3 jours d’élimination, L-DOPA a été administré en aigu et la sévérité des dyskinésies évaluée. Nous avons trouvé que l'ondansétron 0,0001 mg/kg en combinaison avec L-DOPA, a significativement diminué la sévérité des dyskinésies par rapport à L-DOPA seul. Ondansétron 0,0001 mg/kg, administré en même temps que L-DOPA, a retardé le développement des dyskinésies. L'action anti-dyskinétique de l'ondansétron n'a pas compromis le bénéfice thérapeutique conféré par la L-DOPA. Ces résultats suggèrent que l'antagonisme des récepteurs 5-HT3 est une stratégie thérapeutique potentiellement nouvelle et efficace pour soulager la sévérité et prévenir le développement des dyskinésies.L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson’s disease However, with chronic administration of L-DOPA, patients develop motor complications such as dyskinesia. Previous studies have shown that 5-HT3 receptor blockade reduces dopamine levels within the basal ganglia, suggesting that it could mitigate the aberrant dopamine release that characterises the dyskinetic state. Here, we investigated the effects of the highly-selective 5-HT3 antagonist ondansetron at diminishing the expression of established, and preventing the development of L-DOPA-induced dyskinesia in the 6-hydroxydopamine-lesioned rat. In the first set of experiments, rats were primed with L-DOPA to induce abnormal involuntary movements (AIMs), after which L-DOPA was administered, in combination with ondansetron or vehicle. The effect of ondansetron on L-DOPA anti-parkinsonian action was subsequently determined by the cylinder test. In the second set of experiments, rats were administered effective doses of ondansetron, started concurrently with L-DOPA for 22 days, during which dyskinesia severity was monitored. After a 3-day washout period, an acute challenge of L-DOPA was administered and AIMs severity was assessed. We found that acute challenges of ondansetron 0.0001 mg/kg in combination with L-DOPA, significantly diminished the severity of AIMs compared to L-DOPA alone. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, attenuated the priming process leading to the development of dyskinesia. The anti-dyskinetic action of ondansetron did not compromise the therapeutic benefit conferred by L-DOPA. These results suggest that 5-HT3 receptor antagonism is a potentially new and effective therapeutic strategy to alleviate the severity, and prevent the development of dyskinesia

Levodopa-induced dyskinesia in Parkinson disease: Current and Evolving Concepts.

Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence

Multi-modal Imaging and Cognitive Profiles in de novo Parkinson’s Disease

The overall aim of my PhD was to study the correlations between cognitive functions, neurodegeneration and functional alterations in diffuse projection systems. To this aim we plan to combine formal neuropsychological testing, structural and functional imaging and in-vivo quantitative assessments of the dopaminergic, serotonergic and cholinergic systems. Through a multi-modal imaging approach, we had the chance to deeply understand neuroanatomical and neurochemical basis of cognition in its whole, in a large cohort of de novo Parkinson’s Disease (PD) patients. Our study cohort ranges from 30 to 96 of de novo PD patients, who underwent 18F- fluorodeoxyglucose Positron Emission Tomography ([18F]FDG-PET), used as a marker of regional neurodegeneration; [123I]Ioflupane Single Photon Emission Computed Tomography ([123I]FP-CIT-SPECT, as a marker of dopaminergic impairment in the basal ganglia and in the cortex as well as a proxy marker of serotonergic deafferentation in the thalamus; and quantitative electroencephalography (qEEG) recordings, used instead as a marker of cholinergic deafferentation. We combined these imaging methods with formal neuropsychological testing, a social cognition test and multiple clinical variables. In this work we aim to answer to three main scientific questions: i) Does social cognition in de novo PD patients have a specific cortical and neurochemical signature? ii) Is there a mediated effect between diffuse projection systems degeneration and cortical metabolism as well as on regional expression of monoaminergic transmission in the deep grey matter? iii) Are specific cognitive domains impaired in de novo PD patients and are they differently affected by regional metabolism and diffuse projection systems degeneration? In Chapter 3 we investigated the topographical and neurochemical bases of Theory of Mind (ToM), which refers to the ability to attribute mental states to others and to predict, describe, and explain behaviour based on such mental states, using multi-tracer molecular imaging and quantitative electroencephalography in a group of 30 drug-naïve, de novo PD patients. ToM was assessed using the “Reading the Mind in the Eyes Task” (RMET), while general cognition with the Mini Menta State examination (MMSE). We found that PD patients performed significantly worse at RMET compared to 60 healthy controls, as well as a significant positive correlation between RMET performance and regional metabolism in the superior temporal gyrus and the insula, and an inverse correlation with [123I]FP-CIT thalamic specific binding ratio values, as expression of serotonin deafferentation. On the other hand, MMSE correlated with qEEG posterior Theta/Alpha power, confirming its independency from social cognition. In Chapter 4, using multi-tracer molecular imaging, we assessed in a cohort of 96 drug-naïve, de novo PD patients the association between cortical metabolism and dopaminergic and serotonergic systems deafferentation of either striatum or thalamus, and whether this association was mediated by either striatum or thalamus metabolism. We found that the impact of deep grey matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in this population. We showed a significant direct correlation between bilateral temporo-parietal metabolism and caudate dopaminergic innervation, as well as a significant correlation between prefrontal metabolism and thalamus serotonergic innervation, which were, respectively, mediated by striatal and thalamic metabolism. In Chapter 5, we evaluate the association between neurotransmitter impairment, brain metabolism and cognition in a cohort of 95 drug-naïve, de novo PD patients, using [18F]FDG-PET images as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT for dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological tests battery. We found positive correlations between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic expression and working memory, (iii) qEEG slowing in the posterior leads and both memory and visuo-spatial functions