Motivation intrinsèque pour le choix dans la maladie de Parkinson : implication des ganglions de la base et du système dopaminergique

Humans and other animals appear to frequently base decisions on value attribution that is often not clearly linked to extrinsic outcomes. For example, they prefer opportunities to choose, even when these have no positive impact on future rewards. Thus, access to free choice may be intrinsically rewarding, a form of motivation that invigorates an agent to perform behaviors in and of themselves. This rewarding nature of choice suggests the implication of the basal ganglia system, which is strongly modulated by the dopaminergic system. Dopamine neuron degeneration is responsible for the symptoms of Parkinson's disease (PD). While treatments improve motor function, they can induce behavioral changes. For example, some PD patients treated with dopaminergic treatment show altered sensitivity to extrinsic rewards. Some patients treated with subthalamic nucleus (STN) stimulation, an essential structure in the basal ganglia system, may suffer from impulsive decisions and altered learning from extrinsic rewards. We sought to understand how extrinsic and intrinsic motivations act together during decision making. We developed a new paradigm to identify choice preference as an intrinsic reward in healthy humans as well as patients with PD. First, in healthy subjects, we established that humans prefer choice opportunities for their own sake, independent of the extrinsic rewards associated with these opportunities. We then studied PD patients ON and OFF treatment, which allowed to manipulate the dopaminergic system and basal ganglia that are involved in processing of extrinsic reward. In one patient group, treatment consisted of acute dopamine replacement therapy, and in second patient group treatment consisted of deep brain stimulation (DBS) of the subthalamic nucleus (STN). We found that PD patients ON treatment preferred opportunities to choose even though these did not afford more extrinsic rewards. However, patients lose this preference in conditions that diminish the quantity of dopamine in their brains or by reducing the activation of medial prefrontal cortical areas via deep brain stimulation. In particular, we used probabilistic tractography of cortical fibers from DBS stimulation sites to show that higher connectivity with the right dorsal anterior cingulate cortex was associated with increased choice preference induced by STN-DBS. In the group treated with dopaminergic medication, patients with higher chronic doses of dopaminergic medication showed an increased choice preference. These results advance our understanding of the neurocognitive determinants of intrinsic reward and its interplay with general motivational processes by unmasking motivational mechanisms associated with behavioral impairments observed in PD.La préférence pour des situations comportant du choix a été observés chez l’humain et plusieurs espèces animales. Cette préférence pour le choix présente des avantages qui semblent prévaloir sur l’obtention de récompenses plus basiques. Le choix pourrait présenter un caractère intrinsèquement motivant. Ce caractère récompensant du choix suggère l’implication du système des ganglions de la base, impliqué dans les processus de prise de décision et de pérennisation des actions, modulé fortement par le système dopaminergique, responsable de la valuation des stimuli. La dégénérescence des neurones dopaminergiques et l’altération des ganglions de la base qui en résulte, provoque les symptômes de la maladie de Parkinson. Alors que les traitements améliorent la fonction motrice, ils peuvent induire des modifications comportementales. Par exemple, certains patients parkinsoniens sous traitement dopaminergique présentent une sensibilité accrue aux récompenses extrinsèques. Certains patients traités par stimulation du noyau subthalamique (NST), noyau essentiel des ganglions de la base, peuvent souffrir d’une prise de décisions impulsives. Ce travail de recherche utilise un nouveau paradigme permettant de caractériser la préférence pour le choix comme récompense intrinsèque. Dans une première étape, le sujet a la possibilité de choisir librement ou non. Dans une seconde étape, il choisit entre deux images celle qui délivre le plus de récompenses. Pour limiter le biais d’exploration, les sujets ont réalisé un apprentissage préalable des contingences de récompenses. Des sujets sains, des patients parkinsoniens avec traitement dopaminergique et d’autres traités par stimulation cérébrale profonde du NST ont été inclus. Les patients parkinsoniens ont réalisé la tâche sans (OFF) et avec traitement (ON). Afin d’examiner si des patterns de connectivité pourraient expliquer les réponses des patients stimulés, la tractographie probabiliste des fibres corticales incluses dans le volume de tissu activé au sein du NST a été analysée. Premièrement, chez des sujets sains, nous avons établi que les humains préfèrent les possibilités de choix pour elles-mêmes, indépendamment des récompenses extrinsèques associées à ces possibilités. Chez les patients, il existe un effet aigu de la stimulation du NST, les sujets ON préférant le choix à hauteur de celle des sujets sains, indépendamment des récompenses extrinsèques qu’ils ont reçus. Chez les patients OFF, la préférence pour le choix diminue près du seuil d’indifférence (50%). Il existe une connectivité accrue avec le cortex cingulaire antérieur dorsal droit chez les patients ayant le plus d’effet. Les patients avec traitement dopaminergique présentaient une préférence pour le choix accru si leurs doses quotidiennes étaient plus élevées. Ces résultats font progresser notre compréhension des déterminants neurocognitifs de la récompense intrinsèque et de son interaction avec des processus motivationnels généraux en démasquant les mécanismes associés aux troubles comportementaux observées dans la maladie de Parkinson

Intrinsic motivation for free choice in Parkinson's disease : involvement of the basal ganglia and the dopaminergic system

La préférence pour des situations comportant du choix a été observés chez l’humain et plusieurs espèces animales. Cette préférence pour le choix présente des avantages qui semblent prévaloir sur l’obtention de récompenses plus basiques. Le choix pourrait présenter un caractère intrinsèquement motivant. Ce caractère récompensant du choix suggère l’implication du système des ganglions de la base, impliqué dans les processus de prise de décision et de pérennisation des actions, modulé fortement par le système dopaminergique, responsable de la valuation des stimuli. La dégénérescence des neurones dopaminergiques et l’altération des ganglions de la base qui en résulte, provoque les symptômes de la maladie de Parkinson. Alors que les traitements améliorent la fonction motrice, ils peuvent induire des modifications comportementales. Par exemple, certains patients parkinsoniens sous traitement dopaminergique présentent une sensibilité accrue aux récompenses extrinsèques. Certains patients traités par stimulation du noyau subthalamique (NST), noyau essentiel des ganglions de la base, peuvent souffrir d’une prise de décisions impulsives. Ce travail de recherche utilise un nouveau paradigme permettant de caractériser la préférence pour le choix comme récompense intrinsèque. Dans une première étape, le sujet a la possibilité de choisir librement ou non. Dans une seconde étape, il choisit entre deux images celle qui délivre le plus de récompenses. Pour limiter le biais d’exploration, les sujets ont réalisé un apprentissage préalable des contingences de récompenses. Des sujets sains, des patients parkinsoniens avec traitement dopaminergique et d’autres traités par stimulation cérébrale profonde du NST ont été inclus. Les patients parkinsoniens ont réalisé la tâche sans (OFF) et avec traitement (ON). Afin d’examiner si des patterns de connectivité pourraient expliquer les réponses des patients stimulés, la tractographie probabiliste des fibres corticales incluses dans le volume de tissu activé au sein du NST a été analysée. Premièrement, chez des sujets sains, nous avons établi que les humains préfèrent les possibilités de choix pour elles-mêmes, indépendamment des récompenses extrinsèques associées à ces possibilités. Chez les patients, il existe un effet aigu de la stimulation du NST, les sujets ON préférant le choix à hauteur de celle des sujets sains, indépendamment des récompenses extrinsèques qu’ils ont reçus. Chez les patients OFF, la préférence pour le choix diminue près du seuil d’indifférence (50%). Il existe une connectivité accrue avec le cortex cingulaire antérieur dorsal droit chez les patients ayant le plus d’effet. Les patients avec traitement dopaminergique présentaient une préférence pour le choix accru si leurs doses quotidiennes étaient plus élevées. Ces résultats font progresser notre compréhension des déterminants neurocognitifs de la récompense intrinsèque et de son interaction avec des processus motivationnels généraux en démasquant les mécanismes associés aux troubles comportementaux observées dans la maladie de Parkinson.Humans and other animals appear to frequently base decisions on value attribution that is often not clearly linked to extrinsic outcomes. For example, they prefer opportunities to choose, even when these have no positive impact on future rewards. Thus, access to free choice may be intrinsically rewarding, a form of motivation that invigorates an agent to perform behaviors in and of themselves. This rewarding nature of choice suggests the implication of the basal ganglia system, which is strongly modulated by the dopaminergic system. Dopamine neuron degeneration is responsible for the symptoms of Parkinson's disease (PD). While treatments improve motor function, they can induce behavioral changes. For example, some PD patients treated with dopaminergic treatment show altered sensitivity to extrinsic rewards. Some patients treated with subthalamic nucleus (STN) stimulation, an essential structure in the basal ganglia system, may suffer from impulsive decisions and altered learning from extrinsic rewards. We sought to understand how extrinsic and intrinsic motivations act together during decision making. We developed a new paradigm to identify choice preference as an intrinsic reward in healthy humans as well as patients with PD. First, in healthy subjects, we established that humans prefer choice opportunities for their own sake, independent of the extrinsic rewards associated with these opportunities. We then studied PD patients ON and OFF treatment, which allowed to manipulate the dopaminergic system and basal ganglia that are involved in processing of extrinsic reward. In one patient group, treatment consisted of acute dopamine replacement therapy, and in second patient group treatment consisted of deep brain stimulation (DBS) of the subthalamic nucleus (STN). We found that PD patients ON treatment preferred opportunities to choose even though these did not afford more extrinsic rewards. However, patients lose this preference in conditions that diminish the quantity of dopamine in their brains or by reducing the activation of medial prefrontal cortical areas via deep brain stimulation. In particular, we used probabilistic tractography of cortical fibers from DBS stimulation sites to show that higher connectivity with the right dorsal anterior cingulate cortex was associated with increased choice preference induced by STN-DBS. In the group treated with dopaminergic medication, patients with higher chronic doses of dopaminergic medication showed an increased choice preference. These results advance our understanding of the neurocognitive determinants of intrinsic reward and its interplay with general motivational processes by unmasking motivational mechanisms associated with behavioral impairments observed in PD

Brain morphometry predicts individual creative potential and the ability to combine remote ideas

International audienceFor complex mental functions such as creative thinking, inter-individual variability is useful to better understand the underlying cognitive components and brain anatomy. Associative theories propose that creative individuals have flexible semantic associations, which allows remote elements to be formed into new combinations. However, the structural brain variability associated with the ability to combine remote associates has not been explored. To address this question, we performed a voxel-based morphometry (VBM) study and explored the anatomical connectivity of significant regions. We developed a Remote Combination Association Task adapted from Mednick's test, in which subjects had to find a solution word related to three cue words presented to them. In our adaptation of the task, we used free association norms to quantify the associative distance between the cue words and solution words, and we varied this distance. The tendency to solve the task with insight and the ability to evaluate the appropriateness of a proposed solution were also analysed. Fifty-four healthy volunteers performed this task and underwent a structural MRI. Structure–function relationships were analysed using regression models between grey matter (GM) volume and task performance. Significant clusters were mapped onto an atlas of white matter (WM) tracts. The ability to solve the task, which depended on the associative distance of the solution word, was associated with structural variation in the left rostrolateral prefrontal and posterior parietal regions; the left rostral prefrontal region was connected to distant regions through long-range pathways. By using a creative combination task in which the semantic distance between words varied, we revealed a brain network centred on the left frontal pole that appears to support the ability to combine information in new ways by bridging the semantic distance between pieces of information

Intrinsic motivation for choice varies with individual risk attitudes and the controllability of the environment.

When deciding between options that do or do not lead to future choices, humans often choose to choose. We studied choice seeking by asking subjects to first decide between a choice opportunity or performing a computer-selected action, after which they either chose freely or performed the forced action. Subjects preferred choice when these options were equally rewarded, even deterministically, and traded extrinsic rewards for opportunities to choose. We explained individual variability in choice seeking using reinforcement learning models incorporating risk sensitivity and overvaluation of rewards obtained through choice. Model fits revealed that 28% of subjects were sensitive to the worst possible outcome associated with free choice, and this pessimism reduced their choice preference with increasing risk. Moreover, outcome overvaluation was necessary to explain patterns of individual choice preference across levels of risk. We also manipulated the degree to which subjects controlled stimulus outcomes. We found that degrading coherence between their actions and stimulus outcomes diminished choice preference following forced actions, although willingness to repeat selection of choice opportunities remained high. When subjects chose freely during these repeats, they were sensitive to rewards when actions were controllable but ignored outcomes-even positive ones-associated with reduced controllability. Our results show that preference for choice can be modulated by extrinsic reward properties including reward probability and risk as well as by controllability of the environment

Choice seeking is motivated by the intrinsic need for personal control

When deciding between options that do or do not lead to future choices, humans often choose to choose. We studied choice seeking by asking subjects to decide between a choice opportunity or performing a computer-selected action. Subjects preferred choice when these options were equally rewarded, even deterministically, and were willing to trade extrinsic rewards for the opportunity to choose. We explained individual variability in choice seeking using reinforcement learning models incorporating risk sensitivity and overvaluation of rewards obtained through choice. Degrading perceived controllability diminished choice preference, although willingness to repeat selection of choice opportunities remained unchanged. In choices following these repeats, subjects were sensitive to rewards following freely chosen actions, but ignored environmental information in a manner consistent with a desire to maintain personal control. Choice seeking appears to reflect the intrinsic need for personal control, which competes with extrinsic reward properties and external information to motivate behavior. Author summary Human decisions can often be explained by the balancing of potential rewards and punishments. However, some research suggests that humans also prefer opportunities to choose, even when these have no impact on future rewards or punishments. Thus, opportunities to choose may be intrinsically motivating, although this has never been experimentally tested against alternative explanations such as cognitive dissonance or exploration. We conducted behavioral experiments and used computational modelling to provide compelling evidence that choice opportunities are indeed intrinsically rewarding. Moreover, we found that human choice preference varied according to individual risk attitudes, and expressed a need for personal control that competes with maximizing reward intake

Exploration Deficits Under Ecological Conditions as a Marker of Apathy in Frontotemporal Dementia

International audienceApathy is one of the six clinical criteria for the behavioral variant of frontotemporal dementia (bvFTD), and it is almost universal in this disease. Although its consequences in everyday life are debilitating, its underlying mechanisms are poorly known, its assessment is biased by subjectivity and its care management is very limited. In this context, we have developed “ECOCAPTURE,” a method aimed at providing quantifiable and objective signature(s) of apathy in order to assess it and identify its precise underlying mechanisms. ECOCAPTURE consists of the observation and recording of the patient's behavior when the participant is being submitted to a multiple-phase scenario reproducing a brief real-life situation. It is performed in a functional exploration platform transformed into a fully furnished waiting room equipped with a video and sensor-based data acquisition system. This multimodal method allowed video-based behavior analyses according to predefined behavioral categories (exploration behavior, sustained activities or inactivity) and actigraphy analyses from a 3D accelerometer. The data obtained were also correlated with behavioral/cognitive tests and scales assessing global cognitive efficiency, apathy, cognitive disinhibition, frontal syndrome, depression and anxiety. Here, bvFTD patients (n = 14) were compared to healthy participants (n = 14) during the very first minutes of the scenario, when the participants discovered the room and were encouraged to explore it. We showed that, in the context of facing a new environment, healthy participants first explored it and then engaged in sustained activities. By contrast, bvFTD patients were mostly inactive and eventually explored this new place, but in a more irregular and less efficient mode than normal subjects. This exploration deficit was correlated with apathy, disinhibition and cognitive and behavioral dysexecutive syndromes. These findings led us to discuss the presumed underlying mechanisms responsible for the exploration deficit (an inability to self-initiate actions, to integrate reward valuation and to inhibit involuntary behavior). Altogether, these results pave the way for simple and objective assessment of behavioral changes that represents a critical step for the evaluation of disease progression and efficacy of treatment in bvFTD

Two critical brain networks for generation and combination of remote associations

International audienceRecent functional imaging findings in humans indicate that creativity relies on spontaneous and controlled processes, possibly supported by the default mode and the fronto-parietal control networks, respectively. Here, we examined the ability to generate 10 and combine remote semantic associations, in relation to creative abilities, in patients with focal frontal lesions. Voxel-based lesion-deficit mapping, disconnection-deficit mapping and network-based lesion-deficit approaches revealed critical prefrontal nodes and connections for distinct mechanisms related to creative cognition. Damage to the right medial prefrontal region, or its potential disrupting effect on the default mode network, affected the ability to generate remote ideas, likely by altering the organization of semantic associations. Damage to the left rostrolateral prefrontal region and its connections, or its potential disrupting effect on the 15 left fronto-parietal control network, spared the ability to generate remote ideas but impaired the ability to appropriately combine remote ideas. Hence, the current findings suggest that damage to specific nodes within the default mode and fronto-parietal control networks led to a critical loss of verbal creative abilities by altering distinct cognitive mechanisms

Functional connectivity correlates of reduced goal-directed behaviors in behavioural variant frontotemporal dementia

International audienceWe explored the resting state functional connectivity correlates of apathy assessed as a multidimensional construct, using behavioral metrics, in behavioral variant frontotemporal dementia (bvFTD). We recorded the behavior of 20 bvFTD patients and 16 healthy controls in a close-to-real-life situation including a free phase (FP-in which actions were self-initiated) and a guided phase (GP-in which initiation of actions was facilitated by external guidance). We investigated the activity time and walking episode features as quantifiers of apathy. We used the means ((FP + GP)/2) and the differences (FP-GP) calculated for these metrics as well as measures by questionnaires to extract apathy dimensions by factor analysis. We assessed two types of fMRI-based resting state connectivity measures (local activity and seed-based connectivity) and explored their relationship with extracted apathy dimensions. Apathy in bvFTD was associated with lower time spent in activity combined with walking episodes of higher frequency, lower acceleration and higher duration. Using these behavioral metrics and apathy measures by questionnaires, we disentangled two dimensions: the global reduction of goal-directed behaviors and the specific deficit of self-initiation. Global apathy was associated with lower resting state activity within prefrontal cortex and lower connectivity of salience network hubs while the decrease in self-initiation was related to increased connectivity of parietal default-mode network hubs. Through a novel dimensional approach, we dissociated the functional connectivity correlates of global apathy and self-initiation deficit. We discussed in particular the role of the modified connectivity of lateral parietal cortex in the volitional process

Curr Neurol Neurosci Rep

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes

Symptoms assessment and decision to treat patients with advanced Parkinson’s disease based on wearables data

International audienceBody-worn sensors (BWS) could provide valuable information in the management of Parkinson’s disease and support therapeutic decisions based on objective monitoring. To study this pivotal step and better understand how relevant information is extracted from BWS results and translated into treatment adaptation, eight neurologists examined eight virtual cases composed of basic patient profiles and their BWS monitoring results. Sixty-four interpretations of monitoring results and the subsequent therapeutic decisions were collected. Relationship between interrater agreements in the BWS reading and the severity of symptoms were analyzed via correlation studies. Logistic regression was used to identify associations between the BWS parameters and suggested treatment modifications. Interrater agreements were high and significantly associated with the BWS scores. Summarized BWS scores reflecting bradykinesia, dyskinesia, and tremor predicted the direction of treatment modifications. Our results suggest that monitoring information is robustly linked to treatment adaptation and pave the way to loop systems able to automatically propose treatment modifications from BWS recordings information