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Motivational deficit is a core clinical manifestation of depression and a strong predictor of treatment failure. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. According to decision theory, apathy could result either from biased subjective estimates (of action costs or outcomes) or from dysfunctional processes (in making decisions or allocating resources).Here, we combined a series of behavioral tasks with computational modeling to elucidate the motivational deficits of 35 patients with unipolar or bipolar depression under various treatments compared with 35 matched healthy control subjects.The most striking feature, which was observed independent of medication across preference tasks (likeability ratings and binary decisions), performance tasks (physical and mental effort exertion), and instrumental learning tasks (updating choices to maximize outcomes), was an elevated sensitivity to effort cost. By contrast, sensitivity to action outcomes (reward and punishment) and task-specific processes were relatively spared.These results highlight effort cost as a critical dimension that might explain multiple behavioral changes in patients with depression. More generally, they validate a test battery for computational phenotyping of motivational states, which could orientate toward specific medication or rehabilitation therapy, and thereby help pave the way for more personalized medicine in psychiatry.

Jean Talairach is world-renowned for his development of stereo-electroencephalography, and remains the most cited French neurosurgeon to date with his stereotactic atlas of the human brain. Zanello et al. explore the life of Jean Talairach, including his training as a psychiatrist and his military service during WW2.

International audience; Identifying factors whose fluctuations are associated with choice inconsistency is a major issue for rational decision theory. Here, we investigated the neuro-computational mechanisms through which mood fluctuations may bias human choice behavior. Intracerebral EEG data were collected in a large group of subjects (n=30) while they were performing interleaved quiz and choice tasks that were designed to examine how a series of unrelated feedbacks affect decisions between safe and risky options. Neural baseline activity preceding choice onset was confronted first to mood level, estimated by a computational model integrating the feedbacks received in the quiz task, and then to the weighting of option attributes, in a computational model predicting risk attitude in the choice task. Results showed that (1) elevated broadband gamma activity (BGA) in the ventromedial prefrontal cortex (vmPFC) and dorsal anterior insula (daIns) was respectively signaling periods of high and low mood, (2) increased vmPFC and daIns BGA respectively promoted and tempered risk taking by overweighting gain vs. loss prospects. Thus, incidental feedbacks induce brain states that correspond to different moods and bias the evaluation of risky options. More generally, these findings might explain why people experiencing positive (or negative) outcome in some part of their life tend to expect success (or failure) in any other.

Objectives: Bipolar disorder (BD) is defined by alternation of depressive and (hypo)manic states. An essential dimension related to mood fluctuations is reward sensitivity. The expression of mood disorders can be modulated by environmental factors and life events, as well as by their subsequent learning related to reward or punishment sensitivity. According to the dimensional focus of the Research Domain Criteria, BD subtypes may be conceptualized as a spectrum in which reward sensitivity is a key dimension of pathology. Here, we examine reward maximizations vs. punishment avoidance learning in patients with BD during intercritical phase to test this hypothesis. Methods: Patients with BD-I (n=45), BD-II (n=34) and age and gender matched (n=30) healthy controls (HC) participated to the study. They performed an instrumental learning task designed to dissociate reward-based from punishment-based reinforcement learning. Computational modeling was used to identify the mechanisms underlying reinforcement learning performance.Results: Behavioral results showed a significant reward learning deficit across BD subtypes compared to HC. Conversely, BD-I patients performed better during punishment avoidance learning than BD-II patients. Computational analysis indicated that the observed reward-based learning deficit was captured by a lower reinforcement magnitude in both BD subtypes, when compared to HC. The punishment-based learning deficit was captured by a higher choice randomness in the BD-II compared to BD-I patients’ group.Conclusions: Our results are consistent with the reward hyposensitivity theory in BD. Furthermore, our results also suggest that studying punishment avoidance learning across BD subtypes could be useful for classification and consequent treatment tailoring in BD.

Background and Hypothesis Motivation deficit is a hallmark of schizophrenia that has a strong impact on their daily life. An alteration of reward processing has been repeatedly highlighted in schizophrenia, but to what extent it involves a deficient amplification of reward representation through conscious processing remains unclear. Indeed, patients with schizophrenia exhibit a disruption of conscious processing, whereas unconscious processing appears to be largely preserved. Study Design To further explore the nature of motivational deficit in schizophrenia and the implication of consciousness disruption in this symptom, we used a masking paradigm testing motivation both under conscious and unconscious conditions in patients with schizophrenia (n = 31) and healthy controls (n = 32). Participants were exposed to conscious or subliminal coin pictures representing money at stake and were subsequently asked to perform an effort-task by squeezing a handgrip as hard as possible to win this reward. Study Results We observed a preserved effect of unconscious monetary rewards on force production in both groups, without any significant difference between them. By contrast, in the conscious condition, patients with schizophrenia were less sensitive to rewards than controls. Our results confirm that unconscious incentives have effects on exerted forces in the general population, and demonstrate that patients with schizophrenia exhibit a dissociation between an impaired conscious motivation and a preserved unconscious motivation. Conclusions These findings suggest the existence of several steps in motivational processes that can be differentially affected and might have implication for patient care.

Resume Depuis les annees 1950, l’arsenal therapeutique permettant de lutter contre la depression s’est considerablement enrichi. De la decouverte des inhibiteurs de la monoamine oxydase (IMAO) a celle de la ketamine, ces percees pharmacologiques ont marque l’histoire de la psychiatrie et guide la recherche sur la physiopathologie de la depression, cette pathologie devastatrice affectant entre 10 et 20 % de la population mondiale. Nous proposons dans cet article une courte revue historique des differentes options therapeutiques developpees au cours du siecle passe et des consequences qu’ont eu ces innovations. Nous realisons ensuite un etat des lieux de la plus recente de ces decouvertes, celle des effets antidepresseurs de la ketamine (et de son enantiomere S, l’esketamine), spectaculaires de par leur delai d’apparition et leur efficacite meme dans les formes les plus resistantes de depression. De meme que la decouverte des IMAO et des tricycliques a permis de concevoir une theorie monoaminergique de la depression, l’etude des mecanismes d’actions de la ketamine pourrait permettre de comprendre le role de la transmission glutamatergique ou de la neuro-inflammation dans la neurobiologie de cette pathologie, d’affiner nos connaissances sur sa physiopathologie cognitive ou encore de transformer en profondeur les representations des cliniciens sur cette maladie.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of mono-amine oxidase inhibitors (MAOIs) to the antidepressant effect of ketamine, several pharmacological breakthroughs made the history of psychiatry. These discoveries oriented the research about the pathophysiology of depression, which is one of the most disabling diseases worldwide affecting 10 to 20% of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the discovery of the antidepressant effects of ketamine (and its S-enantiomer, esketamine), the lastest development in depression treatment. Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the “monoaminergic hypothesis of depression” to emerge, unravelling the mechanisms of ketamine's antidepressant effects should highlight the role of glutamatergic system and neuro-inflammation in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression and to deeply transform the clinical representations of depressive disorder.

Apathy is a core symptom in patients with behavioural variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behaviour, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behaviour depends on a cost–benefit optimization trading off the estimated effort (related to the behaviour) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 patients with bvFTD and 40 matched healthy controls using computational analyses of behavioural responses in a comprehensive series of behavioural tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks in patients with bvFTD compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in patients with bvFTD. More broadly, they provide novel behavioural tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.

In high stakes situations, people sometimes choke under pressure, performing below their abilities. Here, we suggest a novel mechanism to account for this paradoxical effect of motivation: the automatic adjustment of action vigour to potential reward. Although adaptive on average, this mechanism may impede fine motor control. Such detrimental effect was observed in three studies (n = 74 in total), using behavioural tasks where payoff depended on the precision of handgrip squeezing or golf putting. Participants produced more force for higher incentives, which aggravated their systematic overshooting of low-force targets. This reward bias was specific to action vigour, as reward did not alter action timing, direction or variability across trials. Although participants could report their reward bias, they somehow failed to limit their produced force. Such an automatic link between incentive and force level might correspond to a Pavlovian response that is counterproductive when action vigour is not instrumental for maximizing reward.

Summary Interoception, the perception of internal bodily states, is thought to be inextricably linked to affective qualities such as anxiety. Although interoception spans sensory to metacognitive processing, it is not clear whether anxiety is differentially related to these processing levels. Here we investigated this question in the domain of breathing, using computational modeling and high-field (7 T) fMRI to assess brain activity relating to dynamic changes in inspiratory resistance of varying predictability. Notably, the anterior insula was associated with both breathing-related prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low versus moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multi-modal analyses of data from fMRI, computational assessments of breathing-related metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels from perceptual sensitivity to metacognition, with strong effects seen at higher levels of interoceptive processes., Highlights • A novel trial-by-trial breathing-related interoception task during fMRI at 7 T • Anxiety relates to differences in breathing perception, metacognition, and learning • Anterior insula activity reflects respiratory predictions and prediction errors • Anterior insula activity during interoceptive predictions differs with anxiety, Measuring brain activity while manipulating breathing resistance, Harrison et al. demonstrate that activity in the anterior insula reflects breathing-related predictions and prediction errors. Furthermore, prediction-related brain activity is altered with anxiety, along with sensitivity of and insight into breathing perceptions. These findings elucidate the link between breathing perception and anxiety.

Autism is a neurodevelopmental condition defined on clinical criteria related to diminished social reciprocity and stereotyped behavior. An influential view explains autism as a social motivation disorder characterized by less attention paid to the social environment and less pleasure experienced with social rewards. However, experimental attempts to validate this theory, by testing the impact of social reward on behavioral choice and brain activity, has yielded mixed results, possibly due to variations in how explicit instructions were about task goals. Here, we specified the putative motivation deficit as an absence of spontaneous valuation in the social domain, unexplained by inattention and correctible by explicit instruction. Since such deficit cannot be assessed with behavioral measures, we used functional neuroimaging (fMRI) to readout covert subjective values, assigned to social and nonsocial stimuli (faces and objects), either explicitly asked to participants (during a likeability judgment task) or not (during age or size estimation tasks). Value-related neural activity observed for objects, or for faces under explicit instructions, was very similar in autistic and control participants, with an activation peak in the ventromedial prefrontal cortex (vmPFC), known as a key node of the brain valuation system. The only difference observed in autistic participants was an absence of the spontaneous valuation normally triggered by faces, even when they were attended for age estimation. Our findings, therefore, suggest that in autism, social stimuli might fail to trigger the automatic activation of the brain valuation system.

Highlights • Chlorpromazine, an FDA-approved drug, inhibits clathrin-mediated endocytosis • CPZ acts as an antiviral against SARS-CoV-1 and MERS-CoV • We evidenced antiviral activity of CPZ against SARS-CoV-2 in monkey and human cells • Because of CPZ high distribution in lungs, CPZ IC50 may translate in clinical routine • CPZ brain distribution could be of high interest for neurological forms of COVID-19, Introduction Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. The aim of this in vitro study was to test CPZ against a SARS-CoV-2 isolate in monkey and human cells. Material and methods Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in presence of different concentrations of CPZ. Supernatants were harvested at day 2 and analysed by RT-qPCR for the presence of SARS-CoV-2 RNA. Cell viability was assessed on non-infected cells. Results We evidenced an antiviral activity of CPZ against SARS-CoV-2 in monkey VeroE6 cells with an IC50 of 8.2 µM, a CC50 of 13.5µM and a SI of 1.65. In human A549-ACE2 cells, CPZ was also associated with an anti-SARS-CoV-2 activity, with an IC50 of 11.3 µM, a CC50 of 23.1 µM and a SI of 2.04. Discussion Even though the measured SI are low, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine because of CPZ high biodistribution in lungs and in saliva. Also, CPZ brain distribution could be of high interest for treating or preventing the neurological and psychiatric forms of COVID-19. Conclusions These preclinical findings support clinical investigation of the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.

In uncertain environments, accurate decision-making requires integrating ambiguous or conflicting signals – a cognitive inference process thought to require n-methyl-d-aspartate (NMDA) synaptic receptors. Here we characterized the causal impact of human NMDA receptor hypofunction on cognitive inference using placebo-controlled infusions of ketamine in a visual cue combination task. Participants tested under ketamine showed elevated uncertainty, together with impaired cognitive inference despite intact visual processing. This behavioral effect of ketamine was associated in patterns of electrical brain activity with degraded and unbalanced coding of presented cues in associative cortex, followed by premature response preparation in motor cortex. Through quantitative simulations, we propose that these cognitive alterations reflect an urge to explain away the elevated uncertainty triggered by ketamine. This compensatory mechanism may cause the emergence of psychotic symptoms observed under chronic NMDA receptor dysfunction, but also forge unusually strong beliefs when confronted with uncertainty in everyday life.

International audience; ObjectivesThe ongoing COVID-19 pandemic has caused approximately 2,350,000 infections worldwide and killed more than 160,000 individuals. In Sainte-Anne Hospital (GHU PARIS Psychiatrie & Neuroscience, Paris, France) we have observed a lower incidence of symptomatic forms of COVID-19 among patients than among our clinical staff. This observation led us to hypothesize that psychotropic drugs could have a prophylactic action against SARS-CoV-2 and protect patients from the symptomatic and virulent forms of this infection, since several of these psychotropic drugs have documented antiviral properties. Chlorpromazine (CPZ), a phenothiazine derivative, is also known for its antiviral activity via the inhibition of clathrin-mediated endocytosis. Recentin vitro studies have reported that CPZ exhibits anti-MERS-CoV and anti-SARS-CoV-1 activity.MethodsIn this context, the ReCoVery study aims to repurpose CPZ, a molecule with an excellent tolerance profile and a very high biodistribution in the saliva, lungs and brain. We hypothesize that CPZ could reduce the unfavorable course of COVID-19 infection among patients requiring respiratory support without the need for ICU care, and that it could also reduce the contagiousness of SARS-CoV-2. For this purpose, we plan a pilot, multicenter, randomized, single blind, controlled, phase III therapeutic trial (standard treatment vs. CPZ + standard treatment).ConclusionThis repurposing of CPZ for its anti-SARS-CoV-2 activity could offer an alternative, rapid strategy to alleviate infection severity. This repurposing strategy also avoids numerous developmental and experimental steps, and could save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easily managed side effects.; ObjectifsLa pandémie mondiale actuelle de COVID-19 a touché environ 2 350 000 personnes et fait plus de 160 000 morts. Nous avons observé dans le GHU PARIS Psychiatrie & Neurosciences (site Sainte-Anne, Paris, France) une incidence moins importante de formes symptomatiques de COVID-19 chez les patients que dans notre personnel soignant. Notre hypothèse est que les traitements psychotropes pourraient avoir une action prophylactique sur le SARS-CoV-2. Cette hypothèse est cohérente avec les propriétés antivirales connues de plusieurs psychotropes au premier rang desquels la chlorpromazine (CPZ). En plus de ses effets antipsychotiques classiques, plusieurs études in vitro ont également démontré une activité antivirale de cette phénothiazine via l’inhibition de l’endocytose dépendante des clathrines. Récemment, des études ont révélé un effet anti-MERS-CoV et anti-SARS-CoV-1 de la CPZ.MéthodesDans ce contexte, l’étude reCoVery, basée sur le repositionnement de la CPZ – molécule avec un excellent profil de tolérance et une biodistribution très élevée dans la salive, les poumons et le cerveau – vise à tester l’hypothèse que la CPZ pourrait diminuer l’évolution défavorable de l’infection COVID-19 chez des patients oxygénorequérants sans nécessité de soins en réanimation mais aussi réduire la contagiosité du SARS-CoV-2. Nous allons réaliser pour cela un essai thérapeutique pilote de phase III multicentrique, randomisé, contrôlé (traitement standard vs CPZ + traitement standard) et en simple insu.ConclusionLe repositionnement de la CPZ comme antiviral anti-SARS-CoV-2 offre une stratégie alternative et rapide pour atténuer la propagation du virus ainsi que la gravité et la létalité du COVID-19.

Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. In this study, we describe the in vitro testing of CPZ against a SARS-CoV-2 isolate in monkey and human cells. We evidenced an antiviral activity against SARS-CoV-2 with an IC50 of ∼10μM. Because of its high biodistribution in lung, saliva and brain, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine. This extrapolation is in line with our observations of a higher prevalence of symptomatic and severe forms of COVID-19 infections among health care professionals compared to patients in psychiatric wards. These preclinical findings support the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.

Clinical assessment of motivation disorders, such as apathy or compulsivity, is currently based on psychometric scales that do not provide any mechanistic insight susceptible to better target therapeutic intervention. Here, we expose a new approach that consists in phenotyping motivation states by fitting computational models to the behavioral responses made by patients in choice and/or learning tests. A computational phenotype is nothing but a set of fitted parameters that capture key motivational dimensions such as sensitivity to reward, punition, effort, delay and risk. These motivational dimensions have already been assessed in many neurological and psychiatric conditions, and related to clinical dimensions in a transnosographic manner. In some cases, computational phenotyping has also been applied to potential treatments, establishing correspondence with motivation disorders and hence opening a new avenue for personalized medicine. For instance, apathy related to reduced reward sensitivity might be better treated with dopaminergic than serotonergic medication.

Background and case presentation Electroconvulsive therapy (ECT) is a common therapeutic procedure in psychiatry associated with a low rate of complications. We report a rare case of subdural hematoma (SDH) associated with ECT. Clinical presentation: a 64 year old woman, with a medical history of persistent depression which required ECT six years previously, underwent ECT following a new acute episode. After four ECT sessions, a left hemiparesis occurred. Brain CT scan revealed a right SDH. The patient underwent surgery and fully recovered three months after the drainage of the hematoma. We conducted a review of all cases in which SDH was associated to ECT. Conclusion Early stage brain imaging is indispensable prior to starting ECT. Moreover, a previous medical history of SDH may not be a contraindication to ECT. In these situations, a clinical and radiological follow-up by both the psychiatrist and the neurosurgeon during all the ECT sessions is highly recommended.

The mere expectation of dyspnoea contributes to shape the lives of patients with chronic respiratory diseases: approaches addressing anticipatory mechanisms will provide new therapeutic avenues for persistent dyspnoea in the near future https://bit.ly/3mkv6US

The influence of mood on choices is a well-established but poorly understood phenomenon. Here, we suggest a three-fold neuro-computational account: (1) the integration of positive and negative events over time induce mood fluctuations, (2) which are underpinned by variations in the baseline activities of critical brain valuation regions, (3) which in turn modulate the relative weights assigned to key dimensions of choice options. We validate this model in healthy participants, using feedback in a quiz task to induce mood fluctuations, and a choice task (accepting vs. declining a motor challenge) to reveal their effects. Using fMRI, we demonstrate the pivotal role of the ventromedial prefrontal cortex and anterior insula, in which baseline activities respectively increase and decrease with theoretical mood level and respectively enhance the weighting of potential gains and losses during decision making. The same mechanisms might explain how decisions are biased in mood disorders at longer timescales., Nature Communications, 9, ISSN:2041-1723

Do respiratory diseases alter emotional interactions? Becoming dyspnoeic distorts our identification of others9 fearhttp://ow.ly/JkxF30hJGFH

Contrary to common psychosurgical practice in the 1950s, Dr. Jean Talairach had the intuition, based on clinical experience, that the brain connectome and neuroplasticity had a role to play in psychosurgery. Due to the remarkable progress of pharmacology at that time and to the technical limits of neurosurgery, these concepts were not put into practice. Currently, these concepts are being confirmed by modern techniques such as neuroimaging and computational neurosciences, and could pave the way for therapeutic innovation in psychiatry.Psychosurgery commonly uses a localizationist approach, based on the idea that a lesion to a specific area is responsible for a deficit opposite to its function. To psychosurgeons such as Walter Freeman, who performed extensive lesions causing apparently inevitable deficit, Talairach answered with clinical data: complex psychic functions cannot be described that simply, because the same lesion does not provoke the same deficit in different patients. Moreover, cognitive impairment did not always follow efficacious psychosurgery. Talairach suggested that selectively destructing part of a network could open the door to a new organization, and that early psychotherapy could encourage this psychoplasticity. Talairach did not have the opportunity to put these concepts into practice in psychiatric diseases because of the sudden availability of neuroleptics, but connectomics and neuroplasticity gave rise to major advances in intraparenchymal neurosurgery, from epilepsy to low-grade glioma. In psychiatry, alongside long-standing theories implicating focal lesions and diffuse pathological processes, neuroimaging techniques are currently being developed. In mentally healthy individuals, combining diffusion tensor imaging with functional MRI, magnetoencephalography, and electroencephalography allows the determination of a comprehensive map of neural connections in the brain on many spatial scales, the so-called connectome. Ultimately, global neurocomputational models could predict physiological activity, behavior, and subjective feeling, and describe neuropsychiatric disorders.Connectomic studies comparing psychiatric patients with controls have already confirmed the early intuitions of Talairach. As a striking example, massive dysconnectivity has been found in schizophrenia, leading some authors to propose a “dysconnection hypothesis.” Alterations of the connectome have also been demonstrated in obsessive-compulsive disorder and depression. Furthermore, normalization of the functional dysconnectivity has been observed following clinical improvement in several therapeutic interventions, from psychotherapy to pharmacological treatments. Provided that mental disorders result from abnormal structural or functional wiring, targeted psychosurgery would require that one be able: 1) to identify the pathological network involved in a given patient; 2) to use neurostimulation to safely create a reversible and durable alteration, mimicking a lesion, in a network compatible with neuroplasticity; and 3) to predict which functional lesion would result in adapted neuronal plasticity and/or to guide neuronal plasticity to promote recovery. All these conditions, already suggested by Talairach, could now be achievable considering modern biomarkers and surgical progress.

Motivation deficits, such as apathy, are pervasive in both neurological and psychiatric diseases. Even when they are not the core symptom, they reduce quality of life, compromise functional outcome and increase the burden for caregivers. They are currently assessed with clinical scales that do not give any mechanistic insight susceptible to guide therapeutic intervention. Here, we present another approach that consists of phenotyping the behaviour of patients in motivation tests, using computational models. These formal models impose a precise and operational definition of motivation that is embedded in decision theory. Motivation can be defined as the function that orients and activates the behaviour according to two attributes: a content (the goal) and a quantity (the goal value). Decision theory offers a way to quantify motivation, as the cost that patients would accept to endure in order to get the benefit of achieving their goal. We then review basic and clinical studies that have investigated the trade-off between the expected cost entailed by potential actions and the expected benefit associated with potential rewards. These studies have shown that the trade-off between effort and reward involves specific cortical, subcortical and neuromodulatory systems, such that it may be shifted in particular clinical conditions, and reinstated by appropriate treatments. Finally, we emphasize the promises of computational phenotyping for clinical purposes. Ideally, there would be a one-to-one mapping between specific neural components and distinct computational variables and processes of the decision model. Thus, fitting computational models to patients' behaviour would allow inferring of the dysfunctional mechanism in both cognitive terms (e.g. hyposensitivity to reward) and neural terms (e.g. lack of dopamine). This computational approach may therefore not only give insight into the motivation deficit but also help personalize treatment.

International audience; Mimetic desire (MD), the spontaneous propensity to pursue goals that others pursue, is a case of social influence that is believed to shape preferences. Autism spectrum disorder (ASD) is defined by both atypical interests and altered social interaction. We investigated whether MD is lower in adults with ASD compared to typically developed adults and whether MD correlates with social anhedonia and social judgment, two aspects of atypical social functioning in autism. Contrary to our hypotheses, MD was similarly present in both ASD and control groups. Anhedonia and social judgment differed between the ASD and control groups but did not correlate with MD. These results extend previous findings by suggesting that basic mechanisms of social influence are preserved in autism. The finding of intact MD in ASD stands against the intuitive idea that atypical interests stem from reduced social influence and indirectly favors the possibility that special interests might be selected for their intrinsic properties.

Background:Anhedonia is a core symptom of major depression and a key prognostic factor that is often poorly explored in clinical trials of major depressive disorder (MDD). Beyond symptomatic remission, psychosocial functioning also reveals difficulty in achieving remission in patients with MDD. The main objective of this study was to explore the interrelationships between social functioning and anhedonia on a longitudinal basis.Methods:In total, 1570 outpatients treated for MDD with agomelatine were included. Severity of depression and levels of anhedonia and of psychosocial functioning were assessed at inclusion and at 10–14 weeks, with specific standardized scales (MADRS, QFS, SHAPS, CGI). Multivariate regression and mediation analyses were performed.Results:Using multivariate regression, we showed that improvement of anhedonia was the strongest predictor of improvement in psychosocial functioning (odds ratio = 7.3 [4.3–12.1] P < 0.0001). In addition, mediation tests confirmed that the association between improvement of depressive symptoms and improvement of social functioning was significantly underpinned by the improvement of anhedonia over time. Finally, we explored the determinants of the dissociation of the response, i.e., the persistence of psychosocial dysfunctioning despite a symptomatic response to antidepressant treatment, which remains a widespread situation in clinical practice. We showed that this dissociation was strongly predicted by persistence of anhedonia.Conclusion:Our results suggest that anhedonia is one of the strongest predictors of psychosocial functioning, along with symptomatic remission, and should be carefully assessed by health professionals, in order to optimize pharmacological as well as non-pharmacological management of depression.

International audience; How does the human visual system accommodate expertise for two simultaneously acquired symbolic systems? We used fMRI to compare activations induced in the visual cortex by musical notation, written words and other classes of objects, in professional musicians and in musically naïve controls. First, irrespective of expertise, selective activations for music were posterior and lateral to activations for words in the left occipitotemporal cortex. This indicates that symbols characterized by different visual features engage distinct cortical areas. Second, musical expertise increased the volume of activations for music and led to an anterolateral displacement of word-related activations. In musicians, there was also a dramatic increase of the brain-scale networks connected to the music-selective visual areas. Those findings reveal that acquiring a double visual expertise involves an expansion of category-selective areas, the development of novel long-distance functional connectivity, and possibly some competition between categories for the colonization of cortical space.

Patients with schizophrenia suffer from perceptual visual deficits. It remains unclear whether those deficits result from an isolated impairment of a localized brain process or from a more diffuse long-range dysconnectivity within the visual system. We aimed to explore, with a reading paradigm, the functioning of both ventral and dorsal visual pathways and their interaction in schizophrenia. Patients with schizophrenia and control subjects were studied using event-related functional MRI (fMRI) while reading words that were progressively degraded through word rotation or letter spacing. Reading intact or minimally degraded single words involves mainly the ventral visual pathway. Conversely, reading in non-optimal conditions involves both the ventral and the dorsal pathway. The reading paradigm thus allowed us to study the functioning of both pathways and their interaction. Behaviourally, patients with schizophrenia were selectively impaired at reading highly degraded words. While fMRI activation level was not different between patients and controls, functional connectivity between the ventral and dorsal visual pathways increased with word degradation in control subjects, but not in patients. Moreover, there was a negative correlation between the patients' behavioural sensitivity to stimulus degradation and dorso-ventral connectivity. This study suggests that perceptual visual deficits in schizophrenia could be related to dysconnectivity between dorsal and ventral visual pathways.

BackgroundAnhedonia is a core dimension of major depressive disorder (MDD). Paradoxically, the association between anhedonia and social impairment is poorly known.ObjectiveTo determine the longitudinal relationships between depressive symptoms, anhedonia, and social functioning in depressed patients treated with agomelatine.Material and methodOne thousand five hundred and seventy patients with MDD starting treatment with agomelatine prescribed by their GPs were included in a prospective study (follow-up: 10 to 14 weeks). Patients were assessed at baseline and at the end point of the study, using the MADRS to assess antidepressant efficacy, the SHAPS scale and an original visual analog scale exploring the subjective pleasure felt by patients in their main leisure activity to measure anhedonia, and the QFS to measure social functioning in its qualitative and quantitative dimensions. In addition to the univariate analyses, a mediation path analysis was performed using the Sobel test.ResultsThe results showed a robust and significant improvement in symptoms of depression, anhedonia, and social functioning. The correlations between the SHAPS and QFS scores were high and significant. Subsequent analyses showed that amelioration of anhedonia is a significant mediating variable between the progression of depressive symptoms and social functioning (Δ QFS G = –14.3, P < 0.0001) and explains around one third of the variance of the model (35.37%).ConclusionAnhedonia, a major dimension of depression, provides specific insights into the understanding of the complex links between residual symptoms of MDD and social functioning. In conclusion, improving the evaluation of anhedonia is a fundamental issue in primary care.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Letter-position tolerance varies across languages. This observation suggests that the neural code for letter strings may also be subtly different. Although language-specific models remain useful, we should endeavor to develop a universal model of reading acquisition which incorporates crucial neurobiological constraints. Such a model, through a progressive internalization of phonological and lexical regularities, could perhaps converge onto the language-specific properties outlined by Frost.

International audience; Identifying letters and their relative positions is the basis of reading in literate adults. The Local Combinations Detector model hypothesizes that this ability results from the general organization of the visual system, whereby object encoding proceeds through a hierarchy of neural detectors that, in the case of reading, would be tuned to letters, bigrams, or other letter combinations. Given the increase of receptive fields by a factor of 2 to 3 from one neural level to the next, detectors should integrate information only for letters separated by at most 2 other characters. We test this prediction by measuring the impact of letter spacing on reading, purifying this effect from confounding variables. We establish that performance deteriorates non-linearly whenever letters are separated by at least 2 blank spaces, with the concomitant emergence of a word length effect. We then show that this cannot be reduced to an effect of physical size nor of visual eccentricity. Finally, we demonstrate that the threshold of about 2 spaces is constant across variations in font size. Those results support the hypothesis that the fast recognition of combinations of nearby letters plays a central role in the coding of words, such that interfering with this representation prevents the parallel analysis of letter strings.

International audience; Expert readers exhibit a remarkable ability to recognize handwriting, in spite of enormous variability in character shape-a competence whose cerebral underpinnings are unknown. Subliminal priming, combined with neuroimaging, can reveal which brain areas automatically compute an invariant representation of visual stimuli. Here, we used behavioral and fMRI priming to study the areas involved in invariant handwritten word recognition. Compared to printed words, easily readable handwritten words caused additional activity in ventral occipitotemporal cortex, particularly in the right hemisphere, while difficult handwriting also mobilized an attentional parietofrontal network. Remarkably, however, subliminal repetition effects were observed across printed and handwritten styles, whether easy or difficult to read, both behaviorally and in the activation of the left visual word form area (VWFA). These results indicate that the left inferotemporal VWFA possesses an unsuspected degree of fast and automatic visual invariance for handwritten words, although surprisingly this invariance can be reflected both as repetition suppression and as repetition enhancement.

Visual word recognition has been proposed to rely on a hierarchy of increasingly complex neuronal detectors, from individual letters to bigrams and morphemes. We used fMRI to test whether such a hierarchy is present in the left occipitotemporal cortex, at the site of the visual word-form area, and with an anterior-to-posterior progression. We exposed adult readers to (1) false-font strings; (2) strings of infrequent letters; (3) strings of frequent letters but rare bigrams; (4) strings with frequent bigrams but rare quadrigrams; (5) strings with frequent quadrigrams; (6) real words. A gradient of selectivity was observed through the entire span of the occipitotemporal cortex, with activation becoming more selective for higher-level stimuli toward the anterior fusiform region. A similar gradient was also seen in left inferior frontoinsular cortex. Those gradients were asymmetrical in favor of the left hemisphere. We conclude that the left occipitotemporal visual word-form area, far from being a homogeneous structure, presents a high degree of functional and spatial hierarchical organization which must result from a tuning process during reading acquisition. © 2007 Elsevier Inc. All rights reserved. Fil: Vinckier, Fabien. Inserm; Francia Fil: Dehaene, Stanislas. Inserm; Francia Fil: Jobert, Antoinette. Inserm; Francia Fil: Dubus, Jean Philippe. Hôpital Universitaire Pitié Salpêtrière; Francia Fil: Sigman, Mariano. Inserm; Francia. Universite Paris-sud Xi; . Cea/dsv; . Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Cohen, Laurent. Inserm; Francia. Hôpital Universitaire Pitié Salpêtrière; . Cea/dsv

Fast, parallel word recognition, in expert readers, relies on sectors of the left ventral occipito-temporal pathway collectively known as the visual word form area. This expertise is thought to arise from perceptual learning mechanisms that extract informative features from the input strings. The perceptual expertise hypothesis leads to two predictions: (1) parallel word recognition, based on the ventral visual system, should be limited to words displayed in a familiar format (foveal horizontal words with normally spaced letters); (2) words displayed in formats outside this field of expertise should be read serially, under supervision of dorsal parietal attention systems. We presented adult readers with words that were progressively degraded in three different ways (word rotation, letter spacing, and displacement to the visual periphery). Behaviorally, we identified degradation thresholds above which reading difficulty increased non-linearly, with the concomitant emergence of a word length effect on reading latencies reflecting serial reading strategies. fMRI activations were correlated with reading difficulty in bilateral occipito-temporal and parietal regions, reflecting the strategies required to identify degraded words. A core region of the intraparietal cortex was engaged in all modes of degradation. Furthermore, in the ventral pathway, word degradation led to an amplification of activation in the posterior visual word form area, at a level thought to encode single letters. We also found an effect of word length restricted to highly degraded words in bilateral occipitoparietal regions. Those results clarify when and how the ventral parallel visual word form system needs to be supplemented by the deployment of dorsal serial reading strategies.

Les troubles de la motivation constituent une dimension essentielle de nombreuses pathologies psychiatriques. Ils sont associés à un handicap considérable, interfèrent avec l’observance des traitements et restent peu accessible à ceux-ci. Pourtant, les déficits motivationnels restent évalués en clinique au travers de questionnaires qui ne permettent pas de déterminer quelles sont les perturbations sous-jacentes à ces troubles au niveau neurophysiologique. L’objet de cette présentation est de montrer quel peut être l’apport d’une approche computationnelle pour identifier des cibles thérapeutiques aux niveaux cognitif et cérébral. Nous présenterons dans un premier temps un projet de batterie motivationnelle regroupant un ensemble de tests d’effort, de prise de décision ou d’apprentissage. Nous verrons comment la modélisation computationnelle du comportement dans ces tests permet d’extraire un petit nombre de variables – les K, ou paramètres libres – constituant en quelque sorte un profil motivationnel du sujet, en termes de sensibilité à la récompense, à la punition, à l’effort ou au délai. Nous verrons également comment il est d’ores et déjà possible de relier certains de ces paramètres libres à des mécanismes biologiques précis, que ce soit à l’échelle de la neuromodulation ou de régions cérébrales, et comment certains de ces tests ont pu être utilisés pour caractériser différents troubles neuropsychiatriques. Enfin, nous présenterons les premiers résultats de la validation de cette batterie dans deux maladies psychiatriques, la dépression et la schizophrénie. Nous discuterons comment cette batterie pourrait à plus long terme être utilisée pour :– cartographier, en termes de mécanismes cognitifs et de dysfonctionnement cérébraux, le déficit motivationnel à l’œuvre dans ces pathologies ;– prédire l’évolution des déficits et l’effet des différents traitement possibles ;– personnaliser la prise en charge du patient.

The visual system of literate adults develops a remarkable perceptual expertise for printed words. To delineate the aspects of this competence intrinsic to the occipitotemporal “what” pathway, we studied a patient with bilateral lesions of the occipitoparietal “where” pathway. Depending on critical geometric features of the display (rotation angle, letter spacing, mirror reversal, etc.), she switched from a good performance, when her intact ventral pathway was sufficient to encode words, to severely impaired reading, when her parietal lesions prevented the use of alternative reading strategies as a result of spatial and attentional impairments. In particular, reading was disrupted (a) by rotating word by more than 50°, providing an approximation of the invariance range for words encoding in the ventral pathway; (b) by separating letters with double spaces, revealing the limits of letter grouping into perceptual wholes; (c) by mirror-reversing words, showing that words escape the default mirror-invariant representation of visual objects in the ventral pathway. Moreover, because of her parietal lesions, she was unable to discriminate mirror images of common objects, although she was excellent with reversible pseudowords, confirming that the breaking of mirror symmetry was intrinsic to the occipitotemporal cortex. Thus, charting the display conditions associated with preserved or impaired performance allowed us to infer properties of word coding in the normal ventral pathway and to delineate the roles of the parietal lobes in single-word recognition.