Effort avoidance as a core mechanism of apathy in frontotemporal dementia.

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.

Sour grapes and sweet victories: How actions shape preferences.

Classical decision theory postulates that choices proceed from subjective values assigned to the probable outcomes of alternative actions. Some authors have argued that opposite causality should also be envisaged, with choices influencing subsequent values expressed in desirability ratings. The idea is that agents may increase their ratings of items that they have chosen in the first place, which has been typically explained by the need to reduce cognitive dissonance. However, evidence in favor of this reverse causality has been the topic of intense debates that have not reached consensus so far. Here, we take a novel approach using Bayesian techniques to compare models in which choices arise from stable (but noisy) underlying values (one-way causality) versus models in which values are in turn influenced by choices (two-way causality). Moreover, we examined whether in addition to choices, other components of previous actions, such as the effort invested and the eventual action outcome (success or failure), could also impact subsequent values. Finally, we assessed whether the putative changes in values were only expressed in explicit ratings, or whether they would also affect other value-related behaviors such as subsequent choices. Behavioral data were obtained from healthy participants in a rating-choice-rating-choice-rating paradigm, where the choice task involves deciding whether or not to exert a given physical effort to obtain a particular food item. Bayesian selection favored two-way causality models, where changes in value due to previous actions affected subsequent ratings, choices and action outcomes. Altogether, these findings may help explain how values and actions drift when several decisions are made successively, hence highlighting some shortcomings of classical decision theory.

The next psychoactive drugs: From imipramine to ketamine.

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.

Depuis les années 1950, l'arsenal thérapeutique permettant de lutter contre la dépression s'est considérablement enrichi. De la découverte des inhibiteurs de la mono-amine oxydase (IMAO) à celle de la kétamine, ces percées pharmacologiques ont marqué l'histoire de la psychiatrie et guidé la recherche sur la physiopathologie de la dépression, cette pathologie dévastatrice affectant entre 10 et 20 % de la population mondiale. Nous proposons dans cet article une courte revue historique des différentes options thérapeutiques développées au cours du siècle passé et des conséquences qu'ont eues ces innovations. Nous réalisons ensuite un état des lieux de la plus récente de ces découvertes, celle des effets antidépresseurs de la kétamine (et de son énantiomère S, l'eskétamine), spectaculaires de par leur délai d'action et leur efficacité même dans les formes les plus résistantes de dépression. De même que la découverte des IMAO et des tricycliques a permis de concevoir une théorie monoaminergique de la dépression, l'étude des mécanismes d'actions de la kétamine pourrait permettre de comprendre le rôle 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 représentations des cliniciens sur cette maladie.

Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine.

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases.

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.

Neuroplasticity and the brain connectome: what can Jean Talairach's reflections bring to modern psychosurgery?

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.

Origins and consequences of mood flexibility: a computational perspective.

A stable and neutral mood (euthymia) is commended by both economic and clinical perspectives, because it enables rational decisions and avoids mental illnesses. Here we suggest, on the contrary, that a flexible mood responsive to life events may be more adaptive for natural selection, because it can help adjust the behavior to fluctuations in the environment. In our model (dubbed MAGNETO), mood represents a global expected value that biases decisions to forage for a particular reward. When flexible, mood is updated every time an action is taken, by aggregating incurred costs and obtained rewards. Model simulations show that, across a large range of parameters, flexible agents outperform cold agents (with stable neutral mood), particularly when rewards and costs are correlated in time, as naturally occurring across seasons. However, with more extreme parameters, simulations generate short manic episodes marked by incessant foraging and lasting depressive episodes marked by persistent inaction. The MAGNETO model therefore accounts for both the function of mood fluctuations and the emergence of mood disorders.

Mood fluctuations shift cost-benefit tradeoffs in economic decisions.

Mood effects on economic choice seem blatantly irrational, but might rise from mechanisms adapted to natural environments. We have proposed a theory in which mood helps adapting the behaviour to statistical dependencies in the environment, by biasing the expected value of foraging actions (which involve taking risk, spending time and making effort to get more reward). Here, we tested the existence of this mechanism, using an established mood induction paradigm combined with independent economic choices that opposed small but uncostly rewards to larger but costly rewards (involving either risk, delay or effort). To maximise the sensitivity to mood fluctuations, we developed an algorithm ensuring that choice options were continuously adjusted to subjective indifference points. In 102 participants tested twice, we found that during episodes of positive mood (relative to negative mood), choices were biased towards better rewarded but costly options, irrespective of the cost type. Computational modelling confirmed that the incidental mood effect was best explained by a bias added to the expected value of costly options, prior to decision making. This bias is therefore automatically applied even in artificial environments where it is not adaptive, allowing mood to spill over many sorts of decisions and generate irrational behaviours.

Reward and punishment learning deficits among bipolar disorder subtypes.

BACKGROUND: Reward sensitivity is an essential dimension related to mood fluctuations in bipolar disorder (BD), but there is currently a debate around hypersensitivity or hyposensitivity hypotheses to reward in BD during remission, probably related to a heterogeneous population within the BD spectrum and a lack of reward bias evaluation. Here, we examine reward maximization vs. punishment avoidance learning within the BD spectrum during remission. METHODS: Patients with BD-I (n = 45), BD-II (n = 34) and matched (n = 30) healthy controls (HC) were included. 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 performances. RESULTS: Behavioral results showed a significant reward learning deficit across BD subtypes compared to HC, captured at the computational level by a lower sensitivity to rewards compared to punishments in both BD subtypes. Computational modeling also revealed a higher choice randomness in BD-II compared to BD-I that reflected a tendency of BD-I to perform better during punishment avoidance learning than BD-II. LIMITATIONS: Our patients were not naive to antipsychotic treatment and were not euthymic (but in syndromic remission) according to the International Society for Bipolar Disorder definition. CONCLUSIONS: Our results are consistent with the reward hyposensitivity theory in BD. Computational modeling suggests distinct underlying mechanisms that produce similar observable behaviors, making it a useful tool for distinguishing how symptoms interact in BD versus other disorders. In the long run, a better understanding of these processes could contribute to better prevention and management of BD.

Vagus nerve stimulation allows to cease maintenance electroconvulsive therapy in treatment-resistant depression: a retrospective monocentric case series.

Context: The use of vagus nerve stimulation (VNS) to reduce or stop electroconvulsive therapy (ECT) in treatment-resistant depression seems promising. The aim of this study was to investigate the efficacy of VNS on the reduction of ECT sessions and mood stabilization. Methods: We conducted a monocentric retrospective case series of patients who suffered from treatment-resistant depression, treated with ECT and referred to our center for VNS. We investigated the number and the frequency of ECT sessions before and after VNS implantation. Secondary criteria consisted in the Montgomery Åsberg Depression Rating Scale (MADRS) score, number of medical treatments, dosage of the main treatment and length of hospital stays before and after VNS. Additionally, we sent an anonymous survey to psychiatrists and other physicians in our institution to investigate their knowledge and perception of VNS therapy to treat treatment-resistant depression. Results: Seven patients benefited from VNS: six (86%) were female (mean age of 51.7 +/- 16.0 years at surgery), and five (71%) suffered from bipolar depression (three type I and two type II). All patients were followed up at least 2 years post-implantation (range: 27-68 months). Prior to VNS, six patients were treated by maintenance ECT. After VNS, three (43%) patients did not require maintenance ECT anymore, and three (43%) patients required less frequent ECT session with a mean 14.7 +/- 9.8 weeks between sessions after VNS vs. 2.9 +/- 0.8 weeks before VNS. At last follow-up, 4 (57%) patients had stopped ECT. Five (71%) patients implanted with VNS were good responders (50% decrease relative to baseline MADRS). According to the survey, psychiatrists had a significantly better perception and knowledge of ECT, but a worse perception and knowledge of VNS compared to other physicians. Conclusion: VNS is a good option for treatment-resistant depression requiring maintenance ECT dependence. Larger on-going studies will help broaden the implanted patients while strengthening psychiatrists' knowledge on this therapy.

Medical Students' Learning Process During Simulated Patient Consultations in Psychiatry: A Grounded Theory Study.

INTRODUCTION: Recent changes in psychiatric care and teaching, which limit patient contact for medical students, can be partially overcome by simulation-based education in psychiatry. The authors explored the learning processes of medical students during meetings with simulated patients to inform efforts to improve this teaching. METHODS: After recruiting 81 undergraduate medical students from 3 universities to participate in 6 simulation sessions in psychiatry, the authors purposively sampled 21 students to participate in face-to-face individual semistructured interviews analyzed with constructivist grounded theory. Integration of this analysis with those of the simulation consultation videotapes and the debriefing audiotapes improved the triangulation process. RESULTS: Three organizational themes were identified: developing and structuring representations of psychiatry; integrating subjectivity into learning; and refining and developing psychiatric praxis. Given the broad and in-depth learning that occurs, simulation in psychiatry should respect content validity of SP portrayals to ensure appropriate learning. However, psychological fidelity seems to provide adequate realism while retaining feasibility. Psychiatric simulation also requires the encouragement of student self-confidence and well-being. Within a reflective framework, simulation triggers cognitive reframing, which can alleviate fears and prejudice toward people with mental disorders. CONCLUSIONS: The holistic interactive learning process involved in simulation can address the complexity of the personal and interpersonal features needed in psychiatry.

Early effects predict trajectories of response to esketamine in treatment-resistant depression.

BACKGROUND: The efficacy of esketamine in treatment-resistant depression (TRD) has been confirmed. However, its administration is expensive and restrictive, with limited knowledge on how long the treatment should be continued. Predicting the treatment outcome would benefit patients and alleviate the global treatment cost. We aimed to define distinct trajectories of treatment response and assess their predictability. METHODS: In this longitudinal study, two independent samples of patients with unipolar or bipolar TRD were treated with esketamine in real-world settings. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before each esketamine administration. Latent class analyses were used to define trajectories of response. RESULTS: In the original sample (N = 50), we identified two classes whose trajectories depicted response and non-response, respectively. The model was validated in the confirmatory sample (N = 55). Class membership was influenced by a few baseline characteristics such as concomitant benzodiazepine medication, number of depressive episodes or polarity. On the other hand, after only two esketamine administrations, the MADRS score predicted the 90-day trajectory of response with an accuracy of 80 %. LIMITATIONS: This observational study is not placebo-controlled. Therefore, its results and their generalizability need to be confirmed in experimental settings. CONCLUSIONS: After the first administrations of esketamine, the MADRS score has a good capacity to predict the most plausible trajectory of response. While thresholds and their predictive values need to be confirmed, this finding suggests that clinicians could base on MADRS scores their decision to discontinue treatment because of poor remaining chances of treatment response.

Towards a universal neurobiological architecture for learning to read.

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.

Premature commitment to uncertain decisions during human NMDA receptor hypofunction.

Making accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction.

Preserved Unconscious Processing in Schizophrenia: The Case of Motivation.

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.

Efficacy of Transcranial Direct-Current Stimulation in Catatonia: A Review and Case Series.

Catatonia is a severe neuropsychiatric syndrome, usually treated by benzodiazepines and electroconvulsive therapy. However, therapeutic alternatives are limited, which is particularly critical in situations of treatment resistance or when electroconvulsive therapy is not available. Transcranial direct-current stimulation (tDCS) is a promising non-invasive neuromodulatory technique that has shown efficacy in other psychiatric conditions. We present the largest case series of tDCS use in catatonia, consisting of eight patients in whom tDCS targeting the left dorsolateral prefrontal cortex and temporoparietal junction was employed. We used a General Linear Mixed Model to isolate the effect of tDCS from other confounding factors such as time (spontaneous evolution) or co-prescriptions. The results indicate that tDCS, in addition to symptomatic pharmacotherapies such as lorazepam, seems to effectively reduce catatonic symptoms. These results corroborate a synthesis of five previous case reports of catatonia treated by tDCS in the literature. However, the specific efficacy of tDCS in catatonia remains to be demonstrated in a randomized controlled trial. The development of therapeutic alternatives in catatonia is of paramount importance.