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.

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.

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.

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.

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.

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.

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.

Elevated Effort Cost Identified by Computational Modeling as a Distinctive Feature Explaining Multiple Behaviors in Patients With Depression.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Intracerebral mechanisms explaining the impact of incidental feedback on mood state and risky choice.

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.

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.

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.

Interoception of breathing and its relationship with anxiety.

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.

Absence of covert face valuation in Autism.

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.

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine.

INTRODUCTION: Urgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells. MATERIALS AND METHODS: Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells. RESULTS: CPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 µM, half maximal cytotoxic concentration (CC50) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 µM, CC50 of 23.1 µM and SI of 2.04. DISCUSSION: Although the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19. CONCLUSIONS: These preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.

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.