Premature commitment to uncertain decisions during human NMDA receptor hypofunction

Salvador, Alexandre; Arnal, Luc H.; Vinckier, Fabien; Domenech, Philippe; Gaillard, Raphaël; Wyart, Valentin

doi:10.1038/s41467-021-27876-3

Cited by 11 publications

(8 citation statements)

References 67 publications

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“…However, this question goes beyond the scope of our study. Ketamine in healthy controls is used as a pharmacological model of early psychosis to perturb brain mechanisms that reduce uncertainty and how EEs are used to update beliefs . More studies are needed to disentangle the specific effects of ketamine on belief updating and belief-updating biases in different participant cohorts.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression

et al. 2022

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ImportanceClinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses.ObjectiveTo evaluate whether ketamine alters belief updating and how such cognitive effects are associated with the clinical effects of ketamine.Design, Setting, and ParticipantsThis study used an observational case-control protocol with a mixed-effects design that nested 2 groups by 2 testing time points. Observers were not blinded. Patients with treatment-resistant depression (TRD) and healthy volunteer participants aged 34 to 68 years were included. Patients with TRD were diagnosed with major depressive disorder or bipolar depression, had a Montgomery-Åsberg Depression Rating Scale score greater than 20, a Maudsley Staging Method score greater than 7, and failed to respond to at least 2 prior antidepressant trials. Exclusion criteria were any other psychiatric, neurological, or neurosurgical comorbidities, substance use or addictive disorders, and recreational ketamine consumption. Data were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021.ExposuresPatients with TRD were observed 24 hours before single ketamine infusion, 4 hours after the infusion, and 4 hours after the third infusion, which was 1 week after the first infusion. Healthy control participants were observed twice 1 week apart without ketamine exposure.Main Outcomes and MeasuresMontgomery-Åsberg Depression Rating Scale score and belief updating after belief updating when patients received good news and bad news measured by a cognitive belief-updating task and mathematically formalized by a computational reinforcement learning model.ResultsOf 56 included participants, 29 (52%) were male, and the mean (SEM) age was 52.3 (1.2) years. A total of 26 patients with TRD and 30 control participants were included. A significant group × testing time point × news valence interaction showed that patients with TRD updated their beliefs more after good than bad news following a single ketamine infusion (controlled for age and education: β = −0.91; 95% CI, −1.58 to −0.24; t216 = −2.67; P = .008) than controls. Computational modeling showed that this effect was associated with asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after ketamine 0.36 [SEM, 0.03], t25 = 3.8; P &lt; .001) and partially mediated early antidepressant responses (path a*b: β = −1.00 [SEM, 0.66]; t26 = −1.53; z = −1.98; P = .04).Conclusions and RelevanceThese findings provide novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression

et al. 2022

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“…3 ), and this could be tested experimentally by using pharmacological or optogenetic manipulations. A recent study has compared stimulus integration in human participants in sessions where they have been administered the N -methyl- d -aspartate receptor antagonist ketamine or a placebo ( 59 ). Reduced excitability under ketamine led to more recency PKs (more leaky integration), consistent with a reduction in excitatory drive in our model.…”

Section: Discussionmentioning

confidence: 99%

Flexible integration of continuous sensory evidence in perceptual estimation tasks

Esnaola-Acebes

Roxin

Wimmer

2022

Proc. Natl. Acad. Sci. U.S.A.

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Temporal accumulation of evidence is crucial for making accurate judgments based on noisy or ambiguous sensory input. The integration process leading to categorical decisions is thought to rely on competition between neural populations, each encoding a discrete categorical choice. How recurrent neural circuits integrate evidence for continuous perceptual judgments is unknown. Here, we show that a continuous bump attractor network can integrate a circular feature, such as stimulus direction, nearly optimally. As required by optimal integration, the population activity of the network unfolds on a two-dimensional manifold, in which the position of the network’s activity bump tracks the stimulus average, and, simultaneously, the bump amplitude tracks stimulus uncertainty. Moreover, the temporal weighting of sensory evidence by the network depends on the relative strength of the stimulus compared to the internally generated bump dynamics, yielding either early (primacy), uniform, or late (recency) weighting. The model can flexibly switch between these regimes by changing a single control parameter, the global excitatory drive. We show that this mechanism can quantitatively explain individual temporal weighting profiles of human observers, and we validate the model prediction that temporal weighting impacts reaction times. Our findings point to continuous attractor dynamics as a plausible neural mechanism underlying stimulus integration in perceptual estimation tasks.

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“…Prior theoretical work explains the relationship between dopamine (dys)regulation, psychosis, and probabilistic reasoning (Fletcher & Frith, 2009;Howes & Kapur, 2009), and empirical evidence has supported the common role of dopamine (dys)regulation in influencing uncertainty about the world (Adams et al, 2020;Reed et al, 2020), adjusting harmful intent and externalising attributions (Barnby et al, 2020b;Newman-Taylor et al, 2020), and increasing psychotic experiences (Nour et al, 2018;Voce et al, 2019). Likewise, glutamate dysregulation -also suggested in the development of delusions upstream from dopamine dysregulation (Corlett et al, 2007;2016;Howes & Kapur, 2009) -increases decision noise in preclinical trails in rhesus monkeys (Cavanagh et al, 2020) and the premature commitment to suboptimal choices in experimental human trials (Salvador et al, 2022) using NMDA blockade. While we do not use psychopharmacological manipulations in this paper, evidence to date is consistent with dopaminergic signalling being causally implicated in the basic computational processes underlying decision making (e.g., decision temperature) and should also be tested to assess whether changes to dopamine signalling also underlies uncertainty about a social partner, and whether this added uncertainty mediates increases in harmful intent attributions.…”

Section: Discussionmentioning

confidence: 99%

The computational relationship between reinforcement learning, social inference, and paranoia

Barnby¹,

Mehta²,

Moutoussis³

2022

Preprint

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Theoretical accounts suggest heightened uncertainty about the state of the world underpin aberrant belief updates, which in turn increase the risk of developing a persecutory delusion. However, this raises the question as to how an agent’s uncertainty may relate to the precise phenomenology of paranoia, as opposed to other qualitatively different forms of belief. We tested whether the same population (n=750) responded similarly to non-social and social contingency changes in a probabilistic reversal learning task and a modified serial Dictator game, and the influence of paranoia on both. We fitted computational models that included closely related parameters that quantified the rigidity across contingency reversals, and the uncertainty of individuals about the environment/their partner. Consistent with prior work we show that, after reversals, pre-existing paranoia was independently associated with uncertainty around a partner’s behavioural policy and rigidity in harmful intent attributions in the social task, and in the probabilistic task, larger decision temperatures and commitment to suboptimal cards. We show relationships between decision temperature in the non-social task and priors over harmful intent attributions and uncertainty over beliefs about partners in the social task. Our results converge across both classes of model, suggesting paranoia is associated with a general uncertainty over the state of the world (and agents within it) that takes longer to resolve, although we demonstrate that this uncertainty is expressed asymmetrically in social contexts. Our model and data allow clarification of cognitive mechanisms that explain persecutory delusions and provide testable, phenomenologically relevant predictions for causal experiments.

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Premature commitment to uncertain decisions during human NMDA receptor hypofunction

Cited by 11 publications

References 67 publications

Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression

Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression

Flexible integration of continuous sensory evidence in perceptual estimation tasks

The computational relationship between reinforcement learning, social inference, and paranoia

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