Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication

© 2023 The Author(s). Published by Elsevier Inc on behalf of the Society of Biological Psychiatry. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background The nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD. Methods We recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win-stay and lose-shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness. Results Unmedicated patients with OCD were impaired on the deterministic reversal task under punishment only at the first and third reversals compared with both control participants and medicated patients with OCD, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups. Conclusions Both perseveration and increased shifting can be observed in OCD, depending on test conditions including the predictability of reinforcement. Perseveration was related to clinical severity and remediated by serotonergic medication.Peer reviewe

Serotonin depletion amplifies distinct human social emotions as a function of individual differences in personality

Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370Abstract: Serotonin is involved in a wide range of mental capacities essential for navigating the social world, including emotion and impulse control. Much recent work on serotonin and social functioning has focused on decision-making. Here we investigated the influence of serotonin on human emotional reactions to social conflict. We used a novel computerised task that required mentally simulating social situations involving unjust harm and found that depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—enhanced emotional responses to the scenarios in a large sample of healthy volunteers (n = 73), and interacted with individual differences in trait personality to produce distinctive human emotions. Whereas guilt was preferentially elevated in highly empathic participants, annoyance was potentiated in those high in trait psychopathy, with medium to large effect sizes. Our findings show how individual differences in personality, when combined with fluctuations of serotonin, may produce diverse emotional phenotypes. This has implications for understanding vulnerability to psychopathology, determining who may be more sensitive to serotonin-modulating treatments, and casts new light on the functions of serotonin in emotional processing

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans.

Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.NIH

Association between childhood trauma and risk for obesity: a putative neurocognitive developmental pathway

Funder: Zhangjiang LabFunder: the Shanghai AI Platform for Diagnosis and Treatment of Brain DiseasesFunder: the Project of Zhangjiang Hi-Tech District Management CommitteeFunder: Shanghai (grant 2016-17)Funder: BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics); Grant(s): MR/N027558/1Funder: Associazione Emma e Ernesto Rulfo per la Genetica Medica (IT)Funder: the Swedish Research Council FORMASFunder: the Medical Research CouncilFunder: the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College LondonFunder: the Human Brain Project (HBP SGA 2)Funder: the Fondation de France, the Fondation pour la Recherche MédicaleFunder: the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant)Funder: Paris Sud University IDEX 2012Funder: cross-NIH alliance that funds Big Data to Knowledge Centres of ExcellenceAbstract: Background: Childhood trauma increases the risk for adult obesity through multiple complex pathways, and the neural substrates are yet to be determined. Methods: Participants from three population-based neuroimaging cohorts, including the IMAGEN cohort, the UK Biobank (UKB), and the Human Connectome Project (HCP), were recruited. Voxel-based morphometry analysis of both childhood trauma and body mass index (BMI) was performed in the longitudinal IMAGEN cohort; validation of the findings was performed in the UKB. White-matter connectivity analysis was conducted to study the structural connectivity between the identified brain region and subdivisions of the hypothalamus in the HCP. Results: In IMAGEN, a smaller frontopolar cortex (FPC) was associated with both childhood abuse (CA) (β = − .568, 95%CI − .942 to − .194; p = .003) and higher BMI (β = − .086, 95%CI − .128 to − .043; p < .001) in male participants, and these findings were validated in UKB. Across seven data collection sites, a stronger negative CA-FPC association was correlated with a higher positive CA-BMI association (β = − 1.033, 95%CI − 1.762 to − .305; p = .015). Using 7-T diffusion tensor imaging data (n = 156), we found that FPC was the third most connected cortical area with the hypothalamus, especially the lateral hypothalamus. A smaller FPC at age 14 contributed to higher BMI at age 19 in those male participants with a history of CA, and the CA-FPC interaction enabled a model at age 14 to account for some future weight gain during a 5-year follow-up (variance explained 5.8%). Conclusions: The findings highlight that a malfunctioning, top-down cognitive or behavioral control system, independent of genetic predisposition, putatively contributes to excessive weight gain in a particularly vulnerable population, and may inform treatment approaches

Borehole dilution tests to measure leachate flow at a recirculation landfill

The recirculation and infiltration of leachate in landfills may be carried out to facilitate the flushing of contaminants and accelerate the stabilisation of waste. Flushing contaminants through recirculation relies on the movement of fluids through the landfill body to basal drains, which will predominantly be driven by gravity. Leachate recirculation and infiltration measures commenced at de Kragge II landfill (Bergen op Zoom, The Netherlands) in March 2018. Up to 90 m3/day of treated leachate is recirculated into the top of a 20 m deep, 5 ha landfill cell through 14 horizontal drains installed at the surface. Poor connectivity between the waste and the basal drainage system has resulted in saturated conditions forming in the lower 7-8 m of the landfill. Knowledge about the leachate flow within the waste body is essential for evaluating the success of the stabilisation measures. To investigate the flow regime within the saturated waste, 22 Single Borehole Dilution tests were carried out in 13 piezometers atdifferent depths, between 8.4 and 18.1 m below ground level, and locations across the landfill cell. Tests were repeated in a number of the piezometers to demonstrate repeatability. Flow was measured in all piezometers. Calculated Darcy flow velocities ranged between 0.01 and 1.02 m/day, with the highestvelocities measured in the deepest piezometers. Four tests were carried out in one nest of piezometers installed at different depths, with the leachate recirculation system switched off for two days prior to and during the test. Although flows were somewhat higher in two of the piezometers, it was not possible to conclude whether the infiltration of leachate significantly influences flow

Persistence of Amygdala–Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear

After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory