Between persistence and flexibility: the neuromodulation of cognitive control

In the realm of cognitive science, the quest to understand cognitive control has persisted for decades. Traditional notions of cognitive control have focused on inhibition through the prefrontal cortex, but this dissertation challenges that perspective with a more comprehensive framework: The Metacontrol State Model (MSM). The MSM proposes that cognitive control emerges from the interplay between two opposing systems – one promoting flexibility and the other promoting persistence. These systems interact to shape our cognitive processing styles, thereby influencing our ability to effectively regulate our actions. This dissertation explores questions such as why individuals exhibit differences in cognitive control capacity and how state-related changes and trait-related predispositions impact cognitive control function. The overarching goal of this dissertation is to empirically test the MSM model and shed light on the factors that influence cognitive control. Through a series of experiments, it seeks to understand how altered states of consciousness, achieved through meditation techniques or serotonergic psychedelics, affect the balance between intentional and habitual processes. Additionally, it examines the extent to which individual trait biases serve as trans-diagnostic markers in various psychopathologies. This work comprises a literature review and six empirical articles. By integrating theory and empirical research, this dissertation takes us on a journey into the intricate world of cognitive control, shaping our understanding of how it influences our lives. European Research Council (ERC)Action Contro

Reply to Mathot and Naber: Neuroimaging shows that pupil mimicry is a social phenomenon

Social decision makingAction Contro

Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting

IntroductionTaking microdoses (a mere fraction of normal doses) of psychedelic substances, such as truffles, recently gained popularity, as it allegedly has multiple beneficial effects including creativity and problem-solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics, it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults.MethodsDuring a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were expected to be manifested.ResultsWe found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected.ConclusionWhile this study provides quantitative support for the cognitive-enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results, we speculate that psychedelics might affect cognitive metacontrol policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.Action Contro

Effects of psilocybin microdosing on awe and aesthetic experiences: a preregisterd field and labbased study

Action Contro

Psilocybin microdosing does not affect emotion-related symptoms and processing:: a preregistered field and labbased study

Action Contro

Inositol Hexakisphosphate-Induced Autoprocessing of Large Bacterial Protein Toxins

Large bacterial protein toxins autotranslocate functional effector domains to the eukaryotic cell cytosol, resulting in alterations to cellular functions that ultimately benefit the infecting pathogen. Among these toxins, the clostridial glucosylating toxins (CGTs) produced by Gram-positive bacteria and the multifunctional-autoprocessing RTX (MARTX) toxins of Gram-negative bacteria have distinct mechanisms for effector translocation, but a shared mechanism of post-translocation autoprocessing that releases these functional domains from the large holotoxins. These toxins carry an embedded cysteine protease domain (CPD) that is activated for autoprocessing by binding inositol hexakisphosphate (InsP6), a molecule found exclusively in eukaryotic cells. Thus, InsP6-induced autoprocessing represents a unique mechanism for toxin effector delivery specifically within the target cell. This review summarizes recent studies of the structural and molecular events for activation of autoprocessing for both CGT and MARTX toxins, demonstrating both similar and potentially distinct aspects of autoprocessing among the toxins that utilize this method of activation and effector delivery

Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling

Characterization of Rhodamine-123 as a Tracer Dye for Use In In vitro Drug Transport Assays

Fluorescent tracer dyes represent an important class of sub-cellular probes and allow the examination of cellular processes in real-time with minimal impact upon these processes. Such tracer dyes are becoming increasingly used for the examination of membrane transport processes, as they are easy-to-use, cost effective probe substrates for a number of membrane protein transporters. Rhodamine 123, a member of the rhodamine family of flurone dyes, has been used to examine membrane transport by the ABCB1 gene product, MDR1. MDR1 is viewed as the archetypal drug transport protein, and is able to efflux a large number of clinically relevant drugs. In addition, ectopic activity of MDR1 has been associated with the development of multiple drug resistance phenotype, which results in a poor patient response to therapeutic intervention. It is thus important to be able to examine the potential for novel compounds to be MDR1 substrates. Given the increasing use rhodamine 123 as a tracer dye for MDR1, a full characterisation of its spectral properties in a range of in vitro assay-relevant media is warranted. Herein, we determine λmax for excitation and emission or rhodamine 123 and its metabolite rhodamine 110 in commonly used solvents and extraction buffers, demonstrating that fluorescence is highly dependent on the chemical environment: Optimal parameters are 1% (v/v) methanol in HBSS, with λex = 505 nm, λem = 525 nm. We characterise the uptake of rhodamine 123 into cells, via both passive and active processes, and demonstrate that this occurs primarily through OATP1A2-mediated facilitated transport at concentrations below 2 µM, and via micelle-mediated passive diffusion above this. Finally, we quantify the intracellular sequestration and metabolism of rhodamine 123, demonstrating that these are both cell line-dependent factors that may influence the interpretation of transport assays