Biology subjects

de Wit, H.

Publications and source records attributed to de Wit, H..

11 recordsLinked to original sources

bioRxiv2025

Multiple sclerosis-associated HLA demarcates EBV-specific CD8+ T cells with an exhausted and brain residency phenotype

Specific HLA class I subtypes as well as circulating antibodies against Epstein-Barr virus (EBV) have been associated with increased susceptibility to develop multiple sclerosis (MS). It is currently unclear whether and how these risk factors are functionally related. Here, we assessed the impact of MS risk allele HLA-B7 and protective allele HLA-A2 on the effector phenotype of EBV-specific CD8+ T cells and if this corresponds with anti-EBV IgG titers. For this, we selected HLA-A2+ and/or HLA-B7+ donors with and without MS and analyzed HLA-restricted, EBV- specific CD8+ T cells with different fine-specificities using 38 color-based spectral flow cytometry. In contrast to HLA-A2-restricted CD8+ T cells, HLA-B7-restricted CD8+ T cells showed a confined response to EBV, which was mainly directed against latent peptide EBNA3A(379-387). These HLA-B7-restricted EBV-specific CD8+ T cells expressed higher levels of CNS residency markers CXCR3 and CD20 and were most abundant in fresh single-cell suspensions derived from different post-mortem CNS compartments of an HLA-A2+B7+ MS donor. Moreover, HLA-B7- restricted EBV-specific CD8+ T cells displayed a more exhausted phenotype (PD- 1+CD244+CD160+KLRG1+TIGIT+) that stood out in the blood from people with MS (pwMS). Accordingly, in the blood, increased IgG titers against EBV were found for pwMS carrying HLA- B7 but lacking HLA-A2, which seemed to coincide with HLA-B7-restricted EBV-specific CD8+ T cells having such an effector phenotype. These data support a model in which the confined response against EBV makes circulating HLA-B7-restricted CD8+ T cells less able to control EBV and more prone to infiltrate the CNS in pwMS.

immunology↗

bioRxiv2025

Methamphetamine modulates functional connectivity signatures of sustained attention and arousal

Building on evidence that psychostimulants modulate whole-brain functional connectivity signatures of sustained attention, we examined how a single dose of methamphetamine (MA, 20 mg) changes network-level functional organization and sustained attention in healthy adults. Using a within-subject, placebo-controlled design, we tested whether MA selectively affects behavioral and fMRI connectivity signatures of sustained attention and arousal. Under MA, participants showed improved sustained attention task performance as well as functional connectivity signatures of higher sustained attention and arousal. These network changes emerged consistently across resting-state and task-based fMRI, indicating that MA influences attention- and arousal-related networks regardless of cognitive context. Furthermore, a support vector classifier distinguished functional connectivity patterns observed during the MA and placebo conditions, identifying connections overlapping with networks related to arousal. Together, these findings align with prior work on other psychostimulants like methylphenidate, showing that MA modulates sustained attention and related large-scale brain networks. By revealing how MA modulates attention-relevant brain connectivity patterns, our results highlight the utility of psychostimulants as causal tools for probing the robustness, generalizability, and interpretability of brain-based biomarkers of behavior.

neuroscience↗

bioRxiv2024

Methamphetamine-induced adaptation of learning rate dynamics depend on baseline performance.

The ability to calibrate learning according to new information is a fundamental component of an organisms ability to adapt to changing conditions. Yet, the exact neural mechanisms guiding dynamic learning rate adjustments remain unclear. Catecholamines appear to play a critical role in adjusting the degree to which we use new information over time, but individuals vary widely in the manner in which they adjust to changes. Here, we studied the effects of a low dose of methamphetamine (MA), and individual differences in these effects, on probabilistic reversal learning dynamics in a within-subject, double-blind, randomized design. Participants first completed a reversal learning task during a drug-free baseline session to provide a measure of baseline performance. Then they completed the task during two sessions, one with MA (20 mg oral) and one with placebo (PL). First, we showed that, relative to PL, MA modulates the ability to dynamically adjust learning from prediction errors. Second, this effect was more pronounced in participants who performed moderately low at baseline. These results present novel evidence for the involvement of catecholaminergic transmission on learning flexibility and highlights that baseline performance modulates the effect of the drug.

neuroscience↗

bioRxiv2022

Unique Effects of Sedatives, Dissociatives, Psychedelics, Stimulants, and Cannabinoids on Episodic Memory: A Review and Reanalysis of Acute Drug Effects on Recollection, Familiarity, and Metamemory

Despite distinct classes of psychoactive drugs producing putatively unique states of consciousness, there is surprising overlap in terms of their effects on episodic memory and cognition more generally. Episodic memory is supported by multiple subprocesses that have been mostly overlooked in psychopharmacology and could differentiate drug classes. Here, we reanalyzed episodic memory confidence data from 10 previously published datasets (28 drug conditions total) using signal detection models to estimate 2 conscious states involved in episodic memory and 1 consciously-controlled metacognitive process of memory: the retrieval of specific details from ones past (recollection), noetic recognition in the absence of retrieved details (familiarity), and accurate introspection of memory decisions (metamemory). We observed that sedatives, dissociatives, psychedelics, stimulants, and cannabinoids had unique patterns of effects on these mnemonic processes dependent on which phase of memory (encoding, consolidation, or retrieval) was targeted. All drugs at encoding except stimulants impaired recollection, and sedatives, dissociatives, and cannabinoids at encoding impaired familiarity. The effects of sedatives on metamemory were mixed, whereas dissociatives and cannabinoids at encoding tended to enhance metamemory. Surprisingly, psychedelics at encoding tended to enhance familiarity and did not impact metamemory. Stimulants at encoding and retrieval enhanced metamemory, but at consolidation, they impaired metamemory. Together, these findings may have relevance to mechanisms underlying unique subjective phenomena under different drug classes, such as blackouts from sedatives or deja vu from psychedelics. This study provides a framework for interrogating drug effects within a domain of cognition beyond the global impairments on task performance typically reported in psychopharmacology. Public significance statementThis systematic review and reanalysis of several datasets indicate that sedatives (alcohol, zolpidem, triazolam), dissociatives (ketamine, dextromethorphan), psychedelics (psilocybin, MDMA), stimulants (dextroamphetamine, dextromethamphetamine), and cannabinoids (THC) can each have idiosyncratic effects on episodic memory, differentially impairing certain mnemonic processes while sparing or even facilitating others. Such findings inform how different drugs can produce unique subjective phenomena and provide a framework for future work to differentiate the effects of psychoactive drugs within a domain of cognition.

neuroscience↗

bioRxiv2019

Δ9-Tetrahydrocannabinol (THC) impairs visual working memory performance

With the increasing prevalence of legal cannabis use and availability, there is an urgent need to identify cognitive impairments related to its use. It is widely believed that cannabis, or its main psychoactive component {Delta}9-tetrahydrocannabinol (THC), impairs working memory, i.e., the ability to temporarily hold information in mind. However, our review of the literature yielded surprisingly little empirical support for an effect of THC or cannabis on working memory. We thus conducted a study with 3 main goals: (1) quantify the effect of THC on visual working memory in a well-powered sample (2) test the potential role of cognitive effects (mind wandering and metacognition) in disrupting working memory, and (3) demonstrate how insufficient sample size and task duration reduce the likelihood of detecting a drug effect. We conducted two double-blind, randomized crossover experiments in which healthy adults (N=23, 23) performed a reliable and validated visual working memory task (the "Discrete Whole-Report task", 90 trials) after administration of THC (7.5 and/or 15 mg oral) or placebo. We also assessed self-reported mind wandering (Exp 1) and metacognitive accuracy about ongoing task performance (Exp 2). THC impaired working memory performance (d = .65), increased mind wandering (Exp 1), and decreased metacognitive accuracy about task performance (Exp 2). Thus, our findings indicate that THC does impair visual working memory, and that this impairment may be related to both increased mind-wandering and decreased monitoring of task performance. Finally, we used a down-sampling procedure to illustrate the effects of task length and sample size on power to detect the acute effect of THC on working memory.

pharmacology and toxicology↗

bioRxiv2018

Genome-wide association studies of impulsive personality traits (BIS-11 and UPPSP) and drug experimentation in up to 22,861 adult research participants

BackgroundImpulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse.\n\nMethodsIn collaboration with the genetics company 23andMe, Inc., we performed several genome-wide association studies (GWAS) on measures of impulsive personality traits (the short version of the UPPSP Impulsive Behavior Scale, and the Barratt Impulsiveness Scale [BIS-11]) and drug experimentation (the number of drug classes an individual has tried in their lifetime) in up to 22,861 male and female adult research participants of European ancestry.\n\nResultsImpulsive personality traits and drug experimentation showed SNP-heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with the UPPSP Sensation Seeking subscale (P = 8.3 x 10-9, rs139528938) and showed a suggestive association with drug experimentation (P = 3.0 x 10-7, rs2163971; r2 = 0.68 with rs139528938); CADM2 has been previously associated with measures of risky behaviors and self-reported risk tolerance, cannabis initiation, alcohol consumption, as well as information speed processing, body mass index (BMI) variation and obesity. Furthermore, genetic variants in the CACNA1I locus were significantly associated with the UPPSP Negative Urgency subscale (P = 3.8 x 10-8, rs199694726). Multiple subscales from both UPPSP and BIS showed strong genetic correlations (>0.5) with drug experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPSP and BIS subscales were genetically correlated with attention-deficit/hyperactivity disorder (rg = 0.30-0.51, p < 8.69 x 10-3), supporting their validity as endophenotypes.\n\nConclusionsOur findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.

genetics↗

bioRxiv2018

Latent Structure of Risk Perception

Risk-taking behavior affects many aspects of life, including maladaptive behaviors such as illicit substance use, unsafe driving, and risky sexual behavior. Risk-taking has been measured using both self-report measures and behavioral tasks designed for the purpose, but there is little consensus in the associations among measures and our understanding of the latent constructs underlying different forms of risk is limited. In the present study we examined the construct of risk using data from over 1000 young adults who completed measures of risk-taking, including self-reports of perception of risk, propensity to engage in risky behaviors and performance on behavioral tasks designed to measure risk. To examine the latent structure of risk preferences, we conducted a principal component analysis (PCA). The PCA revealed a latent structure of three distinct components of risk-taking behavior: \"Lifestyle Risk Sensitivity\", \"Financial Risk Sensitivity\", and \"Behavioral Risk Sensitivity\", which consisted only of the Balloon Analogue Risk Task (BART; Lejuez et al., 2002). As expected, risk-taking and perception of risk differed in men and women. Yet, the PCA components were similar in men and women. Future work utilizing additional measures of risk-taking behavior in more heterogeneous samples will help to identify the true biobehavioral constructs underlying these behaviors.

neuroscience↗

bioRxiv2018

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2-4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.

genetics↗

bioRxiv2018

Conditioning nausea in a laboratory setting: A pilot study

Cancer patients can experience nausea as they approach the place where they have received chemotherapy treatment. This nausea is likely the result of Pavlovian conditioning, where the previously neutral environment acquires conditioned properties, in this case conditioned nausea, because its association with feeling ill. To investigate this phenomenon under controlled conditions, we studied the acquisition of conditioned nausea using a distinct environment paired with an emetic drug in healthy young adults. We measured two indices of conditioning: i) conditioned place aversion, and ii) conditioned drug-like (nausea) responses. Healthy volunteers (N=32) first rated their preference for two testing rooms, and then underwent four conditioning sessions in which they received either syrup of ipecac (5 ml) or placebo. A Paired Group (PG; N=17) always received ipecac in their initially preferred room and placebo in the other, while an Unpaired Group (UG; N=15) received ipecac and placebo in both rooms. Conditioned responses were assessed with i) time spent in each room, ii) room liking and preference, and iii) feelings of nausea in each room. There was no evidence of conditioned place aversion as measured by either time spent or ratings of room liking. However, the PG did report a small increase in nausea in the ipecac-paired room. Although the conditioned responses in this study were not robust, this procedure is a first step towards studying conditioned aversive drug responses in humans, which will enable development of future studies to prevent or treat anticipatory nausea.

animal behavior and cognition↗

bioRxiv2017

Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association (GWAS) study of the Alcohol Use Disorder Identification Test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20,328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the chip-heritability of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 x 10-7; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 x 10-7; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using LD score regression, we identified positive genetic correlations between AUDIT score and AUD, high alcohol consumption, and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment, and additional unexpected negative correlations with BMI/obesity and attention-deficit/hyperactivity disorder (ADHD). We conclude that conducting a genetic study using data from a population unselected for AUD and responding to an online questionnaire may represent a cost-effective strategy for elucidating the etiology of AUD.

genetics↗

bioRxiv2017

Genetics of the Research Domain Criteria (RDoC): genome-wide association study of delay discounting

Delay discounting (DD), which is the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated SNP was rs6528024 (P = 2.40 x 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype, and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition, and body weight.

genetics↗