The landscape of open science in behavioral addiction research: Current practices and future directions.

Open science refers to a set of practices that aim to make scientific research more transparent, accessible, and reproducible, including pre-registration of study protocols, sharing of data and materials, the use of transparent research methods, and open access publishing. In this commentary, we describe and evaluate the current state of open science practices in behavioral addiction research. We highlight the specific value of open science practices for the field; discuss recent field-specific meta-scientific reviews that show the adoption of such practices remains in its infancy; address the challenges to engaging with open science; and make recommendations for how researchers, journals, and scientific institutions can work to overcome these challenges and promote high-quality, transparently reported behavioral addiction research. By collaboratively promoting open science practices, the field can create a more sustainable and productive research environment that benefits both the scientific community and society as a whole.

Operationalization and measurement of compulsivity across video gaming and gambling behavioral domains.

BACKGROUND: Compulsivity is the hallmark of addiction progression and, as a construct, has played an important role in unveiling the etiological pathways from learning mechanisms underlying addictive behavior to harms resulting from it. However, a sound use of the compulsivity construct in the field of behavioral addictions has been hindered to date by the lack of consensus regarding its definition and measurement. Here we capitalize on a previous systematic review and expert appraisal to develop a compulsivity scale for candidate behavioral addictions (the Granada Assessment for Cross-domain Compulsivity, GRACC). METHODS: The initial scale (GRACC90) consisted of 90 items comprising previously proposed operationalizations of compulsivity, and was validated in two panel samples of individuals regularly engaging in gambling and video gaming, using exploratory structural equation modeling (ESEM) and convergence analyses. RESULTS: The GRACC90 scale is unidimensional and structurally invariant across samples, and predicted severity of symptoms, lower quality of life, and negative affect, to similar degrees in the two samples. Additionally, poorer quality of life and negative affect were comparably predicted by compulsivity and by severity of symptoms. A shorter version of the scale (GRACC18) is proposed, based on selecting the 18 items with highest factor loadings. CONCLUSIONS: Results support the proposal that core symptoms of behavioral addictions strongly overlap with compulsivity, and peripheral symptoms are not essential for their conceptualization. Further research should clarify the etiology of compulsive behavior, and whether pathways to compulsivity in behavioral addictions could be common or different across domains.

Gaming passion contributes to the definition and identification of problematic gaming.

Even if for most people playing video games is a healthy leisure activity, a minority of vulnerable users present an excessive use associated to negative consequences (e.g., psychosocial maladjustment, sleep interference) and functional impairment. The current study first aims to identify psychological factors that contribute to discriminate highly involved (but healthy) gamers from problematic gamers. For that purpose, we used a cluster analysis approach to identify different groups of gamers based on their profiles of passion towards gaming (using the Dualistic Model of Passion). Another objective of the present study is to explore, using supervised machine-learning, how gaming disorder symptoms, assessed within the substance use disorder framework (e.g., tolerance, withdrawal), might be linked to harmonious and/or an obsessive passion for gaming. Three distinct clusters of gamers were identified based on their passion profiles, including risky gamers, engaged gamers, and casual gamers. Supervised machine-learning algorithms identified that specific gaming disorder symptoms (salience, mood modification, tolerance, low level of conflict) were predominantly related to harmonious passion, whereas others (withdrawal, high level of conflict, relapse) were more directly related to obsessive passion. Our results support the relevance of person-centered approaches to the treatment of problematic gaming.

The associative learning roots of affect-driven impulsivity and its role in problem gambling: A replication attempt and extension of Quintero et al. (2020).

Background and aims: Negative/positive urgency (NU/PU) refers to the proneness to act rashly under negative/positive emotions. These traits are proxies to generalized emotion dysregulation, and are well-established predictors of gambling-related problems. We aimed to replicate a previous work (Quintero et al., 2020) showing NU to be related to faulty extinction of conditioned stimuli in an emotional conditioning task, to extend these findings to PU, and to clarify the role of urgency in the development of gambling-related craving and problems. Methods: 81 gamblers performed an acquisition-extinction task in which neutral, disgusting, erotic and gambling-related images were used as unconditioned stimuli (US), and color patches as conditioned stimuli (CS). Trial-by-trial predictive responses were analyzed using generalized linear mixed-effects models (GLME). Results: PU was more strongly related than NU to craving and severity of gambling problems. PU did not influence acquisition in the associative task, whereas NU slightly slowed it. Extinction was hampered in individuals with high PU, and a follow-up analysis showed this effect to depend on relative preference for skill-based and casino games. Discussion and conclusions: Results suggest that resistance to extinction of emotionally conditioned cues is a sign of malfunctioning emotion regulation in problematic gambling. In our work, the key effect was driven by PU (instead of NU), and gambling craving and symptoms were also more closely predicted by it. Future research should compare the involvement of PU and NU in emotion regulation and gambling problems, for gamblers with preference for different gambling modalities (e.g., pure chance vs skill games).

Pictograms to aid laypeople in identifying the addictiveness of gambling products (PictoGRRed study).

The structural addictive characteristics of gambling products are important targets for prevention, but can be unintuitive to laypeople. In the PictoGRRed (Pictograms for Gambling Risk Reduction) study, we aimed to develop pictograms that illustrate the main addictive characteristics of gambling products and to assess their impact on identifying the addictiveness of gambling products by laypeople. We conducted a three-step study: (1) use of a Delphi consensus method among 56 experts from 13 countries to reach a consensus on the 10 structural addictive characteristics of gambling products to be illustrated by pictograms and their associated definitions, (2) development of 10 pictograms and their definitions, and (3) study in the general population to assess the impact of exposure to the pictograms and their definitions (n = 900). French-speaking experts from the panel assessed the addictiveness of gambling products (n = 25), in which the mean of expert's ratings was considered as the true value. Participants were randomly provided with the pictograms and their definitions, or with a standard slogan, or with neither (control group). We considered the control group as representing the baseline ability of laypeople to assess the addictiveness of gambling products. Each group and the French-speaking experts rated the addictiveness of 14 gambling products. The judgment criterion was the intraclass coefficients (ICCs) between the mean ratings of each group and the experts, reflecting the level of agreement between each group and the experts. Exposure to the pictograms and their definition doubled the ability of laypeople to assess the addictiveness of gambling products compared with that of the group that read a slogan or the control group (ICC = 0.28 vs. 0.14 (Slogan) and 0.14 (Control)). Laypeople have limited awareness of the addictive characteristics of gambling products. The pictograms developed herein represent an innovative tool for universally empowering prevention and for selective prevention.

Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells.

On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we presumed that PEPCK-M could play a role in this process by offsetting key metabolites into glycosyl moieties using alternative substrates. PEPCK-M inhibition using iPEPCK-2 promoted entosis in the absence of glucose, whereas its overexpression inhibited entosis. PEPCK-M inhibition had a direct role on total protein glycosylation as determined by Concanavalin A binding, and the specific ratio of fully glycosylated LAMP1 or E-cadherin. The content of metabolites, and the fluxes from 13C-glutamine label into glycolytic intermediates up to glucose-6-phosphate, and ribose- and ribulose-5-phosphate, was dependent on PEPCK-M content as measured by GC/MS. All in all, we demonstrate for the first time that protein glycosylation defects precede and initiate the entosis process and implicates PEPCK-M in this survival program to dampen the consequences of glucose deprivation. These results have broad implications to our understanding of tumor metabolism and treatment strategies.

How to pin a compulsive behavior down: A systematic review and conceptual synthesis of compulsivity-sensitive items in measures of behavioral addiction.

Experimental models identify the transition from choice to compulsivity as the main mechanism underlying addiction. In behavioral addictions research, however, the adjective compulsive is used to describe virtually any kind of excessive or dysregulated behavior, which hinders the connection between experimental and clinical models. In this systematic review, we adopted a preliminary definition of compulsive behavior based on previous theoretical work. Subsequently, a systematic review following PRISMA guidelines was conducted (a) to identify the validated instruments, currently used in behavioral addictions research, that include items that are sensitive (intendedly or not) to compulsivity, and (b) to categorize those items into differentiable operationalizations of compulsivity. Six operationalizations of compulsivity emerged from item content analysis: 1. Automatic or habitual behavior occurring in absence of conscious instrumental goals; 2. Behavior insensitive to negative consequences despite conscious awareness of them; 3. Overwhelming urge or desire that impels the individual to initiate the activity and jeopardizes control attempts; 4. Bingeing, or inability to stop or interrupt the activity once initiated, resulting in an episode substantially longer or more intense than intended; 5. Attentional capture and cognitive hijacking; and 6. Inflexible rules, stereotyped behaviors, and rituals related to task completion or execution. Subsequently, a list of 15 representative items per operationalization was elaborated for independent assessment and identification of delimitation problems. A high degree of agreement was reached in assessing them as instantiating compulsivity, as well as in their assignment to the corresponding categories. However, many of them were also considered overinclusive, i.e., uncapable of distinguishing compulsivity from value-based momentary choice. To increase their discriminative value, items in future compulsivity scales should be refined to explicitly mention disconnection between behavior and declarative goals. Further research on factorial structure of a pool of items derived from these operational definitions is warranted. Such a factorial structure could be used as an intermediate link between specific behavioral items and explanatory psychobiological, learning, and cognitive mechanisms.

Compulsive Sexual Behavior Disorder should not be classified by solely relying on component/symptomatic features •.

The paper by Sassover and Weinstein (2022) contributes to a timely and complex debate related to the classification of Compulsive Sexual Behavior Disorder (CSBD). The recent inclusion of CSBD as an impulse-control disorder in the ICD-11 has generated debate since a competitive view is that CSBD should rather be classified as an addictive disorder. Sassover and Weinstein (2022) reviewed existing evidence and concluded it does not support the conceptualization of CSBD as an addictive disorder. Although we agree regarding the relevance and timely nature of considering the classification of CSBD, we respectfully disagree with the position that relying on the components model of addiction (Griffiths, 2005) is the optimal approach for determining whether or not CSBD is an addictive disorder. In this commentary, we discuss potential pitfalls of relying on the components model to conceptualize CSBD as an addictive disorder and argue that considering a process-based approach is important for advancing this timely debate.

ß Cell-specific deletion of Zfp148 improves nutrient-stimulated ß cell Ca2+ responses.

Insulin secretion from pancreatic ß cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that ß cell-specific deletion of Zfp148 (ß-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from ß­Zfp148KO and control mice fed both a chow and a Western-style diet. ß-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. ß-Zfp148KO islets also exhibited elevated sensitivity to amino acid-induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of ß-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, ß-Zfp148KO islets displayed enhanced insulin secretion in response to l-glutamine and activation of glutamate dehydrogenase. Understanding pathways controlled by ZFP148 may provide promising strategies for improving ß cell function that are robust to the metabolic challenge imposed by a Western diet.

On the pitfalls of conceptualizing excessive physical exercise as an addictive disorder: Commentary on Dinardi et al. (2021).

This commentary challenges some of the proposals made in the opinion paper entitled "The expanded interactional model of exercise addiction" by Dinardi, Egorov, and Szabo (2021). We first question the usefulness of the (expanded) interactional model of exercise addiction to determine the psychological processes underlying distress and functional impairment in excessive physical exercise. We then consider the authors' use of the Self-Determination Theory to model exercise addiction, which risks the misclassification of strenuous, but adaptive, patterns of physical exercise as exercise addiction. We finally address broader concerns regarding the idea that maladaptive exercising could be conceptualized as an addictive disorder.

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

Association patterns of cannabis abuse and dependence with risk of problematic non-substance-related dysregulated and addictive behaviors.

Co-occurrence of drug misuse with other dysregulated behaviors is common. This study was aimed at exploring the associations between the risk of presenting a clinically relevant condition involving non-substance-related addictive or dysregulated behaviors (as measured by the MultiCAGE CAD-4 screening), and cannabis abuse/dependence (CAST/SDS) scores, and the role of gender therein. Participants were recruited using stratified probabilistic sampling at the University of Granada. Mann-Whitney's U tests were used to compare male and female students in SDS and CAST scores. Associations between gender and MultiCAGE scores were estimated using the γ ordinal correlation index, and tested with χ2. For each MultiCAGE dimension, a Poisson-family mixed-effects model was built with either SDS or CAST as the main input variable, while controlling for nicotine and alcohol dependence, and relevant sociodemographic variables. Incidence rate ratios (IRR) were computed for SDS/CAST effects, and the significance threshold was family-wise Bonferroni-corrected. Gender differences were significant for cannabis dependence/abuse and all MultiCAGE scores for non-substance-related conditions, with males showing higher risk scores for excessive gambling, excessive internet use, excessive video gaming, and hypersexuality, and females presenting higher scores in dysregulated eating and compulsive buying. Cannabis dependence and abuse were significantly associated with a higher risk of problematic video gaming. These associations were mostly driven by males. Importantly, although risk of problematic video gaming was specifically associated with cannabis abuse/dependence, there was only a weak non-significant association between problematic video gaming and alcohol use scores. Risk of alcohol use problems, in turn, was strongly associated with all other non-substance-related problems (problematic gambling, excessive Internet use, dysregulated eating, compulsive buying, and hypersexuality). These differential associations can cast light on the etiological similarities and dissimilarities between problematic substance use and putative addictive behaviors not involving drugs.

Correction: Mental Fatigue Might be Not So Bad for Exercise Performance After All: A Systematic Review and Bias-Sensitive Meta-Analysis.

[This corrects the article DOI: 10.5334/joc.126.].

PEPCK-M recoups tumor cell anabolic potential in a PKC-ζ-dependent manner.

BACKGROUND: Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is expressed in all cancer types examined and in neuroprogenitor cells. The gene is upregulated by amino acid limitation and ER-stress in an ATF4-dependent manner, and its activity modulates the PEP/Ca2+ signaling axis, providing clear arguments for a functional relationship with metabolic adaptations for cell survival. Despite its potential relevance to cancer metabolism, the mechanisms responsible for its pro-survival activity have not been completely elucidated. METHODS: [U-13C]glutamine and [U-13C]glucose labeling of glycolytic and TCA cycle intermediates and their anabolic end-products was evaluated quantitatively using LC/MS and GC/MS in conditions of abundant glucose and glucose limitation in loss-of-function (shRNA) and gain-of-function (lentiviral constitutive overexpression) HeLa cervix carcinoma cell models. Cell viability was assessed in conjunction with various glucose concentrations and in xenografts in vivo. RESULTS: PEPCK-M levels linearly correlated with [U-13C]glutamine label abundance in most glycolytic and TCA cycle intermediate pools under nutritional stress. In particular, serine, glycine, and proline metabolism, and the anabolic potential of the cell, were sensitive to PEPCK-M activity. Therefore, cell viability defects could be rescued by supplementing with an excess of those amino acids. PEPCK-M silenced or inhibited cells in the presence of abundant glucose showed limited growth secondary to TCA cycle blockade and increased ROS. In limiting glucose conditions, downregulation of PKC-ζ tumor suppressor has been shown to enhance survival. Consistently, HeLa cells also sustained a survival advantage when PKC-ζ tumor suppressor was downregulated using shRNA, but this advantage was abolished in the absence of PEPCK-M, as its inhibition restores cell growth to control levels. The relationship between these two pathways is also highlighted by the anti-correlation observed between PEPCK-M and PKC-ζ protein levels in all clones tested, suggesting co-regulation in the absence of glucose. Finally, PEPCK-M loss negatively impacted on anchorage-independent colony formation and xenograft growth in vivo. CONCLUSIONS: All in all, our data suggest that PEPCK-M might participate in the mechanisms to regulate proteostasis in the anabolic and stalling phases of tumor growth. We provide molecular clues into the clinical relevance of PEPCK-M as a mechanism of evasion of cancer cells in conditions of nutrient stress.

Are methamphetamine users compulsive? Faulty reinforcement learning, not inflexibility, underlies decision making in people with methamphetamine use disorder.

Methamphetamine use disorder involves continued use of the drug despite negative consequences. Such 'compulsivity' can be measured by reversal learning tasks, which involve participants learning action-outcome task contingencies (acquisition-contingency) and then updating their behaviour when the contingencies change (reversal). Using these paradigms, animal models suggest that people with methamphetamine use disorder (PwMUD) may struggle to avoid repeating actions that were previously rewarded but are now punished (inflexibility). However, difficulties in learning task contingencies (reinforcement learning) may offer an alternative explanation, with meaningful treatment implications. We aimed to disentangle inflexibility and reinforcement learning deficits in 35 PwMUD and 32 controls with similar sociodemographic characteristics, using novel trial-by-trial analyses on a probabilistic reversal learning task. Inflexibility was defined as (a) weaker reversal phase performance, compared with the acquisition-contingency phases, and (b) persistence with the same choice despite repeated punishments. Conversely, reinforcement learning deficits were defined as (a) poor performance across both acquisition-contingency and reversal phases and (b) inconsistent postfeedback behaviour (i.e., switching after reward). Compared with controls, PwMUD exhibited weaker learning (odds ratio [OR] = 0.69, 95% confidence interval [CI] [0.63-0.77], p < .001), though no greater accuracy reduction during reversal. Furthermore, PwMUD were more likely to switch responses after one reward/punishment (OR = 0.83, 95% CI [0.77-0.89], p < .001; OR = 0.82, 95% CI [0.72-0.93], p = .002) but just as likely to switch after repeated punishments (OR = 1.03, 95% CI [0.73-1.45], p = .853). These results indicate that PwMUD's reversal learning deficits are driven by weaker reinforcement learning, not inflexibility.

Decision-making (in)flexibility in gambling disorder.

BACKGROUND: Behavioral flexibility -the ability to dynamically readjust our behavior in response to reward contingency changes- is often investigated using probabilistic reversal learning tasks (PRLT). Poor PRLT performance has been proposed as a proxy for compulsivity, and theorized to be related to perseverative gambling. Previous attempts to measure inflexibility with the PRLT in patients with gambling disorder have, however, used a variety of indices that may conflate inflexibility with more general aspects of performance in the task. METHODS: Trial-by-trial PRLT acquisition and reacquisition curves in 84 treatment-seeking patients with gambling disorder and 64 controls (non-gamblers and non-problem recreational gamblers) were analyzed to distinguish between (a) variability in acquisition learning, and (b) reacquisition learning in reversed contingency phases. Complementarily, stay/switch responses throughout the task were analyzed to identify (c) premature switching, and (d) sensitivity to accumulated negative feedback. RESULTS AND INTERPRETATION: Even after controlling for differences in acquisition learning, patients were slower to readjust their behavior in reversed contingency phases, and were more prone to maintain their decisions despite accumulated negative feedback. Inflexibility in patients with gambling disorder is thus a robust phenomenon that could predate gambling escalation, or result from massive exposure to gambling activities.

Does mental fatigue impair physical performance? A replication study.

The aim of this study is to replicate the hypothesis that mental fatigue impairs physical performance in a pre-registered (https://osf.io/wqkap/) within-subjects experiment. 30 recreationally active adults completed a time-to-exhaustion test (TTE) at 80% VO2max in two separate sessions, after completing a mental fatigue task or watching a documentary for 90 min. We measured power output, heart rate, (session) rating of perceived exertion (RPE) and subjective mental fatigue. Bayes factor analyses revealed extreme evidence supporting the alternative hypothesis that the mental fatigue task was more mentally fatiguing than the control task, BF01 = 0.009. However, we found moderate-to-strong evidence for the null hypothesis (i.e., no evidence of reduced performance) for average time in TTE (BF01 = 9.762) and anecdotal evidence for the null hypothesis in (session) RPE (BF01 = 2.902) and heart rate (BF01 = 2.587). Our data seem to challenge the idea that mental fatigue has a negative influence on exercise performance. Although we did succeed at manipulating subjective mental fatigue, this did not impair physical performance. However, we cannot discard the possibility that mental fatigue may have a negative influence under conditions not explored here, e.g., individualizing mentally fatiguing tasks. In sum, further research is warranted to determine the role of mental fatigue on exercise and sport performance.