Publications by authors named "José C Perales"

95 Publications

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

EMBO Mol Med 2021 Sep 11;13(9):e13929. Epub 2021 Aug 11.

Experimental Nephrology, Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.

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.
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http://dx.doi.org/10.15252/emmm.202113929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422079PMC
September 2021

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

PLoS One 2021 10;16(8):e0255872. Epub 2021 Aug 10.

Mind, Brain, and Behavior Research Center (CIMCYC), University of Granada, Granada, Spain.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255872PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354435PMC
August 2021

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

J Cogn 2021 19;4(1):32. Epub 2021 Jul 19.

Departamento de Psicología Básica, Universidad Autónoma de Madrid, ES.

[This corrects the article DOI: 10.5334/joc.126.].
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http://dx.doi.org/10.5334/joc.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300579PMC
July 2021

Gambling-Specific Cognitions Are Not Associated With Either Abstract or Probabilistic Reasoning: A Dual Frequentist-Bayesian Analysis of Individuals With and Without Gambling Disorder.

Front Psychol 2020 26;11:611784. Epub 2021 Jan 26.

Department of Experimental Psychology, Mind, Brain, and Behavior Research Center (CIMCYC), Universidad de Granada, Granada, Spain.

Background: Distorted gambling-related cognitions are tightly related to gambling problems, and are one of the main targets of treatment for disordered gambling, but their etiology remains uncertain. Although folk wisdom and some theoretical approaches have linked them to lower domain-general reasoning abilities, evidence regarding that relationship remains unconvincing.

Method: In the present cross-sectional study, the relationship between probabilistic/abstract reasoning, as measured by the Berlin Numeracy Test (BNT), and the Matrices Test, respectively, and the five dimensions of the Gambling-Related Cognitions Scale (GRCS), was tested in a sample of 77 patients with gambling disorder and 58 individuals without gambling problems.

Results And Interpretation: Neither BNT nor matrices scores were significantly related to gambling-related cognitions, according to frequentist (MANCOVA/ANCOVA) analyses, performed both considering and disregarding group (patients, non-patients) in the models. Correlation Bayesian analyses (bidirectional BF) largely supported the null hypothesis, i.e., the absence of relationships between the measures of interest. This pattern or results reinforces the idea that distorted cognitions do not originate in a general lack of understanding of probability or low fluid intelligence, but probably result from motivated reasoning.
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http://dx.doi.org/10.3389/fpsyg.2020.611784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873942PMC
January 2021

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

Cancer Metab 2021 Jan 7;9(1). Epub 2021 Jan 7.

Department of Physiological Sciences, School of Medicine, University of Barcelona, Feixa Llarga s/n, 08907, L'Hospitalet del Llobregat, Spain.

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/Ca 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-C]glutamine and [U-C]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-C]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.
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http://dx.doi.org/10.1186/s40170-020-00236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791766PMC
January 2021

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

Addict Biol 2021 07 3;26(4):e12999. Epub 2021 Jan 3.

Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/adb.12999DOI Listing
July 2021

Decision-making inflexibility in a reversal learning task is associated with severity of problem gambling symptoms but not with a diagnosis of substance use disorder.

BMC Psychol 2020 Nov 10;8(1):120. Epub 2020 Nov 10.

Department of Experimental Psychology; Mind, Brain and Behavior Research Centre (CIMCYC), University of Granada, Granada, Spain.

Background: Decisions made by individuals with disordered gambling are markedly inflexible. However, whether anomalies in learning from feedback are gambling-specific, or extend beyond gambling contexts, remains an open question. More generally, addictive disorders-including gambling disorder-have been proposed to be facilitated by individual differences in feedback-driven decision-making inflexibility, which has been studied in the lab with the Probabilistic Reversal Learning Task (PRLT). In this task, participants are first asked to learn which of two choice options is more advantageous, on the basis of trial-by-trial feedback, but, once preferences are established, reward contingencies are reversed, so that the advantageous option becomes disadvantageous and vice versa. Inflexibility is revealed by a less effective reacquisition of preferences after reversal, which can be distinguished from more generalized learning deficits.

Methods: In the present study, we compared PRLT performance across two groups of 25 treatment-seeking patients diagnosed with an addictive disorder and who reported gambling problems, and 25 matched controls [18 Males/7 Females in both groups, M(SD) = 25.24 (8.42) and 24.96 (7.90), for patients and controls, respectively]. Beyond testing for differences in the shape of PRLT learning curves across groups, the specific effect of problematic gambling symptoms' severity was also assessed independently of group assignment. In order to surpass previous methodological problems, full acquisition and reacquisition curves were fitted using generalized mixed-effect models.

Results: Results showed that (1) controls did not significantly differ from patients in global PRLT performance nor showed specific signs of decision-making inflexibility; and (2) regardless of whether group affiliation was controlled for or not, gambling severity was specifically associated with more inefficient learning in phases with reversed contingencies.

Conclusion: Decision-making inflexibility, as revealed by difficulty to reacquire decisional preferences based on feedback after contingency reversals, seems to be associated with gambling problems, but not necessarily with a substance-use disorder diagnosis. This result aligns with gambling disorder models in which domain-general compulsivity is linked to vulnerability to develop gambling-specific problems with exposure to gambling opportunities.
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http://dx.doi.org/10.1186/s40359-020-00482-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654010PMC
November 2020

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

J Cogn 2020 Oct 9;3(1):38. Epub 2020 Oct 9.

Departamento de Psicología Básica, Universidad Autónoma de Madrid, ES.

There is an ongoing debate in the scientific community regarding whether a state of mental fatigue may have a negative effect upon a range of objective and subjective measures of human performance. This issue has attracted attention from several fields, including sport and exercise sciences. In fact, a considerable body of literature in the sport science field has suggested that performing a long and demanding cognitive task might lead to a state of mental fatigue, impairing subsequent exercise performance, although research in this field has shown contradictory results. Here, we performed a meta-analysis to investigate these inconsistent findings. The analysis yielded small-to-medium effects of mental fatigue on exercise performance, = 0.50, and RPE, = 0.21. However, a three-parameter selection model also revealed evidence of publication or reporting biases, suggesting that the bias-corrected estimates might be substantially lower (0.08 and 0.10, respectively) and non-significant. In sum, current evidence does not provide conclusive support for the claim that mental fatigue has a negative influence on exercise performance.
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http://dx.doi.org/10.5334/joc.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546119PMC
October 2020

Decision-making (in)flexibility in gambling disorder.

Addict Behav 2021 01 3;112:106534. Epub 2020 Jul 3.

Department of Experimental Psychology, Mind, Brain and Research Center (CIMCYC), Universidad de Granada, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.addbeh.2020.106534DOI Listing
January 2021

The associative underpinnings of negative urgency and its role in problematic gambling behavior.

Addict Behav 2020 12 2;111:106533. Epub 2020 Jul 2.

Department of Experimental Psychology. Mind, Brain and Behavior Research Center (CIMCYC), University of Granada, Spain.

Background: Negative urgency -the tendency to lose control under the influence of strong negative emotions- has been proposed to be a sign of malfunctioning emotion regulation mechanisms, and to contribute to severity and complications of gambling disorder and other externalizing behaviors.

Aims And Method: This study is aimed at (1) testing whether negative urgency is linked to resistance to extinction in an emotional associative learning task in a sample of 70 participants, 65 of whom were active gamblers (with emotional pictures as unconditioned stimuli, and color patches as conditioned stimuli [CS]); and (b) exploring the link between these two variables (negative urgency and resistance to emotional extinction) and clinical manifestations of gambling (severity and craving). Mixed-effects generalized models were used to analyze trial-by-trial predictive responses during acquisition and extinction for erotic, disgusting, and gambling-related pictures.

Results And Conclusions: Acquisition of CS-elicited responses remained unaffected by negative urgency, whereas extinction was hampered in individuals with high negative urgency, especially for CSs associated with erotic and gambling-related pictures. Moreover, negative urgency predicted higher craving scores, and these predicted more severe gambling-related symptoms. This finding resonates with the well-known involvement of emotion regulation processes in craving control. However, extinction was not independently related to craving. This lacking effect suggests that negative urgency is a broad construct, and although some of its components are directly related to faulty extinction (and generalized emotion dysregulation), such components are not the same negative urgency shares with difficulties of craving control.
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http://dx.doi.org/10.1016/j.addbeh.2020.106533DOI Listing
December 2020

Dissociable Effects of Executive Load on Perceived Exertion and Emotional Valence during Submaximal Cycling.

Int J Environ Res Public Health 2020 08 2;17(15). Epub 2020 Aug 2.

Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, 18071 Granada, Spain.

Endurance physical exercise is accompanied by subjective perceptions of exertion (reported perceived exertion, RPE), emotional valence, and arousal. These constructs have been hypothesized to serve as the basis for the exerciser to make decisions regarding when to stop, how to regulate pace, and whether or not to exercise again. In dual physical-cognitive tasks, the mental (executive) workload generated by the cognitive task has been shown to influence these perceptions, in ways that could also influence exercise-related decisions. In the present work, we intend to replicate and extend previous findings that manipulating the amount of executive load imposed by a mental task, performed concomitantly with a submaximal cycling session, influenced emotional states but not perceived exertion. Participants (experienced triathletes) were asked to perform a submaximal cycling task in two conditions with different executive demands (a two-back version of the n-back task vs. oddball) but equated in external physical load. Results showed that the higher executive load condition elicited more arousal and less positive valence than the lower load condition. However, both conditions did not differ in RPE. This experimental dissociation suggests that perceived exertion and its emotional correlates are not interchangeable, which opens the possibility that they could play different roles in exercise-related decision-making.
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http://dx.doi.org/10.3390/ijerph17155576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432348PMC
August 2020

Does Emotion Regulation Predict Gains in Exercise-Induced Fitness? A Prospective Mixed-Effects Study with Elite Helicopter Pilots.

Int J Environ Res Public Health 2020 06 11;17(11). Epub 2020 Jun 11.

Department of Experimental Psychology, University of Granada, 18071 Granada, Spain.

Emotion regulation (ER) is a strong predictor of different aspects of mental health and wellbeing. However, only recently has ER been examined in relation to physical activity and its effects on fitness. In the present study, 26 elite helicopter pilots, serving in the Spanish Air Force, were physically trained for 6 months, and their level of fitness (maximum oxygen consumption and time to exhaustion in a treadmill-running test) was assessed before and after that period. Additionally, two indices of emotion regulation (general adaptiveness of ER strategies, as measured by the Emotion Regulation Questionnaire (ERQ), and negative urgency, as measured by the UPPS-P questionnaire) measured at baseline were used as prospective predictors of fitness improvement. After controlling for individual features, baseline fitness, and type of training, better emotion regulation strategies (more cognitive reappraisal plus less expressive suppression) predicted larger fitness gains ( = 0.028). Incidental emotion regulation, as measured by the negative urgency index, failed to predict pre-post-fitness changes ( = 0.734). These results suggest that fostering emotion regulation skills may improve the effectiveness of fitness training programs.
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http://dx.doi.org/10.3390/ijerph17114174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312943PMC
June 2020

Does mental fatigue impair physical performance? A replication study.

Eur J Sport Sci 2021 May 30;21(5):762-770. Epub 2020 Jun 30.

Centro de Investigación, Mente, Cerebro y Comportamiento, Departamento de Psicología Experimental (CIMCYC), Universidad de Granada, Granada, España.

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% VOmax 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, BF = 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 (BF = 9.762) and anecdotal evidence for the null hypothesis in (session) RPE (BF = 2.902) and heart rate (BF = 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.
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http://dx.doi.org/10.1080/17461391.2020.1781265DOI Listing
May 2021

Emotional and non-emotional facets of impulsivity in eating disorders: From anorexia nervosa to bulimic spectrum disorders.

Eur Eat Disord Rev 2020 07 24;28(4):410-422. Epub 2020 Mar 24.

CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.

Objective: Impulsivity and difficulties in regulating emotions are considered to be transdiagnostic characteristics of patients with eating disorders (EDs). The study aimed to investigate trait impulsivity and inhibitory components of impulsivity, related or unrelated to emotions in patients with EDs.

Method: A total of 17 patients with anorexia nervosa (AN), 16 patients with bulimic-spectrum EDs (BSD) and 20 healthy control (HC) participants completed an impulsivity scale (UPPS-P) before performing an emotional inhibitory control task during electroencephalography (EEG) acquisition.

Results: Higher trait impulsivity in EDs than HC (with higher scores among BSD patients) was observed. However, no differences in behavioural measures or neural indexes [event-related potential (ERP)] of emotional and non-emotional inhibitory control were observed between patients and HC.

Conclusion: The present results highlighted negative urgency, an impulsive personality trait related to emotions, as a common feature of AN and BSD. Lack of perseverance, a trait which is less related to emotions, specifically characterises patients with BSD. On the other hand, behavioural and ERP data did not show altered inhibitory control in EDs, for either general or emotional-related response inhibition.
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http://dx.doi.org/10.1002/erv.2734DOI Listing
July 2020

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca.

Cells 2019 12 19;9(1). Epub 2019 Dec 19.

Department of Physiological Sciences, School of Medicine, University of Barcelona, Feixa Llarga s/n, 08907 L'Hospitalet del Llobregat, Barcelona, Spain.

Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca/ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the metabolite directly into the cell increased cytosolic calcium and NFAT activity. PEP-stirred cytosolic calcium was also responsible for the calmodulin (CaM) dependent phosphorylation of c-Myc at Ser62, resulting in increased activity, probably through enhanced stabilization of the protein. Protein expression of several c-Myc targets also correlated with PEP levels. Finally, the participation of PEPCK in this axis was interrogated as it should directly contribute to PEP through cataplerosis from TCA cycle intermediates, especially in glucose starvation conditions. Inhibition of PEPCK activity showed the expected regulation of PEP and calcium levels and consequential downstream modulation of NFAT and c-Myc activities. Collectively, these results suggest that glucose and PEPCK can regulate NFAT and c-Myc activities through their influence on the PEP/Ca axis, advancing a role for PEP as a second messenger communicating metabolism, calcium cell signaling, and tumor biology.
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http://dx.doi.org/10.3390/cells9010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017135PMC
December 2019

Learning to lose control: A process-based account of behavioral addiction.

Neurosci Biobehav Rev 2020 01 14;108:771-780. Epub 2019 Dec 14.

Addictive and Compulsive Behaviours Lab. Institute for Health and Behaviour, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Institute of Psychology, University of Lausanne, Lausanne, Switzerland; Centre for Excessive Gambling, Lausanne University Hospitals (CHUV), Lausanne, Switzerland.

Learning psycho(bio)logy has developed a solid corpus of evidence and theory regarding behavior control modes. The present article briefly reviews that literature and its influence on recent models in which the transition from goal-directed to compulsive behavior is identified as the main process underlying substance use disorders. This literature is also relevant to non-substance addictive disorders, and serves as basis to propose a restricted definition of behavioral addiction relying on the presence of behavior-specific compulsivity. Complementarily, we consider whether some activities can become disordered while remaining mostly goal-driven. Based on reinforcement learning models, relative outcome utility computation is proposed as an alternative mechanism through which dysfunctional behaviors (even not qualifying as addictive) can override adaptive ones, causing functional impairment. Beyond issues of conceptual delimitation, recommendations are made regarding the importance of identifying individual etiological pathways to dysregulated behavior, the necessity of accurately profiling at-risk individuals, and the potential hazards of symptom-based diagnosis. In our view, the validity of these recommendations does not depend on the position one takes in the nosological debate.
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http://dx.doi.org/10.1016/j.neubiorev.2019.12.025DOI Listing
January 2020

Brief group-delivered motivational interviewing is equally effective as brief group-delivered cognitive-behavioral therapy at reducing alcohol use in risky college drinkers.

PLoS One 2019 10;14(12):e0226271. Epub 2019 Dec 10.

Mind, Brain and Behavior Research Centre, University of Granada, Granada, Spain.

College students are particularly vulnerable to risky alcohol use, which increases their likelihood of developing an alcohol use disorder in the future. As such, preventing and reducing alcohol use among college students should be a priority for health and social policies. This work was aimed to show that brief group-delivered MI is as effective as brief-group CBT at reducing alcohol use in college students. Eighty-nine college students (69 females; mean age = 21.01, SD = 2.85) with risky alcohol use, as measured by the AUDIT-C, were assigned to two groups, receiving three sessions of either brief group-delivered MI or CBT (bMI/bCBT). Alcohol use was assessed 3 and 6 months after the interventions, and analyzed according to an Intention-to-treat design. Changes in alcohol use at both points (relative to baseline) as well as post-intervention scores of intention to continue treatment and satisfaction with the psychologist were compared across groups, using one-sided Bayesian t-tests. Alcohol use decreased in both groups at the 3- and 6-months measurement points (relative to baseline). However, using bCBT superiority as an alternative hypothesis and the absence of such superiority as a point-null hypothesis, the Bayes factors supported the null at both the 3- and the 6-months follow-up (BF01 = 7.13, and BF01 = 5.22 respectively). Furthermore, the intention to continue treatment was substantially higher in the bMI group (BF10 = 9.77). These results are considerably robust to changes in analyses' priors. This study suggests that bCBT is not more effective than bMI at reducing alcohol use in our college student group (in which females are overrepresented). Additionally, bMI showed higher intention to continue treatment scores. The comparable results of brief and group-delivered CBT and MI interventions in alcohol use reduction allows clinicians to select treatments based on their own skills or preferences without any detriment to efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903743PMC
April 2020

Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M.

Biomed Pharmacother 2020 Jan 15;121:109601. Epub 2019 Nov 15.

Department of Physiological Sciences, School of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Spain. Electronic address:

Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued.

Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts.

Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity.

Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
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http://dx.doi.org/10.1016/j.biopha.2019.109601DOI Listing
January 2020

Maladaptive player-game relationships in problematic gaming and gaming disorder: A systematic review.

Clin Psychol Rev 2019 11 31;73:101777. Epub 2019 Oct 31.

Institute of Psychology, University of Lausanne, Lausanne, Switzerland; Addictive and Compulsive Behaviours Lab, Institute for Health and Behaviour, University of Luxembourg, Esch-sur-Alzette, Luxembourg.

While certain player vulnerabilities are known to increase risk of gaming disorder (GD), the topic of maladaptive player × game relationships in GD has received limited attention. This review aimed to: (1) identify game types associated with GD symptomatology; and (2) evaluate individual differences (e.g., age, personality, depression) in the relationship between gaming and GD symptomatology. A systematic review of six databases identified 23 studies of the relations between game types and GD, including 13 studies employing multivariate analyses. Player vulnerabilities implicated in GD included impulsivity, risk-taking, psychopathological symptoms (e.g., depression, anxiety), and stronger gaming motivations (e.g., escapism, achievement). MMORPG involvement had the strongest positive association with GD. Problematic MMORPG players tend to have a socially anxious profile and may be attracted to the work-like roles and conventions of this genre. Problematic players of shooters tend to score higher on measures of sensation-seeking and impulsivity than other players. These findings suggest that GD may develop more readily and at more severe levels in complex, endless, socially driven games, irrespective of person-level characteristics. Some player vulnerabilities may selectively increase risk of GD for certain game types. Further research should investigate different player-game interactions to refine current models and interventions for GD.
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http://dx.doi.org/10.1016/j.cpr.2019.101777DOI Listing
November 2019

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study.

Transl Psychiatry 2019 08 5;9(1):186. Epub 2019 Aug 5.

Lyon Neuroscience Research Center - INSERM U1028 - CNRS UMR5292, PSYR2 Team, University of Lyon, Lyon, France.

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.
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http://dx.doi.org/10.1038/s41398-019-0520-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683128PMC
August 2019

The paradoxical relationship between emotion regulation and gambling-related cognitive biases.

PLoS One 2019 5;14(8):e0220668. Epub 2019 Aug 5.

Mind, Brain and Behavior Research Center (CIMCYC), University of Granada, Granada, Spain.

Background: Gambling behavior presents substantial individual variability regarding its severity, manifestations, and psychological correlates. Specifically, differences in emotion regulation, impulsivity, and cognitive distortions have been identified as crucial to describe individual profiles with implications for the prevention, prognosis, and treatment of gambling disorder (GD).

Aims And Method: The aim of the present study was to investigate the associations of gambling-related cognitions (measured according to the GRCS model) with impulsivity (UPPS-P model) and emotion regulation (CERQ model), in a sample of 246 gamblers with different levels of gambling involvement, using mixed-effects modelling to isolate theoretically relevant associations while controlling for the potentially confounding effects of sociodemographic and clinical covariates.

Results: Affective/motivational dimensions of UPPS-P impulsivity positive urgency and sensation seeking, on the one hand, and CERQ emotion regulation strategies reappraisal, rumination and blaming others, on the other, independently and significantly predicted distorted gambling-related cognitions.

Conclusions: These results (a) reinforce the ones of previous studies stressing the relevance of emotional and motivational processes in the emergence of gambling-related cognitive distortions; and (b) replicate the seemingly paradoxical finding that gamblers use emotion regulation strategies customarily considered as adaptive (i.e. reappraisal) to strengthen and justify their biased beliefs about gambling outcomes and controllability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681951PMC
March 2020

Types of Emotion Regulation and Their Associations with Gambling: A Cross-Sectional Study with Disordered and Non-problem Ecuadorian Gamblers.

J Gambl Stud 2019 Sep;35(3):997-1013

Department of Experimental Psychology, Facultad de Psicología, Mind, Brain, and Behavior Research Center (CIMCYC), University of Granada, Campus de Cartuja s/n, 18071, Granada, Spain.

This cross-sectional study was aimed at investigating the role of emotional regulation in regular gambling in a sample of 197 disordered and non-problem gamblers from Ecuador. Two proxies were used as measures of behavioral signs of generalized emotion dysregulation (UPPS-P emotion-driven impulsivity) and intentional emotion regulation strategies (ERQ), and their associations with gambling cognitions (as measured by the GRCS questionnaire), gambling behavior (SOGS), and comorbid alcohol and drug misuse (MultiCAGE), were explored. For analyses, impulsivity traits, including emotion-driven impulsivity scores, were used as inputs to predict dispositional variables (ERQ strategies and GRCS cognitions), and clinically relevant behavioral outputs, while controlling for gambling severity. Hypotheses were based on previously published work, although the analysis has been improved (using hierarchical linear mixed-effects modelling), and homogenized in covariate control, and decision threshold stringency. Results were as follows: (1) After controlling for relevant covariates, UPPS-P sensation seeking was positively associated with gambling cognitions, whereas positive urgency was positively associated with cognitive biases (interpretative bias, control illusion, and predictive control) but not with other gambling cognitions. (2) Among emotion regulation strategies, reappraisal, but not suppression, was associated with gambling cognitions. (3) Negative urgency was distinctively associated with suppression, but not with reappraisal. And (4), no impulsivity dimensions significantly predicted drug or alcohol misuse, although negative urgency fell just below the decision threshold. These results reinforce the importance of emotion regulation processes in the cognitive and behavioral manifestations of gambling. Most importantly, they suggest a dissociation between the role of model-free dysregulation of negative emotions (as measured by UPPS-P negative urgency), as a key contributor to gambling complication and general psychopathology; and the one of strategic emotion regulation, in fueling gambling-related cognitive distortions.
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http://dx.doi.org/10.1007/s10899-019-09868-7DOI Listing
September 2019

The relationship between vigilance capacity and physical exercise: a mixed-effects multistudy analysis.

PeerJ 2019 6;7:e7118. Epub 2019 Jun 6.

Department of Psychology, Universidad Loyola Andalucía, Seville, Spain.

A substantial body of work has depicted a positive association between physical exercise and cognition, although the key factors driving that link are still a matter of scientific debate. Here, we aimed to contribute further to that topic by pooling the data from seven studies ( = 361) conducted by our research group to examine whether cardiovascular fitness (VO), sport type participation (externally-paced (e.g., football or basketball) and self-paced (e.g., triathlon or track and field athletes) vs. sedentary), or both, are crucial factors to explain the association between the regular practice of exercise and vigilance capacity. We controlled for relevant variables such as age and the method of VO estimation. The Psychomotor Vigilance Task was used to measure vigilance performance by means of reaction time (RT). The results showed that externally-paced sport practice (e.g., football) resulted in significantly shorter RT compared to self-paced sport (e.g., triathlon) and sedentary condition, depicting larger effects in children and adolescents than in adults. Further analyses revealed no significant effect of cardiovascular fitness and self-paced sport practice, in comparison to the sedentary condition, on RT. Our data point to the relevance of considering the type of sport practice over and above the level of cardiovascular fitness as crucial factor to explain the positive association between the regular practice of exercise and vigilance capacity.
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http://dx.doi.org/10.7717/peerj.7118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556370PMC
June 2019

Phenotypes in Gambling Disorder Using Sociodemographic and Clinical Clustering Analysis: An Unidentified New Subtype?

Front Psychiatry 2019 29;10:173. Epub 2019 Mar 29.

Department of Psychiatry, University Hospital of Bellvitge-IDIBELL, Barcelona, Spain.

Gambling disorder (GD) is a heterogeneous disorder which has clinical manifestations that vary according to variables in each individual. Considering the importance of the application of specific therapeutic interventions, it is essential to obtain clinical classifications based on differentiated phenotypes for patients diagnosed with GD. To identify gambling profiles in a large clinical sample of = 2,570 patients seeking treatment for GD. An agglomerative hierarchical clustering method defining a combination of the Schwarz Bayesian Information Criterion and log-likelihood was used, considering a large set of variables including sociodemographic, gambling, psychopathological, and personality measures as indicators. Three-mutually-exclusive groups were obtained. Cluster 1 ( = 908 participants, 35.5%), labeled as "high emotional distress," included the oldest patients with the longest illness duration, the highest GD severity, and the most severe levels of psychopathology. Cluster 2 ( = 1,555, 60.5%), labeled as "mild emotional distress," included patients with the lowest levels of GD severity and the lowest levels of psychopathology. Cluster 3 ( = 107, 4.2%), labeled as "moderate emotional distress," included the youngest patients with the shortest illness duration, the highest level of education and moderate levels of psychopathology. In this study, the general psychopathological state obtained the highest importance for clustering.
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http://dx.doi.org/10.3389/fpsyt.2019.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450083PMC
March 2019

The gambling craving experience questionnaire: Psychometric properties of a new scale based on the elaborated intrusion theory of desire.

Addict Behav 2019 08 27;95:110-117. Epub 2019 Feb 27.

Psychological Sciences Research Institute, Université catholique de Louvain, Louvain-la-Neuve, Belgium; Addictive and Compulsive Behaviours Lab, Institute for Health and Behaviour, University of Luxembourg, Luxembourg; Centre for Excessive Gambling, Lausanne University Hospitals (CHUV), Switzerland.

Both research and clinical practice acknowledge the importance of craving as a maintenance and relapse factor in gambling disorder. The elaborated intrusion theory (EIT; Kavanagh et al., 2005) of desire has been extensively investigated in relation to psychoactive substance or food cravings but, to date, has scarcely been studied in relation to gambling. In such a context, developing an assessment tool of gambling craving based on the EIT is warranted. To fill this gap in the literature, we aimed to develop and test the psychometric properties of a gambling-adapted version of the Craving Experience Questionnaire (CEQ; May et al., 2014), which is the best established measure of craving theoretically anchored in the EIT. An online survey that included the gambling CEQ (g-CEQ) and a craving induction procedure was administered to 274 community participants involved in gambling at least a few times a year. Concurrent and convergent validity were explored through correlations with a scale that measured gambling urge and with a series of questionnaires that measured disordered gambling symptoms, gambling cognitions, and gambling motives. The confirmatory factor analyses supported the validity of the expected three-factor model of the "strength" and "frequency" forms of the g-CEQ and showed better model fit than a one-factor solution, corroborating the initial structure of the CEQ. Furthermore, the scale has good internal consistency and its validity is supported by correlations with gambling-related constructs. The g-CEQ is thus a theoretically and psychometrically sound instrument to measure gambling craving based on the EIT.
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http://dx.doi.org/10.1016/j.addbeh.2019.02.023DOI Listing
August 2019

Reconsidering the roots, structure, and implications of gambling motives: An integrative approach.

PLoS One 2019 22;14(2):e0212695. Epub 2019 Feb 22.

Mind, Brain and Behavior Research Center (CIMCYC), University of Granada, Granada, Spain.

Rationale And Method: Accurately identifying motives to gamble is crucial in the functional analysis of gambling behavior. In this study, a data-driven approach was followed to clarify the factor structure underlying a pool of motives for gambling, selected from the Gambling Motives Questionnaire-Financial (GMQ-F), and the Reasons for Gambling Questionnaire (RGQ), in a sample of regular problem and non-problem gamblers. Additionally, the role of gambling motives in the relationship between root behavioral activation/inhibition systems (BIS/BAS) and gambling severity, frequency, and preferences was explored using structural equation modelling (SEM).

Results And Conclusions: The present study identified Social, Financial, and Fun/thrill-related gambling motives factors, but also a fourth factor in which some positive and negative reinforcement-based motives were grouped into a single and broader Affect regulation factor. This Affect regulation factor shared variance both with BIS and BAS-related measures, and was the only direct predictor of disordered gambling symptoms. The Fun/thrill factor was directly related to frequency of participation in high-arousal, skill-based games, and all factors were related to participation in lower-arousal, chance games (with Social motives negatively predicting both participation in the latter and total severity). In the SEM model, measures of BIS/BAS sensitivity were connected to gambling behavior only through gambling motives. Based on measures of items' specificity, a shortened Spanish scale (the brief Gambling Motives Inventory, bGMI) is proposed to assess gambling motives in accordance with the observed 4-factor structure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212695PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386301PMC
November 2019

Sex differences in the association between impulsivity and driving under the influence of alcohol in young adults: The specific role of sensation seeking.

Accid Anal Prev 2019 Mar 17;124:174-179. Epub 2019 Jan 17.

Mind, Brain and Behavior Research Centre, University of Granada, Spain; Andalusian Observatory on Drugs and Addictions, Spain. Electronic address:

Introduction: There is an outstanding need to identify predictors of driving under the influence of alcohol (DUI) among young adults, particularly women. Impulsivity, or the tendency to act without thinking, is a predictor of DUI, but the specific facets of impulsivity that predict DUI and their interaction with sex differences remain unclear. We aimed to investigate sex differences in the link between impulsivity facets and DUI. Moreover, we sought to replicate previous findings regarding sex differences on impulsivity, and associations between impulsivity facets and DUI.

Method: A total of 506 university students participated in the study (males, n = 128; females, n = 378). Participants completed measures of impulsivity (UPPS-P short version), alcohol use (AUDIT-C), frequency of DUI episodes and related perception of risk. The UPPS-P assesses five facets of impulsivity: sensation seeking, (lack of) premeditation and perseverance and positive and negative urgency.

Results: Men showed higher sensation seeking and lack of perseverance, alcohol use and DUI frequency and lower risk perception than women. DUI frequency was negatively associated with perception of risk and positively associated with alcohol use and the five impulsivity facets. After controlling for alcohol use and risk perception, only lack of premeditation was associated with DUI frequency in the whole sample. Sensation seeking was positively associated with DUI frequency only in women.

Discussion: The link between lack of premeditation and DUI suggest that pre-drinking planning strategies can contribute to prevent risky driving. In women, specific links between sensation seeking and DUI suggest the need for personality-tailored prevention strategies.
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http://dx.doi.org/10.1016/j.aap.2018.12.024DOI Listing
March 2019

Impulsivity and problem awareness predict therapy compliance and dropout from treatment for gambling disorder.

Adicciones 2019 Apr 1;31(2):147-159. Epub 2019 Apr 1.

Centro de Investigación Mente, Cerebro y Comportamiento (CIMCYC). Universidad de Granada, Granada. España. Universidad de Guayaquil, Guayaquil. Ecuador..

This study investigates the predictive value of impulsivity traits (as measured by the UPPS-P impulsive behaviour scale) and relevant covariates (sociodemographics, gambling severity, dysphoric mood, other potentially addictive behaviours, and non-verbal intelligence) with regard to treatment dropout and level of adherence to therapy guidelines and instructions in patients with gambling disorder. Sixty-six patients seeking treatment for gambling disorder, and recruited to participate in a larger protocol (G-Brain), were initially assessed in impulsivity traits and relevant covariates in the first six months after admission. Of these, 24 patients dropped out (DO) and 42 patients remained in therapy (NDO) during the subsequent 6-month follow-up period. A multivariate analysis of impulsivity subscales suggested prospective differences between DO and NDO, with affect-driven dimensions (positive and negative urgency) seemingly driving these differences. Among these, only positive urgency independently predicted a slight increase in the drop-out probability. In the NDO group, a higher degree of adherence to therapy was independently predicted by lower sensation-seeking scores and stronger awareness of gambling-related problems. Results suggest the presence of affect-driven impulsivity traits as dropout predictors in patients with gambling disorder. Awareness of gambling-related problems and lower sensation-seeking enhanced compliance with therapeutic guidelines and instructions.
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http://dx.doi.org/10.20882/adicciones.1041DOI Listing
April 2019

Exploring the direct or inverse association of physical activity with behavioral addictions and other self-regulation problems.

Adicciones 2019 Jan 1;31(1):18-32. Epub 2019 Jan 1.

Health, Medical and Neuropsychology Unit; Leiden University.

This cross-sectional survey study had the aim of clarifying the relationships between leisure time physical activity (LTPA) and non-drug-re-lated self-regulation problems (non-drug-related SRPs), including behavioral addictions, and the role of impulsive personality traits therein. Spanish university students (N = 329; Mage = 21.20) completed questionnaires for each of these constructs. Fitness and Bodybuilding LTPA was negatively associated with video gaming-related SRPs, r = -.13, p = .019, 95% CI (bootstrapped) [-.23, -.02], and positively associated with sex-related SRPs, r = .16, p = .005, 95% CI (bootstrapped) [.04,  .30]. Endurance LTPA was associated with higher scores in eating-related SRPs, r = .17, p = .003, 95% CI (bootstrapped) [.02,  .31]. The proportion of participants presenting scores above the clinically significant threshold in eating-related SRPs was 2.64 times higher for respondents in an Excessive Endurance LTPA cluster compared to the other respondents, Fisher's exact test, p = .017, OR = 3.10, 95% CI [1.26, 7.63], and the proportion of participants reporting vomiting to control weight was 2.12 times higher, Fisher's exact test, p = .040, OR = 2.43, 95% CI [1.06, 5.57]. The associations were largely independent of impulsive personality traits. We identified an elevated risk of eating pathology in a subgroup of participants with anomalously high participation in endurance physical activity. This overlap is consistent with the secondary dependence hypothesis of exercise addiction.
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http://dx.doi.org/10.20882/adicciones.926DOI Listing
January 2019
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