Psychological and neurobiological markers in individuals with gambling disorder (GD) could reflect transdiagnostic vulnerability to addiction or neuroadaptive consequences of long-term gambling. Using an endophenotypic approach to identify vulnerability markers, we tested the biological relatives of cases with GD. Male participants seeking treatment for GD (n = 20) were compared with a male control group (n = 18). Biological siblings of cases with GD (n = 17, unrelated to the current GD group) were compared with a separate control group (n = 19) that overlapped partially with the GD control group. Participants completed a comprehensive assessment of clinical scales, neurocognitive functioning, and fMRI of unexpected financial reward. The GD group displayed elevated levels of self-report impulsivity and delay discounting, and increased risk-taking on the Cambridge Gamble Task. We did not observe impaired motor impulsivity on the stop-signal task. Siblings of GD showed some overlapping effects; namely, elevated impulsivity (negative urgency) and increased risk-taking on the Cambridge Gamble Task. We did not observe any differences in the neural response to win outcomes, either in the GD or sibling analysis compared with their control group. Within the GD group, activity in the thalamus and caudate correlated negatively with gambling severity. Increased impulsivity and risk-taking in GD are present in biological relatives of cases with GD, suggesting these markers may represent pre-existing vulnerability to GD.
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Verdejo-García A, Lawrence AJ, Clark L. Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies. Neurosci Biobehav Rev. 2008;32:777–810.
Bechara A. Risky business: emotion, decision-making, and addiction. J Gambl Stud. 2003;19:23–51.
Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: changes in grey matter induced by training. Nature. 2004;427:311–2.
Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.
Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW. Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits. Biol Psychiatry. 2010;68:770–3.
Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD. Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci. 2012;16:81–91.
Black DW, Monahan PO, Temkit M’hamed, Shaw M. A family study of pathological gambling. Psychiatry Res. 2006;141:295–303.
Walters GD. Behavior genetic research on gambling and problem gambling: a preliminary meta-analysis of available data. J Gambl Stud. 2001;17:255–71.
Mann K, Lemenager T, Zois E, Hoffmann S, Nakovics H, Beutel M, et al. Comorbidity, family history and personality traits in pathological gamblers compared with healthy controls. Eur Psychiatry. 2017;42:120–8.
Hodgins DC, Schopflocher DP, el-Guebaly N, Casey DM, Smith GJ, Williams RJ, et al. The association between childhood maltreatment and gambling problems in a community sample of adult men and women. Psychol Addict Behav. 2010;24:548–54.
Slutske WS, Eisen S, True WR, Lyons MJ, Goldberg J, Tsuang M. Common genetic vulnerability for pathological gambling and alcohol dependence in men. Arch Gen Psychiatry. 2000;57:666–73.
Lobo DSS. Genetic aspects of gambling disorders: recent developments and future directions. Curr Neurol Neurosci Rep. 2016;3:58–66.
Kräplin A, Dshemuchadse M, Behrendt S, Scherbaum S, Goschke T, Bühringer G. Dysfunctional decision-making in pathological gambling: Pattern specificity and the role of impulsivity. Psychiatry Res. 2014;215:675–82.
Michalczuk R, Bowden-Jones H, Verdejo-Garcia A, Clark L. Impulsivity and cognitive distortions in pathological gamblers attending the UK National Problem Gambling Clinic: a preliminary report. Psychol Med. 2011;41:2625–35.
MacKillop J, Amlung MT, Few LR, Ray LA, Sweet LH, Munafò MR. Delayed reward discounting and addictive behavior: a meta-analysis. Psychopharmacol. 2011;216:305–21.
Chowdhury NS, Livesey EJ, Blaszczynski A, Harris JA. Pathological gambling and motor impulsivity: a systematic review with meta-analysis. J Gambl Stud. 2017;33:1213–39.
Kovács I, Richman MJ, Janka Z, Maraz A, Andó B. Decision making measured by the Iowa Gambling Task in alcohol use disorder and gambling disorder: a systematic review and meta-analysis. Drug Alcohol Depend. 2017;181:152–61.
Wilson MJ, Vassileva J. Decision-making under risk, but not under ambiguity, predicts pathological gambling in discrete types of abstinent substance users. Front Psychiatry. 2018;9:239.
Zois E, Kortlang N, Vollstädt-Klein S, Lemènager T, Beutel M, Mann K, et al. Decision-making deficits in patients diagnosed with disordered gambling using the Cambridge Gambling task: the effects of substance use disorder comorbidity. Brain Behav. 2014;4:484–94.
Lawrence AJ, Luty J, Bogdan NA, Sahakian BJ, Clark L. Problem gamblers share deficits in impulsive decision-making with alcohol-dependent individuals. Addiction. 2009;104:1006–15.
Grant JE, Chamberlain SR, Schreiber LRN, Odlaug BL, Kim SW. Selective decision-making deficits in at-risk gamblers. Psychiatry Res. 2011;189:115–20.
Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci. 2005;8:1450–7.
Stevens L, Verdejo-García A, Goudriaan AE, Roeyers H, Dom G, Vanderplasschen W. Impulsivity as a vulnerability factor for poor addiction treatment outcomes: a review of neurocognitive findings among individuals with substance use disorders. J Subst Abus Treat. 2014;47:58–72.
Luijten M, Schellekens AF, Kühn S, Machielse MWJ, Sescousse G. Disruption of reward processing in addiction: an image-based meta-analysis of functional magnetic resonance imaging studies. JAMA Psychiatry. 2017;74:387–98.
Reuter J, Raedler T, Rose M, Hand I, Gläscher J, Büchel C. Pathological gambling is linked to reduced activation of the mesolimbic reward system. Nat Neurosci. 2005;8:147–8.
De Ruiter MB, Veltman DJ, Goudriaan AE, Oosterlaan J, Sjoerds Z, Van Den Brink W. Response perseveration and ventral prefrontal sensitivity to reward and punishment in male problem gamblers and smokers. Neuropsychopharmacology. 2009;34:1027–38.
Balodis IM, Kober H, Worhunsky PD, Stevens MC, Pearlson GD, Potenza MN. Diminished frontostriatal activity during processing of monetary rewards and losses in pathological gambling. Biol Psychiatry. 2012;71:749–57.
Romanczuk-Seiferth N, Koehler S, Dreesen C, Wüstenberg T, Heinz A. Pathological gambling and alcohol dependence: neural disturbances in reward and loss avoidance processing. Addict Biol. 2015;20:557–69.
Sescousse G, Janssen LK, Hashemi MM, Timmer MHM, Geurts DEM, Ter Huurne NP, et al. Amplified striatal responses to near-miss outcomes in pathological gamblers. Neuropsychopharmacology. 2016;41:2614–23.
Sescousse G, Barbalat G, Domenech P, Dreher J-C. Imbalance in the sensitivity to different types of rewards in pathological gambling. Brain. 2013;136:2527–38.
Miedl SF, Fehr T, Meyer G, Herrmann M. Neurobiological correlates of problem gambling in a quasi-realistic blackjack scenario as revealed by fMRI. Psychiatry Res. 2010;181:165–73.
Blum K, Gardner E, Oscar-Berman M, Gold M. ‘Liking’ and ‘wanting’ linked to Reward Deficiency Syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry. Curr Pharm Des. 2012;18:113–8.
Gold MS, Badgaiyan RD, Blum K. A shared molecular and genetic basis for food and drug addiction: overcoming hypodopaminergic trait/state by incorporating dopamine agonistic therapy in psychiatry. Psychiatr Clin North Am. 2015;38:419–62.
Robinson TE, Berridge KC. Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci. 2008;363:3137–46.
Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18:247–91.
Limbrick-Oldfield EH, van Holst RJ, Clark L. Fronto-striatal dysregulation in drug addiction and pathological gambling: consistent inconsistencies? NeuroImage: Clin. 2013;2:385–93.
Büchel C, Peters J, Banaschewski T, Bokde ALW, Bromberg U, Conrod PJ, et al. Blunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents. Nat Commun. 2017;8:14140.
Whelan R, Watts R, Orr CA, Althoff RR, Artiges E, Banaschewski T, et al. Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature. 2014;512:185–9.
Heinrich A, Müller KU, Banaschewski T, Barker GJ, Bokde ALW, Bromberg U, et al. Prediction of alcohol drinking in adolescents: Personality-traits, behavior, brain responses, and genetic variations in the context of reward sensitivity. Biol Psychol. 2016;118:79–87.
Ersche KD, Turton AJ, Chamberlain SR, Müller U, Bullmore ET, Robbins TW. Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes for drug dependence. Am J Psychiatry. 2012;169:926–36.
Ferris J, Wynne H. The Canadian problem gambling index. Final report. Ottawa: Canadian Centre on Substance Abuse; 2001.
Wechsler D. Wechsler abbreviated scale of intelligence: WASI. 1999.
Beck AT, Steer RA, Brown GK. Manual for Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation; 1996.
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893–831.
Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. for the Ambulatory Care Quality Improvement Project. The AUDIT Alcohol Consumption Questions (AUDIT-C): An Effective Brief Screening Test for Problem Drinking. Arch Intern Med. 1998;158:1789.
Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363–71.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom K-O. The Fagerström test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86:1119–27.
Kessler RC, Hwang I, LaBrie R, Petukhova M, Sampson NA, Winters KC, et al. DSM-IV pathological gambling in the National Comorbidity Survey Replication. Psychol Med. 2008;38:1351–60.
Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abus Negl. 2003;27:169–90.
Lesieur HR, Blume SB. The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers. Am J Psychiatry. 1987;144:1184–8.
Cyders MA, Smith GT, Spillane NS, Fischer S, Annus AM, Peterson C. Integration of impulsivity and positive mood to predict risky behavior: development and validation of a measure of positive urgency. Psychol Assess. 2007;19:107–18.
Kirby KN, Petry NM, Bickel WK. Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. J Exp Psychol Gen. 1999;128:78–87.
Logan GD, Cowan WB, Davis KA. On the ability to inhibit simple and choice reaction time responses: a model and a method. J Exp Psychol Hum Percept Perform. 1984;10:276–91.
Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, et al. Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology. 1999;20:322–39.
Chase HW, Clark L. Gambling severity predicts midbrain response to near-miss outcomes. J Neurosci. 2010;30:6180–7.
Clark L, Lawrence AJ, Astley-Jones F, Gray N. Gambling near-misses enhance motivation to gamble and recruit win-related brain circuitry. Neuron. 2009;61:481–90.
Clark L, Studer B, Bruss J, Tranel D, Bechara A. Damage to insula abolishes cognitive distortions during simulated gambling. Proc Natl Acad Sci USA. 2014;111:6098–103.
van Timmeren T, Zhutovsky P, van Holst RJ, Goudriaan AE. Connectivity networks in gambling disorder: a resting-state fMRI study. Int Gambl Stud. 2018;18:242–58.
Segarra N, Metastasio A, Ziauddeen H, Spencer J, Reinders NR, Dudas RB, et al. Abnormal Frontostriatal Activity During Unexpected Reward Receipt in Depression and Schizophrenia: Relationship to Anhedonia. Neuropsychopharmacology. 2016;41:2001–10.
Clark L, Boileau I, Zack M. Neuroimaging of reward mechanisms in Gambling disorder: an integrative review. Mol Psychiatry. 2019;24:674–93.
Leyton M, Vezina P. Striatal ups and downs: their roles in vulnerability to addictions in humans. Neurosci Biobehav Rev. 2013;37:1999–2014.
Fauth-Bühler M, Zois E, Vollstädt-Klein S, Lemènager T, Beutel M, Mann K. Insula and striatum activity in effort-related monetary reward processing in gambling disorder: the role of depressive symptomatology. NeuroImage: Clin. 2014;6:243–51.
van Holst RJ, Veltman DJ, Büchel C, Van Den Brink W, Goudriaan AE. Distorted expectancy coding in problem gambling: is the addictive in the anticipation? Biol Psychiatry. 2012;71:741–8.
Billieux J, Lagrange G, Van der Linden M, Lançon C, Adida M, Jeanningros R. Investigation of impulsivity in a sample of treatment-seeking pathological gamblers: a multidimensional perspective. Psychiatry Res. 2012;198:291–6.
Navas JF, Billieux J, Perandrés-Gómez A, López-Torrecillas F, Cándido A, Perales JC. Impulsivity traits and gambling cognitions associated with gambling preferences and clinical status. Int Gambl Stud. 2017;17:102–24.
Volkow ND, Wang G-J, Begleiter H, Porjesz B, Fowler JS, Telang F, et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families. Arch Gen Psychiat. 2006;63:999.
Tuvblad C, Gao Y, Wang P, Raine A, Botwick T, Baker LA. The genetic and environmental etiology of decision-making: a longitudinal twin study. J Adolesc. 2013;36:245–55.
Wilson D, da Silva Lobo DS, Tavares H, Gentil V, Vallada H. Family-based association analysis of serotonin genes in pathological gambling disorder: evidence of vulnerability risk in the 5HT-2A receptor gene. J Mol Neurosci. 2013;49:550–3.
Lobo DSS, Aleksandrova L, Knight J, Casey DM, el-Guebaly N, Nobrega JN, et al. Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models. Mol Psychiatry. 2015;20:1002–10.
Comings DE, Rosenthal RJ, Lesieur HR, Rugle LJ, Muhleman D, Chiu C, et al. A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics. 1996;6:223–34.
Qin H, Zeng J, Chen H, Deng L, Su L, Can Your DNA. Influence your bet-placing? the impact of cannabinoid receptor 1 gene on gambling tasks. Front Hum Neurosci 2018;12:458.
Nees F, Tzschoppe J, Patrick CJ, Vollstädt-Klein S, Steiner S, Poustka L, et al. Determinants of early alcohol use in healthy adolescents: the differential contribution of neuroimaging and psychological factors. Neuropsychopharmacology. 2012;37:986–95.
Morales AM, Jones SA, Ehlers A, Lavine JB, Nagel BJ. Ventral striatal response during decision making involving risk and reward is associated with future binge drinking in adolescents. Neuropsychopharmacology. 2018;43:1884–90.
Galvan A, Hare TA, Parra CE, Penn J, Voss H, Glover G, et al. Earlier development of the accumbens relative to orbitofrontal cortex might underlie risk-taking behavior in adolescents. J Neurosci. 2006;26:6885–92.
Hoogendam JM, Kahn RS, Hillegers MHJ, van Buuren M, Vink M. Different developmental trajectories for anticipation and receipt of reward during adolescence. Dev Cogn Neurosci. 2013;6:113–24.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:830–3.
Hommer DW, Bjork JM, Gilman JM. Imaging brain response to reward in addictive disorders. Ann N Y Acad Sci. 2011;1216:50–61.
Clark L, Bechara A, Damasio H, Aitken MRF, Sahakian BJ, Robbins TW. Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making. Brain. 2008;131:1311–22.
Li Y, Wang Z, Boileau I, Dreher J-C, Gelskov S, Genauck A, et al. Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study. Transl Psychiatry. 2019;9:186.
Goodwin BC, Browne M, Rockloff M, Rose J. A typical problem gambler affects six others. Int Gambl Stud. 2017;17:276–89.
Slutske WS, Zhu G, Meier MH, Martin NG. Genetic and environmental influences on disordered gambling in men and women. Arch Gen Psychiatry. 2010;67:624–30.
Vitaro F, Hartl AC, Brendgen M, Laursen B, Dionne G, Boivin M. Genetic and environmental influences on gambling and substance use in early adolescence. Behav Genet. 2014;44:347–55.
Hoehne A, Richard-Devantoy S, Ding Y, Turecki G, Jollant F. First-degree relatives of suicide completers may have impaired decision-making but functional cognitive control. J Psychiatr Res. 2015;68:192–7.
Cavedini P, Zorzi C, Piccinni M, Cavallini MC, Bellodi L. Executive dysfunctions in obsessive-compulsive patients and unaffected relatives: searching for a new intermediate phenotype. Biol Psychiatry. 2010;67:1178–84.
The authors wish to thank the study participants and the clinical team at Imanova, Centre for Imaging Sciences. The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Funding and disclosure
This study was funded by the Medical Research Council- MRC G1100554 (Clark). E.H.L.O. works as a postdoctoral fellow at the Centre for Gambling Research at UBC which is supported by funding from the Province of British Columbia and the British Columbia Lottery Corporation (BCLC), a Canadian Crown Corporation. She has received a speaker honorarium from the Massachusetts Council on Compulsive Gambling (U.S.A.) and accepted travel/accommodation for speaking engagements from the National Council for Responsible Gambling (U.S.A.), the International Multidisciplinary Symposium on Gambling Addiction (Switzerland) and the Responsible Gambling Council (Canada). She has not received any further direct or indirect payments from the gambling industry or groups substantially funded by gambling. ALH has received Honoraria paid into her Institutional funds for speaking and Chairing engagements from Lundbeck, Lundbeck Institute UK, Janssen-Cilag; received research grants or support from Lundbeck, GSK; consulted by but received no monies from Opiant and Lightlake. HBJ is Director of the NPGC, London, Spokesperson on Behavioural Addictions for Royal College of Psychiatrists, and Board member of International Society of Addictions Medicine. LC is the Director of the Centre for Gambling Research at UBC, which is supported by funding from the Province of British Columbia and the British Columbia Lottery Corporation (BCLC), a Canadian Crown Corporation. LC receives funding from the Natural Sciences and Engineering Research Council (Canada). LC has received a speaker/travel honorarium from the National Association for Gambling Studies (Australia) and reviewing honoraria from the National Center for Responsible Gaming (US) and Gambling Research Exchange Ontario (Canada). He has not received any further direct or indirect payments from the gambling industry or groups substantially funded by gambling. He has provided paid consultancy to, and received royalties from, Cambridge Cognition Ltd. relating to neurocognitive testing. IM, REC, RSAF, ST have no sources of funding or potential conflict of interests to be declared.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.