Inhoud presenta5e Verslaving: recente neurobiologische inzichten en therapeu5sche implica5es. Introduc5on epidemiology Neurobiology Treatment Conclusions Geert Dom PC Broeders Alexianen, Boechout Universiteit Antwerpen (UA, UZA Neurobiologisch een poligene5sch bepaalde, progressieve hersenaandoening met een extreem heterogeen fenotype Risk Factors for Alcoholism or Drug Dependence GENETIC Specific genes G X E Interaction ENVIRONMENTAL Family, Peers Workplace Comorbidity Early onset Ini)a)e gebruik: - (Thuis) milieu - persoonlijkheid Pathogenese factoren? Transi'e verslaving: - Gene$sch - Neurobiologische kwetsbaarheid - Peer omgeving Epidemiology Substance use paqerns Dependence Use addic)on Toename gebruik en misbruik: - Peer groep - - gene5sch - - persoonlijkheidstrekken - Neurobiologisch o.m. decision making con)nua)on 1
Life5me Prevalence of Substance Use Disorders in NCS- R Substance Tobacco Drug Use, Drug Addicts and Treatment Total Popula5on: N = 16.000.000 Regular Users year prevalence Addicts year prevalence Treated Addicts year prevalence Percentage in treatment 4.000.000 4.000.000 minimal minimal Alcohol 10.000.000 350.000 30.000 8-10% Benzodiazepines 500.000 250.000 minimal minimal Heroin (poly) 26.000 25.000 17.500 70% Cocaine (poly) >30.000 >20.000 5.000 20% Cannabis 500.000?? 3.000?? Kessler, R. C. et al. Arch Gen Psychiatry 2005;62:593-602. XTC 70.000?? 300?? Burden of disease aqributable to alcohol and tobacco Epidemiologie: vaststellingen! Prevalen5e van middelenproblemen is hoog! Gevolgen middelenproblemen massaal Prevalen5e van middelenproblemen is laag! The World Health Report, WHO, 2002. Inhoud presenta5e Neural Circuitry Mediating the Activation of Goal-Directed Behavior Introduc5on epidemiology Neurobiology Treatment Conclusions CONTROL INHIBITORY CONTROL PFC SCC MOTIVATION/ DRIVE ACG NAcc Amy g Hipp VP REWARD MEMORY/ LEARNING 2
Neurobiologie Pathways to addic'on: Life- span developmental perspec5ve on e5ology of alcohol/drug use and abuse Addic$on = developmental disorder Premorbid vulnerability Start in early adolescence Addic5on progressive disorder Addic5on hypofunc5onality reward system Addic5on = Hypersensi5vity reward system Addic5on = hypofunc5onality self- control Externalizing: 1. Phenotype: symptom clustering Babor et al. (2003), Cloninger, Lesh,. 2. Family clustering 3. Genetic polymorphisms? 4. Endophenotypes Pathways to addic'on: Life- span developmental perspec5ve on e5ology of alcohol/drug use and abuse ``Inability/unwillingness or failure to inhibit behaviral impuses despite negative consequences 1. Phenotype: symptom clustering Babor et al. (2003), Cloninger, Lesh,. 2.?? 3.?? 4.?? Externalizing pathway -disinhibition - novelty/sensation seeking - Antisocial behavior - Impulsivity - Aggressiveness delinquency Externalizing: Internalizing Six Longitudinal studies ``des5ny MaQers`` Addic5on 103, S1, 2008 Childhood >>40 y. Genotype Behavioral undercontrol or impulsivity 1. Childhood behavioral control 2.Parental alcoholism 2. ADDICTION IS A DEVELOPMENTAL DISEASE % in each age group who develop firsttime cannabis use disorder Wong et al. 2006 starts in adolescence and childhood 1.6% 1.4% 1.2% 1.0% Early age drinking 14y. 0.6% 0.8% 0.4% 0.2% Problem drinking in adolescence (Ellickson et al., 2003; Ferguson et al., 1994) Adult alcohol abuse or dependence (Pitkanen et al., 2005; York et al., 2004) 0.0% 5 10 15 18 25 30 35 40 45 50 55 60 65 70 Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003 3
Neurobiologie Addic5on = developmental disorder Addic$on& Psychiatry = progressive disorder Addic5on hypofunc5onality reward system Addic5on = Hypersensi5vity reward system Addic5on = hypofunc5onality self- control Figure 4. The Three Stages of Addictiona aacute drug effects occur widely in dopamine terminal fields in the circuit shown in Figure 1. Neuroadaptations mediating the transition from recreational drug use to addiction endure for a finite period after discontinuation of repeated drug administration and initiate the changes in protein expression and function that emerge during withdrawal and underlie the behavioral characteristics of end-stage addiction, such as craving, relapse, and reduced ability to suppress drug seeking. Hersenfuncties, Hersenstructuren en Neurotransmitters Functies Structuren Neurotransmitters Initiatie Anhedonie Conditionering Craving Importantie Attentional Bias Gewoontevorming Disinhibitie Conflictregistratie Ventral Tegmental Area (VTA) Nucleus Accumbens (NcA) Nucleus Accumbens (Ventrale Striatum) Amygdala Thalamus Prefrontal Cortex (, ACC) Putamen, NcCaudatus (Dorsale Striatum) DLPFC ACC Endorfines (µ-receptors) Dopamine Dynofhines (κ-receptors) Dopamine CRH Glutamaat Dopamine Dopamine Noradrenaline, 5HT GABA, Glutamaat Neurobiologie Addic5on = developmental disorder Addic5on progressive disorder Addic$on hypofunc$onality reward system Addic5on = Hypersensi5vity reward system Addic5on = hypofunc5onality self- control Onthoudingssymptomen Locus Ceruleus (LC) Noradrenaline Glutamaat Van den Brink, 2005, 2006; Van Ree, 2002; de Vries and Schippenberg, 2002; Kreek et al, 2002; Kosten and George, 2002; Koob, 2003 Natural Rewards Elevate Dopamine Levels" Drugs of Abuse 150" Engage Systems in the Motivation and 100" Pleasure Pathways 50" of the Brain 0" % of Basal DA Output" 200" FOOD" Empty" Box"Feeding" NAc shell 0" 60" 120" 180" Time (min)" DA Concentration (% Baseline)" 200" 150" 100" SEX" Female Present" Sample" 1" 2" 3" 4" 5" 6" 7" 8" Number" 15" 10" 5" 0" Copulation Frequency" Mounts" Intromissions" Ejaculations" Di Chiara et al., Neuroscience, 1999.! Fiorino and Phillips, J. Neuroscience, 1997.! 4
Effects of Drugs on Dopamine Release" % of Basal Release" 1100" 1000" 900" 800" 700" 600" 500" 400" 300" 200" 100" 0" Accumbens" AMPHETAMINE" DA" DOPAC" HVA" 0" 1" 2" 3" 4" 5 hr" Time After Amphetamine" % of Basal Release" 400" 300" 200" 100" 0" Accumbens" COCAINE" DA" DOPAC" HVA" 0" 1" 2" 3" 4" 5 hr" Time After Cocaine" Your Brain on Drugs Today" Front of Brain" Back of Brain" 1-2 Min" 3-4" 5-6" YELLOW shows places in brain where cocaine goes (striatum)" % of Basal Release" 250" 200" 150" 100" 0" 0" 1" 2" 3 hr" Time After Nicotine" NICOTINE" Accumbens" Caudate" % of Basal Release" 250" 200" 150" 100" 0" Accumbens" MORPHINE" Dose (mg/kg)" 0.5" 1.0" 2.5" 10" 0" 1" 2" 3" 4" 5hr" Time After Morphine" Di Chiara and Imperato, PNAS, 1988! 6-7" 7-8" 8-9" 9-10" 10-20" 20-30" Fowler et al., Synapse, 1989.! Dierenmodellen Eleva$ons in ICSS Reward Thresholds During Withdrawal Sure! Wanna look for some cheese with me? Allosta5c Change in Mood State associated with Transi5on to Drug Addic5on Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129. 5
DA D2 Receptor Availability Dopamine D2 Receptors are Lower in Addiction Beeldvormend onderzoek Cocaine Meth DA" DA" DA" DA" DA " DA " DA DA " DA " " DA" DA " DA " Reward Circuits Non-Drug Abuser Alcohol DA" DA" DA" DA" DA " DA" Heroin Control Addicted Reward Circuits Drug Abuser Effect of Cocaine Abuse on Dopamine D2 Receptors CRAVING INDUCTION IN A PET SETTING normal subject ΔCRAVING 5 N = 13 4 3 2 1 0-1 Neutral Cocaine STIMULI Conditioned Association 2.5" 2.0" 1.5" cocaine abuser (1 month post) 1.0".5" cocaine abuser (4 months post) Nature Video Cocaine Video Childress et al., Am. J. Psychiatry, 1999! 0" Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Neurobiologie Signal Intensity (AU) Cingulate Ant. Cing. Addic5on = developmental disorder Addic5on progressive disorder Addic5on hypofunc5onality reward system Addic5on = Hypersensi5vity reward system Addic$on = hypofunc$onality self- control Cocaine Film Erotic Film IFG Controls Cocaine Users Garavan et al., Am. J. Psychiatry, 2000. 6
Wat toont beeldvorming ivm PFC? Structurele beeldvorming Func5onele beeldvorming Metabolisme en receptor densiteit WiQe stof - verbindingsbanen Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Inhibitory Control CG PreF Striatum Salience Attribution control cocaine abuser umol/100g/min umol/100gr/min 65 60 55 50 45 40 35 r = 0.7, P < 0.001 30 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 90 80 70 60 50 Cocaine Abusers METH Abusers 40 r = 0.7, P < 0.005 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 DA D2 Receptors (Bmax/kd) Verslaving: een gebrek aan wilskracht om aan drugs te weerstaan. Een neurocogni5ef perspec5ef Neurocogni5ef onderzoek?aanwijzingen voor prefronatale stoornissen in zelfregula5e processen? Decision making Impulse controle o Motorische impulsiviteit o Perceptuele impulsiviteit Samen = gebrek aan wilskracht Wilskracht = Een combina)e van vasthoudendheid en zelf- discpline die iemand het mogelijk maakt om bepaalde dingen te doen ondanks de moeilijkheden die daarmee gepaard gaan. Het help ons opofferingen te verdragen met het oog op latere voordelen. Dom et al. (2005). British Journal Psychiatry 7
Decision making: Iowa Gambling task Circuits betrokken bij decision making CONTROL INHIBITORY CONTROL MOTIVATION/ DRIVE PFC SCC ACG NAcc Hipp VP REWARD Afwegen onmiddelijke voordelen versus..latere negatieve gevolgen Risico nemen Kick seeking Amy g MEMORY/ LEARNING Assessing circuitry implicated in tagging expectations with emotional significance Alc Dep Tabac Illicit Drug & PSA PG VMPFC ACC Amygdala/ Ventral Striatum 3.5 3 2.5 2 1.5 1 0.5 Control > MA t-values 5 4 3 2 1 MA > Control Hypoactivity in VMPFC Schizo frenis CD Behavioral self control or ``willpower`` Mesolimbic PFC executive Stress Adolescentie OCD MD BD London et al. ADHD ASP D BPD Boulemia Conclusion I" Non-Addicted Brain Addicted Brain Neurobiology Control Control Conclusions Saliency Drive NOT GO Saliency Drive GO Memory Memory Source: Adapted from Volkow et al., Neuropharmacology, 2004.! 8
Conclusion II: Addiction is a chronic medical disorder with the brain as a target organ! High Neurocognitieve stoornissen in zelfregulatie bij verslaving Impliciete cognitieve Inhibitie stoornissen veranderingen: Motorisch Herinneringen Verslaving Perceptueel Attentional Bias Controleverlies Prikkels en respons Gebruik Craving Ondanks negatieve gevolgen Control Cocaine Abuser Prefrontale regio GAC DLPC VMPfC Stoornis besluitvorming VMPfC Insua GAC Amygdala Mesolimbisch Amygdala Striatum NAc VTA Low Inhibitie processen Motivationele processen Healthy Heart Diseased Heart Sources: From the laboratories of Drs. N. Volkow and H. Schelbert Acute effecten Middelen gebruik Neurotoxische Gevolgen Chronisch Middelen gebruik Voorafbestaand stoornissen Inhibitie functies Gevolgen van Langdurig/intensief middelngebruik Toename importantie Neurotoxische Gevolgen Langdurig Middelen gebruik Vooraf bestaande Stoornissen Motivationele functies Neurocognitieve stoornissen bij verslaving en behandelimplicaties Verslavingsproblemen Therapeu5sche implica5es Stoornissen Impulscontrole Stoornissen Besluitvorming Stoornissen Impliciete cognitie Training Zelfcontrole vaardigheden Inspelen directe behoefte bevrediging Contingency strategieën CRA Attentional retraining Cue exposure (?) Behandeling <> onderliggende factor Ontwikkelingsstoornis: behavioral disinhibi5e pathway. Stoornis in de cogni5eve zelfregula5e: Impuls controle Besluitvorming <> directe behoeje Stoornis in het beloningssysteem Overma5ge aandacht Ongevoeligheid beloningssysteem Progressieve stoornis Schade door langdurig gebruik Ontwikkelingsstoornis: vroege interven5e 9
May 2008 - Vol. 103 s1, Destiny Matters: Childhood and Adolescent Prediction of Adult Alcohol Use and Abuse in Six Multi-decade Longitudinal Studies Page 1-109 1. Good Behavior Game (GBG): classroom behavior manegement used by teachers in first- and second grade classrooms.follow-up impact ages 19-21. 2. Intervention aimed to socialize children to student role and reduce aggressive, disruptive behaviors (antecedents of later SUD and ASPD). Hypthesis Design Childhood aggressive & Disruptive behavior Randomized first & second grade Alcohol A & D Drug A & D Regular smoking Continued disruptive behavior Pychiatric symptoms 6 GBG Classes = 238 Children 6 internal control classes = 169 Children ASPD Delinquency School failure Suicide ideation Depressive & anxiety The etiological question is: Is the specific antecedent of early aggressive, disruptive behavior part of the causal processes that lead to drug abuse/dependence or is it just a preceding early correlate? Answer: If the GBG can influence A&D outcome, this provides an argument for causal relationship. 2 year GBG implementation Results after 1 year = diminishment aggressive/disruptive behavior boys. Follow-up 19-21 years Stoornissen in zelfregula5e Psychosociaal Alle `oude` interven5es: hervalpreven5e, func5e analyse, Impulse controle: DGT, training Delay discoun5ng: CM & CRA Farmacologisch An5- E (toparimaat) Cogni5ve enhancer: Methylfenidaat Modafinil dexamfetamine 10
AQen5onal bias Ongevoeligheid reward - anhedonie Psychosociaal AQen5onal retraining Farmacologisch Acamprosaat Naltrexone Subs5tu5e Methadone- boprenorfine S5mulan5a Psychosociaal S5mula5e CM & CRA? ACT / mindfullness Farmacologisch DA an5deprieva (e.g. bupropion) S5mulan5a: modafinil TCS Progressieve stoornis Belang van vroeg detec5e/behandeling Belang van langdurige behandeling Verslaving en Medicamenteuze Interven$es Medicatie Cocaineverslaving Nog geen bewezen- effec$ve medicamenteuze behandeling beschikbaar Veelbelovend Disulfiram Modafinil Topiramate/Baclofen/Tiagabine Naltrexone Rimonabant Varenicline Deep Brain Stimulation Verslaving en Neurofysiologische Interven$es 11
Neurobiologie en Biofeedback Repeated Reward Detection Threshold Disinhibition Attentional Bias Cue-Reactivity Craving BioFeedback Relapse Conflict Registration Conflictregistratie bij Cocaineverslaafden EEG Biofeedback en Verslaving Am J Drug Alcohol Abuse. 2005;31(3):455-69. ScoQ WC, Kaiser D, Othmer S, Sideroff SI Effects of an EEG biofeedback protocol on a mixed substance abusing popula$on. This study examined whether an EEG biofeedback protocol could improve outcome measures for a mixed substance abusing inpa5ent popula5on. METHOD: One hundred twenty- one volunteers undergoing an inpa5ent substance abuse program were randomly assigned to the EEG biofeedback or control group. EEG biofeedback included training in Beta and SMR to address aqen5onal variables, followed by an alpha- theta protocol. Subjects received a total of 40 to 50 biofeedback sessions. The control group received addi5onal 5me in treatment equivalent to experimental procedure 5me. The Test of Variables of AQen5on (TOVA), and MMPI, were administered with both tester and subject blind as to group placement to obtain unbiased baseline data. Treatment reten5on and abs5nence rates as well as psychometric and cogni5ve measures were compared. RESULTS: Experimental subjects remained in treatment significantly longer than the control group (p <0.005). Of the experimental subjects comple5ng the protocol, 77% were abs5nent at 12 months, compared to 44% for the controls. Experimental subjects demonstrated significant improvement on the TOVA (p<.005) ajer an average of 13 beta- SMR sessions. Following alpha- theta training, significant differences were noted on 5 of the 10 MMPI- 2 scales at the p<.005 level. CONCLUSION: This protocol enhanced treatment reten5on, variables of aqen5on, and abs5nence rates one year following treatment. Inderdaad toch enige keuze? Cogni5ve Control of Drug Craving Inhibits Brain Reward Regions in Cocaine Abusers Nora D. Volkow, et al. (Epub) Figure 1. Measures for self-reports of craving and for the Cocaine Craving Questionnaire and for the cardiovascular measures (heart rate, systolic and diastolic blood pressure) obtained prior to (lighter bars) and 30 minutes after initiation of the video (darker bars) or for the corresponding time period for the baseline. Craving measures were higher for cocaine-cue no inhibition (NI) than for cognitive inhibition (CI) or for the baseline condition whereas cardiovascular measures significantly increased for both NI and CI but not for baseline. *** p < 0.005, * p < 0.05. 12
SPM results for the comparison of the cocaine- cue video with cogni5ve inhibi5on (CI) versus the cocaine- cue video with no- inhibi5on (NI) and loca5on of the ROI for the NAcc (red circles) and the medial (blue oval) shown for the contralateral hemisphere. The SPM showed significantly lower metabolism in right NAcc and right medial (m) in CI when compared with NI. Regression slope for the differences in metabolism between CI versus NI in right NAcc and in right inferior frontal cortex BA 44 (r = - 0.62, p < 0.005). Volkow et al. conclude Cocaine abusers may retain some ability to inhibit craving. = toch wat keuze vrijheid?! Strengthening fronto- accumbal regula5on may be therapeu5cally beneficial. Neurobiologie en Hersenstimulatie Repeated Reward DBS rtms Detection Threshold Disinhibition Attentional Bias Cue-Reactivity Craving Relapse Conflict Registration Transcraniele Magnetische Stimulatie bij Cocaineverslaafden 13
Besluit Conclusies Vanuit neurobiologische oogpunt is verslaving een hersen aandoening met volgende kenmerken: Een ontwikkelingsstoornis Progressieve stoornis Pathogenese op drie poten: Stoornissen in de zelfregula5e Stoornissen thv van beloningsysteem Stoornissen tgv van middelen gebruik Behandeling moet zich enten op de pathogene5sche factoren. 14