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Contributions of impulsivity and compulsivity to neuropsychiatric disorders such as addiction

Dublin 2013. Contributions of impulsivity and compulsivity to neuropsychiatric disorders such as addiction. TW Robbins Dept. of Psychology &. Compulsivity. Impulsivity. OCD. ADHD. Impulsive choice; steeper reward discounting Delay aversion

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Contributions of impulsivity and compulsivity to neuropsychiatric disorders such as addiction

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  1. Dublin 2013 Contributions of impulsivity and compulsivity to neuropsychiatric disorders such as addiction TW Robbins Dept. of Psychology &

  2. Compulsivity Impulsivity OCD ADHD • Impulsive choice; steeper reward discounting • Delay aversion • Lack of consideration when making decisions • Change in response criterion • Timing impairment • Stereotypy • Rigid strategies or attentional set • Inappropriate persistence of habits: despite outcome devaluation or negative consequences; • Perseveration in reversal learning and resistance to extinction • Motor • Disinhibition • Impaired ability to stop a response or sequence • e.g SSRT task Mania Schizophrenia, Autism Substance Abuse/Eating Disorders Personality Disorders ““actions which persist inappropriate to the situation, have no obvious relationship to the overall goal and which often result in undesirable consequences” (Dalley et al 2011) “actions which are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation and that often result in undesirable consequences” (Daruna & Barnes, 1993)

  3. Cortico-striatal circuits, chemical neuromodulation, executive function and neuropsychiatric disorders Human reward system Zald Alexander et al Noradrenaline Dopamine Serotonin

  4. Dopamine D2 Receptors are persistently decreased in the brains of addicts: COCAINE METH Dopamine D2 Receptor Availability ALCOHOL Normals Abusers cause or effect?! Volkow et al., 1999

  5. The relationship between striatal D2/3 receptors and PFC activity in cocaine abusers Volkow 2008

  6. Impulsivity in human substance abusers: The evidence: cause or effect?! See also H de Wit 2009 • Stimulant abusers • Filmore & Rush 2002; Li et al 2006, 2008; Monterosso et al 2005; Hester & Garavan 2004; Kaufman et al 2003; Verdejo-Garcia et al 2007; Conrod et al 2009 • Opiate abusers mixed • Kirby & Petry 2004; Verdejo-Garcia et al 2007 • Alcoholics • Noel et al 2007; Townshend & Duka 2005. • Nicotine • Bickel et al 1999; Spinella et al 2002; reversible effects Heil et al 2006 • MDMA, cannabis not clear.

  7. Measuring impulsivity in rats and humans • Delayed gratification/reinforcement (Ainslie, Bradshaw, Evenden, Mazur, Rachlin, Richards, etc) • Temporal discounting • Probability discounting • Stop-signal reaction time task (Logan, de Wit/Richards) • 5-Choice serial reaction time task • Premature, anticipatory responses; ‘false alarms’ • (Carli et al, Harrison et al 1997; Chudasama et al 2003) High impulsives ‘’zippy’

  8. Vulnerability to drug addiction: ‘impulsive rats’ exhibit enhanced cocaine iv self-administration on the Ahmed & Koob ‘binge-access” procedure Dalley et al, Science 2007

  9. Compulsive drug seeking in rats: persistence despite aversive outcomes 1) seeking lever RI60 Inside operant chamber seek 2) taking lever FR 1 cocaine take 3) seeking lever RI60 punishment seek Punishment of cocaine seeking: 50% of seeking cycles result in access to the taking lever; 50% of seeking cycles result in punishment (mild footshock).

  10. High impulsivity on the 5-CSRTT predicts an enhanced transition to compulsive cocaine seeking/taking Belin D., Mar A.C., Dalley J.W., Robbins T.W., Everitt B.J., Science (2008)

  11. 0.7 low impulsive high impulsive 1.2 1.6 2.7 dorsal striatum dorsal striatum ventral striatum ventral striatum Reduced dopamine D2/3 receptors in the ventral striatum - [18F]-fallypride uptake – correlates with impulsivity Dalley et al., Science 2007

  12. Autoradiographic analysis of DA receptors in high and low impulsives Jupp et al 2013 EJN

  13. GABA-ergic and structural neuronal markers in the nucleus accumbens core predict trait-like impulsivity in rats Caprioli et al in press VBM e d

  14. Defining brain networks associated with ‘waiting’ impulsivity PFC HC AMG ACC VTA PLd PLv NAcb core Raphe IL NAcb shell LC ‘Bottom-up Dysregulation’ Dalley, Everitt, Robbins Neuron 2011 ‘Top-down Dyscontrol’

  15. High impulsive rats also show steep reward discounting (like effects of lesions of N. Acc. Core region) Choice for the large reinforcer Robinson et al 2009 Cardinal et al 2001 Science

  16. Relevance to human drug addiction? Impulsivity as an endophenotype Methamphetamine use

  17. Impulsivity as an endophenotype for human stimulant abuse Ersche, Turton, Pradham, Bullmore, Robbins Biol. Psychiat. 2010

  18. CUE A + Excellent! You WON! + TARGET Touch screen Time (s) + Total: £51 + -£1 +£1 Space Bar Feedback +50p -10p B +1.5 SD -0.5 +0.5 Human 5 choice serial reaction time task Voon et al 2013 RT Mean fastest RT

  19. Validation of the human 5-choice serial reaction time task in healthy volunteers (hv), stimulant abusers (stim), and recreational cannabis use (rec) Group P<0.00004 Premature responses (Voon et al 2013 Biol. Psychiat)

  20. > > > > > Logan’s Stop-signal reaction time task for assessing motor inhibition The task measures the participant’s ability to inhibit a pre-potent response BEEP! Stop-signal occurs on 25% trials. Aron et al 2003 Eagle & Robbins 2003 De Wit & Richards 2002

  21. Defining neural networks associated with ‘Stopping’ impulsivity PFC dPM SMA/pre–SMA M1 SNc Caudate- putamen Raphe DA-D1 ACC Th GP LC DA-D2 RIFG/OFC STN Dalley, Everitt, Robbins, Neuron 2011

  22. > Stop signal deficit in siblings of chronic stimulant abusers: Possible endophenotype for stimulant addiction? beep Ersche, Bullmore, Robbins et al 2011 Science 2012

  23. Compulsivity Impulsivity OCD ADHD • Impulsive choice; steeper reward discounting • Delay aversion • Lack of consideration when making decisions • Change in response criterion • Timing impairment • Stereotypy • Rigid strategies or attentional set • Inappropriate persistence of habits: despite outcome devaluation or negative consequences; • Perseveration in reversal learning and resistance to extinction • Motor • Disinhibition • Impaired ability to stop a response or sequence • e.g SSRT task Mania Schizophrenia, Autism Substance Abuse/Eating Disorders Personality Disorders ““actions which persist inappropriate to the situation, have no obvious relationship to the overall goal and which often result in undesirable consequences” (Dalley et al 2011) “actions which are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation and that often result in undesirable consequences” (Daruna & Barnes, 1993)

  24. Ikemoto 2007 - similar organization in rat brain From voluntary actions to habits: The ventral to dorsal striatal shift: Ascending neural spirals from shell to core to dorsal striatum goal-directed drug seeking & taking pavlovian conditioning drug seeking & taking habits vulnerability, impulsivity compulsive drug seeking abstinence/ relapse Everitt & Robbins 2005 Haber et al. 2000

  25. Associative learning in addiction Instrumental conditioning Action-Outcome Learning Response (Drug or Drug-paired cue) (Seeking, Taking) Reinforcer Voluntary control over environment: Goal-directed behaviour Phenomena:Drug use and abuse Habit learning Stimulus Response Reinforcer Automatic, less goal-directed response to environment Phenomena: Drug habits and compulsive behaviour

  26. Goal-directed action is thought to be subserved by the PFC and the caudate (DMS in rodents) Habit learning is subserved by the DLS in rats, and its homologue, the putamen in humans Tanaka et al, 2008 Valentin, Dickinson & O’Doherty, 2007 Yin et al, 2004 Also Larger In Sibs of Stimulant Abusers! Ersche et al 2012 Tricomi et al, 2009

  27. Obsessive-compulsive disorder

  28. Disruption in the Balance BetweenGoal-Directed Behavior and Habit Learning inObsessive-Compulsive Disorder Gillan, Papmeyer, Morein-Zamir, Sahakian, Fineberg, Robbins, S de Wit American Journal of Psychiatry 168, 718-726 (2011)

  29. Stimulus Outcome Response Brief Training: 9 trials Extended Training: 90 trials Devaluation Test 1 Devaluation Test 2 * Enhanced avoidance habits in OCD? Gillan, Morein-Zamir, Urcelay, Voon, Sule, Fineberg, Sahakian & Robbins, Biol Psychiatry 2013

  30. Reduced OFC connectivity and compulsive symptoms in OCD and Stimulant-Dependent Individuals Meunier, Ersche, Robbins, Bullmore, et al 2011 Neuroimage

  31. Robbins et al 2012 TICS

  32. BCNI Collaborators BJ Sahakian N Fineberg ET Bullmore KD Ersche V Voon S Morein C Gillan H Garavan (Vermont) R Whelan (Dublin) S de Wit (Amsterdam) S Chamberlain G Urcelay A-M Apergis-Schoute BJ Everitt J Dalley D Belin (Poitiers) A Roberts H Clarke D Eagle A Mar A Fernando D Caprioli M Moreno (Almeria) DEconomidou A Bari (Charleston) D Theobald

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