1. From Intoxication to Addiction: Neurobiological Substrates for Hubris? Paul Fletcher pcf22@cam.ac.uk Bernard Wolfe Health Neuroscience Fund The Intoxication of Power: From Neurosciences to Hubris in Healthcare and Public Life. Royal Society of Medicine October 2012

3. Speculations on the neurobiology of hubris syndrome Impaired risk appraisal Inability to foresee undesirable outcomes Dangerous decision-making (with ensuing harm). Highly unlikely to be localisable to a single region or neurotransmitter system

4. From Intoxication to Addiction: Neurobiological Substrates for Hubris?

5. What do we mean by addiction? Drug addiction – a chronic relapsing state characterised by: –Compulsion to seek/take drugs –Loss of control –Emergence of a negative emotional state Latterly, research focus has shifted from the acute effects (the high and the come-down) to addiction as an evolving condition characterised by neuroadaptation Koob and Volkow, Neuropsychopharmacology, 2010

6. Withdrawal/ Negative affect Preoccupation/ anticipation (Craving) Binge/Intoxication Impulsive (arousal/excitement)  Drug  Pleasure Compulsive (anxiety/stress)  Drug  Relief (+)ve(-)ve Goal-directed behaviours Habitual behaviours

7. From Intoxication to Addiction: Neurobiological Substrates for Hubris?

8. Interim summary We have two syndromes that entail impaired risk appraisal inability to foresee undesirable outcomes dangerous decision-making (with consequent harm) And for one (addiction) we have a sophisticated, though incomplete, understanding of the endophenotype and neurobiological basis. Does the addiction model help us to understand Hubris Syndrome?

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11. Summary… Hubris Addiction Poor Decisions Impaired risk appraisal Incorrigbility Low self-esteem Guilt Anxiety Depression Habitual behaviours -Stimulus-driven -Narrowed repertoire -Devoid of goals

12. further thoughts – dopamine function in an uncertain world.

13. A few simple principles… Successful interaction with our environment entails accurate predictions Prediction-based actions are rapid and efficient We must therefore be sensitive to (sometimes) subtle environmental regularities

14. Prediction error – a key signal in learning ΔV = α β (λ – ΣV) Fiorillo et al

15. Brain marker for PE-dependent learning Fletcher et al Nature Neurosci, 2001 Turner et al Cereb Cortex, 2004 Corlett et al Neuron, 2004 Murray et al, Molecular Psych, 2007; Corlett et al, Arch Gen Psych 2006; Brain 2007

16. Prior knowledge Current input Prediction Error Update signal

17. What happens when uncertainty is great? Prior knowledge Current input Prediction Error Update signal

18. Prior knowledge Prediction Error Update signal Stress Personality Intoxication Arousal Current input

19. From Intoxication to Addiction: Neurobiological Substrates for Hubris?