1. Value-based decision-making and the prefrontal cortex JON WALLIS

2. Animal models of decision-making Action selection Vigor/Arousal Motivation Cortex Accumbens Hypothalamus

3. Outline Define the theoretical constructs underpinning our understanding of decision-making Discuss the anatomical and functional homologies between humans and monkeys Describe my research into the role of frontal cortex in decision-making Clinical and pharmacological implications

4. Types of decision-making Value-based decision-making no right or wrong subjective objective reality Perceptual decision-making Decision boundary ‘CAT’‘DOG’

5. Theoretical constructs: perceptual decision-making

6. Theoretical constructs: value-based decision-making

7. Neuropsychology and choice behavior Which is more blue? Perceptual decision-making Value-based decision-making Which do you prefer? Lateral PFC Orbital/medial PFC Fellows and Farah (2007)

8. Outline Define the theoretical constructs underpinning our understanding of decision-making Discuss the anatomical and functional homologies between humans and monkeys Describe my research into the role of frontal cortex in decision-making Clinical and pharmacological implications

9. PFo homology

10. PFm homology

11. Role of PFo in valuation 218218 114114 122122 144144 1 12 1 16 Chosen Value : Padoa-Schioppa and Assad (2006) 3 1 12 =

12. Neuroimaging and valuation Fast for 4 hours Bid on 40 different food items Given 3 dollars ($1.50) ($2.00) Hare et al (2008)

13. PFo and “neuronal currency” Payoff + Time Effort Risk - - - +

14. (1500 ms) Choice 9 6 4 2 1 Probability Encoding decision variables across PFC

15. All three variables: abstract value Kennerley et al (2009, J Cog Neuro) Value Pictures Appear Go Cue

16. One variable (cost) Kennerley et al (2009, J Cog Neuro) Value

17. Two variables (payoff and cost) Kennerley et al (2009, J Cog Neuro) Value

18. Recording locations PFl PFo PFm

19. PFl PFo PFm Prevalence of different types of value encoding Kennerley et al (2009, J Cog Neuro) Cost

20. Complex types of value encoding are in PFm Kennerley et al (2009, J Cog Neuro) % neurons PFm PFo PFl The importance of PFo and PFcs for decision-making, may depend on their ability to multiplex different decision parameters.

21. Cost-benefit analysis Reward (mls) Effort (lbs) Effort-based decision-making Reward (mls) Delay (s) Delay-based decision-making 5 8 11 141.8 3 4.2 5.4

22. Probability of selecting picture

23. RewardEffort Value 0.4 g 0.1 g 5 lbs 14 lbs PFm neuron: net value

24. Outline Define the theoretical constructs underpinning our understanding of decision-making Discuss the anatomical and functional homologies between humans and monkeys Overview of our current understanding of the role of frontal cortex in decision-making Overview of the pharmacological results based on this understanding

25. Clinical implications: depression Depression is associated with metabolic and neurochemical changes in PFm also characterized by anhedonia and anergia does this reflect changes to the effort/reward function? Decreased metabolic activity in depressed patients

26. Clinical implications: delay-based decision-making Impulsive decisions occur in: –substance abusers (e.g. Monterosso et al 2001) –schizophrenics (e.g. Heerey et al 2007) –alcoholics (Boettiger et al 2007) –individuals with the COMT 158 Val/Val genotype (Boettiger et al 2007)

27. Pharmacological considerations: dopamine dopamine agonists make rats more patient (e.g. Floresco et al 2008) or more impulsive (e.g. Cardinal et al 2001) –dose-response curve? OFC 6-OHDA lesions make rats more patient (Kheramin et al 2004) DELAY-BASED DECISION-MAKING: nucleus accumbens dopamine depletion makes rats lazy (Salamone et al 1994) PFm D1 antagonist infusion makes rats lazy (Schweimer & Hauber 2006) EFFORT-BASED DECISION-MAKING:

28. Pharmacological considerations: serotonin blockade of serotonin synthesis makes rats more impulsive (Denk et al 2004) in vivo microdialysis reveals changes in serotonin metabolite levels in PFm during delay-based decision-making (Winstanley et al 2006) DELAY-BASED DECISION-MAKING: blockade of serotonin synthesis has no effect (Denk et al 2004) EFFORT-BASED DECISION-MAKING:

29. Conclusions the orbital and medial prefrontal areas are particularly important for decision-making there is good anatomical and functional homology between these regions in the human and monkey disparate clinical symptoms (e.g. anhedonia, impulsivity) might be better understood as disorders of underlying decision-making calculations

30. Conclusion Emotional/Social dysfunction Reward processing Behavioral and clinical level Single neuron, genetic and pharmacological level

31. Conclusion Emotional/Social dysfunction Valuation and decision-making Reward processing Behavioral and clinical level Single neuron, genetic and pharmacological level Computational level

32. Acknowledgements Steven Kennerley Asst. Prof. University College London Antonio Lara Graduate student Chung-Hay Luk Graduate student Jen Sloan Graduate student Shima Ovaysikia Research assistant