1. Stress Hormones, Cortical Control and Decision Making Israel Liberzon M.D. Theophile Raphael Professor of Neuroscience, Professor of Psychiatry and Psychology, U of Michigan Mental Health Service, Ann Arbor VAMC

2. Acknowlegments This work is supported by NIMH R24 MH075999 Psychiatry, U of M: Stephan Taylor, James Abelson, Luan Phan, Robert Welsh Shaun Ho, Sarah Garfinkel Psychology U of M: Richard Gonzales Psychology, Columbia: Kevin Ochsner, Tor Wager, Ed Smith Disclosure and Conflict of Interest: None

3. Cognition Appraisal, Memory and Decision Making Developing Translational Center University of Michigan & Columbia University Hypotheses: 1. Cognitive, emotional, and somatic (CES) processes interact in reciprocally interconnected feedback loops 2. Ineffective CES interaction can lead to dysfunctional behavior and psychopathology Strategy: Using somatic (cortisol) manipulations, we evaluated impacts in the domains of memory and decision making using neuroanatomical (fMRI), behavioral, and neuroendocrine outcome measures

4. Decision Making and Stress  The curvature of the decision weighting function ( γ ) is associated with  DLPFC (Tobler, 2008)  Ventral Striatum (Hsu, 2009)  dACC (Paulus, 2006)  The loss aversion is associated with  VMPFC & ventral striatum (Tom, 2007) Stress is known to affect decision making (e.g. Starcke, Wolf, Markowitsch & Brand, 2008) and in turn decision making under risk can be stress inducing leading to cortisol release. Animal data suggest that high corticosterone (cortisol analogue) affects food choices (rats Teegarden and Bale 2008 ), aggressive food seeking and the ability to problem solve in the future (seabird chicks Kitaysky, Kitaiskaia, Piatt & Wingfield 2003 ) To date, no study has investigated the neurocircuitry underlying modulation of decision making induced by cortisol.

5. A system that responds to challenges! cortisol Adrenocorticotropin Hormone (ACTH) A system with a rhythm! Limbic-Hypothalamic-Pituitary-Adrenal Axis Glucocorticoids- cortisol Mobilization of glucose from stores Mobilization of a.a. from protein stores Increase cardio-vascular tone Inhibit all other functions that are not essential for immediate survival

6. LHPA “STRESS” AXIS Glucocorticoids (cortisol) PVN CRH AVP ACTH CRH AVP Hippocampus Pituitary Adrenal The Limbic-Hypothalamic-Pituitary-Adrenal Axis

7. Loss Aversion fMRI Study by Tom et al. (2007) “Neural” loss aversion should have “Mixed Gamble” vs. the mean of “Gains Only” and “Losses only” Gambles

8. Non-Linearity of Decision Weighting Function & the Difference between Prospect Theory and EU Theory - Hsu, et al 2009 Prospect Theory – EU Theory Expected Utility Theory (Diagonal Line) Prospect Theory (Curved Line)

9. Decision Making Task 3.8~9.8 secondsSelf-paced, < 6000 ms, median = 2.48 sec X Y X’ Y’ P’ 1-p’ P 1-p  40 subjects, 20 M, 20F (age: 18~37 years old, mean = 22.7 yr)  Treatment groups: Hydrocortisone (100mg) (10 M, 10 F)  Placebo Group (10 M, 10 F)  2 Sessions for each subjects started at 1 or 2pm  1st session: Decision Making Task at Baseline  fMRI at 3:20 or 4:20 pm (~100 min after oral intake)  2nd session: Decision Making Task (Treatment effect)

10. Gains Only Mixed Losses only Three types of trials: Gains Only, Losses Only, Mixed (42 trials/type) Each trial has two gambles (left and right) each gamble has two possible outcomes (X, Y) each possible outcome has a probability (p, 1-p)

11. Loss aversion (λ) Non-Mixed vs Mixed Reward Discriminability (α) Gains Only Value Function (v(x) = x α, if x > 0; v = - λx α, if x < 0) Probability Discriminability (  γ ) All DM trials Decision Weighting Function (w(p) = δp γ / (δp γ + (1-p) γ ))

12. 1 st session Baseline ~18 mins long 2 nd session Treatment On ~ 120 mins after drug Drug (Cort/Plcb)

13. Behavioral Results Cortisol Placebo Baseline In scanner Value Function (v(x) = x α, if x > 0; v = - λ x α, if x < 0)

14. Behavioral Results ~contd BaselineIn scanner Decision Weighting Function (w(p) = δp γ / (δp γ + (1-p) γ )) Cortisol Placebo

15. Cortisol and Decision Making Cortisol InsulaAmygdala/SLEA Reward processing sensitization Striatum (Caudate and Putamen) Reduced probability processing

16. Thank You