1. Expectations and individual differences in cognitive and affective control Collaborators Columbia Kevin Ochsner Ed Smith Martin Lindquist Emily Stern Joy Hirsch University of Michigan Christian Waugh Barb Fredrickson Steve Taylor Israel Liberzon Ken Casey Doug Noll Tom Nichols Jon-Kar Zubieta MBBH Brain Group Jim Rilling Jonathan Cohen Bob Rose Ed Smith Steve Kosslyn Richie Davidson Margaret Kemmeny

2. One who has control over the mind is tranquil in heat and cold, in pleasure and pain, and in honor and dishonor. –Bhagavad Gita

3. If you are distressed by anything external, the pain is not due to the thing itself, but to your estimate of it; and this you have the power to revoke at any moment –Marcus Aurelius

4. Abraham, sacrificing his son Iago, manipulating Othello

5. Structure What is control? –Define terms: goals, expectations, and control –Control theory and principles of self-regulation Brain mechanisms of expectancy –Expectations in the control of attention –Expectations in the control of pain –Expectations in the control of emotion

6. What is control? Control: The use of goals to regulate a process Goal: A representation of an ideal state to be achieved –May change depending on current state –Two ways goals shape regulation: by comparison with feedback and/or expectations Feedback: A representation of a state or process to be regulated Expectation: A prediction about a future state of the world or self Control: The comparison of feedback and/or predictions with ideal states, and the use of comparison information to alter an ongoing process

7. Developments in control theory Ancient macedonia: Float regulators, passive control systems Enlightenment/Industrial era: Bernoulli, Maxwell, Routh 1960’s: classical control theory –Feedback systems to maintain equilibrium –Adopted by neurobiologists and cognitive scientists –Critical ideas: equilibrium, set points, comparators From Cabanac, 2001 Ideal/goal: Built into the machine

8. Developments in control theory Ancient macedonia: Float regulators, passive control systems Enlightenment/Industrial era: Bernoulli, Maxwell, Routh 1960’s: classical control theory –Feedback systems to maintain equilibrium –Adopted by neurobiologists and cognitive scientists –Critical ideas: equilibrium, set point, comparators From Cabanac, 2001 Input

9. Control in brain self-regulation Physiological homeostasis: (food intake, blood pressure, temperature) –Feedback is everywhere: Basic neural circuits are composed of feedback mechanisms –Set point: A primitive representation of an ideal or goal state of the system. How much should I weigh? –Debate about whether these processes are ‘controlled’ through feedback or not From Cabanac, 2001 Neural representation of goal Neural error-detection mechanism Interoception

10. Control of Emotions and emotional behavior Goals (ideals) are an essential component –Internal regulatory goal: control behavior & experience for its own sake –External regulatory goal: Control outcomes Situational context leads to goal formation Neural representation of goal Neural error-detection mechanism Interoception or exteroception

11. Developments in control theory Ancient macedonia: Float regulators, passive control systems Enlightenment/Industrial era: Bernoulli, Maxwell, Routh 1960’s: classical control theory –Feedback systems to maintain equilibrium –Adopted by neurobiologists and cognitive scientists –Critical ideas: equilibrium, set point, comparators Modern control theory –Adaptive control: control settings adjust to optimize performance (Analogue to strategy) –Neural networks –Borrows concepts from neurobiology –Focus on reactive control; Expectations largely absent

12. Structure What is control? –Define terms: goals, expectations, and control –Control theory and principles of self-regulation Brain mechanisms of expectancy –Expectations in the control of attention –Expectations in the control of pain –Expectations in the control of emotion

13. Control of attention Cognitive science/neuroscience –Use tasks that tap basic information processing –Highly controlled tasks –Identify mechanisms for voluntarily focusing attention and selecting responses –Assumed to generalize: ‘free will’ or ‘cognitive flexibility’

14. Control of attention Instructions: If the center letter you are about to see is an H, raise one index finger. If the center letter is an S, raise two fingers.

15. Control of attention HHH

16. Control of attention SSS

17. Control of attention SHS

18. Comparing Response Interference Tasks B X M S-R CompatibilityFlankerGo-No/go blocked compatible or incompatible responses blocked congruent or incongruent flankers blocked 80% “go” versus 50% “go” responses; Event related analysis Wager, T. D., Sylvester, C. C., Lacey, S., Nee, D. E., Franklin, M. S., and Jonides, J. (2005), Neuroimage

19. Triple inhibition: Results Go / no-go Flanker SRC y = 20 mm x = 6 mm z = 45 mm (FDR corrected) Wager et al., 2005

20. Common response selection regions Activated in each taskPerformance-related

21. Control of attention How did you perform the task? –Instruction: “Respond to the center item” –Goal: make a correct response –Generate expectation: Important information in center, irrelevant information peripheral. –Maintain expectation: activity in brain must be maintained to interact with later stimulus processing –Bias perceptual mechanisms: Subgoal: enhance perception of center, block periphery –Expectancy generation = establishing a task set –This expectation of relevance, and the subsequent shaping of perception, is ‘attention’

22. A computational model of control Example task: name the color in which this word is printed: RED Activation of task demand (context) by cue: Expectancy-based control Activation of task demand (context) by error monitoring: Feedback-based control

23. Meta-analysis of executive working memory: common regions in control tasks

24. Common response selection regions Performance-related More frontal and insular activity: Poorer performance Why? Less neural efficiency for poor performers, requiring more activation? More difficult task for that participant, more control necessary? Activations reflect reactive control needed more in poor performers?

25. Feedback- or expectancy-based control? Activation could reflect: –Expectancy generation –Expectancy maintenance –Error signal –Application of feedback-based control –Adjustments to the controller (strategy/learning shifts) –Meta-cognitive evaluation of performance

26. Cued attention: Evidence for expectancy-based control Cue period: Enhances visual cortex responses to attended locations Responses significant even before stimulus appears -- Evidence for expectation-based control Hopfinger et al., Nat. Neurosci. 2000

27. Cued attention: Evidence for expectancy-based control Cue period: Activation of dorsal frontal, cingulate, parietal cortices Hopfinger et al., Nat. Neurosci. 2000

28. Feedback- or expectancy-based control? Activation likely to reflect: –Expectancy generation –Expectancy maintenance But is frontal activity due to a general alerting response, or to specific task preparation?

29. 6 s Response: UP Response: UP No response 2200ms N W UP W W UP Informative trials (P or W) Non-informative trials (N/P or N/W) 6 s X Control trials + Cued-attention interference ER fMRI, N=15 P’s respond to position or meaning (W) of words (up, down, left, right) Cues are informative (P/W) or not (N) 50% catch trials to separate task-set preparation from response selection Stern et al., in preparation

30. Informative vs. Non-informative cues during Anticipation ‘Attention network’ L IFJ/ PMC Ant. insula Stern et al., in preparation

31. Control of attention Anterior prefrontal, insular, cingulate, and parietal cortices Commonly activated in many tasks that require ‘controlled’ response selection and attention All regions can be activated by expectations, even anterior insula / frontal operculum; but most frequently superior frontal regions. Failure to exercise expectancy-based control (poor performers) may result in reactive, feedback-based activation

32. Structure What is control? –Define terms: goals, expectations, and control –Control theory and principles of self-regulation Brain mechanisms of expectancy –Expectations in the control of attention –Expectations in the control of pain –Expectations in the control of emotion

33. Control of pain Does ‘cognitive control’ over attention generalize to other domains, like pain and emotion? Does affective information activate the ‘attention network,’ and is this information linked to affective regulation? Strategy: Manipulate expectancies about pain, examine neural correlates of expectancies and their impact on pain processing

34. Pain processing systems From VLPFC, OFC (medial)

35. Pain Expectancy Escape Endure/ Ignore Fight Decision circuit Immobilize/ Recover Control circuit Off On Right: Fields, 2004, Nat. Rev. Neurosci Placebo

36. What is the placebo effect? Placebo effect: Improvement of signs or symptoms caused by administration of a treatment with no intrinsic beneficial effects. In pain, analgesia caused by a sham treatment (e.g., an injection of saline, an inert ointment) Placebo treatment is a manipulation of expectancy and appraisal of meaning. –A tool for studying meaning generation, mechanisms of belief, and brain-body interactions

37. The placebo panacea Over 4,000 ancient remedies, largely placebo Shapiro; in Harrington, Anne (ed.), The placebo effect Modern placebo effects in major clinical disorders: heart disease, arthritis, pain, depression, Parkinson’s disease

38. Are placebo effects real? Many things have been called ‘placebo effects’ (Klein, Shapiro, Kirsch, Hrobartsson) Natural history Spontaneous symptom fluctuation Regression to the mean Sampling bias Hawthorne effects Demand characteristics in reporting Active mechanisms?

39. Placebo effects in reported pain Behavior Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate control Experience Demand characteristic n = 50 Placebo causes 22% decrease in pain Placebo

40. The demand characteristic hypothesis Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Demand characteristic fMRI predictions: No changes in pain regions during pain

41. Opioids and placebo effects Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Placebo effects are reversible by the opioid antagonist naloxone (Fields, Levine, Gracely, Benedetti) Taken as evidence that placebo effects are not only demand characteristics Evidence for psychological control of pain at the spinal level? (Melzack and Wall, 1965) Opioids ? ?

42. The gate control hypothesis Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control fMRI predictions: Placebo reduces activity throughout sensory and affective pain processing regions Opioids

43. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic Opioids (medial)

44. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic fMRI predictions: Placebo reduces activity in affective pain networks Opioid binding effects in frontal and limbic regions

45. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic From VLPFC, OFC (medial)

46. fMRI studies Study 1: Shock on R forearm (n = 24) Study 2: Heat on L forearm (n = 23, selected placebo responders) Treatment with an inert ointment (Vasoline) –Placebo treatment: participants told that treatment was lidocaine –Control treatment: participants told that treatment was a ‘control cream’ to control for having ointment applied to skin Testing on placebo and control-treated skin fMRI design: Separate anticipation from experience of pain

47. fMRI trial design Time during Trials + 20 s HeatRate pain rating 4 s Rest + 40 - 50 s Ready! 1 s Cue + 1-16 s Anticipation x = 9.77 SD = 6.04 x = 6.82 SD = 4.18 + 1-12 s Rest Anticipatory activityPain-induced activity

48. Placebo effects during pain CL-INS Shock Early Heat, correlation Shock Late Heat, main effects (C > P) AB C rACC CL-INS CL- TH CL-INS D E F Shock Late Heat, main effects (C > P) PHCP Study 1 Study 2 Placebo-induced decreases in: Insula ‘interoception’ (Craig) correlates with subjective pain Anterior cingulate ‘pain affect’ (Rainville, hypnosis) Dorsomedial thalamus ‘limbic’ thalamus involved in emotional responses Parahippocampal cortex Pain anxiety (Ploghaus)

49. Anticipation of pain: Placebo > Control B Study 1 OFC Study 1 A Midbrain DLPFC C Study 2 DLPFC r =.51 r =.60 Study 2 DE

50. Opioid release correlated with reported placebo in [ 11 C] Carfentinil PET Direct effects of opioids in appraisal

51. Expectancy-induced control DLPFC activation, as in cognitive control OFC activation: Generation of expectancies –Expectancies of pain relief –Altered significance of incoming nociceptive stimuli –Opioid activity directly altered by placebo in OFC PAG activation –Opioid activity elicited in expectation of placebo (?) –‘Affective decision’ circuit –Opioid activity correlated with placebo in PAG

52. Structure What is control? –Define terms: goals, expectations, and control –Control theory and principles of self-regulation Brain mechanisms of expectancy –Expectations in the control of attention –Expectations in the control of pain –Expectations in the control of emotion

53. General mechanisms of expectancy? Appraisal as a general mechanism –In pain, leads to altered significance of stimulation –In emotions, leads to altered thoughts, feelings and action tendencies –In Parkinson’s disease, leads to increased self-efficacy Ochsner et al. Regulation of emotion Mayberg et al. Placebo in depression

54. Opioid increases F Firestone 1996 A Adler 1997 N Wagner 2001 P Petrovic 2002 Emotion regulation L Levesque 2003 C Ochsner 2002 O Ochsner 2004 H Phan 2004 B Bishop 2004 Placebo W Wager 2004, antic. G Wager 2004, pain I Lieberman 2004 V Petrovic 2002 T Petrovic 2005 M Mayberg 2002 Dorsal FrontalOrbitofrontal Lateral Frontal Medial Frontal Increased activity in self-regulation tasks LR LR

55. Expectations and Emotion How does expectation of an emotional picture influence neural responses? Do patterns of expectancy distinguish emotionally resilient individuals from nonresilient ones? Resilience: Ability to deal effectively with life adversity Sample: 15 resilient and 15 nonresilient individuals picked from extremes of sample on ego resilience scale (e.g., Block 1989).

56. Task Design

57. Aversive – Expected: VMPFC * Aversive – Relief is significant at p <.005

58. Aversive – Expected: Temporal pole * Relief – Expected is significant at p <.05

59. Aversive – Expected/Relief: Amygdala

60. Threat – Safety: LOFC Nonresil > Resil OFC: Negative expectancy, less for resilient individuals Nonresilient individuals respond to aversive cue

61. Threat – Safety: LOFC Nonresil > Resil OFC: Negative expectancy, less for resilient individuals Nonresilient individuals respond to aversive cue

62. Aversive – Expected*: LOFC Resil > Nonresil * Aversive – Relief is significant at p <.05 OFC: Resilient individuals do not respond until aversive picture

63. Aversive – Relief: RVLPFC Resil > Nonresil RVLPFC: Resilient individuals show decrease in response to neutral pictures when expecting aversive. Nonresilient show increases.

64. Correlations – Safety-VMPFC During expectation VMPFC during Safety cue Resilience.53** Hope- Agency.50** Extraversion.40* BAS – Reward resp..51** Positive emotions – 2 weeks.45* Negative emotions – 2 weeks -.50**

65. Correlations of LOFC during Threat to Pictures Relief Neutral PictureAversive Picture

66. Emotion and expectancy Expectation of aversive stimuli elicits OFC activity. More expectancy in nonresilient individuals. Co-localized with expectancy effects in pain Lower aversive OFC expectancy effects correlated with greater deactivation of VMPFC to ‘relief’ pictures, and with broad measures of optimism Resilience: shift away from aversive expectations

67. Final conclusions Expectancy, or predictions about future states (including emotional experiences) is an important factor in shaping experience. Expectations provide ways of controlling behavior without experiencing adverse consequences first. Emerging circuit in ventrolateral PFC/anterior insula and orbitofrontal cortex links expectancies across cognitive and emotional domains Much more to learn! Underlying functions of these regions; impact on emotional health and cognitive ability; ways of modifying expectations and their effects in the brain.

68. Thank you!

69. Threat cues in the brain

70. Relief: VLPFCExpect: VLPFC Resilience-.60**-.20 Optimism-.62**-.48* Extraversion-.42*-.12 Positive feelings-.51**-.33 BAS – Reward responsiveness -.55**-.32 Trait positivity-.51**-.27

71. Threat – Safety: VMPFC Nonresil > Resil

72. Conclusions Nonresilient activate more MPFC/LOFC in response to the threat cue Nonresilient activate more RVLPFC to relief pictures than Resilient This activation in the LOFC to the threat cue predicts RVLPFC response to the relief neutral pictures If LOFC -> negative expectations and RVLPFC -> negative labelling, then for NR, their negative expectations drive their negative labelling of a neutral picture. Resilient people are better able to discriminate negative from neutral events -> may lead to quicker recovery

73. Relief – Expected: SMG Overall

74. Expected – Relief: ACC/MPFC

75. Increases in activity with placebo Study 1 - Anticipation Study 2 - Anticipation Study 2 - Pain

76. Placebo effects in S2 Use meta-analysis as a broad ROI Identify S2 in individual participants by individual pain response Evidence against early blockade of nociception as a major factor

77. Opioid drug effects in S2 Increases in S2 with verum opioid analgesics (e.g., Casey) Increased inhibitory input –Metabolic activity in interneurons -> Tonic increase –Could make S2 more responsive to frontal input

78. Opioid drug effects in prefrontal cortex Casey et al., 2000 Wagner et al., 2001 Adler et al., 1997

79. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic Demand characteristic Activation of appraisal networks before and during pain Changes in pain-processing regions Opioids x Pain experience Reductions in ‘affective’ pain regions Opioid release directly in appraisal networks Gate control (early blockade) Reductions in ‘affective’ pain regions Increased activation in S2  x

80. Wagner 2001 - Remi produces dose- dependent decrease in PAG Wagner, 2001 Remifentanil-induced decreases

81. Opioid drug effects in S2 Increases in S2 with verum opioid analgesics (e.g., Casey) Increased inhibitory input –Metabolic activity in interneurons -> Tonic increase –Could make S2 more responsive to frontal input

82. Y = 1 Experiment 1Experiment 2 dorsal amygdala Amygdala: Control > Placebo

83. Peak Heat: Placebo activates right frontal, sensorimotor, and parietal cortex Heat-responsive Regions of interest (ROIs) Inferior parietal Premotor Dorsolateral PFC

84. A process model of expectancy-based regulation Warning cue Belief Placebo treatment Expectancy pre-appraisal Noxious stimulus Pain appraisal Context level Input level Lateral PFC ACC, OFC, VLPFC Insula, thalamus, S2 Anxiety Vase et al., Price et al. Attention Petrovic et al., Brooks et al., others

85. Peak Heat: Placebo activates right frontal, sensorimotor, and parietal cortex P > C,.005 / 60 voxels Superior parietal lobule/ precuneus Sensorimotor cortex Dorsolateral and Dorsomedial prefrontal cortex Premotor cortex * Replicated in Rilling, Wager et al., in prep.

86. Clustering in component space Make meaningful groups of regions Inferential testing of null hypothesis: no grouping Black: + correlation Blue: - correlation (p <.05 corrected)

87. The importance of S2 Pain in insula - colors are regions Wager & Feldman Barrett, 2004 Identified 4 insular regions based on anatomy (Mesulam) Studied four task domains: Pain Negative emotions Attention shifting Working memory Computed P(Task | Activity) in each region

88. Task prediction in the insula Pain Recall of emotion Diagnostic value - colors are tasks Can we predict task given brain activity? Green = pain, red = emotional recall, blue = attention, yellow = WM S2 activity is highly diagnostic of pain Bilateral S2 activity occurs ONLY in pain studies If I observe S2 activity, I’m probably in pain. Implications for psychological vs. emotional pain

89. S2 in individual participants Decreases (C > P) in anticipation Increases (P > C) in early and late heat Behavioral placebo effects correlated with…

90. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic Opioids From VLPFC, OFC (medial)

91. Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control Experience Demand characteristic Opioids From VLPFC, OFC (medial)

93. From VLPFC, OFC (medial)

94. Placebo effects in reported pain Behavior Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate control Experience Demand characteristic n = 50 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 ManipulationTest Pain Rating Placebo Control Placebo causes 22% decrease in pain