: Inhibitory Learning and Inhibitory Regulation

Michelle G. Craske, Ph.D. September, 2015 Professor of Psychology Professor of Psychiatry and Biobehavioral Sciences Director, UCLA Anxiety and Depression Research Center

Funded by National Institutes of Mental Health: 1 R01 MH100117 Craske (co-PI) Symptom dimensions of threat- and reward-related neurocircuitry 1 R01MH101453 Craske (PI) Latent constructs: Negative/Positive valence domains in anxiety and depression DARPA Craske (co-PI) Affect Labeling for PTSD 1 R34 MH101359 Craske (co-PI) Cholinergic Decontextualization of Exposure 1 R01 MH065651 Craske (PI) Youth Emotion Project 1 R21 MH081299 Craske (PI) Neural Mediators of Behavior Therapy 1 R03 MH64815 Craske (PI) Markers of Risk for Anxiety 1 R21 MH072259-1 Craske (co-PI) Translating Extinction to Anxiety Treatment In vivo exposure Imaginal exposure Interoceptive exposure Exposure-based therapies, with or without adjunctive coping skills, are highly effective for anxiety, obsessive compulsive and trauma disorders (Norton & Price, 2007; Hofmann & Smits, 2008)

Panic Disorder & Agoraphobia Social

Posttraumatic Stress Disorder Specific Phobia

Obsessive Compulsive Disorder Generalized Treatment Refusal

25-30% (Issakidis & Andrews, 2004; Garcia-Palacios et al., 2007)

Treatment Attrition

15-30% (Haby et al., 2006)

Treatment Non-response

40-50% (Loerinc et al., in submission; Rapee et al., 2009)

Return of Fear and Relapse

19-62% (Craske & Mystkowski, 2006; Ginsburg et al., 2014) Treatment Refusal

25-30% (Issakidis & Andrews, 2004; Garcia-Palacios et al., 2007)

Treatment Attrition

15-30% (Haby et al., 2006)

Treatment Non-response

40-50% (Loerinc et al., in submission; Rapee et al., 2009)

Return of Fear and Relapse

19-62% (Craske & Mystkowski, 2006; Ginsburg et al., 2014) Treatment Refusal

25-30% (Issakidis & Andrews, 2004; Garcia-Palacios et al., 2007)

Treatment Attrition

15-30% (Haby et al., 2006)

Treatment Non-response

40-50% (Loerinc et al., in submission; Rapee et al., 2009)

Return of Fear and Relapse

19-62% (Craske & Mystkowski, 2006; Ginsburg et al., 2014) Treatment Refusal

25-30% (Issakidis & Andrews, 2004; Garcia-Palacios et al., 2007)

Treatment Attrition

15-30% (Haby et al., 2006)

Treatment Non-Response

40-50% (Loerinc et al., in press; Rapee et al., 2009)

Return of Fear and Relapse

19-62% (Craske & Mystkowski, 2006; Ginsburg et al., 2014) What are the mechanisms of exposure therapy? What are the mechanisms of exposure therapy?

How can mechanisms of exposure-based learning be optimized to enhance response rate and reduce return of fear? Experimental Laboratory

Clinical Subclinical Experimental Laboratory

Clinical Preclinical Experimental Laboratory

Clinical Subclinical

Experimental Laboratory

Clinical Subclinical Habituation model “Stay in the situation until fear subsides” Habituation model “Stay in the situation until fear subsides”

Is fear reduction predictive of outcome? FEAR HABITUATION DURING EXPOSURE

Subjective and Exposure to roof top: Acrophobia (N=31) physiological Estimated Marginal Means of MEASURE_1 responses typically habituate 60

50

40

30

20

10

1 2 3 4 5 6 7 8 9 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0

minutes FEAR HABITUATION POOR PREDICTOR OF OUTCOME

Within session habituation: Contaminant anxiety (Kircanski, Mystkowski, Mortazavi, Baker & Craske, 2011, J Beh Th & Exp Psych) FEAR HABITUATION POOR PREDICTOR OF OUTCOME

Within session habituation: Public speaking anxiety (Culver, Stoyanova, & Craske, 2012, J Beh Th & Exp Psych) FEAR HABITUATION POOR PREDICTOR OF OUTCOME

Within session habituation: Public speaking anxiety (Culver, Stoyanova, & Craske, 2012, J Beh Th & Exp Psych)

Replicated: Public speaking anxiety (Niles et al., in submission) Spider phobia (Kircanski et al, 2012) Acrophobia (Baker et al., 2010) PAVLOVIAN FEAR LEARNING

Fear Acquisition Fear Extinction Extinction Test A A A

Tone-shock pairings Tone Presentations Tone Presentations Peters et al., 2010, Science • Fear reduction during or at end of extinction training not predict fear at test • Differential fear at test despite equivalent fear reduction during extinction

o Animal studies: Rescorla, 2006; Plendl, Wolfgang et al., 2010; Callaghan et al., 2014

o Human studies: Prenoveau, Craske et al., 2013; Brown, LeBeau & Craske, in submission MECHANISMS OF EXTINCTION • Formation of competing associations (Bouton, 1993) o original CS-US association not erased but left intact

US

CS MECHANISMS OF EXTINCTION • Formation of competing associations (Bouton, 1993) o original CS-US association not erased but left intact o secondary CS-noUS association formed and competes with original association

US No US

CS MECHANISMS OF EXTINCTION • Formation of competing associations (Bouton, 1993) o original CS-US association not erased but left intact o secondary CS-noUS association formed and competes with original association

Heart Attack No Heart Attack

Elevated Heart Rate MECHANISMS OF EXTINCTION • Formation of competing associations (Bouton, 1993) o original CS-US association not erased but left intact o secondary CS-noUS association formed and competes with original association

Rejection Not Rejected

Frown PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

?

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

FEAR

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

FEAR Passage of Time

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

FEAR Different Context

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

Unpaired Adverse FEAR Event

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

Repairing with FEAR Adverse Event

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Fear Reduction Threat Expectancy CS=US

?

Nonthreat Expectancy CS=noUS PRE-EXPOSURE------EXPOSURE------POST-EXPOSURE

Threat Expectancy CS=US

NO FEAR

Nonthreat Goal: non-threat expectancy Expectancy sufficiently strong and CS=noUS retrievable to compete with and inhibit threat expectancy Neural mechanisms (e.g., Shin & Liberzon, 2010) • Fear acquisition: amygdala activation • Fear extinction: vmPFC activation down-regulates amygdala

N=10 healthy controls vmPFC activation during extinction test (t=3.20, p<.05) vmPFC negatively correlated with amygdala activity (r=-.85, p<.05) (Burklund, Nusslock & Craske, 2011) How can inhibitory learning be maximized during exposure therapy? How can inhibitory learning be maximized during exposure therapy?

How can inhibitory learning be maximally retrieved at a later point in time, after completion of exposure therapy? INHIBITORY LEARNING AND ANXIETY

• Individuals with anxiety disorders show deficits in inhibitory learning or regulation o Extinction learning (Craske et al., 2008; Lissek et al., 2005; Milad et al., 2009; Milad et al., 2013; McLaughlin et al., 2015) o Safety learning (Craske et al., 2009; 2011) o Transfer of safety (Jovanovic et al., 2009; 2010; 2012; Liao & Craske, 2013) 16 trials 8 CS+, 8 CS- acquisition

Tone CS+

CS-

0 s 7 s 8 s 8 trials 4 CS +, 4 CS- extinction

CS+

CS-

0 s 7 s 8 s 8 trials 4 CS +, 4 CS- extinction test: 1-2 weeks spontaneous recovery

CS+

CS-

0 s 7 s 8 s DEFICITS IN EXTINCTION LEARNING

Conditioning: F(1, 110) = 7.88, p < .001, β = -.15 Craske, M.G., Waters, A., Bergman, L., Extinction: F(1, 55) = 6.19, p = .003, β = -.10 Naliboff, B., Lipp, O., & Ornitz, E. (2008). Is Extinction retest: F(1, 50) = 9.54, p = .003, β = -.09 aversive learning a marker of risk for anxiety disorders in children? Behaviour Research and Therapy, 46, 954-967. DEFICITS IN EXTINCTION LEARNING

Replicated across multiple anxiety disorders and anxious groups (Lissek et al., 2005; Milad et al., 2013; McLaughlin et al., 2015)

Conditioning: F(1, 110) = 7.88, p < .001, β = -.15 Craske, M.G., Waters, A., Bergman, L., Extinction: F(1, 55) = 6.19, p = .003, β = -.10 Naliboff, B., Lipp, O., & Ornitz, E. (2008). Is Extinction retest: F(1, 50) = 9.54, p = .003, β = -.09 aversive learning a marker of risk for anxiety disorders in children? Behaviour Research and Therapy, 46, 954-967. DEFICITS IN EXTINCTION LEARNING

Deficits in vmPFC at extinction retest (Milad et al., 2009; Milad et al., 2013; McLaughlin et al, 2015)

Conditioning: F(1, 110) = 7.88, p < .001, β = -.15 Craske, M.G., Waters, A., Bergman, L., Extinction: F(1, 55) = 6.19, p = .003, β = -.10 Naliboff, B., Lipp, O., & Ornitz, E. (2008). Is Extinction retest: F(1, 50) = 9.54, p = .003, β = -.09 aversive learning a marker of risk for anxiety disorders in children? Behaviour Research and Therapy, 46, 954-967. TRANSLATION

Bullied on Anxious child fearful of playground bullies

Anxious child remains Bullies are fearful of rehabilitated rehabilitated and no bullies longer bully DEFICITS IN SAFETY LEARNING (INHIBITORY)

8 baseline trials 8 context trials 8 baseline trials 8 context trials

Safe – Danger Phases

Shock

5 35 15 45 15 45 5 35 5 35 15 45 15 45 5 35 + + + + + + + + + + + + + + + + 0 55 0 55 0 55 0 55 0 55 0 55 0 55 0 55 SAFE NO SHOCK WILL BE GIVEN DANGER SHOCK MAY BE GIVEN

0 Count down 55 DEFICITS IN SAFETY LEARNING (INHIBITORY)

8 baseline trials 8 context trials 8 baseline trials 8 context trials

Safe – Danger Phases

Shock

5 35 15 45 15 45 5 35 5 35 15 45 15 45 5 35 + + + + + + + + + + + + + + + + 0 55 0 55 0 55 0 55 0 55 0 55 0 55 0 55 5 Low Medium High 4.5

4

3.5 EMG magnitude [ln] EMG magnitude 3

2.5 1 to 4 5 to 8 1 to 4 5 to 8 Distal Distal Distal Distal 1 to 4 5 to 8 1 to 4 5 to 8 Proximal Proximal Proximal Proximal

Baseline Context Safe Threat Safe Threat Baseline Context

Pre-contraction Post-contraction

Contextual Threat Explicit Threat Contextual Threat

Craske, M.G., Waters, A., Nazarian, M., Mineka, S., Zinbarg, R.E., Griffith, J.W., Naliboff, B. & Ornitz, E. (2009). Does neuroticism in adolescents moderate contextual and explicit threat cue modulation of the startle reflex? Biological Psychiatry, 65, 220-226. DEFICITS IN INHIBITION OF FEAR TO SAFE CUES

5 Low Medium High 4.5

4

3.5 EMG magnitude [ln] EMG magnitude 3

2.5 1 to 4 5 to 8 1 to 4 5 to 8 Distal Distal Distal Distal 1 to 4 5 to 8 1 to 4 5 to 8 Proximal Proximal Proximal Proximal

Baseline Context Safe Threat Safe Threat Baseline Context

Pre-contraction Post-contraction

Contextual Threat Explicit Threat Contextual Threat

Craske, M.G., Waters, A., Nazarian, M., Mineka, S., Zinbarg, R.E., Griffith, J.W., Naliboff, B. & Ornitz, E. (2009). Does neuroticism in adolescents moderate contextual and explicit threat cue modulation of the startle reflex? Biological Psychiatry, 65, 220-226. DEFICITS IN SAFETY LEARNING (INHIBITORY)

Before Contraction After Contraction p<.05

Craske, M.G., Wolitzky-Taylor, K.B., Mineka, S., Zinbarg, R., Waters, A.M., Vrshek-Schallhorn, S., Epstein, A., Naliboff, B., & Ornitz, E. (2011). Elevated responding during safe conditions as a specific risk factor for anxiety versus depression: Evidence from a longitudinal investigation. Journal of Abnormal Psychology, 121, 315-324. DEFICITS IN SAFETY LEARNING (INHIBITORY)

Before Contraction After Contraction p<.05

Craske, M.G., Wolitzky-Taylor, K.B., Mineka, S., Zinbarg, R., Waters, A.M., Vrshek- Predicted by Schallhorn, S., Epstein, A., Naliboff, B., & Ornitz, E. (2011). Journal of Abnormal Psychology, 121(2), 315-324. adolescent adversity

Wolitzky-Taylor, K., Vrshek-Schallhorn, S., Wateres, A., Mineka, S., Zinbarg, R., Ornitz, E., & Craske, M.G. (i2013). Clinical Psychological Science, 2, 202-213. TRANSLATION

Bullied on Anxious child fearful of playground bullies

Anxious child fearful of other kids who are not bullies DEFICITS IN TRANSFER OF SAFETY Prior training AX+, BX- Test of inhibition phase: does B safety transfer to A (relative to novel C)

Scream Recall list & cold of words pressor

Liao, B., & Craske, M.G. (2013). The impact of state anxiety on fear inhibition. Journal of Experimental Psychopathology, 4, 148-160. DEFICITS IN TRANSFER OF SAFETY Prior training AX+, BX- Test of inhibition phase: does B safety transfer to A (relative to novel C)

Deficits in transfer of safety in PTSD (Jovanovic et al., 2009; 2010; 2012)

Scream Recall list & cold of words pressor

Liao, B., & Craske, M.G. (2013). The impact of state anxiety on fear inhibition. Journal of Experimental Psychopathology, 4, 148-160. TRANSLATION

Bullied on Anxious child fearful of playground bullies

Bullies Anxious child remains accompanied by fearful of bullies teachers who prevent bullying How can inhibitory learning be maximized during exposure therapy?

How can inhibitory learning be maximally retrieved at a later point in time, after completion of exposure therapy?

Especially for anxious individuals who show deficits in inhibitory learning or regulation Craske et al., 2008 Craske et al., 2012 Craske et al., 2014 WEAN SAFETY SIGNALS & BEHAVIORS

VIOLATE CONSOLIDATION EXPECTANCIES PHARMACOLOGICALLY

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL RETRIEVAL Strength & CUES, MULTIPLE INHIBITORY CONTEXTS, Retrievability REGULATION CHOLINERGIC AFFECT ANTAGONIST of Inhibitory LABELING Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? VIOLATE EXPECTANCIES VIOLATE EXPECTANCIES

The greater the mismatch between expectancy and outcome, the greater the learning (Rescorla & Wagner, 1972) VIOLATE EXPECTANCIES VIOLATE EXPECTANCIES

Greater changes in US expectancy during extinction predict less fear at test (β=-.258, t(60)=-2.28, p<.05, partial η2=.08) (Brown, LeBeau & Craske, in submission) VIOLATE EXPECTANCIES VIOLATE EXPECTANCIES

Design conditions of exposure to maximally violate expectancies (Craske et al., 2008, 2012, 2014) Acrophobia Pre BAT NDC DC Repeated trials One trial Duration = uncertainty Duration = certainty + 10 min ITI (2 days) (2 days)

Post BAT

4-week Follow-Up BAT

Baker, A., Mystkowksi, J., Culver, N., Yi, R., Mortazavi, A., & Craske, M.G., (2010). Does habituation matter? Emotional processing theory and exposure therapy for acrophobia.Behaviour Research and Therapy, 48, 1139-43. Acrophobia 7.0 (2.0) trials 2.0 (0.0) trials Pre BAT NDC DC Repeated trials One trial Duration = uncertainty Duration = certainty + 10 min ITI (2 days) (2 days)

Post BAT

4-week Follow-Up BAT

Baker, A., Mystkowksi, J., Culver, N., Yi, R., Mortazavi, A., & Craske, M.G., (2010). Does habituation matter? Emotional processing theory and exposure therapy for acrophobia.Behaviour Research and Therapy, 48, 1139-43. Acrophobia 26.2 (14.6) 16.8 (18.6) mins covaried Pre mins covaried BAT NDC DC Repeated trials One trial Duration = uncertainty Duration = certainty + 10 min ITI (2 days) (2 days)

Post BAT

4-week Follow-Up BAT

Baker, A., Mystkowksi, J., Culver, N., Yi, R., Mortazavi, A., & Craske, M.G., (2010). Does habituation matter? Emotional processing theory and exposure therapy for acrophobia.Behaviour Research and Therapy, 48, 1139-43. Acrophobia Questionnaire – Anxiety Subscale: One trial as effective as multiple trials

70 65 60 55 DC NDC 50 45 40 35 Pre Post Follow-Up

Baker, A., Mystkowksi, J., Culver, N., Yi, R., Mortazavi, A., & Craske, M.G., (2010). Does habituation matter? Emotional processing theory and exposure therapy for acrophobia.Behaviour Research and Therapy, 48, 1139-43. Acrophobia Questionnaire – Anxiety Subscale: One trial as effective as multiple trials

70 65 Early 60 Session 55 Cues DC NDC 50 45 40 35 Pre Post Follow-Up

Baker, A., Mystkowksi, J., Culver, N., Yi, R., Mortazavi, A., & Craske, M.G., (2010). Does habituation matter? Emotional processing theory and exposure therapy for acrophobia.Behaviour Research and Therapy, 48, 1139-43. TYPICAL EXTINCTION CURVE

4,50

4,00

3,50 Asymptote 3,00

2,50

2,00

1,50

1,00

0,50

0,00 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 • Learning curve asymptotes o prevents any further learning from occurring (Rescorla & Wagner, 1972) o there is no more surprise! VIOLATE EXPECTANCIES: DEEPENED EXTINCTION

4,50

4,00 CS 3,50

3,00

2,50

2,00

1,50

1,00

0,50

0,00 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63

• Add second CS at point of asymptote o inflate US expectancy and enhance learning on subsequent trials (Rescorla, 2006) o enhance attentional salience of CS (Pearce & Hall, 1980) VIOLATE EXPECTANCIES: DEEPENED EXTINCTION

Culver, N., Vervliet, B., & Craske,M.G. (2014). Using the Rescorla-Wagner model to maximize exposure therapy effects for anxiety disorders. Clinical Psychological Science

Acquisition Extinction Phase 1 Extinction Phase 2 Single Compound VIOLATE EXPECTANCIES: DEEPENEDEXTINCTION VIOLATE EXPECTANCIES: Culver, Vervliet,N., Craske,M.G. the & Rescorla (2014). B., Using Skin conductance response exposure therapy effects disorders. anxietyfor SCR to at Extinction Test Clinical Psychological Science Clinical - Wagner maximizemodel to t(30) = 4.7, 4.7, = t(30) p < .001 < p t(30)=3.13, p < .005

t(34)=2.9, p<.01

Culver, N., Vervliet, B., & Craske,M.G. (2014). Using the Rescorla-Wagner model to maximize exposure therapy effects for anxiety disorders. Clinical Psychological Science VIOLATE EXPECTANCIES: PARTIAL REINFORCEMENT

4,50

4,00 US

3,50

3,00

2,50

2,00

1,50

1,00

0,50

0,00 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 • Add US o inflate US expectancy and enhance learning on subsequent trials (Rescorla, 2006) o enhance attentional salience of CS (Pearce & Hall, 1980) o decrease context specificity (Bouton, 1993) CS+ during Extinction Control 0.9 Reinforced

0.8 Culver, Stephens & Craske 0.7 (in submission) 0.6

0.5

0.4

0.3

0.2 Skin Conductance Response 0.1 Group X Time: b = 0.02, 0 t(895) = 5.04, p < 0.001 -0.1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Trial Figure 7

Group X Time: b = 0.33, t(895) = 6.01, p < 0.001 CS+ from End of Extinction to Spontaneous Recovery Test Control 0.7 Reinforced Culver, Stephens & Craske 0.6 (in submission)

0.5

0.4

0.3

0.2 Skin Conductance Response

0.1 Group x Time : F(1,21) = 10.11, p < 0.01, η2 = 0.44 0 End of Extinction Spontaneous Recovery Test Trial Figure 15

Group x Time : F(1,21) = 7.44, p < 0.05, η2 = 0.33 Culver, Stephens & Craske (in submission)

CS+ during Reacquisition 0,8 Control Partial Reinforced

0,6 b = 0.09*

b = - 0.06 0,4

0,2

0 0 1 2 3 4 5 Skin Conductance Response (SCR) Trial Figure 2

Group x Slope, b = -0.15, t(115) = -2.70, p = 0.01. Craske et al., 2008; Craske et al., 2012; Craske et al., 2014 WEAN SAFETY SIGNALS & BEHAVIORS

VIOLATE CONSOLIDATION EXPECTANCIES PHARMACOLOGICALLY

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL RETRIEVAL Strength & CUES, MULTIPLE INHIBITORY CONTEXTS, Retrievability REGULATION CHOLINERGIC AFFECT ANTAGONIST of Inhibitory LABELING Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? Attention to CS

• Attention is critical to learning

• Training to attend to CS+ (dot probe) led to less spontaneous recovery of fear (Liao & Craske, in prep) VIOLATION OF EXPECTANCIES: CLINICAL APPLICATION

• Design exposures to violate expectancies from outset • Add fear stimuli within exposure trial . driving exposure…..add interoceptive exposure . contaminant exposure….add another contaminant • Occasional negative outcomes within exposure trial . social rejections . panic attacks (e.g., yohimbine) • Attend in order to learn • Role of o May attentuate “violation of expectancy – not surprised” before and during exposure o Consolidate learning after exposure Craske et al., 2008; Craske et al., 2012; WEAN SAFETY Craske et. al., 2014 SIGNALS & BEHAVIORS

CONSOLIDATION VIOLATE OF LEARNING EXPECTANCIES DCS

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL Strength & RETRIEVAL CUES, INHIBITORY MULTIPLE Retrievability REGULATION CONTEXTS, AFFECT CHOLINERGIC of Inhibitory LABELING ANTAGONIST Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? VARIABILITY

• Random and variable practice enhances retrievability of newly learned information (Magill & Hall, 1990) • Effortful training increases storage strength (Soderstrom & Bjork, 2015) • Increases retrieval cues (Estes, 1966) • Generates a rule that captures the invariance among tasks (Schmidt & Bjork, 1992)

• In contrast, traditional exposure based treatments employed blocked and constant practice Rowe, M.K., & Craske, M.G. (1998). Effects of varied-stimulus exposure training. Behaviour Research and Therapy, 36, 719-734. Lang, A.J., & Craske, M.G. (2000). Manipulations of exposure based therapy to reduce return of fear: a replication. Behaviour Research and Therapy, 38, 1-12 Autonomic arousal and subjective distress did NOT Lang, A.J., & Craske, M.G. (2000). Manipulations of exposure based therapy to reduce return of fear: a habituate in Varied replication. Behaviour Research and Therapy, 38, 1-12 Group Exposure RV Group BM Group Session

Look at close (2 min.) Look at close (7 min.) Session 1 … … Spread on body (12 Spread on body (7 min.) min.)

Spread on body (6 min.) Look at close (7 min.) Session 2 … … Look at close (8 min.) Spread on body (7 min.)

Look at close (7 min.) Look at close (12 min.) … Session 3 … Spread on body (7 Spread on body (2 min.) min.)

Same number of exposure tasks (total and with each item), and total minutes of exposure Heart Rate to Novel Contaminant 85 d=.37

80

75

HR RV Group 70 BM Group

65

60 PRE POST 2WFU Occasion

Kircanski, K., Mortazavi, A., Castriotta, N., Baker, A., Mystkowski, J., Yi, R., & Craske, M.G. (2011). Challenges to the traditional exposure paradigm: variability in exposure therapy for contamination fears. Journal of Behavior Therapy and Experimental Psychiatry, 43, 745-751. Higher variability throughout exposure, less fear at follow-up, above and beyond starting fear, peak fear, ending fear, or habituation, R2 = .19

Kircanski, K., Mortazavi, A., Castriotta, N., Baker, A., Mystkowski, J., Yi, R., & Craske, M.G. (2011). Journal of Behavior Therapy and Experimental Psychiatry, 43, 745-751. Higher variability throughout exposure, less fear at follow-up, above and beyond starting fear, peak fear, ending fear, or habituation, R2 = .19

Replicated: Culver, N., Stoyanova, M.S., & Craske, M.G. (2012). Journal of Behavior Therapy and Experimental Psychiatry, 43, 787-793.

Niles, A & Craske, M.G. (in submission)

Kircanski, K., Mortazavi, A., Castriotta, N., Baker, A., Mystkowski, J., Yi, R., & Craske, M.G. (2011). Journal of Behavior Therapy and Experimental Psychiatry, 43, 745-751. VARIABLILITY: CLINICAL APPLICATION

. Methods of Variability

 stimuli

 approach to stimuli

 order from hierarchy

 duration of exposures

 time between exposures Craske et al., 2008; Craske et al., 2012; WEAN SAFETY Craske et. al., 2014 SIGNALS & BEHAVIORS

CONSOLIDATION VIOLATE OF LEARNING EXPECTANCIES DCS

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL Strength & RETRIEVAL CUES, INHIBITORY MULTIPLE Retrievability REGULATION CONTEXTS, AFFECT CHOLINERGIC of Inhibitory LABELING ANTAGONIST Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? CONTEXT SPECIFICTY

Extinction is context specific  context renewal when tested in a context that differs from extinction context; new context reactivates the excitatory CS=US association

F(1,30) =5.79, p < 0.05, n2 = 0.16 F(1,30) =11.81, p < 0.005, n2 = 0.28 Culver, N., Stoyanova, M., & Craske, M.G. (2011). Clinical relevance of retrieval cues for attenuating context renewal of fear in participants fearful of public speaking. Journal of Anxiety Disorders, 25, 284-292 CONTEXT SPECIFICTY

Extinction is context specific  context renewal when tested in a context that differs from extinction context; new context reactivates the excitatory CS=US association

Replicated Rodriguez, B.I., Craske, M.G., Mineka, S., & Hladek, D. (1999). Context-specificity of relapse: Effects of therapist and environmental context on return of fear. Behaviour Research and Therapy, 37, 845-862.

Mystkowski, J., Craske, M.G., & Echiverri, E. (2002) Treatment context and return of fear in spider phobia. Behavior Therapy, 33, 399-416

Mystkowski, J., Echiverri, A., Labus, J., & Craske, M.G. (2006). Mental reinstatement of context and return of fear in spider phobia. Behavior Therapy, 37, 49-60.

F(1,30) =5.79, p < 0.05, n2 = 0.16 F(1,30) =11.81, p < 0.005, n2 = 0.28 Culver, N., Stoyanova, M., & Craske, M.G. (2011). Clinical relevance of retrieval cues for attenuating context renewal of fear in participants fearful of public speaking. Journal of Anxiety Disorders, 25, 284-292 OFFSET CONTEXT RENEWAL

• Multiple contexts (Vansteenwegen et al., 2007; Balooch, Neumann, & Boschen, 2012)

 situations (e.g., alone, with others, at home, in familiar and unfamiliar places, therapy and non-therapy)  internal (medications, caffeine) contexts  initial acquisition context RETRIEVAL CUES

12 No Renewal Renewal

10

8

6

4 Demonstrated Renewal Demonstrated Number of Participants Number Who 2

0 NN NR RN RR Group χ2 = 9.211 (p < 0.05) Culver, N., Stoyanova, M., & Craske, M.G. (2011). Clinical relevance of retrieval cues for attenuating context renewal of fear in participants fearful of public speaking. Journal of Anxiety Disorders, 25, 284-292 MENTAL REINSTATEMENT RETRIEVAL

“Remember what happened and what you learned last time, and where all of that took place.”

Mystkowski, J., Echiverri, A., Labus, J., & Craske, M.G. (2006). Mental reinstatement of context and return of fear in spider phobia. Behavior Therapy, 37, 49-60. CONTEXTUAL LEARNING AND HIPPOCAMPUS

• Context specificity of extinction mediated by hippocampus; encoding of spatial-temporal contexts (Fanselow, 2000)

• “Downregulation” of hippocampus during extinction eliminates context specificity in rodents o Lesion o Pharmacological: Scopolamine - blocks acetylcholine at cholinergic receptors

Zelikowsky, Pham & Fanselow (2012)

SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP .6mg SCOP Context A Acquisition ? Context B Extinction Virtual Reality

Seven Sessions Biweekly: 7 speeches per session SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP .6mg SCOP Context A Acquisition ? Context B Extinction Virtual Reality

Seven Sessions Biweekly: 7 speeches per session SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP Context B .6mg SCOP Virtual Reality (Same) Context A Acquisition ? Context B Extinction Virtual Reality

Seven Sessions Biweekly: 7 speeches per session SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP Context B .6mg SCOP Virtual Reality (Same) Context A Acquisition ? Context B Extinction Virtual Reality

Seven Sessions Biweekly: 7 speeches per session SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP Context B .6mg SCOP Virtual Reality (Same) Context A Acquisition ? Context B Extinction Virtual Reality

Seven Context C Sessions Virtual Reality Biweekly: (Different) 7 speeches per session SCOPOLAMINE TO DECONTEXTUALIZE EXPOSURE

Day 1 to Day 28------Day 32

Placebo .2mg SCOP .4mg SCOP Context B .6mg SCOP Virtual Reality (Same) Context A Acquisition ? Context B Extinction Virtual Reality

Seven Context C Sessions Virtual Reality Biweekly: (Different) 7 speeches per session Craske et al., 2008; Craske et al., 2012; WEAN SAFETY Craske et. al., 2014 SIGNALS & BEHAVIORS

CONSOLIDATION VIOLATE OF LEARNING EXPECTANCIES DCS

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL Strength & RETRIEVAL CUES, INHIBITORY MULTIPLE Retrievability REGULATION CONTEXTS, AFFECT CHOLINERGIC of Inhibitory LABELING ANTAGONIST Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? NEGATIVE AND POSITIVE VALENCE

• CS+ acquires negative valence that is relatively resistant to extinction

• Negative valence CS+ predicts fear reinstatement (Hermans et al., 2005; Zbozinek, Hermans, Prenoveau, Liao & Craske, 2014; Zbozinek, Holmes, & Craske, in press)

• Positive affect induction increased positive valence CS+ post extinction and decreased fear reinstatement (Zbozinek, Holmes & Craske, in press) NEGATIVE AND POSITIVE VALENCE

• CS+ acquires negative valence that is relatively resistant to extinction

• Negative valence CS+ predicts fear reinstatement (Hermans et al., 2005; Zbozinek, Hermans, Prenoveau, Liao & Craske, 2014; Zbozinek, Holmes, & Craske, in submission)

“It’s your birthday, and your partner • Positive affect inductionreaches increased over to you positive with a present. valence You CS+ open it and feel incredibly happy.” post extinction and decreasedImagine the fearscenario reinstatement and rate vividness (Zbozinek, Holmes & Craske, inof submission) the image. Positive Valence Training Exposure Video to Live Test Test Spider Neutral

Valence Reinstatement Training Video Dour & Craske, in sumbission Positive Valence Exposure Training to Live Video Test Test Spider Neutral

Valence Reinstatement Training Video Dour & Craske, in sumbission Positive Valence Exposure Training to Live Video Test Test Spider Neutral

Valence Reinstatement Training Video * *

PVT < Control post-valence training (B=-0.85, SE=.41, p=.04, CI=-1.65--.05) PVT < Control spontaneous recovery (B=-1.14, SE=.42, p=.01, CI=-1.96--0.33) Dour & Craske, in submission Dour & Craske, in submission Craske et al., 2008 Craske et al., 2012 WEAN SAFETY Craske et. al., 2014 SIGNALS & BEHAVIORS

CONSOLIDATION VIOLATE OF LEARNING EXPECTANCIES DCS

ATTEND TO STIMULUS

OFFSET CONTEXT RENEWAL Strength & RETRIEVAL CUES, INHIBITORY MULTIPLE Retrievability REGULATION CONTEXTS, AFFECT CHOLINERGIC of Inhibitory LABELING ANTAGONIST Learning

CONSOLIDATION SCHEDULING POSITIVE VALENCE

VARIABILITY OF STIMULUS & EMOTION

ERASE FEAR MEMORY: RECONSOLIDATION? AFFECT LABELING

Extinction: primarily vmPFC inhibits amygdala, especially at extinction test (Sotres-Bayon, Cain, & Le Doux, 2006)

Affect Labeling (implicit form of emotion regulation): Disruption Theory (Lieberman, 2007)

Language Increased Decreased Improved in response Activation Amygdala management to of the Activity of negative emotional RVLPFC affect stimuli

mPFC Figure 1. Sample screens of each condition, plus the fixation crosshair. Affect Labeling

Lieberman, M. D., Eisenberger, N. I., et al. (2007). Putting Feelings Into Words. Psychological Science, 18, 421-8 AFFECT LABELING: SOCIAL ANXIETY DISORDER 1,4

1,2

1

Affect Label 0,8

Gender Label 0,6

0,4

0,2 Amygdala Parameter Estimates Parameter Amygdala

0 HC SP SP+Anx SP+Dep

15 30 19 18 -0,2 Group

Burklund, L.J., Craske, M.G., Taylor, S.E., & Lieberman, M.D. (2014). Altered emotion regulation capacity in social phobia as a function of comorbidity. Social Cognitive Affective Neuroscience. DEFICITS IN IMPLICIT EMOTION REGULATION

• Anxious individuals show deficits in implicit emotion regulation (i.e., inhibitory regulation) • Treatment implications • strategies to strengthen RVLPFC inhibition of amygdala responses • affect labeling training • Spider fearful: exposure to spider images with and without labeling (Tabibnia, Lieberman & Craske, 2008) AFFECT LABELING TRAINING: SPIDER PHOBIC

Labeling Reappraisal

E.g., “Sitting in front of the E.g., “Sitting in front of the ugly spider makes me little spider is not very nervous.” dangerous for me.”

Distraction Exposure-Alone

E.g., “There is a table in front of the couch in my den.”

Kircanski, K., Lieberman, M.D., & Craske, M.G. (2012). Feelings into words: contributions of language to exposure therapy. Psychological Science, 23, 1086-1091.

AFFECT LABELING TRAINING: SPIDER PHOBIC

Kircanski, K., Lieberman, M.D., & Craske, M.G. (2012). Feelings into words: contributions of language to exposure therapy. Psychological Science, 23, 1086-1091. AFFECT LABELING TRAINING: SPIDER PHOBIC

I feel: Nervous Afraid Scared Panicked

More Anxiety Words Less Fear Responding at used During Exposure Re-Test

Kircanski, K., Lieberman, M.D., & Craske, M.G. (2012). Feelings into words: contributions of language to exposure therapy. Psychological Science, 23, 1086-1091. AFFECT LABELING: PUBLIC SPEAKING ANXIETY

I feel ______The audience will ______1) Anxious 1) Laugh at me 2) Angry 2) Judge me negatively 3) Sad 3) Think I’m weird 4) Other 4) Other

Niles, Lieberman & Craske (in press) Behaviour Research & Therapy AFFECT LABELING: PTSD

Right now I feel ______about my trauma

Calm Angry Sad Other Right now I feel angry about my ______trauma

Painful Distant Violent Other MECHANISMS OF AFFECT LABELING DURING EXPOSURE

• Augments extinction • enhances attention to phobic stimulus (Pearce & Hall, 1980) • enhances disconfirmation of expectancy (Rescorla & Wagner, 1972)

• Parallel, complementary inhibitory regulation

TAD Sample

• N = 61 (NAT=41, PAT=20) • 100% at least one anxiety disorder – GAD 55% - OCD 15% – SAD 53% - PTSD 8% – PD 38% - SP 8% – AG 28% • 73% at least one mood disorder – MDD (single, recurrent) 68% – PDD 13% - DD 8%

CONCLUSIONS

• The long term success of exposure therapy depends on strength and retrievability of inhibitory associations and underlying neural regulation

• Fear reduction within exposure therapy is an index of performance but not of learning and long term outcome CONCLUSIONS

Overlaps • Exposure outcomes enhanced by: with • design exposure to violate explicit expectancies behavioral testing • addition of fear cues model • occasional negative outcomes • attend to fear cues • variability of fear cues • multiple contexts, retrieval cues, mental reinstatement, and scopolamine (?) • positive valence or positive affect training • affect labeling (physiological and behavioral outcomes)