1. A randomized Controlled Trial of Treatment with Cognitive Behavioral Therapy (ACT). - Does treatment increase the activity of default network in patients suffering from schizophrenia, measured with fMRI? Fredrik Livheim Georgios Makris Ioannis Pantziaras Cave Sinai

2. 1.To study treatment effects of CBT/ACT in schizophrenia. 2.Are the treatment effects mediated by changes observable by increased default network activity, as observed with fMRI? Study Aims

3. Background (treatment) Three studies made on short (less then 10 hour) ACT interventions and Schizophrenia, the first: Gaudiano, B. A., & Herbert, J. D. (2006). Acute treatment of inpatients with psychotic symptoms using Acceptance and Commitment Therapy: Pilot results. Behaviour Research & Therapy, 44(3), 415-437. 40 psychiatric inpatients with psychotic symptoms were randomly assigned to enhanced treatment as usual (ETAU) or ETAU plus 3 individual sessions of ACT.

4. OUTCOME IN FAVOR OF ACT: Less affective symptoms, Better overall improvement, Less social impairment, and distress associated with hallucinations. More participants in the ACT condition reached clinically significant symptom improvement at discharge. Less 4-month rehospitalisation rates in ACT group WHY? Decreases in the believability of hallucinations Gaudiano, B. A., & Herbert, J. D. (2006). Acute treatment of inpatients with psychotic symptoms using Acceptance and Commitment Therapy: Pilot results. Behaviour Research & Therapy, 44(3), 415-437. Background (treatment, study 1)

5. Bach, P., Hayes, S. C. & Gallop, R. (in press). Long term effects of brief Acceptance and Commitment Therapy for psychosis. Behavior Modification. 80 psychiatric inpatients with psychotic symptoms were randomly assigned to enhanced treatment as usual (ETAU) or ETAU plus 4 individual sessions of ACT. OUTCOME : ACT group had higher symptom reporting! BUT 50% less rehospitalisation rates Effects explained by lower symptom believability Background (treatment, study 2)

6. Bach, P., Hayes, S. C. & Gallop, R. (in press). Long term effects of brief Acceptance and Commitment Therapy for psychosis. Behavior Modification. Effects holds at one year follow up Background (treatment, study 2)

7. A study of emotional upheaval following a psychotic break, White et al (in press) and found lower rates of depression and fewer crisis calls in the three months following 10 sessions of ACT. White, R.G., Gumley, A.I., McTaggart, J., Rattrie, L., McConville, D., Cleare, S, & Mitchell G. (in press). A feasibility study of Acceptance and Commitment Therapy for emotional dysfunction following psychosis. Behaviour Research and Therapy. Background (treatment, study 3)

8. Background (fMRI & DTI) Previous studies: The neurobiology of self-awareness in Schizophrenia – a fMRI study. (Shad et al. 2012)  Self-awareness (SA) is one of the core domains of higher cortical functions and is frequently compromised in schizophrenia.  Deficits in SA have been associated with functional and psychosocial impairment in this patient population.

9. A meta-analysis of 27 studies by Northoff et al. (2006) identified three clusters of medial wall activations during self- vs other directed stimuli, centred in: -medial prefrontal, -dorsal anterior cingulate, and -posterior cingulate regions, that showed increased activation when tasks required judgements about the self-relevance of stimuli, irrespective of the stimulus domain or sensory modality. They advocate an integrated cortical–subcortical midline system underlying the human self. Background (fMRI & DTI)

10. Buckner et al. 2012. The Brain’s Default Network - Anatomy, Function, and Relevance to Disease Background (fMRI & DTI) The default network can help for understanding mental disorders including autism, schizophrenia, and Alzheimer’s disease. Adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world

11. Carhart-Harrisa et al. 2011. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Background (fMRI & DTI)

12. Carhart-Harrisa et al. 2011. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Background (fMRI & DTI) Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

13. Methods

14. 1.A sample of 60 in-patients suffering from paranoid schizophrenia. Randomization to either CBT/ACT enhanced treatment as usual (ACT-TAU) or enhanced treatment as usual (E-TAU). 2.Measurements before and after treatment, as well as 1 year after treatment. 3.fMRI and DTI the day before start of treatment and one day after treatment termination. Study groups

15. 4. Exclusion: a) Due to treatment: - Not speaking Swedish - Psychosis induced by dementia b) Due to fMRI: - left-handed - pregnant or breast-feeding - metal implants or claustrophobia Study groups

16. Treatment  Acceptance and Commitment Therapy (ACT), a form of Contextual CBT.  Delivered in small groups, max 6 persons  Hypothesis for presenting problems, largely through a)Weak sense of self b)Avoidance of painful experiences in “the now” (experiential avoidance) c)Vulnerability, biological/genetic predispositions, often in combination with environmental factors (abuse, trauma etc.)

17. Treatment  Hypothesis for improvements, largely through: a)More stable sense of self. Through training in Relational Frames, multiple exemplar training in stimulus equivalence and the relational frames I-YOU, HERE-THERE, NOW- THEN. This will have spill over effects on contecting the “I- Here-Now”. a)Seeing delusions and hallucinations as they are. Through training in de-fusion. This will also give exposure, and increase acceptance. … and this is done in the context of helping participants contact what they hold as important in life.

18. Treatment (believability) - Seeing delusions and hallucinations as they are

19. Treatment (the self in ACT) The self in ACT is believed to be natural by-products of verbal behaviour, language (Hayes 1995). Deictics and complex behavior: Self discrimination of multiple behaviors “I’m eating icecream” “I’m driving back” “I’m doing some yard work” And of multiple thoughts, feelings and sensations “I feel sad” “I feel miserable” Lead to Discriminating the perspective of “I” as the absolute invariant

20. Treatment (the self in ACT) I eat breadI eat ice cream I eat a steak I eat chocolate I hear musicI hear a driving carI hear birds singingI hear my mother calling I see a deskI see you comingI see a bright futureI see and hear a dog I touch the screenI touch my faceI touch into the waterI touch the hot pan I go to my officeI go homeI go into the darkI go back to school I think of my workI think of your painI think of lunchtimeI think of my father I am goodI am badI am a husbandI am a doctor

21. Treatment (the self in ACT) I eat breadI eat ice creamI eat a steakI eat chocolateI hear musicI hear a driving carI hear birds singingI hear my mother calling I see a deskI see you comingI see a bright futureI see and hear a dog I touch the screenI touch my faceI touch into the waterI touch the hot pan I go to my officeI go homeI go into the darkI go back to school I think of my workI think of your painI think of lunchtimeI think of my father I am goodI am badI am a husbandI am a doctor

22. Treatment (the self in ACT) I eat breadI eat ice creamI eat a steakI eat chocolateI hear musicI hear a driving carI hear birds singingI hear my mother callingI see a deskI see you comingI see a bright futureI see and hear a dog

23. THEN NOW YOU I HERE THERE RFT Take on the Formation of Self and Perspective Taking

24. The I-Here-Nowness of Awareness is the Foundation of Perspective Taking Self-as-context

26. 3 Tesla, with DTI, SPM conversion software 1.fMRI: Gives functional activity measures. 2.DTI: Gives connectivity images of different active components in self-concept activity in the brain. DTI helps interpreting fMRI data and establishing how activated foci are linked together through networks. Method

27. 1.fMRI: Gives functional activity measures: -Activation and deactivation of self-related tasks in different domains employing different stimuli such as trait adjectives, memories, emotions. -Self-related imagery and self-talk on audio and visual input via headphones and googles. -Own and other’s personality traits vs. unrelated to me-you (deiactic frame). Method

28. Outcome measures: 1. Time to re-admissions: Measured with: Patient register 2. Improved quality of life: Measured with: PQVS (Subjective Life Quality Profile), strengths: 2 measurements. QUALY. 3. Acceptance of positive symptoms? Measured with: AAQ2 (Acceptance and action questionnaire)

29. Outcome measures: 4. Self-awareness: Measured with: Situational self awareness scale (SSAS) 5. Life functioning: Measured with: Life Functioning Questionnaire (LFQ), work, friends etc. 6. Changes in default network activity Measured with fMR and DTI

30. Outcome measures: 7. Depressive state Measured by Calgary Depression Scale (CDS), SZ sens. 8. Anxiety Measured by Becks Anxiety Inventory (BAI) 9. Distress and believability: Rating from 0-100. For the distress (“On a scale of 0 - 100, how distressed are you when you hear voices?) Rating from 0-100. For the believability (“On a scale of 0 -100,, to what degree do you believe that X (e.g., gang members are stalking you, the voices telling you that you are a bad person) is true?)

31. If treatment is effective, it can relieve large amounts of human suffering It has the potential to decrease large societal costs. The economic costs of schizophrenia are especially large due to: - Treatment adherence - Relapse - Inpatient admission The treatment can easily be introduced incommon clinical praxis Significance

32. This study will give answers to what neurological underpinnings that are correlated to treatment effects With better understanding of neurobiological correlates, we can develop optimized treatments in the future. Significance

33. If treatment is effective, it can relieve large amounts of human suffering. It has the potential to decrease large societal costs. The economic costs of schizophrenia The treatment can easily be introduced incommon clinical praxis. Support for theories of what neurological underpinnings correlated to treatment effects With better understanding of neurobiological correlates, we can develop optimized treatments in the future. Significance

34. Thanks for your attention! Georgios Makris Ioannis Pantziaras Cave Sinai Fredrik Livheim