Fredrik Livheim Georgios Makris Ioannis Pantziaras Cave Sinai

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

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. Background (treatment, study 1) • 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 believabilityof 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.

5. Background (treatment, study 2) • 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

6. Background (treatment, study 2) • 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

7. Background (treatment, study 3) • 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.

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. Background (fMRI & DTI) • A meta-analysisof 27 studies by Northoff et al. (2006) identifiedthree clusters of medial wallactivationsduringself- vs otherdirected stimuli, centred in: • medial prefrontal, • dorsal anteriorcingulate, and • posteriorcingulate regions, • thatshowedincreasedactivationwhen tasks requiredjudgementsabout the self-relevanceof stimuli, irrespectiveof the stimulus domain or sensorymodality. • Theyadvocate an integratedcortical–subcorticalmidline system underlying the human self.

10. Background (fMRI & DTI) Buckner et al. 2012. The Brain’s Default Network - Anatomy, Function, and Relevance to Disease • The default networkcanhelp for understanding mental disorders including autism, schizophrenia, and Alzheimer’sdisease. • Adaptive rolesof the default network for usingpastexperiencesto plan for the future, navigate social interactions, and maximize the utilityof moments whenweare not otherwiseengaged by the externalworld

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

12. Background (fMRI & DTI) Carhart-Harrisa et al. 2011. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. • Psilocybincaused a significantdecrease in the positive couplingbetween the mPFC and PCC • Theseresultsstronglyimplythat the subjectiveeffectsofpsychedelicdrugsarecaused by decreasedactivity and connectivity in the brain’skeyconnectorhubs, enabling a stateofunconstrainedcognition.

13. Methods

14. Study groups • 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). • Measurements before and after treatment, as well as 1 year after treatment. • fMRI and DTI the day before start of treatment and one day after treatment termination.

15. Study groups • 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

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 • Weak sense of self • Avoidance of painful experiences in “the now” (experiential avoidance) • Vulnerability, biological/genetic predispositions, often in combination with environmental factors (abuse, trauma etc.)

17. Treatment • Hypothesis for improvements, largely through: • 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”. • 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 am bad I am good I am a husband I am a doctor I think of my father I think of lunchtime I think of your pain I think of my work I go back to school I go into the dark I go home I go to my office I touch the screen I touch my face I touch into the water I touch the hot pan I see and hear a dog I see a bright future I see you coming I see a desk I hear my mother calling I hear birds singing I hear a driving car I hear music I eat chocolate I eat ice cream I eat bread I eat a steak

21. Treatment (the self in ACT) I am bad I am good I am a husband I am a doctor I think of my father I think of lunchtime I think of your pain I think of my work I go back to school I go into the dark I go home I go to my office I touch the screen I touch my face I touch into the water I touch the hot pan I see and hear a dog I see a bright future I see you coming I see a desk I eat chocolate I hear my mother calling I hear birds singing I hear a driving car I eat ice cream I eat bread I eat a steak I hear music

22. Treatment (the self in ACT) I eat bread I eat ice cream I eat a steak I eat chocolate I hear music I hear a driving car I hear birds singing I hear my mother calling I see a desk I see you coming I see a bright future I see and hear a dog

23. YOU HERE NOW I THEN 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. Method • 3 Tesla, with DTI, SPM conversion software • fMRI: Gives functional activity measures. • 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.

27. Method • 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).

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 activityMeasured with fMR and DTI

30. Outcome measures: • 7. Depressive stateMeasured by Calgary Depression Scale (CDS), SZ sens. • 8. AnxietyMeasured 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. Significance • 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 in common clinical praxis

32. Significance • 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.

33. Significance • 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 in common 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.

34. Thanks for your attention! GeorgiosMakris IoannisPantziaras Cave Sinai Fredrik Livheim