1. Psychotic Disorders of the Brain: Basic and Clinical Neuroscience Better Outcomes Cameron S. Carter MD Department of Psychiatry and Center for Neuroscience cameron.carter@ucdmc.ucdavis.edu

2. Overview What we know about brain pathology in schizophrenia and bipolar disorder How we are using this knowledge to improve outcomes

3. 3 types of symptoms Positive Negative Cognitive/disorganization

4. Is schizophrenia a brain disorder?

5. JOHNSTONE AND CROW LANCET 1976

8. Effects of hemodynamic activation on BOLD signal in the brain: a) paramagnetic properties of Hb and b) overly zealous regulation of perfusion of the brain

9. Higher Cognitive Functions In Schizophrenia Attention Memory Language Disturbances Emotional processing Manifestation of Impaired Cognitive Control

10. Cognitive Control..when habitual responding won’t do and you have to use a representation of a task or goal to guide behavior…

11. GREEN

13. Gross Functional Impairment in the Brain Macrocircuit Abnormalities Yoon et al, American J. Psychiatry 2008

15. Neuronal Oscillations? * Encoding and processing occurs when a population of neurons fires at the same time AND with the same frequency. Asynchronous firing Synchronous firing Sometimes populations of neurons will fire at different times from each other (asynchronously), and sometimes they fire together (synchronously).

17. Frontal Cortical Induced Gamma Band Activity

18. Disrupted cortical function in schizophrenia Selective reduction in gray matter thickness Subtle alterations in cellular structure and function, unbalancing excitation and inhibition Disrupted local circuit function Loss of prefrontal control of networks Negative symptoms and cognitive impairment What about positive symptoms?

19. McGlashan 1984-the Chestnut lodge study

20. Alterations in dopamine neurotransmission The classical dopamine hypothesis (too much dopamine in schizophrenia) rested on the observation that DA releasing drugs can cause psychosis, and the discovery that antipsychotics were dopamine antagonists.

21. Alterations in dopamine neurotransmission C11 Racolpride displacement reflects DA release

22. Increased subcortical DA related to psychosis

23. Alterations in dopamine neurotransmission Decreased prefrontal activity (DA based or otherwise) may lead to subcortical DA dysregulation and psychosis Decreased PFC function VTA Increased DA +

24. Improving Outcomes New therapies for negative symptoms and cognitive impairments –Medication treatments –Brain training –Brain Stimulation Early Intervention

25. Medication Treatment for Cognitive and Negative Symptoms Not dopamine blockers, added on to antipsychotic treatment Most target cortical function, especially the prefrontal cortex Increase neuromodulators, dopamine, norepinephrine, cholinergic/nicotinic, gaba-ergic to improve local circuit function No unequivocal successes yet but progress

26. Cognitive Training Many approaches being developed Not just for schizophrenia, also ADHD, MCI

27. Vinogradov/Posit Science Study Protocol AUDITORY MODULE 50 hours VISUAL MODULE 30 hours COGN. CONTROL MODULE 20 hours Assessment Assessments:Clinical and Neuropsych Bloods (BDNF, serum antichol, plasms neuroleptic levels) MEG, fMRI

28. Baseline Cognitive Performance Auditory Training Subject Group (AT) N = 40 Computer Games Control Group (CG) N = 30

29. Change in Cognitive Performance post-training minus baseline age-adjusted z-scores 50 hours of computerized neuroplasticity-based auditory training (AT) vs. 50 hours of a computer games (CG) control condition. Results of Repeated Measures ANOVA, controlling for age and baseline cognitive performance, showed significant differences between AT and CG subject groups on measures of Global Cognition, Verbal Learning and Memory, and Verbal Working Memory at trend level.

30. PRELIMINARY 6-MONTH DATA: DURABILITY (AT = 22, CG = 10) Fisher, Holland, Subramaniam, Vinogradov, Schiz Bull, 2009

31. Brain Stimulation Transcranial Magnetic Stimulation Direct Current Stimulation

32. http://earlypsychosis.ucdavis.edu

33. Early Intervention for Psychosis Duration of untreated psychosis a strong predictor of treatment response and long term outcome Typically about 18 months in the US Early identification and intervention to brain this down Established psychosis The “psychosis risk syndrome”

34. PACE, PRIME, OPUS and PIER 12 month outcome

35. EDAPT Model Family based approach Rapid, crisis-oriented initiation of treatment Expert evaluation of clinical and risk status!!! Psychoeducational multifamily groups Case management and Medical Management using key Assertive Community Treatment methods –Integrated, multidisciplinary team; rapid response; continuous case review –Targeted pharmacological intervention as needed!!! Supported employment and education Collaboration with schools, colleges and employers Substance abuse treatment, as indicated Detailed outcomes measurement The EDAPT Program/SacEDAPT

36. U.C. Davis Innovation Overcoming Schizophrenia and Bipolar Disorder Overcoming Schizophrenia and Bipolar Disorder 1 person at a time Basic research into brain development and function CENTER FOR NEUROSCIENCE Early Intervention EDAPT/SacEDAPT Novel Treatments for Cognitive Deficits and Negative Symptoms TCAN Group

37. Division of Clinical Neuroscience UC Davis Friends of Psychiatry

38. REGISTER ONLINE AT http://cme.ucdavis.edu/conferences