1. Neurocognitive Deficits in Schizophrenia Colin Hawco, PhD Oct 5 2015 York University

2. Magnitude of Cognitive Deficits in Schizophrenia Meta-Analysis: 204 studies, 7420 patients and 5865 controls Heinrichs & Zakzanis. Neuropsychology. 1998 Jul;12(3):426-45. SD below mean of controls

3. Trajectory of Cognitive Deficits Lewandowski et al. Psychol Med. 2011 Feb;41(2):225-41.

4. Cognitive Deficits Predict Functional Outcomes Functional Outcomes Learning & Memory Attention Executive Function Green. Am J Psychiatry. 1996; 153:321-330 Velligan et al. Schizophr Res. 1997 May 3;25(1):21-31.

5. Cognitive Deficits and Short-Term Clinical Outcome Controls (n = 31) Good Outcome (n = 73) Poor Outcome (n = 78) Clinical outcome assessed at 6 months Good outcome: > 2 on all global SAPS and > 3 on all global SANS (except attention) Bodnar et al. The British Journal of Psychiatry 2008 193: 297-304

6. Domain specific vs. generalized deficits?  MATRICS Consensus Battery based on domain specific hypothesis Speed of Processing Attention/Vigilance Working Memory Verbal Learning and Memory Visual Learning and Memory Reasoning and Problem Solving  If generalized deficit, why engage in long neuropsych testing? Probably a combination Generalized deficits, with some domains affected more than others Variability in specific domains across individuals?

7. Patient Z-score Above average cognition Severe cognitive impairments Hierarchical Clustering of Cognition in First Episode Psychosis

8. Why such a large deficit for Trails B? Highly multi-factorial test Scored by time, allowing “unlimited failure”

9. Select, via consensus, specific tasks to evaluate different cognitive functions Emphasis on imaging “Domain specific” in approach Tasks intended to be highly specific to a particular cognitive domain or function Avoids “multifactorial” problem of traditional neuropsychological tests

10. Verbal Memory and Encoding Strategies Incidental encoding (supported ‘deep’ encoding) vs. Intentional encoding (instruction to memorize) Bonner-Jackson et al., Psychiatry Research: Neuroimaging 164 (2008) 1–15

11. Controls > patients Patients > controls Meta analysis of fMRI studies of Memory Encoding Ragland et al. Am J Psychiatry 2009; 166:863–874 Memory deficits mainly related to prefrontal cortex

12. LTM effects (high subsequent memories) Working and Long-term Memory Interactions Greater DLPFC activity for rehearse over reorder related to less negative symptoms Ragland et al., NeuroImage 59 (2012) 1719–1726 Green Control Red Schizophrenia

13. Patients with Schizophrenia have a Deficit in Source Monitoring Keefe et al., Schizophrenia Research 57 (2002) 51 – 67 -Tendency to attribute internally generated stimuli to an external source - Particularly in patients who hallucinate Wang et al. Schizophrenia Research 125 (2011) 136–142

14. fMRI of Source Memory in Schizophrenia - Encoding session with two tasks - Source memory: identifying the task associated with a word - 13 Patients and 13 controls Green: Controls Red: Schizophrenia Ragland et al. Schizophr Res. 2006, 87(1-3):160-171.

15. Recognition: Person Place Object Source Memory in Schizophrenia: An fMRI VR Study Lisa Buchy

16. Controls Schizophrenia Person > object Place > object Person AND place > object Object > person Object > place Object > person AND place

17. Schizophrenia vs. Controls

19. Cognitive insight in Schizophrenia

20. Current Project: TMS-fMRI during working memory in Schizophrenia 2 sec 6 sec 2 sec Single TMS pulse at 500ms into delay High TMS vs. Low TMS 500ms TMS to assess Maintenance vs. manipulation 4000ms as a control: Manipulation should have completed and now maintaining Jennifer Steeves Reorder + TMS-fMRI gives us a measure of temporally specific connectivity

21. Treating Cognitive Deficits Behavioural Interventions: Cognitive remediation – Transfer effects? Efficacy? Duration? Pharmaceutical Interventions: Aripiprazole Neural Modulation: rTMS, TDCS – Efficacy? Duration of effects? Combined approaches – Brain stimulation combined with cognitive remediation

22. Neurological effects of Cognitive Remediation Changes from CRT Working memory (HCL > SCZ) WM and CRT Affective processing CRT Changes activity in the left prefrontal cortex, thalamus, caudate, and right anterior insula and parietal cortex Some regions showing changes overlap areas where SCZ shows reduced activity during working memory. There is some suggestions that CRT normalized brain function as opposed to compensatory patterns. Ramsay and McDonald. Schiz Bulletin. 20015,

23. Future of Brain Stimulation: Targeting?

24. Summary Cognitive deficits are present throughout the lifespan and functionally important. While generalized deficits may be present, some domain specificity exits (e.g. worse verbal memory) Multi-factorial nature of neuropsychological test may affect results and interpretations Cognitive neuroscience approach may better detect specific effects (but longer tests limit utility) Patients show deficits across a range of brain regions, often reduced activity. Particularly in HUB regions (e.g. DLPFC). Reduced activity related to less supporting cognitive processing? Understanding and treating these deficits may lead improved outcome and quality of life for these patients.

25. Merci! Martin Lepage Jeff Daskalakis Faranak Farzan George Foussias Aristotle Voineskos Jennifer Steeves

26. Yoon et al., Am J Psychiatry 2008; 165:1006–1014 Functional Connectivity and Cognition AX-BX continuous performance task Control > SCZ BX-AX Controls showed increased connectivity between DLPFC and these regions while patients did not.