Mercè Madre Rull mmadrer@gmail FIDMAG Research Foundation Hermanas Hospitalarias

1. Neuroimaging data help to clarify the nosological status of schizoaffective disorder (SAD)? Mercè Madre Rull mmadrer@gmail.com FIDMAG Research Foundation Hermanas Hospitalarias Barcelona, Spain

2. Overview • Previous Neuroimaging data of SAD • Functional Imaging SAD • Structural Imaging SAD • Discussion VBM fMRI FA

3. Why neuroimaging in SAD? • Clinical studies comparing SAD with SZ and BP are not conclusive. • Differences in neuroimaging between SAD, SZ and BP might help to clarify their boundaries. • Useful for clarifying SAD nosology. • Findings could add valuable information to the diagnostic classification and might have consequences for treatment trials. • SAD might constitute a middle point of a continuum between SZ and BP disorder. • SAD is not an atypical form of SZ or BP, nor an independent mental disorder. Cheniaux et al, 2008. Review - SAD shares features of both SZ and BP. • SAD resembles more SZ than BP in most of the demographic and clinical categories. Pagelet al, 2013. Meta-analysis

4. fMRI studies so far in SAD

5. Study 1 Brain functional abnormality in schizoaffective disorder: an fMRI study M. Madre, E. Pomarol-Clotet, P. McKenna, J. Radua, J. Ortiz-Gil, F. Panicali, J. M. Goikolea, E. Vieta, S. Sarró, R. Salvador and B. L. Amann. Psychological Medicine 2013 Jan;43 (1):143-53. Study 2 Trait or state? A longitudinal neuropsychological evaluation and fMRI study in schizoaffective disorder M Madre, J Radua, R Landin-Romero, S Alonso-Lana, R Salvador, F Panicali, E Pomarol-Clotet, BL. Amann. Schizophrenia Research 2014  Nov; 159(2-3):458-64.

6. Study 1 Study 2 32 acute Schizoaffective patients 16 schizomanic episode 16 schizodepressive episode Vs. 32 healthy subjects 22 Schizoaffective patients in clinical remission Vs. 22 healthy subjects Follow-up > 2 months of clinical remission Inclusion criteria Diagnosis of SAD bipolar type (DSM-IV, RDC) Age 18-65 years. IQ ≥ 70 Right handed No history of brain trauma or neurological disease. No Alcohol/substance abuse within 12 months prior to participation

7. N-back task • Working memory task: block design • Two levels of memory load: 1-back and 2-back * * * * * P P F F P F K K K P U P P U A A Baseline 1-back MRI acquisitions in a 1.5 Tesla GE Signa scanner 2-back • Exclusion criteria:movement >3.0 mm, poor task performance • Results showed: 2-back vs. Baseline contrast

8. Study 1 Brain functional abnormality in schizo-affective disorder: an fMRI study. Whole brain analysis of healthy subjects and acute schizoaffective patients Activations (blue) De-activations (pink) Healthy subjects (n=32) Acute Schizoaffective patients (n=32) . Madre et al, 2013

9. Study 1 ROIs derived from the differences between the whole brain analyses of acute schizoaffective patients vs. H.S Mean BOLD response between manic, depressive and H.S. Left precentral cortex (DLPFC) Reduced activation in acute schizoaffective Left middle temporal cortex Bilateral parietal cortex Failure of deactivation in acute schizoaffective Anterior cingulate cortex Madre et al, 2013

10. Thebrain’s Default Mode Network (DMN) DMN anterior node Medial prefrontal cortex Anterior cingulate cortex DMN posterior node Posterior cingulate cortex Precuneus Buckner et al, 2008

11. Mental illnesses and alterations of the DMN Schizophrenia: Failure of de-activation in the MPFC, using different tasks (Milanovic et al. 2011, Pomarol-Clotet et al. 2008, Whitfield-Gabrieli et al. 2009). Some studies have additionally found failure to de-activate in the posterior cingulate cortex (Salgado-Pineda et al. 2011, Schneider et al. 2011). Bipolar Disorder: Failure of de-activation in the MPFC during mania (Pomarol-Clotet et al. 2011) depression (Fernandez-Corcuera et al. 2012) and euthymia (Pomarol-Clotet et al. 2014), using working memory tasks. Failure of de-activation in the posterior cingulate cortex in euthymia, using a verbal fluency task (Allin et al. 2010) DMN dysfunction as a trait-like feature. Broyd et al, 2009. Review

12. Study 2 Trait or state? A longitudinal neuropsychological evaluation and fMRI study in schizoaffective disorder Acute episode vs. clinical remission in schizomanic and schizodepressive patients No activation changes Depressive patients vs. remission (n=12) Whole-brain paired t-test. Manic patients vs. remission (n=12) Reversible frontal hypo-activation Mean BOLD response in the ROIs during the acute phase and clinical remission in manic patients. Madre et al, 2014

13. Study 2 Trait or state? A longitudinal neuropsychological evaluation and fMRI study in schizoaffective disorder Schizoaffective patients in clinical remission (n=22) Healthy subjects (n=22) versus Failure of deactivation in remitted schizoaffective • Reversible frontal hypo-activation in acute manic SA that normalized in clinical remission, as a state-like feature. • DMN dysfunction is a trait-like feature of SAD. Madre et al, 2014

14. Resting-state fMRI using ICA: 12 discriminating regions (a) SupraMarginal L (b) Frontal-Medl-Orb R (c) Cingulatel-Ant L (d) Cingulatel-Post L (e) Frontall-Med_Ord R (f) Parietall-Inf L (g) Insula R (h) Parietall-Inf L (i) Precuneus R (j) Cerebelluml-Crus2 L (k) Suppl-Motor Area L HC = 20 SZ = 20 BP = 20 SAD manic = 20 SAD depressive = 13 BP HC SZ SADM SADD Yuhui Du et al, 2014

15. Structural studies so far in SAD CT: Structural computed tomography, vMRI: volumetric magnetic resonance imaging, VBM: Voxel Based Morphometry, DTI: Diffusion Tensor Imaging

16. Gray matter volume differences within the DSM-IV Diagnosis among patients groups and healthy comparison subjects SZ=146 vs. HC=200 Psychotic-BP=115 vs. HC=200 SAD=90 vs. HC=200 Ivleva et al. 2013

17. Study of gray matter volume reduction in SZ, SAD and BP compared to HC 45 SZ vs. 45 HC 45 SAD vs.45 HC 45 BP vs. 45 HC Amann et al. Acta Psyc Scand, 2015

18. VBM comparison of the combined patient group with the healthy controls Ventromedial Prefrontal cortex Bilateral frontal superior cortex Bilateral temporo-insular-parietal cortex Cerebellum Boxplots of the mean values of gray matter volume reduction in SAD (n=45), SZ (n=45) and BP (n=45). Amann et al. Acta Psyc Scand, 2015

19. Surface-based brain morphometry and diffusion tensor imaging in schizoaffective disorder: A multimodal approach 45 Schizoaffective vs. 45 Healthy subjects Surface-based morphometry Cortical Thickness (CT) Cortical Volume (CV) Surface Area (SA) Landín et al. 2015 (under review)

20. Surface-based brain morphometry and diffusion tensor imaging in schizoaffective disorder: A multimodal approach 45 Schizoaffective vs. 45 Healthy subjects Diffusion Tensor Imaging (DTI) White Mater • Corpus callosum • Bilateral anterior limb of internal capsule • Left superior longitudinal fasciculus FA • White Mater • Corpus callosum • Corona radiata • Grey Matter: • Frontal cortex • Temporal lobes • Left parahippocampal gyrus • right rectus • Left fusiform • Bilateral thalamic nuclei MD Landín et al. 2015 (under review)

21. Surface-based brain morphometry and diffusion tensor imaging in schizoaffective disorder: A multimodal approach 45 Schizoaffective vs. 45 Healthy subjects Multimodal analysis CV MD FA Surface-based morphometry DTI White matter Grey matter Landín et al. 2015 (under review)

22. Conclusions: Functional MRI studies in SAD • Few fMRI studies in SAD • Acute SA patients show reduced prefrontal activation (DLPFC) implicated in working memory tasks, similar to the ‘hypofrontality’ described in SZ and in some studies of BP. • Reversible frontal hypo-activation in acute manic SA patientswhen compared to clinical remission, as a state-like feature of SAD. • DMN dysfunction is a trait-like feature of SAD. Described in both SZ and BP. • SAD is an independent disorder, although depressive type shares high similarities with SZ in functional network patterns. (Madre et al, 2013; Madre et al, 2014; Yuhui Du et al, 2014 )

23. Conclusions: Structural MRI studies in SAD • Prior sMRI studies in SAD with important limitations. • Grey matter: • Widespread pattern of CV reduction (CT reduction) • Increased MD in both cortical and subcortical regions • White matter: • Widespread FA reduction • Increased MD • Two VBM studies comparing SAD with SZ and BP with similar results. • Structural changes in SAD are more similar to SZ than to BP. (Landin et al, 2015; Ivleva et al, 2013; Amann et al, 2015)

24. What implications do the findings have for the nosological status ofschizoaffective disorder? • SAD shares some fMRI similarities with both SZ and BP, supporting the continuum hypothesis • This is in line with genetic (Cardno and Owen, 2014) and neurocognitive data (e.g. Amann et al, 2013). • DMN dysfunction seems a common trait in all three pathologies. • Both fMRI and sMRI data support the hypothesis that SAD might be closer to SZ than to BP, suggesting it could be a subtype of SZ or an intermediate form of illness but skewed towards schizophrenia. • This in line with a recent clinical review (Pagel et al, 2013) and older literature which considers SAD as a subtype of SZ (Lehman, 1975; Welner et al, 1977). • Future studies are needed in SAD and comparing the three pathologies, using new techniques to confirm these hypotheses.

25. Acknowlegdement • FIDMAG ResearchFoundation • Hermanas Hospitalarias • CIBERSAM • Instituto Carlos III • Stabilization Contract grant (CES 12/024) • to B.L. Amann • CP06/00359 • PI071278 • PI10/02622 mmadrer@gmail.com