1. Cristina PATRU (1) with help of David RESER (2) (1) Department of Psychiatry, Hôpitaux Universitaires de Genève, Switzerland (2) Department of Physiology, Monash University, Melbourne, Australia October, 19 th, 2015, Chicago

2. Claustrum and delusion : accident, coincidence or real link ?

3. AuthorsStudy Within study prevalence of delusions Results Bruen, et al. 2008 In vivo, MRI 31 patients / Alzheimer’s disease 16% of patients High delusion scores correlated significantly with low grey mater density values in : - right inferior frontal gyrus - right inferior parietal lobule - left inferior and medial frontal gyri - left claustrum. Cascella, et al. 2011 In vivo, MRI Schizophrenia 43 patients 70% of patients Significant inverse correlations between ratings of the severity of delusions and volumes of : - the left claustrum - the right insula. No significant correlation between cerebral grey mater volume and ratings of hallucinations. Radaelli 2012 In vivo, MRI 73 patients Bipolar disorder type I 34 delusional and 39 non- delusional bipolar patients Lower GM volume in prefrontal areas and in the insula in delusional patients compared to non-delusional patients. Bernstein, et al. 2015 Post-mortem 14 patients / schizophrenia 15 normal control subjects 57% of patients (8/14 patients) exhibit positive symptoms (no specific data for delusions and hallucinations frequency) Estimated claustrum volume reductions were between 25 and 30% of controls. Moreover, when dividing the schizophrenia group (14 patients) into “paranoid schizophrenia” (8 patients) and “residual schizophrenia” (6 patients) subgroups, the significant bilateral volume reductions in schizophrenia subjects were found to be (mainly) caused by the paranoid schizophrenia group Where is this idea coming from?

4. Cristina PATRU (1) with help of David RESER (2) (1) Department of Psychiatry, Hôpitaux Universitaires de Genève, Switzerland (2) Department of Physiology, Monash University, Melbourne, Australia October, 19 th, 2015, Chicago

5. What are we talking about? Definitions Delusion – abnormal belief - reality distortion, heterogenous concept Psychosis - disorder-"loss of contact with reality" Psychotic symptoms Confusions Delirium – confusional state Limitations linked on delusions investigation Not a constant symptom Included in a large box with other symptoms Does animal experience delusion? – no reliable model Limitations linked on the exploration of the claustrum No specific link (1 lesion -1 deficit) Thin structre difficuly to separate from adjacent structures on usual fMRI Extended structure – ribbon-like anatomy – difficult surgical acces and electrode postion influence results – topography Still more difficult for the endopiriform nucleus –are we talking about same things? Relatively deep structure – not easy to explore on EEG, MEG Often igored – not often explored as a subcortical structure Difficult to explore directly in humans – Koubeissi, 2014 Variability between species

6. Is the claustrum is good candidate in delusional ideas genesis? Bipolar disorder type I Schizophrenia Alzheimer disease And others Studies… Koubeissi, 2014 NHALE (Matsuzono, 2013)

7. Is the claustrum is good candidate in delusional ideas genesis? Structural and functional connectivity of the claustrum – the hub Recent hypotheses surrounding claustrum function(s) The "orchestra conductor“ hypothesis (Crick and Koch in 2005), Sensory integration/coincidence detection hypothesis (Smythies et al., 2012) Modulation/switching of cortical functional networks hypothesis(Reser, et al. 2014) Modulation of selective attention (Gal et al., 2015) Several tracks could be investigated concerning this candidature The claustrum and the limbic system, Kappa opioid receptor model Sensory gating and attention model Claustrum as a component of behavioural and psychological-level models of delusions

8. Glu/excitatory Pyramidal Neurons NMDA receptor GABA/inhibitory Parvalbumine Interneurons GABA A receptor mesolimbic dopamine pathway thalamic dopamine pathway PFC midline / intralaminar Th H NAcc VTA Only Midline Th GP Cl KOR (?) Ser?????/5-HT2AR/DEMIREVA DRN Amygdaloid complex Ser Anterior cingulate Controlat Cl striatum

9. Bak Remedios Sensory gating

10. Claustrum as a component of behavioral and psychological-level models of delusions Mammalian brain is a Bayesian prediction engine – it compares incoming sensory signals against internal, learned representations of the external world and allow the brain to make predictions with little error sensory-motor representations are encoded in the oscillatory dynamics of the thalamocortical circuit Corlett and colleagues : delusions arise from responses of brain circuits to prediction errors - the delusional patient does not take past experiences appropriately into account. The individual variations in thought (at the origin of delusions) and behaviour, could rise from oscillatory activity across thalamocortical networks. BUT the claustrum offers a more plausible locus for this activity lesions of the thalamus are not generally associated with psychotic symptoms, in contrast to the lesions of the claustrum-pulvinar-insula region rapid, polymodal, internal vs. external computations could be efficiently mediated by the claustrum, by its connectivity.

11. Conclusions and perspectives Hypothesis or “illusion”? Further research to solve the dilemma Understanding the basic science of the claustrum Studies in animal models - Genetic manipulation of the CL? Two CL-specific markers identified, Gnb4 and Gng2, with high degree of overlap with the 5- HT2AR population? Studies in humans? Functional imagery? Better discrimination of symptoms and brain structures? MRI, PET, EEG, combination Deep electrodes recordings when accidentally located in the claustrum? More studies, more results

12. Thanks to the claustrum! * It’s your turn….. * Debate