(Visual) Endophenotypes in schizophrenia research

Objective: Schizophrenia is a heterogeneous disease strongly influenced by genetic disposition. However, genetic studies have shown that each single nucleotide polymorphism (SNP) contributes very little to the disease. For this reason, endophenotypes, located in between the genetic and clinical level, have become of great interest. Due to its heterogeneity, schizophrenia is likely not caused by one abnormality. Here, we asked the question to what extent deficits in various endophenotypes tap into the same deficits of schizophrenia. Methods: We tested schizophrenia patients, their relatives, and controls with a battery of perceptual and cognitive tests, such as visual backward masking, out of body experience, the Wisconsin Card Sorting Test (WCST), verbal fluency, and the continous performance task (CPT). Results: First, we found that visual backward masking is an extremely sensitive endophenotype of schizophrenia. Deficits are specific to the psychosis spectrum and not evident in depressive patients and abstinent alcoholics. As expected from an endophenotype, not only the patients but also their siblings show clear performance deficits, as well as adolescents with psychosis. Both genetic analysis and EEG recordings point to deficiencies in the cholinergic system. We then compared performance in visual backward masking with other tests. Surprisingly, performance in most tests did not correlate with each other. Conclusions: Our results suggest that each endophenotype is sensitive to different abnormal mechanisms. Schizophrenia is much more complex than previously thought. Heterogeneity can be best attacked by the combined investigation of sensitive endophenotypes.

Hallucination Engineering: From Neuroscience Robotics to Hallucinations in Health and Disease

Eva Blondiaux

My thesis focuses on a psychotic symptom called the presence hallucination (PH). PHs are defined as the false perception that someone is nearby when no one is actually present. PHs can occur in various populations, ranging from healthy subjects (when exposed to extreme conditions) to neurological (e.g. epileptic, Parkinsonâs disease patients) and psychiatric patients (e.g. schizophrenia). Our group has designed a robotic device that allows to safely induce PH in healthy subjects, in a controlled manner, using different sensorimotor conflicts (Blanke et al., 2014). The aim of my thesis was to unravel the brain regions and mechanisms associated with PH and explore how the neuroscientific understanding of PH can improve diagnostics of different clinical populations with hallucinations. In Chapter 2, I investigated the brain networks associated with a category of complex phenomena named autoscopic phenomena (AP). AP include PHs and three other forms: autoscopic hallucinations, heautoscopies, and out-of-body experiences. AP are rare phenomena, defined as illusory reduplication involving a double of oneâs own body seen or felt in extrapersonal space. Lesion network mapping analysis was used to identify the brain networks associated to each AP. My data showed that each AP is characterised by specific connectivity networks consistent with their phenomenology. All AP also share common brain connectivity. In Chapter 3, using an MR-compatible robot able to induce PH, I investigated the brain regions and mechanisms of robot-induced PH in healthy subjects using fMRI. I combined these data with the results of my lesion network mapping analysis in neurological patients with focal brain damage associated with PH (Chapter 3). Both networks (i.e. robot-induced PH-network in healthy subjects and symptomatic PH-network) were merged together to identify the key regions involved in PH, defining a common PH-network. The relevance of this common PH-network was then assessed and confirmed in patients with Parkinsonâs disease (PD), revealing a difference in functional connectivity within this network between PD patients experiencing symptomatic PH compared to patients without such symptoms. Further, I studied the functional connectivity within the common PH-network in 22q11.2 deletion syndrome (DS) subjects (i.e. subjects with high risks (30%) of developing schizophrenia) (Chapter 4) and in psychotic patients with passivity experiences (Chapter 5). Studying PH in these population is relevant since PH is frequent in schizophrenia. In both populations, a reduced functional connectivity in the common PH-network was revealed. In Chapter 4, I also assessed the sensitivity to the sensorimotor conflicts and the proneness to experience robot-induced PH in 22q11DS subjects and age-matched controls. Results showed a lack of sensitivity in sensorimotor modulation for the sense of agency, further corroborated by a lack of delay dependency in experiencing robot-induced PH in 22q11DS subjects compared to controls. In summary, by coupling robotic technology with neuroimaging, a common PH-network was delineated and was found relevant in different clinical populations. These findings are important since PH can be present at early stages before the apparition of more severe symptoms. Therefore, our results can lead to more robust diagnostic tools and early treatment intervention, which might significantly improve prognosis in those patients.

EPFL2020

Visual masking in Schizophrenia: an endophenotype and its neural correlates

Ophélie Gladys Favrod, Michael Herzog, Maya Roinishvili

Objective: In visual backward masking, a target is followed by a mask, which deteriorates performance on the target. Masking is a very sensitive endophenotype for schizophrenia. Patients and their siblings (to a lesser extent) show strong performance deficits. Here, we investigate EEG correlates of masking across the schizophrenia continuum. Method: We measured high-density EEG, while performing a masking task. We report the Global Field Power (GFP), which is the standard deviation across all electrodes. Results: First, schizophrenia patients (n=90) have strongly reduced GFP amplitudes as compared to controls (n=76). The reduced amplitudes imply an attention allocation deficit in schizophrenia associated with the cholinergic system. Second, patients with first episodes psychosis (n=21) have reduced GFP amplitudes when compared to controls (n=20), but higher amplitudes when compared to schizophrenia patients (n=22). The neural correlates are in an intermediate state, implying a progressive development of the disease through time. In addition, the amplitudes remain stable for at least one year (n=11), suggesting that further deficits emerge slowly over time. Third, healthy participants with high schizotypal traits (n=25) have reduced GFP amplitudes compared to low schizotypal participants (n=20). These deficits are similar to the ones of patients, though strongly attenuated, showing that the mechanism is independent of the state of an individual (i.e., health or disease). Fourth, healthy relatives of schizophrenia patients (n=55) have higher GFP amplitudes compared to controls. We propose that the relatives use a compensation mechanism to counterbalance for their masking deficits. Finally, patients with the 22q11.2 deletion syndrome (n=19), who have a 30% risk for schizophrenia, have slightly higher GFP amplitudes when compared to controls (n=18). Conclusion: Observers with psychosis related traits or symptoms have difficulties to enhance faint visual information 200 ms after onset which explains their lower performance in visual backward masking.

2019

Fronto-Temporal Disconnection Within the Presence Hallucination Network in Psychotic Patients With Passivity Experiences

Olaf Blanke, Eva Blondiaux, Nathan Quentin Faivre, Alessandra Griffa, Patric Hagmann, Jevita Potheegadoo, Pierre Progin, Giulio Rognini, Roy Salomon, Giedre Stripeikyte

Psychosis, characterized by hallucinations and delusions, is a common feature of psychiatric disease, especially schizophrenia. One prominent theory posits that psychosis is driven by abnormal sensorimotor predictions leading to the misattribution of self-related events. This misattribution has been linked to passivity experiences (PE), such as loss of agency and, more recently, to presence hallucinations (PH), defined as the conscious experience of the presence of an alien agent while no person is actually present. PH has been observed in schizophrenia, Parkinson’s disease, and neurological patients with brain lesions and, recently, the brain mechanisms of PH (PH-network) have been determined comprising bilateral posterior middle temporal gyrus (pMTG), inferior frontal gyrus (IFG), and ventral premotor cortex (vPMC). Given that the experience of an alien agent is a common feature of PE, we here analyzed the functional connectivity within the PH-network in psychotic patients with (N = 39) vs without PE (N = 26). We observed reduced fronto-temporal functional connectivity in patients with PE compared to patients without PE between the right pMTG and the right and left IFG of the PH-network. Moreover, when seeding from these altered regions, we observed specific alterations with brain regions commonly linked to auditory-verbal hallucinations (such as Heschl’s gyrus). The present connectivity findings within the PH-network extend the disconnection hypothesis for hallucinations to the specific case of PH and associates the PH-network with key brain regions for frequent psychotic symptoms such as auditory-verbal hallucinations, showing that PH are relevant to the study of the brain mechanisms of psychosis and PE.

2021