Identifying 22q11.2 Deletion Syndrome and Psychosis Using Resting-State Connectivity Patterns

The clinical picture associated with 22q11.2 deletion syndrome (22q11DS) includes mild mental retardation and an increased risk of schizophrenia. While the clinical phenotype has been related to structural brain network alterations, there is only scarce information about functional connectivity in 22q11DS. However, such studies could lead to a better comprehension of the disease and reveal potential biomarkers for psychosis. A connectivity decoding approach was used to discriminate between 42 patients with 22q11DS and 41 controls using resting-state connectivity. The same method was then applied within the 22q11DS group to identify brain connectivity patterns specifically related to the presence of psychotic symptoms. An accuracy of 84% was achieved in differentiating patients with 22q11DS from controls. The discriminative connections were widespread, but predominantly located in the bilateral frontal and right temporal lobes, and were significantly correlated to IQ. An 88% accuracy was obtained for identification of existing psychotic symptoms within the patients group. The regions containing most discriminative connections included the anterior cingulate cortex (ACC), the left superior temporal and the right inferior frontal gyri. Functional connectivity alterations in 22q11DS affect mostly frontal and right temporal lobes and are related to the syndrome's mild mental retardation. These results also provide evidence that resting-state connectivity can potentially become a biomarker for psychosis and that ACC plays an important role in the development of psychotic symptoms

Altered structural network architecture is predictive of the presence of psychotic symptoms in patients with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) represents a homogeneous model of schizophrenia particularly suitable for the search of neural biomarkers of psychosis. Impairments in structural connectivity related to the presence of psychotic symptoms have been reported in patients with 22q11DS. However, the relationships between connectivity changes in patients with different symptomatic profiles are still largely unknown and warrant further investigations. In this study, we used structural connectivity to discriminate patients with 22q11DS with (N = 31) and without (N = 31) attenuated positive psychotic symptoms. Different structural connectivity measures were used, including the number of streamlines connecting pairs of brain regions, graph theoretical measures, and diffusion measures. We used univariate group comparisons as well as predictive multivariate approaches. The univariate comparison of connectivity measures between patients with or without attenuated positive psychotic symptoms did not give significant results. However, the multivariate prediction revealed that altered structural network architecture discriminates patient subtypes (accuracy = 67.7%). Among the regions contributing to the classification we found the anterior cingulate cortex, which is known to be associated to the presence of psychotic symptoms in patients with 22q11DS. Furthermore, a significant discrimination (accuracy = 64%) was obtained with fractional anisotropy and radial diffusivity in the left inferior longitudinal fasciculus and the right cingulate gyrus. Our results point to alterations in structural network architecture and white matter microstructure in patients with 22q11DS with attenuated positive symptoms, mainly involving connections of the limbic system. These alterations may therefore represent a potential biomarker for an increased risk of psychosis that should be further tested in longitudinal studies

Études sur la connectivité cérébrale dans le syndrome de microdélétion 22q11: Quelles conclusions peut-on en tirer? Quels liens peut-on faire avec les symptômes psychotiques?

La microdélétion 22q11.2 (del22q11) est une maladie génétique rare conférant aux patients atteints un risque de 30 à 40% de développer une schizophrénie. La del22q11 est aujourd'hui étudiée dans le but de comprendre les mécanismes cérébraux associés au développement d'un trouble psychotique et d'identifier les marqueurs de risque génétique transposables dans la population générale. Le développement de nouvelles techniques de neuroimagerie permet d'étudier in vivo la connectivité cérébrale. Depuis une dizaine d'années, 17 articles sur la connectivité cérébrale structurelle et 4 articles de connectivité cérébrale fonctionnelle ont été publiés dans la del22q11. Ce travail a pour but de fournir une revue de cette littérature pour essayer de dégager un phénotype de connectivité cérébrale associé à la del22q11. Il vise également à identifier les associations entre dysconnectivité et psychose décrites dans la del22q11 et les comparer avec des modèles de dysconnectivité développés dans la schizophrénie non syndromique

MRI resting-state connectivity in 22q11.2 deletion syndrome : functional network alterations and underlying structure

Le syndrome de microdélétion 22 est associé à un haut risque de développer une schizophrénie et est étudié en neuroimagerie dans le but de mieux comprendre les corrélats neuronaux qui sous-tendent le développement d'une psychose. Plusieurs études montrent le lien entre des anomalies de la connectivité cérébrale et les symptômes psychotiques, mais celui-ci reste encore mal compris. Ce travail a pour but de décrire les altérations du réseau cérébral fonctionnel dans la microdélétion 22 et de les mettre en lien avec l'émergence des symptômes psychotiques dans cette population. Les résultats démontrent la présence précoce d'une attente de la connectivité cérébrale fonctionnelle, notamment liée à la présence de symptômes psychotiques prodromaux. Ce travail décrit également comment ces atteintes affectent l'organisation du réseau chez les jeunes et les adultes porteurs de la délétion et illustre au travers d'une analyse préliminaire de la connectivité multimodale, les rapports complexes entre structure et fonction cérébrale

A Mini Review on the Contribution of the Anterior Cingulate Cortex in the Risk of Psychosis in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that causes a high risk of developing schizophrenia, thus representing a unique model for the investigation of biomarkers of psychosis. Cognitive and clinical risk factors have been identified as reliable predictors of schizophrenia in patients with 22q11DS and are currently used in the clinical practice. However, biomarkers based on neuroimaging are still lacking, mainly because of the analytic approaches adopted so far, which are almost uniquely based on the comparison of 22q11DS patients with healthy controls. Such comparisons do not take into account the heterogeneity within patients with 22q11DS, who indeed show various clinical manifestations. More recently, a number of studies compared measures of brain morphology and connectivity between patients with 22q11DS with different symptomatic profiles. The aim of this short review is to highlight the brain alterations found in patients with 22q11DS fulfilling ultra-high risk (UHR) criteria. Findings point to alterations in brain morphology and connectivity in frontal brain regions, and in particular in the anterior cingulate cortex, in patients with 22q11DS presenting UHR symptoms. These alterations may represent valuable biomarkers of psychosis in 22q11DS

Morphological brain changes associated with negative symptoms in patients with 22q11.2 Deletion Syndrome

Approximately 30% of individuals with 22q11.2 Deletion Syndrome (22q11DS) develop schizophrenia during adolescence/early adulthood, making this syndrome a model for the disorder. Furthermore, negative symptoms exist in up to 80% of patients diagnosed with 22q11DS. The present study aims to uncover morphological brain alterations associated with negative symptoms in a cohort of patients with 22q11DS who are at-risk for developing schizophrenia. A total of 71 patients with 22q11DS aged 12 to 35 (54% females) with no past or present diagnosis of a schizophrenia were included in the study. Psychotic symptom scores were used to divide patients into subgroups by means of a cluster analysis. Three major subgroups were evident: patients with low negative and positive symptoms; patients with high negative symptoms and low positive symptoms; and patients with high negative and positive symptoms. Cortical volume, thickness and gyrification were compared between subgroups using FreeSurfer software. Results showed that patients with high negative symptoms, compared to those with low negative symptoms, have decreased gyrification in the medial occipito-temporal (MOT) and lateral temporo-parietal (LTP) cortices of the left hemisphere, and in the medial temporal (MT)/posterior cingulate (PCC) cortices of the right hemisphere. These findings suggest that high negative symptoms are associated with gyrification reductions predominantly in medial occipital and temporal regions, which are areas implicated in social cognition and early visual processing. Furthermore, as cortical folding develops in utero and during the first years of life, reduced gyrification may represent an early biomarker predicting the development of negative symptoms.status: publishe