Dysmaturation Observed as Altered Hippocampal Functional Connectivity at Rest Is Associated With the Emergence of Positive Psychotic Symptoms in Patients With 22q11 Deletion Syndrome

BACKGROUND: Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia. METHODS: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. RESULTS: Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. CONCLUSIONS: Our findings suggest a critical period of prefrontal cortex & ndash;hippocampal & ndash;striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.

Large-scale functional network reorganization in 22q11.2 deletion syndrome revealed by modularity analysis

Fikret Isik Karahanoglu, Jonas Richiardi, Marie Schaer, Maude Schneider, Dimitri Nestor Alice Van De Ville

The 22q11.2 deletion syndrome (22q11DS) is associated with cognitive impairments and a 41% risk of developing schizophrenia. While several studies performed on patients with 22q11DS showed the presence of abnormal functional connectivity in this syndrome, how these alterations affect large-scale network organization is still unknown. Here we performed a network modularity analysis on whole-brain functional connectomes derived from the resting-state fMRI of 40 patients with 22q11DS and 41 healthy control participants, aged between 9 and 30 years old. We then split the sample at 18 years old to obtain two age subgroups and repeated the modularity analyses. We found alterations of modular communities affecting the visuo-spatial network and the anterior cingulate cortex (ACC) in both age groups. These results corroborate previous structural and functional studies in 22q11DS that showed early impairment of visuo-spatial processing regions. Furthermore, as ACC has been linked to the development of psychotic symptoms in 22q11DS, the early impairment of its functional connectivity provide further support that ACC alterations may provide potential biomarkers for an increased risk of schizophrenia. Finally, we found an abnormal modularity partition of the dorsolateral prefrontal cortex (DLPFC) only in adults with 22q11DS, suggesting the presence of an abnormal development of functional network communities during adolescence in 22q11DS. (C) 2016 Elsevier Ltd. All rights reserved.

Elsevier Masson2016

Shoulder Apprehension Impacts Large-Scale Functional Brain Networks

Sven Haller, Dimitri Nestor Alice Van De Ville

BACKROUND AND PURPOSE: Shoulder apprehension is defined as anxiety and resistance in patients with a history of anterior glenohumeral instability. It remains unclear whether shoulder apprehension is the result of true recurrent instability or a memorized subjective sensation. We tested whether visual presentation of apprehension videos modifies functional brain networks associated with motor resistance and anxiety. MATERIALS AND METHODS: This prospective study includes 15 consecutive right-handed male patients with shoulder apprehension (9 with right shoulder apprehension, 6 with left shoulder apprehension; 27.5 +/- 6.4 years) and 10 healthy male right-handed age-matched control participants (29.0 +/- 4.7 years). Multimodal MR imaging included 1) functional connectivity tensorial independent component analysis, 2) task-related general linear model analysis during visual stimulation of movies showing typical apprehension movements vs control videos, 3) voxel-based morphometry analysis of GM, and 4) tract-based spatial statistics analysis of WM. RESULTS: Patients with shoulder apprehension had significant (P < .05 corrected) increase in task-correlated functional connectivity, notably in the bilateral primary sensory-motor area and dorsolateral prefrontal cortex and, to a lesser degree, the bilateral dorsomedial prefrontal cortex, anterior insula, and dorsal anterior cingulate cortex (+148% right, +144% left). Anticorrelated functional connectivity decreased in the higher-level visual and parietal areas (-185%). There were no potentially confounding structural changes in GM or WM. CONCLUSIONS: Shoulder apprehension induces specific reorganization in apprehension-related functional connectivity of the primary sensory-motor areas (motor resistance), dorsolateral prefrontal cortex (cognitive control of motor behavior), and the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex and anterior insula (anxiety and emotional regulation).

American Society of Neuroradiology2014

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

Jonas Richiardi, Marie Schaer, Maude Schneider, Dimitri Nestor Alice Van De Ville

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.

Springer Verlag2014

Shoulder Apprehension Impacts Large-Scale Functional Brain Networks

Sven Haller, Dimitri Nestor Alice Van De Ville

American Society of Neuroradiology2014