Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia?

Abstract

The 22q11.2 deletion syndrome (22q11DS) is a widely recognized genetic model allowing the study of neuroanatomical biomarkers that underlie the risk for developing schizophrenia. Recent advances in magnetic resonance image analyses enable the examination of structural connectivity integrity, scarcely used in the 22q11DS field. This framework potentially provides evidence for the disconnectivity hypothesis of schizophrenia in this high-risk population. In the present study, we quantify the whole brain white matter connections in 22q11DS using deterministic tractography. Diffusion Tensor Imaging was acquired in 30 affected patients and 30 age- and gender-matched healthy participants. The Human Connectome technique was applied to register white matter streamlines with cortical anatomy. The number of fibers (streamlines) was used as a measure of connectivity for comparison between groups at the global, lobar and regional level. All statistics were corrected for age and gender. Results showed a 10% reduction of the total number of fibers in patients compared to controls. After correcting for this global reduction, preserved connectivity was found within the right frontal and right parietal lobes. The relative increase in the number of fibers was located mainly in the right hemisphere. Conversely, an excessive reduction of connectivity was observed within and between limbic structures. Finally, a disproportionate reduction was shown at the level of fibers connecting the left fronto-temporal regions. We could therefore speculate that the observed disruption to fronto-temporal connectivity in individuals at risk of schizophrenia implies that fronto-temporal disconnectivity, frequently implicated in the pathogenesis of schizophrenia, could precede the onset of symptoms and, as such, constitutes a biomarker of the vulnerability to develop psychosis. On the contrary, connectivity alterations in the limbic lobe play a role in a wide range of psychiatric disorders and therefore seem to be less specific in defining schizophrenia.

Figure 1. Three-dimensional representations of the virtual fibers with significant differences between patients and controls.

Inside the three-dimensional cortical view of each hemisphere in light grey, each segment of the fibers are represented with 3 canonical directional color gradients, green for anterior-posterior axis, blue for bottom-up axis and red for left-right axis. Virtual fibers have been regrouped in “Tube” shape by TrackVis Software (http://trackvis.org/). Part A represents the decrease in the left fronto-temporal connections comprising the arcuate and the uncinate fasciculus (Video S5). Part B represents the increase in the frontal lobe intra connections (Video S1) and the decrease in the left occipital intra connections (Video S8). Part C shows the increase in the right parietal intra connections (Video S2) and parieto-occipital connections (Video S3). Part D illustrates the decrease in bilateral limbic intra and inter connections (Video S4, S7 and S9) and the left parieto-limbic connections (Video S6).