Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome

Abstract

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk.

Molecular Substrates of Altered Axonal Growth and Brain Connectivity in a Mouse Model of Schizophrenia

“…Our findings of microscopic structural alterations in axonal branching in conjunction with current and previous finding of altered synaptic transmission and plasticity in cortical synapses of Df(16)A +/− mice (Fenelon et al, 2011, 2013) offers a plausible neural substrate that may underlie the mesoscopic scale neuroimaging findings. In addition, there is accumulating data linking neuroimaging measures with the psychosis phenotype in 22q11.2 deletion carriers providing support for the notion that structural and functional dysconnectivity is particularly relevant to the psychosis phenotype in 22q11DS (Kates et al, 2014; Perlstein et al, 2014; Jalbrzikowski M et al 2014; Ottet et al, 2013b). In that respect, our data suggests that the altered axonal connectivity that emerge as a result of deficits in neuronal palmitoylation contribute to the psychiatric deficits associated with the 22q11 deletion.…”

“…Existing structural and functional neuroimaging work in 22q11.2 deletion carriers have detected structural abnormalities in white matter volumetric and DTI measures as well as altered resting state functional connectivity (Jalbrzikowski M et al 2014; Baker et al, 2011; Ottet et al, 2013b; Schreiner et al, 2014). Together these studies found an overall global loss of connectivity as well as deficits in long-range connectivity in children with 22q11.2 deletions.…”

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

“…Previous structural neuroimaging studies have shown that frontal lobe volume is preserved in children and decreased in adults with the microdeletion (Gothelf et al, 2008), which suggests an excessive pruning of frontal lobe connections during adolescence (Schaer et al, 2009). The presence of abnormal pruning is also supported by DTI studies showing that white matter abnormalities in 22q11DS are likely related to axonal damage (Jalbrzikowski et al, 2014;Kikinis et al, 2012). However, according to computational models, pruning plays a role in shaping modular communities (Stam, Hillebrand, Wang, & Van Mieghem, 2010;Vertes et al, 2012) by favoring connections between distant but functionally Fig.…”

“…Indeed, diffusion tensor imaging (DTI) studies [reviewed in (Gothelf, Schaer, & Eliez, 2008)] have reported relationships between microstructural irregularities of the white matter tracts and cognitive symptoms including arithmetic difficulties, and deficits in attention and social capacities (Barnea-Goraly, Eliez, Menon, Bammer, & Reiss, 2005;Radoeva et al, 2012;Simon et al, 2008). Similar alterations have been associated with the intensity of schizotypal traits (Sundram et al, 2010) and psychotic symptoms (Jalbrzikowski et al, 2014;Radoeva et al, 2012).…”

Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms

“…The syndrome is characterized by a copy number variation (CNV), namely a deletion of over 40 genes on one copy of chromosome 22 (Karayiorgou et al 1995; Murphy et al 1999). White matter abnormalities are present in 22q11DS and include reduced FA in interhemispheric connections, as well as across the frontal, parietal , temporal and limbic regions (Villalon-Reina et al 2013; Sundram et al 2010; Simon et al 2005; Barnea-Goraly et al 2003; Kates et al 2015; Perlstein et al 2014; Deng et al 2015; da Silva Alves et al 2011; Jalbrzikowski et al 2014; Radoeva et al 2012; Barnea-Goraly et al 2005) . Abnormalities in maturational trajectories of white matter development (based on cross-sectional data) have also been reported in children and young adults with 22q11DS (Jalbrzikowski et al 2014).…”