White matter microstructural abnormalities of the cingulum bundle in youths with 22q11.2 deletion syndrome: Associations with medication, neuropsychological function, and prodromal symptoms of psychosis

Abstract

Background The 22q11.2 Deletion Syndrome (22q11.2DS) is regarded as an etiologically homogenous model for understanding neuroanatomic disruptions associated with a high risk for schizophrenia. This study utilized diffusion tensor imaging (DTI) to analyze white matter microstructure in individuals with 22q11.2DS. We focused on the cingulum bundle (CB), previously shown to be disrupted in patients with schizophrenia and associated with symptoms of psychosis. Methods White matter microstructure was assessed in the anterior, superior, and posterior CB using the tractography algorithm in DTIStudio. Neuropsychological function, presence of prodromal symptoms of psychosis, and medication history were assessed in all participants. Results Relative to controls, young adults with 22q11.2DS showed alterations in most DTI metrics of the CB. Alterations were associated with positive prodromal symptoms of psychosis. However, when individuals with 22q11.2DS were divided by usage of antipsychotics / mood stabilizers, the medicated and non-medicated groups differed significantly in axial diffusivity of the anterior CB and in fractional anisotropy of the superior CB. DTI metrics did not differ between the medicated group and the control group. Conclusions Results suggest that the microstructure of the CB is altered in individuals with 22q11.2DS, and that those alterations may underlie positive prodromal symptoms of psychosis. Our findings further provide preliminary evidence that antipsychotic / mood stabilizer usage may have a reparative effect on white matter microstructure in prodromal 22q11.2DS, independent of the potential effects of psychosis. Future studies of white matter pathology in individuals with 22q11.2DS should test for potential effects of medication on white matter microstructure.

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

“…The effect of antipsychotic and mood stabilizer medication was reported previously in cingulum bundle in this data set and had a reparative outcome: It was observed that the subgroup of youth with 22q11DS that was given a low dose of antipsychotic or mood stabilizer medication currently or in the past, had the same FA and AD values in the cingulum bundle as the controls, while the non-medicated subjects with 22q11DS had significantly lower values in FA and AD (Kates et al 2015). While in our current analysis, the subjects with the high score on BPRS-psychosis symptoms were more medicated than those with a low score, the AD values were lowest in the subjects with high score on BPRS-psychosis symptoms.…”

“…Further, our previous study by Perlstein et al (2014) and by Kates et al (2015), showed evidence of reduced FA in anterior limb of the internal capsule and the uncinate fasciculus, as well as reduced FA in the cingulum bundle, respectively. In these studies the tracts were preselected and tractography measures were used to determine whether or not these tracts were affected.…”

“…The subjects were between the ages of 16 and 20 years and were recruited at SUNY Upstate Medical University, Syracuse, NY. The same subjects’ images were used in two tractography studies of white matter microstructure (Perlstein et al 2014; Kates et al 2015) and in an atlas-based study of white matter microstructure on a subset of study participants, i.e., 48 out of 97 study subjects (Radoeva et al 2012). For participants with 22q11DS, deletion of the chromosomal region 22q11.2 was confirmed by Fluorescent-In-Situ-Hybridization (FISH).…”

“…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).…”

White matter microstructural deficits in 22q11.2 deletion syndrome

“…DTI facilitates the in vivo study of brain white matter (WM) microstructure (Mori et al, 2008), and typical DTI measures include fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD). Alterations in these metrics are reported in 22q11DS (Barnea-Goraly et al, 2003; da Silva Alves et al, 2011; Deng et al, 2015; Kates et al, 2015; Kikinis et al, 2012; Martin et al, 2014; Ottet et al, 2013; Padula et al, 2015; Radoeva et al, 2012; Scariati et al, 2016; Sundram et al, 2010; Villalon-Reina et al, 2013), and some of the patterns observed are similar to deficits in SZ (Kyriakopoulos et al, 2008; Roalf et al, 2015; Thomason and Thompson, 2011), adolescents with psychosis (Davenport et al, 2010; White et al, 2007) and youth at risk for developing psychosis (Epstein et al, 2013; Lee et al, 2013). In contrast to structural gray matter findings, DTI results in 22q11DS are more inconsistent.…”