Abstract
Introduction22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.MethodsHigh-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10–25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.ResultsRelative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.ConclusionDifferential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.
Highlights
For statistical analyses corresponding to the third aim of our study, we examined the relationship between cortical thickness (CT) and surface area (SA) and Structured Interview for Prodromal Syndromes (SIPS) positive symptom scores in 22q11.2 microdeletion syndrome (22q11DS)
Because some statistical trends emerged for specific structures we covaried for scanner site in all subsequent analyses
These analyses yielded several novel findings: 1) measures of volume, CT, and SA indicate distinct patterns of group differences, involving reduced cortical volume and SA in occipito-parietal, temporal and anterior cingulate cortices, whereas increased CT was observed in multiple frontal regions and the insula; 2) multiple regions, including the fusiform gyrus, showed cortical thinning with increasing age in typically developing controls, but this pattern of age-associated cortical thinning was not present in 22q11DS; and 3) increased CT in the right medial orbitofrontal cortex was associated with greater severity of positive symptoms in 22q11DS
Summary
⁎ Corresponding author at: UCLA Psychiatry & Biobehavioral Sciences, Box 956968, 300 Medical Plaza, Rm. 2267, Los Angeles, CA 90095-6968, USA. Recent evidence regarding the genetic architecture of schizophrenia suggests that rare genetic mutations, known as copy number variations (CNVs), may play a larger role in the disorder's etiology than was previously believed. One of the best-known CNVs associated with schizophrenia is the 22q11.2 microdeletion syndrome (22q11DS). Individuals with 22q11DS have substantially elevated rates of psychotic illness, as high as 32% (Gothelf et al, 2007a), making it one of the largest known risk factors for developing schizophrenia. 22q11.2 deletions account for about 1–2% of schizophrenia cases in the general population (Bassett et al, 2010). The core clinical phenotype in schizophrenia patients with 22q11DS does not differ from
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