Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms

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.

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

“…Differences in global and local GM volumes as well as surface and thickness have been observed in similar regions in 22q11.2 deletion carriers, another largeeffect-size genetic risk factor for psychiatric conditions (49)(50)(51). They are also reminiscent of decreased regional volumes in brain areas associated with emotion and face processing demonstrated in individuals with a 7q11.23 deletion (52,53).…”

Morphological brain changes associated with negative symptoms in patients with 22q11.2 Deletion Syndrome

“…However, more interestingly, 30-40% of patients experience high negative symptoms only. Despite their high prevalence, negative symptoms are not yet well characterized in patients with 22q11DS, and the studies investigating the relationship between symptoms severities and psychotic symptoms often referred to positive symptoms only (Jalbrzikowski et al, 2013, Kates et al, 2011, Kunwar et al, 2012.…”

“…For instance, altered cortical thickness in the orbitofrontal cortex (Jalbrzikowski et al, 2013), volumetric reductions in the temporal lobe (Kates et al, 2011), and reductions in overall gyrification (Kunwar et al, 2012) have been related to positive symptoms in these patients. Cortical thickness reductions in left superior frontal gyrus and in the fusiform and lingual gyri have also been observed in patients with 22q11DS who have been diagnosed with schizophrenia compared to those who have not (Schaer et al, 2009).…”

Altered Brain Structure-Function Relationships Underlie Executive Dysfunction in 22q11.2 Deletion Syndrome

“…Patients with 22q11DS show alterations in brain morphology across cortical and subcortical regions, with prefrontal regions relatively preserved [24,25]. Specifically, relative to typically developing controls, 22q11DS patients show reduced cortical volume in occipitoparietal, temporal, and anterior cingulate cortices, and increases in cortical thickness in medial prefrontal regions as well as the insula [24,26,27,28].…”

“…Specifically, relative to typically developing controls, 22q11DS patients show reduced cortical volume in occipitoparietal, temporal, and anterior cingulate cortices, and increases in cortical thickness in medial prefrontal regions as well as the insula [24,26,27,28]. While total brain volume is typically smaller or not different from controls [25,26,28], Jalbrzikowski et al [24] found increased thickness of the bilateral medial orbitofrontal, middle, and inferior frontal cortices in youth with 22q11DS compared to controls. Mouse models of 22q11DS have shown altered neuronal frequency in layers II/III of the medial prefrontal cortex (PFC), a characteristic that relates directly to performance on tasks of EF [29].…”