Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome

Abstract

IntroductionSubjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis.Materials and MethodsStructural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning.Results22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT.ConclusionA shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.

Neurobiological perspective of 22q11.2 deletion syndrome

“…40 Several studies have reported reduced local gyrification in children and adolescents with 22q11.2 deletion syndrome compared with healthy controls and this finding could be indicative of neurodevelopmental pathology. [41][42][43] Altered trajectories of cortical thickness have been reported in individuals with 22q11.2 deletion syndrome, with slow thinning in children and accelerated thinning in adolescents. 44 The largest neuroimaging study to date in children and adults with 22q11.2 deletion syndrome (aged 8-50 years) reported a clear cortical phenotype in individuals with 22q11.2 deletion syndrome in comparison to controls, with thicker cortex bilaterally in major regions, thinner cortex in the superior temporal, cingulate, and parahippocampal cortex, and global reductions of surface area.…”

“…45 This decline, which might reflect loss of functional neurons, could be linked to the decrease in verbal IQ observed in children and young people with 22q11.2 deletion syndrome before onset of psychotic symptoms. 46 Bakker and colleagues 43 found reduced gyrification in young adults with a 22q11.2 deletion (some with a history of psychosis and on antipsychotics) compared with individuals without 22q11.2 deletion at clinical ultra-high risk for psychosis, indicative of early neurodevelopmental pathology. In the latter group, cortical thickness of the insula was consistently lower than in individuals with 22q11.2 deletion syndrome, which could suggest defective pruning processes during adolescence in 22q11.2 deletion syndrome.…”

“…In the latter group, cortical thickness of the insula was consistently lower than in individuals with 22q11.2 deletion syndrome, which could suggest defective pruning processes during adolescence in 22q11.2 deletion syndrome. 43 With respect to ASD, a study 47 used surface area as a marker for underlying neurobiology of ASD and reported substantial differences between unmedicated individuals with 22q11.2 deletion syndrome with ASD and those without.…”

Cortical morphology development in patients with 22q11.2 deletion syndrome at ultra-high risk of psychosis

“…Second, when comparing patients with 22q11DS to healthy controls, a number of factors can account for the differences observed between the groups, such as the cognitive impairments and the lower IQ. The studies conducted to date showed alterations in cortical thickness, volume and gyrification in association to more severe positive symptoms (Schaer et al 2009; Gothelf et al 2011; Kates et al 2011; Jalbrzikowski et al 2013; Schmitt et al 2015; Bakker et al 2016), and reduced gyrification in association to higher negative symptoms (Mihailov et al 2017) in patients with 22q11DS. Furthermore, longitudinal investigations revealed altered developmental trajectories associated with higher positive symptoms severity in patients with the syndrome (Radoeva et al 2017; Ramanathan et al 2017).…”

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size

“…Some evidence suggests that neuroanatomic regions typically disrupted in idiopathic schizophrenia are also linked to psychosis in 22q11DS. Lower frontal and superior temporal gyrus (STG) gray matter volumes were observed in adults with 22q11DS and a schizophrenia diagnosis, relative to 22q11DS adults without schizophrenia [ 19 , 27 , 28 ]. Kates et al [ 29 ] also found that progressive volumetric decreases in STG predicted later psychotic symptoms in 22q11DS youth, and lower cingulate gyrus volume was associated with more severe psychotic symptoms [ 30 ].…”