Maude Schneider

Sex differences in thickness, and folding developments throughout the cortex

While significant differences in male and female brain structures have commonly been reported, only a few studies have focused on the sex differences in the way the cortex matures over time. Here, we investigated cortical thickness maturation between the age of 6 to 30 years, using 209 longitudinally-acquired brain MRI scans. Significant sex differences in the trajectories of cortical thickness change with age were evidenced using non-linear mixed effects models. Similar statistical analyses were computed to quantify the differences between cortical gyrification changes with age in males and females. During adolescence, we observed a statistically significant higher rate of cortical thinning in females compared to males in the right temporal regions, the left temporoparietal junction and the left orbitofrontal cortex. This finding is interpreted as a faster maturation of the social brain areas in females. Concomitantly, statistically significant sex differences in cortical folding changes with age were observed only in one cluster of the right prefrontal regions, suggesting that the mechanisms underlying cortical thickness and gyrification changes with age are quite distinct. Sexual dimorphism in the developmental course of the cortical maturation may be associated with the different age of onset and clinical presentation of many psychiatric disorders between males and females.

Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

IMPORTANCE Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

Risk Factors and the Evolution of Psychosis in 22q11.2 Deletion Syndrome: A Longitudinal 2-Site Study

OBJECTIVE 22q11.2 Deletion syndrome (22q11.2DS) is associated with high rates of schizophrenia, other neuropsychiatric disorders, and cognitive deficits. The objectives of this 2-center study were to longitudinally assess the trajectories of psychiatric disorders in 22q11.2DS from childhood to adulthood, and to identify risk factors for their emergence. METHOD A total of 125 children and adults with 22q11.2DS were evaluated at 2 time points, baseline and follow-up (4 years apart), using standardized psychiatric and cognitive measures. RESULTS The rate of mood disorders tended to decrease during childhood and increase during late adolescence. Statistically significant predictors for the presence of a psychotic disorder as well as the severity of positive symptoms at follow-up were identical, and consisted of an anxiety disorder at baseline, lower baseline Full Scale IQ, and a greater decrease in verbal IQ scores between time points. Nine of 10 individuals with an emerging psychotic disorder had an anxiety disorder at baseline. The age of onset for a psychotic disorder was between 14 and 22 years in 82.6% of cases. CONCLUSIONS It is important to evaluate the presence of anxiety disorders in children and adolescents with 22q11.2DS, as they are major risk factors for the emergence of psychotic disorders, which usually occur during late adolescence in this at-risk population.

Deviant dynamics of EEG resting state pattern in 22q11.2 deletion syndrome adolescents: A vulnerability marker of schizophrenia?

Previous studies have repeatedly found altered temporal characteristics of EEG microstates in schizophrenia. The aim of the present study was to investigate whether adolescents affected by the 22q11.2 deletion syndrome (22q11DS), known to have a 30 fold increased risk to develop schizophrenia, already show deviant EEG microstates. If this is the case, temporal alterations of EEG microstates in 22q11DS individuals could be considered as potential biomarkers for schizophrenia. We used high-density (204 channel) EEG to explore between-group microstate differences in 30 adolescents with 22q11DS and 28 age-matched controls. We found an increased presence of one microstate class (class C) in the 22q11DS adolescents with respect to controls that was associated with positive prodromal symptoms (hallucinations). A previous across-age study showed that the class C microstate was more present during adolescence and a combined EEG-fMRI study associated the class C microstate with the salience resting state network, a network known to be dysfunctional in schizophrenia. Therefore, the increased class C microstates could be indexing the increased risk of 22q11DS individuals to develop schizophrenia if confirmed by our ongoing longitudinal study comparing both the adult 22q11DS individuals with and without schizophrenia, as well as schizophrenic individuals with and without 22q11DS.

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

Resting-state networks in adolescents with 22q11.2 deletion syndrome: Associations with prodromal symptoms and executive functions

Atypical functional connectivity in the maturing brains of 22q11.2 deletion syndrome (22q11DS) may contribute to the expression of early psychotic symptoms commonly reported by these youths. This studys objective was to examine functional connectivity in cerebral networks at rest (Resting-State Networks; RSNs) and their relationship to symptomatic and neuropsychological characteristics putting them at very high risk factor for developing psychosis. Twenty-seven adolescents with 22q11DS and 33 typically developing control adolescents matched for age, gender and handedness underwent an 8-minute resting state functional MRI session. RSNs identification procedure employed Independent Component Analysis (ICA). We tested for potential group differences in functional connectivity within-networks. Then, we examined relationships between network connectivity and symptomatic/neuropsychological characteristics in the 22q11DS group. A total of nine resting-state networks were identified. Between-group differences suggested both increased and decreased functional connectivity in the 22q11DS group, involving the default-mode, sensorimotor, visuo-spatial, and high level visual networks. Finally, atypical connectivity in the default-mode network, specifically within the left superior frontal gyrus region, correlated with prodromal symptom intensity and neuropsychological performances in the 22q11DS group. The results suggest that atypical functional connectivity may sustain both increased vulnerability to psychosis and characteristic cognitive impairments in 22q11DS.

Reduced Fronto-Temporal and Limbic Connectivity in the 22q11.2 Deletion Syndrome: Vulnerability Markers for Developing Schizophrenia?

The 22q11.2 deletion syndrome (22q11DS) is a widely recognized genetic model allowing the study of neuroanatomical biomarkers that underlie the risk for developing schizophrenia. Recent advances in magnetic resonance image analyses enable the examination of structural connectivity integrity, scarcely used in the 22q11DS field. This framework potentially provides evidence for the disconnectivity hypothesis of schizophrenia in this high-risk population. In the present study, we quantify the whole brain white matter connections in 22q11DS using deterministic tractography. Diffusion Tensor Imaging was acquired in 30 affected patients and 30 age- and gender-matched healthy participants. The Human Connectome technique was applied to register white matter streamlines with cortical anatomy. The number of fibers (streamlines) was used as a measure of connectivity for comparison between groups at the global, lobar and regional level. All statistics were corrected for age and gender. Results showed a 10% reduction of the total number of fibers in patients compared to controls. After correcting for this global reduction, preserved connectivity was found within the right frontal and right parietal lobes. The relative increase in the number of fibers was located mainly in the right hemisphere. Conversely, an excessive reduction of connectivity was observed within and between limbic structures. Finally, a disproportionate reduction was shown at the level of fibers connecting the left fronto-temporal regions. We could therefore speculate that the observed disruption to fronto-temporal connectivity in individuals at risk of schizophrenia implies that fronto-temporal disconnectivity, frequently implicated in the pathogenesis of schizophrenia, could precede the onset of symptoms and, as such, constitutes a biomarker of the vulnerability to develop psychosis. On the contrary, connectivity alterations in the limbic lobe play a role in a wide range of psychiatric disorders and therefore seem to be less specific in defining schizophrenia.

Altered auditory processing in frontal and left temporal cortex in 22q11.2 deletion syndrome: a group at high genetic risk for schizophrenia.

In order to investigate electroencephalographic (EEG) biomarkers of auditory processing for schizophrenia, we studied a group with a well known high-risk profile: patients with 22q11.2 deletion syndrome (22q11 DS) have a 30% risk of developing schizophrenia during adulthood. We performed high-density EEG source imaging to measure auditory gating of the P50 component of the evoked potential and middle to late latency auditory processing in 21 participants with the 22q11.2 deletion and 17 age-matched healthy controls. While we found no indication of altered P50 suppression in 22q11 DS, we observed marked differences for the first N1 component with increased amplitudes on central electrodes, corresponding to increased activations in dorsal anterior cingulate and medial frontal cortex. We also found a left lateralized reduction of activation of primary and secondary auditory cortex during the second N1 (120ms) and the P2 component in 22q11 DS. Our results show that sensory gating and activations until 50ms were preserved in 22q11 DS, while impairments appear at latencies that correspond to higher order auditory processing. While the increased activation of cingulate and medial frontal cortex could reflect developmental changes in 22q11 DS, the reduced activity seen in left auditory cortex might serve as a biomarker for the development of schizophrenia, if confirmed by longitudinal research protocols.

Predominant negative symptoms in 22q11.2 deletion syndrome and their associations with cognitive functioning and functional outcome

22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition associated with increased risk for schizophrenia. No study do date has explored how positive and negative symptoms of psychosis are distributed among individual patients with 22q11.2DS and if distinct patterns of symptoms can be identified. Negative symptoms being more frequent than positive symptoms in 22q11.2DS, we expected that a high number of patients would display predominant negative symptoms (PNS), whereas predominant positive symptoms would be less frequently reported. The present study aims at investigating the cognitive deficits and functional outcome associated with distinct patterns of psychotic symptoms in 22q11.2DS. 63 adolescents and young adults with 22q11.2DS participated in this study. Each participant underwent a clinical and a cognitive evaluation. A cluster analysis was used to identify groups of individuals with distinct patterns of symptoms. Individuals from the different clusters were then compared on a series of cognitive measures and on functional outcome. Three clusters of individuals were identified: low levels of symptoms, PNS, and high levels of symptoms. Individuals with PNS had significantly lower visual memory scores and decreased processing speed compared to participants with low levels of symptoms. They were also rated as having lower functional and occupational outcome. The present results indicate that one third of adolescents and young adults with 22q11.2DS display PNS. This pattern of symptoms was associated with specific cognitive deficits and decreased functional outcome. Future studies are needed to examine the developmental trajectories of these individuals and assess their risk of conversion to full-blown psychosis.

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations.