Raquel E. Gur’s research while affiliated with The Children's Hospital of Philadelphia and other places

Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1+/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.

“Summer slide” refers to seasonal variation in children’s performance on academic assessments, characterized by decreased performance following an extended school vacation. While this phenomenon has been described by teachers and caregivers and investigated in small-scale studies using linear models of academic performance, no large-scale studies have quantified cyclical, seasonal variation in children’s standardized cognitive assessment scores. Using four large-scale datasets (total n=23,251; Adolescent Brain Cognitive Development Study: n=11,040, 9-11y; Philadelphia Neurodevelopmental Cohort: n=9,416, 8-22y; Growing Up in Singapore Towards healthy Outcomes: n=342, 7y; Oregon ADHD-1000: n=843, 7-21y), we model time-of-year using generalized additive models with cyclic cubic splines. In school-age children but not young adults, we found cognitive performance minima following school vacation (July-September in the U.S.; November-January in Singapore) across cognitive domains. These results demonstrate a generalizable small-magnitude decrease in children’s cognitive performance aligning seasonally with school vacation.

Psychopathology and cognitive ability indicators correlate, within each other, in a way that is well-captured by hierarchical factor models, but integrating both into a single hierarchical framework remains a challenge. Because both aspects of behavior presumably reflect aberrant cerebral function, the highest-order latent variable in such a model would be the “c” (for cerebral) factor. We estimated a tri-factor model of “c” in N=9,494 children and young adults from the Philadelphia Neurodevelopmental Cohort using the Penn Computerized Neurocognitive Battery and the GOASSESS clinical interview. We tested the validity of factor scores resulting from this model by relating them to external criteria, including global functioning, parent education, socioeconomic status, intracranial volume, and longitudinal clinical outcome. Fit of the structural model was acceptable (CFI = 0.98; SRMR = 0.030), and scores correlated with external criteria as expected (functioning = 0.27; parent education = 0.43; socioeconomic status = 0.47; intracranial volume = 0.39; clinical outcome Cohen d = 0.30 and 0.57). For most criteria, the effect for the “c” factor was larger than either the “p” or “g” factors alone. These results provide evidence for the feasibility and potential utility of modeling the “c” factor when cognitive and clinical data are both available.

Background: Schizophrenia (SCZ) is characterized by a disconnect from reality that manifests as various clinical and cognitive symptoms, and persistent neurobiological abnormalities. Sex-related differences in clinical presentation imply separate brain substrates. The present study characterized deep brain morphology using shape features to understand the independent effects of diagnosis and sex on the brain, and to determine whether the neurobiology of schizophrenia varies as a function of sex. Methods: This study analyzed multi-site archival data from 1,871 male (M) and 955 female (F) participants with SCZ, and 2,158 male and 1,877 female healthy controls (CON) from twenty-three cross-sectional samples from the ENIGMA Schizophrenia Workgroup. Harmonized shape analysis protocols were applied to each site's data for seven deep brain regions obtained from T1-weighted structural MRI scans. Effect sizes were calculated for the following main contrasts: 1) Sex effects; 2) Diagnosis-by-Sex interaction; 3) within sex tests of diagnosis; 4) within diagnosis tests of sex differences. Meta-regression models between brain structure and clinical variables were also computed separately in men and women with schizophrenia. Results: Mass univariate meta-analyses revealed more concave-than-convex shape differences in all regions for women relative to men, across diagnostic groups (d = -0.35 to 0.20, SE = 0.02 to 0.07); there were no significant diagnosis-by-sex interaction effects. Within men and women separately, we identified more-concave-than-convex shape differences for the hippocampus, amygdala, accumbens, and thalamus, with more-convex-than-concave differences in the putamen and pallidum in SCZ (d = -0.30 to 0.30, SE = 0.03 to 0.10). Within CON and SZ separately, we found more-concave-than-convex shape differences in the thalamus, pallidum, putamen, and amygdala among females compared to males, with mixed findings in the hippocampus and caudate (d = -0.30 to 0.20, SE = 0.03 to 0.09). Meta-regression models revealed similarly small, but significant relationships, with medication and positive symptoms in both SCZ-M and SCZ-F. Conclusions: Sex-specific variation is an overriding feature of deep brain shape regardless of disease status, underscoring persistent patterns of sex differences observed both within and across diagnostic categories, and highlighting the importance of including it as a critical variable in studies of neurobiology. Future work should continue to explore these dimensions independently to determine whether these patterns of brain morphology extend to other aspects of neurobiology in schizophrenia, potentially uncovering broader implications for diagnosis and treatment.