J Eric Schmitt1, John J DeBevits2, David R Roalf3, Kosha Ruparel3, R Sean Gallagher3, Ruben C Gur3, Aaron Alexander-Bloch3, Tae-Yeon Eom4, Shahinur Alam5, Jeffrey Steinberg5, Walter Akers5, Khaled Khairy6, T Blaine Crowley7, Beverly Emanuel8, Stanislav S Zakharenko4, Donna M McDonald-McGinn8, Raquel E Gur9. 1. Brain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, Philadelphia, Pennsylvania; Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: eric.schmitt@stanfordalumni.org. 2. Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. 3. Brain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, Philadelphia, Pennsylvania. 4. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee. 5. Center for Bioimage Informatics, St. Jude Children's Research Hospital, Memphis, Tennessee. 6. Center for In Vivo Imaging and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee. 7. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 8. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 9. Brain Behavior Laboratory, Neurodevelopment and Psychosis Section, Department of Psychiatry, Philadelphia, Pennsylvania; Division of Neuroradiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract
BACKGROUND: The presence of a 22q11.2 microdeletion (22q11.2 deletion syndrome [22q11DS]) ranks among the greatest known genetic risk factors for the development of psychotic disorders. There is emerging evidence that the cerebellum is important in the pathophysiology of psychosis. However, there is currently limited information on cerebellar neuroanatomy in 22q11DS specifically. METHODS: High-resolution 3T magnetic resonance imaging was acquired in 79 individuals with 22q11DS and 70 typically developing control subjects (N = 149). Lobar and lobule-level cerebellar volumes were estimated using validated automated segmentation algorithms, and subsequently group differences were compared. Hierarchical clustering, principal component analysis, and graph theoretical models were used to explore intercerebellar relationships. Cerebrocerebellar structural connectivity with cortical thickness was examined via linear regression models. RESULTS: Individuals with 22q11DS had, on average, 17.3% smaller total cerebellar volumes relative to typically developing subjects (p < .0001). The lobules of the superior posterior cerebellum (e.g., VII and VIII) were particularly affected in 22q11DS. However, all cerebellar lobules were significantly smaller, even after adjusting for total brain volumes (all cerebellar lobules p < .0002). The superior posterior lobule was disproportionately associated with cortical thickness in the frontal lobes and cingulate cortex, brain regions known be affected in 22q11DS. Exploratory analyses suggested that the superior posterior lobule, particularly Crus I, may be associated with psychotic symptoms in 22q11DS. CONCLUSIONS: The cerebellum is a critical but understudied component of the 22q11DS neuroendophenotype.
BACKGROUND: The presence of a 22q11.2 microdeletion (22q11.2 deletion syndrome [22q11DS]) ranks among the greatest known genetic risk factors for the development of psychotic disorders. There is emerging evidence that the cerebellum is important in the pathophysiology of psychosis. However, there is currently limited information on cerebellar neuroanatomy in 22q11DS specifically. METHODS: High-resolution 3T magnetic resonance imaging was acquired in 79 individuals with 22q11DS and 70 typically developing control subjects (N = 149). Lobar and lobule-level cerebellar volumes were estimated using validated automated segmentation algorithms, and subsequently group differences were compared. Hierarchical clustering, principal component analysis, and graph theoretical models were used to explore intercerebellar relationships. Cerebrocerebellar structural connectivity with cortical thickness was examined via linear regression models. RESULTS: Individuals with 22q11DS had, on average, 17.3% smaller total cerebellar volumes relative to typically developing subjects (p < .0001). The lobules of the superior posterior cerebellum (e.g., VII and VIII) were particularly affected in 22q11DS. However, all cerebellar lobules were significantly smaller, even after adjusting for total brain volumes (all cerebellar lobules p < .0002). The superior posterior lobule was disproportionately associated with cortical thickness in the frontal lobes and cingulate cortex, brain regions known be affected in 22q11DS. Exploratory analyses suggested that the superior posterior lobule, particularly Crus I, may be associated with psychotic symptoms in 22q11DS. CONCLUSIONS: The cerebellum is a critical but understudied component of the 22q11DS neuroendophenotype.
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