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Original Investigation |

Structural Brain Abnormalities in Youth With Psychosis Spectrum Symptoms

Theodore D. Satterthwaite, MD, MA1; Daniel H. Wolf, MD, PhD1; Monica E. Calkins, PhD1; Simon N. Vandekar, BS2; Guray Erus, PhD3; Kosha Ruparel, MS1; David R. Roalf, PhD1; Kristin A. Linn, PhD2; Mark A. Elliott, PhD3; Tyler M. Moore, PhD1; Hakon Hakonarson, MD, PhD4; Russell T. Shinohara, PhD2; Christos Davatzikos, PhD3; Ruben C. Gur, PhD1,3; Raquel E. Gur, MD, PhD1,3
[+] Author Affiliations
1Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia
2Department of Biostatistics and Clinical Epidemiology, University of Pennsylvania, Philadelphia
3Department of Radiology, University of Pennsylvania, Philadelphia
4Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
JAMA Psychiatry. 2016;73(5):515-524. doi:10.1001/jamapsychiatry.2015.3463.
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Importance  Structural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth.

Objective  To investigate the presence of structural brain abnormalities in youth with PS symptoms.

Design, Setting, and Participants  The Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children’s hospital health care network between November 1, 2009, and November 30, 2011.

Main Outcomes and Measures  Measures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally.

Results  Following exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume (P = 1.8 × 10−10) and expanded white matter volume (P = 2.8 × 10−11). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score = 5.2 and cluster size of 1225 for the right and maximum z score = 4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity.

Conclusions and Relevance  Structural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions.

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Figure 1.
Youth With Psychosis Spectrum Symptoms Have Volumetric Deficits That Progress With Age

A, Youth with psychosis spectrum symptoms have diminished gray matter volume regardless of whether intracranial volume (ICV) is included as a model covariate. B, Youth with psychosis spectrum symptoms have expanded white matter volume when smaller head size is accounted for by covarying for ICV. In both gray matter and white matter, these abnormalities become more marked at later ages in adolescence and young adulthood. Shaded regions represent 95% CIs.

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Figure 2.
Multifocal Gray Matter Volume Reduction in Youth With Psychosis Spectrum Symptoms

Voxelwise between-group analysis of gray matter volume reveals that youth with psychosis spectrum symptoms have diminished gray matter volume across multiple brain regions, including the precuneus, posterior cingulate, bilateral medial temporal lobe, frontal pole, and orbitofrontal cortex. The image was thresholded at z score > 2.3, corrected P < .01. The minimum cluster size is 255 voxels. Further details are listed in eTable 1 in the Supplement.

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Figure 3.
Reduced Medial Temporal Volume in Youth With Psychosis Spectrum Symptoms Develops in Early Adolescence

A, Voxelwise examination of nonlinear group × age interactions reveals significant differences in the developmental pattern of bilateral medial temporal lobe. Whereas intracranial volume–adjusted medial temporal volumes are stable in typically developing youth, youth with psychosis spectrum symptoms lose medial temporal volume in late childhood and early adolescence, resulting in lower medial temporal lobe volumes bilaterally by mid-adolescence. The image was thresholded at z score > 2.3, corrected P < .01. The minimum cluster size is 255 voxels. The x and y coordinates are in MNI. B, The mean volume is plotted within these clusters vs psychosis spectrum symptom severity while adjusting for covariates. Shaded regions represent 95% CIs. Further details are listed in eTable 2 in the Supplement.

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Figure 4.
Dimensional Severity of Psychosis Spectrum Symptoms Is Associated With Diminished Volume in Bilateral Medial Temporal Lobe

A, Voxelwise regression of dimensional psychosis spectrum symptoms within the psychosis spectrum sample reveals bilateral clusters of diminished volume in the medial temporal lobe. The image was thresholded at z score > 2.3, corrected P < .01. The minimum cluster size is 150 voxels. The x and y coordinates are in MNI. B, The mean volume is plotted within these clusters vs psychosis spectrum symptom severity while adjusting for covariates. Shaded regions represent 95% CIs. Further details are listed in eTable 3 in the Supplement.

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