Hippocampal shape abnormalities of patients with childhood-onset schizophrenia and their unaffected siblings

Abstract

Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers.

Method: Two hundred twenty-five anatomic brain magnetic resonance images were obtained from 103 patients with COS, 169 from their 79 healthy siblings, and 255 from 101 age- and sex-matched healthy volunteers (age range = 9-29 years). The hippocampus was segmented using FreeSurfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at more than 6,000 vertices on the left and right hippocampal surfaces. Longitudinal data were examined using mixed model regression analysis.

Results: Patients with COS showed significant bilateral inward deformation in the anterior hippocampus. Healthy siblings also showed a trend for anterior inward deformation. However, the trajectory of shape change did not differ significantly between the groups. Inward deformations in the anterior hippocampus were positively related to positive symptom severity, whereas outward surface displacement was positively related to overall functioning.

Conclusion: This is the first and largest longitudinal three-way analysis of subregional hippocampal shape abnormalities in patients with COS and their healthy siblings compared with healthy controls. The anterior hippocampal abnormalities in COS suggest the pathophysiologic importance of this subregion in schizophrenia. The trend level and overlapping shape abnormalities in the healthy siblings suggest a more subtle, subregionally specific neuroanatomic endophenotype.

FIGURE 1

Hippocampal shape of patients with childhood-onset schizophrenia (COS). Note: Statistical maps show significant differences in vertex distances between patients with COS and healthy volunteers (NV) at the average age (17.4 years). The color bar shows t values obtained at each hippocampal surface location, masked to show a color other than green only at vertices with a two-tailed probability value that survives false discovery rate (FDR) correction. Positive t values indicate significant outward deformation in the hippocampal surface of patients with COS compared with healthy volunteers, whereas negative t values indicate inward surface deformation. In the superior view, the anterior hippocampus is toward the bottom of the panel; in the inferior view, the anterior hippocampus is toward the top of the panel.

FIGURE 2

Hippocampal shape of healthy siblings. Note: Statistical maps show significant differences in vertex distances from the results of t tests at each vertex between the groups at the average age (17.4 years). The color bar shows t values obtained at each hippocampal surface location, masked to show a color other than green only at vertices with a two-tailed probability value with p < .05; these results did not survive false discovery rate (FDR) correction. Positive t values indicate significant outward deformation in the hippocampal surface of healthy siblings of patients with childhood-onset schizophrenia (SIB) compared with healthy volunteers (NV), whereas negative t values indicate inward surface deformation.

FIGURE 3

Relations of clinical symptoms to hippocampal surface deformations in patients with childhood-onset schizophrenia (COS). Note: Statistical maps show vertices with positive relations with (A) Children’s Global Assessment Scale (CGAS), (B) Scale for the Assessment of Positive Symptoms (SAPS), and (C) Scale for the Assessment of Negative Symptoms (SANS) clinical measurement scores. The color bar shows t values obtained at each surface vertex location, masked to show a color other than green only at surface locations with two-tailed probability values with p < .05. None of these correlations survived false discovery rate (FDR) correction for multiple analyses. Positive t values (warm colors) indicate a higher score correlated with outward deformation in the hippocampal surface of patients with COS, whereas negative t values (cool colors) indicate a higher score correlated with inward surface deformation. (D) Statistical maps showing significant differences in vertex distances between patients with COS and healthy volunteers (NV) at the average age are shown for reference.