Date of Award

January 2013

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Dorothy Stubbe

Second Advisor

Andres Martin

Subject Area(s)

Medicine, Psychobiology

Abstract

Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, with hippocampal volume deficits being a consistently reported abnormality in schizophrenia, although the sub-regional specificity of the deficits has not been characterized. We explored the nature and developmental trajectory of sub-regional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers.

Method: 255 anatomic brain MRI scans were obtained from 103 patients with COS, 169 scans from their 79 healthy siblings, and 255 scans from 101 age and gender matched healthy volunteers, across ages 9-29 years. The hippocampus was segmented using FreeSurfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at over 6000 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. The healthy siblings also showed a trend for anterior inward deformation. The three groups did not differ in the trajectory of hippocampal shape or volume changes over time. Inward deformations in the anterior hippocampus were positively related with positive symptom severity, while outward surface displacement was positively related to overall functioning.

Conclusions: This is the first and largest longitudinal three-way analysis of sub-regional hippocampal shape abnormalities in patients with COS, and their healthy siblings, compared to healthy controls. The abnormalities seen in the anterior hippocampus of patients with COS possibly suggest disturbed frontal-hippocampal connectivity. A trend towards mild overlapping shape abnormalities in the healthy siblings suggests a more subtle, subregionally-specific neuroanatomical endophenotype.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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