Hippocampal volume deficits and shape deformities in young biological relatives of schizophrenia probands

Abstract

Hippocampal volume decrement may be one of the changes that most closely pre-date schizophrenia onset. Studying hippocampal developmental morphology in adolescent or young adult biological relatives of schizophrenia probands has the potential to further our understanding of the neurodevelopmental etiology of schizophrenia and to discover biomarkers that may aid its early identification. We utilized an artificial neural network segmentation algorithm to automatically define and reliably measure MRI hippocampus volumes. We compared 46 young, nonpsychotic biological relatives of probands against 46 healthy controls without family history of schizophrenia and 46 schizophrenia probands (age range=13 to 28 years). We further contrasted hippocampal shape differences using spherical harmonic functions and assessed how obstetric complications (a trigger for aberrant in utero neurodevelopment) may contribute to hippocampal abnormalities. Similar to schizophrenia probands, unaffected biological relatives of probands had significantly smaller hippocampus volumes than controls; which correspond to inward displacements in shape deformities principally in the anterior hippocampal subregions. Examination of hippocampus volume-age relationships indicate that hippocampus volume normally decreases with age during late adolescence through early adulthood. In contrast, relatives of probands did not show these age-expected changes. Deviant hippocampus volume-age relationships suggest aberrant hippocampal neurodevelopment among biological relatives. Relatives with a history of obstetric complications had significantly smaller left and right hippocampi than relatives without obstetrics complications, including a dose relationship such that greater number of birth complications correlated with smaller hippocampus. Similar hippocampal volume deficits-obstetric complications relationships were observed among schizophrenia probands. Hippocampal abnormalities in schizophrenia are likely to be mediated by different neurobiological mechanisms, including factors associated with obstetric complications which occur during early neurodevelopment. Other brain maturational anomalies affecting the hippocampus in schizophrenia may manifest closer to illness onset in adolescence/early adulthood.

Figure 1

Comparison of hippocampal shape between 46 relatives of schizophrenia probands and 46 healthy volunteers using spherical harmonic analysis: T-maps reveal significant shape differences in the heads of bilateral hippocampi primarily over superior (a) and less so in the inferior (b) surfaces (red and yellow areas; raw p≤.05); Displacement maps over superior (c) and inferior (d) surfaces (mean distances displaced inward (green) or outward (red) in relatives compared to healthy volunteers) further indicate that sub-regions where relatives differed significantly from healthy volunteers correspond to inward displacements.

Figure 2

Comparison of hippocampal shape between 46 schizophrenia probands and 46 healthy volunteers using spherical harmonic analysis: T-maps reveal significant shape differences in the heads of bilateral hippocampi primarily over both superior (a) as well as inferior (b) surfaces (red and yellow areas; raw p≤.05); Displacement maps over superior (c) and inferior (d) surfaces (mean distances displaced inward (green) or outward (red) in probands compared to healthy volunteers) further indicate that sub-regions where schizophrenia probands differed significantly from healthy volunteers correspond to inward displacements.

Figure 3

Comparison of left (a) and right (b) hippocampus volume-age correlations in healthy volunteers without family history of schizophrenia, biological relatives of schizophrenia probands and schizophrenia probands.

Figure 3

Comparison of left (a) and right (b) hippocampus volume-age correlations in healthy volunteers without family history of schizophrenia, biological relatives of schizophrenia probands and schizophrenia probands.

Figure 4

Effects of obstetric complications on hippocampus volume in biological relatives of schizophrenia probands and in schizophrenia probands: (a) Correlations between hippocampus volumes and total number of obstetric complications; (b) Comparison of hippocampus volumes between relatives subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=25) versus More than 1 obstetric complication (N=21); (c) Comparison of hippocampus volumes between schizophrenia probands subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=30) versus More than 1 obstetric complication (N=16).

Figure 4

Effects of obstetric complications on hippocampus volume in biological relatives of schizophrenia probands and in schizophrenia probands: (a) Correlations between hippocampus volumes and total number of obstetric complications; (b) Comparison of hippocampus volumes between relatives subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=25) versus More than 1 obstetric complication (N=21); (c) Comparison of hippocampus volumes between schizophrenia probands subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=30) versus More than 1 obstetric complication (N=16).

Figure 4

Effects of obstetric complications on hippocampus volume in biological relatives of schizophrenia probands and in schizophrenia probands: (a) Correlations between hippocampus volumes and total number of obstetric complications; (b) Comparison of hippocampus volumes between relatives subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=25) versus More than 1 obstetric complication (N=21); (c) Comparison of hippocampus volumes between schizophrenia probands subgrouped by median number of obstetric complications: Zero or 1 obstetric complication (N=30) versus More than 1 obstetric complication (N=16).