Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder

Abstract

Objective: Early-onset bipolar disorder is thought to be a particularly severe variant of the illness. Continuity with the adult form of illness remains unresolved, but preliminary evidence suggests similar biological underpinnings. Recently, we observed localized hippocampal decreases in unmedicated adults with bipolar disorder that were not detectable with conventional volumetric measures. Using the same three-dimensional mapping methods, we sought to investigate whether a similar pattern exists in adolescents with bipolar disorder.

Method: High-resolution brain magnetic resonance images were acquired from 16 adolescents meeting DSM-IV criteria for bipolar disorder (mean age 15.5 +/- 3.4 years, 50% female) and 20 demographically matched, typically developing control subjects. Three-dimensional parametric mesh models of the hippocampus were created from manual tracings of the hippocampal formation.

Results: Controlling for total brain volume, total hippocampal volume was significantly smaller in adolescent patients with bipolar disorder relative to controls (by 9.2%). Statistical mapping results, confirmed by permutation testing, revealed significant localized deformations in the head and tail of the left hippocampus in adolescents with bipolar disorder, relative to normal controls. In addition, there was a significant positive correlation between hippocampal size and age in patients with bipolar disorder, whereas healthy controls showed an inverse relation.

Discussion: Localized hippocampal deficits in adolescent patients with bipolar disorder suggest a possible neural correlate for memory deficits observed in this illness. Moreover, age-related increases in hippocampal size in patients with bipolar disorder, not observed in healthy controls, may reflect abnormal developmental mechanisms in bipolar disorder. This possibility must be confirmed by longitudinal studies.

Fig. 1

A, Schematic representation of the hippocampal subfields mapped onto a representative hippocampal surface (definitions based on Duvernoy and West and Gundersen41). B, Depiction of three-dimensional parametric surface model of the hippocampus, which is created using anatomical surface modeling software and composed of discrete triangular tiles that are spatially uniform and can be averaged across subjects. A three-dimensional medial curve is derived from each individual hippocampus (arrows, B). The distance from this axis to the surface is the dependent variable in regression analyses. See Method section for details.

Fig. 2

Hippocampal (HP) volumes. The mean ± SEM for total volume of the right and left hippocampi in early-onset patients with bipolar disorder and typically developing controls. This difference was significant for the left hippocampus (p = .03), with a trend toward a volume decrease in the right hippocampus as well (p = .06).

Fig. 3

Statistical three-dimensional maps show local decrease in the hippocampal formation in adolescent patients with bipolar disorder (BPs) relative to typically developing control subjects in terms of statistical significance (A) and percentage of difference (B). Maps indicate significant localized deficits in the head and tail of the left hippocampus in adolescents with bipolar disorder relative to normal controls, which were most pronounced in hippocampal subfields approximately corresponding to the subicular region. The right hippocampus is on the left side of the figure.

Fig. 4

Linear regression scatterplot for absolute hippocampal volume (in cubic millimeters) by age. Patients with early-onset bipolar disorder show a positive correlation of age with hippocampal volume (r² = 0.30; p = .03). In contrast, hippocampal volume in typically developing controls showed a nonsignificant inverse correlation with age (r² = 0.14; p = .10). The age × diagnosis interaction was highly significant (p = .01).

Fig. 5

Statistical three-dimensional maps showing the correlation of age with regional hippocampal differences, in terms of statistical significance (top) and Pearson correlation coefficient r (bottom). The correlation maps (bottom row) show the regional strength of the association between hippocampal radial distance and age in typically developing controls (left) and subjects with bipolar disorder (right), indicating primarily negative effects with age in controls and positive effects in subjects with bipolar disorder. Again, the right hippocampus is on the left side of the figure.