Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder

Abstract

Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder (21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients (by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis 1 subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.

Figure 1

(a) Topographic correspondence of pathology on blank MR-based models of the hippocampal formation of normal controls. Based on Duvernoy (Duvernoy, 1988), where neuropathologic areas are shown in seven equally spaced coronal slices spanning the entire length of the hippocampus. CA, cornu ammonis. (b) Depicts the surface of the hippocampus, traced in consecutive coronal magnetic resonance image sections, which is composed of discrete triangular tiles that are spatially uniform and can be averaged across subjects. A 3-D medial curve is derived from each individual hippocampus (arrows in part b). The distance from this axis to the surface is the dependent variable in the regression analyses. See ‘Methods’ section of the text for details.

Figure 2

Hippocampal volumes. The mean7SEM for total volume of the right and left hippocampus in each subject group (lithium-treated bipolar patients, unmedicated bipolar patients, and healthy controls).

Figure 3

Statistical 3-D maps showing local differences in hippocampal structures between unmedicated patients with BP and control subjects, in terms of percent difference (a) and statistical significance (c). The pattern of findings is remarkably similar in unmedicated bipolar patients vs lithium-treated bipolar patients (b and d). The right hippocampus is on the left side of the figure.

Figure 4

Statistical 3-D maps showing local differences in hippocampal structures between lithium-treated patients with BPD and control subjects, in terms of percent difference (a) and statistical significance (b). Again, the right hippocampus is on the left side of the figure.