Greater cortical gray matter density in lithium-treated patients with bipolar disorder

Abstract

Background: The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures.

Methods: We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 +/- 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 +/- 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations.

Results: Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8).

Conclusions: These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

Figure 1

Cortical GMD maps: gray matter differences on the lateral brain surfaces. Maps of the mean GMD for bipolar subjects (n = 28) (A) and control subjects (n = 28) (B) are shown on a color coded scale where red colors denote areas of greater GMD at the cortex and blue colors relatively lower GMD. While both groups show relatively higher GMD in temporal regions, particularly perisylvian cortex, greater GMD in widespread areas of frontal cortex appears specific to the bipolar group (A, B). In (C), the mean difference in gray matter in the bipolar group, relative to healthy control subjects, is expressed as a percentage and shown color coded (blue colors: no difference; red colors: greater increase). On the right lateral (left panel) and left lateral (right panel) cortical surfaces, gray matter differences are seen primarily in superior and middle frontal gyri (BA 4, 6, 8, and 9), the inferior temporal gyrus, and superior parietal cortex surrounding the central sulcus. The significance of these differences is plotted in (D) as a map of p-values. GMD, gray matter density; BA, Brodmann area.

Figure 2

Cortical GMD maps: gray matter differences on the medial brain surfaces. Group difference maps (C) show mean percent differences in gray matter density between the bipolar group average (A) and the control group average (B), according to the color bar. The significance of these differences is plotted in (D) as a map of p-values. As can be seen in (A) and (B), areas of relatively high cortical GMD are more widespread in the cingulate gyrus in bipolar patients as compared with control subjects. Group differences were maximal in the cingulate gyrus (bilaterally, but left more extensive than right), extending along the dorsomedial extent of the interhemispheric fissure. In these regions, GMD was 10% to 15% above the control average (p < .05). In the left hemisphere, the GM difference is highly significant in a broad area encompassing posterior and anterior cingulate cortex, extending posteriorly to extrastriate regions and anteriorly to ventromedial PFC (C) (right panel). In the right medial wall (C) (left panel), differences are more circumscribed to cingulate and occipital cortex. GMD, gray matter density; GM, gray matter; PFC, prefrontal cortex.

Figure 3

Comparison of brain volumes in lithium-treated versus untreated patients with bipolar disorder and healthy control subjects. Means and standard error measures (error bars) are shown for the three groups (Li+, Li−, and control subjects), for gray and white matter volumes of the left and right cerebral hemispheres (A), lobar gray matter (B), and lobar white matter (C). There were no differences in white matter volume between the groups, but lithium-treated bipolar patients had significantly greater gray matter volumes (9.1%, left; 8.7%, right), although patients not on lithium did not differ from normal control subjects (A). In addition, lobar gray matter volumes were significantly increased in lithium-treated bipolar patients versus control subjects (B), whereas lobar white matter volumes did not significantly differ between Li+, Li−, and control subjects (C). Li+, treated with lithium; Li−, not treated with lithium.

Figure 4

Cortical GMD increase as a function of lithium usage. Statistical significance maps of GMD for bipolar patients treated with lithium versus control subjects (A). The previously observed differences in GMD become even more robust when the analysis is restricted to patients treated with lithium only (n = 20) versus control subjects (n = 28). Widespread areas of greater gray matter concentration are observed in diffuse cortical areas, particularly in left cingulate and paralimbic association cortices, and bilaterally in visual association cortex (BA 18 and 19). However, GMD in bipolar patients who were not taking lithium (Li−; n = 8) did not differ significantly from control subjects in any cortical region (B). GMD, gray matter density; BA, Brodmann area; Li−, not treated with lithium.

Figure 5

Scatterplot depicting quadratic relationship between duration of lithium usage (in weeks) and mean cortical GMD. A significant quadratic relationship was observed between weeks on lithium and overall gray matter density [R² = .38, F = 5.13(17), p = .018], indicating that duration of lithium treatment accounts for 38% percent of the variance in gray matter volume in lithium-treated bipolar patients. GMD, gray matter density.