Mapping corpus callosum morphology in twin pairs discordant for bipolar disorder

Abstract

Callosal volume reduction has been observed in patients with bipolar disorder, but whether these deficits reflect genetic vulnerability to the illness remains unresolved. Here, we used computational methods to map corpus callosum abnormalities in a population-based sample of twin pairs discordant for bipolar disorder. Twenty-one probands with bipolar I disorder (mean age 44.4 ± 7.5 years; 48% female), 19 of their non-bipolar co-twins, and 34 demographically matched control twin individuals underwent magnetic resonance imaging. Three-dimensional callosal surface models were created to visualize its morphologic variability and to localize group differences. Neurocognitive correlates of callosal area differences were additionally investigated in a subsample of study participants. Bipolar (BPI) probands, but not their co-twins, showed significant callosal thinning and area reduction, most pronounced in the genu and splenium, relative to healthy twins. Altered callosal curvature was additionally observed in BPI probands. In bipolar probands and co-twins, genu and splenium midsagittal areas were significantly correlated with verbal processing speed and response inhibition. These findings suggest that aberrant connections between cortical regions--possibly reflecting decreased myelination of white matter tracts--may be involved in bipolar pathophysiology. However, findings of callosal thinning appear to be disease related, rather than reflecting genetic vulnerability to bipolar illness.

Figure 1.

(a) Pointwise distances between the medial curve (in red) and the callosal top and bottom surfaces are calculated to obtain a thickness measure at each point on the callosal surface. (b) Subdivision of the CC into 5 areas according to the modified Witelson scheme (Clarke and Zaidel 1994; adapted from Ballmaier et al. 2008).

Figure 2.

Callosal area differences. Bipolar probands differed significantly from both their co-twins (P < 0.05) and control twins (P = 0.007); callosal area in non-bipolar co-twins was intermediate between that of bipolar probands and controls but was not significantly different from that of controls (P = 0.61). Statistical analyses covary for 2/3 root of TBV, but raw values are presented in figure for illustrative purposes.

Figure 3.

Group differences in callosal thickness. CC maps comparing BP probands, their non-bipolar co-twins, and control twin subjects. (A) Modified Witelson partitioning scheme. The anterior midbody of the CC showed a significant area reduction in BP1 probands relative to both control twins and their non-bipolar co-twins. Posterior midbody and anterior third (genu) areas were significantly reduced in BP probands relative to healthy control twins, with a similar trend toward area reduction relative to their non-ill co-twins. Splenium area was also significantly reduced in BP versus control twins. (B) Left panel depicts reduction of callosal thickness in BPI probands, expressed as a percentage relative to healthy control twin subjects. Right panel depicts corrected statistical maps (FDR) showing P values for group differences (BPI vs. controls) in callosal thickness. (C) Reduced callosal thickness in BPI probands, expressed as a percentage (left) and map of P values (right), relative to their non-bipolar co-twins. (D) Nonsignificant reduction of callosal thickness in co-twins of BP probands, expressed as a percentage (left) and map of P values (right), relative to healthy control twin subjects.

Figure 4.

Differences in callosal morphology. Callosal shape profiles mapped in groups defined by biological risk for bipolar disorder. Average anatomical mesh models of the CC are shown in different colors to illustrate differences between groups, indicating genetic and disease-related effects on callosal morphology. From the top, average callosal shape profiles are mapped in the following: 1) bipolar probands versus healthy control twins; 2) bipolar probands versus non-bipolar co-twins; and 3) unaffected co-twins of bipolar probands versus control twins.