Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces: state versus trait vulnerability markers of depression in bipolar disorder

Abstract

Background: Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD).

Methods: Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined.

Results: The BD versus HC showed significantly greater right amygdala-OFC FC (p < or = .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001).

Conclusions: In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC-FA relationships in BD and HC require further study.

Figure 1

Mean blood oxygen level dependent (BOLD) signal change in orbitomedial prefrontal cortex (red) and amygdala (green) a priori regions of interest in bipolar disorder (BD) and healthy control individuals (HC) to all faces (neutral, mild, and intense emotional) in each experiment shown, three orthogonal views (top-down: coronal, sagittal, and axial). Left panel: BOLD signal change in BD and HC in the happy experiment. Right panel: BOLD signal change in BD and HC in the sad experiment. A priori orbitofrontal cortex (OFC) and amygdala regions were defined with the Wake Forest University PickAtlas software in the SPM atlas toolbox, on the basis of the Talairach Daemon database. For OFC regions of interests, the voxelwise threshold was p ≤ .001. At a less stringent threshold (voxelwise p ≤ .05), BOLD signal was observed in bilateral amygdala in BD and HC in each experiment.

Figure 2

Right panel: axial views showing a schematic representation of functional connectivity (FC) abnormalities in BD versus HC in the sad experiment to all faces. The arrows symbolize FC between amygdala and OFC. The template on which the FC data are depicted is the standard Montreal Neurological Institute 152 1-mm brain template showing the fractional anisotropy (FA) white matter skeleton used for tract-based spatial statistics analysis of diffusion tensor imaging data (shown in light-green) and between-group differences in FA in bilateral uncinate fasciculus (UF): decreased FA in a cluster in blue in the right UF, and increased FA in clusters in red-yellow in the left UF. The red ovoid is a representation of the amygdala region of interest. Left panel: a bar graph depicting significantly greater right amygdala-OFC FC to all faces in BD versus HC in the sad experiment (p < .001). Vertical axis: estimated marginal means of FC values. The error bars show SDs of FC in each group. BA, Brodmann area; other abbreviations as in Figure 1.

Figure 3

Right panel: axial views showing a schematic representation of FC abnormalities in BD versus HC in the happy experiment to intense faces. The arrows symbolize FC between amygdala and OFC. The template on which the FC data are depicted is the standard Montreal Neurological Institute 152 1-mm brain template showing the FA white matter skeleton used for tract based spatial statistics analysis of diffusion tensor imaging data (shown in light-green) and between-group differences in FA in bilateral UF: decreased FA in a cluster in blue in the right UF, and increased FA in clusters in red-yellow in the left UF. The red ovoid is a representation of the amygdala region of interest. Left panel: a bar graph depicting significantly reduced bilateral amygdala-OFC FC to intense faces in BD versus HC in the happy experiment (p < .007). Vertical axis: estimated marginal means of FC values. The error bars show SDs of FC in each group. Abbreviations as in Figure 1.