Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies

Abstract

Background: Although early interventions in individuals with bipolar disorder may reduce the associated personal and economic burden, the neurobiologic markers of enhanced risk are unknown.

Methods: Neuroimaging studies involving individuals at enhanced genetic risk for bipolar disorder (HR) were included in a systematic review. We then performed a region of interest (ROI) analysis and a whole-brain meta-analysis combined with a formal effect-sizes meta-analysis in a subset of studies.

Results: There were 37 studies included in our systematic review. The overall sample for the systematic review included 1258 controls and 996 HR individuals. No significant differences were detected between HR individuals and controls in the selected ROIs: striatum, amygdala, hippocampus, pituitary and frontal lobe. The HR group showed increased grey matter volume compared with patients with established bipolar disorder. The HR individuals showed increased neural response in the left superior frontal gyrus, medial frontal gyrus and left insula compared with controls, independent from the functional magnetic resonance imaging task used. There were no publication biases. Sensitivity analysis confirmed the robustness of these results.

Limitations: As the included studies were cross-sectional, it remains to be determined whether the observed neurofunctional and structural alterations represent risk factors that can be clinically used in preventive interventions for prodromal bipolar disorder.

Conclusion: Accumulating structural and functional imaging evidence supports the existence of neurobiologic trait abnormalities in individuals at genetic risk for bipolar disorder at various scales of investigation.

Fig. 1

Selection of studies identified through database searching for inclusion in the review and meta-analysis.

Fig. 2

Meta-analysis of intracerebral volume in controls and individuals at genetic risk for bipolar disorder. Lower and upper limits indicate 95% confidence intervals. Negative values indicate reduced volumes.

Fig. 3

Meta-analysis of grey matter volume in controls, individuals at genetic risk for bipolar disorder (HR) and patients with the disorder. (Top) controls versus HR, (bottom) patients with bipolar disorder versus HR. Lower and upper limits indicate 95% confidence intervals. Negative values indicate reduced volumes.

Fig. 4

Activation likelihood estimate voxel-based meta-analysis of functional magnetic resonance imaging studies of individuals at enhanced genetic risk for bipolar disorder (HR > controls, p < 0.001), independent of task. The coordinates are displayed in Talairach space.