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

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 gen -etic 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 neurobio-logic trait abnormalities in individuals at genetic risk for bipolar disorder at various scales of investigation.