Neural Abnormalities in Bipolar Disorder: A Meta-Analysis of Functional Neuroimaging Studies

Abstract

IntroductionBipolar I disorder (BD-I) is a chronic and recurrent mood disorder characterized by alternating episodes of depression and mania; it is also associated with substantial morbidity and mortality and with clinically significant functional impairments. While previous studies have used functional magnetic resonance imaging (fMRI) to examine neural abnormalities associated with BD-I, they have yielded mixed findings, perhaps due to differences in sampling and experimental design, including highly variable mood states at the time of scan.ObjectivesThe purpose of this study is to advance our understanding of the neural basis of BD-I and mania, as measured by fMRI activation studies, and to inform the development of more effective brain-based diagnostic systems and clinical treatments.MethodsWe conducted a large-scale meta-analysis of whole-brain fMRI activation studies that compared participants with BD-I, assessed during a manic episode, to age-matched healthy controls. Following PRISMA guidelines, we conducted a comprehensive PubMed literature search using two independent coding teams to evaluate primary studies according to pre-established inclusion criteria. We then used multilevel kernel density analysis (MKDA), a well-established, voxel-wise, whole-brain, meta-analytic approach, to quantitatively synthesize all qualifying primary fMRI activation studies of mania. We used ensemble thresholding (p<0.05-0.0001) to minimize cluster size detection bias, and 10,000 Monte Carlo simulations to correct for multiple comparisons.ResultsWe found that participants with BD-I (N=2,042), during an active episode of mania and relative to age-matched healthy controls (N=1,764), exhibit a pattern of significantly (p<0.05-0.0001; FWE-corrected) different activation in multiple brain regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.ConclusionsThis study supports the formulation of a robust neural basis for BD-I during manic episodes and advances our understanding of the pattern of abnormal activation in this disorder. These results may inform the development of novel brain-based clinical tools for bipolar disorder such as diagnostic biomarkers, non-invasive brain stimulation, and treatment-matching protocols. Future studies should compare the neural signatures of BD-I to other related disorders to facilitate the development of protocols for differential diagnosis and improve treatment outcomes in patients with BD-I.Disclosure of InterestNone Declared