Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals

Abstract

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega-and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R 2 = 0.041, P corr < 0.001) and cingulum (right: R 2 = 0.041, left: R 2 = 0.040, P corr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

“…The authors found white matter microstructure alterations principally within the cingulum, the main pathway in the limbic system, and in interhemispheric connectivity by the corpus callosum. 247 Thus, DTI studies have shown consistent abnormalities in regions associated with emotional regulation as well as in structures that integrate these regions interhemispherically.…”

“…The results showed that offspring of parents with BD had lower functional connectivity between the right ventral striatumleft caudal anterior cingulate in response to loss; and higher functional connectivity between the right pars orbitalis-left and right orbitofrontal cortex in response to reward, indicating potential neural markers for the risk of BD. 255 Despite the impressive advances in technology and interesting neuroimaging findings associated with a psychiatric diagnosis, 247 as well as the response to treatment and risk identification, 255,256 there is still no direct clinical application of brain imaging at this moment in psychiatry.…”

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

“…Future multisite brain-imaging machine learning studies will begin to move towards sharing of more detailed individual subject data, not only a selection of discrete features or site-level results derived from a single modality; unsupervised machine learning techniques may offer potential to better understand the heterogeneity in the disorder. The ENIGMA-BD DTI WG conducted both a mega-and meta-analysis of 3033 subjects (1482 BD and 1551 controls) 69 . Both analyses found lower FA in patients with BD compared with healthy controls in most brain regions, with the highest effect sizes in the corpus callosum and cingulum.…”

“…Zhang-James 94 ; Hess et al 92 Reduction in bilateral amygdala, striatal, and 97 ; van Rooij et al 8 Altered morphometry in the cognitive and affective parts of the striatum, frontal cortex and temporal cortex in ASD. BD 44 11,100 (3100) 8- 86 Favre et al 69 ; Nunes et al 23 ;…”

Altered White Matter Microstructural Organization in Post-Traumatic Stress Disorder across 3,049 Adults: Results from the PGC-ENIGMA PTSD Consortium

“…Here, we applied this approach to investigate the microstructural organization of white matter in PTSD. The ENIGMA DTI workflow 38 , which has successfully identified white matter compromise in schizophrenia 39 , bipolar disorder 40 , major depression 41 , and 22q11.2 deletion syndrome 42 , among others, was used by 28 cohorts to process their DTI data locally. We hypothesized the largest effects of compromised microstructure will be evident in the fronto-limbic tracts, such as the cingulum, uncinate, fornix, and corpus callosum; these tracts are strongly implicated in behavioral deficits of PTSD such as emotion regulation, working memory, and episodic memory 10,16,19,20,24,43 .…”