Mapping brain asymmetry in health and disease through the ENIGMA consortium

Abstract

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

Keywords: autism spectrum disorder; brain asymmetry; brain laterality; major depressive disorder; mega-analysis; meta-analysis; obsessive-compulsive disorder; structural imaging.

FIGURE 1

Population average regional asymmetries of cortical thickness, and surface area. Colors indicate the directions and effect sizes (Cohen's d) of average interhemispheric differences, with red indicating leftward asymmetry (i.e., a greater left‐side than right‐side measure), and blue indicating rightward asymmetry. The maps were created using the “ggseg” R package based on meta‐analyzed data from more than 17,000 subjects (Kong, et al., 2018)

FIGURE 2

Population average regional asymmetries of subcortical volumes. Colors indicate the directions and effect sizes (Cohen's d) of average inter‐hemispheric differences; red indicates leftward asymmetry (i.e., a greater left‐side than right‐side measure), and blue indicates rightward asymmetry. The maps were created using the “ggseg” R package based on meta‐analyzed data from more than 15,000 subjects (Guadalupe et al., 2017)

FIGURE 3

Brain asymmetry in disorders, as compared to healthy controls. Cohen's d effect sizes of the associations between disorder diagnosis and AIs. The d values are overlaid on the left hemisphere for visualization. Positive Cohen's d values (red) indicate mean shifts towards greater leftward or reduced rightward asymmetry in cases relative to controls, and negative Cohen's d values (blue) indicate mean shifts towards greater rightward asymmetry or reduced leftward asymmetry in cases relative to controls. Significant effects after FDR correction in each study are highlighted by a black boundary and a green arrow (i.e., cortical asymmetry effects for ASD and subcortical asymmetry effects for ASD and pediatric OCD). The maps are reproduced from data in de Kovel, Aftanas, et al. (2019), Kong et al. (In press), and Postema et al. (2019). Sample sizes were up to: 1773 ASD versus 1,722 controls, 2,254 MDD versus 3,504 controls (cortical), 2,540 MDD versus 4,230 controls (subcortical), 501 pediatric OCD versus 439 controls, 1,777 adult OCD versus 1,654 controls