Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review

Abstract

Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.

Keywords: autism; autism spectrum disorder; cortical thickness; cortical volume; grey-white matter tissue contrast; gyrification; neuroanatomy; surface area.

FIGURE 1

Schematic of neuroimaging features mentioned in this review.

FIGURE 2

Schematic of the development of the described neuroimaging features (A: cortical thickness, B: surface area, C: cortical volume, D: local gyrification index, and E: grey-white matter tissue contrast) in childhood, adolescence, and adults in neurotypicals (shown in blue) and autistic individuals (displayed in orange), where upward arrows indicate increases, horizontal arrows indicate stagnation/plateau, and downward arrows indicate decreases. Where research has been inconclusive/contradicting, multiple arrows are presented. Please note that this schematic is not comprehensive: different growth trajectories have been reported both within studies (e.g., for different brain regions) and between studies. For more information concerning neuroanatomical differences and their trajectories in autism, see e.g (Courchesne et al., 2007; Ecker et al., 2014, 2015; Zielinski et al., 2014; Lange et al., 2015; Mensen et al., 2016; Li et al., 2021).