Alcohol use and grey matter structure: Disentangling predispositional and causal contributions in human studies

Abstract

Alcohol use is a growing global health concern and economic burden. Alcohol involvement (i.e., initiation, use, problematic use, alcohol use disorder) has been reliably associated with broad spectrum grey matter differences in cross-sectional studies. These findings have been largely interpreted as reflecting alcohol-induced atrophy. However, emerging data suggest that brain structure differences also represent pre-existing vulnerability factors for alcohol involvement. Here, we review evidence from human studies with designs (i.e., family-based, genomic, longitudinal) that allow them to assess the plausibility that these correlates reflect predispositional risk factors and/or causal consequences of alcohol involvement. These studies provide convergent evidence that grey matter correlates of alcohol involvement largely reflect predisposing risk factors, with some evidence for potential alcohol-induced atrophy. These conclusions highlight the importance of study designs that can provide causal clues to cross-sectional observations. An integrative model may best account for these data, in which predisposition to alcohol use affects brain development, effects which may then be compounded by the neurotoxic consequences of heavy alcohol use.

Keywords: MRI; alcohol; brain structure; causal; genetics; predisposition.

Figure 1.. Schematic of experimental designs used to interrogate the association between alcohol use and brain metrics.

Study Type denotes experimental designs and exemplar papers. Diagrams provide illustrations of the study design and associations tested. Implications highlight conclusions that can be drawn from the study design. Pros emphasize strengths of the study type, while Cons summarize the limitations.

Figure 2:. Regions with convergent evidence for causal and/or predispositional effects:

Regions where 2 or more different experimental designs have found evidence for either a causal effect or a predispositional effect. Arrows reflect the direction of association. Modalities are combined unless otherwise specified, as there is as yet limited evidence for modality-specific effects. Note that the inferior frontal gyrus is not highlighted, as there is no convergent evidence for any single area in this region, even though associations in overlapping areas have been identified. Similarly, regions with inconsistent directional associations (i.e., the supramarginal gyrus, the lateral occipital cortex, and the precentral and postcentral gyri) are also not shown.

Figure 3:. An integrative model.

Predispositional risk (genetic and/or environmental) is associated with different trajectories of brain development and aging, leading to different brain metrics. The onset of chronic alcohol use occurs in the context of these developmental differences. Heavy and chronic alcohol use leads to brain metric reductions. Note that the age of 21 was chosen for illustrative purposes, as this represents the legal drinking age in most states within the United States and celebrating the 21st birthday is frequently associated with excessive drinking in the United States (Rutledge et al., 2008).