Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

BACKGROUND: Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife. METHODS: We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances. RESULTS: Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning-predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco. CONCLUSIONS: These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.

Long-term Neural Embedding of Childhood Adversity in a Population-Representative Birth Cohort Followed for 5 Decades.

BACKGROUND: Childhood adversity has been previously associated with alterations in brain structure, but heterogeneous designs, methods, and measures have contributed to mixed results and have impeded progress in mapping the biological embedding of childhood adversity. We sought to identify long-term differences in structural brain integrity associated with childhood adversity. METHODS: Multiple regression was used to test associations between prospectively ascertained adversity during childhood and adversity retrospectively reported in adulthood with structural magnetic resonance imaging measures of midlife global and regional cortical thickness, cortical surface area, and subcortical gray matter volume in 861 (425 female) members of the Dunedin Study, a longitudinal investigation of a population-representative birth cohort. RESULTS: Both prospectively ascertained childhood adversity and retrospectively reported adversity were associated with alterations in midlife structural brain integrity, but associations with prospectively ascertained childhood adversity were consistently stronger and more widely distributed than associations with retrospectively reported childhood adversity. Sensitivity analyses revealed that these associations were not driven by any particular adversity or category of adversity (i.e., threat or deprivation) or by childhood socioeconomic disadvantage. Network enrichment analyses revealed that these associations were not localized but were broadly distributed along a hierarchical cortical gradient of information processing. CONCLUSIONS: Exposure to childhood adversity broadly is associated with widespread differences in midlife gray matter across cortical and subcortical structures, suggesting that biological embedding of childhood adversity in the brain is long lasting, but not localized. Research using retrospectively reported adversity likely underestimates the magnitude of these associations. These findings may inform future research investigating mechanisms through which adversity becomes embedded in the brain and influences mental health and cognition.

Pattern Similarity Analyses of FrontoParietal Task Coding: Individual Variation and Genetic Influences.

Pattern similarity analyses are increasingly used to characterize coding properties of brain regions, but relatively few have focused on cognitive control processes in FrontoParietal regions. Here, we use the Human Connectome Project (HCP) N-back task functional magnetic resonance imaging (fMRI) dataset to examine individual differences and genetic influences on the coding of working memory load (0-back, 2-back) and perceptual category (Face, Place). Participants were grouped into 105 monozygotic twin, 78 dizygotic twin, 99 nontwin sibling, and 100 unrelated pairs. Activation pattern similarity was used to test the hypothesis that FrontoParietal regions would have higher similarity for same load conditions, while Visual regions would have higher similarity in same perceptual category conditions. Results confirmed this highly robust regional double dissociation in neural coding, which also predicted individual differences in behavioral performance. In pair-based analyses, anatomically selective genetic relatedness effects were observed: relatedness predicted greater activation pattern similarity in FrontoParietal only for load coding and in Visual only for perceptual coding. Further, in related pairs, the similarity of load coding in FrontoParietal regions was uniquely associated with behavioral performance. Together, these results highlight the power of task fMRI pattern similarity analyses for detecting key coding and heritability features of brain regions.