New Study Challenges Assumptions About Neuroanatomy and Substance Use Disorder
For years, the assumption in the addiction field has been that changes in brain structure observed in young people who use alcohol or other substances are due to exposure to these substances. However, a recent study published online on December 30, 2024, in JAMA Network Open challenges this view.
The study, led by Alex P. Miller, PhD, an assistant professor at Indiana University’s Department of Psychiatry, indicates that certain neuroanatomical features, including larger brain and cortical volumes, can be detected in children before they are exposed to any substances. This finding adds to the growing body of evidence suggesting that individual brain structure, environmental exposure, and genetic risk factors may influence the likelihood of developing a substance use disorder.
Neuroanatomy: A Predisposing Factor?
Previous research has shown that substance use is linked to lower gray matter volume, thinner cortex, and poor white matter integrity. These changes have traditionally been attributed to the effects of alcohol and illicit drugs. However, recent longitudinal and genetic studies suggest that these variations in brain structure might also be predisposing factors that increase the risk of substance use.
To investigate this further, the researchers analyzed data from 9,804 children (average age 9.9 years at baseline, 53% boys, 76% White) participating in the Adolescent Brain Cognitive Development (ABCD) Study across 22 U.S. sites. The study aims to track brain and behavioral development from middle childhood to early adulthood.
Data on substance use, including alcohol, nicotine, cannabis, and other illicit drugs, were collected via in-person and phone interviews. MRI scans provided detailed brain structural information, including various measures of global and regional brain volumes, thickness, surface area, sulcal depth, and subcortical volume.
Significant Brain Differences
The analysis revealed that children who initiated substance use before age 15, especially those who started with alcohol (90%), exhibited larger global neuroanatomical indices. These included increased whole brain volume, total intracranial volume, cortical volume, subcortical volumes, and total cortical surface area.
Regionally, substance users had thinner cortices in frontal regions but thicker cortices in other brain lobes. They also showed larger regional brain volumes, deeper sulci, and variations in cortical surface area.
Additional analyses focused on the initiation of alcohol, nicotine, and cannabis use. Alcohol use was linked to greater left lateral occipital volume and thicker para-hippocampal gyri in both hemispheres. Users also had thinner superior frontal gyri on both sides. Nicotine use was associated with smaller right superior frontal gyrus volume and deeper sulci in the left lateral orbitofrontal cortex. Cannabis use correlated with thinner left precentral gyrus and smaller volumes in the right inferior parietal gyrus and right caudate.
While the findings for nicotine and cannabis were statistically significant, they are not clinically informative for individual cases. However, they do challenge existing theories of addiction.
Associations Precede Substance Use
A post hoc analysis of the 1,203 youth who started using substances after the baseline neuroimaging session found that many brain differences were present before substance use initiation. This finding challenges the idea that these neuroanatomical changes are solely due to substance exposure. Instead, it suggests that they may be predisposing risk markers.
The study acknowledges potential limitations, including unmeasured confounders and incomplete data. However, the researchers argue that longitudinal designs and genetically informative components make this study a significant contribution to addiction research.
Reevaluating Causal Assumptions
An editorial published alongside the study by Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development at the University of Minnesota Twin Cities, underscores the need to reassess causal assumptions underlying brain disease models of addiction. The large sample size and longitudinal design of the ABCD Study provide crucial insights into both larger and smaller effects.
The editorial praises the study for allowing researchers to move beyond temporal precedence towards causal inference and mechanism identification, thanks to its family study design, twin subsamples, and DNA collection.
The study was funded by the National Institutes of Health, and the authors and editorialists reported no relevant conflicts of interest.
“The hope is that these types of studies, in conjunction with other research on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” says Dr. Miller.
This groundbreaking research opens new avenues for understanding the complex interplay between brain structure, genetic predisposition, and substance use. As more data emerges, our approach to treating and preventing substance use disorders may also evolve.
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