An exciting new study published in Science this week attempts to answer the chicken-or-egg question pervasive in drug addiction research of, “Which comes first, drug use or brain abnormalities?” Dr. Karen Ersche from the University of Cambridge* approaches this question with a new perspective, investigating the biological siblings of dependent drug users. And as is the case with most seemingly dichotomous questions in science, the answer is: both.
Dr. Ersche’s group studied 50 stimulant-dependent individuals, 50 of their healthy, non-dependent biological siblings, and 50 unrelated control volunteers on a barrage of cognitive tests, personality measures, and brain imaging techniques. Throughout the assessments, there was a striking pattern of similar responding between the drug users and their siblings, significantly differing in their results from the control participants. Specifically, drug users and their siblings were both significantly more impaired on the Stop Signal Reaction Time Task (SSRT), a test of inhibitory control that measures how well an individual can stop an ongoing response when triggered. Impulse control and inhibition are traits known to be impaired in drug-dependent individuals, and poor performance on the SSRT has previously been associated with an increased risk for drug abuse. However, these dysfunctions have long been debated as to whether they can be attributed to accumulated years of drug use and its effects on the brain, or are instead a predisposing factor that places an individual at an increased risk for drug dependence. In the current study, sibling participants performed as poorly on the SSRT as drug-dependent individuals, requiring more time to inhibit their actions. This would suggest that poor impulse control is a shared trait that is present in drug-dependent individuals before the onset of abuse. However, impaired inhibition is clearly not a determining variable, as dysfunction in the siblings did not lead to subsequent drug abuse or dependency.
The brains of stimulant users and their siblings were also structured similarly as compared to control volunteers, with an increase in gray matter in limbic and striatal regions such as the amygdala and putamen, areas important in emotion regulation and habit formation. Drug addiction is often seen as a disorder involving dysfunctional habits, and the putamen is implicated in the acquisition of these compulsive behaviors, targeted by an influx of dopamine and commonly a site of subsequent adaptations in the brains of heavy drug users. Additionally, the postcentral gyrus was significantly smaller in both groups as compared to healthy volunteers, indicating further pre-morbid differences.
Finally, white matter tract integrity, the neuron fibers that travel throughout the brain relaying messages from one region to another, were less intact in both the drug users and their siblings, signifying a decrease in brain connectivity in these groups as compared to the control participants. This was particularly evident in the inferior frontal gyrus, a region implicated in impulse control, supporting the findings of impaired self-regulation characteristic of compulsive drug users. Changes in connectivity in this area were also associated with an increase in impulse control dysfunction on the SSRT, with decreases in this region accounting for 6% of the variability in SSRT scores. Additional damage to white matter tracts and gray matter regions were also seen in the stimulant-dependent group, correlating with years of stimulant abuse and suggesting further damage and dysfunction due to chronic drug use itself.
Taken together, the abnormalities in the limbic and striatal regions, which have projections to the frontal cortex, as well as the decrease in frontal cortical volume and impaired connectivity between these key areas, confirms prior research indicating the importance of the cortico-limbic-striatal circuitry in drug dependence. These differences in the brains and behaviors of drug users and their siblings could potentially serve as endophenotypes for the development of drug dependence, characterized as stable inherited traits that are seen in clinical disorders and that can serve as indicators or predictors of pathology, both in patients and in their biological relatives. As such, these abnormalities in key regions for drug addiction could act as biomarkers for an increased risk of dependence.
However, the key question arises as to what protective factors could exist in the siblings to prevent them from trying or developing dependence on drugs. Sharing 50% of their genetic make-up, as well as familial environments growing up, drug-sibling pairs have highly similar brains and behaviors. However, clearly the differences that do exist between these groups are incredibly important. Early drug experimentation may exacerbate the structural abnormalities seen in these individuals, increasing the risk for later dependency, or even creating an epigenetic effect as has been seen in previous studies investigating early cigarette smoking and its link to later drug dependence. Alternatively, protective factors in the siblings could include greater education, outside interests or hobbies growing up, or even an increase in exercise and physical activity.
The question of the path to drug dependency is still very much open, however this study may take us one step closer to finding the answer.
*Disclaimer: I am a member of the Ersche lab at Cambridge, but was not involved in this study.