A frontal brain region may be a potential biomarker for the early stages of nicotine addiction

In a recent article published in Nature Communications, researchers examined the distinct roles of left and right ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) in initiating and sustaining smoking behavior among young adolescents.

The team used cross-lagged longitudinal analysis and Mendelian randomization analysis to pursue evidence that vmPFC GMV is an early-stage biomarker of nicotine addiction.

Background

Of all addictive behaviors, cigarette smoking is the most prevalent worldwide and a leading cause of adult mortality.

Several preclinical and in-human studies have shown that nicotine exposure during adolescence increases the risk of nicotine dependence by age 18, while teenage non-smokers are not likely to develop dependence. Quitting is notoriously difficult for adolescent smokers.

So far, clinical interventions have focused on chronic addicts, even though there is a much larger population with pre-addiction. Hence, there is a need to find and elucidate the biological underpinnings of the initiation and sustenance of smoking behavior during adolescence.

During the adolescence to early adulthood phase, the growth curve of brain GMV attains a peak, including peak axon myelination and synaptic pruning. While occurring throughout adolescence, these brain maturational processes cause brain re-organization, which improves adaptive behavior, such as risky decision-making. 

Previous studies have implicated the prefrontal cortex (PFC) to risk adjustment responses as it develops structurally and functionally during adolescence. Any disruption in the development of such critical neural networks, such as vmPFC, a key node in the cortico-mesolimbic dopaminergic system, could disturb some critical aspects of cognitive function, such as risk adjustment giving rise to maladaptive behaviors, such as addiction. 

Yet, researchers have not reached a consensus regarding an association between brain development changes and smoking during adolescence, and biological mechanisms governing these processes also remain elusive.

About the study

In the present study, researchers analyzed the large dataset from the IMAGEN project, a longitudinal neuroimaging genetic study conducted among 2000 healthy adolescents.

First, they assessed their neuroimaging and behavioral data at ages 14 (baseline), followed up with subsequent follow-ups at ages 19 and 23.

Next, they used the European School Survey Project on Alcohol and Other Drugs (ESPAD) scores to measure each participant’s smoking status at each time point, where a score of >0 indicated they were smokers.

The team had structural images and behavioral scores of 807 participants (55% females) at baseline and follow-up, of which 181 participants smoked before the baseline interview. Of these, 166 participants (over 50%) continued smoking at follow-ups. The remaining 260 and 366 participants comprised the control and follow-up smoker groups (FU-S) respectively.

Results

The study results showed that reduced GMV in the left vmPFC was associated with increased rule-breaking about smoking. The reduced GMV in the right vmPFC further strengthened smoking behavior by heightening the hedonic aspect of the smoking experience. In other words, an accumulation of hedonic experiences led to the reinforcement of addictive behavior.

Environmental factors, for example, parental smoking, were not associated with GMV in the left vmPFC at baseline, thus indicating its independent contributions. Therefore, adolescents with smaller left vmPFC could potentially require additional social support in order to lessen their exposure to risky environments.

Further, it is suggested that non-drug rewards at the early stage of substance use could potentially aid the prevention of a transition to substance dependency.

Based on these observations, the authors proposed a reinforcement loop underlying the sustenance of smoking, where smoking behavior could reduce GMV in the right vmPFC, leading to uninhibited, higher sensation seeking, thus, further promoting future smoking behavior.

Psychotropic drugs that preserve GMV in the right vmPFC or enhance its function could be potential treatments for addiction.

Conclusions

The reduction in the left vmPFC GMV had a possible causal influence on rule-breaking behavior that potentially led to the initiation of substance use.

Subsequently, the substance-induced changes in the right vmPFC GMV modulated hedonic effects of substance use for future substance use sustenance.

Overall, this study painted a possible causal account of how nicotine abuse starts and becomes an addiction. More importantly, it highlighted how interventions targeting the early stages of nicotine addiction during adolescence could prove highly beneficial.