Asymmetry in the Nucleus Accumbens May Be Linked with Substance Dependence

This study found that:

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  • People with some types of substance dependence exhibited less rightward asymmetry of the nucleus accumbens than did people without dependence.
  • The reduced asymmetry in the nucleus accumbens was observed specifically in people with alcohol or nicotine dependence, but not in those with cocaine, methamphetamine, or cannabis dependence.

Although the left and right hemispheres of the brain superficially look symmetrical, there are actually some important asymmetries—known as lateralization. For example, the cortex of the left hemisphere is thicker in some regions than the cortex of the right hemisphere, and its surface area is smaller. Asymmetry is also seen in certain brain regions that have been implicated in functions primarily residing in one hemisphere (i.e., lateralized functions), such as language and visuospatial processing. These asymmetries reflect left–right hemispheric differentiation and vary as a function of age and sex. Asymmetries can also vary with psychiatric diagnosis, and several studies have shown that substance use can affect left and right brain functions differently.

A recent NIDA-funded study now shows that normal asymmetry in the volume of the right and left nucleus accumbens is reduced in people with substance dependence. “We have demonstrated that investigating brain asymmetry has the potential to provide us with new insights in understanding substance use disorders,” says Dr. Zhipeng Cao from the University of Vermont, the study’s lead author.

People with Substance Dependence Show Less Rightward Asymmetry of the Nucleus Accumbens

To study the effect of substance dependence on asymmetry in brain structure, Dr. Cao and co-investigators from several national and international institutions analyzed brain magnetic resonance imaging (MRI) datasets from people with or without substance dependence that had been assembled by the Addiction Working Group of the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium. The team compared structural asymmetries of cortical and subcortical regions between about 1,800 individuals with a diagnosis of alcohol, nicotine, cocaine, methamphetamine, or cannabis dependence and about 1,000 control participants without substance dependence.

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Figure. Asymmetry in the Nucleus Accumbens Was Reduced in People With Substance Dependence Compared With Those Without Dependence  Significantly reduced rightward asymmetry was found both when the researchers combined MRI data from all participants with substance dependence (left panel) and when they looked specifically at participants dependent on alcohol or nicotine, but not in those dependent on cocaine, methamphetamine, or cannabis (right panel). See full text description at end of article.

The investigators conducted two separate analyses of brain asymmetries. The first analysis combined data from all individuals who were substance dependent, regardless of the substance involved; the second analysis separated participants based on the substance they were dependent on. Both analyses revealed that while the nucleus accumbens normally is larger in the right hemisphere than in the left hemisphere (i.e., shows rightward asymmetry), this rightward asymmetry was reduced in people who were substance dependent (see Figure). None of the other brain regions examined exhibited such differences in asymmetry between people with and without substance dependence. The substance-specific analyses further indicated that reduced rightward asymmetry in the nucleus accumbens was associated with dependence on alcohol and nicotine, but not with dependence on cocaine, methamphetamine, or cannabis.

These findings are particularly interesting because the nucleus accumbens has a central role in various cognitive functions related to drug use, such as motivation, reward, and reinforcement learning, and morphological abnormalities in this brain region have been linked to substance dependence. “Our findings suggest that the disrupted structural asymmetry of this structure can be a characteristic of the addiction population,“ says Dr. Cao. Whether the observed reduced asymmetries in people with substance dependence were pre-existing or resulted from the impact of substance use will require further investigation. He also cautions, “We had fewer participants with cocaine, methamphetamine, or cannabis dependence in the current analysis, which may hamper detection of subtle effects on brain asymmetry. Future analyses with more participants will help clarify whether reduced rightward asymmetry of the nucleus accumbens is specific to alcohol and nicotine dependence.”

This research was supported by NIDA grants DA047119, DA014100, DA023248, DA044749, DA045189, DA040032, DA020726, DA018307, and DA024859.

Text Description of Figure

The bar chart illustrates the degree of rightward asymmetry in the nucleus accumbens in people with and without substance dependence. The vertical y-axis represents the degree of rightward asymmetry; there are no specific units. The left panel shows bars representing people without dependence (left bar) and with any form of substance dependence (right bar). A horizontal black line indicates that the difference in rightward asymmetry between people without dependence and people with dependence was statistically significant. The right panel shows bars representing people without dependence (left bar) and with dependence only on alcohol, nicotine, cocaine, methamphetamine, or cannabis (from left to right). Horizontal black lines indicate that the differences between people without dependence and those with dependence on alcohol or nicotine were statistically significant.


Cao, Z., Ottino-Gonzalez, J., Cupertino, R. B., et al. Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working GroupAddiction Biology, January 28;e13010, 2021. Advance online publication.