Cocaine Addiction and Gender-Specific Associations: Is there an Interaction Effect Between Gender and Cocaine Dependance on Brain Structure and Grey Matter Volume?

Use of cocaine, like other drugs of abuse, induces long-term changes in the brain. Brain imaging studies have repeatedly revealed altered brain structure among individuals with substance use disorder and addiction. Structural abnormalities related to cocaine addiction have been most seen in the prefrontal cortex. The prefrontal cortex is a structure composed of several sub-regions-regions, all of which are implicated in various executive functions – a set of skills important for behavior control and essential for addiction recovery. Furthermore, addiction is frequently associated with reduced gray matter volume (GMV) within these frontal regions, as well as impairment of the executive functions to which they contribute.  

The findings from previous studies suggest that GMV in frontal-cortical and limbic regions is susceptible to cocaine-associated reductions in cocaine-dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue-induced craving and stress reactivity. Moreover, the variability of GMV in select brain areas between men and women highlights the importance focus of the present study. Exploration of the interaction effects between gender and cocaine dependence on brain structure was investigated using voxel-based morphometry (VBM). This technique uses magnetic resonance imaging (MRI) to investigate focal differences in GMV. Additionally, this technique was paired with the incorporation of the ENIGMA Addiction consortium, consisting of protocols for multi-site neuroimaging analyses to study the neurobiological basis of addiction. Therefore, the objective of the present study was to use the ENIGMA Addiction Consortium to investigate gender differences in VBM-derived GMV in CD individuals compared to individuals without CD/matched control, and to assess whether gender moderates the association between duration of cocaine use and GMV.  

To test these areas of suspicion, 420 individuals were pooled from seven member sites within the ENIGMA Addiction Consortium and T1-weighted brain MRI scans were used on CD individuals and non-CD individuals (control group). Pooling data across sites was an important step toward providing information that might lead to a better understanding of the neuroanatomical substrates of cocaine use disorder with potential implications for the care of these individuals.  

The current study results add to the literature documenting gender differences in the development, course, and pattern of GMV atrophy associated with cocaine dependence in humans. Results demonstrate differences predominantly in frontal regions, with CD individuals having lower GMV. With respect to gender differences, women had greater GMV in many frontal and temporal regions, as well as in the thalamus, caudate, gyrus, lateral cerebellum, and greater GMV in the supplementary motor cortex compared to men. Gender and diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CD compared to control group). The insula has extensive connections with frontal, sensory, and other limbic regions of the brain, serving in a host of functions related to addiction. Both GMV and neural activity within the anterior insula predicted objective measures of interceptive performance and subjective ratings of visceral awareness in healthy volunteers, suggesting that the insula is a neuroanatomical substrate for feeling states. Thus, GMV loss in CD individuals potentially contributes to a desensitized interoceptive system and failure to properly engage in self-reflection/awareness and behavioral control in drug addicted individuals. Furthermore, there is evidence to suggest that structural abnormalities of the insula are associated with greater craving severity and dependence severity in addicted individuals. The present study’s finding of decreased GMV in the insula in CD women (but not men) needs to be considered, along with gender differences demonstrating greater sensitivity and attentiveness to internal signals in women as compared to men.  

Lauren E. Salminen, Meral A. Tubi, Joanna Bright, Sophia I. Thomopoulos, Alyssa Wieand, Paul M. Thompson, Sex is a defining feature of neuroimaging phenotypes in major brain disorders, Human Brain Mapping, 10.1002/hbm.25438, 43, 1, (500-542), (2021).Wiley Online Library