Neuroimaging Findings in Substance Use Disorders

Brain Volume

Differences in brain volume can be measured noninvasively through high-resolution structural magnetic resonance imaging (MRI) scans. Studies investigating differences in gray or white matter volume may manually trace regions of interest in high-resolution MRI scans and calculate volumes; however, automated analysis techniques like brain voxel-based morphometry are more common, as they are less time consuming and easier for comparing multiple brain regions than manual tracing methods. Despite these advantages, automated methods can have problems with accuracy in regions with anatomical variations between subjects, such as folds in the cortex.

Gray Matter Volume

Alcohol dependence is associated with reduced gray matter in the prefrontal cortex, insula, ventral striatum, amygdala, and hippocampus, and gray matter deficits appear more pronounced in female than male patients, suggesting that female patients may be more sensitive to the neurotoxic effects of alcohol. Similarly, a recent voxel-based meta-analysis of gray matter volume comparisons in heavy users of cocaine, methamphetamine, and amphetamine and healthy controls found that the most consistently reported findings were gray matter volume reductions in the insula, thalamus, middle and inferior frontal gyrus, and anterior cingulate. Reduced insula, thalamus, and anterior cingulate volumes have also been correlated with greater methamphetamine cravings in users. Reduced insula and striatal volumes have also been observed in chronic heroin users. A recent meta-analysis on gray matter deficits in marijuana users reported somewhat mixed findings, although reduced hippocampal volumes do appear to be a consistent finding. Finally, tobacco smokers show decreased insula, orbitofrontal, prefrontal, and cingulate cortex volumes. Collectively these findings suggest that gray matter volume deficits are present across different classes of substance use disorders, with insula, prefrontal, and cingulate cortexes commonly affected.

It is unclear to what extent gray matter deficits associated with substance use disorders are a direct consequence of substance use. Prefrontal gray matter deficits were found to worsen over a 5-year period in people with chronic alcoholism, and there is evidence that gray matter deficits are attenuated with extended alcohol abstinence. Similarly, daily morphine administration in patients with chronic pain reduces volumes of orbitofrontal cortex and amygdala providing further evidence that at least some gray matter deficits may be a consequence of chronic use. However, nonabusing individuals who have family histories of alcohol or other substance use disorders (FH+) have reduced amygdala volumes, and although findings in other brain regions are somewhat mixed, this does suggest that at least some gray matter deficits may predate excessive substance use.

White Matter Volume

Alcohol dependent patients have decreased frontal white matter volumes, and these deficits are more pronounced in patients with Wernicke encephalopathy. Similar to sex differences in gray matter deficits, female patients with alcoholism show more pronounced white matter deficits than male patients. There is mixed evidence for greater white matter volume deficits in alcoholic patients with comorbid cocaine dependence and tentative evidence for frontal white matter deficits in cocaine-dependent patients without comorbid alcohol dependence. Findings on white matter volumes in marijuana users are mixed, but frontal white matter volume deficits have been observed in individuals who abused marijuana along with cocaine and or heroin but not alcohol. Similarly, reduced white matter volumes were found in opioid-dependent patients and long-term tobacco smokers. Collectively these findings suggest that frontal white matter volume deficits are also broadly associated with different classes of substance use disorders, although they may be a marker for more extensive substance use than gray matter reductions.

White matter volume deficits appear to be a consequence of problem substance use, at least in the case of alcohol use disorders. White matter volume improvements during abstinence have been documented in alcohol-dependent patients, although it is not clear that full recovery is possible. Unlike gray matter volume deficits, white matter volume deficits have not been reported in nonabusing FH+ individuals, suggesting that these deficits are not present before the onset of problem substance use.

White Matter Microstructure

White matter microstructure can be assessed using diffusion tensor imaging to index fractional anisotropy (FA) of water diffusion in white matter tracts. FA describes the directional selectivity of the random diffusion of water molecules. Higher FA values (maximum theoretical value is 1.0) are observed along heavily myelinated white matter tracts. The structure of the axonal cell membranes and myelin sheath hinders the diffusion of water molecules in all directions except along the fiber tract, thereby producing highly anisotropic water diffusion. Thus decreased FA values in white matter tracts may indicate decreased myelin levels or damage to axons due to processes such as inflammation.

Decreased frontal white matter FA values have been found in nearly all classes of substance use disorders. For instance, alcohol-dependent patients had reduced frontal white matter FA that was associated with higher self-reported impulsivity, longer duration of drinking, and slower processing speeds on cognitive measures. Frontal white matter FA deficits were also present in adolescent binge drinkers, suggesting that relatively limited exposure to large alcohol doses may impair white matter integrity in youths, while frontal white matter FA increases in alcohol-dependent patients with extended abstinence. Similarly, frontal white matter FA deficits have also been reported in cocaine-dependent patients, and FA deficits in cocaine-dependent patients were also associated with greater impulsivity and was more pronounced in individuals who abused additional substances. Similarly, frontal white matter FA deficits have also been observed in individuals who abuse methamphetamine, opioids, marijuana, and tobacco. Collectively, these findings suggest that white matter FA deficits may be a common phenotype across multiple classes of substance use disorders.

Although there is evidence of improvement in frontal white matter FA during abstinence, there is also evidence that FA deficits are at least partially premorbid. Nonabusing FH+ adolescents and young adults have been found to have decreased frontal white matter FA values, and these deficits have been shown to be proportional to the number of biological parents and grandparents with substance use disorders, suggesting a possible hereditary influence. Of interest, similar FA deficits were not observed in FH+ youths with low levels of externalizing behaviors and other risk-related characteristics, suggesting that frontal white matter FA deficits may be closely linked to the behavioral phenotype underlying risk in FH+, typically referred to as behavioral undercontrol or neurobehavioral inhibition.

Collectively, these findings indicate that white matter microstructure deficits are present in individuals with substance use disorders and appear to both partially predate substance use and worsen as a consequence of heavy substance use. Additional studies are needed to determine how frontal white matter FA deficits may contribute to risk of substance use disorder, as well as what specific underlying white matter dysfunctions the decreased FA values reflect.