Published online before print August 9, 2012, doi: 10.3174/ajnr.A3269
AJNR 2012 33: E115

B. Sarikaya^a
aDepartment of Radiology/Neuroradiology
University of Minnesota and
Hennepin County Medical Centers
Minneapolis, Minnesota

I read the article by Kong et al titled “Acute Effects of Alcohol on the Human Brain: Diffusion Tensor Imaging Study” in the May 2012 issue of AJNR with great interest.¹The authors reported novel findings on the world’s oldest and most widely used recreational drug, ethanol, and demonstrated that it leads to some detectable alterations on DTI compared with baseline even after small to moderate amounts (for a regular drinker) of consumption. This report happens to serve as the first article in this field demonstrating DTI changes besides those well-known effects of ethanol on the CNS detectable by other tests. Their findings are extremely interesting, not only in a way linking alcohol consumption to diffusion weighted imaging (which has the same abbreviation as “driving while impaired”); but also the results presented in the article carry a potential for huge implications if validated with future studies. Nevertheless, their findings seem to be somewhat contradictory to what is known so far and extremely questionable as a result of methodologic weaknesses. I would like to address several issues regarding their DTI methodology as well as point out some objections about how the results were evaluated.

As for the methodology, apparently the authors preferred ROI-based analysis over robust automated DTI analysis, which has its own advantages and disadvantages compared with the ROI-based analysis.² However, it is not clear why the authors used 2 different software packages for their analysis and at which step each was used, and why they switched from one software package to the other. On the basis of the images provided, it looks like they performed the analyses with FuncTool software (AW 4.3; GE Healthcare, Milwaukee, Wisconsin) and the need to use DTIStudio (Johns Hopkins University, Baltimore, Maryland) is totally unclear; expert researchers in the field would agree that even though DTIStudio is capable of coregistration to remove eddy current and motion artifacts, it is not very feasible to transfer the data back to FuncTool software, and DTIStudio also has excellent means for drawing the ROIs.

Placement of ROIs was not clearly explained. It was not clear whether these were drawn on anatomic sequences first and then copied on the ADC and fractional anisotropy maps, drawn on one of those generated maps and then copied onto other maps, or drawn separately. The last case would definitely bring additional limitations, such as reproducibility issues. The ROI size was defined as 32 cm², except the internal capsule, for which an ROI size of 26 cm² was used. Depending on the images provided, the ROIs should have been measured in square millimeters rather than square centimeters, and I believe if indeed that was the case, it could merely represent a typographical error in the manuscript preparation step. As a second possibility, if the ROI size represented the total cumulative size of the ROIs drawn on 1 region, then this point should have been stated in the appropriate section. However, methodologic vagueness is not the end of the story. The authors also should have explained how they reached the final values of the ROIs drawn for each area, such as whether they obtained the maximum versus minimum values for each area or averaged the values of all ROIs. Interobserver variability is a significant issue in ROI-based DTI analysis, and the authors did not clarify how the 2 observers drew their ROIs (independently versus in consensus). Absence of an interobserver variability analysis would be another confounding fact in the case of independent analysis.²

Besides the present article, only 1 other article could be identified in the literature investigating the role of DWI/DTI in acute alcohol intoxication, and this article was not cited by the authors. In their 2008 article, Duning et al³ were not able to identify any significant changes in ADC values in 4 subjects. Even though their number of subjects was smaller than that of the present study, their methodology was more consistent; for example, blood-alcohol concentrations were tabulated on the 4 occasions that the subjects underwent DWI. In the same study, the authors used a higher field magnet system, images were normalized and coregistered by using SPM2 software (Wellcome Department of Imaging Neuroscience, London, UK), and broader ROIs were traced on anatomic datasets, indicating that a more robust investigation algorithm was used with lower limitations. Their ROIs were placed to delineate the anatomic regions for more comprehensive evaluation. In the present study, even though the authors mentioned that the blood-alcohol levels were measured, the results were not tabulated. Hence, the statement in the conclusion that “DTI has been shown to be more effective in detecting alcohol-induced changes on the human brain compared with BAC or BrAC” is very hard to accept in the absence of any comparative tabulation.¹

Both studies are subject to a common limitation: understandably, they used alcoholic beverages instead of pure ethanol. Kong et al¹ used Maotai wine, which is made from fermented sorghum, whereas Duning et al³ used pure vodka. Essentially, both products are likely to contain substances besides ethanol that might show CNS effects. Marchiafava-Bignami disease is an unclear entity, initially linked to Chianti wines of Italy, but it has now has been associated with many other types of drinks.⁴Nevertheless, it might still suggest an etiology in addition to ethanol.

Finally, better designed studies with greater numbers of subjects would yield more information on the acute effects of alcohol on DTI parameters. However, even in that case, instead of cytotoxic edema, as proposed by Kong et al,¹ some other mechanisms would be more likely to cause the alterations that could possibly be detected on DTI. Alcohol has been known to exert its effects through different receptors, and γ-amino butyric acid A receptors are emphasized more than the others in that regard. These are essentially ligand-gated ion channels that are potentiated by alcohol and possibly represent acute action of alcohol by causing an influx of Cl⁻ ions, whereas γ-amino butyric acid B receptors act through G proteins and are responsible for more long-term effects.⁵ Ethanol has different types of actions on different neurotransmitter receptors; although it potentiates some, it deactivates the rest, and it is very likely that different imaging findings might be encountered depending on microstructural changes in different parts of the brain.⁵

References

1. Kong LM, Zheng WB, Lian GP, et al. Acute effects of alcohol on the human brain: diffusion tensor imaging study. AJNR Am J Neuroradiol 2012;33:928–34 » Abstract/FREE Full Text
2. Ozturk A, Sasson AD, Farrell JA, et al. Regional differences in diffusion tensor imaging measurements: assessment of intrarater and interrater variability. AJNR Am J Neuroradiol 2008;29:1124–27 » Abstract/FREE Full Text
3. Duning T, Kugel H, Menke R, et al. Diffusion-weighted magnetic resonance imaging at 3.0 Tesla in alcohol intoxication. Psychiatry Res 2008;163:52–60 » CrossRef » Medline
4. Arbelaez A, Pajon A, Castillo M. Acute Marchiafava-Bignami disease: MR findings in two patients. AJNR Am J Neuroradiol 2003;24:1955–57 » Abstract/FREE Full Text
5. Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28:263–74 » Medline

Reply

Published online before print August 9, 2012, doi: 10.3174/ajnr.A3280
AJNR 2012 33: E116

L.M. Kong^a
aDepartment of Radiology
Second Affiliated Hospital
Medical College of Shantou University
Shantou, Guangdong Province, China

I would like to reply to the letter by Basar Sarikaya regarding our published article “Acute Effects of Alcohol on the Human Brain: Diffusion Tensor Imaging Study.”

First, the author of the letter said that it is not clear why we used 2 different software programs for our analysis and at which step and why we switched to the other software. In fact, we performed the analyses only on FuncTool in the AW 4.3 Workstation (GE Healthcare, Milwaukee, Wisconsin) of DTIStudio software (Johns Hopkins University, Baltimore, Maryland), which is capable of coregistration to remove eddy currents and motion artifacts and has excellent means for drawing the ROIs.

Second, was the issue that the placement of ROIs was not clearly explained. In our study, we placed ROIs on anatomic sequences first, and then the same size and shape region of interest was automatically displayed on the ADC and FA maps. We are sorry to say that the region-of-interest size defined as 32 cm², except for the internal capsule for which region-of-interest size was 26 cm², was an error on our part in manuscript preparation. The region-of-interest sizes measured in our images were in square millimeters and not square centimeters.

Third, as to the results in the article by Duning et al (2007), the authors were not able to identify any significant changes in ADC values in the 4 subjects they examined, and, in our study, we found that the sensitivity of different parts of the brain to alcohol was different. The ROIs in some parts of the brain showed significant changes in ADC values, and some did not change after drinking. In our opinion, the different results between the 2 studies are due to the regions of interest of different parts of the brain and individual differences in alcohol clearance of the participants. In our study, to ensure that the alcohol dose received in the study would be within the participants’ normal range of experience, we excluded very heavy drinkers. Participants were asked to refrain from any alcohol for 24 hours before their appointment and to eat a light meal 5–6 hours before their appointment.

Fourth, regarding the statement in the conclusion, “DTI has been shown to be more effective in detecting alcohol-induced changes on the human brain compared with BAC (blood alcohol concentration) or BrAC (breath alcohol concentration),” we found, in both the high- and low-dose groups, that the BrAC was at the highest concentration at 0.5 hours, representing the peak of blood-ethanol concentrations, but the ADC values reached the lowest values at 1 hour post–alcohol administration (Fig 3A, –B, and –E). Significant changes in ADC values in the frontal lobes, thalamus, and middle cerebellar peduncle in our study showed that these areas are more vulnerable to the effects of acute alcohol consumption. Moreover, in our study, when the BrAC descended to 0, we could see that the ADC values in the brain were still lower than those before drinking, which reflects the existence of brain edema. The alterations of blood alcohol content or BrAC cannot directly reflect these changes in brain.

Fifth, the author of the letter said that both studies used alcoholic beverages instead of pure ethanol. Understandably the author’s comment is subject to 1 common limitation. In our study, we used Maotai, a kind of Chinese spirits (Chinese spirits have been distilled mainly from fermented cereals). To our knowledge, besides ethanol, other components of Maotai have little CNS effect.

Finally, we agree that better designed studies with a greater number of subjects would yield more information on the acute effects of alcohol on DTI parameters. We believe that some other mechanism is more likely to cause the alterations that could possibly be detected on functional MR imaging. Ethanol has different actions on different neurotransmitter receptors; while it potentiates some, it deactivates the rest. It is very likely that different imaging findings might be encountered, depending on microstructural changes in different parts of the brain. In our other study, we tried to use MR spectroscopy to investigate the change of metabolites in the rat brain after acute alcoholism at 7T MR imaging, and we also used DTI combined with MR spectroscopy in a study of the acute effects of alcohol on the human brain. We have found some interesting microstructural changes in the brain after administrating alcohol.