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Original Investigation
April 3, 2019

Microstructural White Matter Alterations in Men With Alcohol Use Disorder and Rats With Excessive Alcohol Consumption During Early Abstinence

Author Affiliations
  • 1Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas–Universidad Miguel Hernández de Elche, Sant Joan d’Alacant, Alicante, Spain
  • 2Department of Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  • 3Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  • 4Department of Clinical Psychology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  • 5School of Pharmacy, University of Camerino, Camerino, Italy
JAMA Psychiatry. 2019;76(7):749-758. doi:10.1001/jamapsychiatry.2019.0318
Key Points

Question  Can commonly observed white matter defects in alcohol use disorder be linked to alcohol using a translational diffusion tensor imaging approach, and can it be used to monitor the progression of defects into early abstinence?

Findings  This study of 91 men with alcohol use disorder, 36 healthy male controls, and 27 rats with a high preference for alcohol and 9 control rats found highly similar white matter alterations between species. A similar pattern of progression in diffusion tensor imaging alterations was found in patients and rats during early abstinence (2-6 weeks).

Meaning  The reproducible patterns of alterations in humans and rats support an association with alcohol, and the progression of diffusion tensor imaging alterations into early abstinence suggests an underlying process that evolves soon after cessation of alcohol use.


Importance  Although the detrimental effects of alcohol on the brain are widely acknowledged, observed structural changes are highly heterogeneous, and diagnostic markers for characterizing alcohol-induced brain damage, especially in early abstinence, are lacking. This heterogeneity, likely contributed to by comorbidity factors in patients with alcohol use disorder (AUD), challenges a direct link of brain alterations to the pathophysiology of alcohol misuse. Translational studies in animal models may help bridge this causal gap.

Objective  To compare microstructural properties extracted using advanced diffusion tensor imaging (DTI) in the brains of patients with AUD and a well-controlled rat model of excessive alcohol consumption and monitor the progression of these properties during early abstinence.

Design, Setting, and Participants  This prospective observational study included 2 cohorts of hospitalized patients with AUD (n = 91) and Marchigian Sardinian alcohol-preferring (msP) rats (n = 27). In humans cross-sectional comparison were performed with control participants (healthy men [n = 36]) and longitudinal comparisons between different points after alcohol withdrawal. In rats, longitudinal comparisons were performed in alcohol-exposed (n = 27) and alcohol-naive msP rats (n = 9). Human data were collected from March 7, 2013, to August 3, 2016, and analyzed from June 14, 2017, to May 31, 2018; rat data were collected from January 15, 2017, to May 12, 2017, and analyzed from October 11, 2017, to May 28, 2018.

Main Outcomes and Measures  Fractional anisotropy and other DTI measures of white matter properties after long-term alcohol exposure and during early abstinence in both species and clinical and demographic variables and time of abstinence after discharge from hospital in patients.

Results  The analysis included 91 men with AUD (mean [SD] age, 46.1 [9.6] years) and 27 male rats in the AUD groups and 36 male controls (mean [SD] age, 41.7 [9.3] years) and 9 male control rats. Comparable DTI alterations were found between alcohol and control groups in both species, with a preferential involvement of the corpus callosum (fractional anisotropy Cohen d = −0.84 [P < .01] corrected in humans and Cohen d = −1.17 [P < .001] corrected in rats) and the fornix/fimbria (fractional anisotropy Cohen d = −0.92 [P < .001] corrected in humans and d = −1.24 [P < .001] corrected in rats). Changes in DTI were associated with preadmission consumption patterns in patients and progress in humans and rats during 6 weeks of abstinence. Mathematical modeling shows this process to be compatible with a sustained demyelination and/or a glial reaction.

Conclusions and Relevance  Using a translational DTI approach, comparable white matter alterations were found in patients with AUD and rats with long-term alcohol consumption. In humans and rats, a progression of DTI alterations into early abstinence (2-6 weeks) suggests an underlying process that evolves soon after cessation of alcohol use.