Proton magnetic resonance spectroscopy in alcohol use disorders: a potential new endophenotype?

Alcohol use disorders (AUD) (i.e., alcohol abuse and dependence) are a complex phenotype resulting from interplay among polygenic, sociocultural, and environmental factors. The biological and behavioral heterogeneity demonstrated in AUD are only partially captured by current diagnostic classifications such as those provided by DSM-IV or ICD-10 criteria. Therefore, efforts are underway to define new classification schemes for AUD based on genetic/biological, physiological, and behavioral endophenotypes (e.g., Hines et al., 2005; Moss et al., 2007). We agree with such efforts and their premise that such heterogeneity and complexity can be best studied in more etiologically homogeneous AUD subgroups, which may be characterized by specific endophenotypes, each potentially carrying a differential type or level of genetic susceptibility for AUD. The search for phenotypic markers of risk for AUD has led to identification of several biological variables, including for example, reduced behavioral response to alcohol (Schuckit et al., 1988) and a reduced P300 component of event-related brain potential (for review, see Begleiter and Porjesz, 1999). However, despite extensive investigation in this field, health professionals do not have reliable measures that gauge the risk of developing AUD or experiencing relapse, indicating that further research in this area is needed. Here, we describe findings of in-vivo brain proton magnetic resonance spectroscopy (1H MRS) studies in AUD, which, we propose, should be further explored and expanded regarding their value as a potential endophenotype for AUD. In contrast to cognition or psychosocial factors, for example, a potential MRS-derived endophenotype is more proximal to the biological mechanisms that underlie risk for the development and maintenance of substance use disorders or risk of relapse, such as disturbances in neuronal metabolism, cell membrane function (plasticity) or neurotransmission. The advantages of brain metabolite imaging are that the derived neurobiological measures are objective and, if performed carefully, are not influenced by situational or motivational factors that may affect cognition or accuracy of self-report measures. While these advantages have been attributed to functional MR imaging (fMRI) studies as well, they may be even more apparent with brain 1H MRS measures, which are not subject to the individual variability that is inherent to functional imaging under task-based conditions. As genetic research will continue to identify polymorphisms in a great variety of different genes that may contribute to a predisposition for AUD, related neurobehavioral disorders, and relapse, in vivo MRS, as part of the emerging field of “imaging genomics,” may provide readily accessible and objective neurobiological measures that successfully link genotypes to neurocognition and psychiatric symptomatology in relatively small patient cohorts. With total brain volume as well as white and gray matter volume being highly heritable (Winterer and Goldman, 2003), it is tempting to speculate that MRS-observable metabolites, which are thought to be associated with specific cell types and molecular processes and, thus, to underlie regional morphology, are also under some degree of genetic influence. 1H MRS is a noninvasive neuroimaging method that can assess neurochemistry by measuring concentrations of various endogenous compounds in well-circumscribed brain regions and functionally specific neural pathways in clinical and non-clinical populations. MR spectral abnormalities are easily identifiable in the presence of gross structural abnormalities such as tumors and stroke, where they contribute valuable information to the biochemical disposition of the affected brain tissue. Additionally, MR spectroscopy can identify significant and functionally relevant biochemical abnormalities that occur in the presence of subtle structural irregularities, as is often the case early in the course of many neuropsychiatric and substance use disorders. Finally, 1H MRS can provide highly localized information regarding the functional integrity of brain tissue comprising regions/circuits implicated in the manifestation and/or maintenance of symptoms associated with the disorder in question. In the case of AUD, the variability in the severity and chronicity of the disorder as well as the presence of comorbid conditions (e.g., mood disorders, chronic cigarette smoking, and other conditions tightly coupled to the “typical” individual with AUD and not necessarily leading to research study exclusion) may lead to considerable within-group variance. Thus, regional metabolite patterns and concentration levels we measure by 1H MRS in those afflicted with AUD are likely influenced by premorbid biological and comorbid medical, psychiatric, and substance use disorders. As many of these comorbidities are at least partially related to genetic factors, some of the brain metabolite (and neurocognitive) abnormalities we observe may indeed be pre-morbid in nature. Therefore, accounting for genetic variables can potentially increase our understanding of how genetic factors, such as single nucleotide polymorphisms (SNP) or family history of AUD (FHA), may relate to the individual variability observed in brain metabolite levels and the pattern of neurobiological and neurocognitive abnormalities found in AUD.