Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites.

Long-term chronic alcohol consumption is associated with regional structural and metabolite brain damage, as determined by human neuroimaging studies (e.g., Rosenbloom et al., 1995; Sullivan, 2000). This conclusion has been drawn from studies typically performed in short-term sober alcoholics recruited from substance abuse treatment programs. These treatment-seeking individuals represent only a small fraction of the approximately 9% of American adults who exhibit an alcohol use disorder at some time during their lives (Grant, 1994a,b; Harwood et al., 1994) but never undergo alcoholism treatment. Socially functioning heavy drinkers (HD) often do not recognize that their level of drinking constitutes a problem that warrants treatment. It is unknown to what extent such active HD display structural or metabolic brain damage, whether the spatial pattern of potential damage is similar to that described in sober recovering alcoholics, and to what extent such damage is associated with cognitive deficits that may interfere with daily routines. On the basis of the available literature and epidemiological data, we previously hypothesized (Fein et al., 2002) that alcohol-dependent subjects who seek treatment have more comorbid conditions—including substance abuse, affective symptoms, and other psychopathology—than the socially functioning HD population. Therefore, it cannot be assumed that the brain damage described in alcohol-dependent treatment samples appropriately reflects the type, extent, and magnitude of brain damage possibly present in community samples of socially functioning drinkers. Genetic factors, including a family history of alcoholism (FHA), may play a role in the vulnerability to, and severity of, alcohol-induced brain damage (McGue, 1994). Also, the pattern of heavy drinking, i.e., binge alcohol drinking as opposed to continual heavy drinking, may be a significant and specific contributor to brain damage in chronic alcoholics (Agartz et al., 1999; Crews, 1999; Crews et al., 2000; Fadda and Rossetti, 1998; Hunt, 1993a). Therefore, we examined the effects of FHA and drinking pattern on brain damage. Proton magnetic resonance spectroscopy imaging (1H MRSI) studies of abstinent alcoholics in treatment show alterations of brain metabolites primarily in the frontal lobes, cerebellum, and thalami—mostly brain regions that also show tissue loss at neuroimaging and pathologic changes at autopsy (Sullivan, 2000). These metabolite alterations are consistent with regional neuronal/axonal damage [inferred from N-acetylaspartate (NAA) concentrations] and with changes in glial and general cell membrane metabolism [inferred from myoinositol (mI) measures]. Recently, we showed in a preliminary study that NAA concentrations are indeed low in the frontal WM of active HD (Goldmann et al., 2000); this prompted us to investigate metabolite levels throughout the brains of these individuals by using multislice 1H MRSI. Our primary hypothesis was that in HD compared with light drinkers (LD), NAA is lower and mI is higher in those brain regions that are also affected in recovering alcoholics, i.e., the frontal lobes, cerebellum, and thalamus. A secondary aim was to determine the extent to which the density of FHA affects chronic alcohol-induced brain metabolite changes. Then, we hypothesized that a predominant pattern of binge drinking is associated with greater NAA loss and higher mI than continual heavy drinking. Finally, we assessed the clinical relevance of metabolite alterations by correlation with cognitive test performance and electrophysiological characteristics, knowing that recently abstinent alcoholics have impaired executive or frontal lobe functions (Fein et al., 1990; Oscar-Berman, 2000; Parsons and Nixon, 1993; Ratti et al., 1999) and that heavy social drinkers have been hypothesized to have at least mild cognitive deficits (Parsons and Nixon, 1998). Specifically, we hypothesized that lower frontal lobe NAA in HD is associated with lower executive functioning and working memory and with smaller P3a amplitude, as well as prolonged latency of P3 event-related potentials.