Prefrontal Cortex Volumes in Adolescents With Alcohol Use Disorders: Unique Gender Effects

In the United States, alcohol is the most widely consumed intoxicant among adolescents, with 75% of 12th graders having drank in their lifetime. More startling is that 30% of seniors reported getting drunk in the previous month (Johnston et al., 2005). Given the prevalence of alcohol use during adolescence, its effects on neuromaturation are of great interest. In adults, the prefrontal cortex (PFC) appears to be particularly vulnerable to the neurotoxic effects of alcohol use (Desmond et al., 2003; George et al., 2004; Pfefferbaum et al., 1997, 2001; Schweinsburg et al., 2001; Sullivan et al., 2003). Postmortem studies have found reduced glial and neuronal cell densities in the PFC of adults with alcohol use disorders (AUD) (Miguel-Hidalgo et al., 2006). Morphometric studies have revealed smaller PFC total volume (Kubota et al., 2001; Liu et al., 1998), gray matter (Chanraud et al., 2007; Liu et al., 1998; Pfefferbaum et al., 1997), and white matter volume (Kril et al., 1997; Pfefferbaum et al., 1997) among adults with AUD compared with controls. The more anterior portions of the PFC appear most vulnerable to alcohol-induced neurotoxic effects (Kril et al., 1997). Gender may moderate the effects of alcohol on PFC morphometry. It appears that women with AUD may be more sensitive to the neurotoxic effects of alcohol than men (Agartz et al., 1999; Hommer et al., 2001; Mann et al., 2005; Schweinsburg et al., 2003), although some studies have pointed to relative vulnerabilities in males (Pfefferbaum et al., 2001) and others found no evidence of brain abnormalities among alcoholic females (Kroft et al., 1991; Pfefferbaum et al., 2002). Because neuromaturation continues into late adolescence (Giedd et al., 1996a; Lenroot and Giedd, 2006; Sowell et al., 2004) studies based on adults cannot necessarily generalize to adolescents with AUD, particularly findings in the PFC, a late region to undergo gray matter pruning (Gogtay et al., 2004; Lenroot and Giedd, 2006; Sowell et al., 2004). Maturation of white matter appears to continue into the twenties, with white matter volume typically increasing (Giedd et al., 1999; Jernigan and Gamst, 2005; Paus et al., 2001) and PFC white matter integrity improving (Ashtari et al., 2007; Barnea-Goraly et al., 2005; Watts et al., 2003) from childhood to adulthood, although 1 study found decreased white matter density from ages 16 to 17 (Paus et al., 1999). Gender differences in neuromaturation also exist. Females' frontal gray matter volumes peaks at age 11.0 while males' peak at age 12.1 years on average, and male brains are about 9% larger than females' (Giedd et al., 1996b). Furthermore, in contrast with most prior studies of white matter neuromaturation (e.g., Giedd et al., 1999; Reiss et al., 1996), our laboratory found that among healthy adolescent females ages 12 to 18, PFC white matter volume actually decreased from age 15 to 18, while males' PFC white matter remained relatively stable (Nagel et al., 2006). Thus, as male and female brains mature with somewhat different time courses during adolescence, neurotoxic exposures may have disparate effects. Animal models indicate that adolescence is a period of particular vulnerability to the neurotoxic effects of alcohol (Barron et al., 2005; Carpenter-Hyland and Chandler, 2007; Crews et al., 2000; Spear, 2000). Compared with adults, adolescent animals exposed to alcohol are more likely to demonstrate cognitive, social, and neuronal damage (Crews et al., 2000; Little et al., 1996; Pyapali et al., 1999; Silveri and Spear, 1998; Swartzwelder et al., 1995, 1998; Varlinskaya and Spear, 2006; White et al., 2002; Yttri et al., 2004). Despite that many of these abnormalities are subserved by frontal systems, few studies have examined the PFC morphometric consequences of heavy alcohol use during adolescence in humans. Thus far, human adolescent studies examining the neural effects of heavy drinking have suggested alcohol-related structural (De Bellis et al., 2000, 2005; Medina et al., 2007a; Nagel et al., 2005), and functional (Tapert et al., 2004) abnormalities. Specifically, despite similar performance during a spatial working memory task, adolescents with AUD showed less PFC and cerebellar activation to complete the task with controls, with a greater degree of abnormality linked to lifetime alcohol withdrawal symptoms (Tapert et al., 2004). These results may indicate that the brain compensates for subtle alcohol-induced neuronal insult by relying on other areas (e.g., parietal cortex). A follow-up study revealed that gender moderated the relationship between alcohol use and brain response to this spatial working memory task (Caldwell et al., 2005). That is, after controlling for typical blood alcohol concentrations, girls with AUD demonstrated less frontal cortex response than female controls, while the males showed the opposite pattern. Overall, females demonstrated more alcohol-related abnormalities than males. The only study to date examining PFC morphometry (defined as anterior to the genu) in adolescents with AUD compared a treatment sample of 13- to 21-year olds with AUD and other Axis I disorders (including conduct, depressive, attention deficit hyperactivity, post-traumatic stress, generalized anxiety, bipolar, and cannabis and hallucinogen use disorders) to controls without a history of AUD (De Bellis et al., 2005). Even after controlling for comorbid disorders, males and females with AUD demonstrated smaller PFC total and white matter volumes than controls, although psychiatric contributions cannot entirely be ruled out, and gender-by-group interactions were not found. Therefore, no studies to date have examined PFC volume among adolescents with AUD without comorbid psychiatric disorders. As comorbid psychiatric and other premorbid risk factors for substance use disorders (e.g., familial AUD) are also linked to neurocognitive abnormalities (Kamarajan et al., 2006; Kim et al., 2001; Kruesi et al., 2004; Meyerhoff et al., 2004; Tapert and Brown, 2000), the current study sought to examine the relationship between AUD and PFC structure among adolescents without comorbid mood, attention, or anxiety disorders. Conduct disorder, which is highly prevalent among adolescents with AUD, was statistically controlled for, and family history of substance use disorders was equivalent between the groups. A secondary goal of the study was to examine whether gender moderated the relationship between alcohol use and PFC morphometry.