Changes in neuropsychological functioning over 10 years following adolescent substance abuse treatment.

Alcohol and other drug (AOD) involvement often begins in adolescence, and some teens develop alcohol use disorders that may require professional treatment (Clark, Buckstein, & Cornelius, 2002; Rohde, Lewinsohn, & Seeley, 1996). Previously, Anderson, Ramo, Cummins, and Brown (2010) described six distinct patterns of AOD use during the decade following adolescent treatment for alcohol and other substance use disorders (A/SUD): (1) Abstainers/Infrequent Users, (2) Late Adolescent Resurgence, (3) Emerging Adulthood Resurgence, (4) Frequent Drinkers, (5) Frequent Drinkers/Drug Dependent, and (6) Chronic. This 10-year time period represents a phase of transition into young adulthood (Aseltine & Gore, 2005; Brown et al., 2008; Chassin, Flora, & King, 2004; Kypri, McCarthy, Coe, & Brown, 2004). Anderson et al. (2010) found that long-term AOD use appears to negatively influence educational attainment, occupational and socioeconomic status, and marriage/cohabitation relationships during young adulthood. In addition to the direct impact of AOD use on social and occupational functioning, heavy use may also indirectly affect these outcomes via neurocognitive damage. AOD use tends to peak during a time of ongoing brain development, with normative neuromaturation processes continuing throughout adolescence and into early adulthood (Gogtay et al., 2004; Gogtay & Thompson, 2010). The prefrontal cortex (primarily involved in executive functions and inhibiting impulses) and lateral temporal lobes (responsible for integrating memory, audiovisual information, and object recognition) appear to be the last cortical structures to mature (Gogtay et al., 2004; Jernigan & Gamst, 2005). Neuromaturation in certain brain areas (e.g., the corpus callosum) has been associated with improved neuropsychological abilities in healthy adolescents (Fryer et al., 2008), thus linking brain development to improved cognition. The potential influence of substance use on the brain during neurodevelopment is concerning. In older adults, heavy alcohol use appears to impact several brain regions including the hippocampus (Jernigan et al., 1991; Sullivan, Marsh, Mathalon, Lim, & Pfefferbaum, 1995), which is responsible for learning and remembering new information (Eichenbaum, 1999; Foster et al., 1999; Squire, 1992). Rodent studies suggest that the hippocampus and frontal lobes are vulnerable to heavy alcohol (White & Swartzwelder, 2004) and cannabinoid intake (Hampson & Deadwyler, 2000), and that the juvenile brain is particularly sensitive to ethanol binge-induced brain damage relative to the adult brain (Crews, Braun, Hoplight, Switzer, & Knapp, 2000). Studies of heavy alcohol-use by human teens have reported smaller hippocampal volumes relative to controls (De Bellis et al., 2000; Medina, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007; Nagel, Schweinsburg, Phan, & Tapert, 2005). Other studies have suggested smaller prefrontal white matter volumes in adolescents with AUDs compared to controls (De Bellis et al., 2005; Medina et al., 2008), and adolescent marijuana use has been associated with abnormal cerebellar volumes (Medina, Nagel, & Tapert, 2010). These and other differences in structural brain integrity may relate to brain functioning. Adolescent heavy drinkers have demonstrated different brain activation patterns during spatial working memory (Tapert et al., 2004) and verbal encoding (Schweinsburg, McQueeny, Nagel, Eyler, & Tapert, 2010) on functional magnetic resonance imaging tasks relative to non-using controls, especially in fronto-cerebellar, occipital, and hippocampal regions. Neuropsychological studies of adolescents with A/SUD have also reported deficits in verbal and non-verbal memory (Brown, Tapert, Granholm, & Delis, 2000), language (Moss, Kirisci, Gordon, & Tarter, 1994), executive functioning (Giancola, Mezzich, & Tarter, 1998; Moss et al., 1994), processing speed (Medina, Hanson et al., 2007), IQ, and attention (Tarter, Mezzich, Hsieh, & Parks, 1995). Previously, our group found that in addition to short-term neurocognitive deficits (Brown et al., 2000), youth treated for A/SUD during adolescence developed deficits in visuospatial functioning, attention, and visuospatial construction over the decade following treatment (Hanson, Medina, Padula, Tapert, & Brown, in press; Tapert & Brown, 1999; Tapert, Granholm, Leedy, & Brown, 2002). These previous reports compared baseline functioning during treatment (3 weeks of abstinence) to performance at the various endpoints (4, 8, and 10 years). However, substance involvement varies markedly from mid-adolescence to mid-twenties, and the substance use trajectories identified in Anderson et al. (2010) provide a unique means to examine the concomitant changes in cognition in relation to the fluctuations in substance involvement during this developmental period. Given the salient increases in frequency and intensity of alcohol use during late adolescence and young adulthood (Grant & Dawson, 1997), and recent findings that some youth with SUD appear to only use alcohol in adulthood (Anderson et al., 2010), it is important to consider whether continued use of alcohol alone during this developmental period may be detrimental to neurocognitive functioning. Historically among youth with polysubstance involvement, neurocognitive functioning has been examined in relation to combined use of alcohol and all other drugs. However, the impact of use of multiple substances appears to vary. In general, use of multiple substances is associated with poorer neurocognitive performance. However, in one study, adults who abused alcohol (but not other substances) demonstrated poorer cognitive efficiency than those who abused both alcohol and marijuana (Nixon, Paul, & Phillips, 1998). Similarly, healthy non-abusing teens showed a decrease in verbal memory with the onset of drinking and accumulation of alcohol withdrawal symptoms, yet those who used both marijuana and alcohol appeared unaffected by withdrawal episodes (Mahmood, Jacobus, Bava, Scarlett, & Tapert, 2010). This is consistent with a potential “protective effect” of joint alcohol and marijuana use on hippocampal volumes (Medina, Schweinsburg et al., 2007) and white matter integrity (Jacobus et al., 2009) identified in recent imaging studies. These results suggest that the effects of alcohol alone may differ from the concomitant use of alcohol and other drugs on the brain and cognition. As noted above, withdrawal experience cumulatively provokes cognitive impairment. In mice, repeated alcohol withdrawal episodes appear to negatively affect spatial learning (Freund, 1970). Alcohol-related seizures in human adult alcoholics were associated with smaller temporal lobe white matter volumes (Sullivan, Marsh, Mathalon, Lim, & Pfefferbaum, 1996), and a greater number of alcohol withdrawal episodes was linked with poorer verbal and visual memory (Glenn, Parsons, Sinha, & Stevens, 1988). Among adolescents, more alcohol and drug withdrawal symptoms have been associated with poorer visuospatial function, executive function, attention, and verbal learning and memory (Brown et al., 2000; Hanson et al., in press; Tapert & Brown, 1999; Tapert et al., 2002). Withdrawal and hangover symptoms have also significantly predicted: 1) brain activation during a spatial working memory task in adolescents with AUD (Tapert et al., 2004), 2) decreased white matter integrity among adolescent binge drinkers with no AUD history (McQueeny et al., 2009), and 3) deteriorating attentional skills in boys who initiate heavy drinking (Squeglia, Spadoni, Infante, Myers, & Tapert, 2009). Together, these relationships suggest that withdrawal symptoms may reflect distinct negative effects on brain function and appear to particularly impact memory. The primary goal of this investigation was to identify long-term (ten year) patterns of neuropsychological functioning in relation to the dominant trajectories of AOD use for youth with alcohol and drug use disorder histories during this decade of study. Healthy controls with no A/SUD history were also included for comparison. Based on previous findings, we had three primary hypotheses: We first hypothesized that greater exposure to substances and more persistence of AOD use would be linked to poorer memory, visuospatial skills, attention, and executive functioning during the critical period of development from adolescence to young adulthood. In particular, we expected that cognitive skills would be most impacted during periods of heaviest use but also that adverse cumulative effects would be evident among youth and young adults with the most persistent AOD involvement trajectories. Likewise, we presumed that clinical youth who abstained from substance use over the 10-year follow-up period (Abstainers/Infrequent Users) would perform similarly to community controls without histories of problematic AOD use. Second, we hypothesized that neuropsychological deficits (especially memory) would be associated with heavy use of alcohol (the primary substance used during this period) even when other drugs are not commonly used. Third, we postulated that poorer neurocognitive functioning over the decade that is associated with AOD involvement is more a function of the physiological impact of the substances (as measured by withdrawal symptoms) than dependence symptoms per se (which reflect functional life problems associated with substance use).