Prefrontal Cortex, Thalamus, and Cerebellar Volumes in ...

BRAIN VOLUMES IN YOUTHS 1597
use disorders. Impulsivity is thought to be closely associated
with PFC development during adolescence (Spear, 2000).
Increased impulsivity, which may contribute to early-onset
drinking, is seen in subjects with frontal lobe excisions
(Miller, 1992). Alcoholism has been conceptualized as a
frontal lobe condition (Moselhy et al., 2001). Neuroimaging
studies across modalities have demonstrated the PFC to be
involved in intoxication, craving, and withdrawal with respect
to alcohol and other drugs (Goldstein and Volkow,
2002). In a review of the literature on impulsivity and
addiction in adolescence, Chambers et al. (2003) concluded
that substance use disorders constitute neurodevelopmental
disorders and suggested that the common neurobiological
mechanisms involving PFC motivational brain circuitry
could be substrates for both normative impulsivity and
addictive behavior among adolescents. In our study, PFC
volume variables adjusted for cerebral volumes significantly
correlated with the most number of drinks per maximum
drinking episode, a measure of disinhibition and impulsivity.
High-risk studies with subjects with family histories of
substance use disorders support this idea. Young subjects,
who are offspring of fathers with alcoholism and are at high
familial risk for AUD perform poorly on measures of executive
cognitive function (Giancola et al., 1996; Harden
and Pihl, 1995; Hill, 2004). Individuals at high relative risk
for substance use disorders demonstrated impulsive problems
including conduct disorders (Clark et al., 1998), antisocial
behaviors (Clark et al., 1999), and neurobehavioral
disinhibition (Tarter et al., 2003) in late childhood. Deficits
in PFC-mediated executive functions of decision-making,
sustained attention, verbal fluency abstraction, behavioral
inhibition, working memory, regulation of motivation, and
motor control are seen in ADHD (Barkley, 1997; Ernst et
al., 2003; Pineda et al., 1998), conduct disorder (Dery et al.,
1999; Morgan and Lilienfeld, 2000), major depression
(Rogers et al., 2004), and posttraumatic stress disorder
(Beers and De Bellis, 2002), the most common comorbid
disorders in our AUD subjects. Imaging studies also suggest
PFC abnormalities in all these heterogeneous mental
disorders (De Bellis et al., 2000b; Nolan et al., 2002; Schulz
et al., 2004; Sowell et al., 2003b; Spalletta et al., 2001).
Similar results have been attained in community adolescents,
where neurocognitive deficits in measures of attention
ability predicted substance use disorders 8 years later
(Tapert et al., 2002a). Thus, these childhood psychopathologies
may lead to early substance use disorders and
substance-related problems in adolescence, due to preexisting
PFC vulnerability. Thus, unlike our previous findings
in this sample, where we reported that the adolescent
hippocampus may be more vulnerable to the toxic effects of
an adolescent-onset AUD than an adult with similar years
of drinking (De Bellis et al., 2000a) because hippocampal
volumes correlated positively with the age of onset and
negatively with the duration of an AUD, the findings of
smaller PFC did not correlate with age of onset or duration
of an AUD. This leads to the speculation that delayed PFC
maturation (less myelination of the PFC) may be an inherent
vulnerability that enhances the risk for poorer executive
cognitive functioning and an adolescent-onset AUD.
In this particular study, the negative overall cerebellum
findings in adolescents with an AUD are in contrast with
adult findings (Parks et al., 2002). This may be because of
a longer period of exposure to alcohol consumption is
required to cause alterations in the cerebellum or because
of adolescent cerebellar plasticity (Hansel et al., 2001).
However, we note that there was a significant sex-by-group
effect for males with an adolescent-onset AUD to have
smaller cerebellar volumes than control males. It should be
noted that six of the eight AUD males also had comorbid
ADHD, combined type. Alteration in the frontal-striatal
circuitry underlies the psychopathology of ADHD and
probably causes the related deficits of higher cognitive
functions in these individuals (Berquin et al., 1998; Castellanos
et al., 1996). ADHD boys have a smaller cerebellar
vermis compared with healthy control boys (Berquin et al.,
1998; Castellanos et al., 1996), and in most studies, the
difference is limited to the inferior posterior vermis of the
cerebellum (Castellanos et al., 1996; Mostofsky et al.,
1998). The difference in cerebellar volume in boys with
ADHD has been replicated in girls with similar symptom
severity (Castellanos et al., 2001). A longitudinal study
found that both smaller cerebral and cerebellar volumes in
subjects with ADHD persisted over time and were unrelated
to stimulant treatment (Castellanos et al., 2002).
Overall, recent studies suggest a possible modulating cerebellar
influence on the predominantly right frontal-striatal
circuits involved in ADHD (Giedd et al., 2001). Since
premorbid ADHD is a risk factor for substance use disorders
in adolescent and young adults (Biederman et al.,
1997; Clark et al., 1999), any possible relation between
AUD and other comorbid conditions should be considered
when evaluating structural MRI findings in individuals with
AUD. Our study is limited by the fact that our adolescent
AUD group had extensive comorbidity with other Axis I
disorders. It should be noted that it is rare for an adolescent
with alcohol abuse or dependence not to have another
mental disorder (Clark et al., 1997). Imaging studies of
adult and adolescent AUD are only beginning to address
the issues of comorbidity by examining adults with early
and late onset alcohol dependence. However, studies of
very large samples are needed to examine these issues.
Given that most MRI studies of adults with an AUD do not
examine histories of childhood-onset mental disorders
(ADHD, major depression) in their samples, this is an
important and overlooked research issue that may have
influenced the known brain structural findings in the adult
AUD literature.
In summary, unlike in the mature brain, in which chronic
AUD is characterized by a continuum of graded brain
dysmorphology, our preliminary findings suggest that structural
deficits in the adolescent PFC are associated with an
adolescent-onset AUD in individuals with comorbid mental