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

1596 DE BELLIS ET AL.
Fig. 3. PFC volumes (cm 3 ) adjusted for cerebral volume of adolescents and
young adults with an adolescent-onset AUD and comparison subjects. Female
subjects are shown in circles. Male subjects are shown in squares. Subjects in
blue indicate history of major depression; open circles or squares indicate history
of ADHD.
Fig. 4. Correlation between PFC gray matter volume (cm 3 ) adjusted for cerebral
volume of adolescents and young adults with an adolescent-onset AUD with
the most number of drinks per maximum drinking episode (r s � -0.78, df � 12,
p � 0.0009). Female subjects are shown in circles. Male subjects are shown in
squares. Subjects in blue indicate history of major depression; open circles or
squares indicate history of ADHD.
ebellar vermis volumes did not differ between groups.
There was a significant sex-by-group effect for males with
an adolescent-onset AUD to have smaller cerebellar volumes
than control males. To our knowledge, this is the first
study to examine the association of an adolescent-onset
AUD on the prefrontal, thalamic, and cerebellar morphology
of adolescents and young adults.
There are several possible explanations for the smaller
PFC volumes and PFC white matter volumes found in
adolescents and young adults with adolescent-onset AUD.
Since the PFC is maturing during adolescence, PFC maturation
may be impeded by the neurotoxic effects of alcohol,
despite the significantly different drinking patterns seen in
adolescents, who tend to binge drink relative to adults, who
are more likely to drink daily. Alcohol affects N-methyl-D-
aspartate (NMDA) receptors, a subclass of glutamate receptors
in the PFC that are maturing during adolescence
(Breese et al., 1995; Lovinger, 1993). Alcohol withdrawal
leads to increased excitatory transmission through its effects
on NMDA receptors. This process can result in discrete
excitotoxic neuronal damage or a more severe and
complicated alcohol withdrawal syndrome including withdrawal
seizures (Becker, 1999). Binging, or chronic intermittent
alcohol exposure, may be more neurotoxic to adolescent
neurons secondary to many brief episodes of
withdrawal (Lundqvist et al., 1995; Lundqvist et al., 1994).
However, only two of our AUD subjects had symptoms of
withdrawal. Adolescence is a period of active myelination
in PFC regions (Paus et al., 2001). Alcoholism is also
associated with white matter loss (Harding et al., 1997).
Although the findings of smaller PFC volumes did not
correlate with age of onset or duration of an AUD, significant
negative correlations were seen between PFC and
PFC gray matter volume measures with alcohol consumption
variables. Thus, we may speculate that the smaller PFC
volumes may be a result of the adverse effects of an AUD
on the adolescent PFC either through a direct or indirect
(via withdrawal) toxic effects on adolescent PFC development.
Another explanation for the smaller PFC and PFC
white matter volumes may be that PFC maturation is
impeded by the neurotoxic effects of other illicit substances
on the adolescent brain. Eleven of the 14 subjects
in this study also had cannabis abuse or dependence. The
active component of the marijuana plant, cannabis sativa, is
9-tetrahydrocannabinol, which affects growth factor gene
expression in the adult rat forebrain (Mailleux et al., 1994).
Preclinical data suggest that cannabinoids modulate the
release of neurotransmitters (i.e., L-glutamate, GABA, noradrenaline,
dopamine, serotonin, and acetylcholine) from
axon terminals (Iversen, 2003). Although GABA functions
primarily as an inhibitory neurotransmitter, it can also act
as a trophic factor during nervous system development to
influence events such as proliferation, migration, differentiation,
synapse maturation, and cell death (Owens and
Kriegstein, 2002). Thus, cannabis use disorder through its
effects on GABA and other neurotransmitters may negatively
influence adolescent brain development. Although
multivariate regression analysis examining the results controlling
for the presence of a cannabis use disorder as well
as comorbidity also suggested smaller PFC and smaller
PFC gray and white matter volumes in the AUD subjects
compared with control subjects, because no adolescentonset
AUD subject had an alcohol use disorder only, it is
not impossible to conclude that an adolescent-onset AUD
is toxic to PFC maturation.
A third explanation for the smaller PFC and PFC white
matter volumes of adolescents and young adults with an
adolescent-onset AUD is an inherent vulnerability for delayed
PFC maturation that enhances the risk for poorer
executive cognitive functioning and adolescent substance