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

1592 DE BELLIS ET AL.
Clinical Evaluation
Substance use disorder diagnoses were determined using a modified
form of the Structured Clinical Interview for the DSM-IV (Martin et al.,
2000). Information was gathered by direct interviews because family informants
typically underreport alcohol and drug involvement (Kosten et
al., 1992). For each symptom, ages of onset were recorded to the nearest
month. The interviewers had Masters-level education in mental healthrelated
fields and were individually trained to obtain greater than 90%
agreement with an experienced interviewer. Interrater reliabilities were
high for individual DSM-IV symptoms (� � 0.84 to 1.0) and for AUD
diagnoses (� � 0.94) (Martin et al., 2000). Other Axis I mental disorders
were assessed using a modified version of the Schedule for Affective
Disorders and Schizophrenia for School-Age, Present Episode (K-
SADS-P) (Chambers et al., 1985) and Lifetime Version (K-SADS-E)
(Orvaschel and Puig–Antich, 1987) interview, with both adolescent and
parent(s) as informants. An expanded assessment of posttraumatic stress
disorder (PTSD) was completed as part of the K-SADS Present and
Lifetime Version (Kaufman et al., 1997). Consensus diagnoses were
reached among the interviewer, the assessment coordinator, and a clinically
experienced faculty psychiatrist or psychologist using the best estimate
method (Clark, 1999; Kosten and Rounsaville, 1992), in which a date
of onset, defined as the time at which diagnostic criteria were first met, is
determined for each disorder (Clark et al., 2001). The Lifetime History of
Alcohol Use Interview (Skinner, 1982) was used to collect supplemental
information on alcohol and other abused substances, including the average
quantity and frequency of use and the maximum frequency and
quantity of use for alcohol and seven other drug classes (stimulates
[caffeine, nicotine], sedatives [barbiturates], opioids [heroin, morphine,
codeine], hypnotics [Valium], hallucinogens/PCP, cannabis [marijuana],
inhalants) for each year of a subject’s life. The Alcohol Consumption
Questionnaire (ACQ), which was based on survey instruments that Cahalan
(1981) developed, was used to measure the quantity and frequency
of alcohol consumption in the past year (Cahalan, 1981). The ACQ is a
self-report inventory designed to categorize the average frequency, average
quantity, maximum quantity, frequency of maximum quantity, and
type of alcohol used in the past 12 months to form a yearly alcohol
quantity/frequency grouping (Table 1). The quantity and frequency of
alcohol consumption and other alcohol consumption variables were measured
by a questionnaire using face valid items found to have acceptable
psychometric properties in other studies (Grant et al., 1995; Hasin and
Carpenter, 1998). Quantity variables were based on 0.6-oz. (17-g) ethanol
“standard drinks” (one 12-oz. [340-g] beer, one 5-oz. [142-g] glass of table
wine [12% alcohol by volume], or one 1.5 oz. [42.5 g] of 80-proof hard
liquor), and the frequency variables were calculated as number of occasions
per month.
The alcohol use disorder group consisted of nine with lifetime alcohol
dependence (five males, four females) and five with lifetime alcohol abuse
(three males, two females). AUD subjects were recruited from treatment
programs in the Pittsburgh Area. Comorbidity is common in adolescent
AUD; other studies have shown that a substantial percentage of adolescents
with AUD are comorbid with other substance use disorders (particularly
cannabis), conduct disorder, attention deficient hyperactivity disorder,
mood disorders, and posttraumatic stress disorder (Clark et al., 1997).
In our sample, subjects had a mean of 4.1 � 2.4 and range of 2 to 9 lifetime
Axis I disorders. Comorbidity included the following: other substance
abuse or dependence (cannabis [n � 11], eight males, three females) or
hallucinogens (n � 2, males), major depressive disorder (n � 10; five
males, five females), conduct disorder (n � 8; six males, two females),
posttraumatic stress disorder (n � 7; five males, two females), attentiondeficit
hyperactivity disorder (n � 7; six males, one female), oppositional
defiant disorder (n � 2; two males), generalized anxiety disorder (n � 2;
two females), and bipolar disorder (n � 1, male). It should be noted that
there was overlap in that all AUD subjects with ADHD had conduct
disorder or oppositional defiant disorder, that all AUD subjects with
PTSD except one had major depression, and all AUD subjects with major
depression had a cannabis use disorder except three. The age of onset for
Table 2. Clinical characteristics of adolescents and young adults with an
adolescent-onset AUD
AUD AUD males
(n � 8)
AUD females
(n � 6)
Alcohol abuseAlcohol
dependence
59 35 24
Number of co-morbid
axis I disorders
4.1 � 2.4 4.6 � 1.8 3.3 � 3.0
Number with CUD 11 8 3
Hallucinogen abuse 2 2 0
Number with MDD 10 5 5
Number with PTSD 7 5 2
Number with ADHD 7 6 1
Number with CD 8 6 2
Number with ODD 2 2 0
Number with GAD 2 0 2
Number with bipolar disorder 1 1 0
CUD, Cannabis use disorder; MDD, major depressive disorder; PTSD, posttraumatic
stress disorder; ADHD, attention deficit hyperactivity disorder; CD,
conduct disorder; ODD, oppositional defiant disorder; GAD, generalized anxiety
disorder.
an alcohol use disorder was 15.6 � 2.4 years. Although the mean age of
onset for the 11 subjects with cannabis use disorder was 15.0 � 2.2 years,
for nine of these subjects the alcohol use disorder diagnosis preceded their
cannabis use disorder. Some comorbid disorders preceded (ADHD) or
co-occurred with the AUD (major depression, conduct disorder, bipolar
disorder). See Table 2. Brain structural (cerebral, amygdala, hippocampal,
lateral ventricle) volumes and corpus callosum areas for 12 of the 14
subjects with alcohol use disorder and 24 of the 28 healthy comparison
subjects were previously reported (De Bellis et al., 2000a).
Subjects were excluded from the study if the following were found: 1)
AUD subjects were admitted to the University of Pittsburgh Medical
Center’s General Clinical Research Center to ensure that they did not use
drugs or alcohol before the MRI scan. Thus, AUD subjects were excluded
from the study if the following were found: the use of drugs during the two
weeks before the MR scan (confirmed by a negative urine drug screen 12
hours before the MRI scan), and the use of alcohol within 12 hours of the
MRI scan (confirmed by a negative alcohol breathalyzer test); 2) presence
of a significant medical or neurological illness; 3) gross obesity (weight
greater than 150% of ideal body weight) or growth failure (height under
third percentile); 4) full-scale intelligence below 80, as estimated by the
short form of the Wechsler Intelligence Scale for Children, Third Edition,
or the Wechsler Adult Intelligence Scale, Third Edition; 5) pregnancy; and
6) insufficient English skills for consenting to the protocol. This protocol
was approved by the University of Pittsburgh Institutional Review Board.
Subjects or their parent(s) or legal guardian(s) gave written informed
consent. Adolescents under age 14 years assented before participating in
this protocol. Adolescents 14 years of age and older gave written informed
consent along with the written informed consent of their parent or legal
guardian. Subjects aged 18 years or older gave written informed consent.
Thus, no subject was consented to participate independently of a parent or
legal guardian. Subjects received monetary compensation for participation.
MRI Acquisition
All volumetric MRI scans were performed with the use of a GE
1.5-Tesla Unit (Signa System, General Electric Medical Systems, Milwaukee,
WI) running version 5.4 software located at the University of Pittsburgh
Medical Center (UPMC) MR Research Center. The subject’s head
was aligned in a head holder with foam padding, using soft towels and chin
and forehead straps to minimize head movement. The subject’s nose was
positioned at the 12 o’clock position for alignment, and a gradient echo
localizing axial slice verified this plane. A sagittal series (using TE � 18
msec, TR � 400 msec, flip angle � 90 degrees, acquisition matrix � 256
� 192, NEX � 1, FOV � 20 cm, slices � 21) verified patient position,