Brain Changes in Children and Adolescents With Behavioral Problems

OBJECTIVE:

The goal of this protocol is to investigate the neuro-cognitive underpinnings of the
emotional dysfunction linked to childhood behavioral disturbance; in particular, Conduct
Disorder with elevated callous-unemotional (CU) traits (CD+CU), Conduct Disorder with non
elevated CU traits (CD-CU), but also ADHD. The functional hypotheses that we are testing with
both neuro-cognitive and neuro-imaging paradigms are that: (1) CD+CU, but not ADHD, is
associated with dysfunction in the formation and operational use of stimulus-punishment and,
to a lesser extent, stimulus-reward association information; (2) CD-CU is associated with
heightened threat sensitivity and impairment in executive systems involved in emotional
regulation; and (3) that ADHD and CD-CU, is associated with impairment in executive systems
related to the representation and execution of task demands.

STUDY POPULATION:

160 children with Conduct Disorder (CD) and high CU traits (the CD+CU group); 160 children
with CD and low CU traits (the CD-CU group); 160 children with ADHD; and 160 healthy
volunteer children. All children will be between the ages of 10 and 17. Both males and
females will be enrolled.

DESIGN:

The current study will have two phases: i) neuropsychological assessment and training in an
MRI simulator (up to 4 hours); ii) The MRI scanning session (up to 2 hours, no more than 90
minutes in scanner). Participants, if they are willing, may be invited to participate in more
than one scanning session (up to a maximum of 3 120 minute sessions) or neuro-cognitive
testing session.

OUTCOME MEASURES:

Behaviorally, we predict that children with CD+CU and children with CD-CU will present with
impairment on tasks that involve either the formation or operational use of particular
stimulus-punishment associations (e.g., the subjective value learning task and emotional
interrupt task). However, the nature of this impairment with be qualitatively different. For
example, we predict that youth with CD+CU will show reduced interference by emotional
distracters on the emotional interrupt task but that youth with CD-CU will show decreased
interference. In contrast, we predict that children with ADHD, but no CD, will show no
behavioral impairment on such tasks. However, we predict that children with ADHD and children
with CD-CU will present with impairments on executive function tasks (e.g., the Number Stroop
paradigm). In contrast, we predict that children with CD+CU will show no impairment on these
tasks. At the anatomical level, we anticipate reduced activation of emotional related systems
in children with CD+CU, but increased activation in children with CD-CU, during emotional
impact tasks (in particular, reduced activation of the amygdala, regions of orbitofrontal
cortex and anterior cingulate). We anticipate that the neural response of children with ADHD
during these tasks will be less anomalous. We anticipate that the neural response of children
with ADHD and children with CD-CU during the performance of response control tasks to be
anomalous (with considerable greater recruitment of anterior and posterior compensatory
systems).

- INCLUSION CRITERIA:

1. Individuals with CD + CU: Male and female subjects aged 8-18 who score equal to
or more than 20 on the APSD/PCL-YV. Children with antisocial behavioral problems
on medications with psychotropic effects will be considered if their target
behaviors persist despite the use of medications. In these children, only simple
stimulant medications will be held for 48 hours. These include methylphenidate,
amphetamine and their derivatives including Ritalin, Ritalin SR, Ritalin LA,
Methylin, Methlin ER, Metadate CD, Concerta, Dexedrine, Dextrostat, Dexedrine
Spansule, Adderall, Adderall XR, and Focalin. Medications like Strattera
(atomoxetine), bupropion (Wellbutrin), modafinil (Provigil), or valproic acid
(Depakote), or other mood stabilizers are not safe to stop suddenly and children
taking these medications will not be asked to stop them.

2. Individuals with CD-CU: Male and female subjects aged 8 -18 who score less than
20 on the APSD/PCL-YV. Children with antisocial behavioral problems on
medications with psychotopic effects will be considered if their target behaviors
persist despite the use of medications. In these children, only simple stimulant
medications will be held for 48 hours. These include methylphenidate, amphetamine
and their derivatives including Ritalin, Ritalin SR, Ritalin LA, Methylin,
Methlin ER, Metadate-CD, Concerta, Dexedrine, Dextrostat, Dexedrine Spansule,
Adderall, Adderall XR, and Focalin Medications like Starattera (atomoxetine),
bupropion (Wellbutrin), modafinil (Provigil), or valproic acid (Depakote), or
other mood stabilizers are not safe to stop suddenly and children taking these
medications will not be asked to stop them.

3. Individuals with ADHD: Male and female subjects aged 8-18 who currently meet
DSM-IV criteria for ADHD. The diagnosis will be made on the basis of a K-SADS-PL
interview with the parent and a t score >65 on the hyperactivity-impulsivity
subscale of the Connors Teacher Scale. Participants in this group will have APSD
scores <20.

4. Comparison individuals: Male and female subjects aged 8-18 who are free from any
current or past psychopathology (all will score less than 20 on the APSD/PCL-YV).

EXCLUSION CRITERIA:

1. I.Q.< 75.

2. Ongoing medical illness other than those listed in the inclusion criteria for the
respective groups that require use of any medication that may have psychotropic
effects. For example, a patient with history of mild asthma that did not require
medication may be included, however a patient with asthma requiring use of beta
blockers, steroids, etc. would not be included. For children with ADHD or healthy
volunteer children, a contraindication to discontinuing medication for 48 hours. Only
simple stimulant medications will be held for 48 hours. These include methylphenidate,
amphetamine and their derivative including Ritalin, Ritalin SR, Ritalin LA, Methylin,
Methlin ER, Metadate CD, Concerta, Dexedrine, Dextrostat, Dexedrine Spansule,
Adderall, Adderall XR, and Focalin. Medications like Strattera (atomoxetine),
bupropion (Wellbutrin), or modafinil (Provigil) are not safe to stop suddenly and
children with ADHD taking these medications will not be included.

3. Subjects with psychopathic tendencies who receive a diagnosis of an anxiety or mood
disorder as determined by a clinical and K-SAD review conducted by a psychiatrist will
be excluded. Additionally, children with active psychosis, pervasive developmental
disorders or Tourette s syndrome will be excluded.

4. Children with CD-CU will be evaluated through the KSAD and clinical review by a
psychiatrist. Explicit exclusions include active psychosis, Pervasive Developmental
Disorders and Tourette s syndrome. Children with anxiety disorders will be included
given the high comorbidity of CD-CU and anxiety disorders.

5. Individuals with ADHD will be evaluated through the KSAD and clinical review by a
psychiatrist. Those children who receive diagnosis of mood disorders through this
evaluation process will be excluded. Additional explicit exclusions include active
psychosis, Pervasive Developmental Disorders and Tourette s syndrome. Children with
anxiety disorders will be included given the high comorbidity of ADHD and anxiety
disorders.

6. Any other psychiatric disorder that is sufficiently severe to require specific
treatment, with the exception of those listed in the inclusion criteria for the
respective groups.

7. Neurologic disorder (including seizures).

8. Any metallic objects in the body. Metal plates, certain types of dental braces,
cardiac pacemakers, etc., that are sensitive to electromagnetic fields contraindicate
MRI scans.

9. Claustrophobia: participants will be questioned about potential discomfort in being in
an enclosed space, such as an MRI scanner.