Purpose:
Objective: This protocol uses functional magnetic resonance imaging (fMRI) to examine
neuro-cognitive correlates of pediatric and adult mood and anxiety disorders. The primary
goal of the project is to document, in pediatric anxiety disorders and major depression,
perturbations in brain systems mediating attention biases, fear conditioning, emotional
memory, and response to various forms of motivational stimuli. As one secondary goal, the
project measures the relationship between these factors and treatment response to either
fluoxetine, a specific serotonin reuptake inhibitor (SSRI), cognitive behavioral therapy
(CBT), or interpersonal psychotherapy (IPT). Another secondary goal examines similar
associations in adults.
Study Population: A total of 2530 children, adolescents, and adults will be recruited. Most
subjects will not be able to complete all procedures. We seek to comprehensively study 150
juveniles with only a current anxiety disorder, 60 juveniles with current major depression,
150 juveniles with no psychiatric disorder, 100 adults with major depression, 60 adults with
an anxiety disorder, and 150 adults with no psychiatric disorder. To achieve this, we are
recruiting 2530 individuals.
Design: Subjects will be tested using fMRI paradigms designed to examine brain regions
engaged when processing motivationally salient stimuli, as assessed during attention, memory,
social interaction, reward, and fear-conditioning paradigms. After these initial fMRI tests,
subjects with depression or an anxiety disorder receive treatment. Treatment will comprise
open treatment with either fluoxetine or CBT, augmented with computer-based attention
retraining, delivered in a randomized-controlled design, with random assignment to either
active or placebo attentiontraining regimens. Adolescent subjects then will be re-tested
after eight-weeks using only the attention, memory, and conditioning paradigms.
Outcome Measures: Prior imaging studies note that tasks requiring attention modulation,
emotional memory, social interchange, and fear conditioning engage brain regions previously
implicated in adult mood and anxiety disorders. These regions include most consistently the
amygdala and ventral prefrontal cortex. Moreover, imaging studies of reward function
implicate the striatum and prefrontal cortex in adult mood disorders. As a result, we
hypothesize that attention, memory, social interaction, reward, and conditioning paradigms
will engage the amygdala, ventral prefrontal cortex and striatum in both psychiatrically
healthy and impaired subjects. Moreover, we hypothesize that these healthy and
psychiatrically impaired groups will differ in the degree of engagement.
Juvenile subjects also will be treated for eight-weeks, and a subset will be re-tested with
fMRI. We predict that pre-treatment abnormalities in neural circuitry will predict response
to treatment, such that increased amygdala and prefrontal activation will occur in
individuals who show the strongest response to treatment. Moreover, we hypothesize that
effective treatment will normalize abnormalities in attention and emotional memory, as
manifest in fMRI.
Study summary:
Objective: This protocol uses functional magnetic resonance imaging (fMRI) to examine
neuro-cognitive correlates of pediatric and adult mood and anxiety disorders. The primary
goal of the project is to document, in pediatric anxiety disorders and major depression,
perturbations in brain systems mediating attention biases, fear conditioning, emotional
memory, and response to various forms of motivational stimuli. As one secondary goal, the
project measures the relationship between these factors and treatment response to either
fluoxetine, a specific serotonin reuptake inhibitor (SSRI), cognitive behavioral therapy
(CBT), or interpersonal psychotherapy (IPT). Another secondary goal examines similar
associations in adults. Study Population: A total of 2530 children, adolescents, and adults
will be recruited. Most subjects will not be able to complete all procedures. We seek to
comprehensively study 150 juveniles with only a current anxiety disorder, 60 juveniles with
current major depression, 150 juveniles with no psychiatric disorder, 100 adults with major
depression, 60 adults with an anxiety disorder, and 150 adults with no psychiatric disorder.
To achieve this, we are recruiting 2530 individuals. Design: Subjects will be tested using
fMRI paradigms designed to examine brain regions engaged when processing motivationally
salient stimuli, as assessed during attention, memory, social interaction, reward, and
fear-conditioning paradigms. After these initial fMRI tests, subjects with depression or an
anxiety disorder receive treatment. Treatment will comprise open treatment with either
fluoxetine or CBT, augmented with computer-based attention retraining, delivered in a
randomized-controlled design, with random assignment to either active or placebo
attention-training regimens. Adolescent subjects then will be re-tested after eight-weeks
using only the attention, memory, and conditioning paradigms. Outcome Measures: Prior imaging
studies note that tasks requiring attention modulation, emotional memory, social interchange,
and fear conditioning engage brain regions previously implicated in adult mood and anxiety
disorders. These regions include most consistently the amygdala and ventral prefrontal
cortex. Moreover, imaging studies of reward function implicate the striatum and prefrontal
cortex in adult mood disorders. As a result, we hypothesize that attention, memory, social
interaction, reward, and conditioning paradigms will engage the amygdala, ventral prefrontal
cortex and striatum in both psychiatrically healthy and impaired subjects. Moreover, we
hypothesize that these healthy and psychiatrically impaired groups will differ in the degree
of engagement. Juvenile subjects also will be treated for eight-weeks, and a subset will be
re-tested with fMRI. We predict that pre-treatment abnormalities in neural circuitry will
predict response to treatment, such that increased amygdala and prefrontal activation will
occur in individuals who show the strongest response to treatment. Moreover, we hypothesize
that effective treatment will normalize abnormalities in attention and emotional memory, as
manifest in fMRI.
Criteria:
- INCLUSION CRITERIA:
- ALL JUVENILE SUBJECTS:
- Age: 8 - 17 (subjects who consent as 17- year-olds but turn 18 during the course
of the study will be eligible to complete all procedures completed by other
subjects who consent as 17- year- olds but do not turn 18).
- Consent: can give consent/assent (Parents will provide consent; minors will
provide assent)
- IQ: all subjects will have IQ > 70 (Assessment relies on WASI)
- Language: all subjects will speak English
- ALL ADULT SUBJECTS
- Age: 18-65
- Consent: can give consent
- IQ: all subjects will have IQ>70 (Assessment relies on WASI)
- Language: all subjects will speak English
- ALL SUBJECTS WITH AN ANXIETY DISORDER
- Diagnosis: Current Diagnosis of Social Phobia, Separation Anxiety, Generalized
Anxiety Disorder, or Panic Disorder (Based on K-SADS (juveniles) or SCID
(adults))
- Symptom Severity: Clinically significant, ongoing anxiety symptoms
- Clinical Impairment: Clinically significant, ongoing distress or impairment from
anxiety
- ALL SUBJECTS WITH A MOOD DISORDER
- Diagnosis: Current Diagnosis of Major Depression (Based on K-SADS (juveniles) or
SCID (adults))
- Clinical Impairment: Clinically significant, ongoing distress or impairment from
depressive symptoms
- Symptom Severity: Clinically significant, ongoing depressive symptoms
- ALL PREVIOUSLY ENROLLED ADOLESCENT PATIENTS, HEALTHY VOLUNTEERS, AND HEALTHY
VOLUNTEERS TURNED PATIENTS
- Diagnosis: Current Diagnosis of Social Phobia, Separation Anxiety, Generalized
Anxiety Disorder, or Panic Disorder; No current diagnosis (Based on K-SADS
(juveniles) or SCID (adults))
- Clinical Impairment (as applicable): Clinically significant, ongoing symptoms
(This will be documented by clinician review with patients and their families
during at least two visits with families.)
- Symptom Severity (as applicable): Clinically significant, ongoing symptoms (This
will be documented by clinician review with patients and their families during at
least two visits with families.)
EXCLUSION CRITERIA:
- ALL SUBJECTS
- Any serious medical condition or condition that interferes with fMRI scanning,
and for patients electing medication, any condition that increases risk of SSRI
treatment. (All patients will have complete physical examination and history.
Healthy volunteer participants will be medication- free and have no current
serious medical conditions, based on a review of their medical history.)
- Pregnancy
- Current use of any psychoactive substance; current suicidal ideation; current
diagnosis of attention deficit hyperactivity disorder (ADHD) of sufficient
severity to require pharmacotherapy.
- Current diagnoses Tourette s Disorder, OCD, post-traumatic distress disorder,
conduct disorder
- Past or current history of mania, psychosis, or severe pervasive developmental
disorder
- Recent use of an SSRI; all subjects must have been free of any SSRI-use for at
least one month (fluoxetine six months) and must not have been treated with an
SSRI for their current depressive episode.
- NIMH employees and staff and their immediate family members will be excluded from
the study per NIMH policy
- HEALTHY ADULT SUBJECTS
- Any current psychiatric diagnosis (Assessment relis on SCID)