Brain Response Associated With Parent-based Treatment for Childhood Anxiety Disorders

Specific Aims: Anxiety disorders impact up to one-third of children, cause tremendous
suffering, increase risk for psychiatric and medical morbidity, impair school and social
functioning, and cost billions of dollars each year. Data consistently show that child
anxiety is characterized by amygdala hyperactivity and deficits in prefrontal control of the
amygdala. Emerging data link these disruptions to anxious children's over-reliance on parents
for amygdala-medial prefrontal cortex (mPFC) engagement and anxiety reduction.

In the first phase of this study we aim to demonstrate that an entirely parent-based
psychosocial treatment with no child involvement, Supportive Parenting for Anxious Childhood
Emotions (SPACE), engages an amygdala-mPFC target in anxious children, lessening child
reliance on parents to reduce amygdala reactivity.

Cross-species neurobiological evidence indicates that parental presence reduces amygdala
reactivity and activates the mPFC to reduce offspring anxiety. In humans we recently
demonstrated parental presence increases functional connectivity between their child's mPFC
and amygdala, reducing the child's amygdala reactivity and anxiety. In a healthy sample,
parental engagement of child amygdala-mPFC connectivity was linked to the child's reliance on
parents for help with anxiety. Data from clinically anxious children likewise show parental
presence engages child mPFC, and data we collected since our previous submission demonstrate
that parental presence reduces amygdala reactivity in clinically anxious children.

Offspring's natural reliance on parents for anxiety reduction is magnified in clinically
anxious children. Parents become deeply enmeshed in their child's symptoms through the
process of family accommodation, defined as change in parents' behavior to help the child
avoid or alleviate anxiety. In clinically anxious children, 90% report depending on parents
to reduce their anxiety, and 97% of parents report accommodating their anxious child's
symptoms. These cross-generational patterns of parental entanglement in their child's anxiety
symptoms contribute to the immense burden, distress, and costs of pediatric anxiety (e.g.,
parents missing work to be with their anxious child). Anxious children's reliance on parents
for anxiety reduction may disrupt the child's ability to independently reduce amygdala
reactivity and anxiety.

We developed SPACE to translate these neurobiological and clinical research findings into a
manualized parent-based treatment focused on reducing family accommodation in parents of
anxious children. Preliminary data from a randomized clinical trial show that after 12 weeks
of parents receiving SPACE (N=29), with no therapist-child contact, family accommodation and
child anxiety were significantly reduced. We propose that SPACE engages anxious children's
amygdala-mPFC circuitry, lessening their reliance on parents to reduce amygdala reactivity.

The first phase of the study will examine clinically anxious children's (N=90, 7-10 yrs)
amygdala-mPFC response to fear faces when (A) the child's parent is beside them holding their
hand during the fMRI scan (Parent-Present), and (B) the child is alone during the scan
(Parent-Absent) (within-subjects design). Children with primary separation, social, or
generalized anxiety disorder diagnoses, the most common childhood anxiety disorders, will
serve as participants. Children will complete Parent-Present and Parent-Absent scans PRE- and
POST-SPACE, or PRE- and POST-Parent Educational Support (PES), the comparator treatment that
controls for treatment duration and therapist-parent contact. We expect SPACE will lessen
child reliance on parental presence to engage amygdala-mPFC circuitry and reduce child
amygdala reactivity. Aim 1: Demonstrate SPACE lessens children's reliance on parents to
reduce amygdala reactivity (target engagement). Hyp 1: Child reliance on parental presence to
reduce amygdala reactivity, (i.e., the difference between child amygdala reactivity in the
Parent-Present and Parent-Absent scan), will decrease significantly from PRE- to POST-SPACE,
as compared with PRE- to POST-PES. If Hyp 1 is confirmed we will proceed to the the second
phase of the study.

The second phase of the study will be performed to re-demonstrate target engagement in SPACE,
compared to cognitive-behavioral therapy (CBT); demonstrate target engagement is associated
with symptom reduction in SPACE; and demonstrate SPACE's acceptability/feasibility. The
second phase will enroll 136 clinically anxious children (7-10 yrs), randomly assigned to
SPACE or CBT. Aim 1: Re-demonstrate target engagement in SPACE. Hyp 1: Child reliance on
parental presence to reduce amygdala reactivity will decrease significantly from PRE- to
POST-SPACE, as compared with PRE- to POST-CBT. Aim 2: Demonstrate target engagement is
associated with symptom reduction in SPACE. Hyp 2: Reduction in child anxiety from PRE- to
POST-SPACE will be significantly associated with reduction in child reliance on parental
presence to reduce amygdala reactivity. Aim 3: Establish acceptability and feasibility of
SPACE. Hyp 3: SPACE will be acceptable and feasible to administer, and comparable to CBT. The
second phase will also provide insight into the relative efficacy of SPACE, to inform future
research and development of SPACE.

This study has the potential to provide groundbreaking results, with major public health
impact, on how parent-based treatments can target disrupted neurobiological processes in
children with psychopathology. These novel data will inform decision-making about a
large-scale study (R01) to confirm the efficacy of SPACE and examine personalized treatment
strategies.

Inclusion Criteria:

- Prepubertal

- Clinical diagnosis of primary anxiety disorder

- Must not have another mental illness more impairing than the most impairing anxiety
disorder

- IQ of at least 80.

Exclusion Criteria:

- Neurological disorders (including seizures)

- Organic mental disorders, psychotic disorders, or pervasive developmental disorders

- High likelihood of hurting themselves or others

- Current psychosocial or psychopharmacological treatment

- History of neurological illness or head injury with loss of consciousness > 5 minutes

- Vision or physical disability that interferes with seeing stimuli presented briefly on
computer screen and/or clicking a mouse button rapidly and repeatedly

- Contraindications for MRI scanning (e.g., metal implants, pacemakers, braces,
claustrophobia, pregnancy, weight > 250 pounds).