Brain Response Associated With Parent-based Treatment for Childhood Anxiety Disorders
Phase: NA
Conditions: Anxiety Disorder of Childhood, Separation Anxiety Disorder of Childhood, Social Anxiety Disorder of Childhood, Generalized Anxiety Disorder
Sponsor: Yale University

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HRP-503B – BIOMEDICAL RESEARCH 
PROTOCOL (2017-1)
Protocol Title: Brain response associated with parent-based treatment for childhood anxiety 
disorders
Principal Investigator: Eli Lebowitz
Version Date: Click or tap here to enter text.
(If applicable) Clinicaltrials.gov Registration #: NCT03585010
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SECTION I:
1. Statement of Purpose:
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. This study aims to test whether 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.
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. Anxious 
children’s reliance on parents for anxiety reduction may disrupt the child’s ability to 
independently reduce amygdala reactivity and anxiety.
The study will examine clinically anxious children’s 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 anxiety disorder diagnoses will serve as participants. Children will complete Parent- 
Present and Parent-Absent scans PRE- and POST-SPACE, or PRE- and POST-CBT (Cognitive-
behavioral therapy), an established treatment of equal duration and therapist-parent contact.
Aim 1: Demonstrate SPACE lessens children’s reliance on parents to reduce amygdala 
reactivity (i.e., target engagement).
Aim 2: Demonstrate associations between target engagement and anxiety outcomes.
Aim 3: Establish feasibility and acceptability of SPACE, as well as patient satisfaction.
2. Probable Duration of Project: 5 years.
3. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
Anxiety disorders comprise the most prevalent disorders of childhood and adolescence. If not 
treated successfully, anxiety disorders cause significant short and long-term impairment and 
pose huge financial and societal costs (Costello, Egger, & Angold, 2005) through factors such as 
increased school dropout, teenage childbearing, and lost productivity in the workplace 
(Compton et al., 2004; Greenberg et al., 1999). Despite strong evidence for the efficacy of 
cognitive-behavior therapy (CBT), up to 50% of children remain symptomatic after treatment
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and many continue to meet diagnostic criteria (Compton et al., 2004; Rapee, Schniering, & 
Hudson, 2009). A significant proportion of children remain symptomatic even after combined 
CBT and psychopharmacological treatment (Walkup et al., 2008). Evidence for parental 
influences in the etiology and maintenance of anxiety in children (Ginsburg, Silverman, & 
Kurtines, 1995; Hudson & Rapee, 2002; Rapee et al., 2009) has often led to the reasonable 
assumption that including parents in treatment would enhance effects relative to individual 
CBT (CBT). However, involvement of parents in the therapeutic process has not always yielded 
superior effects compared to CBT alone (Bodden et al., 2008; Heyne et al., 2002; Nauta, 
Scholing, Emmelkamp, & Minderaa, 2001; Spence, 2000; Wood, Piacentini, Southam-Gerow, 
Chu, & Sigman, 2006), as a number of meta- analytic and comprehensive reviews also have 
shown (Barmish & Kendall, 2005; Breinholst,
Esbjorn, Reinholdt-Dunne, & Stallard, 2012; Reynolds, Wilson, Austin, & Hooper, 2012; 
Silverman, Pina, & Viswesvaran, 2008). This study shifts away from past conceptual treatment 
models, which emphasized training parents in specific behavioral skills (e.g., problem solving) 
and instead emphasizes the ways in which parents become enmeshed and entangled in their 
child’s anxiety. Family Accommodation (FA)(Calvocoressi et al., 1995) describes the ways in 
which parents are drawn into their child’s anxiety through participation in the child’s symptoms 
and modification of schedules and routines intended to reduce or prevent the anxiety.
Children’s reliance on parents for protection and regulation of negative affect states can 
contribute to parental entanglement in these symptom-driven dynamics, which may 
perpetuate rather than alleviate child anxiety. FA is highly prevalent among parents of anxious 
children and associated with more severe anxiety symptoms (E. R. Lebowitz et al., 2013). The 
SPACE Program (Supportive Parenting for Anxious Childhood Emotions) (Eli R. Lebowitz & 
Omer, 2013) translates the modification of these patterns of enmeshment and entanglement 
into a series of concrete steps in a manualized treatment protocol aimed to reduce FA and in 
turn, to bring about improvement in child symptoms.
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. 
Parental reduction of child anxiety via amygdala-mPFC circuitry serves an important function 
for children, but can go awry in childhood anxiety disorders. Evidence suggests that in typically 
developing children normative changes during frontoamygdala development correspond to a 
natural shift from child dependence on parents for anxiety reduction toward increased 
independent engagement of amygdala-mPFC circuitry and reduced amygdala reactivity. This 
shift toward independent anxiety reduction is impeded in clinically anxious children, whose 
symptoms are linked to a clear pattern of amygdala hyperactivity and deficits in prefrontal 
control of the amygdala.
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Neurobiological and clinical research support this model, whereby clinically anxious children are 
more dependent on parents for amygdala-mPFC engagement and anxiety reduction. Data from 
clinically anxious children who requested their parent be in the scan room show significant 
impact of parental presence on the mPFC. Clinically, children with anxiety disorders rely heavily 
on parents, who are deeply embroiled and enmeshed in their child’s anxiety symptoms through 
the process of family accommodation, defined as changes in parental behavior to help their 
child to avoid or alleviate anxiety.
4. Research Plan:
The study is a clinical trial involving children with primary anxiety disorders. Children will 
randomly be assigned to one of two treatment conditions.. One condition is Supportive 
Parenting for Anxious Childhood Emotions (SPACE) which focuses on reducing family 
accommodation of child anxiety symptoms. The comparator condition is
cognitive-behavioral therapy (CBT) an established and evidence-based treatment for 
childhood anxiety disorders, of known efficacy.In CBT children will be introduced to and 
discuss the presenting problem, review treatment rationale and goals, work with the therapist 
to devise an anxiety hierarchy, and participate in in-session and out-of-session exposure tasks. 
Additionally, children will be introduced to the cognitive component of treatment by 
identifying faulty cognitions and generating incompatible self-statements, and exploring 
alternatives.  . Families will be randomly assigned to one of the aforementioned conditions. 
After initial screening, children will first participate in a pre-treatment assessment (PRE). The 
PRE assessment will include: a structured interview with child and parent covering anxiety 
symptoms and related conditions, questionnaires completed by child and parent, a brief 
parent-child interaction which is video-taped, collection of blood and saliva (see procedures
below). Following the PRE assessment, eligible patients will be randomized into either SPACE or 
CBT and will undergo a neuroimaging scan using fMRI to examine behavioral and brain 
processes associated with anxiety and fear processing.
In the SPACE treatment condition parents participate in 12 weekly parent-only sessions. In the 
CBT treatment condition children participate in 12 weekly child-only sessions. Parents of 
children assigned to CBT will meet with the child’s therapist three times over the course of 
the treatment study, to be kept informed about their child’s progress and provide helpful 
information to the therapist. Sessions can take place in person at the Yale Child Study Center 
or over secure video-link using the HIPAA approved Zoom software provided by Yale 
University. Participants will choose whether to have the sessions in person or over zoom and 
can elect to have some in person and some over Zoom. Youth and parents will be re-assessed 
after 6 treatment sessions (MID) and after the 12th session (POST). These assessments 
include the same procedures done at the first assessment, except the MID assessment does 
not include clinical interviews. After the 12th treatment session children will also undergo a 
second neuroimaging scan using fMRI. In both treatment conditions participants will be 
invited back for a follow-up visit 6-months from their initial appointment. At this 
appointment, these assessment procedures are the same as the MID assessment, but does 
not include a video-taped interaction or saliva sample.
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Participants who are already enrolled will be invited to electronically complete an optional set 
of questionnaires related to their experiences during the COVID-19 pandemic (Please see 
Measures for list of questionnaires). This part of the study is completely optional. The 
questionnaires will be administered via the HIPAA-secure REDCap platform. Participants will 
receive $15 when they submit the completed questionnaires. 
Assessment Procedures:
Each of these three assessments (PRE, MID, POST) will be conducted in single sessions at our 
clinic by carefully trained independent evaluators (IE). Each assessment session will include 
collection of biological samples, behavioral observation, and self-report measures. During the 
youth interview, the parent will be administered the questionnaires and vice versa.
Questionnaires will be completed using iPads via the HIPAA- compliant REDCap/Qualtrics app. 
In specific circumstances, participants may have the option to complete the questionnaires via 
HIPAA-compliant REDCap/Qualtrics web link outside of the laboratory. For example, during an 
initial visit, if a parent and child have each completed their interview and the child has already 
completed their questionnaires and cognitive testing, a parent may prefer to complete their 
parent-report questionnaires at home to reduce the visit length and reduce burden on the child.
Measures:
Interviews
Anxiety Disorders Interview Schedule (ADIS (Silverman, Saavedra, & Pina, 2001). The ADIS is the 
gold standard in assessing the presence and severity of anxiety disorders in youth and will be 
used to establish the presence of a primary anxiety disorder in potential study participants.
Clinical Global Impressions Scale (CGI (Guy W Editor, 1985). Youth outcome will be assessed on 
a global level using the 7-point CGI Severity Scale, ranging from 1 (not at all) to 7 (among the 
most extremely ill patients). The 7-point CGI Improvement Scale ranges from 1 (very much 
improved) to 7 (very much worse). A CGI Improvement Scale rating of 1 or 2 indicates clinically 
meaningful improvements in anxiety symptom severity. This measure is included because it is 
widely used as an indicator or treatment response.
Pediatric Anxiety Rating Scale (PARS (RUPP Anxiety Study Group, 2002). Using information 
obtained from interviews with parents and youths, an IE scores each of 50 anxiety symptoms as 
either present or absent during the past week. Endorsed symptoms are rated by the IE on 7 
dimensions and each dimension is rated from 0 to 5; total scores range from 0 to 35. The PARS 
has adequate internal consistency (αs .64-.91) and interrater reliability (ICCs .78-.97), sensitivity 
to change in treatment studies, and convergent validity (Walkup et al., 2008). This measure is 
included along with the CGI as recent research has shown it can detect response and remission 
in child anxiety (Caporino et al., 2012). At the pre assessment, the interviewer who conducts 
the ADIS – C/P will conduct the CGI and the PARS rating. At post assessments, an IE will 
complete the ratings.
Child
Self-Reports
The measures listed below will be administered to parents and/or children as indicated in the 
table.
Parent Completes
Child Completes
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Multidimensional Anxiety Scale for Children
Multidimensional Anxiety Scale for Children
Family Accommodation Scale Anxiety
Family Accommodation Scale Anxiety
Parent Phobia Questionnaire
Child Spider Phobia Questionnaire
Couple’s Satisfaction Inventory
Anxiety Sensitivity Index – CASI
Experience in Close Relationships Scale
Kern Attachment Scale
Mood and Feelings Questionnaire – MFQ
Mood and Feelings Questionnaire – MFQ
Child Anxiety Impairment Scale (CAIS)
Child Anxiety Impairment Scale (CAIS)
Client Credibility Questionnaire (CCQ)
Client Credibility Questionnaire (CCQ)
Difficulties in Emotion Regulation Scale
Affective Reactivity Index
Affective Reactivity Index
Intolerance of Uncertainty Scale
Intolerance of Uncertainty Scale
Responses to Uncertainty and Low Environmental 
Structure questionnaire
Responses to Uncertainty and Low Environmental 
Structure questionnaire
Beck Anxiety Inventory
Attention Control Scale
Beck Depression Inventory
Behavioral Inhibition & Activation Scale
Behavioral Inhibition & Activation Scale
Child Behavior Checklist
Parenting Stress Index
Parent Report of Parental Behavior Inventory
Child Report of Parental Behavior Inventory
Perceived Stress Scale
Perceived Stress Scale
Petersen Pubertal Development Scale
Screen for Child Anxiety Related Disorders
Screen for Child Anxiety Related Disorders
Alphabetical Index of Occupations and Industry
MacArthur Scale of Subjective Social Status
Edinburgh Handedness Inventory
Treatment Utilization
Parenting Beliefs about Anxiety Questionnaire 
(PBA-Q)
Supportive Parenting Questionnaire
In order to assess comprehension of the task completed in the MRI scanner, participants will 
complete two study-specific questionnaires: a brief Noise Rating as well as a Shapes Task 
Questionnaire, both of which were designed specifically for this protocol.
Questionnaires related to stress and coping during the COVID-19 pandemic: The following 
questionnaires will be used to assess circumstances, stress, and coping related to the 
COVID-19 pandemic. The Emotion Regulation Questionnaire, Difficulties in Emotion 
Regulation Scale, Emotion Regulation Checklist, Parenting Stress Index, Intolerance of 
Uncertainty Scale, Screening for Child Anxiety and Related Emotional Disorders, Beck 
Depression Inventory, Children’s Depression Inventory, Perceived Stress Scale, Positive and 
Negative Affect Schedule, Kerns Security Scale, and Benevolent Childhood Experiences Scale. 
The Difficulties in Emotion Regulation Scale, Parenting Stress Index, Intolerance of 
Uncertainty Scale, Screening for Child Anxiety and Related Emotional Disorders, Beck 
Depression Inventory, Perceived Stress Scale and Kerns Security Scale are all approved on 
the current protocol and may be re-administered to assess functioning during COVID-19. 
Questions will also be asked from the following measures that have been developed within 
the research community in response to the COVID-19 pandemic: Fear of Illness and Viral 
Evaluation (FIVE), Coronavirus Impact Scale, Coronavirus Health Impact Survey (CRISIS), 
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Epidemic-Pandemic Impacts Inventory, and COVID-19 and Perinatal Experiences (COPE) 
survey. We have also modified the items on the Parental Trauma Response Questionnaire to 
be specific to the COVID-19 pandemic. 
Parent-Child Interaction
Child and mother will engage in a brief video-recorded behavioral interaction, lasting only a few 
minutes, during which they will be asked to solve a puzzle together. The interaction will be 
systematically coded using a well-established, valid and reliable coding system.
Cognitive and Behavioral Task:
Participants will complete several tasks administered by research personnel or on a computer 
to provide measures of cognitive (e.g., intelligence) and behavioral functioning (e.g., associative 
learning).
Wechsler Abbreviated Scale of Intelligence (WASI). We will collect measures of cognitive 
functioning using the WASI (Wechsler, 1999). This is an abbreviated assessment of cognitive 
functioning that is standardized and has been validated for use with children. It consists of four 
subtests: vocabulary, block design, similarities and matrix reasoning.
The computerized tasks will take place inside the MRI scanner. For any children who do not 
complete the MRI scan, they will be offered the opportunity to complete the tasks outside of 
the scanner to obtain behavioral measures. The stimuli will be visual or auditory and may vary 
in emotional valence from positive (e.g., pleasant noise, happy faces) to neutral (e.g., shapes, 
neutral faces) to negative (e.g., metallic noise, fearful faces). Examples of visual stimuli include 
geometric shapes, faces, objects, letters, or places. Examples of auditory stimuli include musical 
instruments (e.g., a chime or gong), metallic sounds, animal sounds, human sounds (e.g., baby 
cooing), or white noise. Participants may be instructed to press different buttons depending on 
the pictures they see on the screen. Participants will be provided with sample stimuli 
comparable in content before the tasks begin. This way, participants will have the opportunity 
to evaluate their comfort level with the stimuli beforehand. Participants will be reminded that 
they may withdraw their participation at any time if they are not comfortable with any of the 
stimuli. There is little risk involved in these tasks other than boredom or some frustration. One
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of the tasks involves a well-established protocol in which the parent enters the scanner 
environment to test the effect of parental presence on child’s processing of emotion (e.g., Coan 
et al., 2006; Conner et al., 2012). Thus, all parents who will be invited to enter the scanner 
environment will complete the same thorough metal screening. For children whose parents 
have contraindications for entering the scanning environment, children can complete this task 
outside of the scanner instead.
Yale Interactive Kinect Environment Software (YIKES). YIKES is a software package developed at 
the Yale Child Study Center (Lebowitz et al., 2015) to allow for more accurate and sensitive 
measurement and study of anxious avoidance. The software creates a game-like environment 
in which a participant attempts to catch target items falling on screen by moving in to the right 
and left and presents pre-programmed stimuli designed to engage avoidance behavior on the 
sides of the screen. The software interacts with the Microsoft Kinect sensor to chart a subject’s 
motion in real time and records their location with high spatial and temporal resolution and 
accuracy. The sensor does not record the video and no images of the participant are stored.
Attention Bias to Threat. Attention bias to threat will be assessed with a probe-detection task 
using the computer software Eprime. Participants (both mother and child) will complete tasks 
using a provided laptop computer and mouse. A centered fixation cross will appear first and will 
be followed immediately by two faces of the same actor expressing different emotions, one 
above the other. Participants will be told that a probe (< or >) will appear on the screen and 
that their task is to push the corresponding mouse button
Blood Samples:
Subjects will be asked to provide us with a small blood sample for our research during the initial 
appointment, and again at the 6-month follow up appointment. The total amount drawn will be 
less than one ounce each time. An experienced and qualified professional will draw the blood 
from a vein near the elbow.
We will also ask for permission to store blood samples for future research projects. If the 
subject agrees, the blood will be stored in a safe place without personal identification and 
retained for future research purposes.
Saliva Sample
To collect a sample of saliva we will subjects to chew on a small cotton swab for about one 
minute, then spit it out into a special sterile container.
MRI:
All participants will be scanned using a 3T scanner located at the Yale Magnetic Resonance 
Research Center or Yale’s Brain Imaging Center. We train children on the tasks in a simulator so 
that they can acclimate to the scanning environment. Prerecorded scanner sounds will be 
played as the participant is in the simulator. We will describe and answer any questions the 
child or parent has about the MRI procedure. The simulator is a replica of the 3T scanner and 
includes speakers for simulating sounds, a screen to simulate visual stimuli, and a motorized 
table for simulating experiences the participant will have in the actual scanner. The participant
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will watch videos and practice the computer tasks while in the simulator. Only after acclimating 
the child to the scanner environment so that both the child and parent are comfortable with 
the procedure, will the child be scheduled for the actual scan. Otherwise the study will be 
terminated.
A member of the research team will accompany the child to the Yale Magnetic Resonance 
Research Center or Yale’s Brain Imaging Center and stay for the duration of the scanning 
session. All participants will undergo a metal/MRI screening prior to entering the MRI 
environment. This will include measuring height, weight, and waist-to-hip ratio. All participants 
will walk through a detector designed to detect metal objects as part of the metal screening.
For females who indicate on the screening that they may be pregnant, the MRI portion of the 
visit will be stopped (the participant may still complete the behavioral task on the computer 
outside of the scanner). This procedure is in accordance with the MRRC’s policy on pregnancy 
(please see attached policy: “Risks of MR Procedures during Pregnancy”). No pregnancy test will 
be administered. In the scanner, the participant will be positioned using foam padding to 
minimize motion and maximize comfort. A head coil will be used to acquire all images. The 
participant’s choice of video will be displayed immediately upon being placed in the scanner 
and will remain on during the acquisition of anatomical scans (10-15 minutes). Immediately 
following these scans, the participant will be asked to play the computer tasks during the fMRI 
scans (30-45 minutes). Then resting-state and diffusion tensor imaging scans will be acquired 
(20-30 minutes). The participant can also view a video of their choice during the diffusion 
tensor imaging scans. In the MR scanner we can communicate with the participant via a 
microphone so the participant can hear the experimenter as the instructions are given.
Participants wear earplugs to reduce noise from the scanner and earphones to allow the 
experimenter to communicate with them. The entire MRI procedure including positioning in 
the scanner will take approximately 60-90 minutes. As stated in the consents, the scan will be 
stopped, and the participant removed from the scanner immediately at any time the 
participant requests to end the scan.
Anatomical MRI will be acquired for localizing the subject's brain in the scanner and to identify 
standard anatomical landmarks for prescribing the other scans. Diffusion Tensor Imaging (DTI) 
will be performed to examine the development of white matter tracts, specifically those 
involving the frontal cortex and amygdala. During acquisition of anatomical and DTI scans the 
participant will be able to watch a video of his/her choice. Resting-state Functional MRI will be 
performed to investigate functional connectivity of hippocampal- frontoamygdala networks at 
rest. Subjects will be asked to keep their eyes open during the image acquisition. Task-based 
Functional MRI will be used to examine brain activation during emotion processing and 
associative learning. For the functional studies, stimulus presentation and response collection 
will be controlled using E-Prime software on a computer located in the MR Center control 
room. Computer images will be projected onto an LCD panel for the participant to see. A fiber 
optics response box will be used for recording behavioral responses (e.g., accuracy, reaction 
time). A typical session will include: collection of anatomical images (10-15 min); task-based 
fMRI including instructions to subject, behavioral task, and functional scan acquisition during
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computer tasks (25-40 minutes); resting-state fMRI (5-10 minutes); and collection of DTI (5-10 
minutes).
Parameters for the pulse sequences are as follows:
- Localizer: Voxel size 0.5x0.5x7.0, FoV=250mm, TR=7.5ms, TE=3.69ms, flip angle = 20 degrees, 
slice thickness=7.0mm, base resolution=256
- Scout: Voxel size 1.6x1.6x1.6 mm, FoV=260mm, slice thickness=1.6mm, TR=3.15ms, 
TE=1.37ms, flip angle=8 degrees, base resolution=160, PAT mode = GRAPPA, accel factor=3
- T1 navigator: Voxel size: 8.0x8.0x8.0, FoV=256mm, slice thickness=8.0mm, TR=9.9ms, TE- 
4.6ms, flip angle=2 degrees, base resolution=32
- T2 navigator: Voxel size: 1.0x1.0x1.0, FoV=256mm, slice thickness=1.0mm, TR=3200ms, 
TE=564ms, base resolution=256mm
- DTI: Voxel size:1.7x1.7x1.7mm, FoV=240mm, slice thickness=1.7mm, TR=4100ms, TE=88ms, 
flip angle 1=90 degrees, flip angle 2 = 180 degrees, echo spacing-0.69ms
- Resting-state fMRI: Voxel size: 2.4x2.4x2.4mm, FoV=230mm, slice thickness=2.4mm, 
TR=809ms, TE=32ms, flip angle=54 degrees, base resolution=96, measurements=375, echo 
spacing=0.52ms, SMS factor=6, SMS shift=3
- Task-based fMRI: Voxel size: 2.4x2.4x2.4mm, FoV=230mm, slice thickness=2.4mm, TR=809ms, 
TE=32.0ms, flip angle=54 degrees, measurements=410, base resolution=96, echo 
spacing=0.52ms, SMS factor=6, SMS shift=3
Galvanic Skin Response. While the subjects are performing the tasks we will also take 
physiological measures of learning, which are reflected by changes in a subjects’ sweat 
response (a measure of the galvanic skin response, GSR). Galvanic Skin Response will be 
collected with electrodes on the subject's hand or foot. During the MRI scan, we will also assess 
physiological measures including heart rate and respiration. These measures are commonly 
used as covariates that index physiological noise in analyses of resting-state fMRI data. All of 
the materials (including the electrodes for the GSR) are non-ferrous (i.e., do not contain iron) 
and can be used safely during testing both in and out of the MRI scanner. They are non-invasive 
and do not cause discomfort to the participant.
5. Genetic Testing
N/A ☐
A. A portion of blood drawn and saliva collected will be saved for genetic testing looking at 
single nucleotide polymorphisms on the oxytocin receptor gene OXTR. These variations have 
been associated with the function of oxytocin system, various aspects of social behavior, and 
have linked parental behavior to the presence of anxiety in children at risk for the development 
of anxiety disorders.
i. the plan for the collection of material or the conditions under which material will be 
received: Samples will be collected together with the plasma collected for Oxytocin level 
analysis, by the department of laboratory medicine
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ii. the types of information about the donor/individual contributors that will be entered 
into a database: Information will include personal and demographic variables including 
geographical location of residence, age, and the variables assessed in this study.
iii. the methods to uphold confidentiality: Samples will be de-identified and stored 
without any personal identifying information. The personal information will be stored 
separately from samples on encrypted computers stored in secure lockedfacilities.
B. What are the conditions or procedures for sharing of materials and/or distributing for future 
research projects? Only the PI and research team will have access to the database and will 
decide on any future use of the genetic samples for research.
C. Is widespread sharing of materials planned? NO
D. When and under what conditions will materials be stripped of all identifiers? If participants 
request that their samples be completely de-identified we will remove all identifying 
information including the subject number key from the samples.
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials? Donor-subjects can withdraw their materials at any time 
or request that the identifiers be removed completely.
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? If participants request that the 
material be withdrawn completely, we will destroy all the material relating to them. If 
they request that it be de- identified, we will remove all identifying information.
F. Describe the provisions for protection of participant privacy Samples will be de-identified and 
stored without any personal identifying information. The personal information will be stored 
separately from samples on encrypted computers stored in secure locked facilities. Only the 
research team will have access to the data or the samples.
G. Describe the methods for the security of storage and sharing of materials: Material will be 
kept securely in refrigeration in locked office/laboratories in secure and locked buildings. The 
electronic information will be kept on encrypted computers in locked cabinets in locked offices.
6. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
The population will include children aged 6-12 with anxiety disorders along with their parents. 
No special groups are being targeted for inclusion apart from the children with anxiety.
7. Subject classification: Check off all classifications of subjects that will be specifically recruited 
for enrollment in the research project. Will subjects who may require additional safeguards or 
other considerations be enrolled in the study? If so, identify the population of subjects 
requiring special safeguards and provide a justification for their involvement.
☒  Children
☐  Healthy
☐ Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners ☐ Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees ☐ Pregnant women and/or fetuses
☐Yale Students
☐ Females of childbearing potential
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NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?
Yes ☐ No ☒
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or 
exclusion? Inclusion Criteria: Children must be a) 6-12 years old; and b) score below 2 on the 
Petersen Pubertal Development Scale; and c) meet DSM-5 diagnostic criteria for a primary 
anxiety disorder; and d) not have
another mental illness more impairing than their most impairing anxiety disorder; and e) have 
an IQ of >80 to minimize neurobiological heterogeneity.
Exclusion Criteria: Children will be excluded for any of the following: a) neurological disorders 
(including seizures), organic mental disorders, psychotic disorders, or pervasive developmental 
disorders; or b) show high likelihood of hurting themselves or others; or c) current psychosocial 
or psychopharmacological treatment. Stable doses of stimulant medications for ADHD will be 
permitted if parent and child, in consultation with the prescriber, agree to not make changes to 
dosage during the study period and to not administer the medication in the 24-hour period 
prior to pre-treatment and post-treatment MRI scans (MRI scans will be arranged on dates the 
child would not be taking a stimulant medication, in consultation with the prescriber and with 
agreement from the parent); or d) history of neurological illness or head injury with loss of 
consciousness > 5 minutes; or e) vision or physical disability that interferes with seeing stimuli 
presented briefly on computer screen and/or clicking a mouse button rapidly and repeatedly; 
or f) have contraindications for MRI scanning (e.g., metal implants, pacemakers, braces, 
claustrophobia, pregnancy, weight > 250 pounds).
Exclusion Criteria – Parent: Parents will be excluded for any of the following: a) pervasive 
developmental disorders, mental retardation, selective mutism, organic mental disorders, 
bipolar disorder, psychotic disorders, drug/alcohol abuse/dependence; b) <1 year living with 
the child prior to admittance; c) suicidal attempt in past 6 months. When a child is excluded, 
the parent is also excluded (unless as parent of another child); when a parent is excluded, the 
child will not participate.
9. How will eligibility be determined, and by whom?
All parents who are interested in participating in this study will be administered a standardized 
telephone screen to ensure their child is experiencing anxiety problems and is eligible for MRI 
(including current psychiatric medications). The brief telephone screen will be completed by 
trained research assistants. If their child is experiencing anxiety problems and is eligible for 
MRI, the family will be scheduled for the Pre Assessment. After signing informed 
consent/assent forms, parents and youth will complete the ADIS: C/P. The purpose of the 
interview is to determine DSM-5 anxiety diagnoses and to rule out exclusionary diagnoses. The 
ADIS: C/P will be completed by one of the study’s personnel. Cognitive testing administered by 
trained research personnel during the evaluation visit will be used to determine eligibility based 
on IQ. Eligibility will be determined after reviewing results of the ADIS: C/P and Pre Assessment 
with key study personnel at a staff meeting.
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At the MRI visit, participants will again be given a thorough metal screening (Yale-MRRC MRI 
Safety Questionnaire) by trained research personnel to ensure that they are still eligible for the 
MRI (e.g., to rule out participants with a change in status of metal in the body, such as a child 
who recently got braces). At any time (during the phone screening prior to enrollment, or after 
enrollment in the study), the research personnel and the PI may determine that a participant is 
not fit to enroll in or continue in the study should they judge that it is in the participant’s best 
interest to do so, if the participant begins a new medication or treatment that would change 
their eligibility, if they (or their parent) do not comply with the study plan, if they repeatedly 
miss appointments, if there is concern about their (or their parent’s) ability to complete the 
interview and/or questionnaires validly and reliably, or for various other administrative 
reasons.
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Interviews and questionnaires: Feeling upset when talking about anxiety or attending to 
anxious thoughts.
Behavioral Interactions: Temporary discomfort when discussing an issue on which child and 
mother disagree.
Blood Draw: Minor discomfort, redness or ecchymosis; Bleeding: Rarely: Phlebitis, infection, 
fainting. The blood draw is an optional component of the study.
Risk to personal information: There is always a risk to confidentiality when personal 
information is collected. See data protection section.
Treatment – SPACE: Not getting better; Getting worse during treatment; Child responding with 
elevated anxiety, distress, or aggression to parents not accommodating the child’s symptoms; 
strain on marital relationship; parent-exacerbated anxiety.
Treatment – CBT: Not getting better; Getting worse during treatment; temporary 
elevated anxiety (e.g. during exposure tasks). 
MRI – Magnetic resonance imaging is considered to be a medically safe procedure, and the 
procedure is painless. There is no evidence for long-term effects of MRI procedures on the 
body. The Food and Drug Administration (FDA) has set recommendations for exposure in MRI 
studies and this study satisfies those criteria. MRI acquisition involves exposure to a strong 
magnet. Thus, the primary risk associated with MRI is risk of injury associated with metal 
objects being drawn into the magnet. These objects could be internal (e.g., metal implants in 
the participant’s body) or external items. In addition, some participants may experience 
transient peripheral nerve stimulation or nausea in the bore of the magnet. Nausea is 
minimized by stabilizing the head. There is minimal risk involved in the collection of 
physiological data (e.g., galvanic skin response) during the MRI. The adhesive on the GSR 
attachments may cause itching or a sticky feeling on participants’ skin in the small area on 
which the electrodes are attached.
The MRI procedure does require participants to lie still with the head and part of the body 
confined in a tunnel-like device for a considerable length of time (60-90 minutes including 
several breaks between the collection of images). Some participants may find the confinement 
in the MRI machine to be claustrophobic, physically uncomfortable, or noisy.
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11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
To minimize risk relating to questionnaire and interview assessments: It is possible that some 
children and adolescents and parents may become slightly anxious or upset when asked to 
attend to their anxious thoughts or feelings as required by these procedures. We anticipate 
such reactions will be short-lived in nature and typically have no significant long-term 
consequences. In fact, many children and parents are likely to benefit from an improved self- 
understanding derived from the completion of these measures. These measures are standard 
and widely used in this age range, and there have been no reports of negative iatrogenic 
effects. Participants and their parents are not required to answer questions during interviews 
or on questionnaires that they find too sensitive.
To minimize risk relating to blood draw: Venipuncture will be performed by qualified and 
experienced personnel in an approved location at the Yale University Department of Laboratory 
Medicine. Trained, qualified and experienced personnel reduce the risk of pain, bleeding, 
redness, inflammation, ecchymosis, phlebitis and infection. Qualified locations reduce risks that 
accompany fainting. The amount of blood to be drawn, not more than 15ml, is well within what 
is permissible and should not present risk. Participants will be able to decline to have the blood 
draw at any time until it is completed.
To minimize risk relating to behavioral interactions: Parent and child will each be able to 
terminate the entire interaction, or part of it at any time. Children and parents will be given 
instructions that they may stop whenever they want. The graduate research associates also 
have been carefully and thoroughly trained in the providing of reassurance. Similar procedures 
have been widely used for many years without report of negative results. In addition, the 
research associate will spend some time with the participants following each assessment 
procedure and discuss the participants’ reactions to the procedure.
To minimize risk relating to treatment: Changes in parents’ behavior (e.g., reducing their 
accommodation of the child’s anxiety) involves some risk of children feeling upset, becoming 
angry, or parents’ experiencing anxiety. Every treatment session includes a review of the past 
week and query for any uncomfortable events. Any description of extreme exacerbation in 
parent or child anxiety; suicidal or self-injurious behavior; or other potentially harmful or 
dangerous event will be reviewed clinically and addressed. The therapists will report any such 
event immediately to the PI. Co-investigator Dr. Silverman has many years of experience 
working with anxious children and their parents, including in multiple large scale clinical trials 
and will oversee the project closely. Upon consultation, a determination will be made about the 
most appropriate manner in which to intervene (e.g., alternative treatment, hospitalization, 
etc.), and the child or parent will be excluded from the study, as necessary.
To minimize risk relating to cognitive and behavioral tasks: Participants can stop the tasks at 
any time and are reminded of this prior to beginning them.
To minimize risk relating to MRI: All FDA guidelines for MRI scanning are carefully observed at 
the Yale MRRC and Yale BIC. All of the scans will be performed using an MRI scanner employing 
pulse sequences and hardware that have been approved by the FDA. The field strength is 3 
Tesla and all relevant operating characteristics (RF power deposition, rate of change of the field 
gradients, coil design) fall within the limits of FDA guidelines.
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Participants will be carefully screened to exclude those who may have metal in or on their 
bodies that cannot be removed. We conduct a thorough metal screening at both the phone 
screening and again at the beginning of the MRI visit to ensure that the participant’s status is 
still safe for MRI scanning. Yale MRRC and Yale BIC rules strictly forbid staff from entering the 
magnet room carrying metal objects.
Because the MRI procedure requires participants to lie still in a tunnel-like device for a 
considerable length of time, some participants can find the confinement or noise 
uncomfortable. We provide ear protection to soften the noise level for participants. We also 
use an extensive simulation procedure at the mock MRI scanner during the first visit to help 
participants acclimate to the MRI environment. Especially for children and adolescents, this is 
helpful to get used to the feeling of staying still in the tunnel and hearing the types of sounds 
that the scanner makes. Participants who experience claustrophobia during the mock MRI scan 
or who endorse claustrophobia on the screening will not be scheduled for the MRI scan. Based 
on our prior publications that have used this procedure, we are confident that the mock scan 
will be helpful for acclimating to the MRI environment (e.g., Gee et al., 2012; Gee et al., 2013a; 
Gee et al., 2013b; Gee et al., 2014; Gee et al., 2016). All participants are given a button to signal 
distress so that they can stop the scan at any time. Participants also use an intercom to 
communicate with the experimenter during the scan.
At all times, participants will have the option to discontinue the scan if they find it to be 
objectionable in any way. We can allow them to take additional breaks, if desired, in between 
image sets, but if that is not acceptable, they are free to discontinue at any time. Participants 
will be paid for their participation in the MRI visit regardless, without any worry of bias because 
of their level of participation.
In accordance with Yale MRRC policy, the MRI scan is for research purposes only. As specified in 
the consent form, participants are explicitly told that the scans are not designed to find 
abnormalities. If a worrisome finding is seen on a scan, a radiologist or other physician will be 
asked to review the relevant images. Based on his/her recommendation (if any), the PI or 
consulting physician will contact the participant, inform the participant of the finding, and 
recommend that the participant seek medical advice as a precautionary measure. However, the 
decision for additional examination or treatment would lie only with the participant and their 
physician.
There is minimal risk involved in the collection of physiological data. Participants can choose 
not to participate at any time if they experience discomfort (e.g., stickiness) from the adhesive 
and can remove the adhesive and wash the skin off at any time.
In the opinion of the PI, scheduling MRI scans on days the child is not taking stimulant 
medication will not increase risks.
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Consent and Assent documents will review all relevant risks and protections, including risk to 
confidentiality, as detailed in the appropriate sections below.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the 
final determination of the risk to subjects.)
a. What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Minimal risk.
b. If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? Minimal risk.
c. Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are 
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety- 
monitoring-plans-templates for
i. Minimal risk
ii. Greater than minimal
The data and safety monitoring plan for this study will follow the guidelines developed 
by the Yale University Biomedical Institutional Review Board and are based on the 
requirements of the NIH and the NIMH guidance on Risk-Based Monitoring 
(https://www.nimh.nih.gov/funding/clinical- research/nimh-guidance-on-risk-based- 
monitoring.shtml). The plan provides a description of the procedure for monitoring and 
evaluating the progress of the intervention trial, and the mechanism for reporting 
adverse events.
Drs. Eli Lebowitz, Ph.D. (PI), Dylan Gee, Ph.D. (Co-I), Wendy Silverman, Ph.D. (Co-I), and 
Hilary Blumberg M.D. (Co-I) will monitor the safety of study participants to ensure that 
they do not incur undue risk. The safety monitoring will focus on clinical functioning of 
the participants as well as the assessment and intervention procedures including fMRI 
assessments. Drs. Lebowitz, Gee, Silverman and Blumberg will also continually reassess 
risks versus benefits throughout the study period.
The level of risk for this study is low. In general, no serious adverse risks are seen 
associated with either the assessment, intervention, or MRI procedures. The assessment 
procedures are widely used, and non-invasive and parent-based treatment has been 
used in many clinical trials and has not been found to carry any significant risk. SPACE is 
a novel intervention but has been piloted in multiple clinical trials and has not been 
found to carry any significant risk.
Dr. Silverman has decades of experience conducting clinical trials for childhood anxiety 
disorders, including of parent-based interventions. Dr. Lebowitz has implemented SPACE 
with many families directly and supervised other clinicians in this approach and has 
served as PI of a randomized clinical trial of SPACE. During the project, as part of the 
safety monitoring procedures, PI Lebowitz and Co-I Silverman will conduct weekly 
supervision meetings with therapists for purposes of monitoring child clinical
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functioning. This will include reviewing therapist notes etc. for monitoring participant 
safety. Dr. Blumberg has decades of experience studying brain response using fMRI in 
children and adults. Dr. Gee has experience using fMRI to study brain response and 
anxiety including in young children and serves as PI on another study utilizing fMRI to 
study brain response and anxiety in childhood. The study team including Drs. Lebowitz, 
Gee, Silverman, and Blumberg will meet weekly to discuss study progress including any 
concerns that arise.
As in any therapeutic endeavor it is possible that some children could react adversely 
during the assessment and/or intervention procedures. All adverse events will be 
carefully monitored by the Co-PIs. The occurrence of any serious unexpected adverse 
event (e.g., threats to one's life and/or others, suicidal attempts, etc.) will be reported 
by the Co-PIs to the university IRB within 5 days. The Co-PIs, Yale University IRB, Yale 
Magnetic Resonance Research Center (MRRC), Yale Brain Imaging Center (BIC), and Yale 
Pediatric Protocol Review Committee (PPRC) have the authority to stop or suspend the 
study or require modifications. The Co-PIs and Co-Is will also make biannual reviews of 
safety and adverse events.
Confidentiality: All subject information will be de-identified and stored separately with 
only a subject identification number. The key to the ID numbers will be stored 
electronically on a secure encrypted computer accessible only with a password by the 
Co-PIs, Co-Is and IRB.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? Write here
ii. What provisions are in place for management of interim results? Write here
iii. What will the multi-site process be for protocol modifications? Write here
13. Statistical Considerations: Describe the statistical analyses that support the study design. 
General Overview. Data management protocols will be used to ensure data integrity. Missing 
values (including fMRI data) will be estimated using chained equation multiple imputation 
algorithms.108 Analyses will focus on least squares test (OLS) of means and modern robust 
estimation procedures94 that rely on Wilcox’s R routines (which generally have more statistical 
power than traditional OLS)95. If non-normality or outliers appear problematic, we will use the 
Wilcox functions base on M estimation. We will examine associations between arm and 
baseline variables to ensure successful randomization. Our analytic approach follows NIH 
guidelines on rigor and reproducibility, including analysis of sex as a potential covariate. Aim 1: 
Demonstrate target engagement. Child reliance on parent for amygdala reactivity reduction 
(calculated as the difference between amygdala reactivity to fear faces in the parent-absent 
compared to parent-present scan, and from hereon referred to as ‘child reliance on parent’) 
will decrease significantly from PRE to POST treatment for children whose parents participate in 
SPACE, as compared with children whose parents participate in CBT. The assessments of 
interest for this question are PRE and POST. The additional time-point (MID) will be useful to 
gain preliminary insights relating to more complex questions of mediation. The OLS analysis is a
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2-group single degree of freedom contrast between SPACE and CBT using child reliance on 
parent at PRE as a covariate to increase statistical power. The single degree of freedom contrast 
focuses on the comparison of covariate-adjusted means at POST. Of interest is whether the 
contrast between arms is statistically significant for child reliance on parent; the direction of 
change will be determined by the sign of the parameter estimates. A dummy variable for the 
two arms (SPACE, CBT) will be included in the OLS analysis, with randomization to SPACE scored 
1 and randomization to CBT scored 0. A statistically significant negative parameter estimate of 
the effect of treatment arm on child reliance on parent indicates that reduction in child reliance 
on parent at POST is significantly greater following SPACE compared with CBT. The same 
analysis will be conducted for mPFC activation and for amygdala-mPFC functional connectivity.
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of 
the section.
A. RADIOTRACERS ☒ N/A
B. DRUGS/BIOLOGICS ☒ N/A
B. DEVICES ☒ N/A
1. Targeted Enrollment: Give the number of subjects:
a. Targeted for enrollment at Yale for this protocol: 226 children and their mothers, for 
a total of 452 participants
b. If this is a multi-site study, give the total number of subjects targeted across all sites: 
Write here:
2. Indicate recruitment methods below. Attach copies of any recruitment materials that will 
be used.
☒  Flyers
☒  Internet/web postings
☐ Radio
☐Tabling
☐Posters
☐  Mass email solicitation
☐ Telephone
☒ Letter (postcard)☒  Departmental/Center website ☐ Television
☐X Blog posting with approved messaging/advertising 
☐Newsletter via email
☐X messaging/advertising on music-listening platforms
☐Medical record review*
☒  Departmental/Center research boards
☐x Newspaper
☒  Departmental/Center newsletters
☒ Web-based clinical trial registries☒ 
Clinicaltrails.gov
☒ YCCI Recruitment database
☒ Other: The Yale Child Study Center Anxiety & Mood Disorders Program sees children with 
anxiety disorders and those who meet study criteria will be offered the opportunity to 
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES
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participate in the study.
☒ Social Media (Twitter/Facebook):
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* Requests for medical records should be made through JDAT as described at
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3. Recruitment Procedures:
a. Describe how potential subjects will be identified. Children will be recruited through 
ongoing evaluations regularly conducted at the Yale Child Study Center. The YCSC has 
existed for over a century and is a major referral source for the community, treating 
children from all over Connecticut (as well as neighboring states). We therefore 
anticipate no difficulty in attaining the projected children and parents for this project. 
After a pre- treatment assessment (PRE), patients will be randomized into either parent- 
only treatment (SPACE) or child-only treatment (CBT).
b. Describe how potential subjects are contacted. Parents who are interested in 
enrolling their child in the study will make initial contact. A phone screen will be 
administered by a study personnel member to ensure their child is experiencing anxiety 
difficulties and is eligible for MRI.
c. Who is recruiting potential subjects? The study personnel including PI and research 
assistants will be responsible for recruiting potential subjects.
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?
☐Yes, all subjects
☒ Yes, some of the subjects
☐No
If yes, describe the nature of this relationship. Some participants may have been assessed or 
treated by members of the research team in the past.
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only. Note: if you are 
collecting PHI as part of a phone or email screen, you must request a HIPAA waiver for 
recruitment purposes.)
Choose one:
☐For entire study
☒ For recruitment/screening purposes only
☐For inclusion of non-English speaking subject if short form is being used and there is no 
translated HIPAA research authorization form available on the University’s HIPAA website at 
hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data: It would be impractical to obtain the subject’s
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authorization because the screening phase occurs over the telephone. That is 
because parents will make initial contact with us prior to enrolling their child in the 
study. During this initial phone contact, a standardized phone screen will be 
completed to ensure that their child is experiencing anxiety problems and is eligible 
for MRI. The following information will be collected: demographic information 
(including youth’s home address, age, sex), referral source, a brief description of 
presenting problem, whether or not the youth is on medication (name and dosage), 
and contraindications for MRI contained on the Yale Magnetic Resonance Research 
Center’s metal screening form or the Yale Brain Imaging Center’s metal screening 
form. We will obtain verbal authorization from the parent by including the following 
language in the telephone script:
“We will keep the information we just talked about in our files until you come in to the Child 
Study Center to sign informed consent and complete the study’s procedures. If you are eligible 
and choose to be part of the study, this information will become part of your study file. If you 
are not eligible or don't come in, we will keep this information until the study is over and then 
we will destroy it. We are required by law to keep this information confidential and we will not 
use it for any purpose other than to see if you qualify for this study and for research oversight.”
ii.
If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data: Write here
6. Process of Consent/Assent: Describe the setting and conditions under which consent/assent 
will be obtained, including parental permission or surrogate permission and the steps taken to 
ensure subjects’ independent decision-making.
For Parents: The PI or study personnel will explain the study to the participants. We will ensure 
that they have understood the terms of consent and their rights and privileges. The explanation 
will include a description of the randomization procedures. After that, if participants are willing 
they will sign the consent form. Separate consent will be requested for the videotaping of the 
parent-child interactions. Those who decline involvement will be offered alternative treatment 
at the Child Study Center Outpatient Clinic, as well as receive referral information for 
alternative appropriate treatment resources.
The investigator assures that the protected health information for which a Waiver of 
Authorization has been requested will not be reused or disclosed to any person or entity other 
than those listed in this application, except as required by law, for authorized oversight of this 
research study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject name, 
purpose, date, recipients, and a description of information provided. Logs are to be forwarded to the
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For Children: Parental informed consent will be obtained prior to the child’s assent. The PI or 
study personnel will explain the study to the participants and to the parents in developmentally 
appropriate terms. The explanation will include a description of the randomization procedures. 
We will ensure that parent and child understand the terms of consent and their rights and 
privileges. After that, if they are willing, parents will provide permission and children will sign 
the written assent. Separate consent will be obtained for the videotaping of the parent-child 
interactions.
The following documents will be used during the consent/assent process:
Compound Authorization and Parental Permission Form Child Assent Form (children 6-12 years 
of age) Videotaping consent form
The session will proceed only when the investigator, the participant, and (for children) his or 
her parent(s) or legal guardian(s) are in full agreement that the procedures are understood and 
the subject's assent (children) and consent (parents or legal guardians) has been obtained.
7. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to 
the research being proposed. The minimal age for participation is six. To ensure that all children 
and parents have understood the consent and are capable of granting consent or assent, the 
member of the research team will briefly discuss those terms with him or her asking one or two 
pertinent questions in age appropriate language. Trained study
personnel are experienced with working with children, adolescents, and adults in a research 
setting, including clinical populations.
8. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use.
This study will only enroll participants who are fluent in English because of the need for 
standardized measures of anxiety and related symptoms.
As a limited alternative to the above requirement, will you use the short form* for consenting 
process if you unexpectedly encounter a non-English speaking individual interested in study 
participation and the translation of the long form is not possible prior to intended enrollment? 
YES ☐ NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same language, 
then the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
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Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated 
HIPAA Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of 
the short form is not available on our website, then the translated short form needs to be submitted to the IRB 
office for approval via modification prior to enrolling the subject. Please review the guidance and presentation 
on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a 
HIPAA waiver in the section above.
9. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a 
full waiver of consent, depending on the study. If you will request either a waiver of consent, or 
a waiver of signed consent for this study, complete the appropriate section below.
☐Not Requesting any consent waivers
☒ Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will 
apply to recruitment activities only)
☐Entire Study (Note that an information sheet may be required.)
☐Requesting a waiver of consent:
☐Recruitment/Screening only (if for recruitment, the questions in the box below will 
apply to recruitment activities only)
☐Entire Study
For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research? YES ☒ NO ☐
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒ NO ☐ 
OR
Does the research pose greater than minimal risk? YES ☐ NO☐
Does the research include any activities that would require signed consent in a non-research context?
YES ☐ NO ☐
For a full waiver of consent, please address all of the following:

Does the research pose greater than minimal risk to subjects?
☐Yes If you answered yes, stop. A waiver cannot be granted.
☐No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐ NO☐

Why would the research be impracticable to conduct without the waiver? Write here

Where appropriate, how will pertinent information be returned to, or shared with subjects at a 
later date?
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SECTION IV: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
1. What protected health information (medical information along with the HIPAA 
identifiers) about subjects will be collected and used for the research? Protected health 
information will include psychiatric diagnoses, parents’ and youth’s ratings on measures 
of anxiety and related symptoms, medical history including history of anxiety disorders, 
and personal demographic information.
2. How will the research data be collected, recorded and stored? All research data will be 
collected by trained research personnel. Data will be collected in hard copy for some 
measures (e.g., semi-structured interview) and computerized form for other measures 
(e.g., Qualtrics-collected self-report and parent-report questionnaires, behavioral tasks 
administered on a computer, MRI scans that are collected via computer and stored on a 
secure server). Telephone screening paper forms will be stored under lock and key 
and/or on the HIPAA-compliant Qualtrics server. Participants who enroll in the study will 
be assigned a study ID code. Data collection will be conducted using the participant’s 
unique study ID code. Behavioral and MRI data with participants’ study ID codes data 
will be stored on a secure Yale-ITS server that only authorized trained study personnel 
can access; hard copies will be stored under lock and key in the secure research- 
dedicated space at Yale (Yale Child Study Center and Kirtland Hall). Only authorized Yale 
personnel will have access to the linking code/PHI files, which will be kept separate from 
the research data in locked files within secure research-dedicated space at Yale (Yale 
Child Study Center and Kirtland Hall), on a secure Yale-ITS server. Subject identifiers and 
linking code will be stored in separate locations within the database and have distinct 
access controls (e.g., different passwords).
3. How will the digital data be stored? ☐ CD ☐ DVD ☒ Flash Drive ☒ Portable Hard 
Drive
☒ Secured Server ☒ Laptop Computer ☒ Desktop Computer ☐ Other
4. What methods and procedures will be used to safeguard the confidentiality and security 
of the identifiable study data and the storage media indicated above during and after 
the subject’s participation in the study? Confidentiality will be maintained by assigning 
each subject a number ID to be used on all data collected. PHI will not be kept on 
portable devices. Any data stored on portable devices will only contain the participant’s 
study ID code (e.g., behavioral data collected on a laptop at the MRI scanner, backup 
copies of MRI scans on a portable hard drive or secured server). All computers and 
databases will be password-protected. Hard copies of all collected data (i.e., surveys and 
questionnaires) will be stored in locked file cabinets. Thus all data will be de-identified, 
coded, and stored in locked cabinets or password protected computer or server in an 
office that is locked. Information that will break subject confidentiality will not be 
shared. Data will only be released upon written consent of youth’s parent and will be 
available for review by the Yale Human Investigation Committee. Only members ofthe
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research team will have access to participants’ protected health information. Consistent 
with recent data-sharing efforts (e.g., 1000 Functional Connectomes Project), data from 
this study may be shared in repositories including those supported by the NIH (e.g., 
NITRC). All data will be anonymized prior to sharing. Genetic data will not be shared.
5. What will be done with the data when the research is completed? Are there plans to 
destroy the identifiable data? If yes, describe how, by whom and when identifiers will be 
destroyed. If no, describe how the data and/or identifiers will be secured. Research data 
will be retained in accordance with Yale and HIPAA guidelines. De- identified data will be 
stored indefinitely (as noted above, archived computer files will not have any identifying 
information); any PHI and linking code with identifiers will be destroyed seven years 
following the end of the study. We will store paper files for seven years at which point 
they will be destroyed by study personnel or professional Yale affiliated service.
6. If appropriate, has a Certificate of Confidentiality been obtained? COC is automatic with 
NIH funded studies
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)
The proposed study has the potential to benefit participants directly and to benefit others who 
currently suffer from anxiety or will in the future.
Direct Benefit: Anxiety disorders cause great distress and carry short and long term negative 
consequences if not successfully treated. Children participating in this study will either receive 
parent-or child-based treatment aimed at improving their symptoms and they can benefit from 
having less anxiety through participation in the study. As such, there is the potential for the 
child to benefit. Parents too can benefit from participation in the study. Child improvement is 
one of the potential benefits to parents. Parents may also benefit from learning how to better 
respond to their child’s symptoms and from being able to actively help their child overcome 
anxiety.
Benefits to others with anxiety: The aim of this study is to enhance outcomes for treatment of 
childhood anxiety.
Societal Benefits: Anxiety disorders are exceedingly common and carry huge societal costs 
through multiple consequences such as decreased work productivity, school dropout, and 
teenage childbearing. Given the limits on the efficacy of current treatment, the investigation of 
a novel intervention, distinct from what is done in current treatment, has the potential for large 
societal benefit. This study will also provide novel and important information on the
All portable devices must contain encryption software, per University Policy 5100. If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and Compliance 
Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
SECTION V: POTENTIAL
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neurobiology of child anxiety and treatment response and may provide the first evidence that 
parent-based treatment can impact a child’s brain functioning, with potential benefits for 
children with anxiety and other problems.
Risk to Benefit: The study has very low risk but the potential to benefit the participants directly, 
other future potential patients, and society at large. Therefore, the low risks to the subjects are 
justified by the potential knowledge to be gained.
1. Alternatives: What other alternatives are available to the study subjects outside of the 
research? CBT or parent training may be provided as standard of care to youth not 
participating in this study.
2. Payments for Participation (Economic Considerations): Describe any payments that will 
be made to subjects, the amount and schedule of payments, and the conditions for 
receiving this compensation. Participants will be compensated $50 for the first MRI visit 
(which is expected to take approximately 2-2.5 hours) or a tablet of equal value. 
Participants will be compensated $100 for the second MRI visit (which is expected to 
take approximately 2-2.5 hours) or tablets of equal value. Participants can choose 
whether to receive the cash or the tablet(s) of equal value. Participants are 
compensated regardless whether they finish the MRI scan so that participants who feel 
uncomfortable with the scan can discontinue without concern about compensation. 
Participants who complete all components of the appointment will receive an 
additional
$50 at each visit. The payment will be given to the parent participant who will provide it 
to the child participant at their discretion. Participants who return for their 6-month 
follow up appointment will be compensated an additional $100 or tablet(s) of equal 
value. There are no other payments to participants.
3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the 
study that will be provided at no cost to subjects. There are no costs to subjects for 
participation in this study, apart from the cost of time and resources involved in arriving 
for treatment and evaluation sessions.
4. In Case of Injury: This section is required for any research involving more than minimal 
risk, and for minimal risk research that presents the potential for physical harm (e.g., 
research involving blood draws).
a. Will medical treatment be available if research-related injury occurs? Write 
here
b. Where and from whom may treatment be obtained? Write here
c. Are there any limits to the treatment being provided? Write here
d. Who will pay for this treatment? Write here
e. How will the medical treatment be accessed by subjects? Write here
N/A –the present study does not involve greater than minimal risk.
In the event that an incidental finding occurs from the MRI scan, the decision as to proceed 
with further examination or treatment lies solely with the participant and their physician. The 
investigators and Yale University are not responsible for any examination and treatment 
expenses that result from the participant’s decision to seek further investigation based upon 
these findings.
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IMPORTANT REMINDERS
Will this study have a billable service? Yes ☐
No☒
A billable service is defined as any service rendered to a study subject that, if he/she was not 
on a study, would normally generate a bill from either Yale-New Haven Hospital or Yale 
Medical Group to the patient or the patient’s insurer. The service may or may not be 
performed by the research staff on your study, but may be provided by professionals within 
either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no 
distinction made whether the service is paid for by the subject or their insurance (Standard of 
Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally includes 
new services or orders placed in EPIC for research subjects.
Are there any procedures involved in this protocol that will be performed at YNHH or one of its 
affiliated entities?
Yes ☐ No ☒
If Yes, please answer questions a through c and note instructions below.
a. Does your YNHH privilege delineation currently include the specific procedure that you 
will perform? Yes ☐
No☐
b. Will you be using any new equipment or equipment that you have not used in the past 
for this procedure? Yes ☐ No ☐
c.
Will a novel approach using existing equipment be applied? Yes ☐ No ☐
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH
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