A Novel Mechanism-Based Treatment for Pediatric Anxiety Disorders
Phase: NA
Conditions: Cognitive Training, Anxiety Disorders
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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[A novel mechanism-based treatment for pediatric anxiety 
disorders] 
 
 
Principal Investigator:   
Chad Sylvester, M.D., Ph.D. 
 
 
 
 
 
 
 
Version Date/Number: 
2 – 12/10/2020  

 
 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
 
Anxiety disorders are the most common form of pediatric psychiatric illness, affecting up 
to 30% of youth by age 18.1 These disorders often produce marked impairment,2 are 
associated with aberrant neurodevelopment,3 and predict high risk for various forms of 
adult psychopathology.4 While successful early intervention can occasionally interrupt 
this cascade,5,6 most affected children remain symptomatic even with the best available 
treatments.7 This study tests a novel, safe, mechanism-based treatment for pediatric 
anxiety disorders: a computer-delivered cognitive training program designed to 
rehabilitate the brain’s ventral attention network (VAN). 90 children between the ages of 
7 and 17 years of age will be enrolled at 2 sites (45 at Washington University and 45 at 
the NIMH). Children will be randomly assigned to active versus placebo cognitive 
training. Clinical symptoms and brain activity (measured with functional magnetic 
resonance imaging: fMRI) will be measured before and after training. This study has the 
potential to provide a novel, safe treatment for anxiety disorders as well as uncover the 
neural associates of this treatment. 
A2 Primary Hypothesis 
 
 
The active cognitive training program decreases symptoms of anxiety in children with 
anxiety disorders relative to sham training. 
A3 Purpose of the Study Protocol 
 
This study protocol is to be used as the working document for the study team to ensure 
that the conduct of the research is consistent with what has been approved by the IRB.  
B Background 
 
B1 Prior Literature and Studies 
 
Anxiety disorders are the most common form of pediatric psychiatric illness, affecting up 
to 30% of youth by age 18.1 These disorders often produce marked impairment,2 are 
associated with aberrant neurodevelopment,3 and predict high risk for various forms of 
adult psychopathology.4 While successful early intervention can occasionally interrupt 
this cascade,5,6 most affected children remain symptomatic even with the best available 
treatments.7 Recent advances in neuroscience elucidate potential brain-based targets 
for novel therapies, which may improve this outlook by providing advances over current 
therapies.3 This study tests a novel, safe, mechanism-based treatment for pediatric 
anxiety disorders: a computer-delivered cognitive training program designed to 
rehabilitate the brain’s ventral attention network (VAN). This study has the potential to 
lead to a novel treatment with a known mechanism of action, which targets a major 
public health problem. 

 
 
 
 
 
 
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Treatments targeting the VAN may reduce anxiety by reducing neural activity associated 
with the involuntary capture of attention by salient stimuli.  Prior research links anxiety 
disorders to an overactive ventral attention network (VAN),8 which encompasses the 
ventrolateral prefrontal cortex (VLPFC) and temporal-parietal junction (TPJ) and 
supports involuntary capture of attention by salient stimuli.9 Infants at risk for anxiety 
disorders exhibit signs of an overactive VAN, including increased attention and 
increased VAN activity in response to novel stimuli, such as new toys and people.10-12 
Moreover, in brain imaging studies, the investigators have linked abnormally increased 
VAN reactivity to anxiety in older children, adolescents, and young adults.13-18 
Importantly, related disorders such as major depression and ADHD are not associated 
with an overactive VAN, suggesting specificity to anxiety.8,19 Taken together, this set of 
findings supports the hypothesis of an overactive VAN in pediatric anxiety disorders and 
suggests that reducing VAN reactivity may have a specific effect in reducing anxiety 
symptoms. Yet, no treatments have been developed to explicitly correct VAN 
dysfunction by directly targeting this network. The treatment tested in this study aims to 
fill that gap. 
Computer-based cognitive training programs provide a safe, tolerable tool to reduce 
VAN reactivity and potentially treat pediatric anxiety disorders. Randomized controlled 
trials already support the use of cognitive training programs with targets different from 
the VAN.20-22  For example, attention bias modification (ABM) trains individuals to ignore 
threatening stimuli in order to improve symptoms of anxiety.23 While promising, this 
treatment generates no more than modest effects on symptoms.24,25 The treatment in 
this study was specifically designed to reduce reactivity of the overactive VAN 
associated with pediatric anxiety disorders, by training individuals to actively ignore 
salient stimuli while maintaining attention on a particular task. By targeting a particular 
brain network that implements a core psychological process disrupted early in the 
developmental pathway to anxiety disorders, this novel treatment could represent a 
major improvement to current cognitive training approaches and may have a more 
substantial impact on symptoms. 
B2 Rationale for this Study 
 
Previous findings support the hypothesis of an overactive VAN in pediatric anxiety 
disorders and suggest that reducing VAN reactivity may have a specific effect in 
reducing anxiety symptoms. Yet, no treatments have been developed to explicitly correct 
VAN dysfunction by directly targeting this network. The treatment studied in this project 
aims to fill that gap. The rationale of this research is that it could lead to a novel, safe, 
mechanism-based treatment for a major public health problem. 
 
C Study Objectives 
 
C1 Primary Aim 
 
Test the efficacy of a novel computer-based cognitive training program in the treatment 
of pediatric anxiety disorders using a pilot double-blind, randomized, placebo-controlled 

 
 
 
 
 
 
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design. The primary outcome will be reduction in symptoms of anxiety as measured by 
the Pediatric Rating Scale (PARS). 
C2 Secondary Aim 
 
Uncover the neural effects of the cognitive training program using functional magnetic 
resonance imaging (fMRI). 
 
C3 Rationale for the Selection of Outcome Measures 
 
The PARS is a clinician-administered measure of pediatric anxiety that incorporates both 
parent and child report.26 Because it includes multiple informants and is anchored by a 
clinician, it has high reliability and validity and is widely used. 
 
D Investigational Agent  
 
D1 Preclinical Data 
 
This is the first study to use this exact computer training regimen for testing in its ability 
to reduce symptoms of anxiety in children with anxiety disorders. Each session of the 
computer game takes approximately 30 minutes and subjects complete 8 total sessions 
over one month. The computer game involves paying attention to parts of the screen 
while distracting square boxes appear at other locations. A target “X” appears at the 
location that participants are paying attention to and the subjects press a button when it 
appears. We have piloted this protocol in 4 healthy children between the ages of 7 and 
17 years of age. The procedure was well tolerated with no adverse events reported in 
any of the subjects. 
D2 Clinical Data to Date  
 
There are no clinical data to date on this computer training program. Other cognitive 
training programs such as attention bias modification that involve similar procedures 
have proven effective for treating anxiety disorders in meta-analyses with no known 
adverse events reported. 
D3 Dose Rationale and Risk/Benefits  
 
The dose is based on dosing of computer-based cognitive training programs in the 
literature. We will have subjects complete between 250 and 300 trials of the training 
program (30 minutes total) for each session; subjects complete 8 total training sessions.  
 
Potential benefits are reduced anxiety and improved attentional control. 
 

 
 
 
 
 
 
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There are no known significant risks to this treatment. Potential mild risks include 
boredom, fatigue, and slight stiffness from sitting in a chair for 30 minutes. 
E Study Design  
 
E1 Overview or Design Summary 
 
The study consists of a Baseline Psychiatric Assessment, Baseline Neuroimaging 
Assessment, Cognitive Training, Follow-up Psychiatric Assessment, and Follow-up 
Neuroimaging Assessment. 
 
Baseline Psychiatric Assessment: Subjects and their primary caregiver undergo a 
psychiatric interview (regarding the child) and answer questions regarding recent 
symptoms. Children also complete 3 different computer games (taking between 60 and 
90 minutes total). These computer games are designed to measure stimulus-driven 
attention, attention bias to threat, and attentional control. 
 
Baseline Neuroimaging Assessment: Subjects undergo fMRI while they perform a task 
that measures their stimulus-driven attention and attention bias to threat. 
 
Cognitive Training: Subjects are randomly assigned to either active or sham training. 
Subjects are blinded to assignment. Both groups complete 8 total sessions of training 
over one month; each session take approximately 30 minutes. 
 
Follow-up Assessment: Subjects complete follow-up Psychiatric and Neuroimaging 
Assessments. These assessments are identical to the corresponding Baseline 
Assessments and are designed to assess behavioral and neural response to training. 
 
E2 Due to COVID-19, participants may be contacted via phone and e-mail 
to participate in some follow-up surveys. Once contacted, we may set 
up a zoom meeting. A member of the research team will explain that 
this is completely optional and will review the online survey process 
with the family over the phone or zoom. If the family agrees to 
participate, the research team member will e-mail a RedCap survey 
link that will start with the consent form. Researcher will walk 
participant through how to complete the surveys over the phone or 
zoom. Participants will have adequate time to review the consent 
document and there will be an e-mail address provided if the 
participant should have any questions. The participants e-signature 
through REdCap will have a time stamp. After the consent is signed, 
research staff will send an electronic copy of the signed consent 
document to the participant via e-mail.Subject Selection and 
Withdrawal  
 
Subjects will be screened over the phone standardized parent-report psychiatric 
instruments (Screen for Anxiety and Related Disorders, SCARED; and Mood and 
Feelings Questionnaire, MFQ). 

 
 
 
 
 
 
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2.a 
Inclusion Criteria  
 
We will recruit children between the ages of 7-17 for this study with current separation 
anxiety disorder, generalized anxiety disorder, and/or social phobia.   
2.a 
Exclusion Criteria  
 
Exclusion criteria include prior diagnoses of ADHD, autism spectrum disorder, 
intellectual disability (IQ<70), a significant medical problem, or current use of 
psychotropic medication other than SSRIs (children who are currently taking an SSRI 
and are still experiencing symptoms of anxiety will not be exluded). 
2.b 
Ethical Considerations  
 
There are no major ethical concerns associated with this study. 
2.c 
Subject Recruitment Plans and Consent Process 
 
Children will be recruited through local schools, pediatricians’ offices, and through Dr. 
Sylvester’s child anxiety clinic by asking staff to present IRB approved recruitment 
materials to potentially interested families. We will also recruit with advertisements, 
press releases, websites, and placement of approved flyers and materials throughout 
the greater Washington University community as well as throughout the St. Louis 
community. 
 
A member of the research team will review screening materials and contact potential 
participants by phone. This member of the research team will provide parent participants 
with information about the study and required elements of consent over the telephone 
prior to obtaining the parent's verbal consent to participate in the screening elements of 
the study (Initial Phone Screen as well as SCARED/MFQ). After obtaining verbal 
consent, a research assistant will administer the Initial Phone/Exclusion Screen to all 
potential participants. If a parent and child meet eligibility criteria for enrollment in the 
study based on their Initial Phone Screen, and parents indicate they wish to continue 
with the study, the research team will arrange an in-person assessment. On the day of 
the in-person assessment, a research assistant will provide ample time for the parents to 
read/review the consent form and will answer any questions the parent may have prior to 
signing. 
2.d 
Randomization Method and Blinding 
 
Subjects will be randomized to active vs. sham treatment on a 50/50 basis. The 
participants and the staff performing the pre- and post- treatment psychiatric interviews 
will remain blinded throughout the study. Study staff administering the treatment will be 
aware of the active vs. sham status of the participant, in order to deliver and monitor the 
appropriate cognitive training program. 
2.e 
Risks and Benefits 
 

 
 
 
 
 
 
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There are minimal risks associated with this study. Parents and children may feel 
uncomfortable or bored during the first assessment during the clinical interview. There is 
also a risk of breach or confidentiality. During the cognitive training, risks for child 
participants include boredom and very slight physical discomfort due to sitting and using 
a chin rest. MRI scans involve no major risks for subjects without implanted metal 
objects. Subjects are extensively screened before scanning and are not allowed to 
participate if they have any implanted metal objects. Additional minor potential risks of 
MRI are discomfort from being in a small space and lying still in one position for a long 
time. There are also loud noises made by the scanner but subjects will wear earphones 
to mask the sound.  
 
 
The benefits to this study are that the treatment could potentially alleviate symptoms and 
distress in a participant. Also the participant is receiving a free diagnostic assessment, 
which typically is expensive and takes a long period of time to get an appointment. 
 
2.f 
Early Withdrawal of Subjects  
Subject participation in the study is completely voluntary and they can choose to 
withdraw at any time. 
2.g 
When and How to Withdraw Subjects  
 
If subjects meet exclusion criteria in their initial in office assessment, they will be 
withdrawn from the study. Subjects may also choose to withdraw from the study at 
anytime. 
 
E3 Study Device   
 
Cognitive Behavioral Training  
3.a 
Description  
 
The cognitive training program is designed by Dr. Sylvester. It is designed to lower 
activity in the VAN by reducing the influence of extraneous, salient stimuli, thereby 
reducing stimulus-driven attention and potentially anxiety.  
 
To begin a trial, subjects fixate a central crosshair; 150 ms later, an arrow “cue” appears 
at the center of the screen and subjects are instructed to voluntarily direct their attention 
toward the location indicated by arrow. Following a random delay of 1, 2, or 3 seconds, 
subjects indicate whether a “target” (that always appears at the location indicated by the 
initial arrow cue). 
 
Active training: In between the presentation of the cue and target, three “distractor” 
boxes appear at irrelevant locations at random times. Subjects are instructed to ignore 
these boxes. It is the active ignoring of these boxes, while maintaining attention 
voluntarily at the cued location that is proposed to reduce subjects’ stimulus-driven 
attention and reduce excessive VAN activity. Sham training: Subjects perform the same 

 
 
 
 
 
 
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number of trials, of the same task, with the exception that the “distractor” boxes never 
appear. Thus, subjects still have to voluntarily direct attention, but they do not get 
practice ignoring irrelevant distractors. Both subjects and clinical interviewers will be 
blinded to active versus sham treatment. Subjects will be randomized to treatment arm. 
3.b 
Treatment Regimen  
Half of the subjects will be randomized to active cognitive training and half will be 
randomized to sham training. Children will participate in 8 total 30-minute training 
sessions, twice a week for 4 weeks. 
3.c 
Method for Assigning Subjects to Treatment Groups  
 
Subjects will be randomized to active vs. sham treatment on a 50/50 basis. 
3.d 
Subject Compliance Monitoring  
 
Subjects will be participating in the cognitive training program twice a week for four 
weeks in the presence of a trained research assistant. 
3.e 
Blinding of Study Drug  
 
Subjects will not be aware if they are participating in the active or sham treatment.  
F Study Procedures  
 
F1 Screening for Eligibility 
 
Subjects will be screened over the phone standardized parent-report psychiatric 
instruments (Screen for Anxiety and Related Disorders, SCARED; and Mood and 
Feelings Questionnaire, MFQ). 
 
F2 Visit 1  
 
Child/Parent In-Office Assessment:  
 
Parents will begin by completing Kiddie Schedule for Affective Disorders and 
Schizophrenia Present and Lifetime Edition (K-SADS-PL), the Pediatric Rating Scale, 
(PARS), and the Family Interview for Genetic Studies (FIGS) with trained research staff. 
These semi-structured interviews will be audio taped and will only be listened to by study 
staff. Parents will also complete additional questionnaires. The child will participate in a 
computer game that is designed to test various aspects of their attention.  
 
The child will rest their chin on a chin rest and their eye movements will be recorded. 
There are three different versions of the game. In each version, the computer game 
involves looking at a central “+” sign and pressing a button when a target appears in 

 
 
 
 
 
 
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either the center of the screen or the periphery. The child will also view different shapes 
and faces (happy, sad, angry, scared, and neutral) while engaged in the computer 
game. Following the game, the child will answer questionnaires (general questionnaire, 
SCARED, Childhood Depression Inventory (CDI), MFQ, and Pubertal Development 
Scale(PDS)) and participate in the child version of the K-SADS and PARS. 
 
F3 Visit 2  
 
Neuroimaging Visit:  
 
MRI Simulation/Stillness Training: Child participants will complete a MRI training session to 
collect data on movement inhibition and prepare subjects for future MRI testing. Research 
indicates that an MRI simulation exercise prior to scanning increases the likelihood of a 
successful scan. Given that, an introduction to/explanation of the scanning procedure and a 
simulation exercise will be introduced at the conclusion of the child assessment. The child 
interviewer will engage the child in an MRI simulation. In this simulation, the child will practice 
lying still in a mock scanner environment. The child will practice lying still while listening to 
recorded MRI sounds and receiving visual feedback of their head movement. Feedback will be 
provided using motion tracking software, MoTrak 3D, connected to a video screen viewed from 
the scanner by the research subject. Subject movement and responsiveness to the training 
procedures will be recorded. Children will also be shown a video in which the scanning center is 
introduced and the scanning procedure is explained to the child. In the video, the child will see 
another child participating in the MRI procedure. 
 
The NEUROIMAGING TRAINING could take place on the same day following the IN-
PERSON ASSESSMENT, on the same day before the NEUROIMAGING VISIT, or on its 
own day, depending on the preference of the participant. 
 
Before the MRI scan, parents will complete the MRI Safety checklist to ensure the child 
safety in the scanner and the child will complete a shortened version. The child will 
complete a 90 minute MRI scan before and after the cognitive training. We acquire a T1-
weighted MP-RAGE, a T2 image, 4 five-minute “resting” functional scans, and 4 four-
minute “task” functional scans. During the resting scans, the subjects with fixate a cross 
and during task blocks, subjects will complete the attention tasks. There will be no 
contrast used for this MRI scan.  
 
F4 Visit 3-10  
 
The child will participate in 8 thirty minute training sessions, twice a week for four weeks. 
They will complete the cognitive training program that has been designed by Dr. 
Sylvester. 
 
On the day of sessions 2, 4, 6, and 8 subjects and parents complete the SCARED either 
in office or by a secure e-mail survey invitation via REDcap  in order to assess anxiety 
over treatment. After session 8, subjects will be asked to rate tolerability of the training 
on a 5 point Likert scale. 
 
F5   Visit 11  

 
 
 
 
 
 
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This visit will be after all 8 training sessions are completed and is identical to visit 1.  
 
F6   Visit 12  
 
This visit will be after all 8 training sessions and visit 11 are completed and is identical to 
visit 2.  
 
Follow-up via Phone/Zoom 
 
A member of the research team will explain that this is completely optional and will 
review the online survey process with the family over the phone or zoom. If the 
family agrees to participate, the research team member will e-mail a RedCap survey 
link that will start with the consent form. Researcher will walk participant through 
how to complete the surveys over the phone or zoom. Participants will have 
adequate time to review the consent document and there will be an e-mail address 
provided if the participant should have any questions. The participants e-signature 
through REdCap will have a time stamp. After the consent is signed, research staff 
will send an electronic copy of the signed consent document to the participant via e-
mail. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
 
Power analyses for two-tailed, two independent groups (active versus sham) 
comparisons were performed using G*Power 3.1. Based on prior work, we expect 
training to have a minimum effect size of 0.3 for changing symptoms of anxiety. Based 
on this effect size, we have 83% power to detect group differences in treatment effects 
(n=90, plus 10% failure). Power calculations are not computed for fMRI analyses 
because we have no effect size estimate; sample size is similar to other recent pilot 
studies. 
 
G2  Interim Monitoring and Early Stopping 
 
Subjects may withdraw from the study at any time. Each cognitive training session takes 
place in the lab. Study staff will converse with study subjects before and after each 
training session in order to assess for any adverse events. 
G3  Analysis Plan / Statistical Methods  
 
The primary outcome will be reduction in symptoms of anxiety as measured by the 
SCARED in study Phase 2. Total SCARED scores at sessions 2, 4, 6, and 8 will be 
subtracted from the baseline SCARED score, yielding a delta SCARED score for each 

 
 
 
 
 
 
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visit. These data will be analyzed with a mixed random effects repeated-measures 
model. In this model, time, treatment (active versus sham), and time x treatment 
interaction are fixed effects; baseline SCARED scores and subject within treatment are 
random effects; and delta SCARED scores are the dependent variable. Our hypothesis 
predicts a significant time x treatment interaction, with a greater decrease in anxiety from 
pre- to post- training in the active relative to the sham group. Secondary outcomes will 
include symptoms of anxiety on the PARS and diagnostic status. 
 
We will test whether active versus sham training significantly reduces symptoms in 
children with anxiety disorders. The primary outcome will be reduction in symptoms of 
anxiety as measured by the PARS. We will perform a 2 x 2 ANOVA with treatment arm 
(active versus sham) and time (pre- versus post-training) as effects of interest. 
 
G4  Missing Outcome Data 
 
We will use an intention-to-treat analysis and carry the last observation forward. 
Because this is a pilot study, we will also compare active versus sham treatment among 
completers in a follow-up analysis.  
G5  Unblinding Procedures  
 
The principal investigator will be made aware of each subject’s assignment after that 
subject has completed all study procedures including post-treatment psychiatric 
assessment. 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
 
Telephone conversations about the study, the consent process, and all portions of the 
study will take place in a private office. All subjects will be marked with a random 
identification number so names will not be recorded on any of the data. All data will be 
stored in locked filing cabinets and on password protected computers. Also, only the 
research team will have access to study information. Participants can refuse to answer 
any questions and withdraw from the study at any time.  
H2 Training  
 
All current study staff have extensive experience in study procedures, based on similar 
prior studies performed in the lab. Any new personnel will be trained by current study 
staff. 
H3 Case Report Forms and Source Documents 
 

 
 
 
 
 
 
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All data will be labeled with a number and not the participant’s name. All electronic data 
will be stored in a locked cabinet and on password protected and encrypted data storage 
devices/computers. Paper/hard copy records will be stored in a locked filing cabinet in a 
locked room. 
H4 Records Retention 
 
All data will be retained and destroyed once the study is completed.   
 
I 
Study Administration 
 
I1 
Organization and Participating Centers 
 
National Institutes of Mental Health, Bethesda, Maryland & Washington University 
School of Medicine, St. Louis, MO 
I2 
Funding Source and Conflicts of Interest 
 
Institutional Grant/Award: FBJH/ICTS 
Federal Agency: NIH, National Institute of Health  
 
ATTENTION AND RELATED FUNCTIONAL BRAIN NETWORKS IN PEDIATRIC 
 
ANXIETY DISORDERS 
 
There are no conflicts of interest.  
I3 
Subject Stipends or Payments  
 
Caregivers and child will be paid a total of $25 an hour together for each in person 
assessment, $50 for the completion of the cognitive training, and an additional $25 per 
hour for neuroimaging sessions.  
 
Caregivers and child will be paid a total of $50 for completion of the follow-up surveys on 
a Forte Card. 
I4 
 Study Timetable 
 
Our goal is to randomize 90 subjects to active versus sham treatment over 18 months at 
two sites (Washington University and the National Institute of Mental Health). To 
achieve, this goal we will recruit, on average, 2.5 subjects per month per site. The 
current plan is to perform this study from January 2018 through June 2019.  
J Publication Plan  
 
Manuscripts reporting the primary outcome of the study as well as the neural effects of 
training will be written at the completion of the study. 

 
 
 
 
 
 
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K  Attachments  
 
K1  Informed consent documents 
Novel Treatment Study Assent  
Novel Treatment Study Imaging Assent  
Novel Treatment Study Imaging Consent  
Novel Treatment Study Informed Consent  
Novel Treatment Consent for Phone Screen  
K2 Questionnaires or surveys 
 
Screen for Anxiety Related Disorders (SCARED)  
Mood and Feelings Questionnaires (MFQ)  
Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime 
Version(K-SADS-PL)  
Childhood Depression Inventory (CDI)  
Attention General Questionnaire  
Contact Information Sheet  
Pediatric Anxiety Rating Scale (PARS)  
Pubertal Development Scale (PDS)  
Family Interview for Genetic Studies (FIGS)  
Conners 
 
L References 
 
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