Neurally Targeted Cognitive Training to Augment Cognitive Behavioral Therapy (CBT) Outcomes in Pediatric Anxiety
Phase: NA
Conditions: Anxiety Disorders
Sponsor: University of Michigan

 
 
 
 
Neurally Targeted Cognitive Training 
to Augment CBT Outcomes in 
Pediatric Anxiety 
 
NCT04157296 
 
IRB Approval Date: July 23, 2021 
 
 

 
 
Neurally Targeted Cognitive Training to Augment CBT 
Outcomes in Pediatric Anxiety 
 
Protocol Number*: 1.0 
National Clinical Trial (NCT) Identified Number:  NCT04157296 
Principal Investigator*: Yanni Liu, Ph.D. 
Sponsor: University of Michigan Medical School 
Grant Title: MICHR Pathway to Independence 
Grant Number*:  AWD003558 
Funded by: MICHR 
Version Number:  9.0 
<19 July 2021> 
 

 
ii 
 
Summary of Changes from Previous Version:  
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.3, 4.1, 5.5, 
8.1.3  
An fMRI may be completed after 4 weeks of at 
home CCT for CBT+CCT group. 
Completing 4 weeks of at-home CCT is 
important as demonstrated by previous Akili 
studies, and may collect brain indexes of 
cognitive control capacity. 
8.1.3 
NIH toolbox assessment/Millisecond cognitive 
test/BRIEF2 questionnaire may be administered  
at fMRI scan following completion of 4 weeks 
of at home CCT for the CBT+CCT group. 
NIH toolbox assessment/Millisecond 
cognitive test/BRIEF2 questionnaire collect 
behavioral indexes of cognitive control 
capacity at same time as MRI. 
 
 
 

 
iii 
 
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the NIH 
terms of award.  
 

 
 
iv 
 
1 
CONTENTS 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities ........................................................................... Error! Bookmark not defined. 
2 
INTRODUCTION ............................................................................................................................................ 1 
2.1 
Study Rationale .................................................................................................................................... 1 
2.2 
Background........................................................................................................................................... 2 
2.3 
Risk/Benefit Assessment .................................................................................................................... 3 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
4 
STUDY DESIGN ............................................................................................................................................. 6 
4.1 
Overall Design ...................................................................................................................................... 6 
4.2 
Scientific Rationale for Study Design................................................................................................ 8 
4.3 
Justification for Intervention ............................................................................................................... 8 
4.4 
End-of-Study Definition ....................................................................................................................... 8 
5 
STUDY POPULATION .................................................................................................................................. 9 
5.1 
Inclusion Criteria .................................................................................................................................. 9 
5.2 
Exclusion Criteria ................................................................................................................................. 9 
5.3 
Lifestyle Considerations ...................................................................................................................... 9 
5.4 
Screen Failures .................................................................................................................................... 9 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 10 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 12 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 12 
6.2 
Fidelity ................................................................................................................................................. 13 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 13 
6.4 
Study Intervention/Experimental Manipulation Adherence.......................................................... 13 
6.5 
Concomitant Therapy ........................................................................................................................ 14 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 15 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 15 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 15 
7.3 
Lost to Follow-Up ............................................................................................................................... 16 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 16 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 16 
8.2 
Safety Assessments .......................................................................................................................... 21 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 22 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 26 
9.1 
Statistical Hypotheses ....................................................................................................................... 26 
9.2 
Sample Size Determination .............................................................................................................. 26 
9.3 
Statistical Analyses............................................................................................................................ 27 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 28 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 28 
10.2 
Protocol Amendment History ........................................................................................................... 35 
11 
REFERENCES ............................................................................................................................................. 37 

Neurally Targeted Cognitive Training to Augment CBT Outcomes in Pediatric Anxiety 
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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances that 
this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
Yanni Liu 
Date: 
9/24/2019 
 
Name*:  Yanni Liu 
 
Title*: Research Assistant Professor 
 
Investigator Contact Information 
Affiliation*: Department of Psychiatry, University of Michigan 
Address: 4250 Plymouth Rd, Ann Arbor, MI 48109 
Telephone: 7349369275 
Email: yanniliu@umich.edu 
 
 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Neurally Targeted Cognitive Training to Augment CBT Outcomes in 
Pediatric Anxiety 
Grant Number: 
MICHR Pathway to Independence AWD003558 
Study Description: 
Anxious youth (ages 7-17) will be recruited and assigned to cognitive 
behavioral therapy (CBT) only or computerized cognitive training 
(CCT) plus CBT groups. Multilevel data (clinical measures of anxiety, 
behavioral and brain indexes of cognitive control capacity) will be 
collected before and after treatment, to examine the extent to which 
CBT+CCT may engage brain and behavior targets related to cognitive 
control, and reduce anxiety symptoms. 
 
Objectives*: 
 
Primary Objective: Examine whether CBT+CCT will further engage the 
task control network (TCN). 
Secondary Objectives: (1) Examine whether CBT+CCT will further 
improve cognitive control capacity; (2) Examine whether CCT will 
augment the CBT outcome 
Endpoints*: 
Primary Endpoint: Brain activation and connectivity in the task-control 
network 
Secondary Endpoints: (1) Behavioral performance in cognitive 
interference task and tasks testing cognitive control capacity such as in 
the NIH toolbox; (2) Anxiety severity and treatment response rate 
Study Population: 
Anxious youth (AY) between the ages of 7 to 17.99 
Phase* or Stage: 
N/A  
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
University of Michigan 
Description of Study 
Intervention/Experimental 
Manipulation: 
Participants will be recruited to either CBT or CBT+CCT. In the CBT 
group, participants will be offered cognitive behavioral therapy (CBT), 
about one hour per week for up to 12 weeks with a therapist targeting 
anxiety symptoms; in the CBT+CCT group, participants will be offered 
additional cognitive training (about half an hour) before each of the 
CBT session for up to 12 weeks. They may also receive up to 4 weeks 
of at home CCT which may be completed for up to two weeks 
immediately prior to beginning CBT and up to the first four weeks of 
CBT (~30 minutes x 5 days per week).   
Study Duration*: 
1 year 
 
Participant Duration: 
4- 6 months 
 
 
 
 
1.2 
SCHEMA  
Flow Diagram  

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Administer Study Intervention Session 1-12 
MRI 2 
Post-intervention assessments  
MRI 1 
Arm 1 
N = 36 
Conduct informed consent process. Perform baseline assessments. 
refer to Section 1.1, Schedule of Activities 
Arm 2 
N = 18 

Neurally Targeted Cognitive Training to Augment CBT Outcomes in Pediatric Anxiety 
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MASC 
CDI 
Med. Ad. 
PARS 
CGI-S/I 
CGAS 
CSSRS 
SCARED-C 
BRIEF2 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
Food & Bev. 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CEQ 
SCARED-C 
SCARED-P 
BRIEF2 
PARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
PARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
WAI 
SCARED-C 
SCARED-P 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
PARS (no 
checklist) 
CGI-S/I 
CGAS 
CSSRS 
TARS 
SCARED-C 
SCARED-P 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
BAI 
BDI 
FAS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
Food & Bev. 
PARS 
CGI-S/I 
CGAS 
CSSRS 
WAI 
Grit 
Life Events 
TARS 
SCARED-C 
SCARED-P 
NIH toolbox 
and/or 
Millisecond 
BRIEF2 
 
1.3 
 SCHEDULE OF ACTIVITIES  
The following assessments and study activities may be done at each time point. For NIH Toolbox and PARS assessments, some variability in administration may occur based on 
subject’s schedule. All assessments completed as part of Dr. Fitzgerald’s study Dimensional Brain Behavior Predictors of CBT Outcomes in Pediatric Anxiety (HUM00118950) will 
not be repeated for this protocol and previously collected data will be used. At P.I. discretion, participants may also not be required to complete an fMRI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEY 
Black 
Administered by Fitzgerald Study 
Red 
Administered by Liu Study 
 
Overall study timeline of participation 
Initial 
Assessment 
Demo. 
SCQ 
CBCL 
BAI 
BDI 
FAS 
SCARED-P 
PDS 
Edin. Hand. 
STAI-C 
OCI 
MASC 
CDI 
PARS 
CGI-S/I 
CGAS 
CSSRS 
KSSADS 
Grit 
Life Events 
WASI 
fMRI Safety 
EFSAT 
MSIT 
Go/No-Go 
Preg. Test 
NIH toolbox 
and/or 
Millisecond 
fMRI 
Med. Ad. 
fMRI Safety 
EFSAT 
MSIT 
Debrief 
Preg. Test 
CBT #1 
CBT #2 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CBT #3 
CBT #4 
CBT #5 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CBT #6 
CBT #7 CBT #8 CBT #9 CBT #10 CBT #11 CBT #12 
fMRI 
Med. Ad. 
fMRI Safety 
EFSAT 
MSIT 
Debrief 
Preg. Test 
CBT-Only Timeline of Events (Primary Arm, Fitzgerald HUM00118950) 

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At-home  
CCT 
SAM 
MASC 
CDI 
Med. Ad. 
PARS 
CGI-S/I 
CSSRS 
Life Events 
Grit 
SCARED-C 
SCARED-P 
CGAS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
CGI-S/I 
CGAS 
Food & Bev. 
CSSRS 
TARS 
CEQ 
SCARED-C 
SCARED-P 
NIH toolbox 
and/or 
Millisecond 
BRIEF2 
PARS 
fMRI 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
CGI-S/I 
CGAS 
CSSRS 
TARS 
WAI 
SCARED-C 
SCARED-P 
PARS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
CGI-S/I 
CGAS 
CSSRS 
TARS 
SCARED-C 
SCARED-P 
PARS (no 
checklist) 
BAI 
BDI 
FAS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
Food & Bev. 
PARS 
CGI-S/I 
CGAS 
CSSRS 
WAI 
Grit 
Life Events 
TARS 
SCARED-C 
SCARED-P 
NIH toolbox 
and/or 
Millisecond 
BRIEF2 
Med. Ad. 
fMRI Safety 
EFSAT 
MSIT 
Debrief 
Preg. Test 
BAI 
BDI 
FAS 
CGI-I (P) 
MASC 
CDI 
Med. Ad. 
Food & Bev. 
PARS 
CGI-S/I 
CGAS 
CSSRS 
WAI 
Grit 
  Life Events 
TARS 
SCARED-C 
SCARED-P 
 
At-home  
CCT 
SAM 
At-home  
CCT 
SAM 
At-home  
CCT 
SAM 
At-home  
CCT 
SAM 
At-home  
CCT 
SAM 
CBT+CCT Timeline of Events (Primary Arm, Liu HUM00169730) 
 
 
 
 
 
 
 
 
 
 
 
 
KEY 
Black 
Administered by Fitzgerald Study 
Red 
Administered by Liu Study 
Blue 
Administered by Liu Study if more than about 6 weeks since collected at RMT #12 
Purple 
Administered by Fitzgerald Study if >3 weeks since collected at RMT #12 
 
Overall study timeline of participation 
 
RMT course of treatment 
 
Time between RMT #12 and fMRI #2 
 
Time between fMRI #2 and beginning at-home CCT 
Med. Ad. 
fMRI Safety 
EFSAT 
MSIT 
Debrief 
Preg. Test 
Demo. 
SCQ 
CBCL 
BAI 
BDI 
FAS 
SCARED-P 
PDS 
Edin. Hand. 
STAI-C 
OCI 
MASC 
CDI 
PARS 
CGI-S/I 
CGAS 
CSSRS 
KSSADS 
Grit 
Life Events 
WASI 
fMRI Safety 
EFSAT 
MSIT 
Go/No-Go 
Preg. Test 
NIH toolbox 
and/or 
Millisecond 
BRIEF2 
Initial 
Assess 
fMRI 
fMRI 
CCT 
SAM 
CBT #4 
CCT 
SAM 
CBT #5 
CCT 
SAM 
CBT #6
CCT 
SAM 
CBT #7 
CCT 
SAM 
CBT #8
CCT 
SAM 
CBT #9 
CCT 
SAM 
CBT #10 
CCT 
SAM 
CBT #11 
CCT 
SAM 
CBT #12 
RMT 
#12 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CSSRS 
TARS 
CGI-S/I 
CGAS 
CCT 
SAM 
CBT #2 
CCT 
SAM 
CBT #3 
CCT 
SAM 
CBT #1 
NIH toolbox 
and/or 
Millisecond 
BRIEF2 
PARS 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
 
Clinically significant anxiety is the most common mental health disorder in early life, affecting 33% of 
youth by adolescence (Merikangas et al., 2010); if not treated effectively, anxiety can impair function at 
school, at home and with friends, and increase risk for psychopathology in later life. Cognitive behavioral 
therapy (CBT) is the first-line treatment for childhood anxiety, but response is heterogeneous, with 40%-
60% of anxious youth continuing to experience impairment from symptoms after treatment (Walkup et al., 
2008). Anxiety has been associated with deficits in capacity for cognitive control, which enables directed 
attention to regulate behavior and emotion. Poor CBT response may relate to disruptions of brain processes 
supporting cognitive control, hindering the ability to cognitively restructure and expose oneself to feared 
situations, as CBT requires. Promoting cognitive control, through activating associated neural circuits, may 
facilitate ability to engage in CBT and pave the way for greater benefit from treatment. 
Cognitive control is mediated by a network of superior parietal, lateral and medial prefrontal cortex 
(i.e., task-control network, TCN) (Menon, 2011) and impaired function in this network characterizes 
anxious compared to healthy youth. Specifically, we have shown hypo-activity of lateral prefrontal cortex 
during cognitive interference in patients with pediatric anxiety disorders compared to healthy youth 
(Fitzgerald et al., 2013); it has also been reported that hypo-connectivity within the task control network 
may contribute to the development of anxiety (Geiger, Domschke, Ipser, Hattingh, Baldwin, Lochner, 
Stein, 2015).  Moreover, our preliminary CBT treatment data suggests that an increase in superior parietal 
cortex activity during cognitive interference associates with a decrease in anxiety severity (Liu, Morrison, 
Hanna, Phan, Monk, Fitzgerald, 2019). These neuroimaging findings from our lab align with an 
accumulating body of evidence that impaired cognitive control capacity, indexed by performance on 
cognitively demanding tasks, associates with increased anxiety symptoms across children and adolescents 
(Han, Helm, Iucha, Zahn-Waxler, and Hastings, Klimes-Dougan, 2016; Hopkins, Lavigne, Gouze, 
LeBailly, and Bryant, 2013; Muris, van der Pennen, Sigmond, and Mayer, 2008). Given these findings, 
behavioral capacity for cognitive control and underlying TCN function may serve as targets for improving 
anxiety through augmentation of CBT effect.  However, no available treatments for anxiety specifically 
target cognitive control. We propose that computerized cognitive training (CCT), through increasing 
cognitive control capacity and engaging the TCN, may augment CBT response. Recent work has 
shown CCT increased cognitive control capacity in children and adults with neurocognitive deficits 
(Marusic et al., 2018; Boivin, Nakasujja, Sikorskii, Opoka, and Giordani, 2016; Giordani et al., 2015); 
other researchers found CCT improved school-administered test performance through priming cognitive 
control function before tests (Wexler et al., 2016). We believe that children who may not respond to CBT 
alone, will benefit from CBT plus CCT, based on the central hypothesis that CCT, delivered immediately 
prior to CBT sessions, will exercise task-control network and thereby facilitate the receipt of CBT.   
 
 
 
 
 

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2.2 
BACKGROUND  
2.2.1 ANXIETY IS PREVALENT IN CHILDREN, CAN CAUSE LIFE-LONG IMPAIRMENT AND 
BETTER TREATMENTS ARE NEEDED.  
Anxiety emerges early in life and affects 33% of youth by adolescence (Merikangas et al., 2010). If 
not treated, anxious symptoms often persist and increase risk of depression, school dropout, substance 
abuse and even suicide in adolescence and adulthood (Achenbach, Howell, McConaughy, and Stanger, 
1995; Zimmermann, Wittchen, Hofler, Pfister, Kessler, and Lieb, 2003; Pine, Cohen, Gurley, Brook, and 
Ma, 1998). CBT is the most widely used therapy to treat childhood anxiety, but less than 60% of affected 
youth respond and many of those treated continue to experience residual symptoms (Walkup et al., 2008). 
Treatment failure may occur when children are unable to mobilize cognitive control to persevere in 
fearful situations, particularly since the most “active ingredient” of CBT is repeated exposure to situations 
that may seem scary, but do not involve actual danger (e.g., starting a new school) (Peris et al., 2015). 
Increasing cognitive control may be an important target for augmenting CBT outcome and reducing 
anxiety in youth.  
2.2.2 ANXIETY IS ASSOCIATED WITH DEFICITS IN COGNITIVE CONTROL, AND ITS 
UNDERLYING TASK-CONTROL NETWORK.  
Cognitive control is the ability to direct attention and cognitive resources to regulate behavior and 
emotion. Behavioral and neuropsychological data have consistently shown increased anxiety symptoms 
associated with lower levels of cognitive control in children and adolescents (Han, Helm, Iucha, Zahn-
Waxler, Hastings, and Klimes-Dougan, 2016; Hopkins, Lavigne, Gouze, LeBailly, and Bryant, 2013; 
Muris, van der Pennen, Sigmond, and Mayer, 2008). At the neural level, cognitive control can be 
measured by functional magnetic resonance imaging (fMRI) in a network encompassing superior parietal, 
dorsal lateral (dlPFC) and medial (mPFC) prefrontal cortex (Menon, 2011). This network is called the 
task-control network (TCN), activated during a variety of cognitive tasks. In adults, increased anxiety has 
been associated with reduced dlPFC activation in cognitive tasks with or without threat stimuli in 
community samples (Bishop, Duncan, Brett, and Lawrence, 2004; Bishop, 2009), interpreted as 
impoverished recruitment of TCN in regulating attention for high-anxious individuals, even when threat is 
absent. Our own study of pediatric anxiety disorders, showed dlPFC hypoactivation in error processing 
during a cognitive interference task in pediatric anxiety, suggesting insufficient engagement of TCN may 
contribute to a deficient capacity for adjusting repetitive anxious thoughts and behavior during an error 
(Fitzgerald et al., 2013). Given these findings, increasing TCN functions may help to reduce the anxiety 
symptoms.  
2.2.3 NEURALLY TARGETED COGNITIVE TRAINING TO INCREASE COGNITIVE CONTROL MAY 
AUGMENT TREATMENT OUTCOME IN PEDIATRIC ANXIETY.  
Increased TCN engagement has been reported to associate with decreased symptoms after CBT in 
pediatric obsessive-compulsive disorder (OCD) (Huyser, Veltman, Wolters, de Haan, and Boer, 2011), 
and we are currently conducting an R01 funded study to determine whether changes in TCN function 
associate with CBT outcome in pediatric patients with non-OCD anxiety disorders. Our preliminary data 
suggests that, as with OCD, increased TCN activation (specifically in superior parietal cortex) associates 
with decreased anxiety from pre- to post-CBT in young patients (Liu, Morrison, Hanna, Phan, Monk, and 
Fitzgerald, 2019). Given the evidence linking cognitive control deficits to anxiety and linking TCN 
engagement to CBT response, the immediate next step is to determine whether strategies to boost TCN 
engagement might facilitate CBT response in young patients.  

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Cognitive training has been applied to a variety of populations across different ages, but it is most 
effective for children when the brain is highly plastic (Diamond and Ling, 2015). In a recent study, 
computerized cognitive training (CCT) games designed to engage TCN showed improved school-
administered test performance in second-grade children through priming cognitive control function before 
tests, and increased academic achievement by enhancing cognitive control over a training period of four 
months (Wexler et al., 2016). Emerging work from our lab shows cognitive training in clinically anxious 
preschoolers, delivered through training camp, has reduced anxiety symptoms, increased cognitive control 
and increased TCN engagement (Hruschak et al., 2019). Guided by these converging lines of evidence, in 
this proposal we will examine whether cognitive training will prime and engage the TCN to augment the 
CBT outcome and reduce childhood anxiety.   
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
2.3.1.1 RISK ASSOCIATED WITH SCREENING AND ASSESSMENTS: 
1)  Risk of boredom or fatigue (likely, not serious). Participants may become tired or bored during the 
assessments and computerized cognitive testing. 
To minimize risk: Participants will be allowed breaks in between testing sections. 
2) Loss of confidentiality around sensitive information (rare, not serious). 
To minimize risk: All subjects are assigned research numbers, and all research information collected 
is linked to the subject only by this number. Great care is taken to remove all identifying information 
from research records. A single tracking file contains links to the research records and subject codes. 
Recruitment tracking files are kept only for the duration of recruitment. Paper records are kept in 
locked file drawers in a locked room, to which only authorized research personnel have access. 
Paper records with identifying information (consent form, payment records) are kept in locked file 
cabinets, physically separate from the research records. Computer records with identifying 
information are kept on secure, password protected servers. Staff members are trained to 
scrupulously protect the confidentiality of sensitive information, and take care to limit the printing of 
documents with identifying information and to avoid unnecessary discussion of subject names. 
Screening forms for subjects who do not qualify for the study will be destroyed, except for 
anonymous information unlinkable to the subjects (such as age, gender, and education). 
However, if a subject may become eligible in the near future, e.g. they need to wait 1 month after a 
recent medication change, we will retain certain records so as not to repeat the assessments, with the 
assent of the potential participant. 
3) Risk of worsening of anxiety symptoms. 
To minimize this risk: Clinically trained study staff will be alert for the emergence of worsening 
anxiety symptoms, as well as suicidal thoughts amongst participants. Weekly assessments will 
monitor symptoms, including suicidality, as part of Dimensional Brain Behavior Predictors of CBT 
Outcomes in Pediatric Anxiety (HUM00118950). In the event of symptom worsening, consultation 
with Dr. Fitzgerald may lead to withdrawing the subject so they can receive treatment outside the 
protocol.  

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4)  Suicide protocol 
For Dimensional Brain Behavior Predictors of CBT Outcomes in Pediatric Anxiety 
(HUM00118950), the suicide protocol begins with assessment of suicidal thoughts, plans, intentions 
and behaviors with the C-SSRS (at screening and at each treatment session). If assessment uncovers 
suicidal plans or intentions or recent behaviors, emergency evaluation will occur, and an appropriate 
plan of action will be followed, e. g. referral to psychiatric emergency room. Dr. Fitzgerald will be 
contacted and will join the decision making process about how to manage the suicidal thoughts or 
behaviors. See “DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL 
MANIPULATION” below for criteria about when we will withdraw a patient from the study for 
suicidality.   
 
2.3.1.2 RISKS ASSOCIATED WITH FMRI SCANNING:  
1)  Discomfort or anxiety (occasional, not serious). There is a minor risk of discomfort or anxiety/panic 
from being in the confined space of the MRI scanner. 
To minimize risk: The risks of discomfort and anxiety will be minimized by custom pads and 
pillows to make the subject as comfortable as possible. The subject is allowed to communicate with 
the machine operator via an intercom and may trigger an audible alarm at any time. Before the 
subject rolls into the bore of the magnetic, he or she is always reminded that they are free to stop the 
study at any time if they become uncomfortable. 
2)  Peripheral nerve stimulation (rare, not serious). Fast imaging sequences, such as those employed in 
this study, have the potential to induce peripheral nerve stimulation (PNS).  PNS can be described as 
a light touching sensation on the skin surface and may cause mild discomfort, but is not harmful to 
the subject.  
To minimize risk: The MRI machine is operated within FDA guidelines so the potential for inducing 
PNS is low. 
3)  Slight dizziness, light-headedness or nausea (rare, not serious). Sometimes subjects report these 
symptoms during or immediately after the scanning session.  
To minimize risk:  If a subject feels light-headed, we will have them get up from the scanner bed 
very slowly, resting with feet dangling for several seconds or more before attempting to stand. 
4)  Magnetic resonance image will reveal a minor or significant lesion in the brain, e. g. a tumor, 
previously unknown to the subject, and requiring additional follow-up. (rare, serious). 
To minimize risk: Subjects will be made aware of the risk of learning about an anomalous finding in 
the study that might require further evaluation with a clinical MRI study.  We will also inform the 
subject that many abnormalities will not be picked up in this study, since the scanning sequences we 
use are not sensitive to many forms of brain pathology.  However, in the event that we find 
something that is very obvious, such as a large tumor, Dr. Liu or Dr. Fitzgerald will personally 
inform the subject by phone call, or in person. No diagnosis will be offered, but the P.I. will 
recommend that the subject pursue a follow-up study with their primary care clinician.   
 
 

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5)  Hearing damage - from loud, vibrating noises made by the scanner (very rare, serious). 
To minimize risk: all subjects will wear earplugs and/or earphones throughout the procedure, which 
attenuate high decibel sounds, but still enable a subject to hear the intercom and respond to questions 
from the investigator while they are in the scanner. 
6)  Injury (very rare, serious). Because the strong electromagnetic fields can move metal objects and 
cause heating, there is a risk that loose objects (jewelry, keys) outside the body could be accelerated 
by the magnetic field, striking and injuring a subject. There is also a risk that the magnetic fields 
could disturb a metal fragment in the body, interfere with an implanted device, such as a pacemaker 
or neurostimulator, or cause metal (including foil-backed medication patches) on or in the body to 
heat up, causing harm. 
To minimize risk: The MRI suite is kept clear of all objects that could be picked up by the magnetic 
field, and all subjects complete a comprehensive MRI screening form prior to entering the scanner, 
which is reviewed by the MRI technologist (trained in clinical MRI) before scanning begins.   
2.3.2 KNOWN POTENTIAL BENEFITS  
 
For all patients, there is a potential benefit from the CBT treatment; for the CBT+CCT group, there is a 
potential additional benefit from the cognitive training.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The proposed experiment should reveal important information about the nature of mental processes 
involved in the pathophysiology of anxiety. It is expected that this information will indirectly lead to the 
development of better forms of treatment for this disorder. There is no other, safer or less-invasive means 
of answering the questions posed by the experiment described above. Strategy has been made to minimize 
each risk, respectively.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
Examine whether CBT+CCT 
will further engage the TCN. 
 
Brain activation and 
connectivity in the task-
control network 
  
We anticipate that CBT+CCT 
relative to CBT alone will result in 
greater engagement of the TCN.  
Secondary 
 
 
 
Examine whether CCT will 
further improve cognitive 
control capacity 
 
 
Behavioral performance in 
cognitive interference task and 
tasks testing cognitive control 
capacity in the NIH toolbox 
We anticipate that CBT+CCT 
relative to CBT alone will result in 
increased cognitive control capacity. 
 
Examine whether CCT will 
augment the CBT outcome. 
 
 
Anxiety severity and 
treatment response rate 
We anticipate that CBT+CCT 
relative to CBT alone will lead to 
more reduction on anxiety severity 
and higher treatment response rate 
Tertiary/Exploratory  
 
 
 
Explore the associations 
between changes in TCN, 
behavioral and CBT outcome 
 
 
Change of TCN activation, 
change of behavior, change of 
CBT outcome 
 
Not applicable 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
We hypothesized that computerized cognitive training (CCT), through engaging the task-control network 
and increasing cognitive control capacity, may augment the CBT response. In this study, eighteen clinically 
anxious children ages 7 to 17 will be recruited and assigned to CBT+CCT for up to 12 weeks; thirty-six 
age- and gender-matched anxious children will be recruited and assigned to CBT only for up to 12 weeks.  
Before and after therapy, all participants may complete structured clinical assessment of anxiety, a 
computerized evaluation of cognitive control capacity (e.g., NIH Toolbox; Zelazo, Anderson, Richler, 
Wallner-Allen, and Beaumont, 2013) and MRI scanning during a cognitive interference task and resting-
state to assess brain activation and functional connectivity in the TCN. However, at P.I. discretion, 
participants may not be required to complete an fMRI. Participants may also complete structured clinical 
assessment of anxiety, computerized evaluation of cognitive control capacity, and MRI scanning during 
therapy. 
This study will be incorporated into an ongoing fMRI study (HUM00118950, PI Fitzgerald) investigating 
dimensional brain-behavioral predictors of CBT outcomes in pediatric anxiety. In the parent R01 
(HUM00118950), 210 youths (7-17 years) with impairing anxiety are being recruited and randomized 2:1 
to receive 12-week CBT or a non-active control therapy, “relaxation and mentorship therapy” (RMT); 

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multilevel data including fMRI, DTI and clinical measures are collected before and after treatment.  As part 
of the parent study, RMT completers are offered study CBT (at no cost), without additional scanning.  
Study activities that may be completed remotely (i.e., Millisecond behavioral assessment, clinical measures 
and assessments, CCT, and CBT through the parent study) will be conducted via an encrypted HIPAA-
compliant video conferencing platform (e.g., BlueJeans, Zoom), phone call, and/or Millisecond/Qualtrics 
links. It will be standard practice to conduct as many procedures remotely as possible to better protect 
subject(s)/parent(s) and staff against the risk of COVID-19. However, when remote visits are not possible 
(e.g., NIH toolbox behavioral assessments, fMRI), in-person visits will be allowed and the study will follow 
all U-M safety guidelines for entering and being in U-M buildings (e.g., COVID screenings, PPE, social 
distancing, etc.).  
Eighteen RMT subjects in the parent study will be recruited to our CBT+CCT group, and thirty-six age- 
and gender-matched CBT subjects in the parent study will be recruited to our CBT control group.  The 
proposed study may add:  
1) For all fifty-four subjects recruited from parent study: 
a. NIH Toolbox and/or Millisecond behavioral assessment before and after the CBT course 
of therapy as well as once before the RMT course of treatment and once at about 3 weeks 
of CBT and another time if completing the fMRI following 4 weeks of at home CCT for 
the CBT+CCT group 
b.  BRIEF2 questionnaire before, after, and at about week 3 of the CBT course of treatment, 
as well as once before the RMT course of treatment and at the fMRI following 4 weeks of 
at home CCT for the CBT+CCT group 
c. Clinical assessment of anxiety at week 3 of CBT treatment. 
2) For patients originally randomized to RMT in the parent study who wish to enroll in the current 
study during their Optional CBT participation:   
a. augmentation of the CBT offered by the parent R01 study with CCT games delivered prior 
to each CBT session (CBT+CCT) along with a brief survey (the Self-Assessment Manikin) 
they may be asked to complete before and after CCT 
b. fMRI following 4 weeks of at home CCT, and fMRI following CBT+CCT completion  
c. Clinical measures and assessments before and throughout the course of CBT treatment 
d. at home CCT (~30 min/day), 5x per week, for up to 4 weeks, for up to two weeks before 
starting CBT and for up to 4 weeks after starting CBT, along with a brief survey (the Self-
Assessment Manikin) they may complete before and after CCT 
Data analyses will compare pre- and post-CBT data from the parent study with pre- and post-CBT+CCT 
data collected for the proposed study. These data will include NIH Toolbox and/or Millisecond measures 
of behavioral capacity for cognitive control; multi-modal assessment of TCN with fMRI, resting state and 
DTI; and, detailed assessment of anxiety symptoms using both clinician-interview and self-report. Pre- to 
post-therapy change in anxiety severity (clinician-measured) will serve as the primary outcome variable; 
regression analyses will be used to test for associations of anxiety change with changes in brain-behavioral 
indices of cognitive control following CBT compared to CBT+CCT. To increase clinical relevance of study 
results, analyses will also consider responder status, a common end point for clinical trials. 
 
 
 
 

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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
We hypothesize that CCT, delivered immediately prior to CBT sessions, will exercise task-control network 
and thereby facilitate the receipt of CBT. So in the control group, age- and gender-matched anxious youth 
received CBT only; their behavioral, brain and clinical data will serve as comparison, to evaluate whether 
CCT will augment the CBT effect.  
 
The aims of this project are to: 
(1) Examine whether CBT+CCT will further engage the TCN. We hypothesize that (a) both groups will 
have increased activation and functional connectivity in task-control network after therapy vs. before 
therapy; however, (b) the increase will be greater in CBT+CCT vs. CBT only group. 
(2) Examine whether CBT+CCT will further improve cognitive control capacity. We hypothesize that (a) 
both groups will have improved behavioral performance on the conflict interference task and tasks testing 
cognitive control capacity included in the NIH Toolbox; however, (b) these effects will be greater in 
CBT+CCT vs. CBT group. 
(3) Examine whether CCT will augment the CBT outcome. We hypothesize that relative to CBT group, 
anxiety severity will be reduced more and treatment response rate will be higher in CBT+CCT group. 
(4) Explore the associations between changes in TCN, behavioral and CBT outcome. We hypothesize 
that increased TCN activation and functional connectivity, and improved behavioral performance on 
cognitive control tests will correlate with better treatment outcome in both groups. 
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
The CBT intervention will consist of up to 12 weekly 60 minute sessions of the manualized therapy, adapted 
from the Coping Cat program, for the treatment of pediatric anxiety disorders. The CBT+CCT intervention 
will consist of ~30 minutes of CCT games prior to each CBT session, to engage cognitive control capacity 
prior to receipt of CBT. They may also receive up to 4 weeks of at home CCT to complete for up to two 
weeks before starting CBT and up to 4 weeks after starting CBT (~30 minutes per session). If assigned, this 
may be done at home 5 days per week. The CCT games will be designed to target focused attention, 
response inhibition, working memory and multiple simultaneous attention to constitute a general executive 
function training, and activate neural systems associated with executive function/cognitive control. 
Difficulty of the games will be titrated individually and by session to avoid boredom and progressively 
activate the functional systems underlying cognitive control, which we hypothesize will optimize 
participant’s ability to engage in, and thus benefit from, in the CBT intervention. For both groups, 
participants will have to complete at least 8 intervention sessions.  
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the baseline assessment, 
at least 8 intervention sessions of CBT (for CBT group) or CCT+CBT (for CBT+CCT group), pre and post 
fMRI scans, NIH toolbox and/or Millisecond assessments, and final independent evaluation. At P.I. 
discretion, participants may be considered to have completed the study even if they have not completed all 
of these activities. 
 
 

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5 
STUDY POPULATION 
Fifty-four clinically anxious youth will be studied (36 CBT, 18 CBT+CCT).  All subjects will be between 
7 and 17.99 years old at the time of initial consent. Subjects will be recruited from an existing R01 study 
at the University of Michigan (HUM00118950, PI Fitzgerald), also referred to as parent study. The R01 
parent study, at year 4 of the five-year period, has successfully recruited and retained over 100 anxious 
youth with moderate or greater levels of symptoms, e.g., PARS score > 10 and CGAS score < 60; it will 
recruit over 100 additional anxious youth randomized 2:1 to CBT and RMT through 05/31/2021. To date, 
nearly all participants randomized to RMT in the parent R01 study have chosen to continue the CBT 
sessions after RMT completion; thus we expect 44 youth to be eligible for the CBT+CCT, providing 
ample opportunity to recruit 36 CBT and 18 CBT+CCT over the one year period of the proposed study. 
Based on the retention rates of therapy (96.2%) and fMRI motion (89%) in the parent R01, we expect to 
have 32 CBT-treated and 14 CBT+CCT-treated anxiety youth with usable pre- and post-treatment data.  
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet the following criteria: 
1. Parent or guardian willing to give informed consent, and children willing to give informed assent 
to participate in the study. 
2. Must be actively enrolled and maintain eligibility in HUM00118950 to participate in the study. 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets the following criteria will be excluded from participation in this study: 
1. Color blindness 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Patients will not be taking any psychotropic medications for 4 weeks prior to beginning the study with the 
exception of stimulants for ADHD. In such cases, patients will be required to maintain a stable dose of 
stimulant medication for 2 weeks prior to fMRI #1. 
 
During the study, we will permit medication for 1) insomnia, e.g. trazodone, temazepam, melatonin, or non-
benzodiazepine GABA-selective agents (at standard dosages) for as long as needed, and 2) agitation, e. g. 
lorazepam, clonazepam for up to 14 days. Initiation of allowable “rescue” medications will be considered 
AEs and data will be collected on them during the scheduled assessments and recorded in the Case Report 
Forms.  NOTE: Initiation of other medications, prior to the end of the study, may be recommended by the 
study psychiatrist or requested by the patient. In this event, the patient will be withdrawn from the study 
and referred to clinical care.   
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are not subsequently 
assigned to the study intervention or entered in the study. Individuals who do not meet the criteria for 
participation in this trial (screen failure) because of meeting one or more exclusion criteria that are likely 
to change over time may be rescreened. Examples include the successful treatment of a previous affective 
disorder, and the lifting of physical activity restrictions previously in place. Rescreened participants will be 
assigned the same participant number as for the initial screening. 

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5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Subjects will be recruited from anxious youth in parent study. All participants will be approached to consent 
to the current protocol after they consent to the parent study.  Age and gender match will be attempted. The 
following recruitment and retention strategy is specified in the parent study: 
 
Recruitment will be from the outpatient psychiatry programs at the University of Michigan Health System, 
from multi-media advertisements (UMClinicalStudies.org, passive advertisements on social media sites and 
Craigslist Ann Arbor, Google Adword campaigns, print and electronic media, radio ads and flyers) and by 
referral from community clinicians.  The recruitment process is designed to limit interference with clinical 
care and assure the informed participation of patient subjects. By obtaining a waiver of consent for 
screening purposes, recruitment is facilitated by pre-review of computer-based medical records to identify 
potential research participants who have contacted the Department of Psychiatry. In addition, we will scan 
UMClinicalStudies.org, the UM registry of individuals who are interested in participating in clinical 
research.  Some of this screening will occur through the structured recruitment activities of University of 
Michigan’s psychiatric department—for example, best practices alert. Paid advertising (e.g., radio, 
newspaper ads, utilizing Survey Research Organization (SRO)) may also be employed, if needed to reach 
recruitment goals.  
 
The study sample will represent the normal to abnormal range of anxiety severity when considered across 
AY and LAY subjects. Thus, we will use a stratified recruitment strategy in which phone screens include 
administration of the DSM-Oriented Scale for Anxiety from the Child Behavior Checklist (CBCL) to 
enhance sampling across this range. Using this data, the study coordinator will track recruitment and 
enrollment of subjects with “high” (i.e., clinically significant anxiety, t-score >60), mid- (t-score 50-60) 
and low- (t-score <50) levels of symptom severity. Note that stratification of high, middle and low anxiety 
severity is intended only to facilitate recruitment across the full range of symptom severity. By contrast, all 
analyses will use linear regression, considering anxiety scores as continuous measures. 
 
Clinic recruitment of pediatric subjects with Anxiety: We may recruit from three sources: 1) patients 
seeking treatment at the UM’s Child and Adolescent Anxiety Program (CAAP, directed by PI Fitzgerald); 
2) primary pediatric UM outpatient clinics and community clinics; and 3) the community. Recruitment from 
this wide demographic will enable targeted enrollment of 210 CBT-eligible AY as well as 70 LAY with 
minimal to no anxiety. On average per year, we will enroll 47 subjects with high- to mid-range anxiety (i.e., 
CBT-eligible AY) and 16 with low-range anxiety. To achieve this goal, we will capitalize on high pediatric 
anxiety patient flow through CAAP (300/year) and an advertising campaign (Facebook, Twitter, Google 
AdWords, targeted flyering) modeled after Dr. Fitzgerald’s ongoing recruitment efforts for her R01 study 
of CBT for OCD (successfully enrolling 4 patients per month). 
 
Dr. Fitzgerald is a member of the UM Psychiatry clinical staff and co-directs the Child Anxiety Clinic. Her 
role in the clinic primarily involves supervision of trainees who deliver direct clinical care to child anxiety 
patients, although Dr. Fitzgerald does see a small number of anxiety patients herself.  If a dual role exists 
in which she is the treating clinician-principal investigator of a patient-potential subject, she will disclose 
this dual role and possible conflict of interest to them.  Moreover, she will emphasize that participation is 
voluntary, that they do not have to participate, and the decision not to participate will not affect their care, 
now or in the future.  A study coordinator (not Dr. Fitzgerald) will reiterate these points as part of the 
formal consent process.  Clinicians outside of the study team may be asked to inquire if patients are 
interested in research participation, and if so, for permission for study team members to contact them. In 
addition, should a physician discuss with the study team a patient they feel likely eligible for the study, a 
study team member will outreach to the patient to offer information on the study with the clinician’s 
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Recruitment of clinic scheduled or wait-listed pediatric subjects with Anxiety: We will contact scheduled 
or wait-listed patients who look like they might have anxiety based on information from their electronic 
medical record.  Then we will contact them by phone, [SECURE] email or MiChart patient portal, 
announcing our affiliation with the U-M Psychiatry Anxiety Disorders clinic, and ask them if they would 
be interested in hearing about a research study involving treatment.  If they are, we will conduct our phone 
screen. 
 
Recruitment of participants not being seen in the Department of Psychiatry:  Through community 
advertisements, we will also screen, assess and enroll participants who are not followed in the Department 
of Psychiatry. Initial screening will occur in a telephone interview.  In many cases, we will request records 
from outside providers to assess eligibility, using standard release of information forms.  For potential 
participants who appear eligible, a face-to-face initial assessment will be scheduled.  A similar process will 
occur with control subjects who respond to advertisements, although medical records will generally not be 
requested 
 
Minimizing the potential for coercion of patients to participate: Because members of the research team are 
involved in clinical care and research, there is the potential that some patients of the study team may be 
recruited.  It will be made clear to all potential subjects that participation is entirely optional and not a 
part of regular treatment.  The bulk of the recruitment process will occur with the study coordinator, who 
does not treat patients in any of the clinical venues where recruitment will occur. Overall, the research 
team is experienced in clinical research and very mindful of the conflict between the dual roles of clinician 
and researcher.  They firmly believe that the safety and desires of the patient take precedence over any 
research protocol, and work hard to assure their patients that research participation is not required for 
treatment.  In the case where a patient of a study team member is recruited, the consent process and 
signature on the informed consent document and will be obtained by the study coordinator. 
 
Payment of participants 
Participants will receive payments for the initial assessment through the parent study. For the current 
protocol, they will receive $10 for each behavioral NIH toolbox and/or Millisecond assessment and BRIEF2 
questionnaire before and after treatment as well as $10 each for the NIH toolbox and/or Millisecond 
assessment and BRIEF2 completed before the RMT course of treatment, and around week 3 of CBT for 
CBT+CCT group as well as when completing the fMRI after completing 4 weeks of at home CCT. 
Participants in the CBT-only group will receive $10 for the clinical assessment of anxiety and BRIEF2 they 
may complete at week 3 of CBT. Participants in the CBT+CCT group will receive $50 per fMRI scan (i.e., 
up to 3 scans - 1 before, 1 during, and 1 after CBT+CCT may be completed if the subject has not participated 
in the parent study; up to 2 scans may be completed if the subject has participated in the parent study and 
already received a pre-CBT+CCT scan). Participants in CBT+CCT group will also receive $15 for each 
CBT+CCT session (up to 12 sessions), $10 for each week of at home CCT training they may complete for 
two weeks before beginning CBT and during the first 4 weeks of CBT, if they complete at least 4 of the 5 
daily trainings. If it is requested for a participant to come back for additional interviews or additional 
practice sessions in the scanner, we will offer the participant $15 for these visits as well. Additional $50 
payment(s) will be provided if they are asked to come in again due to any possible technical difficulties 
with the MRI scanner (but not for repeated scans where participants choose to abort scan and try again at a 
later date).  The parent/guardian will receive the incentive. Payment for all participants will be made in a 
single payment at the completion of their participation in the study.  
 
 
 
 

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6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
Cognitive behavioral therapy: The CBT intervention is administered per the protocol of the parent study. It 
will consist of up to 12 weekly 60-minute sessions of the Coping Cat (ages 7-13) or Cat Project (ages 14-
17) manualized programs that have demonstrated efficacy for the treatment of pediatric anxiety disorders 
(Kendall and Hedtke, 2006; Beidas, Benjamin, Puleo, Edmunds and Kendall, 2010).  Session content 
includes: building rapport, identifying anxious feelings/somatic responses and relaxation skills (Sessions 
1-2); identifying and challenging anxious thoughts, problem-solving, and self-evaluation/reward (i.e., 
cognitive restructuring, Sessions 3-5); and, progressive exposure to anxiety provoking situations (sessions 
6-12). Parenting content is incorporated into two sessions prior to the initiation of cognitive restructuring 
and exposure. On some occasions, it may not be clinically appropriate to include a parent in the sessions. 
This will be determined on an as-needed basis through clinical consensus meeting. Recent research shows 
that cognitive restructuring and exposure (but not relaxation training, RT) are the “active ingredients” of 
Coping Cat CBT. Thus, the Cat protocols have been adjusted for the current trial with RT condensed into 
2 sessions rather than being delivered over 3-4 sessions as in CAMS). This will maintain fidelity to Coping 
Cat content, while reducing the increased likelihood of attrition associated with longer treatment protocols. 
Delivery of CBT intervention over the course of up to 12 (rather than 16) sessions is intended to a) maintain 
fidelity to Coping Cat content and closely mimic its delivery in CAMS (outcomes assessed at week 12) and 
b) minimize boredom and the potential effect on anxiety that could be associated with a longer duration 
control treatment.  
 
Computerized cognitive training: The CCT games are designed to target executive functions such as 
focused attention, response inhibition, working memory and multiple simultaneous attention to constitute 
a general executive function training, and activate neural systems associated with executive 
function/cognitive control. Difficulty of the games will be titrated individually and by session to avoid 
boredom and progressively activate the functional systems underlying cognitive control, which we 
hypothesize will optimize participant’s ability to engage in, and thus benefit from, the CBT intervention.  
These types of games are modelled after existing programs (Brain Powered Games, Giordani et al., 2015; 
Akili Interactive, Anguera, Gunning and Arean, 2017; Brain HQ www.brainhq.com) that help to improve 
executive functions and are well-tolerated by participants of varying ages.   
 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
Cognitive behavioral therapy: CBT treatment will be delivered over the course of up to 12 weeks including 
60 minutes of face-to-face meeting at the clinical setting. CBT may be delivered via remote video 
conference if social distancing policies prohibit this type of in-person interaction (e.g., COVID-19). If a 
remote video conference is not possible, therapy sessions may be scheduled as in-clinic remote visits in the 
Rachel Upjohn Building. 
Computerized cognitive training: The CCT intervention will consist of ~30 minutes of CCT games that 
may be completed prior to CBT sessions 4-12, to engage cognitive control capacity prior to receipt of CBT. 
These sessions of CCT may be completed at home if social distancing policies prohibit this type of in-
person study activity (e.g., COVID-19). Participants may also receive up to four weeks of at home CCT 

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(~30 min/day), 5 days per week, for up to two weeks prior to beginning CBT and up to 4 weeks after 
beginning the 12-week CBT protocol. Participants may complete CCT on an iPad provided by Akili 
Interactive, or they may complete CCT by downloading the application onto their own Akili-compatible 
personal device. 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
The CBT treatments will be delivered by masters or PhD level therapists trained in these modalities.  
Supervision will be provided by an expert in the study of CBT in anxiety disorders. Each therapist will treat 
patients who receive CBT and CBT+CCT.  An evaluator, blind to treatment assignment, will assess the 
patients with the scales described below.  The preference will be assessment in person, but, if required, 
assessment by telephone may be done.  In-house form will be used by clinical psychology supervisor to 
rate therapist adherence to treatment manuals.  
 
Video/audio recording:  We are seeking permission to have some assessments and CBT sessions recorded 
to obtain reliability/fidelity measures.  Not all participants will be recorded; this will be determined by 
needs of the study.  The recordings will be done mainly for the K-SADS and/or PARS assessments and 
therapy sessions. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
There is no randomization in this pilot study. Participants are recruited from the parent study where 
assignment to the two treatment arms (CBT vs RMT) is stratified based on age and gender, using block 
randomization to ensure a 2:1 ratio of participants in CBT vs. RMT group (HUM00118950). In this study, 
we will recruit all possible participants in the RMT group in the parent study to participate in CBT+CCT, 
and recruit age- and gender-matched participants from CBT group. Efforts will be made to keep therapists 
blinded to participant group (i.e., CBT+CCT vs. OPT CBT). 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Assessments (or subsets of questions from these measures) will mainly be completed as part of the parent 
study and utilized for analysis in this protocol. At each time point, assessments may include: 
 
Assessments Completed by Independent Evaluator– Weeks 0, 1, 3, 6, 9 & 12  
a) PARS 
b) Clinical Global Impressions-Severity and Improvement Scale (CGI); (Guy and Bonato 1970).  
 
Assessments by Clinician – Weeks 1-12   
a)    CGI (S/I)  
b)  Treatment Adherence Rating Scale (TARS) A therapist-administered instrument to assess 
patient completion of assigned CBT or RMT homework. 
c)    C-SSRS (since last visit) 
d)    CGAS 
 
 

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Assessments Completed by Subjects – Weeks 1-12  
a) Medication Adherence (also all fMRIs) 
b) MASC – week 1, 3, 6, 912 
c) CDI– week 1, 3, 6, 9, 12 
d) CGI-I (parent report) – week 3, 6, 9, 12. 
e) FAS (parent report) – week 12 
f) BDI (parent report) – week 12 
g) BAI (parent report) – week 12 
h) Beverage and Food Questionnaire – week 3 and 12  
i) GRIT Scale – week 12 
j) SCARED (parent) – week 1, 3, 6, 9, 12 
k) SCARED (child) – week 1, 3, 6, 9, 12 
l) Life Events Checklist – week 12 
 
Other Assessments  
a)    CGAS (Independent Evaluator, Week 0 and 12) 
b)    Credibility/Expectancy Questionnaire (CEQ; Subject, week 3) – A 6-item scale rating the  
        patient’s expectations for treatment success (Devilly & Borkovec, 2000) 
c) Working Alliance Inventory (WAI; Subject, Weeks 6 & 12) -- A 12-item scale rating the  
patient’s feelings about their relationship with the therapist (Horvath & Greenberg, 1989) – 
approximately 5 minutes.   
d) Randomization “guess” form to be completed by Independent Evaluator at week 12 to assess  
blindedness (CBT-only). 
e) Self-Assessment Manikin (SAM; Subject, may be completed before and after each session of 
CCT) – A 3-item scale rating the patient’s feelings of pleasure, arousal, and dominance 
(Bradley & Lang, 1994) – approximately 2 minutes.  
f) Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2; Parent, pre-RMT 
course of treatment, pre- and post-CBT course of treatment as well as week 3 of CBT, and 
when completing fMRI after completion of 4 weeks at home CCT for the CBT+CCT group) – 
at 63-item parent-report scale assessing executive function of the patient (Gioia, Isquith, Guy, 
& Kenworthy, 2015) – approximately 10-15 minutes. 
 
6.5 
CONCOMITANT THERAPY 
Patients will not be taking any psychotropic medications for 4 weeks prior to beginning the study with the 
exception of stimulants for ADHD. In such cases, patients will be required to maintain a stable dose of 
stimulant medication for 2 weeks prior to fMRI #1.  Dr. Fitzgerald will manage patient stimulant 
medications for the duration of the study, meeting with medicated patients 2-4 times, as needed, during the 
up to12-week period of study therapy. 
 
6.5.1 RESCUE THERAPY 
To address participant crises or unusual needs/circumstances that arise, additional treatment sessions (i.e., 
ASAP sessions) can be provided to address these needs and facilitate participant retention. A maximum of 
2 additional off-protocol sessions is allowed for each phase of the study (CBT or CBT+CCT). These could 
include psychotherapy or methods outside of prescribed protocol (e.g. motivational interviewing). 
Additionally, clinical assessment for urgent crisis may be offered and will be scheduled at therapist’s behest, 
participant request or as needed to help reduce dropout. Participants who require more than this limited 
intervention will be withdrawn and clinical care recommended.  

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During the study, we will permit medication for 1) insomnia, e.g. trazodone, temazepam, melatonin, or non-
benzodiazepine GABA-selective agents (at standard dosages) for as long as needed, and 2) agitation, e.g. 
lorazepam, clonazepam for up to 14 days. The study psychiatrist will manage initiation and ongoing 
treatment with these allowable medications during the study.  Initiation of allowable “rescue” medications 
will be considered AEs and data will be collected on them during the scheduled assessments and recorded 
in the Case Report Forms.  NOTE: Initiation of other medications, prior to the end of the study, may be 
recommended by the study psychiatrist or requested by the patient.  In this event, the patient will be 
withdrawn from the study and referred to clinical care.   
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
CBT or CBT+CCT will be stopped in the event of any of the following: 
• 
Suicidal thoughts with specific plans and intentions (Endorse item 4 or 5 on the C-SSRS and the 
judgment of the clinician that risk of suicide is high and imminent) 
• 
Suicide behaviors during the study period (assessed by C-SSRS) 
• 
Hospitalization required for any psychiatric symptoms 
• 
Symptom worsening:  > 25% increased PARS score (referenced to baseline) for more than 2 
assessments in 1 week 
 
Reasons for discontinuation will be documented, and all outcome assessments will proceed as scheduled, 
if possible. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance, i.e. inability or unwillingness to complete study 
intervention or outcome assessments  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up 
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
• 
The study is suspended or canceled 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report 
Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, and are randomized and 

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receive the study intervention, and subsequently withdraw, or are discontinued from the study, will be 
replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for four scheduled visits and 
study staff are unable to contact the participant after at least 3 attempts for each visit.  
 
The following actions must be taken if a participant fails to return for a required study visit: 
 
• 
The experimenter will attempt to contact the participant, reschedule the missed visit within four 
weeks, counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study 
• 
Before a participant is deemed lost to follow-up, the experimenter designee will make every effort 
to regain contact with the participant (where possible, 3 telephone calls and emails). These contact 
attempts will be documented in the participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
8.1.1 SCREENING AND INITIAL ASSESSMENTS 
Participants will complete questionnaires in order to collect basic health and demographics information.  
The initial assessment is completed as part of the parent study and will occur in 1 – 3 sessions, depending 
upon subject convenience. Data collected from this assessment will be used for analysis for this protocol. 
The following evaluations and assessment tools (or subsets of questions from these measures) may be used 
to determine eligibility for the study and gather baseline information:    
1) 
Demographics and medical history form.  An in-house form for basic demographic 
information, medical and family history completed by study team or as self-report. 
2) 
Social Communications Questionnaire (SCQ) (Rutter et al, 2003). A 40-item parent report to 
rule out diagnosis of Autism Spectrum Disorder. 
3) 
Child Behavior Checklist (CBCL), (Achenbach and Rescorla 2001). A 126-item parent-
completed checklist which provides DSM-IV oriented subscales for Depressive Problems, 
Anxiety Problems and Attention Deficit/Hyperactivity Problems (Inattention and 
Hyperactivity/Impulsivity subscales).  Approximately 10 minutes. 
4) 
Beck Anxiety Inventory (BAI; Beck & Steer, 1993).  This 21-item self-report survey measures 
severity of anxiety symptoms in adolescents and adults.  Approximately 5 minutes. 
5) 
Beck Depression Inventory-II (BDI; Beck, Steer, & Brown, 1996).  21-item self-report measure 
assessing adult depression.  Approximately 5 minutes. 
6) 
Family Accommodation Scale (FAS; Lebowitz et al., 2012): 13-item parent report measure 
assessing family accommodation of child symptoms. Approximately 5 minutes. 

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7) 
Screen for Child Anxiety Related Disorders (SCARED Parent and Child Versions): Developed 
by Boris Birmaher, M.D., Suneeta Khetarpal, M.D., Marlane Cully, M.Ed., David Brent, M.D., 
and Sandra McKenzie, Ph.D., Western Psychiatric Institute and Clinic, University of Pittsburgh 
(October, 1995). The SCARED consists of 41 items and 5 factors that parallel the DSM-IV 
classification of anxiety disorders. 
8) 
Tanner stage will be determined by self-report on the Pubertal Development Scale (PDS) 
(Petersen, Crockett et al. 1998). 
9) 
Edinburgh Handedness inventory (Oldfield, 1971).  A 15-item self-report of hand use. 
10) 
State-Trait Anxiety Inventory for Children (STAI-C); (Spielberger, 1973). A self-report, 20-
item scale on anxiety symptoms (trait only) for child subjects.  Approximately 5-10 minutes. 
11) 
Obsessive-Compulsive Inventory (OCI) (Foa, Huppert et al. 2002). An 18-item self-report 
scale for OC behavior, from normal to pathological.  Total scores on this scale range from 0 to 
72, with scores above 21 indicating a likely OCD diagnosis. Approximately 10 minutes. 
12) 
Multidimensional Anxiety Scale for Children (MASC); (March, Parker et al. 1997). Self-report 
assessing anxiety. Approximately 10-15 minutes. 
13) 
Children’s Depression Inventory (CDI); (Kovacs, 1992). Self-report, 28 item scale on 
depressive symptoms. Approximately 5 minutes. 
14) 
Pediatric Anxiety Rating Scale (PARS). A clinician-administered assessment to rate the 
severity of anxiety symptoms associated with common DSM-V anxiety disorders (social 
phobia, separation anxiety disorder, and generalized anxiety disorder) in children.  Total scores 
on this scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. 
Approximately 20–30 minutes. 
15) 
Clinical Global Impressions-Severity and Improvement Scale (CGI-S/I); (Guy and Bonato 
1970).  
16) 
Children’s Global Assessment Scale (CGAS); (Shaffer, Gould et al. 1983).  A single-item 
scale, administered by the clinician. 
17) 
Columbia Suicide Severity Rating Scale, present/lifetime version (Posner, Oquendo et al. 
2007).  A clinician-rated scale assessing suicidal ideation and behavior. Approximately 5 min.  
18) 
 Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS); (Kaufman, Birmaher 
et al., 1997). Standard assessment tool to obtain a diagnosis, may include parent interview.  
Approximately 3-4 hours. 
19) 
Grit Scale: (Duckworth, 2007): 12 item measure. Add up all the points and divide by 12. The 
maximum score on this scale is 5 (extremely gritty), and the lowest scale on this scale is 1 (not 
at all gritty). 
20) 
Life Events Checklist: Adapted from Child and Adolescent Survey of Experiences: Child 
Version (CASE) (Allen and Rapee, 2009). Assessing events people may find bad or upsetting, 
as well as events people may find good or enjoyable. Approximately 15 minutes. 
21) 
Wechsler Abbreviated Scale of Intelligence (WASI). A short-form administration of two sub-
tests of the WAIS (vocabulary and matrix design) to establish IQ. 15 min (can be completed at 
any time prior to fMRI #2). 
22) 
fMRI Safety Screen form to ensure that there are no contraindications for fMRI. This form is 
provided by the fMRI lab and is not included within study documentation. The most current 
version of this screening form will be used at all times to ensure the safety of participants 
undergoing fMRI.  
Electronic data capture:   
Subjects may complete the self-report forms described above using Qualtrics or hardcopy forms.  Qualtrics 
is an Application Service Provider (ASP) with a Software-as-a-Service (SaaS) platform for creating and 
distributing online surveys and related research services. The platform records response data, performs 
analysis, and reports on the data. All services are online and require no download software; only modern 
JavaScript-enabled browsers are required (no Java/JVM or Flash). Surveys are usually taken online within 

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a web browser, with optional SMS surveys and offline methods available for smartphones/tablets. Qualtrics 
has been approved for the University of Michigan research community, and individual investigators access 
the web interface through a University of Michigan Qualtrics portal. Subjects may receive a coded link via 
email which will take them to the required surveys. The emailed link contains no identifiable information 
about the subjects, and once activated, establishes an https encrypted link with the Qualtrics server. Once 
completed, each survey is locked so that re-access is not permitted. We can also adapt the process for each 
subject, e.g. provide access on computers or tablets in the Department of Psychiatry for subjects who do 
wish or cannot use email. Some subjects may request paper, and, if so, paper forms will be provided. 
If desired, subjects can receive the initial assessments either in hard copy or an emailed link ahead of 
attending their initial assessment to limit their time on site. Subjects will be asked to complete the online 
Qualtrics survey prior to their initial evaluation.  A copy of the consent form will be emailed to the subject, 
along with a secure web-link to the Qualtrics site or a copy of the consent form included in the hard copy 
packet.  For this, a waiver of documentation of informed consent will be sought.  If subjects who complete 
these online surveys screen out, their Qualtrics data will be deleted. Data will be downloaded from Qualtrics 
and secondarily stored in a REDCap database to be used for analysis.  
Responses entered by subjects will be available to the clinicians working with the patient subjects in the 
study. Please note that the suicide assessment rating (C-SSRS) is administered by clinicians at every visit. 
Thus, any potentially dangerous clinical condition will be identified in a timely fashion and acted upon 
accordingly. 
 
8.1.2 EXPERIMENTAL NEUROCOGNITIVE TASKS  
 
During the initial screening visit, first fMRI, or first day of therapy, participants may be asked to complete 
an Inhibitory Control Task and NIH toolbox. Participants may also be asked to complete Millisecond. 
• 
Go/no-go task: A typical approach to the study of inhibitory control is the use of 
neuropsychological tasks, such as the “go/no-go” paradigm (Durston, Thomas et al. 2002).  This 
task engages individuals in responding to “go” (target) signals, and occasionally requires them to 
inhibit the response when a “no-go” (no target) signal occurs.  Thus, it measures the ability to 
inhibit a prepotent tendency to respond. The participant is instructed to respond to target stimuli 
(e.g., any letter except “X”) by pressing a button on a computer/iPad and to make no response to 
non-target stimuli (e.g, the letter “X”).  Both misses and false alarms are used to assess accuracy – 
a measure of inhibitory control.  Reaction times for correct trials are also recorded.   
• 
The NIH toolbox Cognition Battery of assessments, if completed, will be administered 
electronically using an iPad, and may be completed before and after the CBT or CBT+CCT 
therapy, as well as before the RMT course of therapy, at week 3, and when completing the fMRI 
following completion of the 4 weeks of at home CCT for CBT+CCT. Tasks may include Flanker 
inhibitory control and attention, Dimensional Change Card Sort, List Sorting Working Memory 
Test, and Pattern Comparison Processing Speed Test; these tasks are not specifically trained in 
CCT to ensure that we measure transfer of training to general cognitive control capacity, rather 
than practice effect on specific tasks. Composite scores will be used to index cognitive control 
capacity. Please note that select NIH toolbox tasks may be conducted via HIPAA compliant 
videoconferencing or screensharing, such as BlueJeans or Zoom, when feasible or necessary (e.g., 
social distancing restrictions due to COVID-19). 
 
• 
The Millisecond cognitive tests may be administered, before and after the CBT or CBT+CCT 
therapy as well as before the RMT course of the therapy, at week 3, and when completing the fMRI 
following completion of the 4 weeks of at home CCT for CBT+CCT. Tasks may include Flanker 

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inhibitory control and attention or Dimensional Change Card Sort; these tasks are not specifically 
trained in CCT to ensure that we measure transfer of training to general cognitive control capacity, 
rather than practice effect on specific tasks. Reaction times and accuracy will be used to index 
cognitive control capacity. These tasks are sent to participants as a link which can be completed on 
a personal device (e.g., computer, tablet). 
 
8.1.3 FMRI SCANS  
 
Staff and subjects/parents will follow the fMRI Lab COVID-19 safety guidelines at all times. 
Overview:  fMRI scans will be performed at two time points for the parent protocol – after the initial 
assessment and prior to the onset of the first course of treatment (~0 - 14 days prior for anxious participants), 
and after the completion of treatment (~0 - 30 days after the last therapy session. For the current protocol, 
an additional scan may be performed following completion of the 4 weeks of at home CCT and at the end 
of CBT+CCT. If more than about 6 weeks have elapsed since their second scan through the parent protocol, 
a repeat scan may be obtained prior to the onset of CBT+CCT. Immediately prior to the fMRI session, we 
will review the MRI protocol, repeat screening for contra-indications to MRI and have subjects remove all 
objects from their person that could be disturbed by the magnetic fields. They will then undergo the fMRI 
session (approximately 1-1.5 hours for setup and acquisition). The fMRI methods described below will be 
the same for each of the scans participants will undergo. Should a participant wish to receive an image of 
their brain, one will be provided. Please note that, at P.I. discretion, participants may not be required to 
complete an fMRI.  
 
 
Assessments prior to each fMRI scan: 
1)  Review of fMRI safety form (copy to fMRI lab) 
2) Urine pregnancy test for women who endorse possibility of pregnancy.   
 
 
Placement in the Scanner:  
When we position a subject in the scanner, head movement will be minimized through: (a) instructions to 
the participant; and (b) packing the head inside the head coil with a system of foam padding and pillows 
that we have found is well-tolerated by the participants, yet limits movement.  Extra care will be taken to 
insure that the participant’s head is positioned as straight as possible since that eases the task of identifying 
landmarks used in positioning slices to be acquired in the fMRI scans. A mirror or MR-compatible goggle 
system projects the computer display output into the bore of the scanner. Stimuli are controlled and 
responses recorded either by E-Prime (PST, Inc., Pittsburgh, PA) or similar lab software. Participants will 
wear a response claw on their hands with buttons in order to make button-press responses during cognitive 
tasks. The stimulus-presentation and response-collection systems have been tested to insure that no artifacts 
are introduced and that there has not been an increase in the image-level noise. The goggle system may 
contain an eye-tracking camera, which can permit the monitoring and possible analysis of eye movements 
during the scan. In addition, MR-compatible earphones may be used and physiological sensors may be 
attached. These sensors consist of a strain gauge, or strap that goes around the torso, to measure respiration, 
and plastic finger cuff, to measure heart rate by plethysmography (although latter may not be used if it is 
redundant with pulse oximeter). These non-invasive sensors are FDA-approved components of the scanner, 
and the fMRI laboratory has begun to incorporate the physiological information into the acquisition 
sequences in order to improve image reconstruction. Because this is an area of data analysis that remains 
under development, we may not employ these sensors in all scans. Once in the scanner, subjects can 
communicate via intercom with the technician running the scanner in the control room. A window separates 
the control room from scanner room, which is sealed off from the outside by a light vacuum seal. In addition 
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the scanner immediately or gain the attention of the technicians, they can trigger an alarm in the control 
room by squeezing the bulb.  
 
Scan Acquisition:  
Scanning will occur on a 3.0 T GE 750 scanner at the University of Michigan fMRI Laboratory. The 
scanning session is described below. While scanning parameters may change, power-monitoring software 
on the scanner will ensure total energy delivered to the subject will remain within FDA guidelines. 
Specifically, the specific absorption rate (SAR) will not be greater than: 1) 4 W/kg averaged over the whole 
body for any period of 15 minutes; 2) 3 W/kg averaged over the head for any period of 10 minutes; 3) 8 
W/kg in any gram of tissue in the head or torso; 4) 12 W/kg in any gram of tissue in the extremities, for any 
period of 5 minutes. Also, in order to keep the time in the scanner to a reasonable length, some non-essential 
acquisitions may be dropped.  
T2w 3-plane localizing images will be acquired followed by a 3D T1w MPRAGE image with 1.0-mm 
isotropic voxels (176 slices, FOV=256 mm, FA=8°, TI=1060 ms, TR=2500 ms, and TE=1.9 ms). Next, a 
3D T2w image (3D CUBE) will be acquired with 1.0-mm isotropic voxels (176 slices, FOV=256 mm, 
TR=3200 ms, and TE=60 ms, and ETL=140). Prospective motion correction (PROMO) will be enabled in 
both T1w and T2w structural scans to reduce the motion artifacts. Multiband DTI images will be acquired 
with 96 gradient directions (including 6 for b=500s/mm2, 15 for b=1000s/mm2, 15 for b=2000s/mm2, 
and 60 for b=3000s/mm2) and 6 T2w (b=0) images. This DTI sequence uses a multiband acceleration 
factor of 3, with no inplane acceleration (1.7-mm isotropic voxels, 81 slices, FOV=240 mm, FA=77°, 
TR=4100 ms, TE=82 ms). Functional multiband EPI T2*-weighted images will be acquired for the fMRI 
task (below) and for two 5-minute eyes-open-with fixation resting-state sequences. Task performance, 
motion, and eye closure will be monitored and recorded by a trained RA throughout the session. These 
images will use a multiband acceleration factor of 6, with no in-plane acceleration (2.4-mm isotropic 
voxels, 60 slices, FOV=216 mm, FA=52°, TR=800 ms, TE=30 ms). 
In the event of technical difficulties with the fMRI scanner, subjects may be asked to complete additional 
fMRI sessions. 
 
 
Experimental tasks which may be completed at each MRI:   
• 
fMRI Task 1 – Emotional Faces Shifting Attention Task: The EF-SAT is a validated, effective 
probe of AT and CC-AT processing, previously reported from our lab. In this block-related design, 
participants view two ‘types’ of stimuli on each trial aggregated in blocks according to task 
instruction (a screen that precedes each block): 1) ‘Match Faces’ – a trio of faces and instructions 
to match one of the two faces (bottom) that expressed the same emotion as the target face flanked 
by a trio of shapes in the same field of view; 2) ‘Match Shapes’ – same instructions but with a trio 
of shapes flanked by a trio of faces in the same field of view. The target and congruent probe face 
display one of four expressions (angry, fearful, happy, neutral) and the other (incongruent) probe 
face always display a neutral (or happy if the target is neutral) expression. Faces will be selected 
from Gur/Upenn stimulus set. The Match Faces instruction requires subjects to attend to angry and 
fearful (relative to happy and neutral) facial expressions to probe AT, while the Match Shapes 
instruction requires subjects to ignore emotional faces in order to attend to shapes to assess CC-
AT. EF-SAT data collection occurs over approximately 12 minutes.  
• 
fMRI Task 2 –  Multisource Interference Task: The MSIT probes cognitive control (CC) by 
eliciting interference between task-relevant and prepotent, but task-irrelevant response tendencies. 
It was originally developed to activate dACC but also engages vlPFC and dlPFC, including in 
pediatric samples.  The MSIT requires subjects to identify the unique number among three digits, 
“1,” “2,” or “3” (e.g., for “311,” the target is “3”) by making a key press with one of three fingers, 
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“3” ring finger. Interference occurs when the target number position is incongruent with its ordinal 
value (e.g., “3” presented at the 1st position) and with different, flanking numbers (e.g., “11”). In 
the control condition, the target number is always presented in a position compatible with its 
ordinal value (e.g., “1” presented in the first position) and flanked by zeroes (e.g., “100”). Our 
event-related version of the MSIT allows for separation of fMRI BOLD signal associated with 
correct incongruent, correct congruent and error trials. We have extensive experience with this 
task, as demonstrated by our preliminary data, and have shown that it reliably activates the dACC, 
as well as vlPFC in children and adolescents with and without anxiety symptoms. MSIT data 
collection occurs over approximately 15 minutes.  
 
Post-scan debriefing: Subjects may answer several questions about how much they were frustrated/flustered 
with the task. Subject will also be asked to complete a Medication Adherence. 
 
8.2 
SAFETY ASSESSMENTS 
 
• 
fMRI Safety Screen form in order to ensure that there are no contraindications for fMRI. This 
form is provided by the fMRI lab and is not included within study documentation. The most current 
version of this screening form will be used at all times to ensure the safety of participants 
undergoing fMRI. 
• 
Columbia Suicide Severity Rating Scale, present/lifetime version (Posner, Oquendo et al. 2007).  
A clinician-rated scale assessing suicidal ideation and behavior.  
• 
Pediatric Anxiety Rating Scale (PARS). A clinician-administered assessment to rate the severity 
of anxiety symptoms associated with common DSM-V anxiety disorders (social phobia, separation 
anxiety disorder, and generalized anxiety disorder) in children.  Total scores on this scale range 
from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. Approximately 20–30 
minutes. Symptom worsening:  > 25% increased PARS score (referenced to baseline) for more than 
2 assessments in 1 week 
 
Any safety-related assessments (C-SSRS administered through the parent study, fMRI screening) or 
primary outcome measure (PARS– independent assessor may administer at weeks 0, 1, 3, 6, 9, and 12; 
missed week 9 will not be reported as a deviation) that are missed for a study visit/week of therapy a 
participant completed will be reported to the IRB as a protocol deviation.  For the independent 
assessments, we will accept a window of ± 1 week. For CBT+CCT group, the 3-week, 6-week, and 9-
week PARS assessments are completed under this protocol only, and a PARS assessment may be 
completed under this protocol prior to beginning at-home CCT treatment if there have been more than 
about 6 weeks since the RMT week 12 PARS.  For the CBT-only group, the 3-week PARS assessment is 
completed under this protocol only. However, for the other assessments, missing or late assessments will 
not be reported as protocol deviations unless they constitute > 10% of the total assessments.  In order to 
accommodate inevitable scheduling conflicts, holidays, etc., participants will be allowed to miss up to 4 
sessions of therapy, and the sessions must be completed within 16 weeks.  These allowances should affect 
neither the scientific integrity nor the safety monitoring provisions of the protocol. 
 
 
 
 
 
 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
Any unfavorable or unintended symptom, sign, or disease associated with a medical treatment or procedure 
that may or may not be related to the treatment or procedure. Adverse events can be related to the treatment 
or to the disorder being treated (e.g. anxiety), as well as to a concurrent disorder or treatment (e.g. MDD or 
its treatment), or they could be entirely unrelated to any of these (e.g., motor vehicle accident). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
An SAE is defined as an AE that meets one of the following conditions: 
• 
Death during the period of protocol-defined surveillance 
• 
Life-threatening event (defined as a subject at immediate risk of death at the time of the event) 
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization during the 
period of protocol defined surveillance  
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse/overdose or cancer. 
 
All SAEs will be: 
• 
recorded on the appropriate SAE Report Form  
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician. 
 
The study will comply with IRB reporting requirements and guidelines for SAEs. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, 
the term “severe” does not necessarily equate to “serious”. 

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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
All Aes will have their relationship to study intervention or study participation assessed with a level of 
specificity appropriate to the study design.  
All adverse events (Aes) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study procedures administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study procedures should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study procedures, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other factors 
may have contributed to the event (e.g., the participant’s clinical condition, other concomitant 
events). Although an AE may rate only as “potentially related” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probably related” or “definitely 
related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study procedures administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study procedures) 
and in which other drugs or chemicals or underlying disease provides plausible explanations (e.g., 
the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
8.3.3.3 EXPECTEDNESS  
 
A clinician with appropriate expertise in treating anxiety will be responsible for determining whether an 
adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the study 
procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor. 

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All Aes, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All Aes occurring while on study will be 
documented appropriately regardless of relationship. All Aes will be followed to adequate resolution. 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for Aes characterized as intermittent. 
A study team member will record events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious Aes) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING  
 
The occurrence of an AE may come to the attention of study personnel during study visits and interviews 
of a study subject presenting for medical care, or upon review by a study monitor. At each treatment session 
subjects will be questioned about putative Aes.  Information to be collected includes event description, time 
of onset, clinician’s assessment of severity (mild, moderate, or severe), relationship to study (assessed by 
the study PI and clinical team), expected versus unexpected, local versus systemic, and time of 
resolution/stabilization of the event. All Aes occurring while in the study will be documented appropriately 
regardless of relationship. All Aes will be followed to adequate resolution. Adverse event reporting will 
occur on the standard IRBMED timetable. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI, a trained member of the study team will be responsible for conducting an 
evaluation of a serious adverse event and shall report the results of such evaluation to the NIH/MICHR and 
the reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than 10 working 
days after the investigator first learns of the event. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
The only anticipated abnormal laboratory values will be the incidental findings from the MRI scan.  
Discovery of a finding:  If an incidental finding on a scan is detected by fMRI technologists and/or study 
personnel, the finding will be reviewed by a neuroradiologist. Any potentially serious abnormalities will be 
brought to the immediate attention of the PI and the clinical team.   
Informing the subject:  PI will then review the finding with the neuroradiologist before bringing it to the 
attention of the subject.  The intention here is to control the circumstances by which the subject is informed 
of the anomaly, making sure that PI Liu is the person who talks to the subject, can answer questions based 
on the neuroradiologist’s reading of the scan, and can gauge the emotional reaction of the subject to the 
news.  The subject will be informed by Dr. Liu personally, either through a phone call or a face-to-face 

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meeting.  While a face-to-face meeting is preferred, this may not be immediately convenient for the subject, 
and we must weigh the relative benefits of the more personal setting versus anxiety engendered by 
anticipating a meeting to discuss something the subject did not expect to hear. 
Informing the subject’s health care provider:  Arrangements will be made to provide a summary of the 
finding to the subject’s personal physician, with the patient’s permission.  In most cases, a follow-up, 
clinical MRI will be recommended, unless the consulting neuroradiologist advises an alternate course.   
 
8.3.8 REPORTING OF PREGNANCY  
 
We will inform the consenting parents of minor participants at the beginning of the process that we will 
respect the confidentiality of our teenage participants.  It is important for us to let teenage participants know 
that they can be honest about sensitive topics without fear of reprisal from their parents.  However, 
participants will also be informed about limits to confidentiality.  If we learn that a subject has potential to 
harm him or herself, or another individual, we will break confidentiality and take steps to prevent harm.  
Similarly, any evidence of potential child abuse will be reported to Child Protective Services. 
8.3.9 DEFINITION OF UNANTICIPATED PROBLEMS 
 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
8.3.10  UNANTICIPATED PROBLEMS REPORTING  
The investigator will report unanticipated problems (Ups) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, Ups will be reported using the following timeline:   
 

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• 
Ups that are serious adverse events (SAEs) will be reported to the IRB and to the study 
sponsor/funding agency within 10 days of the investigator becoming aware of the event  
• 
Any other UP will be reported to the IRB and to study sponsor/funding agency within 30 days of 
the investigator becoming aware of the problem  
• 
All Ups should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for Human 
Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the problem from 
the investigator 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Endpoint(s):  Change in Brain activation and connectivity in the task-control network 
(TCN) 
We hypothesize that (a) both groups will have increased activation and functional connectivity in 
task-control network after therapy vs. before therapy; however, (b) the increase will be greater in 
CBT+CCT vs. CBT only group. Baseline and week 12 assessment will evaluate pre- to post-CBT 
changes in brain activation and function connectivity in the task-control network including fronto-
parietal and cingulo-opercular regions mediating cognitive control. Functional activation and 
connectivity of these brain regions are assessed using a conflict interference computer task 
performed during MRI scanning.   
 
• 
Secondary Endpoint(s):  
(1) Change in behavioral performance on the conflict interference task and tasks testing cognitive 
control capacity included in the NIH Toolbox: We hypothesize that (a) both groups will have 
improved behavioral performance on the conflict interference task and tasks testing cognitive 
control capacity included in the NIH Toolbox; however, (b) these effects will be greater in 
CBT+CCT vs. CBT group. This will be evaluated using two measures of the same construct at 
baseline and week 12. Pre- to post-CBT changes in the behavioral performance in a conflict 
interference task will be collected, as well as composite score from tasks included in the NIH 
toolbox. 
(2) Change in Pediatric Anxiety Rating Score (PARS): We hypothesize that relative to CBT group, 
anxiety severity will be reduced more and treatment response rate will be higher in CBT+CCT 
group. This will be evaluated at baseline and week 12 through the PARS, a 50 question interview-
based tool used to assess for the presence and severity of anxiety symptoms in children and 
adolescents utilizing parental and youth input to guide clinician ratings. The total scores on this 
scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
No pilot data is currently available to enable a power analysis, but the proposed study will generate effect 
sizes for an R01 or R61/R33 application that will build from this pilot study. 
 

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9.3 
STATISTICAL ANALYSES 
9.3.1 GENERAL APPROACH 
 
Data will be analyzed using statistics software such as MATLAB, SPSS and R software. For descriptive 
statistics, means with standard deviation and range will be computed for continuous data (all brain and 
behavioral data and some of the clinical data). In general, statistical significance is reported based on p<0.05 
two-tailed; for the fMRI data, p<0.005 uncorrected or p<0.05 corrected for family-wise error or false 
discovery rate where applicable.  
 
9.3.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
We hypothesize that CCT will further increase TCN activation and connectivity. The hypothesis will be 
tested using 2 (within-subject: pre vs. post) x 2 (between-subject: CBT vs. CBT+CCT) repeated-measures 
ANOVAs on brain activation and connectivity in TCN. 
 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
(1) We hypothesize that CCT will increase cognitive control capacity (measured by NIH toolbox CC 
composite scores and behavioral performance on the MSIT task and/or Millisecond scores). The 
hypothesis will be tested using 2 (within-subject: pre vs. post) x 2 (between-subject: CBT vs. 
CBT+CCT) repeated-measures ANOVAs on behavioral performance. 
(2) Repeated-measure ANOVAs will be conducted to examine effect of CCT on CBT. We hypothesize 
that anxiety severity (i.e., continuous PARS score) will be reduced more in CBT+CCT group, 
relative to CBT group.  Chi-square tests will be used to test for differences in the ratio of CBT 
responders: non-responders between CBT+CCT and CBT group. We hypothesize that CBT+CCT 
will have more responders than the CBT. 
 
9.3.4 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
All clinical, behavioral and neuroimaging measures will be listed by time point when applicable.  
 
9.3.5 EXPLORATORY ANALYSES 
Linear regression models will be built to test whether change in cognitive control indices (behavioral, 
brain activations and functional connectivity) will associate with change on clinical outcomes (PARS 
scores). The standardized parameter estimates in each model will be examined. Secondary logistic 
regression will be conducted on CBT responder status. 
 
 
 
 
 
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written or electronic documentation of informed consent will be completed prior to starting 
the study intervention.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The protocol will begin by having the subject (or their parent[s] for adolescent subjects) provide assent and 
written informed consent. In the case that social distancing policies prohibit this type of in-person study 
activity (e.g., during COVID-19), informed consent will be obtained at the beginning of a remote visit. This 
remote visit will include a review of an oral assent script, assent from the minor subject, and signed 
electronic consent from the subject and their parent/guardian. Electronic informed consent signatures will 
be collected using SignNow. All procedures will adhere to the IRBMED Guidance for use of SignNow for 
Electronic Informed Consent Procedures. Informed consent is a process that is initiated prior to the 
individual’s agreeing to participate in the study and continues throughout the individual’s study 
participation. Extensive discussion of risks and possible benefits of this therapy will be provided to the 
subject/parents. Consent forms (written in non-technical language, understandable by the youngest subject 
to be enrolled in the study) describing in detail the study interventions/products, study procedures, and risks 
will be given to the subject/parent.  Participants may also be presented with a visual timeline of the tasks 
that may be involved in participating in this study, during the consenting process or at another time during 
the study, to aid their understanding of the process. Upon reviewing the document, one of the investigators 
(or their designee) will explain the research study to the subject/parent and answer any questions that may 
arise. The subject/parent will sign the informed consent document prior to any procedures being done 
specifically for the study.  Adolescent subjects will be asked to sign in the assent box on the main consent. 
The subjects may withdraw consent at any time throughout the course of the trial.  The rights and welfare 
of the subjects will be protected by emphasizing that the quality of their medical care will not be adversely 
affected if they decline to participate in this study.  As some of the patients may also be treated by members 
of the study team, we will take special care to emphasize the voluntary nature of participation. NOTE: older 
teens may become legal adults (i.e., reach the age of 18 years) during the course of the study.  If the teen is 
still actively involved in the study (i.e., data collection ongoing), then a new consent form, signed by the 
teen, will be obtained.  However, if the teen reaches 18 years of age after their data collection has been 
completed, we will not re-contact to re-consent.  This approach is intended to avoid burdening study 
participants and their parents.   
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
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study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor/funding agency and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, sponsor, IRB, or other relevant regulatory or oversight body. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by investigator, research staff, and the 
sponsor(s) and funding agency. This confidentiality is extended to the data being collected as part of this 
study. Data that could be used to identify a specific study participant will be held in strict confidence within 
the research team. No personally-identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. Research team will permit access to such records. 
 
The study participant’s contact information will be securely stored for internal use during the study. At the 
end of the study, all records will continue to be kept in a secure location for as long a period as dictated by 
the reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
All paper and computer research records will be identified by subject ID number rather than name or other 
personally identifying information.  Paper records are stored in a double-locked environment to which only 
authorized study team members have access. The link between subject ID and subject name will be kept in 
a separate password protected database. Consent documents and any other forms with identifying 
information will be maintained separately from research data files (identified by subject ID only). 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made available 
to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to 
share data will include proper plans and safeguards for the protection of privacy, confidentiality, and 
security for data dissemination and reuse (e.g., all data will be thoroughly de-identified and will not be 

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traceable to a specific study participant). Plans for archiving and long-term preservation of the data will be 
implemented, as appropriate.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), has 
issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, clinical 
or other human subjects research funded wholly or in part by the federal government.  Recipients of NIH 
funding for human subjects research are required to protect identifiable research information from forced 
disclosure per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). As set forth in 45 
CFR Part 75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered by 
this Policy are required to establish and maintain effective internal controls (e.g., policies and procedures) 
that provide reasonable assurance that the award is managed in compliance with Federal statutes, 
regulations, and the terms and conditions of award. It is the NIH policy that investigators and others who 
have access to research records will not disclose identifying information except when the participant 
consents or in certain instances when federal, state, or local law or regulation requires disclosure. NIH 
expects investigators to inform research participants of the protections and the limits to protections provided 
by a Certificate issued by this Policy. 
 
The assessments in this protocol will ask participants about sensitive topics, such as mental illness, possible 
pregnancy and substance use. We will inform the consenting parents of minor participants at the beginning 
of the process that we will respect the confidentiality of our teenage participants.  It is important for us to 
let teenage participants know that they can be honest about sensitive topics without fear of reprisal from 
their parents.  However, participants will also be informed about limits to confidentiality.  If we learn that 
a subject has potential to harm him or herself, or another individual, we will break confidentiality and take 
steps to prevent harm.  Similarly, any evidence of potential child abuse will be reported to Child Protective 
Services.  Since the assessment will occur along with clinical feedback to the minor participant and parents, 
we will need to discuss clinical situations that require an intervention, such as substance use disorders and 
substance use that interferes with treatment. If we become aware of imminent risk of harm to a parent, steps 
will be taken to ensure safety (e.g. referral to psychiatric emergency services or contacting appropriate 
authorities).  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
The value of this research is significantly enhanced by making the data available for the widest possible 
use, and because of the rapidly changing world of data analysis, it is impossible to predict what future 
research will do with data collected for any particular project in the present.  By keeping the data 
indefinitely, it will become available for projects, yet to be determined.  These include projects run by the 
investigators, as well as those outside the institution through data sharing plans or central repositories.  
Increasingly, the NIH is requiring investigators to include data sharing plans as a part of the overall research 
plan, in order to maximize the benefit from the research.     
When data are transferred to co-investigators and data repositories, de-identification will be performed, 
removing all HIPAA identifiers from the files.  To prevent reconstruction of facial likenesses from 
structural image datasets, we will blur/obscure/strip the information from the MRI image around the face. 
Subjects will be informed in the consent document that the data will be stored and that it may be shared 
with other investigators, both at the University and outside the University, through central databanks.  The 
risk posed to subjects will be very, very small.  Storing the data for an indefinite amount of time will follow 
strict protocols, outlined above, that will ensure the safety of the data and minimize the risk of accidental 
disclosure.  Data that is shared or uploaded to central databanks will be de-identified and will be effectively 
anonymized, since investigators using these central databases will not have access to the keys linking 

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individual subjects to the data.  Furthermore, no data will be shared without an agreement by stewards of 
the central databank to require data use agreements and prevent investigators from even attempting to 
identify subjects.  It is extremely unlikely that an investigator would even be able identify subjects from 
shared data, without already having access to a subject’s identifiers.   
We have chosen not to provide an ‘opt-out’ option in the ICD, which is the practice in some studies 
collecting genetic information.  Having some subjects ‘opt out’ of data sharing presents data tracking 
challenges (making sure that a few datasets among many are not to be shared), and introduces a very real 
risk of accidentally not honoring the desire of a subject to not permit data sharing.  The imaging data in this 
project is different from genetics data, which is also placed in large databanks, because the imaging data is 
significantly less sensitive and has a far lower likelihood of identification, should somebody try to extract 
identity from public databanks.  For example, the data does not contain information about ancestry, disease 
risk or genetic ‘fingerprints’ that can uniquely identify subjects.  Therefore, we feel that with this lower 
risk, it is ethically permissible to not provide an ‘opt-out’ clause.   If subjects object to data sharing, they 
have the option of not participating in the research.  Although our project does provide a potential direct 
benefit in the form of CBT therapy, this treatment is readily available outside of the research protocol. 
In some cases, participants may either be ineligible for the current protocol or be eligible for an additional 
study protocol. In these cases, if participant has indicated in the consent that they would like to be contacted 
for future studies, we will share their contact information with other research teams at the University of 
Michigan for screening purposes, and if eligible, can share some of our data with these investigators to 
assist in their screening and assessment process (per consent form). 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor  
Yanni Liu, Ph.D., Research Assistant Professor 
Kate Fitzgerald, M.D., Associate Professor  
Department of Psychiatry, Michigan Medicine  
Department of Psychiatry, Michigan Medicine 
4250 Plymouth Road 
4250 Plymouth Road 
yanniliu@med.umich.edu 
krd@med.umich.edu 
 
10.1.6 SAFETY OVERSIGHT 
 
The investigators and study team will meet weekly (as close to that as permitted by travel and holidays) to 
monitor the study activities in order to ensure that the human subject protection, study procedures, 
administration, and data collection processes are of high quality and meet the appropriate, regulatory 
guidelines.  No regular monitoring by an external monitor is planned. 
 
10.1.7 CLINICAL MONITORING 
No additional monitoring is required – the nature, size, and complexity of this study does not require 
additional safety monitoring to that provided by the IRB. 
 

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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Research staff will review both the documentation of the consenting process as well 
as a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source documents (see 
Section 10.1.9, Data Handling and Record Keeping) and will ultimately be entered into the study 
database.  To ensure accuracy, research staff will compare a representative sample of source data against 
the database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial related sites, 
source data/documents, and reports for the purpose of monitoring and auditing by the sponsor/funding 
agency, and inspection by local and regulatory authorities. 
 
PI and research team will review data collection and entry periodically to evaluate compliance with the 
protocol and for accuracy; PI and investigators responsible for clinical evaluations will participate in routine 
inter-rater reliability sessions. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the clinical trial staff under the supervision of the investigator. 
The investigator will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study.  Dark ink is required to ensure clarity 
of reproduced copies.  When making changes or corrections, the original entry will be crossed with a single 

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line, and initial and date the change.  For some assessments, subjects may enter information directly onto a 
computer, rather than a paper form.  Only research ID numbers will link these data with the subjects, and 
data will be stored in encrypted form on password-protected, secure computers.  Systems that are only used 
to collect data, such as laptop or tablet computers, will also have research files securely deleted after upload 
to the central database. Data recorded in the electronic case report form (eCRF) derived from source 
documents will be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (Aes), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Michigan Medicine servers in REDCap and/or 
statistical datasets.  Clinical data will be entered directly from the source documents. Research data will be 
maintained on password protected computers, on a secure linux cluster maintained in the Psychiatry 
Affective Neuroimaging Laboratory (PANLab) or on secure UMHS-administered servers. Backup 
procedures include RAID drives with mirroring, and off-site backup.  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Files will be stored in a double-locked environment and access-limited under the purview of the PI.  All 
research records will be identified by subject ID; pre-screening records will be scrubbed of identifiers and 
date shifted to preserve confidentiality.   
 
Study database records will be identified by subject ID, and the link between identifiers and subject ID will 
be maintained by the PI and lab manager.  The link will be destroyed after submission of the NIH final 
report or publication of the primary outcomes manuscript, whichever is later. 
 
These documents should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor/funding agency, if applicable. It is the 
responsibility of the sponsor/funding agency to inform the investigator when these documents no longer 
need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
research staff. As a result of deviations, corrective actions will be developed and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
It will be the responsibility of the investigator to use continuous vigilance to identify and report deviations. 
Protocol deviations will be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
investigator will be responsible for knowing and adhering to the reviewing IRB requirements.  

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10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Considerations for ensuring confidentiality of these shared data are described in Section 10.1.3. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  
 

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10.2 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
12/06/2019 
Changed at-home administration of CCT 
from first 4 weeks of CBT to two weeks 
prior to and the two weeks after the first 
session of CBT. Remove all eligibility 
criteria except: must be enrolled and 
maintain eligibility in parent study; must 
be willing to give informed consent/assent; 
and must not be color blind. Updated fMRI 
scan acquisition methods. 
Allows for ending of at-home CCT 
to align with week 3 to minimize 
overburdening of assessments. As 
parent study eligibility criteria may 
change, streamlines process of 
consenting to the present protocol; 
CCT graphic have signaling colors, 
so cannot be color blind. Wanted to 
provide most up-to-date scan 
techniques. 
3.0 
03/10/2020 
Allows study to approach participants to 
consent after have consented to parent 
study rather than at the same time. Study 
may administer the SAM before and after 
each CCT session. Introduces timeline that 
may be shown to participants. 
Allows flexibility around participant 
and staff schedules. SAM may 
assess participant feelings of 
arousal, pleasure, and dominance as 
related to CCT. Participant timeline 
may aid understanding of flow of 
study events. 
4.0 
05/28/2020 
Participants may download the CCT game 
as an application on their own Akili-
compatible personal device. NIH toolbox 
may be conducted via HIPAA compliant 
videoconferencing/ screensharing (e.g., 
BlueJeans or Zoom). Participants may not 
be asked to complete pre- and/or post-CBT 
fMRI. Participants may be asked to 
complete BRIEF2 before and/or after the 
CBT course of treatment. 
Allows for flexibility regarding 
administration of CCT game rather 
than restricting to Akili-provided 
iPads. Allows more flexibility 
regarding administration of NIH 
toolbox, rather than only 
administering in-person. Ensures 
safety of participants during times of 
social distancing restrictions. 
Provides additional measure of 
cognition/executive functioning. 
5.0 
07/16/2020 
All study activities that may be completed 
remotely will be, and study activities that 
must be done in-person will follow U-M 
safety guidelines. Participants may be 
asked to complete Millisecond behavioral 
assessment before and after CBT or 
CBT+CCT as well as at week 3 for 
CBT+CCT. CBT may be delivered via 
remote video-conference. CCT prior to 
CBT sessions 4-12 may be completed at 
home. Staff and subjects will follow the 
fMRI Lab safety guidelines. Participants 
may be asked to consent remotely, using 
SignNow to obtain electronic signatures. 
Ensures safety of participants and 
staff during times of social 
distancing restrictions (e.g., 
COVID-19). Millisecond provides 
another platform to measure 
cognitive control capacity that can 
be completed remotely. 
6.0 
 
CBT+CCT participants may complete NIH 
toolbox/Millisecond before RMT and be 
paid $10 for this additional task. 
It is preferable to administer NIH 
toolbox at an in-person visit already 
required by the parent study to 

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CBT+CCT participants may complete 
BRIEF before RMT as well as at week 3 of 
CBT. CBT-only participants may complete 
PARS and BRIEF at week 3 of CBT. 
reduce in-person contact, so we are 
administering NIH 
toolbox/Millisecond at the mock 
scan for all participants, pre-
randomization. The BRIEF is paired 
with NIH toolbox/Millisecond 
collection. To better compare CBT-
only and CBT+CCT, want to add 
PARS and BRIEF at week 3 for 
CBT-only. 
7.0 
03/15/2021 
All study activities under the current 
protocol may be administered and at P.I. 
discretion participants may be considered 
complete without doing all study activities. 
The investigator may discontinue a 
participant’s participation in the study if it 
is suspended or canceled. 
Because study funding ends on 
07/31/2021 and completion of all 
study activities takes between 12-28 
weeks, some participants enrolled 
may not be able to complete all 
activities before funding runs out. 
8.0 
04/01/2021 
At-home CCT may be completed for up to 
4 weeks for up to 2 weeks before and up to 
4 weeks after the first session of CBT. 
Participants may be asked to complete 
each MRI task. PARS may be completed 
before at-home CCT if more that 6 weeks 
between RMT week 12 IE and beginning 
at-home CCT. 
Provide more flexibility for 
completion of 4 weeks of at-home 
CCT. Trying to keep scan times 
under 1 hour. Want to get accurate 
measurement of anxiety symptoms 
within reasonable amount of time 
before beginning at-home CCT. 
 
 

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