Neural Mechanisms of Meditation Training in Healthy and Depressed Adolescents: An MRI Connectome Study
Phase: NA
Conditions: Healthy
Sponsor: University of California, San Francisco

Study Product Guidelines and Considerations 
1 of 43 
Version 1.1 
 
 
1 June 2018 
 
ClinicalTrials.gov Document 
 
Project Title: Neural mechanisms of meditation training 
in healthy and depressed adolescents: An MRI 
connectome study 
 
Identifier: NCT04254796 
 
Last approved: September 14, 2020       Uploaded: Feb 2, 2023 

Study Product Guidelines and Considerations 
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Version 1.1 
 
 
1 June 2018 
 
Clinical Intervention                     
Study Protocol 
 
Version 1.2  
 

Study Product Guidelines and Considerations 
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Version 1.1 
 
 
1 June 2018 
FULL PROTOCOL TITLE 
Neural mechanisms of meditation training in healthy and depressed 
adolescents: An MRI connectome study 
 
 
Study Chairman or Principal Investigator:   
Olga Tymofiyeva, PhD, Assistant Professional Researcher, 
Department of Radiology & Biomedical Imaging, University of 
California, San Francisco (UCSF).  
Tony T. Yang, MD, PhD, Professor, Department of Psychiatry, Division 
of Child and Adolescent Psychiatry, Weill Institute for Neurosciences, 
UCSF. 
 
Supported by:  
The National Center for Complementary and Integrative Health  
Grant Number: 1R61AT009864-01A1 
 
Study Intervention Provided by:  
NA 
 
Sponsor of IND (IDE):  
NA 
 

Study Product Guidelines and Considerations 
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Version 1.1 
 
 
1 June 2018 
Tool Revision History 
Version Number: 1.2 
Version Date: 06/22/2020 
Summary of Revisions Made: (1) Delivery of the intervention over Zoom; (2) First visit Part A 
that includes consenting and questionnaires will be conducted over Zoom, using DocuSign; (3) 
All source documents will be signed and stored electronically in DocuSign; (4) Assessments 
including MRI scans to be completed within 4 weeks before/after the intervention; (5) Clarified 
that reported adverse events have to meet the provided definition of an adverse event; (6) Study 
Timeline updated; (7) Inclusion criterion added: “Access to a smartphone, a tablet or a 
computer, on which program “Zoom” can be run for remote participation in the intervention”. 
Version Number: 
Version Date: 
Summary of Revisions Made: 
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Summary of Revisions Made:  
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TABLE OF CONTENTS 
Page 
 
1. STUDY OBJECTIVES ............................................................................................................. 7 
2. BACKGROUND AND RATIONALE .......................................................................................... 7 
3. STUDY DESIGN .................................................................................................................. 11 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................................. 12 
5. STUDY INTERVENTIONS .................................................................................................... 15 
6. STUDY PROCEDURES ......................................................................................................... 18 
7. SAFETY ASSESSMENTS ...................................................................................................... 25 
8. INTERVENTION DISCONTINUATION .................................................................................. 30 
9. STATISTICAL CONSIDERATIONS ......................................................................................... 31 
10. DATA COLLECTION AND QUALITY ASSURANCE ................................................................ 35 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................................. 38 
12. COMMITTEES .................................................................................................................. 39 
13. PUBLICATION OF RESEARCH FINDINGS ............................................................................ 39 
14. REFERENCES .................................................................................................................... 39 
15. SUPPLEMENTS/APPENDICES ........................................................................................... 41 
• Phone Pre-Screening of Inclusion/Exclusion Criteria 
• Informed Consent Form for 14-17-year-old participants   
• Informed Consent Form for 18-year-old participants   
• Medical History Form 
• Inclusion/Exclusion Criteria Form 
• Enrollment/Randomization Form 
• MRI Screening Form 
• SDQ questionnaire 
• Demographics questionnaire 
• Baseline Checklist Form 
• CORS 
• CSRS 
• On Study Visit Checklist  
• Adverse Events Form 
• Serious Adverse Events Form 
• Study Completion Form 
• Protocol Deviation Tracking Log 
• TARA manual 
 

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STUDY TEAM ROSTER  
Olga Tymofiyeva, PhD,  
Department of Radiology & Biomedical Imaging 
University of California, San Francisco 
1700 4th St., Byers Hall Suite 102 
San Francisco, CA 94143 
Phone: +1-415-514-4870 
Fax: +1-415-514-4451 
Olga.Tymofiyeva@ucsf.edu 
 
Tony Yang, MD, PhD, 
Department of Psychiatry, 
University of California, San Francisco  
401 Parnassus avenue, room LP-A322 
Langley Porter Psychiatric Institute 
San Francisco, CA 94143 
Phone: +1-415-476-7797 
Fax: +1-415-502-6361 
Tony.Yang@ucsf.edu 
PARTICIPATING STUDY SITES 
It is a single site study: please see the names and addresses above. 
PRÉCIS  
Study Title  
Neural mechanisms of meditation training in healthy and depressed adolescents: An 
MRI connectome study 
Objectives  
The primary objective will be to study changes in putamen structural connectivity in 
healthy teens with meditation training. Hypothesis: Putamen structural node strength 
will increase in the training group compared to controls. 
R61 Go/No-Go Criteria. Detect an effect size (a threshold of Cohen’s d > 0.20) in 
changes of the primary mechanistic outcome (Putamen structural node strength) 
by the described meditation training in 100 healthy adolescents that are 14-18 years 
old and retain at least 80% of randomized participants for primary outcome 
measurement at the end of the study regardless of adherence to the intervention. 
The secondary objective will be to study changes in emotional problems in healthy 
teens with meditation training. Hypothesis: There will be a significant decrease in 
emotional problems measured with the Strengths and Difficulties Questionnaire 
(SDQ) in the training group compared to controls. 
Design and Outcomes   

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 The current research study design will utilize an individually randomized group 
treatment, open-label, waitlist-controlled clinical trial to test the efficacy and safety of 
our innovative mindfulness meditation intervention (Training for Awareness 
Resilience and Action [TARA]) on the primary outcome (Putamen structural node 
strength) and secondary outcome (emotional problems measured with the Strengths 
and Difficulties Questionnaire [SDQ])  in healthy adolescents between the ages of 14 
to 18 years old. 
 
 Please see below, Section 6.1 (Schedule of Evaluations), for detailed schedule and 
type of evaluations to be performed during the study. 
  
 R61 Overview Diagram of Study Design: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interventions and Duration  
The current study will specifically compare 12-week group meditation training 
intervention (TARA) with a waitlist control group. Each adolescent participant will 
be on study for the period of 12-weeks. 
Sample Size and Population  
The target population for the current study will be 100 healthy female and male 
adolescents that are between the ages of 14 to 18 years old who are randomly 
assigned to the 12-week meditation training intervention (TARA) or waitlist control 
group (50 healthy female and male adolescents between the ages of 14-18 years will 
be assigned to the 12-week meditation training intervention, and 50 healthy female 
and male adolescents between the ages of 14-18 years will be assigned to the waitlist 
control group). Randomization will not be stratified. 
100 healthy  
14-18yo volunteers 
 
random assignment 50/50 
meditation 
training 
 
waitlist 
12-16 
weeks 
(max 20 
weeks) 
time 
interval 
between 
the scans 
Primary mechanistic measure:  
putamen node strength 
  
Functional outcome: internalizing problems (SDQ) 

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1. STUDY OBJECTIVES 
1.1 
Primary Objective 
The primary objective will be to study changes in putamen structural connectivity in 
healthy teens with meditation training. Hypothesis: Putamen structural node strength 
will increase in the training group compared to controls. 
R61 Go/No-Go Criteria. Detect an effect size (a threshold of Cohen’s d > 0.20) in 
changes of the primary mechanistic outcome (Putamen structural node strength) 
by the described meditation training in 100 healthy adolescents that are 14-18 years 
old and retain at least 80% of randomized participants for primary outcome 
measurement at the end of the study regardless of adherence to the intervention. 
1.2 
Secondary Objectives 
The secondary objective will be to study changes in emotional problems in healthy 
teens with meditation training. Hypothesis: There will be a significant decrease in 
emotional problems measured with the Strengths and Difficulties Questionnaire 
(SDQ) in the training group compared to controls.  
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
According to the World Health Organization (WHO), major depressive disorder 
(MDD) is the current leading cause of disability worldwide (Ferrari et al., 2013) and 
adolescence is an especially vulnerable period for the onset of depression. Depression 
has a prevalence by the end of adolescence of 20% (Brent & Birmaher, 2006) 
affecting the development of emotional, cognitive, and social skills which elevates 
the risk for suicide, substance use disorders, legal problems, physical illness, 
exposure to negative life events, early pregnancy, academic difficulties, family and 
friend problems, work problems, and poor psychosocial functioning (Birmaher et al., 
2007; Essex et al., 2003; Infante et al., 2007). Depression during adolescence confers 
a 2- to 3-fold increased risk for adulthood depression (Pine et al., 1998). It is therefore 
of great importance both to develop prevention programs promoting emotional health 
and to intervene early with effective treatment of adolescent depression. Successful 
interventions during adolescence, when brain plasticity is peaking, may recover the 
aberrant neurocircuitry involved in emotional health.  
2.2 
Study Rationale 
Non-pharmacologic approaches are particularly attractive due to the elevated risks of 
side effects related to the use of psychotropic drugs during development (Hetrick et 
al., 2007). Mindfulness meditation approaches are being explored for providing 
systematic training in emotional health (Vago & Silbersweig, 2012) and for treatment 
and prevention of depressive relapse (Kuyken et al., 2016). Our group has provided 
evidence that a meditative training (the same training we plan to use in our proposed 
study) can result in significantly strong effects of depressive symptom reduction in 
depressed adolescents (Henje Blom et al., 2016). 

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In the proposed study, we will use a type of secular mindfulness meditation practiced in the 
Training for Awareness, Resilience, and Action (TARA) (Henje Blom et al., 2014). The training 
was conceived in Dr. Yang’s (co-PI) lab at UCSF as a treatment program for adolescent 
depression. It is a semi-manualized 12-week group intervention, informed by mindfulness- and 
yoga-based techniques, and it takes into account developmental aspects of the adolescent brain 
that is still in the process of maturation (Henje Blom et al., 2014). TARA training includes 
several embodied mindfulness meditation practices (breathing techniques, yoga-based 
movements, and guided meditation), which are accompanied by short psycho-educational 
presentations and group discussions. A more detailed outline of the TARA training is presented 
in the “5.1 Interventions, Administration, and Duration” section below. The TARA program has 
shown excellent retention rates, positive participants’ feedback, and improved functional 
outcomes (Henje Blom et al., 2016). 
 
Scientific Rationale Behind the Hypothesized Primary Mechanism 
 
In the center of our hypothesis is the node strength of the putamen, a region previously 
associated, on one hand, with the onset of meditation practice (Baerentsen et al., 2010) and 
attenuated shrinkage with age in Zen meditators (Pagnoni & Cekic, 2007), and on the other hand, 
with love, compassion, anticipation of pleasure and responses to increasing intensity of 
happiness (Bartels & Zeki, 2004; Klimecki et al., 2013; Surguladze et al., 2003). The graph 
theory measure of node strength (w) represents the sum of the edge weights connecting node i to 
all other nodes and highlights the centrality of the node within the network: w! = ∑
a!"
#
"$%
, 
where aij is the edge weight between nodes i and j, and n is the number of nodes. Importantly, it 
is not an isolated characteristic of a brain region but encompasses multiple white matter fiber 
projections connecting it, in the case of putamen, to motor, somatosensory cortices, limbic 
systems, and, to the largest degree, to frontal areas including the prefrontal cortex (Verstynen et 
al., 2012).  
 
Here, we propose a model of how 
meditation training positively affects 
emotional health in healthy and 
depressed youth, where increase of the 
putamen’s node strength is the 
hypothesized primary mechanism (Fig. 
1). Our model is based on Garland 
Positive Reappraisal model and includes 
the neural mechanism, which links 
meditation practice to emotional health. 
Mindfulness meditation promotes non-
evaluative and non-judgmental 
awareness in response to stimuli and 
even though increasing positive affect is 
not a goal per se in this type of meditation, the Positive Reappraisal theory suggests that 
mindfulness allows for a decentered mode of awareness from which new positive cognitive 
appraisals of self and world can be made (Garland et al., 2009) (Fig. 1). Primary appraisal of a 
stressor stimulus is usually followed by a cognitive process of secondary appraisal in which 
one’s resources and coping options are weighted against the perceived demands of the situation. 
Figure 1. Proposed model of how meditation exerts its positive 
effects on emotional health in healthy and depressed 
adolescents. Based on Garland model of mindfulness and 
Davey model of adolescent depression.  
 
 
 
 
•
Neural circuitry involved: fronto-striatal 
•
Still developing in adolescence 
•
Deficient in adolescent depression 
•
Enhancement with meditation training 
Primary appraisal 
Secondary appraisal 
Positive 
reappraisal 
Mindful 
decentering 
Positive 
emotion 
Stressor stimulus 

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Mindful decentering from this stress appraisal, wherein one attends to the dynamic process of 
consciousness itself rather than its contents, allows one to reappraise the event in a positive 
manner by attributing to it new meaning, in a way that engenders hope, resilience and creativity. 
The reappraisal then results in positive emotions such as compassion, trust, confidence, which in 
turn influence subsequent appraisal processes. 
 
The role of putamen connectivity in meditation. We hypothesize that the transition from mindful 
decentering to positive emotion involves the fronto-striatal circuitry, specifically, the node 
strength of the putamen. The putamen has been implicated in both, onset of meditation practice 
(Baerentsen et al., 2010) and during continuous meditation by Lazar et al. (2000) and Tang et al. 
(2009), who reported increased activity in the putamen. Baerentsen et al. observed patterns of 
activations and deactivations in the brain, including pronounced activation in putamen with the 
onset of meditation practice. Remarkably, a 65% increase of endogenous dopamine release was 
observed in the striatum during meditation (Kjaer et al., 2002). We expect that regular 
engagement of the putamen will increase myelination of the white matter tracks connecting it to 
other regions (including the prefrontal cortex, PFC), which can be probed by using diffusion 
MRI fractional anisotropy (FA) indices as network weights. Our preliminary results in healthy 
adolescents using diffusion tensor imaging (DTI) and tractography (Fig. 2) show a medium-large 
effect of the putamen node strength increase during the meditation training compared to the 
waiting period and correlation of this increase with the self-reported amount of meditation 
practice. All specific statistics will be discussed in following sections. 
 
The role of putamen connectivity in emotional health. The putamen’s involvement in reward-
related behavior and emotions has been well-studied (Lanciego et al., 2012). The basis of 
hedonic feelings has been studied through many different paradigms demonstrating association 
with striatal regions including the putamen (Gorwood, 2008). Increased functionality of the 
putamen is expected to decrease internalizing emotional problems such as feeling 
unhappy/worried/fearful and induce well-being and a more positive emotional tone. In alignment 
with this function of the putamen and its stimulation through meditation, our preliminary 
results in healthy adolescents show a decrease in emotional problems (internalizing subscale of 
the Strengths and Difficulties Questionnaire, SDQ) during the meditation training compared to 
the waiting period. We also observed in our preliminary data an association between the 
decrease in emotional problems and the increase of the putamen node strength, which provides 
support for the proposed model (Fig. 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. From left to right: DTI-based whole-brain tractogram in a healthy adolescent (left image); the corresponding 
graph depicting the connectome with putamen nodes highlighted in red (middle image); tracks connecting the putamen 
with cortical regions in an adolescent brain (right image).  
 

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The role of putamen connectivity in adolescent depression. We also expect that meditation 
training will benefit adolescents suffering from depression by employing the described 
mechanism. Anhedonia – the decrease or loss of the ability to experience pleasure and happiness 
– is a key characteristic of major depressive disorder. Our preliminary results show that 
structural connectivity of the putamen is lower in depressed adolescents compared to healthy 
controls and that this hypoconnectivity is correlated with anhedonia, as we will show in more 
detail below. Gabbay et al. also reported abnormal resting-state functional connectivity of the 
putamen in depressed adolescents that significantly correlated with their levels of anhedonia 
(Gabbay et al., 2013). Since adolescence is a critical neurodevelopmental time period with 
significant remodeling and maturation of the dopaminergic reward system in the brain, Davey et 
al. have proposed a neurodevelopmental model that hypothesizes teen depression is due to the 
failure of the proper neurodevelopment of greater connectivity between the reward areas (i.e., 
putamen) and prefrontal cortical (PFC) areas (Davey et al., 2008). Their theory proposes that 
experiencing pleasurable and positive emotions is necessary for the proper neurodevelopment of 
the reward system during adolescence and that the lack of these experiences leads to the onset of 
adolescent depression. Mindfulness approaches are being explored for treatment and prevention 
of depressive relapse in adults (Kuyken et al., 2016). We have previously demonstrated that a 
meditative training (the training that will be used in this study) can result in a significantly strong 
effect of depressive symptom reduction in clinically depressed adolescents (Henje Blom et al., 
2016). For these reasons, we chose to study meditation training for depressed adolescents as the 
optimization strategy for the R33 phase. As in the R61 phase, we expect increases in putamen 
node strength with practice of meditation. We expect that the mechanistic effect in the putamen 
will be amplified in the population of depressed as compared to healthy teens, which may reflect 
normalization of the putamen function. In our preliminary study of healthy adolescents, we 
observed a stronger increase of putamen node strength in those teens with lower baseline node 
strength. Our results in a small sample of adolescents with MDD show feasibility of recruitment 
and MRI scanning, and they also indicate a stronger increase of putamen node strength compared 
to healthy teens. 
 
The proposed project will advance knowledge of the mechanism of action of meditation training 
by applying the most advanced neuroimaging approaches and by testing the proposed novel 
model (Fig. 1).  
 
Biological and Psychological Relevance 
 
The study population in the R61 phase will be healthy adolescents between the ages of 14-18 
years. By this age, brain systems implicated in basic cognitive processes reach adult levels of 
maturity, whereas those that are active in the reward system are undergoing significant 
remodeling and neurodevelopmental maturation (Davey et al., 2008). The most rapid synaptic 
pruning is thought to occur between the ages of 12 and 16.5 years (Campbell et al., 2012), thus 
presenting an opportunity for long-lasting beneficial adaptations. In the R33 phase, we plan to 
study youth between the ages of 14-18 years who suffer from mild to moderate depression and 
who are under the care of a primary care doctor. During this critical time (14-18 years), the 
incidence of depression peaks and shows a dramatic, approximately three-fold increase 
(Hammen & Rudolph, 1996). 
 

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3. STUDY DESIGN 
The present research study design will utilize an individually randomized 
group treatment, open-label, waitlist-controlled clinical trial to test the 
efficacy and safety of our innovative mindfulness meditation intervention 
(Training for Awareness Resilience and Action [TARA]) on the primary 
outcome (Putamen structural node strength) and secondary outcome 
(emotional problems measured with the Strengths and Difficulties 
Questionnaire [SDQ])  in healthy adolescents between the ages of 14 to 18 
years old. 
The specific unit of assignment and unit of observation are the individual 
study participants. 
Primary outcome: Putamen structural node strength 
Secondary outcome: Emotional problems measured with the Strengths and 
Difficulties Questionnaire (SDQ) 
The study population are 100 healthy adolescents that are 14-18 years old, 
who are randomly assigned to the intervention or waitlist control group (50 
assigned to intervention, 50 assigned to waitlist control who will later receive 
the intervention). 
The entire study will take place at the University of California, San Francisco 
(UCSF). More specifically, all of the MRI scans will take place at the UCSF 
Mission Bay campus. All of the TARA group interventions and subject 
interviews will take place remotely over Zoom. 
The approximate duration of subject enrollment period for the entire trial will 
be 21 months (please see below, R61 Phase Timeline). We plan to run 5 
intervention groups and 5 waitlist control groups. The intervention duration is 
1.5 hours per week for 12 weeks, and MRI scanning and clinical assessments 
will be performed within 2 weeks (maximum 4 weeks) before and after the 
12-week intervention. Thus, each individual participant who is randomly 
assigned to the intervention will be followed for a total duration of up to 20 
weeks (12 weeks of intervention plus up to 4 weeks before the start of the 
intervention plus up to 4 weeks after the end of the intervention). The 
individual participants who are randomly assigned to the waitlist control will 
be similarly followed for approximately 20 weeks. 
 

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Intervention: 12-week group meditation training, Training for Awareness, 
Resilience, and Action (TARA). 
We will use computer-generated randomization with variable blocks sizes of 
4, 6 and 8. Individuals will be randomized with no stratification, matching or 
constraints except the permuted blocks. We will permute 8 blocks of size 8, 2 
blocks of size 6, and 4 blocks of size 4. The treatment assignments will be 1:1 
within each block and assignments within a block will be permuted. The only 
masking will be in the administration of questionnaires and in the 
interpretation of putamen node strength.  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
Healthy female and male adolescents, 14-18 years old. 
We will use Medical History form a (NCCIH Version 1.0). The required 
current status of participants within 4 weeks prior to randomization is absence 
of current medical, neurological, or psychiatric conditions.   
Fluency in English. 
Access to a smartphone, a tablet or a computer, on which program “Zoom” 
can be run for remote participation in the intervention.  
4.2 
Exclusion Criteria 
§ Subjects younger or older than 14-18 years old. 
§ Subjects who are not healthy. We will use Phone Pre-Screener and 
Medical History form a (NCCIH Version 1.0) to exclude any adolescent 
who has been clinically diagnosed with any significant medical disorder 
that would prevent him or her from performing yoga-based movements 
(e.g., cerebral palsy), neurological disorder (e.g., multiple sclerosis, severe 
0
20
40
60
80
100
120
Jul-20
Aug-20
Sep-20
Oct-20
Nov-20
Dec-20
Jan-21
Feb-21
Mar-21
Apr-21
May-21
Jun-21
Jul-21
Aug-21
Sep-21
Oct-21
Nov-21
Dec-21
Jan-22
Feb-22
Mar-22
Cumulative Target Recruitment 
over duration of active grant 
period
Jul-
20
Aug-
20
Sep-
20
Oct-
20
Nov-
20
Dec-
20
Jan-
21
Feb-
21
Mar-
21
Apr-
21
May-
21
Jun-
21
Jul-
21
Aug-
21
Sep-
21
Oct-
21
Nov-
21
Dec-
21
Jan-
22
Feb-
22
Mar-
22
Target Accrual
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
R61 Phase Timeline
Recruitment - Monthly Projection (Cumulative)

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head trauma) or mental health disorder (e.g., psychosis, schizophrenia, 
schizoaffective disorder, major depressive disorder, bipolar disorder, 
ADHD, autism spectrum disorder, anorexia nervosa, PTSD) or has 
intellectual disability, or suicidal ideation or attempt in past 3 months. 
§ Subjects who are taking any psychotropic medication. 
§ MRI contraindications (ferromagnetic objects on or inside the body, e.g., 
braces) and pregnancy. 
§ Pregnancy or any plans to become pregnant during the study is an 
exclusion criterion for entrance into the study. Women of reproductive 
capability will be asked to employ at least one of the following allowable 
contraception methods until they complete their second MRI scan: birth 
control implant, birth control shot, birth control patch, birth control pill, 
condom, internal condom, birth control sponge, cervical cap, spermicide, 
fertility awareness (calendar method), outercourse and abstinence. 
§ The study’s pregnancy-related policy and procedure are as follows. First, 
all female participants will be asked to fill out a pregnancy screening 
questionnaire and then take a urine pregnancy test immediately prior to 
entering the MRI scanner room. Any subject that is either pregnant or 
might possibly be pregnant are not allowed to enter the MRI scanner 
room. Results of the urine pregnancy screening test will be shared with the 
adolescent subject only and not with the adolescent’s parents or legal 
guardians. As per California state confidentiality laws, the results of 
pregnancy tests in minors cannot be shared with the minor’s parent or 
legal guardian without the written permission of the minor. If the 
pregnancy test is positive, we will counsel the teen and give her referrals 
to teen pregnancy resources such as Planned Parenthood. If the participant 
is pregnant, the participant is not allowed to enter the study until the 
pregnancy is over. Second, if the participant who is in the intervention 
group becomes pregnant during the course of the study after the first MRI 
scan, she will be allowed to finish participating in the group intervention 
since there are no known potential adverse effects on the fetus due to 
meditation. However, although there are no known adverse negative 
effects of MRI scans on the fetus, we have decided to be conservative in 
our study and not allow participants who become pregnant during the 
study after the first MRI scan to have the second MRI scan in order to 
minimize any potential risk to the unborn fetus. 
§ Not allowable: Current mindfulness training (e.g. MBSR, MBCT, DBT) 
and/or practice with a typically sitting meditation or yoga of 20 or more 
minutes two or more times per week within 60 days prior to study entry.  
§ Potential adolescent subjects with current drug or alcohol use or 
dependence that, in the opinion of the site investigator, would interfere 
with adherence to the study requirements will be excluded and not allowed 
to enter the study. We will use the Brief Screener for Tobacco, Alcohol, 
and other Drugs (BSTAD) developed by National Institute on Drug Abuse 

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(NIDA) to determine higher risk subjects who will be excluded: 
https://www.drugabuse.gov/adolescent-substance-use-screening-tools. 
§ Potential subjects with an inability or unwillingness to give written 
informed assent or whose legal guardian/representative are unable or 
unwilling to give written informed consent will be excluded and not 
allowed to enter the study. 
4.3 
Study Enrollment Procedures  
Recruitment of potentially eligible participants will be primarily performed 
using IRB-approved ads on internet sites such as Instagram, Facebook, 
Craigslist, Nextdoor. Moreover, recruitment will be performed in the San 
Francisco Unified School District (SFUSD) using IRB-approved flyers. The 
SFUSD is the seventh largest school district in California, educating over 
57,000 students every year. We have substantial experience of working 
successfully with SFUSD Wellness Centers and creating flyers that attract the 
attention of candidate participants. Our flyers have been previously deemed to 
have a clear educational enrichment purpose for SFUSD and we have always 
successfully obtained permission to distribute the printed flyers as well as 
online announcements to SFUSD staff, family, and students through  
http://www.sfusd.edu/en/news/request-to-distribute.html. 
Due to COVID-19, we have transitioned to implementing the vast majority of 
our subject recruitment efforts using the internet and online methods. When 
the school districts (i.e., SFUSD) begin to allow students to enter the school 
campuses, we will resume posting our UCSF IRB-approved flyers at the 
several different school campuses again. Any interested adolescent and/or 
parent of an adolescent who phones or e-mails either the PIs or research 
assistants in response to the UCSF IRB-approved flyer will be considered for 
the study. 
Ancillary recruitment strategies: In addition to recruiting from SFUSD, we 
plan to also recruit healthy adolescents for our study through posting our 
UCSF IRB-approved recruitment flyers at several other recruitment sites 
located throughout San Francisco and the San Francisco Bay Area. 
Prior to enrollment into the study, all potential subjects will be initially 
screened using a Phone Pre-Screener. Study staff performing the screening by 
telephone will complete the checklist to ensure that the potential participant 
meets eligibility criteria to enter the study (please see included Phone Pre-
Screening form).  
 
Adolescents and their parents/guardians will be screened using a semi-scripted 
telephone screening procedure designed to elicit inclusion/exclusion information and 
provide additional information about the study to the caller. The parent and 
adolescent will provide verbal consent to answer some questions over the telephone 
to pre-screen the adolescent regarding eligibility (e.g. age 14-18 years, healthy, 
English-speaking) as well as verbal consent to study participation, and availability 

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for study assessments and classes. The study procedures, including what is involved 
in participating in the training, as well as the MRI visits will be described to potential 
participants and their parents. The goal is to ensure they understand the commitment 
involved in study participation. Those who do not meet eligibility criteria will be told 
that they are not eligible to participate. First visit: Those who meet inclusion criteria 
and give verbal consent will schedule the first visit which will include the 
questionnaire-based assessments (First visit Part A) and baseline MRI scan (First visit 
Part B). The consent form will be mailed or emailed for review prior to the visit. At 
the First visit Part A, which can be conducted over Zoom, the researcher will first 
review the consent form with the adolescent and the parent/guardian, and they will 
both sign the form using DocuSign. Electronic copies of all consent forms will be 
provided to the participant and to the parent or legal guardian, as well as the 
Experimental Subjects Bill of Rights. No adolescents will be contacted or screened by 
the study team before parental verbal consent is obtained. The exception is the 18-
year-old participants who do not need parental consent. 
We will use computer-generated randomization with random blocks sizes ranging 
from 4 to 8 in order to assign a participant to either the TARA intervention group or 
the waitlist control group. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
The TARA intervention is delivered in a semi-manualized form in 12 consecutive, weekly 1.5-
hour sessions by two facilitators (who are trained by Dr. Henje Blom). In case of a remote 
delivery of the intervention, a group size of 8-10 participants allows for a good overview of 
everyone in the group. Participants will be instructed by the TARA facilitators how to best create 
a quiet, temperature-controlled, comfortable practice space in their home, and how to best use 
Zoom and camera on their device. Each participant will receive from us props for their practice 
(a yoga mat, a meditation pillow, an eye pillow, etc.). Daily home practice of TARA skills will 
be encouraged and audio recordings with guided meditations will be provided. The outline of the 
TARA intervention is as follows (for details, see Blom Henje et al., 2014): Module 1: focuses 
on the ability to create a calm and safe inner state through breathing, yoga-based movement and 
guided “body-scan” meditations. A brief psycho-educational module on the psychophysiology of 
stress and respiration is provided. Module 2: includes attention training first targeting external 
stimuli, followed by sensory stimuli and interoceptive awareness. Psycho-education is provided 
on an adapted neuroscience model and the importance of sleep and healthy eating for emotional 
health. Module 3: focuses on recognizing, labeling, and communicating emotions. By aiding 
participants in identifying their emotions and applying skills from modules 1 and 2, the core 
skills are applied in social interaction. In Module 4 a more cognitively based behavioral 
activation approach is introduced, including understanding of social triggers of negative 
emotions and one’s own experiential avoidance strategies and how they may impede obtaining 
desired life goals. A parallel focus on defining personal core values and linking them to behavior 
activation is a thread throughout the intervention that serves as a motivational force to increase 
sustainability and future engagement in salutogenic activity. The meditative practices are 
continued in all modules. 

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The attached TARA Manual provides extensive details on the content of each TARA session 
(please see Appendix).   
 
The TARA sessions will take place remotely over Zoom. 
 
TARA training facilitators: Two facilitators are provided for each class who can support each 
other in creating a safe environment for the participants. The facilitators have many years of their 
own mindfulness practice, so that they may effectively model the mindfulness practices and 
know from their own experience the effect of the different practices that are introduced to the 
participants during the TARA training. We have an available pool of eight TARA facilitators 
who are officially trained to teach TARA. The following four facilitators from this available pool 
of eight are the primary facilitators for this project:  
 
Catherine Shaddix, Psy.D, is a graduate of the doctoral program in clinical psychology at the 
Wright Institute in Berkeley, CA. She completed her pre-doctoral internship at the Infant, Child, 
and Adolescent Division of Psychiatry at the UCSF San Francisco General Hospital. Her 
dissertation research, conducted at the UCSF Osher Center for Integrative Medicine, was a long-
term follow-up study of mindfulness training. In 2015, she was also an intervention design team 
member and facilitator for the TARA groups in adolescents. 
 
Jennifer Shao, MFT, received her Masters in Clinical Psychology at San Francisco State 
University. She is a school-based clinician at Ann Martin Center, CA. She has provided 
individual therapy sessions to children, family therapy and parenting skills training, collateral 
consultation and psychoeducation to parents, teachers, school staff and other providers. Jennifer 
has facilitated mindfulness and play therapy groups within the school setting. Since 2016, she 
has been co-teaching TARA training for adolescents. 
 
Jonathan Weinstock, B.A., has been Program Manager and Mindfulness Teacher at Edgewood 
Center for Children and Families for over 16 years. Edgewood Center for Children and Families 
has served the San Francisco Bay Area for over 150 years by providing the full continuum of 
behavioral and mental health services to children, youth, and families. Jonathan Weinstock has 
been facilitator for TARA groups in adolescents since 2015. 
 
Lisa Lin Baldini, B.A., is expecting her Doctoral Degree in Clinical Psychology from PGSP-
Stanford PsyD Consortium, Palo Alto, California in 2019. She has experience teaching TARA 
groups and she has published scientific peer-reviewed articles on TARA training. In her doctoral 
dissertation, which she defended in 2018, Lisa Baldini studied the effects of TARA on self-
compassion. 
 
Potential adverse effects from the TARA intervention:  Participants could experience restlessness 
or some difficult emotions, like sadness or anger, during some of the class activities or home 
assignments.  To minimize the risks to subjects and this potential adverse effect from the TARA 
intervention, If participants experience difficult emotions during the TARA intervention, they 
can stop the activity and speak to the class leader or study staff. The class leader will talk about 
how to handle difficult emotions that come up during home assignments at the first class, and 

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throughout the course as needed. 
5.2 
Handling of Study Interventions 
To ensure the completeness and accuracy of the data, the study intervention 
accountability records (i.e., On Study Visit Checklist) will be completed at each of 
the TARA intervention sessions when the participants receive the TARA intervention 
training. (Please see On Study Visit Checklist form in Appendix) 
The attached TARA Manual provides extensive details on the content of each TARA 
session (please see Appendix).   
 
The study subjects/patients will know which study group they have been assigned to (i.e., TARA 
intervention or waitlist control). Thus, by necessity, they will be only unblinded to the study 
group assignment.  
 
The TARA Instructors/Practitioners must—by necessity—be only unblinded to the study 
intervention group assignment in order to deliver the TARA intervention to the participants.  
 
All of the Outcome Assessors will be blinded to study group assignment until after the 
database is locked. In order to blind the Outcome Assessors to study group assignment, each 
adolescent subject will be assigned a unique numerical identifier to mask the identity of the 
subject and also mask any private information that is linked to the subject. Coding and 
assignment of the unique numerical identifier will occur at the time of subject consent. This 
unique numerical identifier will be attached to all data acquired from adolescent subjects.  
 
In order to maintain masking (i.e., blinding) of study group assignment, all of the 
participants will be clearly instructed not to discuss with any of the research study staff 
which study group they have been assigned to during the entire duration of the study. 
 
The Data Analysts and Statistician will be blinded to the intervention group assignment until 
after the database is locked. In order to blind the Data Analysts and Statistician to study 
group assignment, each adolescent subject will be assigned a unique numerical identifier to 
mask the identity of the subject and also mask any private information that is linked to the 
subject. 
 
The Data Analysts and Statistician will be unblinded after the database is locked at the time of 
the data analysis. 
 
The Principal Investigators (PIs) will be blinded to the intervention group assignment during the 
entire course of the study until after the database is locked. In order to blind the PIs to study 
group assignment, each adolescent subject will be assigned a unique numerical identifier to 
mask the identity of the subject and also mask any private information that is linked to the 
subject. 
 
Since the safety of all of the participants is of paramount importance, there is a risk of 
inadvertently unblinding of the co-PI, Dr. Yang, if a safety concern arises (e.g., suicidal ideation 

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in a participant). However, even if Dr. Yang is inadvertently unblinded in order to ensure the 
safety of the subject, Dr. Yang and Dr. Tymofiyeva will both remain blinded to both the Primary 
Mechanistic Outcome Measure and Clinical/Functional Outcome Measure for the entire duration 
of the study until after the database is locked. 
5.3 
Concomitant Interventions  
5.3.1 Allowed Interventions 
All interventions are allowed while on study except for the following: mindfulness 
training (e.g. mindfulness-based stress reduction [MBSR], mindfulness-based 
cognitive therapy [MBCT], dialectical behavior therapy [DBT]) and/or practice with 
a typically sitting meditation or yoga of 20 or more minutes two or more times per 
week. 
5.3.2 Required Interventions 
There are no required interventions that are also required in addition to the TARA 
intervention which is the focus of this study. 
5.3.3 Prohibited Interventions 
The following interventions are prohibited while the participant is on study: 
mindfulness training (e.g. mindfulness-based stress reduction [MBSR], mindfulness-
based cognitive therapy [MBCT], dialectical behavior therapy [DBT]) and/or practice 
with a typically sitting meditation or yoga of 20 or more minutes two or more times 
per week. 
5.4 
Adherence Assessment  
Definition of Adherence: The proportion of volunteers randomized to TARA 
training who participate in at least 75% of the sessions. Adherence to the TARA 
study intervention will be assessed by recording the attendance of each of the 
participants at each of the TARA intervention sessions. We expect that at least 80% 
of participants on the TARA arm will attain this level of adherence. Please see below 
section on Data Analyses (Section 9.6) for description of how this information will be 
incorporated into the analysis of the study results. 
6. STUDY PROCEDURES 

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6.1 
Schedule of Evaluations 
Assessment 
Phone 
Pre-
Screeni
ng 
Screening, 
Baseline, 
Enrollment, 
Randomizat
ion: Visit 1 
(Day 0) 
Visit 2 
(TARA
1) 
Visit 3 
(TARA
2) 
Visit 4 
(TARA
3) 
Visit 5 
(TARA
4) 
Visit 6 
(TARA
5) 
Visit 7 
(TARA
6) 
Visit 8 
(TARA
7) 
Visit 9 
(TARA
8) 
Visit 
10 
(TARA
9) 
Visit 
11 
(TARA
10) 
Visit 
12 
(TARA
11) 
Visit 
13 
(TARA
12) 
Follo
wup: 
Final 
Visit 
14 
 
Phone Pre-
Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
Form   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment/Rando
mization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SDQ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI Screening 
Form & urine 
pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Baseline Checklist 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CORS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSRS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
On Study Visit 
Checklist  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Completion  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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6.2 
Description of Evaluations  
6.2.1 Screening Evaluation 
These evaluations occur to determine if the candidate is eligible for the study.    
Definitions of the column headings in the Schedule of Evaluations (Section 6.1):  (1) 
Assessment refers to the specific assessments as listed in the first column that will be 
performed at each of the study visits; (2) Visit 1 (Day 0) refers to all of the 
assessments that will occur at the first study visit; (3) Visits 2 to 13 refer to the 
assessments that will occur at each of the study visits 2 through 13 which correspond 
to the TARA study intervention sessions 1 through 12 (i.e., Study Visit 2 is TARA 
study intervention session 1 since the first TARA study intervention session will take 
place on Study Visit 2); (4) Final Visit 14 refers to all of the assessments that will 
occur on the final study visit which will be Visit 14.  Please note that in the above 
Schedule of Evaluations (Section 6.1), the AE and SAE forms only will be completed 
if an AE and/or SAE are reported by a participant. In addition, if a participant 
prematurely leaves the study, all of the assessments listed under the final study visit 
14 column will be performed. 
A phone pre-screening evaluation will occur to determine if the candidate adolescent 
is eligible for the study prior to the initial visit, and a screening evaluation will occur 
at Visit 1 (Day 0) to determine if the candidate is eligible to enter the study. 
Consenting Procedure 
A trained research staff member who will have at least a college degree (i.e., 
Bachelor’s degree or higher) will perform the following informed consent process. 
Adolescents and their parents/guardians will be screened using a semi-scripted 
telephone screening procedure designed to elicit inclusion/exclusion information and 
provide additional information about the study to the caller. The parent and 
adolescent will provide verbal consent to answer some questions over the telephone 
to pre-screen the adolescent regarding eligibility (e.g. age 14-17 years, healthy, 
English-speaking) as well as verbal consent to study participation, and availability 
for study assessments and classes. The study procedures, including what is involved 
in participating in the training, as well as the MRI visits will be described to potential 
participants and their parents. The goal is to ensure they understand the commitment 
involved in study participation. Those who do not meet eligibility criteria will be told 
that they are not eligible to participate. First visit: Those who meet inclusion criteria 
and give verbal consent will schedule the first visit which will include the 
questionnaire-based assessments (First visit Part A) and baseline MRI scan (First visit 
Part B). The consent form will be mailed or emailed for review prior to the visit. At 
the First visit Part A, which can be conducted over Zoom, the researcher will first 
review the consent form with the adolescent and the parent/guardian, and they will 
both sign the form using DocuSign. Electronic copies of all consent forms will be 
provided to the participant and to the parent or legal guardian, as well as the 
Experimental Subjects Bill of Rights. These forms will be kept in a locked filing 
cabinet and will not have participant ID numbers on them. No adolescents will be 

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contacted or screened by the study team before parental verbal consent is obtained. 
The exception is the 18-year-old participants who do not need parental consent. In 
case any changes may be required to the consent form, the PIs (Drs. Tymofiyeva and 
Yang) will review the consent document and make any changes as they decide are 
required to the consent form.  
Screening 
The allowable range of time prior to study entry during which all screening 
evaluations to determine eligibility must be completed will be 2 months.  
The following screening evaluations will occur in the following sequence of events: 
• Phone pre-screen. The phone pre-screen will occur first. If the potential 
participant meets eligibility criteria, they are invited to the first visit at UCSF 
(Visit 1). If the potential participant does not meet eligibility criteria during 
the phone pre-screen, they are thanked for their interest and informed that they 
do not meet eligibility requirements for the study. The phone prescreen must 
be done within 2 months of enrollment. 
• Visit 1 (Day 0). If the potential subject meets eligibility criteria based on the 
initial phone pre-screen, they are invited to come to their first visit (Visit 1). 
During Visit 1 Part A, which can be conducted over Zoom, the following 
additional screening forms will be completed: (1) Medical History form that 
will ascertain if the patient has any current medical, neurological, or 
psychiatric illnesses that would exclude the subject from enrolling in the 
study; and (2) Inclusion/Exclusion Criteria form that will determine through a 
sequence of “yes” and “no” questions whether the subject meets the full 
inclusion and exclusion criteria to be allowed to enroll into the study. The 
Medical History form and Inclusion/Exclusion criteria forms must both be 
completed the same day as the enrollment into the study. 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
The current study will utilize a single informed signed consent form that describes 
both screening and study procedures. Thus, in the current study, the enrollment date is 
defined as the date all of the screening criteria are met and the individual agrees to 
participate which is also the same date as the randomization date (i.e., Visit 1 [Day 
0]). Please see above, Section 6.1, Schedule of Evaluations Table. The enrollment 
date will be recorded on a case report form (please see included Randomization and 
Enrollment form) along with the allowable window between screening and 
randomization (please see above section, “Screening”, for the precise allowable time 
window between screening and randomization). 
Baseline Assessments 
The following baseline evaluations will occur on Visit 1 (Day 0) of the study:  
• MRI brain scan. An MRI brain scan will be acquired at baseline to compare 

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against the final MRI brain scan that will be obtained at the final visit (Visit 
14). 
• Strengths and Difficulties Questionnaire (SDQ). Emotional problems will be 
assessed in all participants at baseline using the SDQ in order to compare with 
the SDQ that will be collected at the final visit (Visit 14). 
Randomization 
Computer-generated randomization will precede intervention administration in the 
current randomization study. The time window for randomization relative to 
completion of screening and baseline will be 24 hours (i.e., randomization as well as 
completion of screening and baseline will all occur the same day). The time window 
for initiation of study intervention relative to randomization will be 4 (four) weeks. 
6.2.3 Blinding 
There will be one unblinded research assistant (RA) who will be responsible for: (1) 
scheduling and helping set-up the delivery of the TARA intervention, and (2) 
providing unblinded case-by-case reports to the study Independent Monitors (IM); this 
RA will have no access to data and no involvement in data monitoring and analyses. 
Since the Study subjects and TARA Instructors/Practitioners can not be blinded to the 
Intervention group assignment (please see below, Table 1 Blinding Table), there will 
not be an individual authorized to break the blind, circumstances for breaking the 
blind, or procedures for breaking the blind. Which stake holders will be blinded, what 
the stake holders will be blinded to, and the procedures for retaining the blind for the 
different stake holders for the intervention group assignment, primary mechanistic 
outcome measure, and clinical/functional outcome measure are described below in 
Table 1 (please see below, Table 1. Blinding Table). 
 
Table 1. BLINDING TABLE 
 
Stake holder 
Intervention group assignment 
Primary Mechanistic 
Outcome Measure 
Clinical/ Functional Outcome 
Measure 
Study 
subjects/Patients 
Not blinded 
 
The study subjects/patients will 
know which intervention group 
they have been assigned to. 
Thus, by necessity, they will be 
only unblinded to the intervention 
group assignment. 
 
Blinded 
 
The study 
subjects/patients will be 
blinded to the Primary 
Mechanistic Outcome 
Measure for the entire 
duration of the project. 
Blinded 
 
The study subjects/patients 
will be blinded to the 
Clinical/Functional Outcome 
Measure for the entire 
duration of the project. 
Instructors/ 
Practitioners 
Not blinded 
 
The TARA 
Instructors/Practitioners must—
by necessity—be only unblinded 
to the intervention group 
assignment in order to deliver the 
Blinded 
 
All of the TARA 
Instructors/ 
Practitioners will be 
blinded to the Primary 
Mechanistic Outcome 
Blinded 
 
All of the TARA 
Instructors/Practitioners will 
be blinded to the 
Clinical/Functional Outcome 

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TARA intervention to the 
participants.  
 
Measure for the entire 
duration of the study. 
Measure for the entire 
duration of the study. 
Outcome 
Assessors 
Blinded 
 
All of the Outcome Assessors will 
be blinded to group assignment 
until after the database is locked. 
In order to blind the Outcome 
Assessors, each adolescent 
subject will be assigned a unique 
numerical identifier to mask the 
identity of the subject and also 
mask any private information that 
is linked to the subject. Coding 
and assignment of the unique 
numerical identifier will occur at 
the time of subject consent. This 
unique numerical identifier will be 
attached to all data acquired 
from adolescent subjects.  
 
Participants will be instructed not 
to discuss with any of the 
research study staff which group 
they have been assigned to 
during the entire duration of the 
study. 
Blinded 
 
Neuroimaging Outcome 
Assessors will be blinded 
to clinical outcome 
assessments. Similarly, 
Clinical Outcome 
Assessors will be blinded 
to the neuroimaging  
outcome assessments. 
 
The clinical Outcome 
Assessors and 
neuroimaging Outcome 
Assessors will be 
separate study staff who 
will work in separate 
offices located on 
separate campuses at 
UCSF.   
 
The clinical Outcome 
Assessors and 
neuroimaging Outcome 
Assessors will not 
communicate with one 
another regarding the 
outcome of their 
separate assessments at 
any time point during the 
course of the study until 
after the database is 
locked. 
 
Blinded 
 
Clinical Outcome Assessors 
will be blinded to the 
neuroimaging outcome 
assessments. Similarly, 
neuroimaging Outcome 
Assessors will be blinded to 
clinical outcome 
assessments. 
 
The clinical Outcome 
Assessors and neuroimaging 
Outcome Assessors will be 
separate study staff who will 
work in separate offices 
located on separate 
campuses at UCSF.   
 
The clinical Outcome 
Assessors and neuroimaging 
Outcome Assessors will not 
communicate with one 
another regarding the 
outcome of their separate 
assessments at any time 
point during the course of the 
study until after the database 
is locked. 
Data Analysts/ 
Statistician 
Blinded 
 
The Data Analysts and 
Statistician will be blinded to the 
intervention group assignment 
until after the database is locked. 
 
The Data Analysts and 
Statistician will be unblinded after 
the database is locked at the 
time of the data analysis. 
Blinded 
 
The Data Analysts and 
Statistician will be 
blinded to the Primary 
Mechanistic Outcome 
Measure until after the 
database is locked. 
 
The Data Analysts and 
Statistician will be 
unblinded after the 
database is locked at the 
time of the data analysis. 
Blinded  
 
The Data Analysts and 
Statistician will be blinded to 
Clinical/Functional Outcome 
Measure until after the 
database is locked.  
 
The Data Analysts and 
Statistician will be unblinded 
after the database is locked 
at the time of the data 
analysis. 
 
Principal 
Investigators 
Blinded 
 
The Principal Investigators (PIs) 
will be blinded to the intervention 
group assignment during the 
entire course of the study until 
after the database is locked.  
 
Since the safety of all of the 
participants is of paramount 
importance, there is a risk of 
Blinded 
 
The PIs will be blinded to 
the Primary Mechanistic 
Outcome Measure during 
the entire course of the 
study until after the 
database is locked.  
 
Blinded 
 
The PIs will be blinded to the 
Clinical/ Functional Outcome 
Measure during the entire 
course of the study until after 
the database is locked. 

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inadvertently unblinding of the 
co-PI, Dr. Yang, if a safety 
concern arises (e.g., suicidal 
ideation in a participant).  
However, even if Dr. Yang is 
inadvertently unblinded in order 
to ensure the safety of the 
subject, Dr. Yang and Dr. 
Tymofiyeva will both remain 
blinded to both the Primary 
Mechanistic Outcome Measure 
and Clinical/Functional Outcome 
Measure for the entire duration of 
the study until after the database 
is locked. 
 
 
6.2.4 Followup Visits 
The following study visits must be performed on the weeks indicated above in the 
Schedule of Evaluations (please see Section 6.1) plus/minus 5 (five) working days 
(i.e., Monday through Friday, not including weekends and holidays): 
• Visit 1: 
§ Informed Consent Form  
§ Medical History Form 
§ Inclusion/Exclusion criteria form 
§ Enrollment/Randomization form 
§ MRI Screening Form & urine pregnancy test 
§ MRI brain scan 
§ Demographics assessment (electronically in Qualtrics) 
§ SDQ assessment (electronically in Qualtrics) 
§ Baseline Checklist 
• Visit 2 through Visit 13: 
§ Child Session Rating Scale (CSRS) 
• Child Outcome Rating Scale (CORS) including the question: “Has there been 
any significant unfavorable change in your mental or physical health since last 
class?” (please see Appendix. Not a source document.) 
§ Adverse Events (if answered Yes the question above in CORS) 
§ Serious Adverse Events (if answered Yes to the SAE question in the Adverse 
Event form) 
§ On Study Visit Checklist Form (modified to include Treatment 
Administration information) 

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6.2.5 Completion/Final Evaluation.  
The following assessments will be performed at the participant’s final visit (Visit 14): 
• SDQ assessment (electronically in Qualtrics) 
• MRI Screening Form & urine pregnancy test  
• MRI brain scan 
• Child Outcome Rating Scale (CORS) including the question: “Has there been 
any significant unfavorable change in your mental or physical health since last 
class?” (please see Appendix. Not a source document.) 
• Adverse Events (if answered Yes the question above in CORS) 
• Serious Adverse Events (if answered Yes to the SAE question in the Adverse 
Event form) 
• Study Completion form. 
 
For study participants who discontinue the study intervention early, all of the 
following assessments will be performed: 
• SDQ assessment (electronically in Qualtrics) 
• MRI Screening Form & urine pregnancy test  
• MRI brain scan 
• Child Outcome Rating Scale (CORS) including the following question: “Has 
there been any significant unfavorable change in your mental or physical 
health since last class?” (please see Appendix. Not a source document.) 
• Adverse Events (if answered Yes the questions above in CORS) 
• Serious Adverse Events (if answered Yes to the SAE question in the Adverse 
Event form) 
• Study Completion form. 
Potential reasons for early terminations:  (1) participant moves away to a distant part 
of the country or another country outside of the United States, (2) participant is 
involved in a severe motor vehicle accident that precludes the participant from being 
able to continue on with the study, (3) participant is involved in a plane crash that 
results in either death or severe disability that precludes the participant from further 
participation in the study, (4) participant is diagnosed with a severe illness that 
precludes them from being able to continue further with participation in the study. 
Once a study participant has stopped using the study intervention, there are no 
specific requirements (e.g., related to monitoring and reporting of adverse events) for 
follow-up since the study intervention (i.e., TARA) is considered very minimal risk 
by our institution’s IRB.  

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7. SAFETY ASSESSMENTS  
Participant safety will be monitored once an individual is enrolled in the study.  Since 
our institutional IRB has deemed our TARA intervention to be very minimal risk, we 
do not anticipate any significant adverse experiences from our TARA intervention. 
However, to assure comprehensive review of potential safety events, we have 
included the following alphabetical list of expected adverse experiences for the 
TARA study intervention, criteria for management and modification of the TARA 
study intervention regimen or participant assessments if an adverse event occurs: 
1. Experiencing difficult emotions such as sadness or anger during some of the 
TARA intervention class activities or home assignments. If participants 
experience difficult emotions, they can stop the activity and speak to the class 
leader or study staff. The class leader will talk about how to handle difficult 
emotions that come up during home assignments at the first class, and throughout 
the course as needed. 
2. Restlessness. If participants experience restlessness, they can stop the activity and 
speak to the class leader or study staff. The class leader will talk about how to 
handle restlessness that come up during home assignments at the first class, and 
throughout the course as needed. 
 
 
If an adverse event occurs, the AE will be assessed by Dr. Yang (medical director 
and co-PI) and recorded in the Adverse Event form (please see Adverse Event form 
in the Appendix). 
 
7.1 
Specification of Safety Parameters 
To demonstrate the safety of the TARA intervention, we will carefully record all       
adverse events and require that < 15% of the participants experience a grade 2 
(moderate) or grade 3 (severe) adverse event related to the TARA intervention. 
 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
The risk profile of our study intervention (TARA) is very minimal.  Our institutional 
IRB has deemed our TARA study intervention to be very minimal risk. Our published 
peer-reviewed paper using our TARA study intervention in depressed adolescents 
also demonstrates the exceptional safety and very minimal risk of our TARA study 
intervention (Henje Blom et al., 2017). The Methods and Timing for Assessing, 
Recording, and Analyzing Safety Parameters are as follows: (1) At each of the 12 
study TARA intervention visits (i.e., TARA visits 1 through 12 [Study visits 2 to 13] 
as detailed above in section 6.1: Schedule of Evaluations), any and all adverse events 
will be collected and recorded using the Adverse Event form. Any Adverse Event(s) 
will be reviewed by the PIs and a determination of the relationship of the Adverse 
Event to the TARA study intervention will be made by the medical PI (Dr. Yang). 
Based on the study intervention relationship to the Adverse Event as determined by 
Dr. Yang and the severity of the Adverse Event, Dr. Yang and Dr. Tymofiyeva will 
decide upon the appropriate action to take regarding the study intervention (TARA). 

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If the Adverse Event is classified as Serious Adverse Events, the Serious Adverse 
Event form will be filled out.  
7.3 
Adverse Events and Serious Adverse Events  
In the present study, an adverse event and serious adverse event will be defined as 
follows: 
An adverse event (AE) will be defined as any unfavorable and unintended diagnosis, 
symptom, sign (including an abnormal laboratory finding), syndrome or disease 
which either occurs during the study, having been absent at baseline, or if present at 
baseline, appears to worsen. Adverse events will be recorded regardless of their 
relationship to the study intervention.   
A serious adverse event (SAE) will be defined as any untoward medical occurrence 
that results in death, is life threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly. 
Since we do not anticipate any laboratory value changes due to the TARA study 
intervention, no laboratory values will be collected as part of the current protocol; 
thus, no laboratory values will be collected to assess safety. 
Solicited adverse events will be captured in the following manner: (1) the Child 
Outcome Rating Scale (CORS) including the following question: “Has there been any 
significant unfavorable change in your mental or physical health since last class?” 
will be administered at every TARA session (please see Appendix. Not a source 
document.); (2) if the participant answers “no” to this question on the CORS, then no 
additional information will be requested; (3) if the participant answers “yes” to this 
question on the CORS and the reported event meets the definition of an adverse event 
given above, then the research assistant or another study staff member will ask the 
participant for additional details regarding the participant’s answer to the CORS 
question and this information will be recorded in the Adverse Event form within 24 
hours of the TARA study intervention session. 
In order to assure that the reporting and data collection systems avoid double capture 
of solicited and unsolicited events, we have implemented the following items in our 
protocol:  (1) We will ask all of the participants to report any unsolicited events in the 
CORS after the question, “Has there been any significant unfavorable change in your 
mental or physical health since the last class?”; (2) If a participant reports an 
unsolicited event to any of the study staff, the study staff member will ask the 
participant to write down this information in the CORS in order to avoid double 
capture of the event; (3) We also will specifically instruct our research assistants and 
staff to not duplicate the recording (i.e., double capture) of the same solicited and 
unsolicited events; (4) At the weekly clinical trial research lab meetings, the PIs (Drs. 
Tymofiyeva and Yang) will review with the research staff all of the CORS forms, AE 
and SAE forms for the prior week in order to ensure that there is no double capture(s) 
of any solicited and unsolicited event(s).  

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Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the 
study.  
To satisfy the requirement for prompt reporting, unanticipated problems will be 
reported using the following timeline:   
• Unanticipated problems that are serious adverse events will be reported to the 
IRB, Independent Safety Monitors, and NCCIH within 7 days of the investigator 
becoming aware of the event.  
• Any other unanticipated problem will be reported to the IRB, Independent Safety 
Monitors, and NCCIH within 15 days of the investigator becoming aware of the 
problem.  
All unanticipated problems will be reported to appropriate institutional officials (as 
required by an institution’s written reporting procedures), the supporting agency head 
(or designee), and OHRP within one month of the IRB’s receipt of the report of the 
problem from the investigator. 
Adverse Event Reporting 
SAEs that are unanticipated, serious, and possibly related to the study intervention 
will be reported to the Independent Safety Monitors, IRB, and NCCIH in accordance 
with requirements.   
• Unexpected fatal or life-threatening AEs related to the intervention will be 
reported to the NCCIH Program Officer, and Independent Safety Monitors within 
7 days of the investigator becoming aware of the event.  Other serious and 
unexpected AEs related to the intervention will be reported within 15 days. 
• Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the Independent Safety Monitors, IRB, and other oversight 
organizations in accordance with their requirements. and will be reported to 
NCCIH on an annual basis.    
• All other AEs documented during the course of the trial will be reported to 
NCCIH on an annual basis by way of inclusion in the annual report and in the 
annual AE summary which will be provided to NCCIH and to the Independent 
Monitors.  The Independent Safety Monitors Report will state that all AEs have 
been reviewed. 
 
7.4 
Reporting Procedures 
Please see below, Table A, for details of the reporting procedures and timelines, 
including the individual responsible for each step (e.g., the PIs, the Independent 
Monitors, etc.). The medical director, Dr. Yang (co-PI), will make the decision 
regarding determining the relatedness and severity of any and all AEs and SAEs. The 
appropriate AE and SAE forms will be completed. The completed AE and SAE forms 
will be sent and distributed to the appropriate individual or group of individuals (i.e., 

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UCSF IRB, NCCIH) as stated below in Table A (please see below, Table A). The PIs 
will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 days (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation. A research assistant will perform the duties of the 
Internal QA reviewer. 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.  
 
Table A 
 
 
Reporting Changes in Study Status 
During the funding of this study, any action by an IRB, the Independent Monitors, or 
one of the study investigators that results in a temporary or permanent suspension of 
the study will be reported to the NCCIH Program Official within 3 business days of 
notification.  
 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually  
 
Independent Monitors 
Status of all enrolled subjects, as 
of date of reporting  
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
Data entry quality control checks 
on 100% of charts 
Weekly 
QA Reviewer 
Adherence data regarding study 
visits and intervention 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
AEs and rates (including out-of-
range lab values) 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
Annually 
NCCIH 
SAEs (unexpected and related) 
Per occurrence 
PIs, Independent Monitors 
NIH/NCCIH 
SAEs (expected or unrelated) 
Per Occurrence 
PIs, Internal QA Reviewer 
Annually 
Independent Monitors, 
NIH/NCCIH 
Unanticipated Problems 
Monthly 
PIs, Internal QA Reviewer 
Per Policy 
IRB 

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7.5 
Followup for Adverse Events 
The PIs will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 days (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. In the cases of adolescents 
with severe depression or adolescents expressing passive suicidal ideation (i.e., the 
adolescent expresses some potential thoughts of self-harm, but there is no intent or 
plan to harm herself/himself), study participants with commercial or private health 
insurance plans will be referred to the UCSF Langley Porter Psychiatric Institute 
where Dr. Yang (co-PI) sees patients, and study participants without commercial or 
private insurance will be referred to the UCSF Zuckerberg San Francisco General 
Hospital which cares for all patients regardless of their ability to pay. Participants 
expressing imminent suicidal ideation will be placed on an involuntary 5150 72-hour 
hold for danger to self by Dr. Yang. Dr. Yang is a double board certified adult as well 
as child and adolescent psychiatrist who sees patients at UCSF, and he is legally 
authorized to place an involuntary 5150 72-hour hold on the adolescent for danger to 
self (i.e., suicidal ideation) in order to hospitalize the adolescent if needed. The UCSF 
Emergency Room (ER) is located immediately adjacent to the UCSF Langley Porter 
Psychiatric Institute where Dr. Yang’s personal clinical office and research lab are 
located. Following the established written protocols that are currently in place for any 
adolescent who expresses imminent suicidal ideation, Dr. Yang would evaluate and 
place an involuntary 5150 72-hour hold for danger to self on the suicidal adolescent.  
Dr. Yang would then contact the UCSF Langley Porter Psychiatric Institute security 
who are present in the building throughout the entire day and evening to help escort 
the suicidal adolescent to the UCSF ER. The ER physician in consultation with the on 
call child and adolescent psychiatrist would then evaluate the patient in the ER and 
decide whether to hospitalize the patient for the adolescent’s safety and well-being. 
7.6 
Safety Monitoring  
The Independent Monitoring Committee (IMC) for this study is comprised of Drs. 
Robert Hendren, David Becker, and Patrick Phillips. Drs. Hendren, Becker, and 
Phillips are not associated with this research project and work independently of the 
PIs, Drs. Tymofiyeva and Yang. They are not part of the key personnel involved in 
this grant. No member of the Committee has collaborated or co-published with the 
PIs within the past three years. They are qualified to review the patient safety data 
generated by this study because of their unique expertise. Specifically, Dr. Robert 
Hendren, a full Professor and a Board-Certified Child and Adolescent Psychiatrist, 
has devoted his career to the care and research of adolescents. Dr. Hendren has 
exceptional expertise and extensive experience with clinical trial studies in children 
and adolescents. He has served on three IMCs. Dr. David Becker is a Professor of 
Pediatrics who specializes in integrative medicine and behavioral health. Dr. Patrick 
Phillips holds a PhD in medical statistics, and he has significant and extensive 
experience in clinical trials. (Please see the DSMP for the CVs of all members of the 
IMC). 

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8. INTERVENTION DISCONTINUATION  
Participants who have met inclusion/exclusion criteria and been enrolled into the 
study may be discontinued if they no longer meet the study’s inclusion and exclusion 
criteria (e.g., if the patient has started participation in another mindfulness-based 
intervention such as mindfulness-based stress reduction after they have enrolled into 
the TARA study intervention). The PIs (Drs. Tymofiyeva and Yang) will determine 
when criteria are met (i.e., the participant no longer meets the study’s stated inclusion 
and exclusion criteria) for discontinuing intervention for a participant. 
Possible reasons for discontinuation of the study intervention include closure by the 
institute (i.e., UCSF) due to significant concerns over the continued safety of the 
participants such as the occurrence of a natural disaster (e.g., earthquake) that renders 
the buildings at UCSF where the TARA study intervention is being delivered unsafe 
due to structural building damage arising from the earthquake. 
If the TARA study intervention is discontinued for a participant (i.e., the participant 
no longer meets the original study entrance inclusion and exclusion criteria), the 
participant will be followed for one additional visit in order to allow for all of the 
final visit (Visit 14) assessments to be performed. Once the final visit (Visit 14) 
assessments are completed, the participant will no longer continue to be followed 
except to follow any AEs or SAEs as stated above in Section 7.4 (i.e., until 7 days 
[for non-serious AEs] or 30 days [for SAEs] after the last day of study participation). 
A participant who has been enrolled into the study may temporary discontinue 
treatment if the reason for discontinuation (e.g., cold) does not preclude the 
participant from successfully completing the remaining study visits without missing 
greater than 25 percent of the 12 total TARA intervention sessions (i.e., the 
participant must be able to attend and complete at least 75 percent of the 12 total 
TARA intervention sessions) within the timeframe specified in this study (please see 
above, Section 6.1, Schedule of Evaluations). 
While an enrolled participant is temporarily discontinued from the study intervention 
(e.g., cold), no additional evaluations will be performed until the participant resumes 
with participating in the study intervention. Once the participant resumes with 
participating in the study intervention, the evaluations as specified above (please see 
Section 6.1, Schedule of Evaluations) will then be performed based upon which 
session number the participant resumes her/his participation in the study.  
If an enrolled participant is permanently discontinued from study intervention, then 
the participant will be followed for one additional visit in order to allow for all of the 
final visit (Visit 14) assessments to be performed. Once the final visit (Visit 14) 
assessments are completed, the participant will no longer continue to be followed 
except to follow any AEs or SAEs as stated above in Section 7.4 (i.e., until 7 days 
[for non-serious AEs] or 30 days [for SAEs] after the last day of study participation).. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  

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This is a randomized open-label waiting list controlled study of TARA training in 100 
boys and girls aged 14-18 years. They will be individually randomized to 12 weeks of 
group TARA training sessions (50 to TARA training and 50 to waitlist control). The 
randomization is open label because there was concern that it was not possible to 
develop a sham training which would motivate participation and yet have no effects 
on the desired outcomes. 
This study is designed to demonstrate that the TARA training will increase putamen 
connectivity (primary outcome) and decrease emotional problems on the SDQ 
questionnaire (secondary outcome). 
Primary Hypothesis: Putamen structural node strength (primary outcome) will 
increase in the training group compared to controls. 
Secondary Hypothesis: There will be a significant decrease in emotional problems 
measured with the Strengths and Difficulties Questionnaire (SDQ) (secondary 
outcome) in the training group compared to controls. 
In our recent published study (Yuan et al., 2019), we demonstrated that diffusion MRI 
connectome methods can provide reliable and precise network measures, including 
the node strength, in adolescents.  
The SDQ was selected because it is widely used in adolescents to measure 
internalizing problems and has good psychometric properties (Goodman, 2001).  
For more details see section 10.3.3 Metrics. 
     9.2.     Sample Size and Randomization 
The study is powered for medium-large effect size of the meditation training on the 
putamen node strength. With type I error of 0.05, type II error of 0.2 (power of 80%), 
two-sided effect size of a Cohen’s D of 0.6, the required sample size is N=45 subjects 
who will be studied before and after the TARA training. Given the length of the study 
(three months), the required commitment to participation in the training, and based on 
our experience, we assume an attrition rate of 10%; therefore, the target sample size is 
50 subjects per group. Our primary analysis will be a general linear model of putamen 
node strength at week 12 with terms for baseline node strength, treatment assignment 
and participant sex. The primary analysis will be intent to treat and will include all 
randomized participants regardless of treatment receipt or protocol violations.  
The only clustering in the trial will be the group delivery of the TARA intervention. 
We anticipate 4 TARA classes of 10-15 participants. We expect the intraclass 
correlation to be negligible for the following reasons: a) the TARA instructors are 
trained in standard procedures, b) we expect formidable individual level variation. 
We therefore did not include cluster assignment in the sample size calculation. We 
are going to test this assumption in a sensitivity analysis which extended the primary 
analysis by inclusion of treatment by TARA class interaction.   
To standardize TARA delivery, we have included facilitator training and created a 
very detailed TARA manual (please see Appendix). 

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Treatment Assignment Procedures 
We will use computer-generated randomization with variable blocks sizes of 4, 6 and 
8. Individuals will be randomized with no stratification or restricted except the 
permuted blocks. We will permute 8 blocks of size 8, 2 blocks of size 6, and 4 blocks 
of size 4. The treatment assignments will be 1:1 within each block and assignments 
within a block will be permuted. The only masking will be in the administration of 
questionnaires and in the interpretation of putamen node strength.  
The rationale for the use of randomization is to minimize potential biases. 
The study is open label to participants, and thus there is no need for unblinding or 
unblinding procedures. 
9.3  
Definition of Populations 
The intent to treat population will consist of all participants randomized into the trial 
regardless of treatment receipt or protocol violations. 
The per protocol population will consist of all participants in the intervention group 
who participate in at least 75% of TARA training session plus all those in the wait list 
control group. 
9.4 
Interim Analyses and Stopping Rules 
This trial will not have any interim analyses. It is itself a preliminary study which will 
lead to a decision about whether a follow-on study will be conducted in depressed 
adolescent volunteers. 
Safety findings that will trigger a safety review: If 15% of the enrolled study 
participants experience a Grade 2 (moderate) or Grade 3 (severe) adverse event (AE) 
related to the TARA study intervention, then a safety review will occur.  
 
9.5 
Outcomes  
The Primary Outcome and Secondary Outcomes as stated in this section (Sections 
9.5.1 and 9.5.2) will be analyzed as specified in the Data Analyses section below 
(please see below, Section 9.6). The Primary and Secondary Outcomes will be 
determined based upon the data analyses as specified below in Section 9.6 which will 
be performed by the study statistician (Dr. David Glidden). 
9.5.1 Primary Outcome   
The primary outcome is putamen node strength assessed by MRI comparing the value 
before randomization to the one 12 weeks after randomization. 
9.5.2 Secondary Outcomes   
The secondary outcomes include the following: 
Emotional Problems.  Emotional problems will be assessed by the SDQ 
questionnaire comparing the value before randomization (Visit 1) to the one 12 weeks 

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after randomization (Visit 14). 
Other outcomes 
Adherence. The proportion of volunteer randomized to TARA training who 
participate in at least 75% of the sessions. We expect that at least 80% of participants 
on the TARA arm will attain this level of adherence. 
Safety and tolerability of the intervention. Adverse events will be collected at each 
visit and graded, and their attribution to their participation will be assessed. The 
safety of the TARA intervention will be demonstrated if < 15% of the participants 
experience a grade 2 (moderate) or grade 3 (severe) adverse event related to the 
TARA intervention.  
To demonstrate the tolerability of the intervention used in this study, we will use the  
Child Session Rating Scale (CSRS) score. The CSRS is a 4-item self-assessments 
using a 10-cm visual analog scale (Campbell & Hemsley, 2011), with higher scores 
indicating better experience. This measure of tolerability will be completed after each 
session. Participants will rate the session in terms of how much they felt listened to, 
how important the content and activities were to them, how much they liked the 
session, and their overall experience. The intervention will be tolerable if the median 
CSRR is at least 20 in >80% of participants.  
 
Retention. To demonstrate the ability to retain subjects, we will retain at least 80% of 
randomized participants for primary outcome measurement at the end of the study 
regardless of adherence to the intervention. 
9.6 
Data Analyses  
Primary Outcome. To attain the primary objective, we will test the hypothesis that 
an increase in the node strength of the putamen (dependent variable) will be observed 
in the training group compared to the controls. This hypothesis will be tested using an 
analysis of covariance (ANCOVA) accounting for sex and fit by maximum 
likelihood. Stata (College Station, TX) will be used to perform data analyses. The use 
of maximum likelihood mitigates susceptibility to missing data. Examination of 
variable distribution and outlier identification will be performed. We will additionally 
explore age, pubertal status (as determined by the Tanner stage self-report form 
(Tanner et al., 1962)), and pre-training associations with the changes through an 
examination of interaction. Potential pre-/post-training differences in movement 
during MRI will be accounted for by assessing the number of rejected diffusion 
directions. Sex as a biological variable: In all analyses described, sex will be 
included as a factor, we will also test for a randomized arm by sex interaction. 
 
The only clustering in the trial will be the group delivery of the TARA intervention. 
We anticipate 4 intervention arm clusters of 10-15 participants. We expect the 
intraclass correlation to be negligible for the following reasons: a) the TARA 
instructors are trained in standard procedures, b) we expect formidable individual 
level variation. We are going to test this assumption in a sensitivity analysis which 
extended the primary analysis by inclusion of treatment by TARA class interaction. 
We are going to test this assumption in a sensitivity analysis which extended the 

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primary analysis by inclusion of treatment by TARA class interaction.   
To standardize TARA delivery, we have included facilitator training and created a 
very detailed TARA manual (please see Appendix). 
 
In addition, we will examine relationship between changes in node strength of the 
putamen and adherence to sessions, proportion of sessions attended, by performing a 
Spearman rank correlation of TARA adherence (by percentage of sessions attended) 
and change in node strength. We will use ANCOVA analysis with a treatment by 
attendance interaction to estimate the putamen node strength which would be 
achieved with full attendance in all training session. 
 
Secondary Outcome.  
 
Emotional Problems. Our hypothesis is that training will improve emotional 
problems as assessed by the SDQ T-score compared with controls. We will use an 
analysis of covariance (ANCOVA) accounting for sex and fit by maximum 
likelihood. Stata (College Station, TX) will be used to perform data analyses. We will 
additionally explore age, pubertal status (as determined by the Tanner stage self-
report form (Tanner et al., 1962)), and pre-training associations with the changes 
through an examination of interaction. Potential pre-/post-training differences in 
movement during MRI will be accounted for by assessing the number of rejected 
diffusion directions. Sex as a biological variable: In all analyses described, sex will 
be included as a factor, we will also test for a randomized arm by sex interaction. 
 
In addition, we will examine relationship between changes in node strength of the 
putamen and changes in emotion by performing a Spearman rank correlation change 
in node strength through 12 weeks with change in SDQ through 12 weeks.  
 
Other outcomes. 
 
Adherence. We summarize adherence to training including (i) tabulating the number 
of participants on the training arm who complete at least 75% of sessions, (ii) 
calculate the minimum, maximum, median and interquartile range of sessions 
attended by those randomized to the TARA training arm. 
 
Safety and tolerability of the intervention. Adverse events of grade 2 or higher will 
be tabulated between the arms and compared by the Fisher exact test. Tolerance 
scores on the CSRS will be summarized (minimum, maximum, median, interquartile 
range) at each study visiting on the TARA training arm. 
 
We will tabulate the proportion of participants who are retained through 12 weeks 
and complete the MRI exam and SDQ questionnaire. These will be compared 
between the arms by the Fisher exact test. 

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10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
 
Information for each participant will be collected using the following forms and 
procedures: 
o Informed Consent Form (will be obtained and signed by RA via DocuSign) 
o Medical History Form (source document, will be collected and signed by RA via 
DocuSign) 
o Inclusion/Exclusion criteria form (source document, will be filled out and signed 
by RA via DocuSign) 
o Enrollment/Randomization form (source document, will be filled out and signed 
by RA via DocuSign) 
o MRI screening form (will be signed by the MRI technician. Not a source 
document.) 
o MRI brain scan (will be performed using a 3T MRI scanner) 
o Demographics assessment (will be performed electronically in Qualtrics) 
o SDQ assessment (will be performed electronically in Qualtrics) 
o Baseline Visit Checklist (source document, will be filled out and signed by RA 
via DocuSign) 
o Child Session Rating Scale (CSRS) (source document, will be collected and 
signed by RA) 
o Child Outcome Rating Scale (CORS) including the question: “Has there been any 
significant unfavorable change in your mental or physical health since last class?” 
(will be collected by RA. Not a source document.) 
o Adverse Events (source document, if the answer is Yes to the question above in 
CORS, this form will be filled out and signed by RA via DocuSign) 
o Serious Adverse Events (source document, if answered Yes to the SAE question 
in the Adverse Event form, this form will be filled out by RA, signed by PI via 
DocuSign) 
o On Study Visit Checklist Form (source document, will be filled out and signed by 
RA via DocuSign) 
o Study Completion form (source document, will be filled out by RA, signed by PI 
via DocuSign). 
 
All source documents will be signed and stored electronically in DocuSign. Any data, 
forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to 
maintain confidentiality. All computer entry and networking programs will be done 

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using PIDs only. Information will not be released without written permission of the 
participant, except as necessary for monitoring by the UCSF IRB, the NCCIH, and 
the OHRP. 
10.2 Data Management  
It is a single-site study; therefore, the site of operation and the Data Management 
Center are the same site. All the data collection described in the previous section, as 
well as the statistical analysis of the data will take place at UCSF. 
The data collection forms that will be used in the present study are listed and 
described above (please see Sections 6.1, 6.2, 6.2.2, 6.2.4, 6.2.5, and 7.3). 
10.3 Quality Assurance  
10.3.1 Training 
RAs will be training directly by the study PIs, who will also be available for 
questions. Dr. Eva Henje Blom will conduct annual teacher training for the 
facilitators of TARA and monitor treatment fidelity using the 10-item fidelity scale 
(Clarke, 1998), as described in the section 10.3.5. Monitoring below. 
10.3.2 Quality Control Committee  
In addition to the Independent Monitor Dr. Hendren, one of the RAs will be 
appointed as the Internal QA Reviewer.  
The reports that Dr. Hendren will review are specified above in Table A (please see 
Section 10.3.5 below, Table A).  
10.3.3 Metrics 
Primary outcome measure: Putamen structural node strength. In our recent 
published study (Yuan et al., 2019), we demonstrated that diffusion MRI connectome 
methods can provide reliable and precise network measures, including the node 
strength, in adolescents.  
Secondary outcome: Emotional problems measured with the Strengths and 
Difficulties Questionnaire (SDQ). The SDQ was selected because it is widely used in 
adolescents to measure internalizing problems and has good psychometric properties 
(Goodman, 2001).  
10.3.4 Protocol Deviations 
The PIs will use the NCCIH Protocol Deviation Tracking Log form (see Appendix) 
with the following protocol deviation code, to monthly record any and all protocols 
deviations. 
Protocol Deviation Codes: 
A – Consent Procedures 
B – Inclusion/Exclusion Criteria 
C – Concomitant Medication/Therapy 

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D – Laboratory Assessments/Procedures 
E – Study Procedures 
F – Serious Adverse Event Reporting/Unanticipated Adverse Device Effect 
G – Randomization Procedures/Study Drug Dosing 
H – Visit Schedule/Interval 
I – Efficacy Ratings 
J – Other 
Protocol deviations will be recorded in the tracking log as they occur, to ensure 
completeness and accuracy of the data.  
For each deviation the PIs will determine whether the deviation meets IRB and 
NCCIH reporting requirements. 
The PIs will sign each form after it has been completed or immediately prior to a 
monitoring visit. If it has been signed with fewer than five deviations entered into it, 
the next identified deviation will be reported on a new page to ensure that all 
deviations have been reviewed by the PIs. 
Each page will be numbered, and the log will be maintained in the Essential 
Documents Binder, behind the Protocol Deviations tab. The pages will be stored in 
reverse chronological order, with the newest pages of the log placed at the front of the 
section. At the conclusion of the study, the final page of the log will be identified by 
checking the box in the footer. 
10.3.5 Monitoring 
In addition to the Independent Monitors, one of the RAs will be appointed as the 
Internal QA Reviewer. The monitoring of protocol compliance and data quality will 
be conducted in accordance with Table A below. 
Table A 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually  
 
Independent Monitors 
Status of all enrolled subjects, as 
of date of reporting  
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
Data entry quality control checks 
on 100% of charts 
Weekly 
QA Reviewer 
Adherence data regarding study 
visits and intervention 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
AEs and rates (including out-of-
range lab values) 
Monthly 
PIs, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 

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In addition to the monitoring described in Table A above, Dr. Henje Blom will 
monitor treatment fidelity using the 10-item fidelity scale (Clarke, 1998). For that 
purpose, all group sessions will be audio-recorded; the research consent process will 
include consent to audio record groups to facilitate treatment fidelity coding. A 
random sample (20%) of group sessions will be rated by Dr. Henje Blom for 
adherence to the training manual and facilitator competence using the 10-item fidelity 
scale.  
 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document (please see Appendix) and any 
subsequent modifications will be reviewed and approved by the UCSF IRB 
committee responsible for oversight of the study. The consent form is separate from 
the protocol document and included in the Appendix. Two versions of consent form 
are available: for 14-17-year-old participants and for 18-year-old participants.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. For participants who 
cannot consent for themselves, such as those who are under the age of 18 years (e.g., 
minor), the parent or legal guardian of the participant who is a minor must sign the 
consent form. The consent form will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. An electronic DocuSign 
copy will be given to each participant who is at least 18 years old and to the parent or 
legal guardian for each participant who is under 18 years old, and this fact will be 
documented in the participant’s record. Participants 18 years old will sign the consent 
forms themselves since they are legally considered adults. 
11.3 Participant Confidentiality  
Any data, forms, reports, video recordings, and other records that leave the site will 
Annually 
NCCIH 
SAEs (unexpected and related) 
Per occurrence 
PIs, Independent Monitors 
NIH/NCCIH 
SAEs (expected or unrelated) 
Per Occurrence 
PIs, Internal QA Reviewer 
Annually 
Independent Monitors, 
NIH/NCCIH 
Unanticipated Problems 
Monthly 
PIs, Internal QA Reviewer 
Per Policy 
IRB 

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be identified only by a participant identification number (Participant ID, PID) to 
maintain confidentiality. All records will be kept in a locked file cabinet located 
within a locked room that is within a locked building with 24 hours security 
surveillance cameras and 24 hours security personnel guarding and patrolling the 
locked building to ensure that the records will be kept safe and not stolen. All 
computer entry and networking programs will be done using PIDs only. Information 
will not be released without written permission of the participant, except as necessary 
for monitoring by the UCSF IRB, the NCCIH, and the OHRP. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the UCSF IRB, the NCCIH, the 
OHRP, or other government agencies as part of their duties to ensure that research 
participants are protected.  
12. COMMITTEES 
The current study does not have any committees. 
13. PUBLICATION OF RESEARCH FINDINGS  
Publication of the results of this trial will be governed by the policies and procedures 
developed by the co-PIs of the present study (Drs. Tymofiyeva and Yang). We will 
disseminate the results from this research as broadly as possible.  
14. REFERENCES  
Bærentsen KB, Stødkilde-Jørgensen H, Sommerlund B, Hartmann T, Damsgaard-Madsen J, Fosnæs M, 
Green AC. An investigation of brain processes supporting meditation. Cogn Process 11:57-84. 2010. 
Bartels A, Zeki S. The neural basis of romantic love. NeuroReport 11:3829-3824. 2000. 
Birmaher B, Brent D. Practice parameter for the assessment and treatment of children and adolescents with 
depressive disorders. J Am Acad Child Adolesc Psychiatry 46(11):1503-1526. 2007. 
Blom Henje E, Duncan LG, Ho TC, Connolly CG, LeWinn KZ, Chesney M, Hecht FM, Yang TT. The 
development of an RDoC based treatment program for adolescent depression “Training for Awareness, 
Resilience, and Action” (TARA). Front Hum Neurosci 8:630. 2014. PMID: 25191250. PMCID: 
PMC4137278. 
Blom Henje E, Tymofiyeva O, Chesney M, Ho TC, Moran P, Connolly CG, Duncan LG, Baldini L, Weng 
HY, Acree M, Goldman V, Hecht FM, Yang TT. Feasibility and preliminary efficacy of a novel RDoC-
based treatment program for adolescent depression: Training for Awareness Resilience and Action 
(TARA)—A Pilot Study. Front Psychiatry 7:208. 2016. PMID: 28138319. PMCID: PMC5237634. 
Brent DA, Birmaher. Treatment-resistant depression in adolescents: recognition and management. Child 
Adolesc Psychiatr Clin N Am 15(4):1015-34. 2006. 
Campbell AH, Hemsley S. Outcome rating scale and session rating scale in psychological practice: clinical 
utility of ultra-brief measures. Clinical Psychologist 13(1):1-9. 2011. 
Campbell IG, Grimm KJ, Bie E, Feinberg I. Sex, puberty, and the timing of sleep EEG measured adolescent 
brain maturation. Proc Natl Acad Sci USA 109(15):5740-5743. 2012. 

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cortex and the representation of reward. Neurosci Biobehav Rev 32:1-19. 2008. 
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differences in children's later mental health symptoms. J Am Acad Child Adolesc Psychiatry 42(6):728-37. 
2003.  
Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJL, Vos T, Whiteford HA. Burden 
of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 
2010. PLoS Med 10:e1001547. 2013. 
Gabbay V, Ely BA, Li Q, Bangaru SD, Panzer AM, Alonso CM, Castellanos FX, Milham MP. Striatum-
Based Circuitry of Adolescent Depression and Anhedonia. J Am Acad Child Adolesc Psychiatry 52:628-
41.e13. 2013. 
Garland E, Gaylord S, Park J. The Role of Mindfulness in Positive Reappraisal. Explore (NY) 5:37-44. 2009. 
Goodman R. Psychometric properties of the Strengths and Difficulties Questionnaire. J Am Acad Child 
Adolesc Psychiatry 40:1337-1345. 2001. 
Gorwood P. Neurobiological mechanisms of anhedonia. Dialogues Clin Neurosci 10:291-299. 2008. 
Hammen C, Rudolph KD. Childhood depression. In: Mash EJ; Barkley RA, editors. Child psychopathology. 
New York, NY US: Guilford Press 153-95. 1996. 
Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs) for 
depressive disorders in children and adolescents. Cochrane Database Syst Rev 3: CD004851. 2007. 
Infante M, Slattery MJ, Klein MH, Essex MJ. Association of internalizing disorders and allergies in a child 
and adolescent psychiatry clinical sample. J Clin Psychiatry 68(9):1419-25. 2007. 
Kjaer TW, Bertelsen C, Piccini P, Brooks D, Alving J, Lou HC. Increased dopamine tone during meditation-
induced change of consciousness. Cognitive Brain Research 13:255-259. 2002. 
Klimecki OM, Leiberg S, Lamm C, Singer T. Functional neural plasticity and associated changes in positive 
affect after compassion training. Cereb Cortex 23:1552-1561. 2013. 
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S, Segal Z, Speckens A, Teasdale JD, Heeringen KV, Williams M, Byford S, Byng R, Dalgleish T. Efficacy 
of Mindfulness-Based Cognitive Therapy in Prevention of Depressive Relapse: An Individual Patient Data 
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Lanciego JL, Luquin N, Obeso JA. Functional Neuroanatomy of the Basal Ganglia. Cold Spring Harb 
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for understanding the neurobiological mechanisms of mindfulness. Front Hum Neurosci 6:296. 2012. 
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Yuan JP, Henje Blom E, Flynn T, Chen Y, Ho TC, Connolly CG, Dumont R, Yang TT, Xu D, Tymofiyeva 
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PMID: 30398373. PMCID: PMC6444894. 
15. SUPPLEMENTS/APPENDICES 
• 
Phone Pre-Screening of Inclusion/Exclusion Criteria 
• 
Informed Consent Form for 14-17-year-old participants   
• 
Informed Consent Form for 18-year-old participants   
• 
Medical History Form 
• 
Inclusion/Exclusion Criteria Form 
• 
Enrollment/Randomization Form 
• 
MRI Screening Form 
• 
SDQ questionnaire 
• 
Demographics questionnaire 
• 
Baseline Checklist Form 
• 
CORS 
• 
CSRS 
• 
On Study Visit Checklist  
• 
Adverse Events Form 
• 
Serious Adverse Events Form 
• 
Study Completion Form 
• 
Protocol Deviation Tracking Log 
• 
TARA manual