A Longitudinal Study Examining Three RDoC Constructs in Adolescents With Non-Suicidal Self-Injury
Conditions: Self-Injurious Behavior, Deliberate Self-Harm
Sponsor: University of Minnesota

    
   
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-=; 
‘   
   Research Protocol: 
    
A Longitudinal Study Examining Three RDoC    
Constructs in Adolescents with Non-Suicidal Self-Injury    
 
Regulatory Sponsor:    
Kathryn R. Cullen, M.D  
  
Department of Psychiatry    
University of Minnesota    
Funding Sponsor: 
National Institute of Mental Health 
Protocol Number: 
IRB #1605M88102 
Version: 
Version 34 –  April 26, 2022 
CONFIDENTIAL    
    
This document is confidential and the property of the University of Minnesota. No part 
of it may be transmitted, reproduced, published, or used by other persons without 
prior written authorization from the study sponsor.    
1. Table of contents    
1. Table of Contents 
30 
2. Report of prior investigations 
30 
3. Investigational plan 
35 
4. Risk analysis     
 
 
 
 
 
 
 
 
 
57    
5. References    
 
 
 
 
 
 
 
 
 
 
65    
  
    
2. Report of prior investigations    
    
2.1. Non-Suicidal Self-Injury (NSSI) in adolescents is a serious clinical problem. 
NSSI is common in adolescents (prevalence rates range from 13- 23%2) and is 
associated with impaired functioning, high rates of psychiatric hospitalizations, 
and future suicide attempts.3-6 Treatments for NSSI are very limited.7-9 Although 

    
   
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the origins of NSSI likely stem from a combination of biological, psychological and 
social roots, most research to date has focused on clinical features measured by 
self-report. In particular, there has been a major gap in neuroscience research to 
understand the neurobiological underpinnings of NSSI, which has hindered the 
advancement of new, biologically-targeted interventions.    
    
2.2. Applying an RDoC Approach to Advancing Knowledge about NSSI. NSSI is a 
behavior that cuts across psychiatric diagnoses, and the underlying 
circuitry/physiology/cognitive processes are also trans-diagnostic. Therefore the 
RDoC approach is ideally suited for trying to understand the biological roots of 
NSSI.10    
    
The RDoC initiative was developed to address the problem that psychiatry 
research using traditionally-defined psychiatric disorder classification has failed to 
reveal any clinically useful biomarkers. RDoC promotes research that examines 
brain-behavior relationships in basic dimensions of functioning that occur across 
disorders, rather than focusing on patients within diagnostic categories, using 
multiple units of analysis.11,12 Since individuals with NSSI primarily use NSSI to 
regulate negative affect13 and are   
characterized by interpersonal disturbances and negative self-conceptions,14-  
20 and impulsivity,21 candidate RDoC domains for further study include Negative 
Valence, Social Processes and Cognitive Systems. While a range of constructs are 
likely relevant to NSSI, as described below, our pilot data in adolescents with 
NSSI pointed to Sustained Threat, Self-Knowledge and   
Cognitive Control as the most relevant constructs for further examination.    
    
2.3. Importance of Examining the Dynamic Interaction of Neural Systems Across 
Development. Longitudinal studies of at-risk children have demonstrated 
developmental cascades for psychopathology,22 where problems in one system 
emerge as a result of cumulative effects in another system.23-25 RDoC leaders 
have recently articulated: a “neurodevelopmental concept that may enrich RDoC 
investigations is the dynamic interactions of systems across development . Early 
in development, brain circuits across different regions interact dynamically. The 
cumulative consequences of these interactions among developing systems alter 
the course of development. Thus, a deficit occurring early in development can 
give rise to a cascade of more complex deficits as different brain regions mature 
and interact over time. The interaction of differentially maturing brain systems 
with developmental time raises challenges and opportunities for extending basic 
RDoC principles. In particular, it highlights the need to simultaneously examine 
associations among multiple domains of function, brain systems, and/or 
developmental periods, including how these interact with environmental events 
and other contextual factors.”1 To address this, in concert with the multi-modal 
examination of RDoC constructs, it will be critically important to examine the 
dynamic interaction between these constructs across development.    

    
   
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2.4. Sustained Threat: Relevance to NSSI. Since most individuals with NSSI use 
the behavior to regulate negative affect,13 research in Negative Valence domain 
is a natural first step toward understanding the neurobiology of NSSI. In 
particular, the threat system is implicated because of the association between 
NSSI and negative adverse experiences such as child abuse26 and bullying.27,28 
NSSI is typically chronic (e.g. current NSSI predicts future NSSI),3,29,30 
suggesting that Sustained Threat (an aversive emotional state caused by 
prolonged exposure to danger cues) may be more relevant than Acute Threat. 
Sustained Threat may be particularly implicated in those with more 
severe/chronic NSSI; animal models of NSSI have shown that prolonged 
exposure to social defeat leads to increased NSSI severity.31 The detection and 
response to threat stimuli comprises a complex brain/body system. Initially, 
threat triggers a response in the amygdala, which is linked with the anterior 
cingulate cortex (ACC) and prefrontal cortex, regions that monitor conflict, 
interpret, regulate emotional reactivity, and direct behavioral responses.32,33 
Prior research studies in adults34 and adolescents35 with NSSI using fMRI and 
threat stimuli (e.g. negative pictures, fear or angry faces) have shown 
exaggerated amygdala responses. Amygdala-frontal connectivity may be 
impaired in humans and primates with anxiety and exaggerated responses to 
threat.36 This circuit is tightly connected to the neuroendocrine arm of threat 
response. However, two studies that examined hypothalamic-pituitary-adrenal 
(HPA) functioning showed attenuated responses (despite elevated subjective 
emotional experiences) in adolescents37 and young adults with NSSI.38 Hypo-
responsive HPA functioning may suggest an allostatic shift in the threat system 
to accommodate chronic stress. Together these findings suggest significant 
abnormalities in threat response in adolescents with NSSI, but provide an 
example of how multiple units of analysis of a construct may in some cases 
diverge, highlighting the complexity of the system and the need for a multi- 
modal approach.    
    
2.5. Sustained Threat: Developmental Changes. Prior work has demonstrated 
developmental changes in Sustained Threat indices during adolescence. In 
animals, fibers projecting from amygdala to prefrontal cortex continue to mature 
through adolescence and into adulthood.39 Cross-sectional studies comparing 
adolescents to adults have shown that adolescents engage prefrontal regions to a 
lesser degree than adults when faced with threat imagery (fear faces)40 and that 
the ratio of prefrontal/amygdala fear response increases across adolescence.41 
Research examining physiological indices of the threat system have found that 
both cortisol and sympathetic nervous system responses to threat challenges are 
greatest in mid- adolescence as opposed to late childhood / early adolescence, 
and that these indices are correlated with fearful temperament, anxiety and 
depression symptoms in adolescents.42,43 It is possible that adolescents with NSSI 

    
   
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may exhibit aberrant developmental trajectories of these systems, underpinning 
their vulnerability to develop and maintain NSSI.    
    
2.6. Relevance of Self-Knowledge in NSSI. Youth who engage in NSSI commonly 
suffer from poor self-esteem 14-20,44 and difficulties identifying their feelings.45,46 
Self-criticism has been shown to negatively influence the course of NSSI.47,48 
Therefore, Self-Knowledge (the ability to judge one’s current cognitive or 
emotional internal states, traits, and/or abilities) is a promising candidate 
construct to study in this population. We propose that the tendency of individuals 
with NSSI to show negative self-evaluations, and to struggle with handling 
challenges to the self could be associated with disrupted self-referential 
processing. Self-related processes are mediated by the medial cortical network 
(MCN) involving the rostral anterior cingulate, posterior cingulate and 
precuneus.49,50 This network has not yet been directly examined in NSSI research.    
    
2.7. Self-Knowledge: Developmental Changes. Prior work documenting 
developmental changes in brain and behavior indices relevant to Self- Knowledge 
provides the backdrop for understanding aberrant trajectories in adolescent 
NSSI. Adolescents commonly struggle with a sense of identity.51 Adolescence is a 
period of significant development in Self-Knowledge including a growing sense of 
uniqueness and connection with others.52 Comparisons of children/early 
adolescents to adults suggest that, in response to tasks designed to assess self-
evaluation (making judgments about oneself), young people engage MCN to a 
greater extent than adults.53,54 Recently, Pfeifer and colleagues55 showed that 
self-evaluations engaged MCN in children and adolescents, and within this 
network, rostral ACC activation during self evaluations increased from age 10 to 
13.55 Additionally, studies using resting-state fMRI have found that functional 
connectivity within a related/overlapping network (referred to as “default mode”) 
increases through adolescence.56 Vulnerability for and maintenance of NSSI in 
adolescence could involve abnormal development of the MCN.    
    
2.8. Cognitive Control in NSSI. Individuals with NSSI may have increased 
impulsivity. In the RDoC matrix, impulsivity falls under the Cognitive Control 
construct and in particular, the sub-construct Response Inhibition. Research 
paradigms examining Response Inhibition have utilized tasks that require 
inhibiting a prepotent response, such as the Go/No-go or the stop-signal task. 
Research to date investigating Response Inhibition in NSSI has been somewhat 
mixed. Some 57-59 but not all60 studies have suggested that self- reported 
impulsivity is elevated in patients with NSSI. One study found that youth with 
low-severity NSSI demonstrated poor performance on the stop signal task 
compared to youth with high-severity NSSI and healthy controls.61 Another study 
showed that adolescents with NSSI have elevated levels of self-reported 
impulsivity but no group differences with behavioral measures of cognitive 
control.57 Discrepancies in the literature could stem from the possibility that 

    
   
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impulsivity in this population primarily occurs within the context of negative 
affect.62 One study found no stop signal task group differences, but did find that 
patients with NSSI differed from controls with respect to Negative Urgency 
(committing rash decisions when faced with negative emotions).63 Negative 
Urgency has been associated with severity of NSSI 64,65 and has predicted both 
new onset and NSSI maintenance in young adults.66 Further investigation of 
Response Inhibition in NSSI may benefit from its measurement in the context of 
negative emotion, which could be most relevant to NSSI pathology.    
    
2.9. Cognitive Control Systems: Developmental Changes. Developmental research 
to date using tasks such as the Go/Nogo and the stop-signal task have shown 
that performance improves linearly with age from childhood to adulthood.67 
However, the fMRI studies of inhibition have shown mixed findings, with some 
studies showing increased recruitment of frontal areas with age during these 
tasks (“frontalization”)68,69 and other studies showing a pattern of moving from 
diffuse to focal cortical recruitment during such tasks.70 The discrepancies in the 
literature could stem from the need to better tease apart motivational influences 
upon cognitive control systems.1 For example, our co-investigator Dr. Thomas has 
shown that negative emotional contexts disrupt inhibitory control to a greater 
degree in early adolescence than childhood or later adolescence/adulthood.71 The 
onset and maintenance of NSSI in adolescents could involve deficits in the 
development of cognitive control systems, particularly in the context of negative 
emotion.    
    
2.10. Promise of longitudinal studies for charting clinical course of NSSI. Research 
to date has made considerable strides in characterizing the clinical phenomena of 
NSSI such as underlying motivations and psychological predispositions. More 
recently, longitudinal work has even begun to chart clinical trajectories. For 
example, depression symptoms in mid-adolescence predict NSSI chronicity during 
late adolescence, and negative attributional style distinguishes high versus low 
severity NSSI.72 Other work has suggested that self-criticism and self-reported 
impulsive behaviors moderate the course of NSSI.48 However, longitudinal NSSI 
research to date has not incorporated multiple units of analysis including 
neurobiological measurement.    
    
2.11. Summary. NSSI is a highly prevalent, maladaptive behavior that occurs 
across diagnoses and is associated with significant negative outcomes including 
chronicity and risk for suicide. Development of new treatment strategies is limited 
by the currently poor understanding of the neurobiology of NSSI in adolescents. 
An RDoC approach is suitable for investigating the development of abnormal 
brain-behavior relationships relevant to NSSI. Sustained Threat, Self-Knowledge 
and Cognitive Control represent promising candidate constructs for further study 
in adolescents with NSSI.  Measurements within these putative neural systems 
are known to undergo developmental change during adolescence. The status of 

    
   
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current knowledge, in combination with the pilot data from our group described 
below on adolescents with NSSI, provides the backdrop for the current proposal 
that will use multiple units of analysis and a longitudinal approach to examine the   
development and dynamic interaction of these systems across adolescent 
development.    
 
3. Investigational plan    
    
   
3.1    
Objectives of the clinical investigation:    
    
3.1.1 Primary objective.    
    
To test how different units of analysis (circuits, physiology, behavior, self-
report) of Sustained Threat, Self-Knowledge and Cognitive Control relate 
to NSSI severity in post-menarchal adolescent girls aged 12-16 years 
who exhibit a continuum of NSSI severity    
    
3.1.2 Secondary objective(s).    
    
a. To test whether the baseline measures of RDoC constructs listed in 
Aim 1 predict future (after 1 and 2 years) NSSI severity levels.    
    
b. To delineate changes over time in the RDoC measures of Aim 1 across 
adolescence    
    
3.2 
Title of clinical protocol:    
    
Development of Sustained Threat, Self-Knowledge, and Cognitive Control in 
Adolescents with Non-Suicidal Self-Injury    
    
3.3 
Study design:    
    
3.3.1 General study design.    
    
This study is a longitudinal study that consists of three separate in- 
person appointments conducted once a year for a period of 3 years 
including a clinical assessment (interview and questionnaires), the Trier 
Social Stress Test (TSST) and cognitive battery, and a brain MRI. An 
additional “online appointment” will also be completed once a year, 
where participants answer online questionnaires to reduce time spent at 
other 3 appointments.    
 
 

    
   
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3.3.2 Study design schematic.    
    
     
   
3.4    
Subject selection:    
    
3.4.1 General characteristics of the proposed subject population(s).    
    
Female adolescents aged 12-16 years old who are post-menarche with 
varying severity of Non-Suicidal Self-Injury (NSSI)    
    
3.4.2 Anticipated number of research subjects.    
    
The goal is to have baseline data on 152 participants – 38 with no 
history of self-harm, 38 with mild NSSI, 38 with moderate NSSI, and 
38 with severe NSSI. In order to get this amount of data, we estimate 
that up to 200 participants will need to be enrolled into the study 
(anticipating that some participants will not meet inclusion criteria after 
the diagnostic interview, and some will not have usable baseline MRI 
scans). We anticipate that with drop-out, we will have at least 30 
participants per group by the last follow-up visit.    
 
 
 

    
   
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3.4.3 Inclusion/Exclusion criteria.    
    
    
Inclusion Criteria    
Exclusion Criteria    
All Participants    12-16 years old 
Female    
Post-menarche    
Willingness to have 
deidentified data 
shared with RDoCdb    
Male    
Pregnancy    
MRI Incompatibility    
Intellectual Disability    
Major Medical Illness    
Primary Psychotic Disorder  
Bipolar Spectrum Disorder   
Autism Spectrum Disorder   
Current Substance Use    
Disorder1, 2    
Inability to Pass UCSB    
Brief Assessment of    
Capacity to Consent   
(UBACC)   
Non-English Speaker  
    
   
Inclusion Criteria    
≥ 4 past episodes of   
NSSI with significant   
tissue damage  ≥  
1/month frequency     
 
Exclusion Criteria    
NSSI    
Groups  
    
    
    
    
    
    
    
    
    
    
    
    
Severe    
NSSI    
    
    
     
  
Moderate  
NSSI    
    
    
≥ 4 past episodes of  
NSSI with significant 
tissue damage < 
1/month frequency    
     
Mild    
NSSI    
    
    
    
< 4 NSSI episodes with  
significant tissue damage 
OR an unlimited number 
of episodes with mild or 
no tissue damage    
    
   
No NSSI       
Any history of NSSI    
1In the case of a history of substance use, if criteria are met for a substance use 
disorder, it must be in early or sustained remission as defined by the DSM-5.     
2The study will still include individuals meeting criteria for nicotine substance use disorder.    

    
   
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3.5   Study procedures:    
    
3.5.1 Recruitment.    
    
1. We will send letters and study brochures to local clinicians who treat 
adolescent mood disorders.    
    
2. We will post flyers and other advertisements through social media 
(Facebook, Pandora, Tumblr, etc.) and community outlets about our 
study.    
   
   
3. We will be using the services of BUMP Digital Marketing to advertise 
online with Google Ad Words. Upon clicking the link in the 
advertisement, users will be brought to a landing page which 
describes the study and has a link to a REDCap survey. The REDCap 
survey asks for contact information, birth date of the potential 
participant, and also if they have ever self-injured. The REDCap 
survey and responses are to be maintained by the study team, so 
BUMP does not have any access to PHI. We are trying to target our 
NSSI group with these advertisements. After 3 months of Google Ad 
Words, the company has agreed to launch Facebook advertisements 
as a contingency if Google does not perform well.    
    
4. We will screen electronic medical records of adolescents with a history 
of self-injurious behavior treated in the clinics and hospital services of 
the University of Minnesota, Medical Center and Masonic Children’s 
Hospital. We will only look at the records of those patients who have 
not opted-out of having their medical records used for research on the 
Consent for Services form they complete at intake. When potential 
cases are identified, we will contact the treating physician to discuss 
the patient and whether they might be suitable for consideration for 
the study. If yes, we will ask the physician (or they physician may 
choose to delegate this to another member of the treatment team) to 
approach the parent or guardian about the study. The physician (or 
delegated treatment team member) will let parents know that their 
daughter may be eligible to participate in a research study being 
conducted at the University of Minnesota, and will ask the parent or 
guardian whether they would like to be contacted by the research 
team to learn more about the study. The physician (or delegated 
treatment team member) will explain that participation is completely 
voluntary and in no way related to the treatment for their daughter. 
Information about study opportunities will also be provided for 
potential participants on a research board on the unit.  The board will 

    
   
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(a) post information about the study, (b) provide small cards with 
study information that parents can take home, and (c) provide 
permission to contact forms which families may complete if they 
would like the study team to contact them. Families are instructed to 
turn permission to contact forms into the front desk of the unit who 
then deliver the forms to the study team in a secure fashion.    
    
5. We will recruit participants from the Riverside Behavioral Health 
Outpatient Clinic and M Health Fairview Adolescent Day Treatment 
Program using multiple strategies. First, patients in this clinic are 
invited to participate in a research recruitment registry. Patients in 
the Day Treatment Program will be offered a blank version of form for 
their records. Our research staff will use the research registry to 
contact potential participants who have indicated they are interested 
in research using the contact information provided in the registry. 
Secondly, we will use a direct, in-person recruitment approach. 
Research staff will connect with providers in the clinic to discuss 
patients who could be potential participants. For specific patients we 
will ask the provider to give an IRB-approved study brochure to the 
patient, along with a general introduction about the study. The 
research staff will be available to meet with the patient and their 
parent in the clinic to provide further information about the study; 
interested families will have the option to meet briefly with a 
researcher in person to allow face-to-face discussion, or to have the 
researcher follow up with them by phone. The Behavioral Health 
Research Recruitment Committee and Fairview have approved this 
process.   
    
We will post information about the study and business cards with our 
contact information on them on the recruitment boards outside of the 
psychiatry clinic and inpatient units.    
   
6. We will recruit for the study at the Minnesota State Fair in the Driven 
to Discover Research Facility (D2D). We will be sharing the booth 
assigned to the D2D: Games for Brains study. Signs for the booth will 
indicate both studies to attract interested and eligible State Fair 
visitors to our booth. We will have flyers and brochures about the 
study at the booth. For parents or guardians who tell us they have a 
daughter in our study age range (12 to 16) we will encourage them to 
complete a permission to contact form to indicate their interest in 
being contacted about the study and gather their contact information. 
To encourage participation, each eligible family that completes a 
contact form will receive (a) a small item (a pencil or item of 
equal/similar value), and (b) an entry into a drawing for a larger item 

    
   
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($25 target gift card) which will be determined at the end of each 
shift at the fair (5 shifts total).    
6a. We will be recruiting for the study at the Minnesota State Fair 
Driven to Discover Research Facility (D2D) at a recruitment booth for 
our lab again in 2019. We will have flyers and brochures about the 
study at the booth. For parents or guardians who tell us they have a 
daughter in our study age range (12 to 16) we will encourage them to 
complete a permission to contact form to indicate their interest in 
being contacted about the study and gather their contact information. 
We will be giving away small prizes for those who sign their daughter 
up to be contacted.    
    
7. We will be recruiting from PrairieCare. We will share the inclusion and 
exclusion criteria for our study, and PrairieCare will send letters to a 
set of patients that they have determined to be potentially eligible 
based on our criteria and their review of their electronic medical 
record system. In the letters, participants are provided with 
information about the study and contact information about the study.    
    
8. We will use the Fairview research recruitment mailing process. 
Fairview has approved a research letter to be sent to parents of 
female inpatients aged 12-15 who had been admitted to a behavioral 
health unit (6A, 7A, 7ITC, 3C) for any diagnosis. Sixteen year olds will 
not receive letters due to HIPAA and independent clinical/medical care 
laws applying to services independently acquired by adolescents. 
](Fairview policy “Confidentiality  Considerations for Minors”)  to 
parents of patients ages 12-15, because a manual review of consents 
would be required for 16 year old patients.    
   
9. We will send out letters and/or emails describing the study to 
professional, trained school counselors, psychologists, social workers, 
and/or guidance counselors. We will also attach a flyer of the study to 
the communication requesting they share information, as appropriate, 
with parents, adolescents, and other school professionals.    
   
10. We will make presentations about self-harm, self-injury, and research 
findings to middle and high school classrooms, as well as community 
organizations including in-person and online neighborhood groups, 
parent groups, and spiritual groups. Potential participants will not be 
identified by research staff. Potential participants-- or parents of 
potential participants-- will have the opportunity to self-identify and 
request more information about research participation. Flyers and 
business cards, and the Psychiatry Research Registry, will be available 
for interested participants to pass on to their parent/guardians.   

    
   
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11. We will post this study on the Psychiatry Research  
Opportunities website. It will include inclusion/exclusion criteria, the 
reason for the study (what we hope to learn), and contact information 
for the study.   
   
3.5.2 Screening, consent, clinical assessment and diagnostic 
procedures.    
    
(a) 
The parent/guardian of each potential participant will first 
complete an initial, brief telephone interview with a research team 
member. The study will be briefly explained by the team member to the 
parent/guardian (possibly also to the potential participant), and we will 
ask a set of questions about the child’s medical history. This will serve to 
select children likely to meet inclusionary criteria and to screen out 
children who meet exclusionary criteria. Families that are interested in 
pursuing the study and who pass this screen will be scheduled for a 
diagnostic interview.   The diagnostic interview, including the consent 
process will take place via Zoom, a HIPAA-compliant communication 
platforms approved for use at the University of Minnesota. One of the 
members of the research staff will review the study procedures, risks and 
benefits as described in the consent form with the parent/guardian and in 
the assent form with the adolescent. The families will be given time to 
read the materials and ask any questions they have about the study. The 
research staff member will pose a set of questions to the parent/guardian 
and the adolescent to ensure that they fully understand the procedures, 
risks, and voluntary nature of the study. This takes the form of the UCSB 
Brief Assessment of Capacity to Consent (UBACC), which consists of 
questions tailored to this particular study. We will also offer participants 
the opportunity to indicate on their HIPAA form if they would like to allow 
the research team to access to specific portions of their medical records. 
Prior to the appointment, research staff will send copies of the consent 
form and HIPAA Authorization, as available, via email. Participants will be 
able to opt into receiving unencrypted email communication and SMS 
message communication from study staff for reminders about 
appointments or instructions. The participant will not be required to 
communicate via email or SMS messaging, and they may change their 
mind about email or SMS communication at any point during the study by 
informing the study team of their decision.    
 
(b) Due to the longitudinal 3-year nature of the study, participants who 
are 15 or 16 when they enter the study may turn 18 over the course 
of the study. We plan to re-consent these participants as adults, 
using an adult consent form, after they turn 18 and before continuing 

    
   
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participation in the study. The 18 and older participant will be able to 
opt into receiving unencrypted email communication from study staff 
for reminders about appointments or instructions. The participant  
will not be required to communicate via email, and they may change 
their mind about email communication at any point during the study 
by informing the study team of their decision.    
    
(c) To describe our sample and to determine criteria for ineligibility, we 
will screen for the presence of DSM-5 psychiatric diagnoses. We will 
conduct separate clinical interviews with parent and adolescent using 
the The Computerized Kiddie Schedule for Affective Disorders and  
Schizophrenia (KSADS-COMP), a semi-structured clinical interview, 
administered by a clinician using a laptop or tablet that generates 
current and lifetime diagnoses and elicits ages of onset and offset. 
Clinicians will also administer the Children’s Depression Rating Scale- 
Revised (CDRS-R) to both subject and parent to gauge severity of 
depression symptoms.    
 
To reduce participants’ fatigue, the clinical interviews will be limited to 
three hours. Participants who would like to come back and complete 
the interview will be compensated extra for each hour that their 
interview continues for. 
 
   
Clinicians will also complete the following measures with adolescents only:    
    
The Self-Injurious Thoughts and Behaviors Interview (SITBI) to 
assess self-harm. The SITBI measures NSSI frequency in the past 
month, past year, and lifetime; average age of onset; severity of 
injuries (number of injuries per episode, severity of tissue damage -- 
worst point and average), function (automatic versus social, negative 
versus positive) and other information. The participant’s SITBI will be 
used to determine in which of the four NSSI groups they belong. If 
not complete at the first appointment due to time limitations or other 
factors, the study coordinator can administer the assessment to the 
participant at other visits (i.e., TSST, MRI). The clinician will complete 
this through REDCap.    
    
The Beck Scale for Suicidal Ideation (BSSI), a 19-item interview, 
assesses current suicidal ideation, with ratings for active suicidal 
desire, specific suicide plans, and passive suicidal desire. If not 
complete at the first appointment due to time limitations or other 
factors, the study coordinator can administer the assessment to the 

    
   
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participant at other visits (i.e., TSST, MRI). The participant will 
complete this via a REDCap survey. 
    
The Timeline Followback Method TLFB for NSSI, a calendar format 
measure to retrospectively collect behavioral data that was adapted 
from an instrument for alcohol use, will be used to measure NSSI 
episodes that had occurred in the year between visits. The TLFB 
demonstrates good reliability and validity when used over a 1-year 
period. If not complete at the first appointment due to time 
limitations or other factors, the study coordinator can administer the 
assessment to the participant at other visits (i.e., TSST, MRI).  The 
participant will complete this via a REDCap survey. 
 
The Generalized Anxiety 7-Item (GAD-7) scale is a self-report 
instrument covering 7 items, to rate the presence and severity of 
generalized anxiety symptoms. A second portion of the 
questionnaire asks participants to rate the severity of the collective 
problems they have endorsed, from “not difficult at all” to 
“extremely difficult.” If not complete at the first appointment due to 
time limitations or other factors, the study coordinator can 
administer the assessment to the participant at other visits (i.e., 
TSST, MRI).  The participant will complete this via a REDCap survey. 
  
    
The Childhood Trauma Questionnaire (CTQ) is a self-report 
instrument covering 28 items, to rate the presence and severity of 
emotional abuse and neglect, physical abuse and neglect and sexual 
abuse. If not complete at the first appointment due to time 
limitations or other factors, the study coordinator can administer the 
assessment to the participant at other visits (i.e., TSST, MRI). The 
participant will complete this via a REDCap survey. 
    
    
The Wechsler Abbreviated Scale for Intelligence-II (IQ) will be used to 
estimate intellectual functioning. This measure can be administered at 
any visit, but if IQ is determined as below 80 we will have to exclude 
the participant and their data from the rest of the study. The 
Edinburgh Handedness Inventory will be used to determine 
handedness, which will be incorporated into the analysis. This 
measure can also be administered at any visit as will only be used for 
data analysis.   
    
Tanner Staging will be obtained via a self-report questionnaire with 
outline drawings of the pubertal stages. We will include Tanner 

    
   
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stage as covariates in the analyses. As noted by Casey et al.,1 it will 
be critical to understand the learning histories in the environment 
that shape the development of neural systems. The participant will 
complete this via a REDCap survey. 
    
Participants will also complete the Beck Depression Inventory (BDI-2) 
and a modified Everyday Discrimination Scale (EDS) via REDCap 
survey. We will also gather information on urges to self- injure during 
the past week using the Self Injury Assessment  
Scale (SIAS). The administration of these questionnaires (BDI, 
SIAS) is to be flexible, and if the first appointment is becoming too 
long, can be done at the MRI or Trier appointment. These will also 
be completed via REDCap surveys.   
 
In addition, participants will complete the COVID-19 Health Changes 
questionnaire which will be administered to them via RedCap 
survey. 
 
The participant’s primary parent/guardian will complete the Child 
Behavior Checklist (CBCL), Emotion Socialization and Demographics 
forms. All of these will be completed via REDCap surveys. 
 
For participants who have turned 18, we will continue to ask 
the parent or guardian to complete the same measures as they had 
been doing earlier in the study. In the case of participants who have 
turned 18 and who no longer wish to have their parent or guardian 
involved in the study with them, we will have the participant complete 
the demographics form on their own behalf; we will not collect the 
CBCL or the ES measure in those cases, and the KSADS and 
the CDRS will be completed with the participant alone. 
    
(e) After the diagnostic assessment is complete, a consensus meeting 
takes place among the research team to integrate the combined 
information from parent/guardian and adolescent KSADS interviews, 
rating scales and medical records (if available), to confirm the DSM-5 
psychiatric diagnoses. If participants meet the above inclusion criteria 
and do not have any of the exclusion criteria, they will be invited to 
participate in the remaining portions of the study.    
(e.a) "If at the consensus meeting the research team is unable to determine 
final diagnosis, due to discrepant reports from the parent and child, 
or the presence of other confounding factors in the assessment, the 
research team may take one or more of the following steps:    

    
   
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1) 
Request permission to review medical records from prior medical 
or psychiatric evaluations;    
2) 
Request permission to reach out to the adolescent's current or 
past providers to seek their input on the diagnosis; and/or    
3) 
Invite the adolescent and their parent/guardian to participate in 
a follow-up clinical interview (either in person at the ARC or by 
phone) with one of the faculty clinical investigators on the study (Dr. 
Cullen, Dr. Klimes-Dougan, or Dr. Reigstad) to further evaluate the 
potential diagnoses in question with a focus on resolving the 
conflicting information.    
Following these steps, the clinical evaluation team will confirm the 
diagnosis and finalize the inclusion/exclusion determination."    
    
(f) At each of the second and third assessments (12 and 24 months, 
respectively, after the initial assessment), the scales described in (c-
d) will be collected again.    
(g) Participants will be asked to complete a number of additional 
questionnaires (described below) that will be accessible online. All 
questionnaires will be completed at home at the participant’s own 
pace. In total, these online assessments will take participants 
approximately 1 hour and 45 minutes to complete all of the 
questionnaires. Participants will be compensated if they complete the 
questionnaires.    
    
The questionnaires to be completed at home are: Rejection   
Sensitivity Questionnaire – Adolescent Version (RSQ-A),    
Symptoms Checklist 90 (SCL-90), Toronto Alexithymia Scale    
(TAS-20), Satisfaction with Life Scale, The UPPS Impulsive    
Behavior Scale (UPPS-P), and the Positive and Negative Affect    
Schedule (PANAS-X), the Eating Disorder Examination   Questionnaire 
(EDEQ), and the Personality Assessment Inventory for Adolescents 
(PAI-A), the Pittsburgh Sleep Quality Index (PSQI), and the Cash 
Choice Task.    
 
3.5.3 Stress Biology Procedures    
    
At a separate visit (for each of the three assessments, 12 months apart), 
we will use a procedure that is a version of the Trier Social Stress Test 
(TSST) to elicit a mild stress response. It consists of a 5-minute 
preparation period, 5-minute speech period, and a 5- minute mental 
arithmetic task in front of an audience. In the speech part, children are 
asked to describe themselves in front of an audience of 2 adults. Five 

    
   
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samples of salivary cortisol will be collected according to the following 
schedule: prior to and immediately following the TSST, as well as 15, 30 
and 45 minutes following the TSST. Due to the nature of this visit, as we 
are collecting behavioral data that cannot be interrupted while collecting 
saliva samples, there is a possibility that saliva samples may be +/- 
approximately 5 minutes from the intended sample time.    
    
While we are collecting the saliva samples after the completion of the 
TSST, we will have the participant complete a number of cognitive 
batteries including the ANT Task, Attention Bias Task which utilizes an 
eye-tracker, and the Iowa Gambling Task (IGT). In the event that the 
Attention Bias Task is not functional, the Dot- Probe task will instead be 
used as a measure of attention.  
          
Participants will be given contact information of the study PIs and 
coordinators and instructed to call if the TSST triggers any emotional 
difficulties or if they have any questions.    
    
We will also be asking participants to provide home saliva samples, taken 
on a day that is separate from the day of the TSST. We will ask 
participants to complete five saliva samples at home, over the course of 
one day. The five samples should be collected following this schedule: 
right when waking up, 15 minutes after waking up, and 30 minutes after. 
The fourth sample will be collected in the afternoon, to serve as 
comparison to the start time of the TSST (between 1:00PM and 4:00PM), 
and the fifth sample is to be taken at bedtime (approximately 10:00PM). 
As the participants are completing these samples at home and at their 
own discretion, there is a possibility that they will not directly follow the 
sample collection times. The study team provides a letter explaining the 
times that samples should be collected, but does not have control over 
when the adolescent completes there samples.    
We will have participants document the times that they collected their at 
home saliva samples, as well as any medications, caffeine, or events that 
occurred during the day that could affect their saliva samples via a “Daily 
Diary”- a type of self-report form for the day. We will compensate 
participants for their time spent collecting and documenting the saliva 
samples.    
 
Remote Conduct of Study Procedures 
In the interest of disease containment and prevention during COVID-19, 
study staff will use HIPAA-compliant communication platforms approved 
for use at the University of Minnesota (e.g., Zoom) and adjust this visit as 
follows: 

    
   
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(a) 
Participants will be mailed a saliva collection kit prior to the 
scheduled appointment. To ensure data adequacy, participants will 
also receive a set of standardized instructions for collecting saliva 
samples. Participants will complete the attached survey measure in 
the online REDCap platform.  
 
Researchers will meet with participant via Zoom, and ensure that 
the participant still has a private location to complete the study. 
Saliva collection procedures will be reviewed again. After the initial 
acclimation period, the participant will be introduced to two judges 
that will also be on screen.  Participants will receive instructions for 
preparing their speech, will provide the 5-minute speech, and will 
then perform verbal arithmetic for the next 5 minutes as in the in-
person visits.  Participants will be aware that the entire session will 
be recorded for behavioral coding and to ensure proper saliva 
collection. Judges will be trained research assistants who have 
participated in multiple TSST administrations. Judges will not 
provide positive or negative feedback at any point during the study 
and will only display neutral expressions. They will then complete 
the usual surveys via REDCap. 
 
The TSST over Zoom will be recorded and the recording saved on 
a local HST supported computer. The file will then be uploaded to 
Box and the local copy will be deleted.  
 
Participants will be asked to store the samples in their refrigerator 
until that can return the samples by mail via a pre-addressed and 
postage-paid envelope provided by the researchers.  
 
For participants who complete the TSST on zoom, the ANT and IGT 
will be done at the MRI visit.   
 
For participants who prefer to complete visits in person, we will 
conduct the TSST visit at the Masonic Institute for the Developing 
Brain (MIDB). 
 
    
3.5.4 MRI Procedures    
At a separate visit (for each of the three assessments, 12 months apart), 
we will conduct a brain scanning session at the University of  
Minnesota Center for Magnetic Resonance Research (CMRR) using a  
Siemens 3 Tesla Prisma scanner (Erlangen, Germany) and a 32- channel 
coil radio-frequency (RF) head coil. Prior to the scan, subjects will provide 

    
   
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a urine sample for drug screening and fill out an MRI safety 
questionnaire. If the drug screening is positive, we will complete the   
MRI scan but will use the information in our analysis. We will   also gather 
information on urges to self-injure during the past week using the Self 
Injury Assessment Scale (SIAS). Following the scan, participants will 
complete a Resting State Post Scan Questionnaire (RSPSQ), which 
collects data on their experience during the resting state fMRI as well as 
menstrual status. Participants will also provide information about their 
experiences with the fMRI tasks through an Emotion Go No Go 
Questionnaire and a Hariri Post-Scan Questionnaire. Participants will also 
complete the Self-Perception Profile for Adolescents (SPPA) questionnaire 
after the scan. These surveys will be conducted via REDCap.   
The research team will utilize the CMRR Center’s screening tools and 
adhere to the screening SOP during enrollment of all research participants 
in this protocol.  The CMRR Center’s screening tools and SOP are IRB 
approved under the CMRR Center Grant (HSC# 1406M51205) and 
information regarding screening procedures is publically available on the 
CMRR website (CMRR Policies / Procedures).  
Individuals will complete a screening questionnaire for contraindications 
of MRI scanning. Any affirmative responses on the questionnaire will 
result in an interview regarding the possible contraindication. An attempt 
will be made to secure any records to better understand the nature of the 
possible contraindication and this information will be reviewed by the PI, 
MRI Co-Investigator, and CMRR staff at the University of Minnesota. If 
staff suspects metal in a participant’s body, the participant will have the 
option to undergo a low dose, whole body Computed Tomography (CT) 
scan prior to the MRI in order to ensure their safety and eligibility. The CT 
scan will take place at the CMRR at the University of Minnesota. The CT 
scan results will be reviewed by a CMRR radiologist. Based on the results, 
a determination will be made regarding the level of risk to the subject 
and whether they are approved for scanning. If the participant has certain 
problematic iron or steel implants in their body that cannot be removed, 
the subject may not have the scan and will be excluded from that part of 
the study. If the CT scan does not show evidence of problematic metal in 
the body, and the participant is approved for scanning by professionals, 
the results of the CT scan, all risks to the participant, including any 
concerns from the PI, CMRR staff and/or MRI co-investigator, will be 
conveyed to the participant (and if the participant is under 18, the 
parent/guardian) so they can decide whether or not they want to 
complete the MRI procedure. If a participant chooses to undergo a CT 
scan and are subsequently found to be ineligible for the MRI scan, or if 
they decide not to proceed with the MRI scan, they will be compensated 
on a pro-rated hourly basis of $20 per hour. 
 

    
   
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During the COVID-19 pandemic, scans will be conducted in accordance to 
the CMRR policy. Participants will be asked safety screening questions 
ahead of the scan, and will also be given an information sheet issued by 
the CMRR regarding COVID-19 safety.  
 
Moreover, since many of these scans will be conducted months after the 
participants’ latest clinical interview, participants whose interviews would 
have taken place three months prior to the scheduled scan time will be 
asked to complete the BDI-II and SITBI over Zoom again. Lifetime 
questions on the SITBI will be omitted.  
 
The WASI, ANT, and IGT, will also be conducted at the MRI visit due to 
the in-person nature of these tasks/assessments, and the switch to 
remote study procedures for the Intake and Trier.        
    
Anatomical Data. A high-resolution T1 (7 minutes) and T2 ( 6 minutes) 
weighted images will be collected with 0.8mm isotropic voxel resolution. 
Field Map. Two HCP spin echo EPI field map scans (AP and PA phase 
encode, 1 minute total ) will be acquired with voxel parameters matching 
those of the fMRI task acquisition 2mm isotropic voxel resolution and will 
be used to correct the fMRI data for the geometric distortion caused by 
magnetic field inhomogeneity.    
    
Functional Data. All functional data will be acquired using the HCP 
multiband echo planar imaging sequence. Whole brain T2*- weighted 
functional volumes with 2mm isotropic voxel resolution will be obtained 
during rest and in conjunction with the tasks listed below. Resting-state 
fMRI data will be collected for twelve minutes with eyes open while 
viewing a fixation cross. The duration of 12 minutes and the choice of 
fixation cross as the resting condition are selected to optimize 
reliability.120,121 The subject will then complete three tasks –Threat 
(emotion matching task, 1 run @ 7 minutes), Self-Evaluation (or Self vs. 
Change, 2 runs @ 5 minutes each) and the Emotional Go-NoGo ( 2 runs 
@ 5 minutes each) in the scanner.    
    
Diffusion Weighted Imaging. Two whole brain diffusion weighted scans 
(AP and PA phase encode) will be acquired using the CMRR multi-band 
diffusion weighted sequence. These scans have a 1.5mm isotropic voxel 
resolution, include 159 volumes, and last 8 minutes per scan.    
    
3.5.5 Data Sharing with RDoCdb    

    
   
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Every 6 months, data from this study will be submitted to the   Research 
Domain Criteria Database (RdoCdb). RdoCdb is a data  repository run by 
the National Institute of Mental Health (NIMH) that allows researchers 
studying mental illness to collect and share deidentified information with 
each other. Other researchers  nationwide can then file an application 
with the NIMH to obtain access to deidentified study data for research 
purposes. Study information will be de-identified using NIMH’s Global 
Unique Identifier system (GUID) allowing for subjects to be identified   
across research labs without having any personally identifiable 
information being transmitted or shared.   
 
 

    
   
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3.5.6 Schedule of activities (Study Table).    
    
       
Activities    
    
Clinician    
Administered 
(CA)  
Selfreport  
(SR)    
  
or 
    
Child (C)
or Parent/  
 Guardian    
(PG)    
    
Assessment  
 
    
TSST    
    
   
MRI   
   
Online  
  
Y1  Y2  Y3  Y1  Y2  Y3  Y1  Y2  Y3      
Consent/ 
HIPAA    
CA    
PG    
X   
    
    
    
    
    
    
    
    
    
Assent    
CA    
C    
X       
    
    
    
    
    
    
    
    
UBACC    
CA    
PG/C    
X       
    
    
    
    
    
    
    
    
KSADS    
CA    
PG/C    
X   
X   
X       
    
    
    
    
    
    
WASI-II    
CA    
C    
X       
    
    
    
    
    
    
    
    
Edinburgh    
CA    
C    
X       
    
    
    
    
    
    
    
    
Demographic 
s Form    
SR    
PG    
X   
X   
X   
    
    
    
    
    
    
    
TLFB for 
NSSI    
CA    
C    
X   
X   
X       
    
    
    
    
    
    
CDRS-R    
CA    
PG/C    
X   
X   
X       
    
    
    
    
    
    
GAD-7 
SR 
   C 
X 
X 
X 
 
 
 
 
 
 
 
Tanner   
Staging    
SR    
C    
X   
X   
X       
    
    
    
    
    
    
EDS 
SR 
C 
 
X 
X 
 
 
 
 
 
 
 
CTQ    
SR    
C    
X   
X   
X       
    
    
    
    
    
    
SITBI    
CA    
C    
X   
X   
X       
    
    
    
    
    
    
BSSI    
SR    
C    
X   
X   
X       
    
    
    
    
    
    
RSQ-A    
SR    
C    
    
    
    
    
    
    
    
    
    
X    

    
   
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SCL-90    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
PAI-A    
SR    
 
C    
   X X 
X 
    
    
    
    
    
    
  
SPPA    
SR    
C    
    
    
    
    
    
    
X   
X   
X       
TAS-20    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
UPPS-P    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
BDI-II    
SR    
C    
X   
X   
X       
    
    
    
    
    
    
EDE-Q    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
Satisfaction 
with Life    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
PANAS-X    
SR    
C    
    
    
    
    
    
    
    
    
    
X    
PSQI 
SR 
C 
 
 
 
 
 
 
 
 
 
X 
Cash Choice    
SR   
C   
   
   
   
   
   
   
   
   
   
X   
EAC    
SR    
PG    
X   
X   
X       
    
    
    
    
    
    
CBCL    
SR    
PG    
X   
X   
X       
    
    
    
    
    
    
SIAS    
SR    
C    
X   
X   
X       
    
    
X   
X   
X       
COVID-19 
Health 
Changes 
SR 
C 
 
X 
X 
 
 
 
 
 
 
 
Attention   
Bias Task    
CA    
C    
    
    
    
X   
X   
X   
    
    
    
    
IGT    
CA    
C    
    
    
    
X   
X   
X       
    
    
    
ANT    
CA    
C    
    
    
    
X   
X   
X       
    
    
    
TSST    
CA    
C    
    
    
    
X   X   
X   
    
    
    
    
Basal Saliva   
SR    
C    
    
    
    
X   X   
X   
    
    
    
    
Structural   
MRI    
CA    
C    
    
    
    
    
    
    
X   X   
X       
Diffusion   
Tensor    
CA    
C    
    
    
    
    
    
    
X   X   
X       
    

    
   
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Imaging   
(DTI)    
    
   
   
   
   
   
   
   
   
   
   
   
Resting    
State fMRI    
CA    
C    
   
   
   
   
   
   
X   
X   
X      
RSPSQ    
SR    
C    
   
   
   
   
   
   
X   
X   X      
Hariri Task    
CA    
C    
   
   
   
   
   
   
X   
X   X      
HPSQ    
SR    
C    
   
   
   
   
   
   
X   
X   X      
Self-    
Knowledge    
Task    
CA    
C    
   
   
   
   
   
   
 X     X     X       
Emotional    
Go-No-Go    
Task    
CA    
C    
   
   
   
   
   
   
 X     X     X       
EGNGQ    
SR    
C    
   
   
   
   
   
   
X   
X   X      
    
                 3.5.7 Compensation 
 
Payment Method: Participants will be given a pre-paid debit card called Greenphire 
ClinCard. After each completed visit for the study, money will be added to the 
card. The debit card system is administered by an outside company. The company, 
Greenphire, will be given the name of each participant. They will use this information 
only as part of the payment system. The information will not be used for any other 
purposes and will not be given or sold to any other company. Greenphire will not 
receive any information about health status or the study. 
 
Payment received as compensation for participation in research is considered taxable 
income. If payment to an individual exceeds $600 in any one calendar year, the 
University of Minnesota is required to report this information to the Internal Revenue 
Service (IRS). Research payments to study participants exceeding $600.00 during 
any calendar year will result in a FORM 1099 (Miscellaneous Income) being issued to 
the participant and a copy sent to the IRS. 
  
Compensation per Visit (adjusted for the pandemic):  
• 
Clinical assessment visit. For each of the clinical assessment visits, adolescents 
receive $40. As noted above, the clinical interviews are limited to 3 hours to 
limit participant fatigue. If the interviews are not complete in that time frame, 
participants are invited to complete them in an additional session on a 
different day. In that case, they receive $20 per each additional hour for 
completing the interview.  

    
   
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• 
Speech task and cortisol samples. For each of the speech task appointments, 
which take place in person or online, adolescents receive $20. For each time 
they complete the home saliva samples and diary, they will receive $10. 
• 
MRI + cognitive task visits. For each of these in-person visits, which now 
include MRI and cognitive assessments, the adolescents receive $60. If the 
adolescent needs to return to the CMRR to repeat any procedures, such as if 
technical errors occurred during data collection, they will be compensated of 
$20 per each additional hour of time at the CMRR. In the IGT task, the 
participants are told that they will be able to keep any winnings (anything 
above the starting amount of $5.00) but that they will not have to pay if they 
lose money in the game (i.e., if they have less than $5.00 at the end). Any 
winnings (maximum = $5.00) will be added to the usual compensation for that 
visit ($60). 
• 
On-line assessments. Each time they complete the online battery of 
assessments, adolescents will receive $20. If participants prefer to complete 
these in-person, we will arrange a visit at MIDB. 
• 
Lodging may be provided for participants residing out of the state, and 
participants in need of transportation assistance will be compensated for 
transportation.  
• 
Participants will be reimbursed for parking costs related to each visit. 
• 
Compensation is pro-rated according to each completed visit. 
 
  
 
3.6    
Study outcome evaluations:    
    
3.6.1 Study endpoints.    
    
All participants will be asked to complete the clinical assessments, Trier 
Social Stress Test (TSST), online questionnaires, and MRI 3 times, once 
every 12 months.    
    
3.6.2 Sample size determination.    
    
By recruiting 152 participants, we expect a final sample size of 30 
participants in each of the 4 groups with usable data at the third (last) 
study time point. The study is powered to achieve Specific Aims 1 and 3 
based on our cross-sectional pilot data. Type I error is 5% except where 
otherwise specified.    
    
Specific Aim 1. H1A, H1B: With N=152, we will have 85% power to detect 
correlations as small as 0.25 of NSSI severity with RDoC measures. If 
considering NSSI severity on a continuous scale is unreasonable, we have 
85% power to detect group differences in RDoC measures as shown in 
Table 6, using Bonferroni correction of type I error for 6 pairwise 
comparisons among the 4 groups. Larger differences than those listed 
were found in our pilot data; for these outcomes this large of a sample 

    
   
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size is not needed, but the larger sample size will allow testing for 
significant differences in other RDoC indices that showed trends in pilot 
data. H1C: With N=38 per NSSI group with complete data at visit 1, we 
will have 85% power to detect correlations within NSSI group as small as 
0.50 among imaging and clinical measures, or as small as 0.25 if NSSI 
groups can be pooled.    
    
Specific Aim 3 (longitudinal trajectories). With N=30 expected at last 
follow-up per group, we have 85% power to detect group differences in 
changes in circuits as shown in Table 7, using Bonferroni correction of 
type I error for 6 pairwise comparisons among the 4 groups. The 
minimum differences listed are smaller than those observed in our pilot 
exploration of the interaction between age group and NSSI vs. HC group. 
With N=152 recruited, we will have 85% power to detect correlations as 
small as 0.25 of changes in circuits self-reports or physiology with NSSI 
severity.    
    
    
    
Table 6. Minimum detectable differences among NSSI severity groups at baseline and over time    
Sustained Threat    Minimum group difference 
at baseline    
Self-Knowledge    
Minimum group difference 
at baseline    
Rejection  
Sensitivity    
19.2    
Alexithymia (TAS)    
7.6    
Amygdala-Frontal  
RSFC    
0.723    
Rostral-Posterior 
Cingulate RSFC    
.231    
    
Table 7. Minimum detectable differences among NSSI severity groups over time    
Sustained Threat    
Minimum group difference 
in changes    
Self Knowledge    
Minimum group difference 
in changes    
Amygdala activation  
to threat    
0.87    
Rostral ACC- Post. 
cingulate RSFC    
.181    
Frontal activation to 
threat    
1.23    
Precuneus activation to 
threat    
.72    
    
   
3.6.3    
Outcome data and data analysis.    
    
Aim 1: Self-report, physiology, behavior and circuit measures will be 
summarized, by group and overall, graphically and using summary 
statistics to examine and compare their distributions (e.g., mean shifts, 
variability, skewness). In relating NSSI severity to multi-modal 
assessments of Sustained Threat, Self Knowledge and Cognitive Control, 
we will consider continuous scales (based on number of lifetime episodes 

    
   
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and frequency) if NSSI severity varies smoothly, and if not we will 
consider the categorical NSSI groups.    
    
Hypothesis 1A and 1B. We will utilize a supervised learning approach 
for classification (specifically, Distance Weighted Discrimination) to 
identify which individual (1A) and combinations of (1B) characteristics 
(all levels included: neural, clinical, self-report) most strongly 
distinguish the NSSI severity groups from each other. Models will 
adjust for age, IQ, SES, and other covariates (e.g. depressive 
symptoms, family history, adverse experiences) identified as potential 
confounders. Classification accuracy will be quantified using 10-fold 
cross- validation.    
    
Hypothesis 1C. Simple graphical displays of data and their correlations 
across units of analysis will be done, with color- coding by NSSI group 
and construct. We will then use confirmatory factor analysis (CFA) to 
test the hypothesis that all units of analysis (circuits, physiology, 
behavior, self-report) cohere within the proposed RDoC constructs. 
We expect that some of these measures will not converge within 
constructs, in which case exploratory factor analysis (EFA) will be the 
next step to elucidate the latent constructs to which these measures 
do adhere.    
Data reduction: If the factor analysis developed for Hypothesis 1.C. 
strongly identifies underlying latent constructs based on the 
combination of circuits, physiology, behavior, and selfreport, we will 
use the factor loadings as the predictors of NSSI severity rather than 
the separate levels of measurement. The factor analysis can be 
repeated using each visit’s data so that time- updated factor loadings 
can be used in modeling for Aim 3.    
    
For all analyses, model appropriateness will be assessed using 
diagnostics, and transformations, covariate functional forms, and 
models will be altered if needed.    
    
Aim 1 Expected Outcomes: This approach, using all levels of data 
together at baseline, will allow inference of which adolescent 
characteristics best differentiate the NSSI severity groups, separately for 
each pair of groups (e.g., the characteristics distinguishing moderate 
from mild NSSI groups may not be the same as the characteristics that 
distinguishing mild from no NSSI). We expect that within-construct and 
across-construct indices will incrementally predict NSSI severity (H1A and 
H1B), supporting the proposed relevance of these constructs to NSSI. If 
indices from some units predict NSSI severity to a greater extent than 
others, this would guide future researchers in selecting the measures 

    
   
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most predictive of NSSI severity. We expect that within constructs, 
across-unit measures will show some evidence of convergence (H.1.C), 
supporting the proposed conceptualization of the neurobehavioral 
dimensions. If we find evidence of divergence, this could guide future 
research on these constructs (i.e., selection of measures that might have 
stronger inter-relationships, and fine- tune current conceptualization of 
the construct.)    
    
Aim 2. We will use multi-state modeling to examine how baseline 
measures of the 3 study constructs predict NSSI severity at follow- up. In 
this approach, the response is group membership, and we model the 
transition from any group to the other at any time point. Multi-state 
models provide estimates of the transition intensities (reflecting the ‘risk’ 
of transitioning from each state to each other state) as a function of 
patient characteristics, including potential confounders as discussed in 
Aim 1.    
    
Aim 2 Expected Outcomes: We will identify which individual and 
combination of characteristics predict transitions, including which specific 
transitions and the direction of association (e.g., protective vs. risk 
factor).    
    
Aim 3.    
Longitudinal trajectories in RDoC constructs: We will conduct a series of 
repeated measures ANOVAs using linear mixed models, with each RDoC 
index listed above as the outcome and NSSI severity group as the 
between-subject variable, adjusting for covariates such as SES, IQ, 
psychopathology, and treatments received in the intervening periods. In 
these models, we will use age-at-visit rather than date-of-visit as the 
time axis; this will accommodate the inevitable irregularity in actual visit 
dates targeted to occur every 12 months and will align the data across 
participants in time more closely with developmental stages. Because of 
concerns that psychopathology will differ substantially across groups, as 
an alternative to the proposed covariate adjustment, we will consider 
Inverse Probability Weighting (IPW; see e.g. Lunceford and Davidian, Stat 
Med 2004; 23:2937). IPW first predicts the probability of NSSI group 
membership based on, for example, the psychopathology features as well 
as other relevant measures such as family history of these conditions. 
Then the linear mixed models for estimating construct developmental 
trajectories over time are reweighted using the inverse of these estimated 
probabilities, which imposes a covariate balance on the sample. 
Estimated differences in developmental trajectories between NSSI 
severities are then interpreted as differences due to NSSI that we would 
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severity groups. We will estimate the weights using random forests (see 
e.g. Hastie et al., Elements of Statistical Learning, Springer) for a 
multinomial outcome (NSSI severity groups); the random forest approach 
is a more robust way to estimate group probabilities (than e.g. a simple 
multinomial model) and will guard against overfitting.    
    
Missing data considerations: We will compare (within group and between 
groups) the clinical and imaging characteristics of any dropouts to those 
who did not drop out, and use this to inform the interpretation of the 
magnitude and direction of NSSI group differences in longitudinal 
trajectories.    
    
Between-construct dynamic interactions: Through comprehensive 
measurement of the three proposed systems over time, we aim to 
examine dynamic interaction between the systems. For example, we 
anticipate that abnormalities within the sustained threat domain in early 
adolescence could lead to abnormalities in the self- knowledge system at 
a later stage, because of the impact of sustained stress responses on the 
developmental processes of self- perception during adolescence. We 
would predict that this interaction would be associated with a worsening 
or persistent NSSI course. Another possible dynamic interaction could be 
that baseline abnormalities in cognitive control could, over time, 
exacerbate abnormalities in the sustained threat system (because of the 
impact of sustained impairments in self-regulation generally).    
These hypotheses can be tested using cascade analyses (see e.g.  
Klimes-Dougan et al. Devel Psychopath 2010; 22:849). To implement 
such an approach, we will postulate specific ways in which the systems 
might plausibly interact and impact NSSI severity; our postulations will be 
based on psychopathology theory and our clinical experience with NSSI. 
Interaction models will then be built and estimated (one based on each 
postulation) and then compared to each other to identify the model with 
the best fit for predicting NSSI severity.    
    
Aim 3 Expected Outcomes: Adolescents with no NSSI at baseline or the 
follow-ups will demonstrate developmental trajectories similar to that in 
published literature (if any) for healthy adolescents in this age group and 
will be considered as the normative trajectory. Trajectories in adolescents 
with NSSI will deviate from the norm, in a pattern where the adolescents 
with the most severe NSSI will show the most abnormal trajectories. 
Among adolescents whose baseline group assignment is transient NSSI, 
those who ultimately transition to higher-severity NSSI will show more 
abnormal trajectories, whereas those who ultimately remit will show more 
normal trajectories.   

    
   
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4. Risk analysis    
    
4.1 Anticipated risks:    
    
4.1.1 Screening Visit    
    
Our clinical assessment of all adolescents and parents of children 
enrolled in the study involves asking questions about feelings, 
past experiences, and family history. Some of these topics may 
cause the subjects and/or their parents discomfort or distress. 
Participants are encouraged to share only what they feel 
comfortable with and will not be induced to discuss anything that 
makes them too uncomfortable.    
    
4.1.2 Trier Social Stress Test    
    
This procedure is designed to elicit a mild stress response. Some 
participants may become distressed by this procedure. The research 
team members who have been trained to administer the TSST are 
also trained to recognize signs of distress. If at any point the 
participant becomes too stressed, the research staff will stop the 
procedure. Additionally, if the participant wishes to discontinue the 
procedure, they may do so.    
    
4.1.3. MRI and CT Scanning    
    
The device to be used in the study is a 3 Tesla Siemens Prisma MRI 
machine.    
    
The magnet in the scanner may cause electronic devices like 
watches to malfunction, and some metal objects can be pulled into 
the scanner. Participants will be screened prior to the scan to 
make sure they have nothing in their body that could be magnetic 
or affected by the magnetic field of the scanner. Participants will 
be asked to change into scrubs to ensure they have no metal on 
their person.    
    
It may be uncomfortable lying still in the scanner for the amount of 
time required. The participant may experience some stiffness and 
soreness in the muscles from being still. To make participants as 
comfortable as possible, we will provide soft pads to help support the 
next, back, and legs.    
    

    
   
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The scanner itself makes a lot of noise while it is running. This can be 
uncomfortable and may affect the participant's hearing. Participants will 
be asked to wear ear plugs which will significantly reduce the amount  
of noise. Participants will also be wearing headphones in addition to the 
earplugs to allow them to hear the investigators and listen to music.    
    
Some people may become uncomfortable in the scanner because 
they are not comfortable being in enclosed spaces. We will screen 
for claustrophobia before we bring the participant to the scan 
center. They will have the option of using a mock scanner prior to 
going into the scanner to assess their level of comfort. They will 
not be required to participate in the scan or continue the scan if 
they are uncomfortable.    
    
    
There is a chance we might find something abnormal when we 
look at the images of the participant's brain. If a member of the 
research team notices something unusual in the MRI results, they 
will send it to a trained radiologist after the scan so they can be 
assessed for abnormalities. These images will not have any 
identifying information about the patient. If the radiologist 
recommendation is to further investigate the unusual results of 
the pictures, the investigator will contact the participant.    
 
Part of the MRI scan is designed to induce different kinds of 
feelings, both negative and positive. Because of this, it is possible 
that the participant may become sad or distressed by the negative 
pictures. We will encourage the participant to let us know if they 
are feeling upset, and we will plan to discontinue the procedure 
whenever they wish to stop. The participant will be shown 
examples of the images in the scan before going into the scanner. 
If the participant decides that the images would be too much for 
them to tolerate, the scan will be skipped in its entirety. 
 
CT Scan: If the study team suspects that the participant may have metal 
in their body, they will be given the option of having a CT scan. The CT 
scan involves exposure to ionizing radiation in the form of x-rays. 
Everyone receives a small amount of unavoidable radiation each year from 
space and from naturally occurring radioactive materials in the 
environment. The amount of radiation exposure received from a CT scan 
varies according to the size of the patient and the portion of the body that 
is scanned. The low dose CT scan performed for this study gives the body 
the equivalent of about 1 year or less of natural background radiation. At 
such low radiation exposures scientists disagree about the amount of risk, 

    
   
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and there may be no extra risk at all. The radiation discussed here does 
not include any exposure a subject might receive from his/her regular 
medical care. The radiation, and procedures used in this study and any 
other studies may involve risks to an infant, embryo, fetus or nursing 
infant, which are not known at this time.  Therefore, if a subject is 
pregnant, planning to become pregnant, or nursing, they will be told they 
cannot participate in the CT scan and therefore also not the MRI portion of 
this study. 
 
4.1.4. Loss of Confidentiality    
    
As with all research, there is a chance participants may suffer a 
loss of confidentiality. We will do everything in our power to limit 
the chances of this occurring. Information about study subjects will 
be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). Those regulations require a signed subject authorization 
informing the subject of the following:    
    
• 
What protected health information (PHI) will be collected from 
subjects in this study    
• 
Who will have access to that information and why    
• 
Who will use or disclose that information    
• 
The rights of a research subject to revoke their authorization for 
use of their PHI.    
In the event that a subject revokes authorization to collect or use 
PHI, the investigator, by regulation, retains the ability to use all 
information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to 
collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period.    
    
4.1.5 Email Risks    
Participants will be able to opt in to communicating with study staff via 
unencrypted email to arrange their appointments and receive study 
instructions. There are risks associated with email communication, and these 
risks increase when the emails are sent without an encryption service. Risks 
of sending or receiving emails without encryption include, but are not limited 
to:    
 
• 
Others can intercept messages    
• 
If messages are sent or received on an employer-owned device, the 
employer may have the right to save and read the messages. The 

    
   
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internet or cell-phone provider may also have the right to save and read 
email messages.    
• 
A copy of the message may be saved on a device or computer system, 
even if it is deleted.   
• 
If an email address is not typed correctly, it can be sent to the wrong 
person    
• 
Emails can spread computer viruses.    
• 
Others may be able to access messages on devices that were lost, 
stolen, or thrown away.    
• 
If a user changes emails without notifying study staff, they may miss 
communications.    
   
 
 
4.1.6 Text Message Risks   
   
Participants will be able to opt in to communicating with study staff via text 
message to arrange their appointments and receive study instructions. There 
are risks associated with communication via text message. Risks of sending or 
receiving text messages include, but are not limited to:   
• 
Others can intercept messages   
• 
Text messages may be viewed by University of Minnesota staff 
depending on the nature and timing of said messages, and may be 
monitored by the University to ensure appropriate use.   
If messages are sent or received on an employer-owned device, the employer 
may have the right to save and read the messages. The cell-phone provider 
may also have the right to save and read text messages.   
    
    
   
4.2    
Adverse event recording/reporting    
    
4.2.1 Adverse event definitions.    
    
Adverse effect. Any untoward medical occurrence in a clinical study of 
an investigational device; regardless of the causal relationship of the 
problem with the device or, if applicable, other study treatment or 
diagnostic product(s).    
    
Associated with the investigational device or, if applicable, other study 
treatment or diagnostic product(s). There is a reasonable possibility 
that the adverse effect may have been caused by the investigational 
device or, if applicable, the other study treatment or diagnostic 
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Disability. A substantial disruption of a person’s ability to conduct normal 
life functions.    
    
Life-threatening adverse effect. Any adverse effect that places the 
subject, in the view of the investigator-sponsor, at immediate risk 
of death from the effect as it occurred (i.e., does not include an 
adverse effect that, had it actually occurred in a more severe form, 
might have caused death).    
    
Serious adverse effect. Any adverse effect that results in any of the 
following outcomes: death, a life-threatening adverse effect, 
inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.    
    
• Hospitalization shall include any initial admission (even if less than 
24 hours) to a healthcare facility as a result of a precipitating 
clinical adverse effect; to include transfer within the hospital to 
an intensive care unit. Hospitalization or prolongation of 
hospitalization in the absence of a precipitating, clinical adverse 
effect (e.g., for a preexisting condition not associated with a 
new adverse effect or with a worsening of the preexisting 
condition;  admission for a protocol-specified procedure) is not, 
in itself, a serious adverse effect.      
Unexpected adverse effect. Any adverse effect, the frequency, 
specificity or severity of which is not consistent with the risk 
information described in the clinical study protocol(s) or elsewhere in 
the current IDE application, as amended.    
    
Unanticipated adverse device effect. Any serious adverse effect on 
health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or IDE application (including a 
supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects.    
    
4.2.2 Eliciting adverse effect information.    
    
Clinical study subjects will be routinely questioned about adverse effects 
at study visits.    
    

    
   
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4.2.3 Recording and assessment of adverse effects.    
    
All observed or volunteered adverse effects (serious or non-
serious) and abnormal test findings,  will be recorded in the 
subjects’ case histories. For all adverse effects, sufficient 
information will be pursued and/or obtained so as to permit 1) an 
adequate determination of the outcome of the effect (i.e., whether 
the effect should be classified as a serious adverse effect) and; 2) 
an assessment of the casual relationship between the adverse 
effect and the study activities.    
    
Adverse effects or abnormal test findings felt to be associated with 
the studywill be followed until the effect (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to 
the investigator-sponsor.    
    
4.2.3.1 Abnormal test findings:    
    
An abnormal test finding will be classified as an adverse effect if 
one or more of the following criteria are met:    
    
• 
The test finding is accompanied by clinical symptoms.    
• 
The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional 
concomitant drug or other therapy. (Note: simply repeating a test 
finding, in the absence of any of the other listed criteria, does not 
constitute an adverse effect.)    
    
• 
The test finding leads to a change in study dosing or exposure or 
discontinuation of subject participation in the clinical study.    
    
• 
The test finding is considered an adverse effect by the 
investigatorsponsor.    
    
4.2.3.2 Causality and severity assessment:    
    
The investigator-sponsor will promptly review documented 
adverse effects and abnormal test findings to determine 1) if 
the abnormal test finding should be classified as an adverse 
effect; 2) if there is a reasonable possibility that the adverse 
effect was caused by the investigational device or, if 
applicable, other study treatment or diagnostic product(s); 
and 3) if the adverse effect meets the criteria for a serious 
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If the investigator-sponsor’s final determination of causality is 
“unknown and of questionable relationship to the investigational 
device or, if applicable, other study treatment or diagnostic 
product(s)”, the adverse effect will be classified as associated 
with the use of the investigational device or study treatment or 
diagnostic drug product(s) for reporting purposes. If the 
investigator-sponsor’s final determination of causality is 
“unknown but not related to the investigational device or, if 
applicable, other study treatment or diagnostic product(s)”, this 
determination and the rationale for the determination will be 
documented in the respective subject’s case history.    
    
4.2.4 Reporting of adverse effects to the responsible IRB.    
    
In accordance with applicable policies of the University of 
Minnesota Institutional Review Board (IRB), the investigator-
sponsor will report, to the IRB, any observed or volunteered 
adverse effect that is determined to meet all of the following 
criteria: 1) associated with the investigational device or, if 
applicable, other study treatment or diagnostic product(s); 2) a 
serious adverse effect; and 3) an unexpected adverse effect. 
Adverse event reports will be submitted to the IRB in accordance 
with the respective IRB procedures.  Applicable adverse effects will 
be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the investigator-sponsor’s receipt 
of the respective information. Adverse effects which are 1) 
associated with the investigational drug or, if applicable, other 
study treatment or diagnostic product(s); 2) fatal or life-
threatening; and 3) unexpected will be reported to the IRB within 
24 hours of the investigator-sponsor’s receipt of the respective 
information.    
    
Follow-up information to reported adverse effects will be submitted 
to the IRB as soon as the relevant information is available. If the 
results of the sponsor-investigator’s follow-up investigation show 
that an adverse effect that was initially determined to not require 
reporting to the IRB does, in fact, meet the requirements for 
reporting; the investigator-sponsor will report the adverse effect to 
the IRB as soon as possible, but in no event later than 10 calendar 
days, after the determination was made.    
    
   
4.3    
Withdrawal of subjects due to adverse effects:    
    

    
   
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Subjects who experience severe adverse events will be immediately   
withdrawn from the study. Subjects who experience mild to moderate adverse events 
will be allowed to discontinue if they would like to.     
Subjects withdrawn from study participation due to an adverse 
effect will not be replaced as we have included more people than 
necessary in our original sample size for situations such as subject 
withdrawal or bad MRI data.    
    
   
4.4    
Population-specific Considerations    
    
The population being researched in this study has a higher risk for 
suicidal ideation, suicide attempts, and serious injury due to self- 
harm. The research team will monitor depression, suicidal ideation, 
and self-harm behaviors at each assessment. Participants who 
indicate suicidal ideation or significantly increased self-harm 
behaviors will be asked to meet with one of the investigators of the 
study to assess risk.    
    
Participants with suicidal ideation with no plan or intent who agree to a 
safety plan (either developed with the investigator or a pre-existing 
safety plan) will be allowed to continue in the study. The investigator 
will inform parents of the discussion and safety plan (if applicable).    
    
Participants with severe self-harm (requiring stitches or hospitalization), 
suicidal ideation with intent, or those who cannot or will not agree to a 
safety plan will be referred to the Emergency Room. The study team will 
assist with determining the need to call emergency services (e.g. 911, 
county crisis teams) versus recommending that parents transport the 
adolescent to the emergency room on their own. 
       
5. References    
    
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35. 
Plener PL, Bubalo N, Fladung AK, et al. Prone to excitement: adolescent 
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