Examining Reward-Related Predictors and Mechanisms of Change in BA Treatment for Anhedonic Adolescents
Phase: NA
Conditions: Anhedonia
Sponsor: Mclean Hospital

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PRINCIPAL/OVERALL INVESTIGATOR 
Christian A. Webb, Ph.D. 
 
PROTOCOL TITLE 
Examining Reward-Related Predictors and Mechanisms of Change in BA Treatment for 
Anhedonic Adolescents 
 
FUNDING 
NIMH Mentored Patient-Oriented Research Career Development Award (K23) 
Brain & Behavior Research Foundation 
 
VERSION DATE 
April 19, 2022 
I. BACKGROUND AND SIGNIFICANCE 
By 18 years of age, approximately 15% of adolescents will have experienced at least one 
major depressive episode (Avenevoli et al., 2015). Further, 66% of these individuals will 
experience a relapse within 5 years (Kovacs et al., 1994) and 84% will experience a 
recurrent episode during adulthood (Harrington et al., 1996). More recent studies have 
identified anhedonia and related reward circuitry dysfunctions as being critically involved 
in the development and maintenance of depressive symptoms in adolescents (Forbes and 
Dahl, 2012). Given converging evidence of functional abnormalities in reward circuitry 
playing a central role in the pathophysiology of anhedonic symptoms in adolescents, 
treatments that directly target reward-related deficits may prove particularly effective at 
alleviating these core depressive symptoms (Dichter et al., 2009). Moreover, anhedonia is 
an especially important treatment target given that amelioration of the latter symptom is a 
robust predictor of improvement in other depressive symptoms (Bringmann et al., 2015). 
 
II.  SPECIFIC AIMS  
(1) Specific Aim 1: Examine baseline neural and behavioral differences in 35 treatment-
seeking anhedonic adolescents and 35 healthy control adolescents. Specifically, 
participants will complete neural (fMRI reward task), behavioral (Probablistic Reward 
Task; PRT) and self-report (Ecological Momentary Assessment; EMA) measures of 
anhedonia and reward system function. Relative to the healthy control group, the 
anhedonic adolescents will exhibit aberrant reward function on each of these measures, as 
evidenced by: 
(a) Blunted striatal and hyper-active medial prefrontal cortex (mPFC) response to 
reward-related stimuli during the fMRI reward task; 
 
(b) Blunted response bias on the PRT; 
(c) Blunted daily positive affect and increased anhedonia as assessed via EMA.  
 
(2) Specific Aim 2: Examine neural and behavioral predictors and mechanisms of 
symptom improvement in Behavioral Activation (BA) for anhedonic adolescents: 
Anhedonic adolescents will undergo a 12-week protocol of BA treatment. Neural (fMRI) 
and behavioral (PRT) measures will be assessed at pre- and post-treatment, and the EMA 
protocol will involve repeated assessment waves. We hypothesize that: 

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(a) Pre-treatment reward dysfunction (i.e., assessed via baseline fMRI, PRT and 
EMA), controlling for overall pre-treatment levels of depressive symptoms, will predict 
anhedonic (Snaith–Hamilton Pleasure Scale [SHAPS; Snaith et al., 1995]) symptom 
improvement over the course of BA. 
(b) Greater pre- to post-treatment normalization in neural (i.e., striatal and mPFC 
response to fMRI task) and behavioral (i.e., PRT performance) measures will be linked to 
greater anhedonic symptom improvement over the course of treatment.  
(c) Given emerging evidence of decreased cortico-striatal functional connectivity 
to reward-related stimuli in depression (Admon et al., 2015), we expect that BA will 
result in significant increases in cortico-striatal functional connectivity to rewarding 
stimuli from pre- to post-treatment. 
 
(3) Specific Aim 3: Examine association between changes in neural reward circuitry and 
real-world positive affect and anhedonia: The EMA protocol will be implemented to 
acquire a more fine-grained and “real-world” assessment of changes in subjective 
positive affect (PA) and anhedonia, as well as the acquisition and use of BA skills, over 
the course of treatment. We hypothesize that: 
(a) Following BA, participants will report improvements in daily PA and 
anhedonia and increased use of BA skills.  
(b) Integrating across units of analyses (i.e., neural, behavioral and self-report), 
we expect that greater pre- to post-treatment normalization of striatal and mPFC 
response, cortico-striatal connectivity, as well as PRT performance will be associated 
with greater improvements in daily reports of PA and reduced anhedonia, as well as use 
of BA skills. 
 
III. SUBJECT SELECTION 
This study will include two adolescent cohorts, and a parent for each adolescent 
participant. Rather than recruiting adolescents on the basis of DSM-defined Major 
Depressive Disorder (MDD), and in line with the NIMH RDoC initiative, the proposed 
study will recruit treatment-seeking adolescents with elevated anhedonia (as defined by 
the SHAPS) into a brief clinical trial of BA, as well as a healthy control group for 
comparison. Specifically, the two adolescent cohorts will consist of: (A) Anhedonic 
Adolescents: Adolescents who report SHAPS scores ≥ 3;  (B) Healthy Controls: 
Adolescents with no lifetime history of psychopathology and with SHAPS scores = 0. 
Finally, we also propose to include (C) one parent of each participating adolescent to 
complete questionnaires assessing their child’s, as well as their own, mental health. All 
participants will complete an initial assessment at McLean Hospital. Within the 
subsequent week, participants meeting study criteria will be invited back to the lab to 
collect fMRI data probing reward circuitry function. They will also complete a behavioral 
task (PRT) assessing reward responsiveness outside the scanner. Anhedonic adolescents 
completing BA treatment will also fill out self-report measures at the start of each therapy 
session (see Table 1). Following treatment, participants will complete a post-treatment 
assessment within 10 days of the last session, which will be identical to the pre-treatment 
session. Although not receiving BA, the healthy control participants will complete 
corresponding pre-treatment (i.e., initial) and post-treatment (i.e., final) assessments, 

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which will allow for modeling the effects of repeated scans and practice effects (e.g., on 
the PRT). In addition, a smartphone-based EMA protocol will be implemented for both 
the anhedonic sample and healthy control sample involving repeated assessments of 
positive affect (PA) and anhedonia. The EMA protocol will use a smartphone app 
(Beiwe) already approved by both the Partners IRB (protocols 2015P001303; 
2012P000890; 2015P000666) and Partners Research Information Security Office (RISO; 
see attached RISO Approval for Beiwe EMA Application). The latter app will be used for 
Android phones. For participants with iPhones, EMA data will be collected using the 
Metricwire app previously approved by RISO (see attached RISO Approval for 
Metricwire EMA Application) and the IRB (protocol 2015P001303). The schema 
outlining the assessment procedure is presented in Table 1. 
 
Adolescent Cohort 
General Inclusion Criteria: 
• Both genders, any ethnicity 
• Ages 13-18 
• English as first language or English fluency 
• Smartphone with iOS or Android platform (for EMA) 
• Healthy Control Sample: Total SHAPS score = 0; Anhedonic Sample: Total 
SHAPS score  ≥  3. The anhedonic sample must also meet criteria for elevated 
anhedonia on the K-SADS clinical interview (i.e., anhedonia item score > 1). 
 
General Exclusion Criteria: 
• History of head trauma with loss of consciousness for two minutes or more 
• History of seizure disorder  
• Serious or unstable medical illness, including cardiovascular, hepatic, renal, 
respiratory, endocrine, neurologic or hematologic disease 
• Current use of cocaine or stimulant (e.g., amphetamine, cocaine, 
methamphetamine) 
• Current use of dopaminergic drugs (including methylphenidate) 
• Clinical or laboratory evidence of hypothyroidism 
• Systemic medical or neurological illness that could impact fMRI measures of 
cerebral blood flow 
• Color blindness  
• Meet standard exclusion criteria for fMRI scanning (e.g. claustrophobia, cardiac 
pacemakers, neural pacemakers, surgically implanted metal devices, cochlear 
implants, metal braces, or other metal objects in their body); 
• Positive urine pregnancy test 
• Meets criteria for anorexia nervosa (DSM-5 diagnostic code: 307.1) or bulimia 
nervosa (DSM-5 diagnostic code: 307.51) 
 
 
 
 

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A. Anhedonic Adolescents: Anticipated enrollment = 65 
 
Additional Exclusion Criteria: 
• Subjects with suicidal ideation where outpatient BA treatment is determined 
unsafe or inappropriate by the study clinician. These patients will be immediately 
referred to appropriate clinical treatment. 
• History or current diagnosis of any of the following DSM-5 psychiatric illnesses: 
schizophrenia spectrum or other psychotic disorder, bipolar disorder, OCD, 
substance (including alcohol) use disorder within the past 12 months or lifetime 
severe substance use disorder (i.e., meeting former DSM-IV criteria for past 
substance dependence). Simple phobia, social anxiety disorder, panic disorder, 
generalized anxiety disorder, and PTSD will be allowed (unless study clinician 
determines PTSD is primary diagnosis and requires treatment prior to 
depression/anhedonia treatment). 
• Meet criteria for chronic depression (current episode > 2 years) 
• Currently receiving psychotropic treatment or psychotherapy 
• Current use of psychotropic medication with the exception of SSRIs (See section 
on Concomitant Medications (see p. 4)) 
 
 
B. Healthy Control Adolescents: Anticipated enrollment = 65 (age-matched to serve as 
healthy controls).  
 
Additional Exclusion Criteria: 
• Elevated depressive symptoms as assessed in phone screen 
• History of meeting criteria for any DSM-5 psychiatric or substance-related 
disorder 
• Current use of any psychiatric medications  
• First degree relative diagnosed with MDD, Bipolar Disorder or Psychotic 
Disorder 
 
Adult Cohort 
C. Parent: Anticipated enrollment = 70 
Inclusion Criteria: 
• English as first language or English fluency 
 
Concomitant Medications: 
 
Anhedonic adolescents being treating with any SSRI (e.g., fluoxetine (Prozac), 
fluvoxamine (Luvox), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and 
escitalopram (Lexapro)) may participate in the active treatment as long as they have not 
made a change in medication for at least 4 weeks prior to enrollment. Those who are 
being treated with any other psychiatric medications will be excluded. In order to limit 
attrition and to mirror real world clinical practice, participants will be permitted to make 

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changes in the dose of their SSRI during the course of the treatment. If a participant’s 
clinical status worsens to the degree that a new medication is necessary, the participant 
will have the opportunity to complete the BA course and scheduled assessments. 
Analyses will be conducted to determine if there are statistical differences in symptom, 
behavioral, and/or neural measurements between participants on SSRIs versus 
participants on SSRIs plus other psychiatric medications.  
 
Of note, participants’ outpatient psychiatrists will prescribe all medications and study 
personnel will play no role in medication decision-making. Moreover, participants will 
not go through any medication washout as part of this study. Participants who are 
interested in coming off a medication to enter the study will be instructed to discuss this 
with their outpatient psychiatrist. Each participant’s current medication and dosage will 
be tracked via communication with the participant’s parents, unless the participant is an 
adult (18 years old) in which case we will communicate with them directly. This practice 
is consistent with protocol 2012P001844, a study which also focuses on psychotherapy 
for depressed adolescents.  
 
 
Recruitment 
Subjects will be recruited through the following methods: 
• Fliers. Fliers will be hung on the McLean campus as well as throughout the 
greater Boston area (i.e., within a 25-mile radius of the hospital).  
• Internet advertisements. Advertisements will be posted on websites (e.g., 
Craigslist, Facebook, Nextdoor, Rally)  
• Direct mail.  
o Through a Partners-approved vendor, we will mail postcards advertising 
our study to families with adolescents between 13 and 18 years of age. 
The ad will include IRB-approved language adapted from approved study 
fliers. Furthermore, our lab will not receive any demographic information 
about the families who will receive the advertisements, as all of the 
mailing will be done through the approved vendor. Additionally, the ads 
will include the following note: “Note: You are receiving this postcard as 
part of a commercial mailing list of families with adolescents between 13-
18 in the greater Boston area.” 
o Sending a letter to “RODY Yes” patients within Research Patient Data 
Registry (RPDR)  
• Schools. When invited by school administrators, the PI will make presentations in 
schools to school administrators, teachers, and parents. Additionally, the study 
staff will provide study flyers to schools that wish to hang them in guidance 
counselor offices. These presentations and flyers will be available to schools 
within a 25-mile radius of McLean.  
 
Importantly, all study advertisements will either be directed at parents or will specify that 
parent permission is required. If an adolescent initiates contact with study staff, Dr. 
Webb/research assistant (RA) will ask to speak with a parent or ask that the parent calls 

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back to obtain verbal consent before the study is explained or the phone screen 
conducted. Participants responding to ads may either complete an online interest form on 
REDCap, a Partners secure website, or contact Dr.Webb/research assistant directly. If a 
participant contacts us via email with PHI (e.g., parent reporting that their child is 
diagnosed with – or may suffer from – a mental disorder and is seeking treatment), they 
will have to acknowledge that they understand the risks associated with receiving 
unencrypted emails which will be conveyed through the following language “The 
Partners standard is to send email securely. This requires you to initially set up and 
activate an account with a password. You can then use the password to access secure 
emails sent to you from Partners HealthCare. If you prefer, we can send you 
“unencrypted” email that is not secure and could result in the unauthorized use or 
disclosure of your information. If you want to receive communications by unencrypted 
email despite these risks, Partners HealthCare will not be held responsible. Your 
preference to receive unencrypted email will apply to emails sent from this research 
group/study only.” This same statement is also included in study consent forms. 
Alternatively, participants can choose to speak with Dr.Webb/RA over the phone where 
they can agree verbally to receive unencrypted emails. A log will be kept to document the 
agreements. For short email correspondances that lack medical information or diagnoses 
(e.g., sending confirmatory information for appointment or date/time of scheduled phone 
call), formal IRB approval is not needed 
(https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/FAQs-Email-Communication-with-Research-Participans-and-Potential-
Research-Participants.pdf). Dr. Webb/RA will provide details about the study, and if the 
parent and child are interested, they will complete a telephone screen. 
 
IV. SUBJECT ENROLLMENT 
Phone screening 
Telephone screens will be conducted by Dr. Webb or an RA trained by Dr. Webb in 
assessing depression and suicidality. The telephone screens will be conducted according 
to a script, which is included in this submission.  
 
The RA/Dr. Webb will first speak to a parent to ask about their adolescent’s health 
history and MRI safety. If the child is eligible for MRI procedures and their health history 
meets the inclusion/exclusion criteria for the adolescent cohorts, the RA/Dr. Webb will 
conduct a phone screen with the adolescent while the parent is present in the home. The 
adolescent telephone screen will assess current depressive (including anhedonic) 
symptoms. At the end of the adolescent portion of the screen, the RA/Dr. Webb will 
again speak to the parent. If the adolescent indicated an intention to harm him/herself or 
others, the RA/Dr. Webb will inform the parent and encourage the parent to seek 
immediate help. If the phone screen is being conducted by an RA, they will then request a 
phone number at which the parent can be contacted, and the RA will immediately contact 
Dr. Webb, who will take appropriate steps to contact the parent and intervene as per his 
clinical discretion. Eligible adolescents, and one of their parents, will be invited to 
McLean for initial lab-based assessments. 
 

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Consent and Assent Procedures 
At the onset of the initial assessment, eligible participants, both adolescents and parents, 
will complete appropriate assent and consent forms, respectively. When all questions and 
concerns from adolescents and parents have been addressed, adolescents and adults will 
be asked to sign the assent and consent forms, respectively. Adolescents who turn 18 
during the course of the study will be asked to sign a consent form on the first visit after 
their 18th birthday in order to continue to participate. 
 
Due to revised COVID-19 procedures, participants may elect to complete their screening 
session remotely. With the participant’s verbal consent, the research assistant will email a 
copy of the Consent/assent form(s) prior to the remote session. The research assistant and 
participant will discuss all study procedures via telephone or a Partners-issued Zoom 
account (http://pcm.partners.org/services/movi.aspx). The participant will be reminded 
they can withdraw at any time. REDCap eConsent will be used to obtain signatures and a 
signed copy will be distributed to the participant electronically according to ERIS guidance  
(https://confluence.partners.org/display/shareit/27233366/HOX07266265b398484fada0c
1b491a15c5aYOP)  
 
 
V. STUDY PROCEDURES 
A. Parent Initial Assessment – Day 1 (Approximately 1 hour) 
 
Semi-Structured Clinical Interview 
(1) 
Miniature International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) 
The MINI is a structured interview assessing for Axis I psychopathology symptoms (e.g., 
mood, anxiety, substance abuse, psychosis). Each MINI diagnostic module consists of a 
series of screening items followed by questions about specific symptomatology.  
 
Self-Report Measures 
(1) 
Beck Depression Inventory-II (BDI-II; Beck et al., 1996). The BDI-II is a 21-
question self-report inventory for measuring the severity of depression. 
(2) 
Snaith-Hamilton Pleasure Scale (SHAPS, Snaith et al., 1995). This 14-item self-
report questionnaire asks participants to rate their ability to experience pleasure when 
doing various activities. This instrument assesses hedonic capacity. 
(3) 
Temporal Enjoyment of Pleasure Scale (TEPS; Gard et al., 2006). The TEPS is an 
18-item self-report measure assessing anticipatory and consummatory aspects of pleasure 
(4) 
Positive and Negative Affect Schedule – Trait Version (PANAS; Watson et al., 
1988). The PANAS is a 20-item self-report measure that assesses positive and negative 
affect symptoms. 
(5) 
Perceived Stress Scale (PSS; Cohen et al., 1983). The PSS is a 10-item self-report 
questionnaire assessing the extent to which the participant perceives stress in his/her life. 
(6) 
Contact Information & Demographic Forms (Relating to Parent & Child)  
 
Parent-Report of Adolescent Mood and Symptoms 

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(7) 
Mood and Feelings Questionnaire – Parent Report (MFQ-PR, Angold & Costello, 
1987). The MFQ-PR is the parent analogue of the MFQ, completed by adolescent 
participants. It is a parent report of the child’s depressive symptoms. 
(8) 
Multidimensional Anxiety Scale for Children – Parent Report (MASC-PR; 
March, 1997). The MASC-PR is a 39-question parent-report inventory to assess their 
child’s anxiety symptoms. 
(9)  
Adolescent Medical History and Physical Health Form 
 
B. Adolescent Initial Assessment – Day 1 (Approximately 2 hours) 
 
Semi-Structured Clinical Interview 
(1) 
Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS; Kaufman 
et al., 1996). The K-SADS is a semi-structured diagnostic interview to assess current and 
past episodes of psychopathology in children and adolescents. The interviewer will 
record the interview using an audiotape for data coding purposes. 
(2)  
Children’s Depression Rating Scale –Revised (CDRS-R; Poznanski & Mokros, 
1996). The CDRS-R is a 17-item clinical interview tool designed to assess depression 
severity in children and adolescents. 
(3)  
Columbia Suicide Severity Rating Scale – Children’s Lifetime/Recent Version 
(C-SSRS-L/R; Posner et al., 2010). The C-SSRS-L/R assesses lifetime prevalence of 
suicidal ideation and suicidal behavior. 
 
Self-Report Measures 
(4) 
Tanner Staging Questionnaire (TSQ; Tanner & Davies, 1985). The TSQ is a 5-
item self-report measure of pubertal development. 
(5)  
Center for Epidemiological Studies Depression Scale (CES-D; Radloff 1977). The 
CES-D is a 20-item self-report scale that measures severity of depression. 
(6) 
Mood and Feelings Questionnaire (MFQ; Angold & Costello, 1987). The MFQ is 
a 30-item self-report measure assessing depressive symptoms in children. 
(7) 
Multidimensional Anxiety Scale for Children (MASC; March, 1997). The MASC 
is a 39-question self-report inventory to assess anxiety symptoms.  
(8) 
Positive and Negative Affect Schedule – Trait Version (PANAS; Watson et al., 
1988). The PANAS is a 20-item self-report measure that assesses positive and negative 
affect symptoms.  
(9) 
Snaith-Hamilton Pleasure Scale (SHAPS, Snaith et al., 1995) This 14-item self-
report questionnaire asks participants to rate their ability to experience pleasure when 
doing various activities. This instrument assesses hedonic capacity. 
(10) 
Temporal Enjoyment of Pleasure Scale (TEPS; Gard et al., 2006). The TEPS is an 
18-item self-report measure assessing anticipatory and consummatory aspects of pleasure 
(11)  
NEO Five-Factor Inventory-3 (FFI-3; Costa & McCrae, 2010) The questionnaire 
assesses the “big five” personality traits. For this study, only the neuroticism and 
extraversion questions (24 items) will be asked. 
(12)  
Cognitive Triad Inventory for Children (CTI-C; Kaslow et al., 1992). The CTI-C 
is a 36-item scale to assess the child’s negative views of self, world, and future. 

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(13)  
Children’s Depressive Experiences Questionnaire (CDEQ; Abela & Taylor, 
2003). The CDEQ is a 20-item measure to assess dependency and self-criticism. 
Participants respond with the statements “not true,” “sort of true,” or “really true” to 
statements about themselves. 
(14) 
Children’s Response Styles Questionnaire (CRSQ; Abela et al., 2002). The CRSQ 
is a 25-item questionnaire, which asks participants to answer questions about how they 
would respond to depressive symptoms (i.e., using ruminative, distraction, or problem-
solving strategies). 
(15) 
Adolescent Cognitive Style Questionnaire (ACSQ; Hankin & Abramson, 2002). 
The ACSQ assesses cognitive vulnerability to depression using adolescent-specific 
hypothetical situations. The participant rates the extent to which the causes of each of 
these situations are internal, stable, global, due to flaws in the self, and likely to result in 
negative consequences. 
(16) 
Perceived Stress Scale (PSS; Cohen et al., 1983). The PSS is a 10-item self-report 
questionnaire assessing the extent to which the participant perceives stress in his/her life. 
(17) 
Adolescent Life Event Questionnaire – Revised (ALEQ-R; Hankin & Abramson, 
2002). The ALEQ-R is a 57-item self-report questionnaire that asks participants about 
negative life events that have occurred in the previous week. 
(18)     Perceived Criticism Scale (PCS; Renshaw, 2008). The PCS consists of 4 items 
assessing perceived criticism from a parent. 
 
Mock fMRI Scan 
(18) 
Mock Scan Procedure. Each child will receive a “mock scan” that simulates the 
conditions of the actual scanner at the McLean Brain Imaging Center. In particular, 
adolescents will experience the sounds (i.e., repetitive metallic thumping), feel (i.e., 
enclosed within the scanner head coil), and sights (i.e., will see what fMRI equipment 
looks like). During the process, participants will be trained to limit movement. In the 
event that the mock scanner is out of commission, participants will be prepped in detail 
with a description of the sounds (i.e., repetitive metallic thumping), feel (i.e., enclosed 
within the scanner head coil), and sights (i.e., will see what fMRI equipment looks like) 
of the MRI. In addition to habituating to the scan environment, participants will also have 
an opportunity to ask questions about the process. Any and all questions will be 
addressed openly and honestly. Finally, in preparation for the MRI session, participants 
will complete a practice run of the fMRI tasks (see below).  
 
C. Adolescent MRI Session – Day 2 (Approximately 2 hours) 
Adolescent participants satisfying applicable inclusion and exclusion criteria (see above) 
will be invited to return to the McLean Brain Imaging Center. Entry into the scanner 
environment is contingent upon successful completion of an MRI safety form and a 
negative urine pregnancy screen for females. In addition, given the abovementioned 
substance use exclusion criteria, urine screens will be conducted for both male and 
female participants to test for current drug use. All imaging will be performed on the 
McLean Hospital Brain Imaging Center Siemens 3-Tesla (3T) Prisma scanner with a TIM 
upgrade.  A 32-channel head coil will be used in order to improve the ratio of signal to 
noise.  The entire imaging procedures are expected to last approximately 60-90 minutes. 

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 Self-Report Measures and Behavioral Task Prior to the Scanner 
 
Self-Report (see pg. 6-7 for descriptions for 1-4): 
(1) 
CES-D 
(2) 
MFQ 
(3) 
SHAPS 
(4) 
PANAS-State Version 
(5) 
EMA PANAS Forecasting 
 
Behavioral Task 
Probabilistic Reward Task (PRT; Pizzagalli et al., 2005). The PRT is a behavioral 
reinforcement computer-based task examining reward learning in relation to depressive, 
particularly anhedonic, symptoms. Specifically, participants are instructed that the aim of 
the task is to earn as much money as possible. The task consists of 200 trials, divided into 
2 blocks of 100 trials, with blocks separated by a 30-sec break. Each trial will start with 
the presentation of an asterisk for 500 msec in the middle of the screen that serves as a 
fixation point (see below). After 500 msec, a mouthless cartoon face will be presented in 
the center of the screen. After a delay of 500 msec, either a short mouth (11.5 mm) or a 
long mouth (13 mm) will be presented for 100 msec. The face without the mouth will 
remain on the screen until a key response is made. Participants are asked to identify 
which type of mouth was presented by pressing either the “z” key or the “/” key on the 
keyboard (counterbalanced across subjects). For each block, the long and short mouths 
will presented equally often in a pseudorandomized sequence, with the constraint that no 
more than three instances of the same stimulus will be presented consecutively.  
Participants will earn $15.80-$16.20. 
 
Structural MR Imaging 
All subjects will undergo an anatomic MRI protocol, which is a standard set of structural 
MRI images acquired in the axial and coronal planes.  This initial MRI screening/data 
collection will be conducted using the 3 Tesla whole-body clinical MR scanner.  
Structural data will be utilized in three ways; to ensure specific regions of interest are 
visible and localized for correlation with MR data, to ensure subjects are free of 
significant clinical abnormalities, and for potential morphometric analyses.  All structural 
scans will be read and interpreted by a clinical neuroradiologist; in the event that a 
clinical abnormality is detected, the subject will be contacted and their primary care 
physician will be notified.  Structural scanning takes approximately 10 minutes. 
 
Resting State Data Collection 
A brief 6-minute resting state (no task) fMRI scan will be completed by all subjects.  This 
short scanning sequence will be used to assess brain connectivity patterns in the default-
mode network linked to depressive/anhedonic symptoms. fMRI images will be acquired 
using an EPI BOLD sequence with the following parameters: TR=2500 ms, TE=30 ms, 
FOV=224 mm, flip angle=82 degrees, matrix=64x64x40, slice thickness=3.5mm with 3.5 
mm3 isotropic voxels. 

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fMRI Reward Task 
(1) We will use an fMRI card-guessing paradigm commonly employed in depressed and 
healthy adolescents to probe striatal and mPFC activation (e.g., Forbes et al., 2009; Olino 
et al., 2011). Each trial includes both an anticipation period and an outcome period, and 
participants receive win, loss, or no-change feedback for each trial. Participants are told 
that their performance determines a monetary reward to be received after the scan. Trials 
are presented in pseudorandom order with predetermined outcomes. During each 27-sec 
trial, participants have 3 seconds to guess, via buttonpress, whether the value of a visually 
presented card with a possible value of 1–9 is higher or lower than 5. After a choice is 
made, the trial type (reward or loss) is presented visually for 12 seconds (anticipation). 
This is followed by the “actual” numerical value of the card (500 ms), outcome feedback 
(a green upward-facing arrow for win, a red downward-facing arrow for loss, or a yellow 
circle for neutral feedback; 500 ms), and a crosshair presented for 11 seconds (outcome). 
There are no trials involving anticipation of a neutral outcome. That is, neutral feedback 
trials are those with no-win or no-loss outcomes (i.e., no monetary increase or decrease). 
Trials are presented in four runs, with 12 trials per run and a balanced number of trial 
types within runs (i.e., 6 possible-win and 6 possible-loss trials, with a total of three win, 
three loss, and three neutral outcomes). Participants are told that they will receive $1 for 
each win, lose 50 cents for each loss, and experience no change in earnings for neutral 
outcomes. Participants are unaware of the fixed outcome probabilities and are led to 
believe that their performance will determine net monetary gain. All participants will be 
compensated $15 for playing “the money game.” The task takes 23 minutes. 
 
(2) Self-Referent Encoding Task (SRET; Gotlib et al., 2004). The SRET is an information 
processing task that has participants encode and recall adjectives while fMRI data is 
being obtained. We will use 22 depressotypic, 22 socially threatening, and 22 physically 
threatening words. To balance the number of negative and positive words, we used 50 
positive words. Examples of the words include “loving” for the positive category, “sad” 
for the sad emotion category, “teased” for the social threat category, and “choking” for 
the physical threat category. All words will be presented on a computer monitor, and at 
the conclusion of the task, subjects will be asked to recall adjectives presented on the 
screen. The task takes approximately 10 minutes. 
Following the fMRI session we will re-administer the PANAS-State Version. 
 
Sustained Attention to Response Task (SART; Van Schie et al., 2012). In the sustained 
attention to response task (SART; Van Schie et al., 2012), participants are instructed to press the 
spacebar as fast and accurately possible when frequent non-targets (numbers 0-2; 4-9) are 
presented on a computer screen, and to withhold response to an infrequent target (number ‘3’). 
Performance is assessed with RT and errors. A total of 72 targets (on 1040 trials) are randomly 
presented within four blocks of 5 mins each. In addition, 4 probe questions appear (after each 
block) to inquire about mind-wandering: Participants indicate if just prior to the probe, they were 
a) on-task, b) off-task because of an external distraction (e.g., noise), or c) had a task-unrelated 
thought. The frequency (%) of each category is calculated. 
 

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This SART task will allow us to collect important preliminary data on the relationship between 
sustained attention and depressive symptoms (including anhedonia). In addition, the K23 study 
includes EMA measures of rumination and mind-wandering. We wish to test the relation between 
ecologically valid (EMA) measures of rumination/mind-wandering (both linked to depression) 
and sustained attention on a computerized performance task. 
 
 
D. Parent Behavioral Task and Self-Report (Approximately 1 hour) 
 
While the child is completing their questionnaire and the behavioral task (PRT). The 
Parent will complete the BDI-II, SHAPS, PANAS and MFQ-PR. In addition, they will 
complete the PRT. 
 
E. Behavioral Activation (BA) Treatment with Anhedonic Adolescents: 
Paralleling a previously approved protocol (2012P001844), anhedonic adolescents will 
receive 12, 50-minute BA sessions. The study will be embedded within a 12-week 
protocol of BA, implemented following two treatment manuals (Martell et al., 2013; 
McCauley et al., 2015) co-authored by Dr. Sona Dimidjian, Ph.D. (consultant). The 
manuals provide detailed instructions regarding how to administer specific BA 
procedures and techniques, while providing sufficient flexibility for therapists to adapt 
treatment to the idiosyncratic needs of patients. As some 18-year-old participants may no 
longer live at home, 18-year-old (adult) participants who do not live with their parents 
can do therapy on their own without parent involvement. 
 
During the course of treatment, adolescents will complete self-report measures prior to 
selected therapy sessions (see Table 1 for schedule of MFQ, CES-D, SHAPS MASC, 
WAI-S-C, PSS assessments). Additionally, prior to selected sessions, the study clinicians 
will complete measures of depression severity (CDRS-R) and the therapeutic alliance 
(WAI-S-T). Similar to the abovementioned approved protocol (2012P001844), all 
sessions will be videotaped to assess therapist adherence to the BA treatment manual as 
well as competence. All participants will consent to videotaping before beginning the 
study and will be free to leave the study at any time if they are uncomfortable being 
filmed (see attached consent forms). If a participant does not attend a scheduled session, 
the study clinician will contact the participant’s parent (if the participant is a minor) or 
the participant directly (if they are 18). If the study clinician leaves a message and the 
parent or participant does not respond within 24 hours, a second attempt will be made. 
All attempts to contact parents and subjects about missed sessions will be documented. If 
the schedule permits, the therapist will attempt to reschedule the session. 
 
BA sessions will be conducted by Dr. Christian Webb (Ph.D. in clinical psychology), or 
clinical psychology Ph.D. students from McLean Hospital’s psychology internship 
program. The internship program is co-directed by Dr. Throstur Björgvinsson, Ph.D., 
ABPP (consultant), who will provide weekly supervision on treatment implementation 
and supervision of study therapists, supplemented with monthly phone meetings with Dr. 
Dimidjian. Importantly, the internship is based in the Behavioral Health Partial Program 

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(BHPP) at McLean Hospital (Director: Dr. Björgvinsson), and rooted in CBT and BA 
delivered in group and individual therapy formats. Before administering treatment, 
clinicians will complete a 20-hour training and will receive weekly supervision from Dr. 
Webb. Dr. Webb currently serves as a study therapist and group supervisor for the 
abovementioned approved clinical trial of treatment study for depressed adolescents 
(2012P001844). As in the latter trial, clinical psychology Ph.D. students completing 
clinical practica in the BHPP may also serve as study therapists.  
 
 
All study staff assessing depression and suicidality will be trained by Dr. Webb.  Dr. 
Webb has received extensive training in conducting interviews using the K-SADS, CDRS 
MINI, and CSSRS.  During the last 9 years, Dr. Webb has utilized all assessment tools in 
completing large-scale studies. Further, Dr. Webb has provided extensive training and 
supervision for study staff/diagnosticians conducting these interviews. Dr. Webb will 
provide 40 hours of didactic and practical training for all study staff that will conduct 
interviews. Included in this instruction is the assessment of both depressive symptoms 
and suicidality.  Particular attention will be paid to delineating the differences between 
passive suicidal ideation and intent to self-harm.  Additionally, all diagnostic interviews 
will be audiotaped (in contrast to therapy sessions, which will be videotaped) and 
reviewed in order to ensure reliability of diagnoses and assessment. 
Self-Report Process Measures (completed by adolescents at selected therapy sessions): 
(1) Credibility/Expectancy Questionnaire (CEQ; Devilly & Borkovec, 2000). The 
CEQ is a 6-item self-report measure assessing subjects’ perception of the credibility of 
treatment and their expectations of symptom improvement. Participants will complete 
this measure only at the start of session 1. 
(2) Working Alliance Inventory – Short Client Version (WAI-S-C; Horvath & 
Greenberg, 1986). The WAI-S-C is a 12-item self-report measure assessing subjects’ 
perception of the quality of the therapeutic alliance between themselves and their 
(individual or group) therapist. 
(3) Five Facet Mindfulness Questionniare – Short Form (FFMQ-SF; Bohlmeijer et 
al., 2011). The FFMQ is a measure is an abbreviated 24-item measure assessing mindful 
awareness of and engagement with the present moment. 
(4) Behavioral Activation for Depression Scale – Short Form (BADS-SF; Kanter et 
al. 2012). The BADS is a brief 9-item measure designed to assess the acquisition and use 
of behavioral activation skills. 
(5) CES-D (see pg. 6) 
(6) MFQ (see pg. 6) 
(7) SHAPS (see pg. 6) 
(8) MASC (see pg. 6) 
(9) PSS (see pg. 7) 
Clinician-Report Process Measures (completed by study clinicians at selected therapy 
sessions): 

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(1) Children’s Global Assessment Scale (CGAS; Shaffer et al., 1983). The CGAS is a 
single-item clinician report of a child’s overall functioning rated on a scale of 1-100. 
(2) Clinical Global Impression (CGI; Rush et al., 2000). The CGI is a 2-item measure 
of a mental health subject’s current illness severity and improvement over the course of 
treatment. 
(3) Working Alliance Inventory – Short Therapist Version (WAI-S-T; Horvath & 
Greenberg, 1986). The WAI-S-T is a 12-item measure assessing the therapist’s 
perception of the quality of the therapeutic alliance between the subject and clinician. 
(4) Columbia Suicide Severity Rating Scale – Children’s Since Last Visit Version (C-
SSRS-SLV; Posner et al., 2010). The C-SSRS-SLV assesses the prevalence of suicidal 
ideation and suicidal behavior since the last such assessment. 
 (5) CDRS-R (see pg. 6) 
 
Table 1: Assessment Schedule for Anhedonic Adolescents Completing BA 
Table 1. 
Instrument 
Treatment Sessions (Weeks) 
 
Pre 
I 
Pre 
II 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Post 
K-SADS-PL 
C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSQ 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CEQ 
 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
NEO-FFI-3 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
PANAS 
A 
A 
 
 
 
 
 
 
 
 
 
 
 
 
A 
CRSQ 
A 
 
 
 
 
A 
 
 
 
A 
 
 
 
 
A 
ACSQ 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
CTI-C 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
CDEQ 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
ALEQ-R 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
TEPS 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
SHAPS 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
CES-D 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
MFQ 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
C-SSRS-SLV 
C 
 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
CDRS-R 
C 
 
 
 
C 
 
 
C 
 
 
C 
 
 
 
C 
MASC 
A 
 
 
 
A 
 
 
A 
 
 
A 
 
 
 
A 
PSS 
A 
 
 
 
A 
 
 
A 
 
 
A 
 
 
 
A 
FFMQ 
A 
 
 
 
A 
 
 
A 
 
 
A 
 
 
 
A 
BADS 
A 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
PCS 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 
CGAS/CGI 
 
 
C 
 
 
 
 
 
 
 
 
 
 
C 
 
WAI-S-C 
 
 
A 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
WAI-S-T 
 
 
C 
 
C 
 
 
C 
 
 
C 
 
 
C 
 
EMA Forecasting  
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
A 
Neuroimaging (fMRI) 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
A 

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Ecological Momentary Assessement (EMA) 
Consistent with prior research implementing EMA with depressed and healthy 
adolescents by the secondary mentor (Dr. Forbes) and her colleagues (Forbes et al., 
2012), EMA data will be collected over the course of ten 5-day blocks (Thursday-
Monday) distributed over the course of the 12-week BA trial, beginning the week 
following the initial MRI session (Day 2). Prior research from Dr. Forbes’ laboratory 
indicates that collecting EMA data Thursday-Monday is a preferable assessment time 
window for several reasons (e.g., samples time intervals when freedom and behavioral 
choice are most variable [i.e., after school and on weekends] as well as sampling some 
behavior within the structure of the school schedule for comparison). There will be 2 
EMA assessments per day on weekdays and 3 per day on weekends, via smartphone 
alerts signaling self-report items to complete. The EMA assessments will occur between 
4pm Thursday and 9pm Monday at specified time windows distributed throughout each 
day (e.g., 4–7pm). No contact will be made during school hours or between the hours of 
10pm and 11am. At each EMA timepoint, an alert will be sent to the participant’s 
smartphone (iPhone or Android) and they will be instructed to answer questions 
regarding current affect, anhedonia, stress, cognitions and recent activites. In addition, the 
smartphone application also will collect data on the participant’s usage of their phone 
(e.g., time and length of calls and texts, GPS location, movement of the phone; For 
details, see attached Smartphone EMA Data Collection). EMA data collected from 
Android phones will use the Beiwi application (“app”) designed by Jukka-Pekka “JP” 
Onnela, D.Sc. at the Harvard T.H. Chan School of Public Health (Dr. Onnela has a 
previous Partners IRB-approved protocol [#2015P000666] using the Beiwi app to collect 
the same EMA/passive data as proposed in this study. Other recently Partners-approved 
protocols using the Beiwe app include 2015P001303 and 2012P000890). EMA data 
collected from iPhones will use the MetricWire app (previously approved by the IRB: 
protocol 2015P001303). Data collected by both apps are encrypted on the phones and 
uploaded to a secure server (using HIPAA compliant software which has been reviewed 
and approved by Partners RISO) and downloaded by the researcher to the local research 
server in a de-identified format (i.e., subject ID number). At the end of the MRI session, 
the researcher will guide the participant in downloading the app to the participant’s 
smartphone. The researcher will provide orientation to the app and answer any questions 
regarding the EMA assessments and data collected (see attached Smartphone EMA 
Information Sheet, which will be provided to participants). 
 
Participants will be contacted at regular intervals to ensure high EMA 
completion. 
 
 
Behavioral task (PRT) 
 
A 
 
 
 
 
 
 
 
 
 
 
 
 
A 
Ecological Momentary 
Assessment (EMA)† 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
A 
Note. Pre=Pretreatment; Post=Posttreatment; A=Adolescent; C=Clinician. Anhedonic participants complete all 
assessments; Healthy Control participants complete pre- and post-treatment assessments (and EMA). 

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F. Post-Treatment Adolescent Assessment (Approximately 3 hours): 
Within 10 days of the final BA session, anhedonic participants will return for a post-
treatment assessment lasting approximately 3 hours. Healthy control participants will also 
complete the same assessment 12-13 weeks after their initial assessment. Adolescents 
will be asked to complete self-report measures assessing symptoms/affect (MFQ, CES-D, 
SHAPS,  TEPS, MASC, PANAS), stress (PSS, ALEQ-R), cognitive vulnerability (CTI-
C, CRSQ, ACSQ), interpersonal vulnerability (CDEQ), personality (NEO-FFI-3), and 
EMA PANAS Forecasting. Adolescents will aslo complete the same fMRI task and the 
PRT task as completed at the pretreatment/baseline assessment. 
Parents will complete the same self-report (BDI-II, SHAPS, TEPS, PANAS, PSS) and 
parent-report measures (MFQ-PR, MASC-PR) as they completed at the initial 
assessment.  
 
Debriefing for Active Treatment Cohort and Their Parents: 
Within one week of concluding post-treatment study session, the treatment group subject 
and parents will be debriefed. Specifically, the subject and parents will receive a 
summary including: (a) pre- and post-treatment diagnosis, (b) pre- and post-treatment 
changes in depressive and anxious symptoms, (c) recommendations for treatment moving 
forward (if necessary), and (d) a list of clinical resources in the greater Boston 
community if family is interested and/or would benefit from continuing treatment.  
Debriefing for All Subjects 
Following the final assessment, all subjects will be debriefed regarding the two monetary 
reward tasks (i.e, fMRI reward task and the PRT). Specifically, (s)he will outline the 
purpose of the study and explain the purposes of the scans and tasks. The study staff 
member will explain the differential reinforcement schedule utilized in the PRT. They 
will explain the partial contingency between the accuracy of the subject’s choices and 
his/her likelihood of receiving positive feedback, and the rationale for use of this 
paradigm. Similarly, study staff will explain the our interest in probing reward-circuitry 
function during reward anticipation and outcome (i.e., wins, losses, neutral outcomes) for 
the fMRI task. 
G. Follow-up Assessments 
The anhedonic participants completing the BA treatment and the healthy control 
participants will complete follow-up assessments at 3-, 6- and 12- months post-treatment, 
and these assessments will be conducted using REDCap, a secure, Partners-approved tool 
for collecting participant data. During the and 3- and 6-month follow-up assessments, the 
adolescents will be asked to complete self-report symptom measures (CES-D, MFQ, 
SHAPS, TEPS, PANAS, MASC, PSS, ALEQ-R), which will necessitate approximately 
20 minutes. The participating parent will be asked to complete self-report measures 
(BDI-II, SHAPS, TEPS, PANAS, PSS) and a parent-report measure of their child’s 
symptoms (MFQ-PR, MASC-PR). At the 12-month follow-up assessment, adolescents 

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and their parents will complete the above measures, and adolescents will also complete 
additional measures examining cognitive and interpersonal vulnerability (CTI-C, CDEQ, 
CRSQ, ACSQ) necessitating approximately 25 minutes. In addition, in order to assess for 
any changes in diagnoses during the follow-up phase, the K-SADS (including full 
depression module) will be completed over the phone with anhedonic participants at the 
6- and 12-month assessments. Just the depression and anxiety disorder modules of the K-
SADS will be completed over the phone with healthy participants at the 6- and 12-month 
assessments.  Study staff will schedule these assessments at a time when both the parent 
and participating teen will be at home, and staff will speak to the parent before and after 
speaking with the adolescent. 
After completing the 12-month follow-up, participants will be added to an email list to 
receive a quarterly lab newsletter, which will communicate results from our research to 
participating families. Past participants may opt out of receiving this newsletter at any 
time. 
VI. BIOSTATISTICAL ANALYSIS 
Data from this study will consist of demographic information, semi-structured clinical 
interviews (K-SADS, MINI), adolescent self-report symptom measures (MFQ, CES-D, 
SHAPS, TEPS, MASC, PANAS), parent self-report measures (BDI-II, SHAPS, TEPS, 
PANAS, PSS), cognitive vulnerability measures (CRSQ, ACSQ, CTI-C), an 
interpersonal vulnerability measure (CDEQ), stress measures (ALEQ-R, PSS), a 
personality measure (NEO-FFI-3), EMA data, behavioral data (PRT), and MR/fMRI 
data. 
 
Sample Size 
The adolescent portion of the study includes the following cohorts: (a) 35 anhedonic 
adolescents receiving BA and (b) 35 healthy control adolescents. The primary aim is to 
examine whether anhedonic and healthy adolescents differ on baseline neural (fMRI), 
behavioral (PRT) and self-report (EMA) measures of reward function, as well as whether 
behavioral and neural mechanisms prospectively predict and mediate symptom 
improvement among anhedonic adolescents receiving BA. Importantly, within the active 
treatment cohort, analyses will be conducted to determine if there are statistical 
differences in symptom, behavioral, and/or neural measurements between medicated and 
non-medicated depressed adolescents. Additional analyses will examine if there are 
statistical differences between participants on SSRIs versus participants on SSRIs plus 
other psychiatric medications. 
Descriptive and Exploratory Analyses: 
Descriptive statistics and exploratory graphical techniques, such as frequencies, means, 
medians, histograms, and box plots will be used to assess skewness and/or outliers in the 
data. Continuous/quantitative variables will be appropriately transformed when 
necessary, e.g., via log transformation for positively skewed distributions.  For outcomes 
acquired during treatment, the analytical approach will address the type of outcome, as 
well as accommodating the within-individual correlation due to repeated assessments.  In 

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addition, the results will be assessed for sensitivity to dropouts or missing data.  The 
primary analysis will be an intent-to-treat analysis, which includes all subjects.  Of note, 
attempts will be made to continue assessing subjects even if they drop out of treatment. 
Behavioral Variables:  
For the PRT, the primary variable of interest will be Reward Learning, operationalized as 
the increase in response bias (RB) scores from Block 1 to Block 3 [DRB = RB(Block 3) - 
RB(Block 1)]. This variable was selected because it has been repeatedly linked to current 
and future anhedonic symptoms (Pizzagalli et al. 2005; 2008). 
 
EMA-Derived Variables: 
For EMA, the primary variables of interest will be scores on the positive/negative affect 
and anhedonia items over the assessment periods. In addition, passive accelerometer data 
from the Beiwe app will provide data on amount of movement per day, which will be 
used to predict changes in self-reported affect and depressive symptoms. Given the 
longitudinal (i.e., repeated waves of EMA data) and hierarchical (i.e., assessment 
timepoints nested within individuals) structure of the data to be collected, Growth Curve 
Modeling (GCM) will be used to analyse EMA data (see Statistics below). 
 
fMRI Processing:  
fMRI: Gradient echo T2*-weighted echoplanar images will be acquired using the 
University of Minnesota multi-band BOLD EPI sequence (Feinberg et al., 2010; Moeller 
et al., 2010; Xu et al., 2013), which achieves excellent temporal and spatial resolution 
(TR/TE: 1300/35ms; FOV: 224 mm; matrix: 64X64; 78 slices; in-plane resolution: 2mm; 
voxels 2 x 2 x 2mm, multiband factor of 6). The EPI acquisition will use prospective 
motion correction to minimize the effects of subject motion. Analyses will be conducted 
using SPM8 and FreeSurfer (Fischl et al., 2002). Pre-processing will include 
motion/slice-time correction, removal of slow linear trends, intensity normalization, and 
spatial smoothing (6-mm). 
 
Statistics: 
GCM will be used to test the hypothesis that pretreatment reward dysfunction (fMRI, 
PRT, EMA), controlling for overall pretreatment levels of depressive symptoms (BDI), 
will predict anhedonic (SHAPS) symptom improvement over the course of BA. Given 
our multimodal assessment of reward system dysfunction, pretreatment predictors will 
include: (1) self-reported anhedonia (i.e., baseline EMA), 2) neural (i.e., striatal and 
mPFC) response to monetary rewards on the fMRI reward task and (3) reward learning 
scores on the PRT. The dependent variable in these analyses will be anhedonic (SHAPS) 
symptom improvement. GCM is well-suited for handling repeated symptom assessments 
over time (i.e., session-to-session SHAPS scores), as well as accommodating missing 
observations in longitudinal datasets. 
 
With regards to fMRI analyses, data will be analyzed using an ROI approach to evaluate 
a priori hypotheses, followed by a whole-brain analysis to test regional specificity of 
findings. In the first approach, regression coefficients (“beta weights”) will be extracted 

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from ROIs obtained from FreeSurfer’s parcellation. Informed by the relevant literature, 
and consistent with reward circuitry hypotheses, ROIs will include striatal (NAc, 
putamen, caudate) and cortical (mPFC) regions. For each subject and ROI, results of one-
sample t tests (reward feedback > baseline) will be extracted for inclusion in growth 
models estimating SHAPS improvement. In the second approach, whole-brain analyses 
will be run predicting SHAPS improvement. For these analyses, each subject’s data will 
first be re-sampled into Talairach space and random effects analyses will be conducted.  
 
GCM will also be implemented to test the hypothesis that greater pre- to post-treatment 
normalization in neural (i.e., striatal and mPFC response to fMRI task) and behavioral 
(i.e., reward learning on PRT) responsiveness will be associated with greater anhedonic 
symptom improvement over the course of BA treatment. For fMRI analyses, for each of 
the above ROIs and consistent with prior work (Dichter et al., 2009), a Group (AH, HC) 
X Time (Pre-, Post-treatment) X Condition (Monetary Gains, Monetary Losses) 
interaction will be tested. For significant ROIs, pre- to post-treatment change in ROI 
activation will be entered as predictor variables in growth models estimating SHAPS 
improvement. For the behavioral (PRT) analyses, a Group (AH, HC) X Time (Pre-, Post-
treatment) interaction will be tested, followed by correlations between reward learning 
scores and anhedonic (SHAPS) symptom change. 
 
VII.  RISKS AND DISCOMFORTS  
(a) Privacy. A potential risk is a breach of confidentiality. To protect against the loss of 
confidentiality, we will keep all study data locked in a separate file, coded by a unique 
study code number (with names and other personal identifying information kept 
separately).  Further, the consent and assent forms will clearly inform subjects of the 
limits of confidentiality, including the circumstances in which confidentiality may be 
breached such as in cases of suspected child abuse or neglect and dangerousness to self or 
others.  
 
(b) Discomfort. In the event that participants experience discomfort when completing the 
study questionnaires or experimental tasks, they can refuse (a) to answer any questions 
and/or (b) to complete any tasks that make them uncomfortable.  Further, all participants 
may choose to discontinue an assessment session at any time, or, if they wish, to 
withdraw from the study. This will be explained in the informed consent and assent forms 
as well as reiterated orally prior to the onset of the assessment. 
 
(c) Clinical Risk: Adolescents. As in any study examining depressive symptoms, there 
includes the possibility that subjects may experience dangerous or suicidal thoughts. 
(Note that in the current study, the “anhedonic adolescents” cohort is being recruited on 
the basis of elevated anhedonic [SHAPS] symptoms, and are not required to meet DSM 
criteria for Major Depressive Disorder (MDD). MDD is neither an inclusion nor 
exclusion criteria). We do not anticipate that our study procedures will increase suicidal 
risk, but there is a risk that this could occur during the study period. In order to 
effectively monitor and address this issue, this study will employ the same suicidality 
protocol that has been approved by the McLean and Partners IRB for previous studies of 

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this population. If an adolescent indicates intent to harm themselves or others during the 
phone screen, the study staff member conducting the call will inform the parent and 
suggest that they seek immediate help. The staff member will then contact the PI or the 
covering clinician, who will follow up with the parent per their clinical discretion. All 
anhedonic participants receiving BA will complete self-report questionnaires of 
depression, which include items assessing suicidality, as well as a clinician-administered 
suicidality scale, prior to the weekly session, which clinicians will review before 
commencing the session. If an individual endorses increased suicidal thoughts, an 
appropriate clinical recommendation will be made and appropriate actions taken, if 
necessary; this could involve treatment either at McLean Hospital or elsewhere. 
 
In addition, following the completion of every EMA smarphone survey, the following 
message appears on the screen:  “Thank you for completing the survey.  Don’t forget, no 
clinician will see your answers.  So, if you need help or you’re thinking about harming 
yourself, immediately tell your parent, a trusted adult (e.g., teacher, school counselor), 
call 911, or page Dr. Webb (617-855-2000).  
 
(d) Clinical Risk: Adults. Adult participants (i.e., parents of anhedonic and non-anhedonic 
adolescents) will be reminded that they can discontinue an assessment at any time. If an 
adult participant indicates an intention to harm him/herself or others during any portion 
of the study, staff will encourage him/her to seek immediate clinical attention, and Dr. 
Webb will follow up per his clinical discretion. Additionally, study staff will offer to 
provide lists of local resources to any participant indicating elevated symptoms. 
(e) Medication Washout: As has been approved by the McLean/Partners IRB in previous 
studies, individuals who have used medication to treat depression in the past may be 
included in the study if there is an absence of the following psychotropic medications: 8 
weeks for fluoxetine, 4 weeks for neuroleptics, 8 weeks for benzodiazepines, 6 weeks any 
other antidepressants. When individuals contact the laboratory for the initial screening 
and indicate current use of medication to treat depression (see exception pp. 4-5 SSRIs), 
they will not be eligible to participate in the study. In light of these guidelines, no 
medication washout period is permitted. These details are delineated in the applicable 
informed consent form. 
(f) Medication Use: Depressed adolescents endorsing current use of SSRIs may 
participate in the active treatment if they have remained on the same type of SSRI for at 
least 4 weeks. During the course of the treatment, SSRI dose changes are permissible. 
Medication will be prescribed through an outside treater, not affiliated with the study. If 
during the course of the treatment, an adolescent is prescribed medication included in the 
exclusion criteria, the adolescent may complete the entire BA course. Participants will 
continue to complete scheduled assessments as outlined above. 
(g) MRI. The study will be conducted in an MRI scanner approved for routine clinical 
studies in children or adults by the FDA.  Although there are no known risks from these 
scans, there could be adverse effects that are delayed or very mild, such that they have not 

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yet been recognized.  Most people experience no ill effects from these scans, but some 
people do report claustrophobia (fear of being in enclosed small spaces), dizziness, mild 
nausea, headaches, a metallic taste in their mouth, double vision, or sensation of flashing 
lights.  These symptoms, if present, disappear shortly after leaving the scanner. 
 
a) Implants/Prostheses:  The magnetic field of the scanner exerts a force on 
ferromagnetic objects within the field.  This force can cause a ferromagnetic implant, 
such as some brands of aneurysm clips, surgical clips, or prostheses, to move or be 
displaced and cause injury or death.  If the implant is both large and ferromagnetic, 
sufficient currents can be induced in the metal by the magnetic field to cause heating 
of the implant. Individuals with any such devices will be excluded from enrolling in 
the study. 
 
b) Pregnancy:  The safety of the 3.0T MRI scanner for imaging embryos/fetuses has 
not been clearly established.  Therefore, individuals who are pregnant or who are of 
unknown pregnancy status will be excluded. All participants are required to take a 
pregnancy test before entering the scanner environment.  
 
c) Collision Hazard: The magnetic field near the scanner is strong enough to attract 
ferromagnetic objects with great force.  Near the magnet this force can be strong 
enough to pull objects in and cause them to fly down the axis of the magnet.  Such 
objects become projectiles that can cause injury or death.  A security zone has been 
established to prevent ferromagnetic objects from coming into proximity of the 
magnet. The likelihood of a collision in the context of the present experiment is 
thought to be low, much lower than the likelihood in clinical practice. 
 
d) Radio Frequency (RF) and Magnetic Field Interference: Implants electronic 
devices, such as cardiac pacemakers and cochlear implants, may be susceptible to 
interference from the magnetic and RF fields produced by the scanner.  This 
interference may destroy or adversely affect operation of these devices.  Since 
interference to cardiac pacemakers is observed in magnetic fields as low as 13 gauss, 
means have been provided to prevent persons with cardiac pacemakers or other 
implanted electronic devices from entering a zone where the magnetic field exceeds 5 
gauss. Individuals with such devices will be excluded from the study. 
 
e) RF Antenna Effects: If metal wires or electrodes, such as electrocardiograph leads, 
are attached to the subject during imaging, the RF energy radiated by the transmission 
coils of the scanner can induce sufficient electrical currents in the lead wires to cause 
burns where the electrodes or wires contact the skin.  No such leads or wires will be 
employed in the present experiment. 
 
f) Biomagnetic Hazards: It is possible that subtle genetic or molecular changes could 
be caused by the magnetic fields produced by the MR system.  To date, however, no 
harmful biological effects have been demonstrated at the magnetic field strengths and 

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exposure times utilized by the scanner.  At the present time, the likelihood of any 
significant adverse biomagnetic effect is considered to be very low. 
 
g) Clinical Hazards: The confining conditions of the MRI system can precipitate 
claustrophobia in a subject.  Subjects will be screened for possible claustrophobia 
before they are enrolled in the study. 
 
h) Access to MRI Area: Access to all areas exceeding the 5 gauss level will be 
controlled by warning signs, barriers, staffed entry locations, and adequate 
interrogation to assure avoidance of incidents. Access to the magnet room by any 
personnel will be closely controlled for safety of persons, in particular to prevent 
accidental introduction of ferromagnetic objects that could be attracted by the 
magnetic field generated by the MRI system. 
 
(h)  EMA Data Security: Data collected by the EMA app (Beiwe) are encrypted on the 
phones and uploaded to a secure server (using HIPPAA compliant software). These data 
are downloaded by the researcher to the local research server in a de-identified format 
(i.e., under subject ID number). The same password-protections and encryptions 
described above for all other data will also apply to EMA data. 
 
(i) Treatment: If after enrolling in the study, an active treatment participant begins 
medication included in the exclusion criteria, he/she will not be removed from the study. 
Rather, the participant may complete the treatment and study. Medication changes will be 
tracked throughout the course of the study by the BA therapist. 
VIII. POTENTIAL BENEFITS 
Short-Term. The potential benefits of BA are for anhedonic adolescents to experience 
improvement in their anhedonic/depressive symptoms and improved reward system 
functioning (Dichter et al., 2009).  
 
Long-Term. Participants in the current study may potentially experience remittance of 
anhedonic/depressive symptoms, and further, these may contribute to improvement with 
(a) academic performance, (b) social involvement in recreational activities, (c) improved 
interpersonal relationships with peers, classmates, parents, (d) lower likelihood of using 
substance use to dowregulate negative affect or upregulate positive affect, (e) lower 
likelihood of engaging in risky behaviors (e.g., sexual promiscuity, aggression, rule 
breaking) to manage depressive symptoms, (f) improvement in self-esteem and self-
efficacy, and (g) greater mastery of behavioral skills to decrease stress and symptoms of 
depression and anxiety. 
 
Collectively, the research will advance our understanding of the behavioral and 
neurocognitive mechanisms implicated in anhedonia and reward system dysfunction, 
which is expected to ultimately lead to the development of more effective prevention and 
treatment programs that alleviate many of the mental and physical health problems as 
well as economic costs associated with anhedonic and depressive symptoms 

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IX. MONITORING AND QUALITY ASSURANCE 
(a) The PI will have responsibility for continuous monitoring of data and safety of 
subjects in the study.  Data and safety monitoring will take place continuously throughout 
the study’s duration. For participants in the active treatment condition, the study 
clinicians will administer a suicidality assessment before commencing each session, in 
addition to reviewing depressive symptom severity scores on self-report measures. If 
depressive symptoms and/or suicidality increase significantly, an intervention will be 
made during the time of the assessment. The PI will determine if the participant should 
discontinue the study. Additionally, appropriate recommendations will be made and 
appropriate actions taken in collaboration with the adolescent and parents.   
(b) We will report both adverse events and all serious adverse events that occur during 
the course of the trial to the Partners Institutional Review Board.  
 
(c) At the time of the continuing review we will provide the Partners IRB with a 
summary of any unexpected and related adverse events as well as any other unanticipated 
problems that occurred since the last continuing review. 
 
(d) We will also follow the Partners IRB policies for expedited reporting of unexpected 
Adverse Events and Serious Adverse Events. We will report to the IRB any nonserious 
unexpected adverse events and serious adverse events that are related or possibly related 
to a subject’s participation in the research occurring: (a) while a subject is enrolled in the 
study or (b) after study completion, or (c) after subject withdrawal. These events will be 
reported to the Partners IRB within 5 working days/7 calendar days of the date the 
investigator first becomes aware of the problem.  
 
(e) All study staff assessing depression (including anhedonic symptoms) and suicidality 
will be trained by Dr. Webb, who has completed a doctorate in clinical psychology and a 
1-year APA internship at McLean Hospital.  Dr. Webb has received extensive training in 
conducting interviews using the K-SADS, MINI, CDRS, and C-SSRS.   
(f) During the last 9 years, Dr. Webb has utilized all assessment tools in completing 
large-scale studies.  Further, Dr. Webb has provided extensive training and supervision 
for study staff/diagnosticians conducting these interviews.  Dr. Webb will provide 40 
hours of didactic and practical training for all study staff that will conduct interviews.  
Included in this instruction is the assessment of both depressive symptoms including 
suicidality. Particular attention will be paid to delineating the differences between passive 
suicidal ideation and intent to self-harm.  Additionally, all diagnostic interviews will be 
audiotaped (in contrast to therapy sessions, which will be videotaped) and reviewed in 
order to ensure reliability of diagnoses and assessment. 
(g) Throughout the study there may be circumstances where a subject’s participation may 
be terminated by the PI without the subject’s consent.  Specifically, potential reasons for 
participation termination may include: (a) increased participant suicidality, and (b) 
participant no longer satisfies inclusion criteria. Within 24 hours of any issue arising, the 
PI will speak to the parent and child, and if needed, the PI will also help to arrange 

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treatment for the child. It is important to note that this provision is explained in the 
consent forms. 
(h) During the course of the BA sessions, private information will be collected. Such 
information will not be shared with parents as this may inhibit subject responses, and 
potentially, undermine the course of therapy.  Therefore, a provision within the assent 
and consent forms states that parents must waive their right to access private information 
obtained in the context of therapy sessions. However, there are important caveats as 
outlined by the American Psychological Association Guidelines for Psychological 
Practice in Health Care Delivery: (a) subject reports imminent threat to herself, (b) 
subject reports imminent threat to other (i.e., Tarasoff Rule), and (c) subject reports 
current maltreatment and/or past maltreatment which was previously undisclosed (i.e., 
Mandatory Duty to Report Child Abuse and Neglect). If any of these exceptions arise, the 
study clinician will work collaboratively with the subject in order to disclose information 
as outlined in the APA Ethical Guidelines. During these occasions, the PI will be 
immediately contacted, and a report will be filed as early as is feasible to the IRB. 
(i) During this study, we may learn information from subjects that must be reported to 
public health or public safety authorities. We are required by law to report known or 
suspected child abuse. Should a subject disclose such information, we will report it to 
public health or public safety authorities.  
(j) Requests for data sharing 
Some de-identified research data will be shared with Dr. Aaron Kucyi at Northeastern 
University. The shared data will consist of de-identified behavioral (Flanker task) and 
demographic data (age and gender), de-identified resting state fMRI data, de-identified 
structural MRI data and de-identified ecological momentary assessment (EMA) data on 
momentary affect and cognitions. Data shared with Dr. Kucyi will be stored on a secure, 
password-protected server (Northeastern University’s Discovery cluster). Data will be 
transferred securely by using a MGB-approved data sharing service such as Syncplicity, 
or secure file transfer. The primary purpose of the data sharing will be to complete 
analyses for a planned manuscript and grant (NIMH R01) submission focused on the 
relation between EMA-assessed cognitions, including mind-wandering, and attentional 
control brain networks assessed via resting state fMRI. 
 
Some de-identified research data will be shared with Dr. Kathleen Gates at UNC Chapel 
Hill (and possibly other researchers). The shared data will consist of de-identified self-
report questionnaires and ecological momentary assessment (EMA) data on momentary 
affect and cognitions. Data shared with Dr. Gates will be stored on a secure, password-
protected server. Data will be transferred securely by using a MGB-approved data 
sharing service such as Syncplicity, or secure file transfer. The primary purpose of the 
data sharing will be to complete analyses for a planned manuscript focused on the 
relationship between EMA-assessed variables in BA treatment. 
 
X. REFERENCES 

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