Social Withdrawal Following Trauma Exposure: a Neuroeconomic Approach
Conditions: Posttraumatic Stress Disorder
Sponsor: Mclean Hospital

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MCLEAN HOSPITAL IRB 
DETAILED PROTOCOL 
 
 
PRINCIPAL INVESTIGATOR 
 
 
 
 
Elizabeth Olson, Ph.D.  
 
 
Instructor  
 
 
Center for Depression, Anxiety, and Stress Research 
 
 
 
 
 
 
McLean Hospital 
 
 
 
 
 
115 Mill Street  
 
 
 
 
 
Belmont, MA 02478 
 
 
 
 
 
617-855-2281  
 
 
 
 
  
eaolson@mclean.harvard.edu 
 
PROTOCOL TITLE 
Neuroeconomics of Social Behavior Following Trauma Exposure  
 
I. BACKGROUND AND SIGNIFICANCE 
Significance 
Impaired social functioning is a frequent and disabling sequela of trauma-related disorders. PTSD is 
associated with a high rate of severe impairment in quality of life (endorsed by 59% of patients) relative 
to other anxiety disorders, including panic disorder (20%), social phobia (21%), and OCD (26%) 
(Rapaport et al., 2005), with particularly marked impairment in social quality of life, d = 1.53 (Olatunji et 
al., 2007). Mounting evidence indicates that impairment in quality of life in PTSD is strongly related to 
its effect on social functioning (Charuvastra & Cloitre, 2008). Difficulties in interpersonal relationships 
are the problems that PTSD patients most frequently cite as their primary treatment goal (Rosen, 2013). In 
addition to being central, such difficulties are widespread and affect multiple social networks (Dutton et 
al., 2014), including marital relationships (Colman, 2004), and friendships and family relationships 
(Paunovic & Ost, 2004). Social impairments in PTSD fall into two major categories. The first involves 
socially disruptive externalizing behaviors and associated emotions, including anger, interpersonal 
violence, and aggression (Elbogen, 2014; Olatunji et al., 2010). The second involves social detachment, 
withdrawal, and isolation (Rosen, 2013). Social withdrawal, defined here in terms of reduced social 
network size, is of particular interest because of its strong relationship with health outcomes, including 
increased risk of disability (Mendes de Leon et al., 2001), reduced immune response (Pressman et al., 
2005), and increased mortality risk (Shye et al., 1995); most critically, poor social integration is 
associated with a threefold increase in suicide risk (Tsai et al., 2015). Because women are at a 2.3-to-3-
fold increased risk compared to men of developing PTSD following trauma (Breslau et al., 1997; Stein et 
al., 2000), understanding the differential neurobiological pathways that may contribute to the 
development of stress-related disorders in women is particularly critical. Women are more likely than 
men to endorse social detachment following trauma, especially when the trauma involves exposure to 
violence (Hourani et al., 2015). In this project, we propose abnormal reward processing (anhedonia) as a 
specific mechanism underlying social withdrawal in trauma-exposed women, and we present a paradigm 
that capitalizes on advances in neuroeconomics to elucidate the neural underpinnings of social 
withdrawal. Additionally, we propose to identify the possible influences of a stress peptide (pituitary 
adenylate cyclase-activating polypeptide: PACAP) implicated in sex-specific changes in social behavior 
following stress exposure. This contribution is expected to result in a number of tangible and important 
benefits. The first relates to assessment. By using a neuroeconomic paradigm to characterize a profile 
associated with social withdrawal following trauma exposure, it may become possible to develop methods 
to more quickly identify trauma-exposed individuals who are at particular risk for poor health outcomes 
including disability and mortality. The second tangible benefit relates to treatment. By identifying 
alterations in particular reward-related brain regions related to social withdrawal following trauma 

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exposure, we will identify possible future targets for neurobiological interventions. 
 
Anhedonia as a core feature of PTSD.  
Early models of reward functioning in depression and anxiety disorders proposed that hypoactivation of 
approach/reward systems (anhedonia) was a distinguishing feature of depressive disorders (Clark & 
Watson, 1991; Davidson, 1994). Perhaps in part because PTSD was classified as an anxiety disorder in 
DSM-IV, the importance of anhedonia in PTSD was underemphasized. However, a wealth of 
accumulating evidence indicates that anhedonia is a core feature in trauma-related disorders. This is 
reflected in the reconceptualization of PTSD outlined in DSM-5: “[m]any individuals who have 
been exposed to a traumatic or stressful event exhibit a phenotype in which, rather than anxiety- or fear-
based symptoms, the most prominent clinical characteristics are anhedonic and dysphoric symptoms.” 
Several lines of evidence support this re-conceptualization emphasizing the centrality of anhedonia in 
PTSD. First, on selfreport measures, PTSD is associated with decreased positive emotionality (d = -1.91: 
Frewen et al., 2012) and with increased hedonic deficits (d = 1.88, Frewen et al., 2012). Second, 
participants with PTSD show abnormal behavior on reward-based learning tasks (Sailer et al., 2008), 
including decreased key-pressing for primary rewards (Elman et al., 2005), lack of increased satisfaction 
after receiving unexpected rewards, and reduced satisfaction upon reward delivery (Hopper et al., 2008). 
Third, neuroimaging studies have identified abnormal neural responses to positive stimuli and reward in 
PTSD (Jatzko et al., 2006), including reduced nucleus accumbens (NAcc) and mPFC activity 
(Felmingham et al., 2014; Sailer et al., 2008). Fourth, recent factor analyses of DSM-5 PTSD symptoms 
support the importance of anhedonia in PTSD, suggesting that it is a separate factor from negative affect 
(Liu et al., 2014; Pietrzak et al., 2015). Directly relevant to the proposed research and highlighting the 
clinical importance of focusing on anhedonia, among all PTSD factors (including re-experiencing, 
avoidance, negative affect, anhedonia, externalizing behaviors, anxious arousal, and dysphoric arousal), 
anhedonia is the strongest predictor of quality of life and self-reported mental functioning, and is a 
significant predictor of depressed mood and suicidal ideation (Pietrzak, 2015). To summarize, there is 
strong empirical support for the claim that anhedonia is a prominent and important feature in PTSD. In 
spite of this clinical evidence, anhedonia in PTSD has received surprisingly scant attention in 
neurobiological research. 
 
One potential explanation for the presence of anhedonia in PTSD is that it is attributable to comorbid 
disorders, including major depressive disorder (MDD) and/or substance use disorders. Estimates for 
comorbid MDD in PTSD samples reach the 50% range (Kessler et al., 1995; Rytwinski et al., 2013); 
comorbid alcohol abuse/dependence (51.9%) and drug abuse/dependence (34.5%) also are elevated 
(Kessler et al., 1995). Because anhedonia is a well-documented feature of MDD (Pizzagalli et al., 2008; 
Pizzagalli, 2014) and alcohol/substance use disorders (Corral-Frias et al., 2015; Franken et al., 2007), one 
could argue that this comorbidity accounts for anhedonia in PTSD. However, there is evidence that PTSD 
is associated with anhedonia even in the absence of or beyond these comorbid disorders. Specifically, 
PTSD patients with and without MDD endorse anhedonia at comparable rates: 67% in comorbid PTSD-
MDD, and 63% in PTSD-only (Franklin & Zimmerman, 2001). Moreover, the aforementioned behavioral 
and fMRI abnormalities in reward processing persist even when analyses are restricted to non-depressed 
individuals with PTSD or recent substance use disorder (Felmingham et al., 2014; Hopper et al., 2008). 
Thus, there is substantial evidence that anhedonia is an important feature in PTSD even after accounting 
for effects attributable to comorbid disorders. 
 
Reward processing, neural circuitry, and social withdrawal  
There is growing acknowledgment of the key role of motivation/goal-directed behavior in shaping social 
interactions (Crick & Dodge, 1994). The subjective experience of social interaction can serve as a 
primary reward, recruiting mesolimbic reward circuitry in thes ame manner as other primary rewards 
(Pfeiffer et al., 2014). From a neurobiological perspective, anhedonia is conceptualized as a 
transdiagnostic phenomenon involving blunted reward circuitry responses (e.g. Corral-Frias et al., 2015). 

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This project focuses on three reward processing regions: the ventral striatum (VS), dorsal striatum (DS), 
and mPFC. The mPFC is involved in comparing the subjective values of rewards during decision-making 
(Kable & Glimcher, 2009; Plassman et al., 2010; Wang et al., 2014). The VS (including the NAcc and 
portions of the caudate and putamen: Haber, 2011) encodes the reward value of stimuli (Knutson et al., 
2001; O’Doherty et al., 2002), while the DS (caudate and putamen) codes the reward value of responses 
(Balleine et al., 2007; O’Doherty et al., 2004). fMRI tasks requiring active reward-related decision-
making may elicit DS rather than VS activity (Dichter et al., 2009; O’Doherty et al., 2004). Social 
anhedonia is associated with altered corticostriatal functional connectivity in both VS and DS (Wang et 
al., 2016). Similarly, hedonic deficits in VS and DS have both been identified using task-based fMRI in 
MDD (Pizzagalli et al., 2009). Abnormalities in reward processing circuitry can result in social 
disturbances (e.g., withdrawal) and increased risk for psychiatric disorders (Meyer-Lindenberg & Tost, 
2012); reduced brain responsivity to social reward has been proposed to underlie social withdrawal in 
autism (Barman et al., 2015; Chevallier et al., 2012) and schizophrenia (Gromann et al., 2013). PTSD 
modeling in rats confirms the presence of an anhedonic subtype (28% of affected animals) involving 
altered NAcc and mPFC function and connectivity (Ritov et al., 2016). 
 
Neuroeconomic reward hypothesis of social preferences.  
In the present study, we propose to use a neuroeconomic game in order to capture altered social reward 
signaling in the VS, DS, and mPFC in trauma-exposed individuals. The use of economic games to probe 
social behavior in psychiatric disorders has been rapidly expanding. Importantly, these paradigms allow 
for formal operationalization of social emotions (Kishida & Montague, 2013). Economic exchange games 
use behavioral measures that are stripped of the complex environmental features that often accompany 
these emotions (King-Casas et al., 2005), and allow these processes to be assessed even when participants 
cannot articulate the underlying emotions (Zak, 2007). The neuroeconomic reward hypothesis of social 
preferences states that certain complex social behaviors such as non-selfish behavior and cooperation 
occur because these types of social interactions have special inherent hedonic or reward value, which is 
instantiated in brain regions including the VS, DS, and mPFC that encode the reward value of other types 
of primary reward (Behrens et al., 2008; Fehr & Camerer, 2007; Harris & Fiske, 2010; Insel, 2003; Izuma 
et al., 2010; Pfeiffer et al., 2014). Thus, neuroeconomic tasks can be used to identify the neural signals 
associated with social reward, and have already been robust and replicable in their ability to characterize 
social reward deficits across several disorders involving abnormal social behavior, including autism 
spectrum disorders (Chiu et al., 2008; Izuma et al., 2011), borderline personality disorder (King-Casas 
et al., 2005; King-Casas et al., 2008; Unoka et al., 2009), and psychopathy (Koenigs et al., 2010). 
 
In this study, we will use the Trust Task to probe the neural signals underlying social anhedonia 
following trauma exposure. This paradigm is a particularly sensitive detector of altered social reward 
sensitivity in humans. In the task (Berg et al., 1995; King-Casas & Chiu, 2012; Kishida & Montague, 
2013), one player is the ‘investor,’ and the second player is the ‘trustee.’ The investor is given an 
endowment and sends any amount to the trustee. Whatever portion the investor sends is multiplied, and 
the trustee can then opt to backtransfer any amount of the money to the investor. Critically, previous work 
has demonstrated DS responses consistent with a dopaminergic reinforcement learning signal, that are 
initially generated by the trustee when the partner’s behavior is revealed (King-Casas et al., 2005; Kishida 
& Montague, 2013). This DS activity predicts subsequent increases in reciprocity and has thus been 
characterized as reflecting reward-related processing of a social gesture (Kishida & Montague, 2013), 
making it an ideal probe for detecting abnormalities in social reward processing. The Trust Task has 
previously been shown to be sensitive to abnormalities in social behavior. Participants with borderline 
personality disorder make lower investments, reflecting decreased reward value of the social interaction 
(Unoka et al., 2009; King-Casas et al., 2008). Similarly, compared to healthy controls, individuals with 
social phobia show reduced mPFC activity, again reflecting lower reward value for human interaction 
(Sripada et al., 2009). Trust game performance is sensitive to sex hormones and neuropeptides that play a 
central role in regulating social behavior, consistent with the notion that it captures critical features of 

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social reward (Boksem et al., 2013; Kosfeld et al., 2005; Bartz et al., 2011).  
 
If trauma exposure results in blunting of sensitivity to social reward, then trauma-exposed individuals will 
demonstrate reduced prosocial behavior on neuroeconomic tasks, captured by behavioral abnormalities on 
the Trust Task. Reduced brain responsivity to social reward is a proposed mechanism underlying lower 
motivation to engage in social behavior in individuals with psychopathology (Barman et al., 2015; 
Gromann et al., 2013). Therefore, we hypothesize that, in trauma-exposed populations, the extent of 
social withdrawal (decreased social network size) will be predicted by alterations in both Trust Task 
social behavior and abnormal reward-related signaling in response to social cues on the Trust Task. 
 
There are a few reports of altered Trust Task performance following trauma exposure. Lenow et al. 
(2014, 2015) found that assaulted adolescents showed altered responses to trust violations. Specifically, 
there were clusters in the DS and mPFC (as well as anterior cingulate and insular cortex) where the 
response to unexpected losses scaled with assault severity. This was a small, low-severity sample (15 
assaulted girls, 3 with PTSD), and the task did not use real investment decisions. Cisler et al. (2015) used 
a multi-round trust game to identify behavioral abnormalities in women with PTSD (n = 25), including 
steeper decreases in trust and a slower return to baseline following trust violations. Parameters capturing 
trust game expectancies were related to neural activity in frontal regions on a different reward task. To 
summarize, there are encouraging initial demonstrations that neuroeconomic task behavior and neural 
responses are altered following trauma exposure. The proposed study would be the first fMRI study of 
Trust Task behavior in trauma-exposed adults and would further relate these findings to social anhedonia 
and social withdrawal, as well as to stress peptides. 
 
PACAP: a stress-sensitive peptide  
PACAP is involved in a variety of functional processes, including modulation of the HPA axis via 
regulation of corticotropin releasing factor (CRF). Its role in the stress response is demonstrated by 
animal literature indicating that: (1) chronic unpredictable stress results in increased PACAP in the bed 
nucleus of the stria terminalis (BNST), a major amygdala output pathway (Hammack et al., 2009); (2) 
infusion of PACAP into the amygdala or BNST produces stress-related behaviors (Hammack et al., 
2010; Legradi et al., 2007); and (3) stress hormone synthesis in the HPA axis is PACAP-dependent 
(Stroth & Eiden, 2010). Human studies have further shown that in trauma-exposed women, but not men, 
higher PACAP levels are correlated with increased PTSD symptoms, an effect that persists even after 
controlling for depression (r = 0.497: Ressler et al., 2011). From a genetic perspective, a single nucleotide 
polymorphism (rs2267735) in the PAC1 receptor significantly predicts PTSD diagnosis in females (Almli 
et al., 2013; Ressler et al., 2011; Wang et al., 2013). Consistent with the role of PACAP in modulating 
fear circuitry, women who carry the PAC1 risk allele demonstrate reduced hippocampal activity during 
contextual fear conditioning (Pohlack et al., 2015) and increased amygdala and hippocampal activity in 
response to threat stimuli (Stevens et al., 2014). PACAP/ PAC1 receptor systems are modulated by 
estrogen in fear-sensitive regions (Ressler et al., 2011), highlighting that some portion of the increased 
risk for PTSD in women may be related to the effects of sex hormones (Shansky et al., 2010; Bangasser et 
al., 2010). 
 
PACAP and social affiliation  
Critically, animal work has implicated PACAP in social affiliation. PACAP knockout mice show 
increased social interaction, suggesting that PACAP regulates social withdrawal (Hattori et al., 2012). 
PACAP administration results in loss of approach behavior, but not increased fleeing, suggesting 
that it may be specifically related to social affiliation as opposed to social fear (Donahue et al., 2016). 
Similarly, PAC1-deficient female mice have abnormal initiation of affiliative behavior (Nicot et al., 
2004). The specific mechanism by which PACAP affects social affiliation is currently unknown. Directly 
relevant to the proposed hypotheses, PACAP produces anhedonia in rats through pathways mediated by 
CRF (Dore et al., 2013). 

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Intriguingly, in mice, severe stress is associated with a loss of CRF’s normal ability to increase dopamine 
release in the NAcc (Lemos et al., 2012). Additionally, while PACAP is prominently expressed in the 
hypothalamus, the NAcc has a high density of PACAP binding sites in rats (Masuo et al., 1992), raising 
the possibility that PACAP may directly act in the VS and alter reward processing. Though preliminary, 
this body of literature suggests that elevated PACAP levels may lead to a loss of social reward value 
through altered dopamine release in the VS. A significant limitation of the previous work on PACAP and 
social affiliation is that it has been conducted exclusively in rodents. This study would be the first attempt 
to demonstrate that increased PACAP levels are related to increased social anhedonia and social 
withdrawal in humans. 
 
Summary  
This study will use a neuroeconomic paradigm with state-of-the-art imaging protocols to probe 
abnormal social reward processing underlying social withdrawal in symptomatic trauma-exposed women. 
By also gathering self-report measures of social anhedonia, performance on non-social and social reward 
valuation tasks, and measures of real-world social functioning including social network size, we aim to 
specify how alterations in social reward processing result in social withdrawal and functional impairment. 
To our knowledge, PACAP has not previously been explored in relation to social behavior in humans, 
including trauma-exposed human populations. We will examine social withdrawal and reduced response 
to social reward on the Trust Task in relation to PACAP levels in trauma-exposed women. 
 
II. SPECIFIC AIMS 
 
Specific Aim 1: To identify a neurobehavioral profile on the Trust Task that predicts social withdrawal 
(decreased social network size) following trauma exposure. Compared to the posttraumatic spectrum-non-
socially anhedonic (PTS-nonSA) group and the healthy control (HC) group, the posttraumatic spectrum-
socially anhedonic (PTS-SA) group will demonstrate lower investments on the Trust Task than on the 
non-social risk task, as well as slower learning rates [Hypothesis 1a] and decreased reward-related 
responses during the outcome phase for social versus non-social rewards in the VS, DS, and mPFC 
[Hypothesis 1b]. Across the PTS groups, reduced VS, DS, and mPFC activity during the outcome phase 
of the Trust Task for social rewards will be associated with lower rates of investment on the Trust Task 
and smaller social network size [Hypothesis 2]. Within the PTS groups, decreased VS, DS, and mPFC 
response to social rewards will mediate the relationship between social anhedonia and reduced social 
network size [Hypothesis 3]. PTS individuals with higher self-reported social anhedonia and social 
withdrawal also will show reduced VS-mPFC connectivity for social rewards on the trust task 
[Hypothesis 4].  
 
Specific Aim 2: To identify a potential biomarker that predicts social anhedonia and social withdrawal 
following trauma exposure. We propose to examine social withdrawal and reduced response to social 
reward on the Trust Task in relation to PACAP levels in trauma-exposed women. Elevated PACAP levels 
will be associated with lower investments on the Trust Task, decreased social reward signals during the 
outcome phase for social rewards in the VS, DS, and mPFC, and smaller social network size [Hypothesis 
5]. 
 
III. SUBJECT SELECTION  
 
PHASE 1 (Establishing Trust Task trustee database) 
 
Phase 1 will involve recruiting healthy volunteers (n = 60) to complete the Trust Task in order to 
establish	  a	  database	  of	  trust	  task	  responses	  from	  anonymous	  healthy	  trustees.	  	  
 
Inclusion	  criteria:	  Age	  18-­‐45,	  self-­‐reported	  healthy	  volunteer	  status	  

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Exclusion	  criteria:	  1)	  inability	  to	  provide	  written	  informed	  consent	  in	  English;	  2)	  inability	  to	  see	  
task	  due	  to	  vision	  impairments.	  	  
	  
Participants	  who	  produce	  T-­‐scores	  of	  65	  or	  higher	  on	  any	  Brief	  Symptom	  Inventory	  (BSI)	  subscales	  
will	  not	  be	  eligible	  to	  remain	  in	  the	  Trust	  Task	  participant	  pool. 
 
Sources of subjects and recruitment methods:  
Recruitment	  sources	  will	  include:	  
1) Healthy	  participants	  from	  other	  research	  studies	  at	  McLean	  Hospital	  in	  Belmont,	  MA	  
a. I	  plan	  to	  collaborate	  with	  other	  investigators	  at	  McLean	  Hospital	  who	  will	  ask	  their	  
healthy	  participants	  if	  they	  would	  be	  interested	  in	  participating	  in	  an	  additional	  
study	  which	  will	  take	  approximately	  1/2	  an	  hour	  to	  complete.	  Should	  they	  consent,	  
the	  participants	  will	  stop	  by	  our	  lab	  following	  the	  completion	  of	  the	  other	  
investigators'	  studies,	  receive	  the	  consent	  form	  for	  the	  present	  study,	  and	  complete	  
the	  protocol	  for	  Phase	  1	  participation.	  	  
b. I	  anticipate	  collecting	  Phase	  1	  data	  from	  up	  to	  60	  healthy	  participants	  (in	  order	  to	  
obtain	  usable	  data	  from	  50	  participants	  after	  accounting	  for	  data	  loss).	  
2) Healthy	  adults	  at	  McLean	  Hospital	  in	  Belmont,	  MA.	  	  
a. We	  plan	  to	  recruit	  healthy	  adults	  at	  McLean	  Hospital	  by	  putting	  up	  flyers	  around	  
campus,	  asking	  if	  healthy	  adults	  would	  be	  interested	  in	  participating	  in	  a	  study	  
which	  will	  take	  approximately	  1/2	  an	  hour	  to	  complete.	  Should	  they	  consent,	  the	  
participants	  will	  stop	  by	  our	  lab,	  receive	  the	  consent	  form	  for	  the	  present	  study,	  and	  
complete	  the	  protocol	  for	  Phase	  1	  participation. 
3) Healthy community-based volunteers. We plan to recruit healthy adults through craigslist 
postings, through the procedures described above in (2). 
4) Former Phase 1 participants in protocol 2016P000978. Participants in Phase 1 in that prior study 
completed procedures identical to those in this study (BSI, Trust Task). We plan to recontact 
participants who provided permission to be recontacted and who meet inclusion criteria for this 
study’s Phase 1 pool (age 18-45, BSI T-scores under 65, produced usable Trust Task data). We 
will send them a consent form by mail asking for their permission to include them in this study’s 
Phase 1 participant pool. 
 
PHASE 2 (Main study phase) 
 
Inclusion criteria: female, trauma exposure appropriate to group, for trauma-exposed groups the index 
trauma is actual or threatened physical assault or sexual violence, PCL-5 score 33 and above (for PS-SA 
and PS-nonSA groups), right handedness, age 18-45, English as a first language.  
 
Exclusion criteria: history of neurological illness (including head injury with loss of consciousness > 5 
minutes), medical conditions that may influence neuroimaging (e.g. HIV), current or past DSM-5 Axis I 
disorder (for HC group), history of bipolar disorder or schizophrenia spectrum disorder, contraindications 
for MRI, alcohol dependence in the past 5 years, substance dependence in the past 3 years, daily 
substance use in the past year, prescribed psychotropic medication use in the past month, Wechsler 
Abbreviated Scale of Intelligence- Second Edition (WASI-II) FSIQ < 70. 
 
Sources of subjects and recruitment methods: This project compares three groups: posttraumatic 
spectrum-socially anhedonic (PTS-SA, n = 36), posttraumatic spectrum-non-socially anhedonic (PTS-
nonSA, n = 36), and healthy controls (HC, n = 36). Participants will be recruited from the following 
sources: 1) Recruiting new participants from the Boston metropolitan area through newspaper 

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advertisements, flyers, Internet websites, and word of mouth. 2) Recontacting participants who have 
recently participated in one of this lab’s studies and who previously expressed interest and provided 
written consent to be re-contacted about additional studies. Specifically, these are subjects who have 
participated in: Dr. Isabelle Rosso’s IRB-approved protocols entitled “Cerebral GABA and Fear 
Conditioning in PTSD” (protocol # 2012P001237) and “An investigational study of riluzole effects on 
hippocampus biomarkers” (protocol #2016P002687); Dr. Scott Rauch’s IRB-approval protocol entitled 
“Internet-Based Cognitive Behavioral Therapy Effects on Depressive Cognitions and Brain Function” 
(protocol # 2012P000131); Dr. Elizabeth Olson’s IRB-approved protocol entitled “ Reward valuation in 
posttraumatic stress disorder: contribution of nucleus accumbens-insula circuitry” (protocol # 
2016P002890). These subjects will be re-contacted by phone or email, using contact information that they 
previously provided. 
 
IV. SUBJECT ENROLLMENT 
 
PHASE 1 (Establishing Trust Task trustee database) 
 
As	  previously	  discussed,	  Phase	  1	  participants	  will	  be	  healthy	  adults	  at	  McLean	  Hospital.	  Should	  
these	  participants	  agree	  to	  participate	  in	  the	  present	  study,	  they	  will	  be	  invited	  to	  stop	  by	  the	  
laboratory	  either	  immediately	  preceding	  or	  following	  their	  participation	  in	  the	  other	  investigators'	  
studies,	  if	  applicable.	  	  
	  
Then,	  written	  informed	  consent	  will	  be	  obtained	  upon	  subjects’	  arrival	  on	  their	  first	  visit	  to	  the	  
present	  study.	  An	  investigator	  will	  sit	  down	  with	  subjects	  and	  review	  the	  consent	  form,	  discussing	  
its	  contents,	  including	  the	  study	  procedures	  involved,	  the	  potential	  risks	  and	  benefits	  to	  
participating,	  and	  the	  voluntary	  nature	  of	  participation.	  Subjects	  will	  be	  told	  that	  they	  can	  
discontinue	  their	  participation	  at	  any	  time.	  Subjects	  will	  then	  be	  given	  as	  much	  time	  as	  they	  want	  to	  
read	  through	  the	  consent	  form	  in	  detail.	  They	  will	  be	  given	  the	  opportunity	  to	  ask	  questions,	  and	  to	  
consult	  with	  their	  friends,	  family	  members,	  or	  doctors	  if	  they	  wish.	  If	  desired,	  a	  subject	  may	  take	  the	  
consent	  form	  home	  in	  order	  to	  discuss	  it	  with	  others,	  or	  in	  order	  to	  take	  more	  time	  to	  decide	  
whether	  to	  participate.	  Once	  subjects	  have	  read	  the	  consent	  form,	  have	  had	  all	  their	  questions	  
answered,	  and	  have	  agreed	  to	  participate	  in	  the	  study,	  they	  will	  initial	  the	  bottom	  of	  each	  page	  and	  
sign/date	  the	  final	  page.	  They	  will	  be	  given	  a	  copy	  of	  the	  consent	  form	  for	  their	  records.	  	  	  
	  
The	  informed	  consent	  will	  typically	  be	  collected	  by	  a	  research	  assistant	  trained	  by	  the	  P.I.,	  or,	  in	  
some	  cases,	  by	  the	  P.I.	  
	  
Remuneration	  
	  
Healthy	  control	  participants	  who	  participate	  in	  the	  initial	  phase	  of	  Trust	  Task	  development	  will	  be	  
compensated	  as	  follows.	  They	  will	  not	  be	  paid	  directly	  for	  the	  brief	  study	  visit	  (consisting	  of	  
consent,	  BSI,	  and	  Trust	  Task).	  Rather,	  their	  responses	  to	  possible	  Trust	  Task	  offers	  will	  be	  recorded,	  
and	  they	  will	  be	  paid	  in	  the	  future	  based	  on	  Phase	  2	  participant	  responses.	  After	  each	  Phase	  2	  
participant	  completes	  the	  Trust	  Task,	  one	  trial	  will	  be	  randomly	  selected.	  For	  example,	  if	  Trial	  #13	  
is	  selected,	  and	  Trial	  #13	  involved	  an	  offer	  of	  $6	  from	  the	  Phase	  2	  participant,	  then	  the	  Phase	  1	  
participant’s	  pre-­‐recorded	  decision	  to	  share	  or	  keep	  that	  offer	  will	  be	  used	  to	  determine	  
remuneration	  for	  the	  Phase	  1	  and	  Phase	  2	  participants.	  If	  the	  Phase	  1	  participant	  chose	  to	  share	  the	  
offer,	  then	  the	  quadrupled	  amount	  ($24)	  is	  split	  50-­‐50	  ($12	  to	  the	  Phase	  1	  participant;	  $12	  to	  the	  
Phase	  2	  participant).	  If	  the	  Phase	  1	  participant	  chose	  to	  keep	  the	  offer,	  then	  the	  quadrupled	  amount	  
($24)	  goes	  to	  the	  Phase	  1	  participant	  only	  ($24	  to	  the	  Phase	  1	  participant;	  $0	  to	  the	  Phase	  2	  
participant).	  Because	  of	  the	  random	  nature	  of	  the	  drawing,	  it	  is	  not	  possible	  to	  determine	  in	  

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advance	  the	  exact	  amount	  of	  compensation	  that	  each	  Phase	  1	  participant	  will	  receive.	  The	  possible	  
range	  of	  task-­‐related	  compensation	  starts	  at	  $0.	  In	  the	  extremely	  unlikely	  event	  that	  the	  same	  Phase	  
1	  participant	  trial	  was	  randomly	  selected	  for	  every	  Phase	  2	  participant	  (n	  =	  40),	  and	  that	  trial	  
involved	  the	  maximum	  possible	  payout	  to	  the	  Phase	  1	  participant	  ($40),	  it	  is	  conceptually	  possible	  
that	  a	  single	  Phase	  1	  participant	  could	  earn	  up	  to	  $1600.	  The	  likely	  estimate	  of	  compensation	  for	  
Phase	  1	  is	  approximately	  $50.	  If	  a	  Phase	  1	  participant	  was	  never	  randomly	  selected	  to	  receive	  a	  
payout,	  he	  or	  she	  will	  be	  compensated	  $5	  for	  his/her	  time	  at	  the	  conclusion	  of	  the	  study.	  All	  Phase	  1	  
payments	  will	  be	  made	  by	  mail.	  
	  
Phase	  1	  participants	  who	  produce	  T-­‐scores	  of	  65	  or	  higher	  on	  any	  Brief	  Symptom	  Inventory	  (BSI)	  
subscales	  will	  not	  be	  eligible	  to	  remain	  in	  the	  Trust	  Task	  participant	  pool.	  They	  will	  be	  paid	  $5	  by	  
mail	  at	  the	  end	  of	  the	  study. 
 
PHASE 2 (Main study phase) 
 
Methods of enrollment, include procedures for patient registration and/or randomization 
 
Participants’ initial study contact will be a phone call wherein they will receive a preliminary description 
of the study. During this phone call, a research assistant or other study investigator will convey general 
information about the research study (e.g., general aims, location, duration and remuneration), and 
specific information about the procedures (i.e., type and duration of procedures). They will be asked to 
complete an telephone pre-screening questionnaire (if they have not already done so) to establish whether 
they meet entry criteria on the PCL-5 and RSAS. Participants meeting these criteria will continue with the 
telephone screen. Subjects will also be asked a number of screening questions to determine whether they 
meet the basic selection criteria (see Telephone Screen). After this exchange of initial information, 
subjects will be invited to think about whether they would like to participate in the study. If they express 
interest in participating, they will be scheduled for the study visit. If they request more time to consider 
the decision of whether or not to enroll, they will be provided a phone number to call back with a decision 
(and/or to ask any questions).  
 
Procedures for obtaining informed consent (including timing of consent process) 
 
Written informed consent will be obtained upon subjects’ arrival. An investigator will sit down with 
subjects and review the consent form, discussing its contents, including the study procedures involved, 
the potential risks and benefits to participating, and the voluntary nature of participation. Subjects will be 
told that they can discontinue their participation at any time. Subjects will then be given as much time as 
they want to read through the consent form in detail. They will be given the opportunity to ask questions, 
and to consult with their friends, family members, or doctors if they wish. If desired, a subject may take 
the consent form home in order to discuss it with others, or in order to take more time to decide whether 
to participate. Once subjects have read the consent form, have had all their questions answered, and have 
agreed to participate in the study, they will sign/date the final page. They will be given a copy of the 
consent form for their records.   
 
The initial phone screen and informed consenting generally will be conducted by a research assistant who 
has been trained on both procedures by the P.I., or in some cases by the P.I. After conducting a phone 
screen, the research assistant will review information with the P.I. to confirm whether or not the 
prospective subject meets initial entry criteria and should be scheduled for a study visit.  
 
Remuneration 
 

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Participants who complete the entire study will receive $200 to cover the anticipated eight hours of time 
for study participation. Partial completion of the study will be remunerated at the pro-rated rate of $25 per 
hour for procedures that are completed. Additionally, participants will be compensated for one randomly 
selected Trust Task trial (average anticipated payout per participant: $20). 
 
V. STUDY PROCEDURES 
 
Phase	  1	  
	  
Study	  visits	  and	  parameters	  to	  be	  measured	  	  	  
The	  present	  study	  involves	  a	  single	  visit	  to	  McLean	  Hospital,	  during	  which	  we	  will	  obtain	  measures	  
of	  trust	  task	  behavior	  and	  general	  psychopathology.	  
	  
Procedures	  
Neuroeconomic	  Game	  
The	  paradigm	  will	  be	  a	  multiple	  single-­‐shot	  trust	  task	  (Stanley	  et	  al.,	  2012).	  Each	  participant	  will	  
play	  the	  game	  as	  trustees.	  Players’	  decisions	  to	  all	  possible	  offers	  will	  be	  recorded	  and	  stored	  in	  a	  
database	  to	  be	  used	  in	  participants'	  task	  completion	  during	  Phase	  2.	  On	  each	  trial,	  the	  trustee	  will	  
decide	  to	  ‘share’	  (50-­‐50)	  or	  ‘keep’	  (100%	  to	  trustee)	  each	  amount	  displayed.	  Real	  payments	  for	  one	  
randomly	  selected	  trial	  will	  be	  delivered	  by	  mail	  (to	  the	  trustee).	  	  
	  
Brief	  Symptom	  Inventory	  
All	  subjects	  will	  also	  complete	  the	  Brief	  Symptom	  Inventory,	  a	  53-­‐item	  self-­‐report	  inventory	  of	  
general	  psychological	  functioning	  and	  psychopathology.	  This	  will	  be	  administered	  by	  a	  research	  
assistant	  or	  other	  study	  investigator	  familiar	  with	  its	  content. 
 
PHASE 2 (Main study phase) 
 
The study will require one visit. Briefly, this will include diagnostic interviews to establish eligibility, 
questionnaires and cognitive tasks, a 1-hour MRI scan including task-based FMRI, and a blood draw for 
analysis of PACAP and related hormone levels. 
 
Screening procedures (SCID-5, CAPS-5, WASI-II) will establish eligibility. Participants will then 
complete additional questionnaires and the fMRI scan (see below), playing the repeated, single-shot trust 
game inside the scanner.  
 
Procedures 
 
Psychiatric Interview and Symptom Scales 
Once subjects understand all study procedures and have provided written consent, they will undergo a 
structured psychiatric interview, namely the Structured Clinical Interview for DSM-5 (Research Version: 
SCID-5-RV) and the SCID-5-PD. In addition, PTSD group participants will complete the Life Events 
Checklist for DSM-5 and Clinician-Administered PTSD scale for DSM-5 (CAPS-5) in order to quantify 
trauma exposure and symptom severity. The clinical instruments will be administered by Dr. Olson, who 
is a licensed psychologist with training and experience in these measures. 
 
Questionnaires: Edinburgh Handedness Scale, PTSD Checklist (PCL), Traumatic Life Events 
Questionnaire (TLEQ), Adverse Childhood Experiences scale (ACE), NEO Personality Inventory, Beck 
Depression Inventory, Second Edition (BDI-II), Empathy Quotient (EQ), Social Network Index (SNI), 
Dunbar’s number (Dunbar & Spoors, 1995: List the initials of everyone with whom you had some kind of 

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social contact within the last 30 days). We also will administer an in-house Information Questionnaire 
with questions regarding recent health habits (sleep, eating, substance use, etc.). Questionnaires will be 
administered by a research assistant or other study investigator familiar with their content. 
 
Urine Toxicology 
Once subjects have provided informed consent and have met study selection criteria based on results of 
the interviews, they will be asked to provide a urine sample under the supervision of a research assistant. 
This sample will be tested for cannabinoids, ethanol, amphetamines, opioids, phencyclidine, barbiturates, 
benzodiazepines, and cocaine metabolites (Triage® Drugs of Abuse Panel: Immediate Response 
Diagnostics, San Diego, CA). Female subjects will be informed that their sample will also be used to 
confirm negative HCG status (QuPID One-Step Pregnancy, Stanbio Laboratory, Inc., San Antonio, TX).  
 
Imaging Procedures 
Prior to scanning, subjects will complete standard McLean MR safety screening, including filling out the 
McLean Imaging Center questionnaire that queries about past surgeries and metallic implants that may be 
contraindicated for MR. An MR technician will review this information prior to taking the subject into the 
magnet room. During scanning, subjects will be given earplugs to reduce the noise made by the magnet, 
and subjects will also be given headphones through which they can communicate with the technologist 
and research staff at any time. Head and back support will be provided to minimize discomfort.  
All subjects will undergo high-resolution structural and functional MRI on a 3T Siemens Prisma(Siemens 
Medical Solutions USA Inc., Malvern, PA), whole-body, clinical MR system using a 64 channel phased-
array design RF head coil operating at 123 MHz. Once participants are positioned inside the bore, a three-
plane series of scout images will confirm optimal positioning. Then three series of anatomical whole-
brain images will be acquired, namely i) high-contrast T1-weighted MPRAGE images (using parameters 
optimized for morphometric analysis using Freesurfer software: 128 slices, 2562 matrix, echo time= 
2.7ms; repetition time= 2730 ms; inversion time= 1000ms; flip= 7°, slice thickness= 1.33mm), ii) FLAIR 
and iii) fast spin-echo (FSE) T2-weighted image sets. Anatomical scans will be reviewed by a board-
certified radiologist. If a clinical abnormality is detected, the subject will be excluded from the study, and 
the subject’s physician will be notified upon written release. 
 
fMRI Acquisition and Analysis: MRI data will be acquired on a 3T Siemens Prisma with a 64-channel 
head coil. 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. 
 
Neuroeconomic Game (fMRI task): Multiple, single-shot Trust Task (Stanley et al., 2012). Participants 
will play as investors against real anonymous trustees, drawn from a pool of minimally screened 
participants (Brief Symptom Inventory). Trustees’ decisions to all possible offers will be pre-recorded in 
a database. Prior to the task, the investor will receive an endowment of $30. On each trial, the investor 
will choose to send the trustee $0-$10 (increments of $2). The amount sent will be quadrupled, and the 
trustee’s decision to ‘share’ (50-50) or ‘keep’ (100% to trustee) will be displayed. The game will be 
played as single shots with 50 trustees. Real payments for one randomly selected trial will be delivered in 
person (to the investor) or by mail (to the trustee). There also will be a non-social risk game in which the 
decisions are computer-generated. We will use computational modeling (Rescorla-Wagner model) to 
derive the learning rate (Cisler et al., 2015). Following completion of the Trust Task, one trial will be 
randomly selected for real payout.  
 

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If time permits, diffusion tensor imaging (DTI) images also will be acquired (TR= 7300 ms, TE = 80 ms, 
72 diffusion directions, b = 1000). 
 
PACAP Analysis 
There will be 1 blood draw which will require 9mL of blood, equivalent to approximately 2 
teaspoons.Plasma will be collected in EDTA collection tubes, iced immediately, centrifuged, and stored 
in a -80C freezer. PACAP38 (38-amino acid peptide form) will be quantified via radioimmunoassay by 
the Ressler lab (detailed methods: see Ressler et al., 2011). PACAP activity is influenced by estradiol and 
luteinizing hormone (LH) (Park et al., 2010; Ressler et al., 2011). We will control for this by running 
participants only during cycle days 1-6 and by covarying estradiol, LH, and progesterone levels in 
PACAP analyses. 
 
VI. BIOSTATISTICAL ANALYSES 
 
Hypothesis 1: 1a) Given that increased social anhedonia will be associated with decreased reward 
value for social interactions, we hypothesize that, compared to the PTS-nonSA and HC groups, the 
PTS-SA group will demonstrate lower investments and slower learning rates on the Trust Task than on 
the non-social risk task compared with PTS-nonSA and HC subjects. No differences are anticipated 
between the HC and PTS-nonSA groups. 1b) The HC and PTS-nonSA groups will show greater VS, DS, 
and mPFC responses during the outcome phase of the trust game for ‘share’ versus baseline, compared to 
the PTS-SA group, for the real partner condition (Trust Task), but not for the risk task. Using SPM12, 
first-level analyses will contrast the hemodynamic response to trials involving the revelation of the 
partner’s decision to share versus baseline, thus capturing the VS, DS, and mPFC signals associated with 
positive social interactions. At the second level, groups will be contrasted controlling for age. A priori 
hypotheses will be evaluated using ROIbased analyses, which will be complemented by whole-brain 
analyses (familywise error corrected). All analyses will be performed with and without self-reported 
race/ethnicity as a covariate to identify possible confounds related to this factor. We will control for age 
and smoking status, due to effects on dopamine functioning.  
 
Hypothesis 2: Because social withdrawal will occur in response to reduced social reward value, we 
hypothesize that across the PTS groups, reduced VS, DS, and mPFC activity during the outcome phase of 
the trust game for ‘share’ outcomes will be associated with lower Trust Task investments, greater self-
reported social anhedonia, and smaller social network size. At the second level, multiple regression will 
be performed using self-reported social anhedonia as a continuous covariate of interest; decreased VS, 
DS, and mPFC response to positive social interactions will correlate with increased social anhedonia, 
after controlling for age and total CAPS-5 score.  
 
Hypothesis 3: Within the PTS groups, decreased VS, DS, and mPFC response to ‘share’ outcomes will 
mediate the relationship between social anhedonia and reduced social network size. Mediation analyses 
will be conducted via bootstrapping using the PROCESS Macro (Hayes, 2013) in SPSS. 
 
Hypothesis 4: Because increased VS-mPFC connectivity is associated with increased reinforcement 
learning rates (van den Bos et al., 2012), we predict that PTS individuals with higher self-reported social 
anhedonia and social withdrawal will show reduced VS-mPFC connectivity for social rewards on the 
Trust Task. Using SPM12, a whole-brain psychophysiological interaction (PPI) analysis will be 
conducted using the VS as the seed region of interest. The seed time course will be entered as a regressor 
into the GLM, and the interaction (PPI) regressor will be generated. Task and seed ROI regressors will be 
covaried out to identify voxels where the VS time course has a stronger relationship for social reward 
versus baseline.  
 
Hypothesis 5: Finally, we hypothesize that elevated PACAP levels will be associated with lower 

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investments on the Trust Task; decreased social reward signals during the outcome phase for ‘share’ 
outcomes in the VS, DS, and mPFC; and smaller social network size. 
 
Power Analysis  
Compared to controls, the effect size for alterations in social behavior following trauma exposure is large 
(d ≥ 1.0: Olatunji et al., 2007, 2010). The effect sizes for altered neuroeconomic task performance 
following trauma exposure are medium to large (d = 0.783: Lenow et al., 2014; d = 0.972: Cisler et al., 
2015), while the effect sizes of altered responsivity in the striatum and mPFC in trauma exposed 
populations are in the medium range (d = 0.576-0.773: Sailer et al., 2008). In women, correlations 
between PACAP levels and PTSD symptoms are large (r = 0.497: Ressler et al., 2011). While the Trust 
Task has not previously been used in women with PTSD, Sripada et al (2009) compared individuals with 
social anxiety disorder to healthy controls and found a large group difference for social vs non-social 
reward in the mPFC (d = 0.854). Assuming 15% unusable data, we propose to enroll 36 PTS-SA, 36 PTS-
nonSA, and 36 HC participants, resulting in usable data from 30 subjects per group, resulting in power > 
0.90 to detect group differences. This is comparable with other neuroecomic neuroimaging studies (e.g. 
Kirk et al., 2011: n = 26 in group 1; n = 40 in group 2). 
VII. RISKS AND DISCOMFORTS   
 
Foreseeable Risks and Discomforts 
 
MR Scanning 
MR does not use ionizing radiation. In a small percentage (less than 5%) of subjects, feelings of 
claustrophobia may be experienced while in the scanner, although self-reported claustrophobia will be an 
exclusion criterion (queried during the telephone screen and psychiatric interview). Participation in an 
MR study does require subjects to be exposed to strong magnetic fields, the long-term effects of which 
are unknown. The magnetic fields also require caution given the risk of attraction of ferromagnetic metal 
objects by the high strength magnetic field. Significant risks exist for anyone with metal in their body 
(e.g., shrapnel, pacemaker), requiring exclusion of these subjects from study participation. In addition, 
some subjects find the scanning experience unpleasant because of the noise of the scanner during 
acquisition. In rare cases, a very slight, uncomfortable tingling of the back is induced in some people. 
These risks are the same as those present for a clinical MR scan, and are not increased by the research 
project described herein.  
 
Clinical Interview 
 
It is possible that during the structured clinical interview or rating scales, subjects may become distressed 
when recalling periods of their lives or their current mood state. This can certainly be foreseen for PTSD 
patients recounting their traumatic experiences. Since Dr. Olson has been conducting these interviews 
with PTSD subjects in other studies over the past several years, she has found it useful to plan longer 
time-slots for interviews with PTSD patients, thereby allowing the interview to go at each subject’s pace, 
taking a break if needed, and/or offering a glass of water or other “grounding” pause as needed. None of 
the PTSD subjects interviewed thus far (at least 40) have reported excessive distress or undue 
consequences, and none have been unable or unwilling to complete the clinical interview. 
 
Trust Task 
No risk or discomfort is expected due to the process of completing of this task, however, participants may 
feel mildly frustrated or disappointed about the outcome. 
 
Procedures for Minimizing Risks 
 

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First and foremost, subjects will be informed that they may terminate their study participation at any time, 
for any reason. In addition, the following will be enforced: 
Minimizing Subject Burden 
Subjects who underwent a clinical anatomical MRI at McLean within the past year will not need to repeat 
this scan to be read by the radiologist, as per hospital policies.   
 
MR Scanning 
A number of precautions will be taken to mitigate any possible adverse consequences of participating in 
the scanning protocol. Subjects are interviewed prior to entering the study and specifically queried about 
implanted metal objects and other MR contraindications by trained MR technicians. Following manual 
demetallizing by trained personnel, all subjects pass through a metal detector wand prior to entering the 
scanning room to ensure no stray material has been overlooked. Noise from the gradients is minimized by 
using earplugs and gradient dampening headphones (Resonance Technology). Subjects can communicate 
easily with study personnel through the microphone integrated in their headphones, and can stop the scan 
at any time by squeezing a panic button. Subjects who appear to be claustrophobic or are unable to be 
made comfortable will be removed from the scanner immediately and assessed for stability.  
 
Clinical Interview 
Subjects will be informed that responding to interview questions is voluntary, and that they may decline 
to answer any question. Subjects who decline the interview or any other study procedures will be 
compensated in proportion with their study participation time. As described above, care is taken to 
conduct the interviews at a rate comfortable for subjects, offering breaks as needed. 
Trust Task 
One risk of this task is that participants may feel mildly frustrated or disappointed about the outcome. 
This risk will be minimized by: 1) reminding participants during consent that a variety of financial 
outcomes are possible, including the possibility of not winning much money; 2) allowing participants an 
extra break if they are mildly frustrated or disappointed following the task. We do not anticipate that 
participants will be more severely frustrated or angry, but if this occurs, we will remind them that their 
participation is completely voluntary and that they may withdraw from participation at any time. 
 
Blood Draws 
A blood draw may lead to a small arm bruise and, in rare cases, clot or infection at the site the blood was 
drawn. Some people become light-headed during or immediately after a blood draw.  These are rare 
occurrences and in our experience vast majority of subjects tolerate blood draws well.  Subjects will be 
monitored for 15 minutes following the blood draws to ensure they are doing well. 
Confidentiality 
All subjects will be informed of confidentiality laws (and limits to confidentiality). Confidentiality of 
information collected will be maintained with the assignment of subject identification numbers, which 
will be used in place of subject names in all data spreadsheets, questionnaires and other forms and reports. 
Coding schemes showing the assignment of identification numbers to subject names will be stored in 
locked cabinets at the CDASR. All computerized databases with identifying information will be 
password-protected. All of the data collected will be kept for a minimum of seven years after study 
completion. Onsite access to study data will be limited to the McLean investigators and their staff; any 
sharing of data with external collaborators or entities that analyze the data will be controlled by the 
investigators of this study.   
All subjects will complete MR imaging at McLean Hospital, requiring assignment of a medical record 
number (MRN) for archival purposes. MRNs are generated by a hospital computer database that is only 
accessible by authorized McLean clinical staff. A master list of MRNs with corresponding subject 
numbers will be kept in locked and password-protected files. For clinical scans, which are read and 

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14 
interpreted by a board-certified radiologist, identifying information such as first and last name and date of 
birth also is required per standard hospital policies. All other data and forms derived from the study will 
be coded only with the subject’s study ID number (not MRN) and kept in locked and password-protected 
files. Subjects’ names (or other PHI) will not appear on assessment measures or other data entry forms. 
 
VIII. 
POTENTIAL BENEFITS 
 
Potential benefits to participating individuals 
There are no anticipated direct benefits to individual subjects for participating in this study. That is, for 
the majority of subjects the research data collected are not expected to be personally beneficial to them. 
We have found, however, that some PTSD subjects find it beneficial to learn more about their symptoms 
(e.g., learning that concentration problems can be a symptom of PTSD by virtue of participating in the 
interview). In addition, some subjects may derive future benefit from the clinical MRI scan. Every 
subject’s MRI scan is read and interpreted by a clinical neuroradiologist and kept on file permanently at 
McLean Hospital. This allows individuals to have a baseline MRI scan at no charge, which may be 
accessed by their physicians or other medical persons should the need arise.   
 
Potential benefits to society   
This study will provide novel information on neural mechanisms involved in alterations in reward 
valuation in Posttraumatic Stress Disorder. This may lead to improved behavioral therapies targeting 
specific symptoms of a common and debilitating brain disorder that is currently difficult to treat. 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
Data Monitoring  
The study investigators will be directly responsible for monitoring the data collection, data coding and 
processing, and continual adherence to the IRB-approved protocol. This will be feasible given that the 
study involves low/minimal risk to a manageable number of subjects, and that all data collection and 
storage will take place at a single site. Moreover, the investigators have thorough understanding and 
knowledge of all the procedures and data being collected (neuroeconomic data, demographic data, 
psychiatric data). The validity and integrity of the data will be ensured by having each type of data 
collected and/or supervised by an investigator with relevant expertise:  collection of all psychiatric data 
will be performed and supervised by Dr. Olson, a clinical psychologist. All subject staff will receive 
thorough explanations of all procedures, even those in which they may not be directly involved. The P.I. 
and investigators will conduct quality control checks after every five enrolled subjects, including: 1) 
review all forms and test/interview results, and enter data into spreadsheets; 2) ensure that the different 
subject groups are being recruited with the selection and matching criteria dictated by the scientific aims; 
3) verify that all data are collected and analyzed per protocol privacy and confidentiality policies (see next 
section); 4) conduct interim processing and analyses of neuroeconomic task data to ensure that high-
quality data are being collected, justifying continued collection of data.  
 
Any access to de-identified data by external research collaborators will be controlled by the investigators 
of this study.  
 
Safety Monitoring   
The investigators will be responsible for safety monitoring, overseen by the P.I. This study involves 
minimal/low risk to subjects: 1) the psychiatric questionnaires do not involve safety risks per se but can 
be uncomfortable or distressing; in addition, appropriate measures will be taken if subjects are deemed to 
present a safety risk to themselves or others; 2) the neuroeconomics task does not pose any foreseeable 
risks or discomforts beyond possible mild frustration or disappointment. 
 

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15 
1) Questionnaires and Cognitive Tasks 
Prior to beginning the psychiatric symptom scales, we will remind subjects that their participation is 
voluntary and that they may decline to answer any question(s). If a subject experiences extreme distress 
during the completion of questionnaires, the overseeing study staff member will discontinue the study 
participation for that subject.  
 
If a subject endorses symptoms of active suicidality, including endorsement of suicidality (score of 1, 2, 
or 3) on the BDI-II Question 9, the subject will be evaluated by a licensed doctoral-level clinician via an 
immediate in-person assessment. The doctoral-level clinician will use his/her professional judgment to 
determine whether continued involvement in the study is appropriate, and the subject will be provided a 
list of resources for treatment, including medication and/or face-to-face therapy, if warranted. During 
face-to-face meetings, subjects judged to be at imminent risk for self-harm will be escorted to McLean 
Hospital’s Clinical Evaluation Center (CEC) where they will be evaluated for inpatient admission. 
Similarly, immediate in-person assessment and triage will be conducted by a licensed doctoral-level 
clinician in the unlikely event that a subject reports a threat to an identifiable third person. 
 
2) Neuroeconomics Task 
We will remind subjects that their participation is voluntary and that they may decline to complete the 
neuroeconomics task if they wish.  
 
Adverse event reporting guidelines 
 
Any adverse events will be reported to the Partners Institutional Review Board by the P.I. Reporting will 
follow the guidelines established by Partners Healthcare 
(http://healthcare.partners.org/phsirb/adverse_events.htm) for reporting of adverse events based on their 
seriousness, unexpectedness, and relatedness to the research procedures. As a general policy, any adverse 
event will be reported as soon as possible after the P.I. first becomes aware of it.  
 
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