Cognition and Psychotherapy in PTSD: Mechanisms and Functional Outcomes
Conditions: Posttraumatic Stress Disorder (PTSD)
Sponsor: VA Office of Research and Development

Title: Cognition and Psychotherapy in PTSD 
NCT Number: NCT03641924 
Document Date: 12/18/2020 

NEUROCOGNITIVE FUNCTIONING AND CPT 
 
Abstract=256 words 
Manuscript=25 pages 
Tables=1; Figures=0 
 
 
 
Neurocognitive Predictors of Treatment Outcomes in Cognitive Processing Therapy for 
Posttraumatic Stress Disorder: Study Protocol 
 
David P. Cenkner1, Anu Asnaani2, Christina DiChiara1, Gerlinde C. Harb1, Kevin G. Lynch1,3, 
Jennifer Greene1, & J. Cobb Scott1,3* 
 
1 VISN4 Mental Illness Research, Education, and Clinical Center, Corporal Michael J. Crescenz VA 
Medical Center, 3900 Woodland Ave, Philadelphia, PA, 19104, USA 
2 Department of Psychology, University of Utah, Salt Lake City, UT 84112 
3 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 
19104, USA 
 
 
*Correspondence should be addressed to: J. Cobb Scott, Ph.D., Corporal Michael J. Crescenz VA 
Medical Center, 3900 Woodland Ave., MC 116, Philadelphia, PA 19104 Email: 
scott1@pennmedicine.upenn.edu Voice: 215-662-7388 
 
 
 

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Abstract 
Background: Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and 
costly psychiatric disorder. Evidenced-based psychotherapies, including Cognitive Processing 
Therapy (CPT), are effective in treating PTSD, although a fair proportion of individuals show 
limited benefit from such treatments. CPT requires cognitive demands such as encoding, 
recalling, and implementing new information, resulting in behavioral change that may improve 
PTSD symptoms. Individuals with PTSD show worse cognitive functioning than those without 
PTSD, particularly in acquisition of verbal memory. Therefore, memory dysfunction may limit 
treatment gains in CPT in some individuals with PTSD. Methods and Analysis: Here, we 
present a protocol describing the Cognition and PsychoTherapy in PTSD (CPTPTSD) study, a 
prospective, observational study examining how cognitive functioning affects treatment 
response in CPT for PTSD (NCT# 03641924). The study aims to recruit 105 outpatient veterans 
with PTSD between the ages of 18-70 years. Prior to beginning 12 sessions of CPT, Veteran 
participants will have standardized assessments of mood and functioning and complete a 
comprehensive neurocognitive battery assessing episodic learning, attention and speed of 
processing, language ability, executive control, and emotional functioning. This study aims to fill 
gaps in the current literature by: 1) examining the specificity of memory effects on treatment 
response; 2) exploring how baseline cognitive functioning impacts functional outcomes; and 3) 
examining potential mechanisms, such as memory for treatment content, that might explain the 
effects of baseline memory functioning on PTSD symptom trajectory. Discussion: If successful, 
this research could identify clinically relevant neurocognitive mechanisms that may impact 
PTSD psychotherapy and guide the development of individualized treatments for PTSD.  
 
Keywords: PTSD, memory, psychotherapy research, psychotherapy mechanisms, cognitive 
functioning 
 
 

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INTRODUCTION 
Individuals who experience combat, sexual trauma, and other traumatic events are at 
higher risk for developing posttraumatic stress disorder (PTSD). PTSD is the most common 
mental health diagnosis received by returning Iraq and Afghanistan (OEF/OIF/OND) veterans at 
Veteran’s Administration (VA) facilities (Seal et al., 2007), with lifetime prevalence estimates 
ranging from 8-20% in OEF/OIF veterans (Hoge et al., 2006) and 15-30% in Vietnam veterans 
(Dohrenwend et al., 2006). Within VA, roughly 20% of Veterans who endorse military sexual 
trauma (MST) also have a diagnosis of PTSD (Gilmore et al., 2016). PTSD is frequently chronic 
(Kessler et al., 1995) and is often associated with impaired functioning (Byers et al., 2014). 
Costs for PTSD (e.g., work impairment) are substantial. For example, between 2004 and 2012, 
total expenditures for PTSD rose from 29.6 million to 294.1 million (Institute of Medicine, 2014). 
Taken together, the above considerations illustrate the urgent need to develop effective 
treatments for PTSD. 
Cognitive Processing Therapy (CPT) is a trauma-focused psychotherapy strongly 
recommended for the treatment of PTSD (Resick et al., 2017). CPT is among the frontline 
trauma-focused psychotherapies recommended by the existing VA/DoD Clinical Practice 
Guidelines for the management of PTSD (Department of Veterans Affairs and Department of 
Defense, 2017). CPT is a protocoled cognitive-behavioral therapy which emphasizes cognitive 
therapy techniques to help challenge erroneous beliefs developed or strengthened by traumatic 
events that are maintaining PTSD symptoms and preventing natural recovery from trauma. The 
goal of CPT is to help patients recover from PTSD symptoms by reconciling unhelpful beliefs 
and unprocessed emotions from trauma through both acceptance and the development of more 
balanced, adaptive beliefs. Unfortunately, a fair proportion of individuals show limited benefit 
from a standard course of psychotherapy, including CPT, for PTSD (Larsen et al., 2019). A 
recent meta-analysis of PTSD psychotherapies in veterans showed that a majority of patients 
receiving treatments show clinically significant improvements, but most still meet diagnostic 

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criteria for PTSD, and non-response rates are not insignificant (Steenkamp et al., 2015). To 
develop and refine interventions for individuals with PTSD, there is thus a need to identify 
factors amenable to intervention that may further enhance psychotherapy outcomes for this 
disorder. 
One factor that may impact psychotherapy in PTSD is cognitive functioning. 
Psychotherapy requires patients to encode and consolidate new information, organize this 
information into behavioral plans, and remember and execute these plans. Thus, the capability 
to retrieve specific details from one’s past and encode/retrieve treatment-relevant skills are 
highly relevant for therapeutic change across most types of psychotherapy (Liggan & Kay, 
1999). Critically, numerous studies have shown that individuals with PTSD show poorer 
cognitive functioning than individuals without PTSD (Schuitevoerder et al., 2013; Scott et al., 
2015), including deficits in episodic memory (Brewin et al, 2007), speed of information 
processing (Wrocklage et al., 2016), attention (Vasterling et al., 2002), and executive 
functioning (Aupperle et al., 2012), with the largest effects observed in immediate verbal 
memory (i.e., learning) (Scott et al., 2015). Treatment-seeking individuals with PTSD appear to 
have greater cognitive deficits compared to community-based PTSD samples (Scott et al., 
2015), highlighting the potential relevance of these deficits for clinical practice. Moreover, 
cognitive deficits are uniquely associated with negative functional outcomes in PTSD, including 
occupational performance, social functioning, and quality of life (Geuze et al., 2009; Wrocklage 
et al., 2016). However, despite its potential relevance, cognitive functioning is only beginning to 
be explored as an influential factor in psychotherapy outcomes for PTSD. 
Accumulating research reports remarkably consistent effects of verbal memory deficits 
on psychotherapy outcomes in PTSD. In a small study of civilians in trauma-focused CBT, Wild 
and Gur (2008) reported that non-responders had significantly worse verbal learning (i.e., 
immediate memory) at baseline, and that improvement in PTSD symptoms was positively 
associated with verbal learning performance, even after accounting for pre-treatment PTSD 

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severity and depression. In a larger study of 140 individuals with PTSD, Nijdam and colleagues 
(2015) showed that immediate verbal memory was positively associated with PTSD remission 
and with degree of change in PTSD severity over 16 weeks of treatment. Haaland et al. (2016) 
replicated these findings in a small sample of women veterans, showing that verbal memory at 
baseline was a predictor of psychotherapy response during group therapy with elements of both 
CPT and Prolonged Exposure (PE), another front-line evidence-based psychotherapy (EBP) for 
PTSD. Furthermore, a study of sleep and nightmare treatment in 94 veterans with PTSD 
showed that individuals with lower verbal learning performance at baseline were less likely to 
respond to treatment (Scott et al., 2017). Together, the consistency and robustness of these 
findings have prompted recommendations that verbal memory could serve as a useful and 
readily obtainable predictor of psychotherapy treatment response in PTSD (Etkin, 2015). 
However, limited research has examined the specificity of memory dysfunction in predicting 
treatment outcomes compared to overall cognitive functioning.  
Furthermore, despite accumulating research in this area, no studies to date have 
examined the pathways by which cognitive functioning may affect treatment outcomes. For 
example, one pathway by which cognitive dysfunction may interfere with psychotherapy is by 
directly limiting treatment understanding, learning, or implementation, or interfering with a 
patient’s ability to re-contextualize memories. Evidence from research in substance use 
disorders and depression indicates that worse executive functioning, memory, and overall 
cognitive abilities are associated with poorer recall of treatment information (Harvey et al., 2016; 
Teichner et al., 2002), reduced quality of coping skills acquired (Alexopoulos et al., 2003), and 
fewer treatment objectives achieved (Teichner et al., 2001). However, no studies have been 
conducted in stress-related disorders to determine which aspects of treatment are most affected 
by cognitive deficits. To address this limitation, the proposed project aims to test specific models 
of pathways between memory dysfunction and treatment outcomes by integrating novel insights 
from both cognitive neuropsychology and psychotherapy research. 

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In sum, accumulating evidence indicates that memory dysfunction is prominent in PTSD 
and adversely affects psychotherapy outcomes. Identifying mechanisms underlying the 
relationship between memory dysfunction and poor treatment outcomes is crucial to provide 
empirical guidance regarding appropriate rehabilitation targets to reduce the impact of cognitive 
dysfunction on therapy outcomes. The specific rehabilitation approaches that are most 
appropriate for improving therapy outcomes in PTSD will depend on the specific deficits 
observed, their relationship with therapeutic and functional outcomes, and critical moderators or 
mediators of those relationships. Given convergent findings of associations between cognitive 
functioning and PTSD and its influence on psychotherapy outcomes, the current protocol was 
developed to provide a rigorous examination of such relationships using hypothesis-driven 
models. Notably, no prior studies have examined effects of cognitive functioning on 
psychotherapy outcomes as a primary aim or explored potential mechanisms underlying these 
relationships. The current protocol therefore aims to address several knowledge gaps in the 
literature.  
First, we aim to examine the specificity of memory effects on PTSD symptom response 
and functional outcomes after CPT. Our primary hypothesis is that verbal immediate memory 
(i.e., learning), but not overall cognitive performance, will interact with time to predict PTSD 
symptom changes at post-treatment, such that those with lower verbal learning performance at 
baseline will have less reduction in PTSD symptoms than those with higher verbal learning 
performance. Second, we aim to determine whether specific treatment-related variables (e.g., 
memory for treatment content, treatment adherence) mediate the relationship between memory 
functioning and CPT response, helping to explain how episodic memory functioning might lead 
to poor treatment outcomes. Our primary hypothesis for this aim is that treatment recall at the 
treatment midpoint will mediate the association between verbal immediate memory at baseline 
and treatment outcomes. Finally, in an exploratory fashion, we also aim to examine whether 
alternative models of dysfunctional memory in PTSD, including impairment in autobiographical 

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memory (Barry et al., 2018), emotional memory consolidation (Durand et al., 2019), or 
prospective memory (Scott et al., 2016), might better explain the relationship between memory 
deficits and psychotherapy outcomes. For this aim, our primary hypothesis is that effect size 
comparisons will reveal that verbal learning functioning at baseline exhibits larger effects than 
prospective memory, emotional memory consolidation, or autobiographical memory in predicting 
psychotherapy treatment outcomes. If successful, data from this study could lead to a shift in 
clinical psychotherapy practice for veterans with PTSD and cognitive dysfunction by identifying 
salient, modifiable factors that may impact treatment outcomes. 
METHOD AND ANALYSIS 
Design 
The Cognition and PsychoTherapy in PTSD: Mechanisms and Functional Outcomes 
(CPTPTSD; NCT# 03641924) study is an observational, prospective study aiming to recruit 140 
(n=105 after attrition; see Missing Data below) outpatient veteran participants aged between 18-
70 who meet criteria for PTSD. Veteran outpatients are being recruited from the Corporal 
Michael J. Crescenz Veterans Affairs Medical Center (CMCVAMC) in Philadelphia, 
Pennsylvania.  
Participants 
Participants include veterans who are being referred for EBPs for PTSD (e.g., CPT, PE) 
within the outpatient mental health clinic at CMCVAMC. Participants are referred to the study 
following evaluation from a behavioral health technician, in lieu of transfer to standard outpatient 
psychotherapy appointment for an EBP for PTSD, or by a pre-existing outpatient mental health 
provider. Inclusion criteria includes meeting DSM-5 criteria for PTSD via the Clinician 
Administered PTSD Scale (CAPS-5) and being between the ages of 18-70. Exclusion criteria 
includes moderate or severe substance use disorder (SUD) not in remission for >1 month; daily 
benzodiazepine use; severe psychiatric illness (e.g., schizophrenia); significant current suicidal 
or homicidal intent, including a specific plan; dementia, neurological disorder, or severe TBI (i.e., 

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loss of consciousness > 24 hours); inability to speak or read English; prior completion of CPT; 
and psychiatric hospitalization within 30 days of study entry. To enhance generalizability among 
our sample of veterans with PTSD, participants are allowed to concurrently take medications for 
PTSD and other mental (e.g., depression) or physical health conditions or attend concurrent talk 
or supportive therapy.  
Procedure 
The first recruitment of veteran participants started in July 2019 with recruitment 
expected to be completed in March 2023. Participants undergo study screening to determine 
initial eligibility. Major assessments are conducted with participants at study entry (baseline), 
session 4, session 6, session 8, and at an endpoint assessment at post-treatment. For a full 
breakdown of all assessments administered at these time points, see Table 1. Baseline 
procedures (before starting CPT) include diagnostic interviews, questionnaires assessing mood 
and functioning, a neurocognitive assessment, and exploratory memory measures. After 
baseline, participants answer questionnaires about treatment expectancy and begin a standard 
course of CPT (12 sessions) following standardized protocols (Resick et al., 2017) with our 
study therapists, who are all certified CPT providers within the VA healthcare system. Study 
therapists are provided regular supervision focused on CPT protocol adherence and fidelity 
during the course of the study. Therapists are blind to scores on cognitive measures, and all 
CPT sessions are recorded for fidelity monitoring.  
Following each CPT visit, participants complete a brief questionnaire about adherence 
and application of treatment (see below), as well as the Patient Health Questionnaire (PHQ-9; 
Kroenke et al., 2001) to assess depression symptoms and suicide risk. At CPT sessions 4, 6, 8, 
and 12, participants complete measures of memory for treatment and brief re-assessments of 
PTSD, mood, and functioning.  

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Note that with the outbreak of the novel Coronavirus-19 (COVID-19) in March of 2020, 
all study procedures have moved to a virtual platform, and verbal consent is being conducted, 
as approved by the CMC VAMC IRB.   
Interview Assessments 
During the baseline visit, participants are interviewed by a trained and experienced 
masters-level clinician using the: 1) Clinician Administered PTSD Scale-5 (Weathers et al., 
2013), the gold standard interview for diagnosing PTSD; 2) Mini International Neuropsychiatric 
Interview (MINI) for DSM-5 (Sheehan et al., 2015), a semi-structured interview that yields DSM-
5 Axis I diagnoses for major psychiatric disorders, used for both sample characterization and 
exclusionary criteria; 3) Life Events Checklist-5 (Weathers et al., 2013a), to properly identify an 
index trauma; 4) structured interview for sociodemographic and medical history to obtain 
relevant demographic information and medical history; and 5) Ohio State University TBI 
Identification (Corrigan & Bogner, 2007), a brief structured interview to assess for previous signs 
of traumatic brain injury, for characterization of the sample with regard to head injuries. The 
CAPS is also readministered to each participant at the final visit.  
Self-Report Measures 
Two assessments are administered to capture primary outcomes: 1) PTSD Checklist for 
DSM-5 (PCL-5; Weathers et al., 2013b) to assess PTSD symptoms; and 2) the Social 
Adjustment Scale-Self Report (SAS-SR; Weissman, 1999), a 54-item measure assessing the 
six domains of work, leisure, extended family, romantic relationships, parental, and family unit 
functioning. Two assessments are administered to capture secondary outcomes: 1) the 
Veterans RAND 12-Item Health Survey (RAND-12; Kazis et al., 2006) to measure health-related 
quality of life; and 2) the WHO and Work Performance Questionnaire (HPQ; Kessler et al., 
2004) to measure performance at work and hours missed from work over the previous month.  
Two instruments are administered to capture covariate and predictor outcome variables. 
First, the PHQ-9, as mentioned previously, assesses depressive symptoms. Second, the 

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Combat Experiences Scales (CES; Vogt et al., 2013) is used to characterize participant combat 
exposure.  
Neurocognitive Assessments 
The neurocognitive battery assesses participants’ functioning across a broad range of 
neurocognitive domains using both traditional paper and pencil testing and computerized 
measures from the Penn Computerized Neurocognitive Battery (PennCNB; Gur et al., 2001, 
2010), a widely administered battery with substantial evidence of reliability and validity (Gur et 
al., 2012; Moore et al., 2015; Swagerman et al., 2016). Specifically, episodic learning and 
memory are measured using the California Verbal Learning Test-2 (CVLT-II; Delis et al., 2000), 
WMS-IV Logical Memory Test (Wechsler, 2009), and the Penn Face Memory Test (Thomas et 
al., 2013). Attention and speed of processing is measured using the Penn Continuous 
Performance Test (Kurtz et al., 2001), Trailmaking Test Part A (Bowie & Harvey, 2006), and the 
Penn Digit Symbol Test (Bachman et al., 2010). Language ability is measured using the Penn 
Verbal Reasoning Test (Bilker et al., 2014). Executive control is measured using the Trailmaking 
Test Part B (Bowie & Harvey, 2006), Stroop Color-Word Interference Test (MacLeod, 1991), 
Penn Conditional Exclusion Test (Kurtz et al., 2004), and the Letter N-Back Test (Ragland et al., 
2002). Emotional Functioning is measured using the Penn Emotion Recognition Test (Gur et al., 
2001) and the Penn Emotion Discrimination Test (Gur et al., 2001). Performance Validity is 
measured using the Medical Symptom Validity Test (MSVT; Green, 2004). Finally, IQ is 
estimated using the Wechsler Test of Adult Reading (WTAR; Wechsler, 2001). The entire 
neurocognitive battery is administered by research coordinators who undergo extensive training, 
and measures are administered in a secluded and quiet room with adequate space for 
participant and coordinator. These measures are administered during the baseline visit prior to 
the onset of CPT and after the final session CPT visit.  
Measures of Treatment Processes 

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Presently, there are no ideal measures with extensive evidence of reliability and validity 
to assess treatment adherence, memory for treatment content, and treatment expectancy. Thus, 
measures with strong theoretical foundations and initial evidence of validity were chosen for 
administration. Treatment adherence is measured weekly by the Therapist- and Patient-Report 
versions of the Treatment Adherence Rating Scale (TARS; Dong et al., 2016). The TARS 
assesses 1) if the treatment was comprehended and accepted by the patient as intended, and 
assesses patient acceptance and agreement with the session content. The TARS is 
administered weekly throughout treatment. Patient recall of treatment content is measured using 
the standardized Patient Recall Task (PRT; Lee & Harvey, 2015). The PRT is a free recall task 
that has patients recall as many treatment points as they can remember in 10 minutes. The PRT 
is administered during the midpoint and end of study sessions.  
Treatment expectancy is captured through three measures, including: 1) Expectancy of 
Therapeutic Outcome (ETO; Strauss et al., 2018), a 5-item Likert scale aimed to evaluate 
treatment credibility after the therapist provides the treatment rationale; 2) 
Credibility/Expectancy Questionnaire (CEQ; Devilly and Borkovec, 2000), a 6-item Likert scale 
measuring treatment expectancies for success; and 3) Self-Efficacy Scale (SES; Brown et al., 
2014), a one item questionnaire that asks the participant to rate his or her capability for 
successfully participating in treatment.  
Additional Memory Measures 
Participants also receive three additional measures of memory processes shown to be 
dysfunctional in PTSD, including the Autobiographical Memory Test (AMT; Mark & Broadbent, 
1986), the Emotional Verbal Learning Test (EVLT; Strauss & Allen, 2013), and a modified 
version of the Memory for Intentions Test (MIST; Raskin et al., 2010). The AMT includes twelve 
positive and negative words relevant to depression and anxiety, each presented at once, and 
asks the participant to write a specific memory he or she associates with the provided word. 
Participants are given up to two minutes for each word. The EVLT asks participants to recall 

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words presented from four emotion categories (happiness, sadness, anger, and anxiety) over 
five trials and delayed free recall. The modified MIST is a performance-based test of prospective 
memory (i.e., remembering to remember) over 15 minutes with time-based cues balanced by 
mode of response (i.e., physical vs. verbal) and with variable delay periods (e.g., 2 minute, 10 
minute).  
Data Analysis  
Statistical models used are linear or generalized linear mixed effects regression models, 
and we will use standard residual-based diagnostic approaches to check that model 
assumptions are satisfied (e.g., regarding outliers, observations with high influence or leverage). 
We will examine demographics as covariates in analyses to account for possible confounding of 
memory effects by demographics (e.g., age).  
We will use mixed effects models to examine the effects of verbal learning on overall 
PTSD symptom response, and on overall functioning. Verbal learning will be represented by a 
mean z score of CVLT-2 Trials 1-5 and WMS Logical Memory I. The comparison will be based 
on repeated responses obtained at baseline, mid-point, and end of treatment. The model for 
each outcome will include a random intercept to accommodate between-subject heterogeneity 
(Fitzmaurice et al., 2012). We anticipate that the two primary responses can be modeled as 
continuous measures, and that a linear model will fit the data well. If necessary, we will use 
generalized linear mixed effects models to accommodate skewness or departures from 
normality and linearity. The primary explanatory variables in the models will be baseline verbal 
learning score and time, and their interaction. Time will be coded as a categorical factor 
representing baseline, mid-treatment, and end-of-treatment. The primary analysis will be intent-
to-treat, in which participant data is analyzed regardless of dropout or adherence status, as 
mixed effects models accommodate partial data provided by non-completers. The main effects 
will test whether veterans with lower verbal learning performance will display less reduction in 
PTSD symptoms (PCL-5) across treatment, and less improvement in overall functioning 

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(measured with the SAS-SR), than those with better verbal learning performance. The 
interaction effects will test for variations in these effects across the treatment phase. A further 
question of interest relates to how prediction based on memory-specific aspects is related to 
prediction based on overall cognitive functioning. To address this question, we will generate a 
measure of overall cognitive performance from the other elements in the neurocognitive test 
battery. To facilitate data reduction, and since the PennCNB has been shown to have a strong 
general factor in prior research (Moore, Reise, et al., 2015; Swagerman et al., 2016), we will 
perform a principal component analysis (PCA) for all neurocognitive measures except for the 
memory measures. We will examine the strength of the association between this principal 
component and the memory measures to determine whether the first principal component 
appears to be a reasonable measure of overall cognitive functioning. 
Second, to examine whether mid-treatment levels of treatment engagement (TARS) and 
memory for treatment (PRT) mediate the effects of baseline verbal learning on end of treatment 
PTSD symptoms and overall functioning, we will use a multiple mediator model following 
MacKinnon (2008, Equations (5.2)-(5.4)) to assess effects of verbal learning and the two 
mediators simultaneously. This approach provides the most direct test of our explicit hypothesis 
of mediation but does not make use of the full set of longitudinal data available on the mediators 
and outcomes. Thus, we will supplement it with a set of longitudinal models, which provide more 
information on relationships between the time-course of repeated-measures variables. We do 
not measure verbal learning during treatment, as it is not expected to substantially change over 
the treatment period (Haaland et al, 2016). Thus, we will fit simplified versions of latent growth 
curve models, fitting simultaneous growth curves to mediators and responses, and using verbal 
learning as a non-time-varying baseline covariate. These models can accommodate different 
numbers of time points, and different timepoints, across the mediators and responses. Based on 
the number of time points (4 to 6, depending on mediator and outcome), we expect that linear 
growth curves will be sufficient to describe the trajectories. Our primary model will consider the 

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PTSD outcome and the treatment recall mediator. Our model will allow verbal learning to have 
direct effects on the random intercepts and slopes of the recall and PTSD processes, for the 
PTSD random intercept to have a direct effect on the recall slope, and for the recall intercept 
and slope to have direct effects on PTSD slope. The mediation effect is then the estimated by 
the product of the estimated direct effect of verbal learning on the recall slope, and the direct 
effect of the recall slope on the PTSD slope.  
Third, to determine whether aspects of memory are better predictors of treatment and 
functional outcomes than verbal memory in exploratory analyses, similar mixed effects models 
as the primary analyses will be conducted to examine the effects of baseline autobiographical 
memory, emotional memory, and prospective memory on overall PTSD symptom response.  
Finally, a small set of additional covariates potentially associated with PTSD 
psychotherapy outcomes, including TBI status and depression severity, will be included in 
reruns of our primary analyses. Model selection approaches based on BIC model fit 
comparisons to examine the separate and joint variance explained by primary and additional 
covariates will be used. We will also examine models with interactions between verbal memory 
and these additional covariates to assess whether they act as moderators of memory effects. 
Although exploratory in nature, these covariates will be included as baseline variables in the 
latent growth mediation models. 
Missing Data 
Based on our team’s prior studies, we anticipate a loss of up to 25% of veterans who 
enroll but do not start treatment (note that this study does not involve randomization). Thus, our 
planned enrollment is n=140, although the sample size of those who initiate CPT is expected to 
be n=105.  
Sporadic missing items from a scale may yield a small amount of missing data. We will 
accommodate this in analyses by mean imputation of a total scale score, based on available 
items of all participants at that time point. Mixed-effects models and longitudinal mediation 

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analyses make use of all data provided by participants. The analysis on the combined set of 
complete and incomplete data will be valid if the missing-at-random (MAR) assumption is met; 
in practical terms, this means that a future missed visit can be well-predicted on the basis of 
available data. We will perform sensitivity analyses using selection models (Fitzmaurice et al., 
2012) to assess effects of plausible models for non-MAR dropout on primary hypotheses. We 
will use mixed-effects logistic regression models to predict drop at each timepoint, using 
covariates available at that point. These models will provide estimated probabilities of 
attendance at the timepoints, and we will use (standardized) versions of these probabilities as 
inverse-weights in the analyses for the Aims. For nonlongitudinal mediation analyses, we will 
use a multiple imputation approach to generate ten data sets with missing responses imputed 
for all participants, estimate the models for the secondary hypotheses on each dataset, and 
combine the results to get final estimates that accommodate the variability due to imputation. 
Power Analysis/Sample Size 
We regard our hypothesis on PTSD symptoms as separate from hypotheses on 
functioning, so we use a 5% alpha-level for both outcomes. Prior data (Haaland et al., 2016; 
Nijdam et al., 2015; Scott et al., 2017) suggest a time by verbal learning interaction during 
treatment, where those with higher baseline verbal learning show greater reduction in PTSD 
related outcomes than people with lower baseline verbal learning and retain much of the 
improvement. In the proposed study, we anticipate that the difference will increase steadily 
through the full treatment phase. We base power estimates on the data of Scott et al. (2017) 
and our pilot data (Scott et al., under review). From both of those data, using z-scored versions 
of baseline verbal learning and the response, a one unit increase in verbal learning 
corresponded to an additional 0.15 unit decrease in the estimated change in PTSD outcomes. 
Based on 500 simulated datasets, we have 80% power for that observed effect for the PTSD 
outcome, and 81% power for slightly larger effects (additional decreases of 0.18 per time 
period) for functioning measures. For mediation hypotheses of Aim 2, we use the methods of 

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Fritz and MacKinnon (2007). Using a 5% alpha-level, our attrition reduced sample of 105 yields 
80% power for scenarios with medium or larger effects for the effect of verbal learning on a 
mediator, and the effect of the mediator on the outcome. 
DISCUSSION 
This protocol paper describes an observational prospective study to examine the 
relationship between neurocognitive mechanisms and CPT outcomes in a sample of veterans 
with PTSD. Prior research has identified cognitive deficits in individuals with PTSD, with the 
largest effects in immediate verbal memory (Scott et al., 2015). Moreover, secondary analyses 
of PTSD psychotherapy trials have consistently shown that verbal memory impacts treatment 
outcomes across settings and samples. To our knowledge, the CPTPTSD study will be the first 
to examine whether particular treatment-related variables may mediate the impact of memory 
on PTSD outcomes. Results will identify specific mechanisms underlying the relationship 
between cognitive functioning and psychotherapy outcomes in PTSD, which will inform future 
rehabilitation interventions that specifically target these cognitive deficits and their downstream 
effects. Identifying such targets are essential for developing effective clinical interventions to 
mitigate the effects of memory and other cognitive deficits on psychotherapy treatment 
response. 
Limitations 
 
This study has limitations. First, the protocol is not a randomized controlled trial (RCT), 
and therefore we will not be able to definitively know if symptom changes during CPT that are 
associated with neurocognitive functioning would have happened absent any intervention. 
However, conducting an RCT was not necessary to examine most relationships posed in our 
hypotheses. Second, we have faced numerous challenges with the outbreak of COVID-19, yet 
we have innovated and effectively transitioned much of our protocol to a virtual platform. Lastly, 
our study population is comprised solely of veterans, and results may not generalize to the 
civilian population. However, there is evidence that veteran and civilian PTSD rates are similar 

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after experiencing similar traumas (Patel et al., 2016), and there are minimal differences in 
cognitive functioning in veteran versus civilian samples with PTSD (Scott et al., 2015).    
ETHICS AND DISSEMINATION 
This project was approved and carried out with feedback from the Corporal Michael J. 
Crescenz Veterans Affairs Institutional Review Board. All subjects will provide written or verbal 
consent prior to enrollment into the study.  
Findings from this research will be disseminated in peer-reviewed journals and scientific 
meetings. We will also communicate results and implications to critical stakeholders in the 
veteran and PTSD research communities. Results will also inform the long-term goal of this 
program of research, which is to understand the role of cognitive dysfunction in psychotherapy 
treatment outcomes and identify novel targets for rehabilitation (e.g., memory for the content of 
treatment) that can be translated into clinical practice. Results from this study may also have 
wider clinical applicability, as they could lead to changes in other psychotherapeutic approaches 
for PTSD, as well as other disorders impacting cognition (e.g., traumatic brain injury).  For 
example, “fine-tuned” psychotherapies could be developed to enhance memory for treatment 
content by providing focused memory support interventions, which could be broadly applied to 
help facilitate treatment effectiveness. One novel and promising pathway is to train therapists to 
infuse psychotherapy treatment-as-usual with a memory support intervention to enhance patient 
memory for the content of treatment (Harvey et al., 2014). This intervention involves therapist 
use of eight memory support strategies developed from cognitive psychology and education 
research on learning and memory, such as repeating information, writing down prescribed 
treatment recommendations, and providing cues to facilitate retrieval (see Harvey et al., 2014). 
Initial results from a clinical trial in depression indicate that memory support improves patient 
recall of treatment content and depression outcomes compared to cognitive-behavioral therapy 
alone (Harvey et al., 2016). Thus, if our hypotheses are confirmed, this intervention may be 
useful to adapt and test in future studies of CPT for PTSD.  

NEUROCOGNITIVE FUNCTIONING AND CPT 
 
 
17 
 
 
 

NEUROCOGNITIVE FUNCTIONING AND CPT 
 
 
18 
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Table 1  
Schedule of Measure Administration  
 
 
 
 
  
Baseline 
Post-
CPT 
Session 
1 
Post-
CPT 
Session 
4 
Post-
CPT 
Session 
6 
Post-
CPT 
Session 
8 
End 
of 
CPT 
Interview Measures 
  
  
  
  
  
  
MINI 
● 
  
  
  
  
  
CAPS-5 
● 
  
  
  
  
● 
LEC-5 
● 
  
  
  
  
  
Social/Medical History 
● 
  
  
  
  
  
CES 
● 
  
  
  
  
  
OSU TBI-ID 
● 
  
  
  
  
  
Self-Report Measures 
  
  
  
  
  
  
PCL-5 
● 
  
● 
● 
● 
● 
SAS-SR 
● 
  
● 
● 
● 
● 
RAND-12 QOL 
● 
  
● 
● 
● 
● 
WHO-HPQ 
● 
  
● 
● 
● 
● 
PHQ-9 
● 
● 
● 
● 
● 
● 
Cognitive Assessments   
  
  
  
  
  
Neurocognitive Tests 
● 
  
  
  
  
● 
Treatment Measures 
  
  
  
  
  
  
TARS 
  
  
● 
● 
● 
● 
PRT 
  
  
● 
● 
● 
● 
ETO 
  
● 
  
● 
  
  
CEQ 
  
● 
  
● 
  
  
SES 
  
● 
  
● 
  
● 
Note. MINI = The Mini-International Neuropsychiatric Interview; CAPS-5 = The Clinician 
Administered PTSD Scale-5; CES = Combat Experiences Scale; OSU TBI-ID = Ohio State 
University Traumatic Brain Injury Identification; PCL-5 = The PTSD Checklist for DSM-5; SAS-SR = 
The Social Adjustment Scale-Self Report; RAND-12 QOL = Veterans RAND 12 Item Health Survey; 
WHO-HPQ = WHO Work Performance Questionnaire; PHQ-9 = The Patient Health Questionnaire-9; 
TARS = Treatment Adherence Rating Scale; PRT = Patient Recall Task; ETO = Expectancy of 
Therapeutic Outcome; CEQ = Credibility/Expectancy Questionnaire; SES = Self-Efficacy Scale.