Psychotherapy Effects on Reward Processing in PTSD

Study Overview
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Brief Summary
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The purpose of this study is to identify how trauma-focused psychotherapy changes the function of brain circuitry in posttraumatic stress disorder (PTSD) and how this mediates improvements in the diminished ability to experience positive emotions following a traumatic or extremely stressful life event. In this instance, the investigators will be using cognitive processing therapy (CPT), a widely-utilized and evidence-based treatment for PTSD.

Detailed Description
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The goals of the study are as follows: Quantify, under conditions of safety (no threat), how PTSD psychotherapy alters reward circuit function and information encoding. Hypothesis: Under conditions of safety, treatment will enhance vmPFC ExpVal encoding, enhance VS encoding of PE, and decrease amygdala encoding of PE. Identify how presence of threat augments PTSD psychotherapy effects on reward circuit function and information encoding. Hypothesis: In presence of threat vs. no threat, treatment will attenuate vmPFC ExpVal encoding, attenuate VS encoding of PE, and increase dorsolateral prefrontal cortex encoding of PE. (Exploratory). Identify how, following psychotherapy, changes in reward circuit function and information encoding under conditions of safety and threat are associated with improvements in symptoms of diminished positive affect (DimPA). To accomplish the goals of the study, the investigators propose a neuroimaging-coupled, randomized clinical trial of immediate vs. delayed individual cognitive processing therapy (CPT) in individuals (N=120) with a primary diagnosis of chronic PTSD. The investigators are choosing to focus on the syndromic diagnosis of PTSD in this study vs. DimPA in PTP more generally (which also frequently encompasses MDD as a diagnosis), because: a) trauma-focused psychotherapy has been validated on the syndromic diagnosis of PTSD; and b) providing this treatment to individuals without a PTSD diagnosis may diminish efficacy of the treatment in this sample, obscure detection of therapeutic mechanisms, and may not be clinically advantageous to the participant. Note that large sample-studies indicate that  75% of individuals with a PTSD diagnosis have at least one symptom of DimPA (i.e. Emotional Numbing). Therefore, a diagnostic inclusion criterion is most likely to result in a maximally generalizable sample that will also be sensitive to CPT therapeutic effects. Individuals will undergo, prior to randomization, clinical and neurobiological assessment with fMRI during completion of several reward processing paradigms. Two of these involve both a normal safe context and a threat context manipulation (threat of mild electrodermal shock that is periodically cycled throughout the task). Another paradigm involves making decisions to either approach reward or forego a reward when this decision conflicts with the likelihood of an aversive outcome. This is known as approach-avoidance conflict (AAC). Finally, the investigators will incorporate a paradigm to assess emotion regulation in order to determine how this major aspect of CPT (cognitive reappraisal) relates to changes in reward circuitry function. This battery will provide a comprehensive characterization of reward processing behavior and circuit function and establish its relationship to treatment processes, as well as how such processes may vary as a function of threat.

Official Title
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The Effects of Trauma-focused Psychotherapy on Reward Circuitry Function and Information Encoding

Conditions
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Post Traumatic Stress Disorder, Diminished Pleasure, Anhedonia, PTSD, Chronic PTSD, Chronic Post-Traumatic Stress Disorder

Intervention / Treatment
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* Behavioral: Cognitive Processing Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: English as primary language, and comprehension suitable to understand experimenter instructions. Current and chronic syndromic PTSD, defined as being exposed to a DSM-5 Criterion A traumatic event, with the presence DSM-5 qualifying PTSD symptoms for at least 3 months, as assessed by the Clinician-Administered PTSD Scale for DSM-5. Able and willing to undergo functional magnetic resonance imaging (fMRI). Willingness to participate in repeated assessments and as part of a delayed treatment group. Exclusion Criteria: Evidence of current or prior history of psychosis or bipolar disorder as evidenced by self-report or clinical interview. Active substance dependence within the past 6 months as evidenced by clinical interview. Current regular psychiatric medication use (i.e. antidepressants), except for as-needed benzodiazepine or opiate medication no more than three times per week, on average, or for short-duration stimulant medication for ADHD that can be skipped within 24 hours of study visits. A recent (<6 months) suicide attempt or current active ideation with intent. Unremovable ferrous metal in body. History of neurological disorder, stroke, seizures/convulsions (except febrile seizures in childhood), epilepsy, brain surgery, electroconvulsive or radiation treatment, brain hemorrhage or tumor, or thyroid disorder. Anyone who is pregnant or trying to become pregnant. Current or past year (> 3 sessions), psychotherapy with a prominent exposure or cognitive restructuring component (i.e. EMDR, CBT, DBT, etc.). Previous or current (es)Ketamine treatment and/ or brain stimulation/neuromodulatory treatment (i.e. rTMS, DBS, ECT, etc.). Other ongoing treatment that is likely to confound experimental effects. Previous penetrating head injury/TBI. Mild-to-moderate TBI without penetrating injury is allowable.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomization will be stratified based upon baseline presence/absence of MDD and will occur using pre-specified block randomization with randomly-sized blocks of either 4 or 6 to ensure near-equal distribution of participants with and without comorbid MDD between the two arms over time, while avoiding the ability for study personnel to predict treatment assignment of the next participant. Block size for a two-arm trial should be at least 4 and an even multiple,154 and a block size of 6 will help to present predictability of group assignment and will also neatly result in 10 blocks of 6 and 15 blocks of 4 for at total N of 120. Blocks will involve various orderings of participant assignment, each block will be assigned a number, and a random list generator will then order the block sequences prior to the start of the study. This will ensure equal numbers of participants with and without MDD are assigned to each treatment condition and limit predictability of assignment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Treatment<br>Those individuals randomized to immediate treatment will commence individual cognitive processing therapy (CPT) with an assigned study therapist, following the completion of baseline procedures. | Behavioral: Cognitive Processing Therapy<br>* Cognitive processing therapy is a widely-utilized, empirically-supported treatment developed for PTSD. It is based on a cognitive theory of trauma which emphasizes the impact of trauma on belief systems and the development of stuck points, which are unhealthy, unrealistic, and maladaptive ways of thinking that serve to maintain unhealthy beliefs and reinforce PTSD symptoms.<br>* Other names: CPT;|
| Placebo Comparator: Delayed Treatment<br>Individuals randomized to the delayed treatment condition will be informed after randomization that their treatment will start in 6-8 weeks (the approximate period it will take for individuals in the immediate treatment arm to complete CPT and post-treatment assessments). During this period, the study postdoctoral fellow (who will be unblinded to treatment arm) will maintain regular contact with individuals through weekly phone and e-mail check-ins to maintain participant engagement and to ensure the participant is not experiencing a significant deterioration in mental health or functioning (e.g., developing suicidal ideation or behavior). | Behavioral: Cognitive Processing Therapy<br>* Cognitive processing therapy is a widely-utilized, empirically-supported treatment developed for PTSD. It is based on a cognitive theory of trauma which emphasizes the impact of trauma on belief systems and the development of stuck points, which are unhealthy, unrealistic, and maladaptive ways of thinking that serve to maintain unhealthy beliefs and reinforce PTSD symptoms.<br>* Other names: CPT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within subject beta coefficients for each parametrically modulated regressor of the Reinforcement Learning Task with Threat | A 6 mm sphere will be drawn around each participant's spatially normalized image at coordinates defined by prior findings in the pilot sample and average percent signal changes will serve as each individual's dependent measure. | [10 weeks] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within-subject BOLD contrast for unexpected absence of juice vs. expected absence of juice (negative temporal Prediction Errors). | The changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation between the unexpected absence of juice vs. expected absence of juice. | [10 weeks] | 
| Within-subject BOLD contrast for the unexpected delivery of juice vs. the expected delivery of juice (positive temporal Prediction Errors). | The changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation between the unexpected delivery of juice vs. the expected delivery of juice. | [10 weeks] | 
| BOLD contrast of DECREASE Negative vs. LOOK Negative of the Cognitive Reappraisal Task. | A method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time. | [10 weeks] | 
| BOLD contrast of LOOK Negative vs. LOOK Neutral of the Cognitive Reappraisal Task. | A method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time. | [10 weeks] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, Post Traumatic Stress, Emotional Numbing, CPT, Cognitive Processing Therapy, Therapy, Chronic PTSD