Posttraumatic Stress Disorder (PTSD) is one of the most prevalent service-related mental health conditions in treatment-seeking Veterans, yet even gold standard interventions are not universally effective. Veterans would be greatly served by development of novel intervention approaches for PTSD, particularly those could be easily transportable. The emerging field of neurotherapeutics, which uses computerized training techniques to modulate cognitive processing, is one such approach that has shown promise for improving cognitive and emotional symptoms in mental health disorders. The current proposal represents the first effectiveness study of a cognitive control training intervention for reducing PTSD symptoms in Veterans, with a goal of exploring neurobiological mechanisms of affective and cognitive generalization of training effects.

PTSD is characterized by deficits in "top-down" cognitive control abilities, as evidenced by neuropsychological findings of poor executive functioning and neurobiological evidence of diminished prefrontal cortical activity coupled with exaggerated limbic activity. Cognitive control deficits are causally implicated in re-experiencing symptoms, suggesting that cognitive control may be a novel and effective treatment target. The investigator developed a cognitive control training intervention that has demonstrated initial evidence of efficacy in civilian women with PTSD secondary to sexual assault. However, the effects of this program in Veteran participants and the precise neurocognitive mechanisms of symptom reduction in the intervention remain poorly understood. If training cognitive control directly enhances functioning of specific cognitive systems that are causally implicated in the etiology of emotional and cognitive symptoms, treatment-related improvements in affective symptoms and neuropsychological performance within the trained domain would be predicted. From a neurobiological perspective, training cognition is thought to operate via modification of specific neural substrates, suggesting that training effects should generalize to affective processes relying on shared neural regions. One such affective process is reappraisal (i.e., generating different ways of thinking about emotional content in order to regulate emotion), which requires cognitive control over affective emotional information, and depends on brain circuits identified as key cognitive control regions (e.g., dorsolateral prefrontal cortex, dlPFC). PTSD is characterized by aberrant affective and neurobiological patterns during reappraisal that likely contribute to persistent re-experiencing and hyperarousal symptoms. Training may reduce symptoms by improving neural functioning of cognitive control regions during affective control processes (e.g., reappraisal) that are critical to managing trauma-related affect.

In this proposal, the applicant's prior clinical trials research experience will be integrated with new mentoring in functional neuroimaging (fMRI) to facilitate identification of treatment-related symptom and neural change following cognitive control training. Bridging research on basic neurocognitive mechanisms of PTSD with intervention research in this way will ultimately facilitate precise neurotherapeutic treatment development and personalization techniques. In this randomized controlled trial (RCT), 80 Veterans with PTSD will be assigned to the cognitive control training program developed by the applicant (intervention condition: COGnitive ENhancement Training \[COGENT\]), or a minimal cognitive control program (sham training condition \[ST\]) completed twice week for 8 weeks. The COGENT training program requires participants to repeatedly utilize specific cognitive control functions (i.e., interference control) in the context of a modified working memory capacity task, with the goal of improving performance through implicit, practice-based learning. The primary outcome will be PTSD symptom reduction, and cognitive generalization will be assessed with a brief neuropsychological assessment. To evaluate changes in the neural bases proposed to underlie COGENT, participants will undergo fMRI while completing two cognitive control tasks (affectively neutral and emotionally balanced) before and after treatment. Assessments will occur at baseline, post-treatment, and at follow-up.

Aim 1: To examine the effects of the training program on PTSD and neurocognitive symptoms in Veterans. PTSD symptoms will be measured using the Clinician Administered PTSD Scale (CAPS) interview and neurocognitive functioning will be assessed with Delis Kaplan Executive Functioning System subtests. Individuals completing COGENT are hypothesized to show a) greater reduction in PTSD re-experiencing symptoms and b) improved neurocognitive performance relative to those in ST over time. Exploratory aims will also examine changes in PTSD diagnostic status across groups.

Aim 2: To examine neurobiological changes in COGENT versus ST during neutral and affective cognitive control tasks. Neurobiological response to treatment will be assessed using fMRI during cognitive control tasks (one affectively neutral working memory capacity task and one affectively balanced reappraisal task with negative emotional information). Individuals completing the COGENT program are predicted to demonstrate increased neural activation of dlPFC and anterior cingulate regions from pre- to post-training during the tasks. Exploratory aims will evaluate corresponding physiological change during the affective fMRI task and the utility of fMRI neural functioning at baseline for predicting treatment response.