Identifying clinically relevant neural circuit mechanisms of cognitive control training for PTSD

Va San Diego Healthcare System, San Diego CA

Investigators

Linked publications, trials & patents

Abstract

Posttraumatic stress disorder (PTSD) is prevalent, debilitating, and associated with significant levels of functional impairment in Veterans seeking care at the VA. Despite evidence that current treatments for PTSD are effective, a substantial portion of individuals maintain elevated PTSD symptoms after first line treatments. Mechanistic insight and tools that improve the neurocognitive and affective mechanisms that underlie successful clinical outcomes from evidence-based psychotherapies, like prolonged exposure, are highly needed. One of the most prominent mechanisms associated with therapeutic symptom reduction in PTSD is fear extinction. Indeed, extinction learning is a key theoretical treatment target in exposure-based therapies for PTSD. Fear extinction learning is not only an emotional process, but relies on an individual's cognitive control abilities, including working memory (WM). Under a WM framework, high WM ability offers the ability of an individual to adjudicate the competition between threat and extinction memory expression as they repeatedly encounter feared cues that are no longer threatening. Consistent with this hypothesis, previous investigations and preliminary data from our group shows replicable findings that variation in WM ability is associated with laboratory measures of fear extinction learning including threat expectancy ratings, psychophysiological, and dorsal anterior cingulate cortex (dACC) activity. Our team has also shown that psychophysiological and neural measures of fear extinction is a construct malleable to treatment. Moreover, our preliminary data show that elevated PTSD symptoms are associated with increased dACC and decreased posterior hippocampal activity during fear extinction and that WM ability is negatively associated with PTSD symptom severity. We also show data in civilian populations that a brief WM training (WMT) designed to boost WM is feasible and is effective in enhancing behavioral and neural markers of WM ability, and is feasible in a sample of Veterans with PTSD. Critically, we provide evidence in two independent datasets that 1) WMT is associated with an EEG measure of fear extinction and 2) a decrease in anxiety during exposure trials. These preliminary findings raise the intriguing possibility for the mechanistic link between WM and extinction, and that enhancing WM ability through WMT may also improve fear extinction learning success in Veterans with PTSD. The current proposal aims to answer these questions in two ways. First, in a between-group design, Veterans diagnosed with PTSD will complete 8-sessions of working memory training (WMT) or sham-training (ST) over a four-week period. At pre- and post-training, Veterans will complete a standard fear acquisition & extinction learning task in addition to tasks assaying WM capacity and cognitive control. We will identify whether WMT modulates behavior, psychophysiological, and neural changes in extinction learning. Second, independent of WMT, we will further test the conceptual link between WM and extinction in Veterans with PTSD by testing whether neural circuits associated with high WM capacity and extinction learning are linked. To this end, we will leverage novel computational modeling of extinction learning to track dynamic memory updating to test the conceptual mechanistic link between WM and extinction. To ascertain the relevance to PTSD symptoms, we will compute an exploratory multi-task canonical correlation analysis to identify the multivariate patterns linking WM, fear extinction to specific PTSD symptom sub-clusters. The project is expected to determine if a cognitive control training program targeting WM capacity shows the potential to enhance behavioral and neural markers of fear extinction, mechanisms that are clearly integral to current PTSD treatments. These aims support the VA mission of testing and evaluating innovative treatment targets for PTSD. Results will provide a mechanistic foundation for future clinical trials that test whether adding WMT prior to or in conjunction with exposure-based psychotherapies will improve clinical outcomes and further clarify existing mechanistic and neurobiological models of PTSD and its treatment for Veterans.