Posttraumatic stress disorder (PTSD) is one of the most common service-related mental health conditions among all treatment-seeking Veterans, and the critical lack of advancement in pharmacological treatment of this disorder has recently been termed an urgent crisis by leaders in the field. The absence of progress in developing more effective treatments targeting PTSD stems from an inability to objectively characterize behavioral dysfunction related to PTSD symptoms and link it directly to underlying neural process dysfunction that can be targeted with medications. One of the most encouraging recent developments in the psychopharmacology of PTSD was a randomized controlled trial (RCT) showing that the norepinephrine (NE) and dopamine (DA) reuptake inhibitor methylphenidate (MPH) was associated with a remarkably robust reduction in PTSD symptoms, but the effects of MPH on complex behaviors remains poorly understood, and improved understanding of its mechanism in PTSD will be crucial for individualized patient selection and for development of new interventions targeting similar mechanisms. This application seeks to integrate (a) a computational psychiatry approach with (b) pharmacological intervention with MPH and (c) functional neuroimaging to characterize a complex pharmacologic mechanism in PTSD and assist the development of process- and neural circuit-specific interventions for Veterans with this disabling condition. A core feature across multiple PTSD symptom clusters is a failure to appropriately modulate the salience of cues according to environmental context. MPH, via its NE and DA actions, is known to improve modulation of salience according to context in attention deficit hyperactivity disorder (ADHD), suggesting a similar mechanism may underlie its efficacy in PTSD. The failure of contextual salience regulation in PTSD spans multiple symptom domains, indicating the value of a unifying computational psychopharmacology approach to salience that can go beyond description of disparate symptoms and measure a core underlying process dysfunction and its improvement with MPH. Accumulating evidence indicates that a computational surprise- driven learning paradigm can quantitatively operationalize the deficit in salience modulation as a failure to scale surprise according to environmental volatility (rate of change): (1) In healthy subjects, environmental volatility scales surprise-driven learning via brain NE and DA; this process is impaired in anxious individuals. (2) Our own preliminary data indicate that individuals with PTSD exhibit exaggerated surprise-driven learning in a stable environment. (3) Our own preliminary data indicate that MPH enhances the influence of environmental volatility on surprise-driven learning in healthy subjects. (4) Our own preliminary fMRI data in a sample of combat Veterans indicates that PTSD symptoms are associated with exaggerated activation to surprise in a salience-sensitive region in the posterior parietal cortex in a stable environment. The present application seeks to apply computational modeling and functional neuroimaging to examine surprise-driven learning in a sample of Veterans with PTSD, administered a single dose of MPH and placebo on separate testing sessions in randomized order, to characterize the mechanism of MPH in PTSD. This is an application of computational psychopharmacology, which promises to help address the crisis in psychopharmacology of PTSD in Veterans by specifying new mechanistic targets for intervention, aiding the development of novel interventions and targeting of optimal treatments to individual Veterans. In conjunction with the Research Plan, the Career Plan and Mentoring Plan will allow the applicant to achieve independence as a VA clinician-scientist using computational psychopharmacology and functional neuroimaging to develop novel, personalized interventions for Veterans with PTSD and related disorders. The applicant will ultimately develop a Merit application using similar methods to predict treatment response in Veterans with PTSD to help enable a personalized medicine approach to this severely burdensome disorder.
A substantial majority of Veterans with posttraumatic stress disorder (PTSD) continue to suffer even with the best current medications. New scientific tools are urgently needed to overcome poor understanding of the links between symptoms, brain dysfunction, and the specific effects of medications to develop better and more targeted PTSD treatments. Preliminary research has shown that the stimulant methylphenidate caused robust reduction in PTSD symptoms, but the mechanism of this effect is unknown. This project aims to apply new computational and neuroimaging methods to characterize the mechanism by which methylphenidate improves PTSD in Veterans. It will use these tools to quantitatively measure the effect of methylphenidate in enabling the brain to more flexibly adapt to different environments, thereby reducing the brain?s hyper-reactivity to sensory stimulation. The ultimate goal is to enable individualized treatments for Veterans with PTSD and the development of new, more effective medications for this burdensome disorder.
