This Mentored Research Scientist Development Award (K01) application is a comprehensive training plan to provide the candidate with additional and advanced skills needed to establish an independent program of post- traumatic stress disorder (PTSD) research using neuroimaging methods. The candidate?s prior training in neuroimaging has allowed her to hone many skills necessary to achieve this goal. However, she requires additional training and experience in the following areas: (1) didactic and research training in PTSD; (2) advanced techniques in high-field (7T) MR spectroscopy (MRS), specifically functional MRS (fMRS); (3) programming skills for neuroimaging analyses; and (4) writing and professional development. The proposed study will investigate the neurometabolic and functional correlates of cognitive deficits in PTSD. People with PTSD commonly report difficulties with concentration, attention, and memory in addition to the core symptoms of intrusive thoughts, avoidance, and hyperarousal. These cognitive symptoms can be especially distressing and lead to poor social and occupational function and poor quality of life. Neuropsychological testing indicates that working memory (WM) is one cognitive process affected in PTSD, yet the neural basis of WM dysfunction is not well understood. Understanding the nature of these deficits is important not only because WM is crucial for everyday functioning but also because WM facilitates common treatment strategies, such as cognitive behavioral therapy. Converging evidence points to glutamatergic dysfunction in key brain regions in PTSD. These abnormalities could underlie the differential activation patterns observed with functional imaging when people with PTSD perform WM tasks; however, this has not been directly tested. Magnetic resonance spectroscopy (MRS) has demonstrated great promise in closing this gap with recent in vivo studies of PTSD showing disruptions of glutamate levels. However, none of these studies have correlated these in vivo metabolic measurements with neural activation. Functional MRS (fMRS) can potentially address this issue by measuring neurometabolic changes induced by neural activity in response to stimuli. Unlike traditional MRS, which acquires data during the resting state, fMRS acquires data while participants are engaged in performing a task, thereby providing a dynamic rather than static profile of neurometabolites. In this application, we propose to develop fMRS techniques at 7T to explore the neural mechanisms that contribute to WM deficits in PTSD. This research will combine traditional (static) MRS, functional MRI (fMRI), and advanced dynamic fMRS to investigate the relationship between neural activation during WM and the underlying neurochemistry in PTSD. Since fMRS and fMRI probe different aspects of neuronal firing and synaptic activity, the combined approach of these techniques could better characterize the neurobiology underlying WM deficits in PTSD. If successful, these methods could potentially be used to test the effects of current treatments and identify potential targets for the development of novel medications to improve outcomes for people with PTSD.
The goal of this research proposal is to investigate neurometabolic and functional correlates of working memory deficits in people with post-traumatic stress disorder (PTSD) using state-of-the-art functional magnetic resonance spectroscopy (fMRS). Findings from this project will contribute to a more complete understanding of working memory and how it is affected in people with PTSD and could lead to more effective neuroimaging biomarkers for assessing the effects of current and novel treatment strategies.
