Meredith A. Reid - US grants

? DESCRIPTION (provided by applicant): Schizophrenia is a complex, often debilitating chronic mental disorder that affects over 50 million people worldwide. Cognitive deficits are a core feature of the illness and lead to poor occupational success and long- term functional outcomes. As a result, patients face enormous emotional and financial burdens because of these symptoms. One of the most well-studied cognitive deficits in schizophrenia is working memory. Yet, currently there are no treatments for working memory deficits in schizophrenia, possibly because the neural basis of working memory dysfunction is not well understood. Functional magnetic resonance imaging (fMRI) is one of the most powerful non-invasive ways to investigate dysfunction in psychiatric disorders. In fact, there is a rich body of work using fMRI o examine working memory in schizophrenia, and the dorsolateral prefrontal cortex (DLPFC) has been identified as a key region of working memory dysfunction. Consistent with imaging findings, postmortem evidence indicates alterations in neuronal circuitry in the DLPFC of patients. Given the disruption of several neurotransmitter systems in schizophrenia, including dopamine, glutamate, and gamma- aminobutyric acid (GABA), an important challenge now facing the field is to determine how alterations in neural activation during working memory are linked to changes in the underlying neurochemistry. Functional magnetic resonance spectroscopy (fMRS) can potentially address this issue by measuring neurometabolite changes induced by neural activity in response to stimuli. However, existing fMRS work has largely focused on visual and somatosensory systems. Of those studies, only one has focused on working memory despite its disruption in schizophrenia and other psychiatric illnesses. Furthermore, most fMRS investigations have been performed at lower field strengths, likely limiting the sensitivity of detecting metabolite changes. Due to the paucity of fMRS studies and its potential to investigate the neural basis of working memory dysfunction in schizophrenia, our overall goals are to develop fMRS techniques to examine neurochemistry underlying working memory by linking changes in neural activation to changes in neurometabolites. To accomplish these goals, we propose to implement fMRS at 7T using the N-back working memory task to measure neurometabolite changes in the DLPFC of schizophrenia patients and healthy controls. The proposed research will build on the applicant's previous expertise in MRS and fMRI and allow for training opportunities in high-field 7T acquisition, advanced MRS analysis and quantitation, cognitive neuroscience, and clinical applications. If successful, these experiments will provide a foundation for further investigations into the link between neural activity and changes in neurometabolites during working memory and other cognitive tasks. Ultimately, this research will provide experimental evidence for understanding the neurochemical basis of working memory as well as provide a non-invasive tool for probing correlates of cognitive dysfunction in schizophrenia and for identifying potential targets for the development of novel medications to treat cognitive deficits in schizophrenia.

PROJECT SUMMARY / ABSTRACT 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.

This project aims to combine information and methods from neuroscience and biomedical engineering to map brain circuits that underlie human cognition, emotion, and decision making. Research has shown that these circuits are compartmentalized into specific anatomical regions, which give rise to characteristic brain activity patterns and behavioral responses to stimuli. Advanced imaging methods have been developed to passively localize functional brain anatomy; however, methods are lacking that allow for non-invasive mapping at similarly high resolutions by actively modulating human brain activity. Such methods are needed to inform the development of advanced medical treatments for cognitive and mental health disorders, and to advance next-generation brain-computer interface technologies. Therefore, this project has been designed to achieve three major goals: 1) advance state-of-the-art, functional human brain mapping and brain-computer interface methods, 2) increase the detail of information regarding circuit mechanisms that give rise to human cognition and emotion, and 3) demonstrate potential new approaches to treating brain disorders and injuries. Insights gained from this project can lead to important new insights into the mechanisms by which human deep-brain activity gives rise to cognitive-emotional behaviors, such as social thought processes, impulsivity, and affect.<br/> <br/>To achieve these goals, low-power ultrasound will be pulsed and focused across the skull of human participants into specific anatomical brain regions using image-guided methods to modulate local activity at high spatial resolutions while: 1) recording learning and decision-making outcomes under different behavioral reward and emotional conditions; 2) recording changes in electrical brain activity; and 3) recording changes in the anatomical distribution and concentration of neurotransmitter metabolites. Results from analyses of these data will provide new, high-resolution information regarding how different brain regions cooperate to account for learning and emotion during decision making. The project includes the creation of a national Focused Ultrasound Science and Education program to broaden participation, expand training opportunities, improve education, and cultivate knowledge in neuroscience, engineering, and medicine. Data collected, analytical reports produced, and methods developed in this project will be made publicly available in the Focused Ultrasound Science and Education data repository.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.