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.
Cognitive deficits, including working memory, are a common feature of schizophrenia and lead to poor occupational success and long-term functional outcomes. In this application, we propose to develop functional magnetic resonance spectroscopy (fMRS) to detect neurometabolite changes during a working memory task. This research will benefit our basic understanding of normal brain function as well as provide a non-invasive tool for probing the neurochemical basis underlying working memory dysfunction in schizophrenia with the ultimate goal of identifying potential targets for the development of novel medications to treat cognitive deficits in schizophrenia.
