Towards an Integrated Understanding of Neurotransmitter Dysfunction in Schizophrenia: a Multimodal MR Study 

A prominent view in schizophrenia research proposes that a deficit in GABA function in the hippocampus may lead to hippocampal glutamate excess, which in turn may dysregulate dopamine. Previous research connects elevated levels of dopamine in the striatum to an increase in psychotic symptoms. In this study, we seek to confirm the co-occurrence of these imbalances in individuals with schizophrenia in order to understand the relationship among these neurotransmitter systems and clinical symptoms. We are testing this model in unmedicated individuals with schizophrenia, compared to healthy individuals, using state-of-the-art magnetic resonance spectroscopy (MRS) to non-invasively measure relative levels of Glx (glutamate and glutamine) and GABA in the hippocampus, and using neuromelanin-sensitive MRI (NM-MRI) to quantify concentrations of neuromelanin in the substantia nigra as a proxy for dopaminergic activity. If confirmed, these findings will provide a validated and integrated model of circuit dysfunction that can lead to new therapeutic targets.  

Advancing Functional MRI (fMRI) for Schizophrenia: a Proof-of-Concept for Background-suppressed Dynamic Arterial Spin Label (sbDASL) Imaging  

Prior research in schizophrenia implicates abnormal function in the hippocampus and widespread deficits in functional connectivity in schizophrenia. However, in vivo measurement of hippocampal activity using the traditional blood-oxygen-level dependent (BOLD) MRI method has been limited because this area of the brain is prone to signal dropout and distortion. Background-suppressed dynamic arterial spin labeling (sbDASL) is a newly developed MRI technique that has the potential to overcome the shortcomings of the more commonly used BOLD technique. The purpose of this study is to test reproducibility and sensitivity of sbDASL compared to BOLD. We hypothesize that sbDASL will show improved reproducibility between back-to-back scans of the same individuals and improved sensitivity in detecting functional connectivity changes due to a caffeine challenge. Lastly, we hypothesize that sbDASL will reveal larger effect sizes when comparing the resting state functional connectivity of the hippocampus with associated brain regions and networks in individuals with and without schizophrenia.

Understanding the Role of the Cholinergic System in Schizophrenia: an in vivo [¹⁸F]-VAT PET/MR Study  

Alterations of the cholinergic system in schizophrenia is implicated by several lines of evidence: from higher prevalence of cigarette smoking among patients, to postmortem and genetic studies suggesting deficits in the nicotinic- and muscarinic- cholinergic systems, and models of auditory sensory processing suggesting disrupted cholinergic modulation underlying abnormal gamma rhythms. In light of this, as well as the essential role of the cholinergic system for cognition and modulation of dopamine signaling, which are also abnormal in schizophrenia, we are conducting a proof-of-concept  study using [¹⁸F]VAT, a novel PET tracer for the vesicular cholinergic transporter, to measure cholinergic system activity across the brain in patients with schizophrenia.