Resting and Dynamic Brain Glutamate by MRS In Vivo: Relation to Suicidal Behavior

Project Summary Suicide is a leading cause of premature death in the United States (US). Convergent evidence across genetic, postmortem, and immunohistochemical studies suggest a role for altered glutamate (Glu)—the amino acid neurotransmitter that mediate most of the brain's fast excitatory transmission—in the pathogenesis of suicide. Still, there is little research to-date on brain glutamate concentrations measured in vivo in suicidal populations. Moreover, no study has examined alterations in activity-dependent dynamic glutamate responses underlying mood- and cognition-related risk factors for suicide. This K08 project will use magnetic resonance spectroscopy (MRS) to quantify in vivo steady-state Glu concentrations and dynamic glutamate responses in n=70 currently depressed participants with and without a history of suicidal behavior (MDD+SA and MDD-SA, respectively) and n=30 healthy volunteers (HV). Steady-state Glu will be imaged across the length of the brain using MR spectroscopy imaging (MRSI). We will also use functional MRS (fMRS) to detect activity-dependent changes in glutamate. Participants will complete two functional tasks during MRS scanning: a pain-inducing cold pressor task (CPT) and a neurocognitive task (Stroop); and dynamic glutamate activity (GluΔ) will be measured in response to these tasks. The group design will allow us to parse suicide- and depression-related alterations in Glu signaling. Salivary cortisol measurements will be obtained before and after the MRS scan. Participants will also complete seven days of ecological momentary assessment (EMA) during which they will report on suicidal ideation, affect, and stressors, six times daily. This will allow evaluation of the relationship between Glu signaling and vulnerability to stress-related suicidal ideation/mood symptoms in daily life. We hypothesize that MDD+SAs will exhibit altered cortical Glu concentrations and attenuated responses to physical pain stimulation, compared with MDD-SAs and HVs. We will also evaluate whether dynamic glutamate responses to functional tasks are associated with subjective pain responses, neurocognitive performance, cortisol stress reactivity, and behavioral responses to naturalistic stressors. Understanding the contribution of altered brain glutamate to suicide risk may help to facilitate development of pharmacological treatments that can overcome limitations of existing monoamine-focused antidepressants currently used for treatment of suicide risk.