Task-Related Modulation of Hippocampal Glutamate, Subfield Volumes, and Associative Memory in Younger and Older Adults: A Longitudinal ¹H fMRS Study

¹H fMRS is becoming a well-established technique that is sensitive to measuring task-related and pathology-relevant regional dynamic changes in neurotransmitters such as glutamate. The observed task-related changes in brain glutamate are consistent with new metabolic steady states reflecting the neural output driven by shifts in the local excitatory and inhibitory balance on local circuits. This research has recently published studies demonstrating increased modulation of glutamate during a working memory task as well as differences in steady-state glutamate levels and variability between tasks of varying constraints on behavior.

Examining age difference and age-related changes in task-related Glutamate (Glu) modulation is the main aim of this study. To advance this goal, we introduce the application of in vivo ¹H fMRS. We will assess Glu modulation within the hippocampus (HC), while older and younger participants engage in an associative learning and memory task that we have established as a robust, specific hippocampal challenge in preciously published work. ¹H fMRS provides real-time task-related changes in Glu that is independent of vascular confounds as is with BOLD fMRI and at a temporal resolution of under a minute. The task, the brain location, and the choice of the neurotransmitter (Glu) are highly relevant to aging and AD.

This high-risk high-yield study aims to establish Glu modulation changes as a viable early marker of cognitive decline in the context of structural HC changes and decline in memory performance. The knowledge advancement from this study will be demonstration of a link between changes in task-related Glu modulation in the older adults, HC volume and memory over time. This study will provide important foundations for future multi-occasion longitudinal studies that will advance understanding of individual differences in cognitive development in the late part of the lifespan without misleading inferences from cross-sectional studies and provide a foundation for intervention aimed at mitigating cognitive declines.

  1. Woodcock EA*, Anand C, Khatib D, Diwadkar VA, Stanley JA. Working Memory Modulates Glutamate Levels in the Dorsolateral Prefrontal Cortex during ¹H fMRS. Frontiers in Psychiatry: Neuroimaging and Stimulation. 2018, 9 (66):1-10.
  2. Lynn J*, Woodcock EA, Anand C, Khatib D, Stanley JA. Differences in steady-state glutamate levels and variability between ‘non-task-active’ conditions: Evidence from ¹H fMRS of the prefrontal cortex. NeuroImage. 2018, 172: 554-561.