Differences in steady-state glutamate levels and variability between ‘non-task-active’ conditions: Evidence from 1H fMRS of the prefrontal cortex

Abstract

Proton functional magnetic resonance spectroscopy (H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task-active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of thisH fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non-task-active' steady-state level of glutamate with minimal variability during H MRS investigations.

Working Memory Modulates Glutamate Levels in the Dorsolateral Prefrontal Cortex during 1H fMRS

“…The variance minimization phase consisted of a flashing grayscale checkerboard (centered on-screen; 3Hz) presented for 208s. Previous research in our laboratory demonstrated that the flashing checkerboard minimized glutamate variance better than alternative approaches ( 36 ). The working memory task consisted of seven interleaved repetitions of passive visual fixation [32s; 2s of instructions (“Rest”), 30s of static fixation cross centered on-screen] and letter 2-back [64s; 4s of instructions (“2-back”), 20 capitalized letters presented serially 3s/letter (60s total); each letter was presented on screen for 500ms followed by 2,500ms of blank screen].…”

“…1 H fMRS is a neuroimaging technique that facilitates direct measurement of dynamic neurochemistry levels. Seminal 1 H fMRS research was conducted at high field, but technological advances have made detection of glutamate modulation possible at 3T ( 9 , 15 , 36 ). The 1 H fMRS signal does not differentiate cell type, neuron vs. glia, or compartment, intracellular vs. extracellular, but is directly proportional to the concentration of molecules within the voxel.…”

“…Thus, isolation of task-evoked modulation necessitates accurate measurement of both states, which can be challenging, especially in the dlPFC. We selected the continuous visual fixation cross as our “non-task-active” behavioral paradigm based on prior research ( 36 ). In that study, we found glutamate levels exhibited less variability and lower levels, thus reflecting a better approximation of the “basal” state than other behavioral paradigms tested, such as eyes closed, flashing checkerboard and finger tapping ( 36 ).…”

“…We selected the continuous visual fixation cross as our “non-task-active” behavioral paradigm based on prior research ( 36 ). In that study, we found glutamate levels exhibited less variability and lower levels, thus reflecting a better approximation of the “basal” state than other behavioral paradigms tested, such as eyes closed, flashing checkerboard and finger tapping ( 36 ). This is consistent with results herein that glutamate levels significantly increased across time during the interleaved passive visual fixation, reflecting less constrained behavior and a poor measurement of the “basal” state, while 2-back glutamate levels were unchanged across task blocks.…”

Functional magnetic resonance spectroscopy in patients with schizophrenia and bipolar affective disorder: Glutamate dynamics in the anterior cingulate cortex during a working memory task

“…The number of errors seen in the schizophrenia group for the 0-back condition suggests this was challenging for some participants and glutamatergic measures may have already increased from a resting condition level, preventing changes between the 0-back and 2-back conditions from being detected. Recent work has noted the importance of the 'non-task-active' behavioural paradigm in 1 H-fMRS studies and suggests a continuous visual fixation cross exhibits less variability and lower levels of glutamate and therefore providing a better approximation of baseline state than other behavioural paradigms including eyes closed, flashing checkerboard or finger tapping (Lynn et al, 2018). An alternative explanation for the worse performance in the schizophrenia group that should also be considered is that of aberrant salience (Kapur, 2003), whereby these patients may be more likely to be inappropriately processing stimuli in their environment that would normally be considered irrelevant, and as a result might be less able/or willing to engage with and focus attention to the task in question.…”