Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation

Abstract

Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (¹H fMRS) observed significant dlPFC glutamate modulation during letter 2-back performance, indicative of working memory-driven increase in excitatory neural activity. Acute stress has been shown to impair working memory performance. Herein, we quantified dlPFC glutamate modulation during working memory under placebo (oral lactose) and acute stress conditions (oral yohimbine 54 mg + hydrocortisone 10 mg). Using a double-blind, randomized crossover design, participants (N = 19) completed a letter 2-back task during left dlPFC ¹H fMRS acquisition (Brodmann areas 45/46; 4.5 cm³). An automated fitting procedure integrated with LCModel was used to quantify glutamate levels. Working memory-induced glutamate modulation was calculated as percentage change in glutamate levels from passive visual fixation to 2-back levels. Results indicated acute stress significantly attenuated working memory-induced glutamate modulation and impaired 2-back response accuracy, relative to placebo levels. Follow-up analyses indicated 2-back performance significantly modulated glutamate levels relative to passive visual fixation during placebo but not acute stress. Biomarkers, including blood pressure and saliva cortisol, confirmed that yohimbine + hydrocortisone dosing elicited a significant physiological stress response. These findings support a priori hypotheses and demonstrate that acute stress impairs dlPFC function and excitatory activity. This study highlights a neurobiological mechanism through which acute stress may contribute to psychiatric dysfunction and derail treatment progress. Future research is needed to isolate noradrenaline vs. cortisol effects and evaluate anti-stress medications and/or behavioral interventions.

Keywords: (1)H fMRS; Dorsolateral prefrontal cortex; Glutamate; Noradrenaline; Stress; Working memory.

Figure 1–

The experimental paradigm is depicted. Flashing checkerboard (3Hz; 208s) was followed by five repetitions (blocks) of alternating periods of passive visual fixation (32s; 2s instructions “Rest”, 30s static fixation cross) and letter 2-back (64s; 4s instructions “2-back”, 20 serial capitalized letters [3s/letter]).

Figure 2–

A) The voxel location is depicted in orthonormal slices. The voxel (15×20×15mm; 4.5cm³) was placed in the left dlPFC (Brodmann Areas 45/46) based on our prior research (Woodcock et al., 2018b). B) Immediately following the ¹H fMRS letter 2-back task, BOLD fMRI data were collected during two repetitions of letter 2-back (identical task parameters) during both experimental sessions. BOLD fMRI activation (2-back > passive visual fixation) during the placebo session and the ¹H fMRS voxel are depicted on orthonormal slices. C) BOLD fMRI activation (2-back > passive visual fixation) during the stress session and the ¹H fMRS voxel are depicted on orthonormal slices.

Figure 3–

A) Letter 2-back response accuracy (% correct) across task blocks is depicted. Participants responded more accurately across task blocks on average during placebo (blue) than stress (green). Paired t-test: *p < .05, **p < .01. B) Letter 2-back response latency (ms) across task blocks is depicted. Response latency decreased across task blocks for both experimental sessions. Error bars: ± 1 SEM.

Figure 4–

Glutamate modulation was calculated separately for early and late 2-back as the percentage change in glutamate levels during each task block relative to the preceding block of passive visual fixation. A) Mean early 2-back glutamate modulation is depicted across task blocks for the placebo (blue) and stress (green) sessions. B) Mean late 2-back glutamate modulation is depicted across task blocks for the placebo (blue) and stress (green) sessions. C) Mean glutamate levels for each task phase (passive visual fixation [light gray], early 2-back [red], and late 2-back [blue]) during the placebo session are depicted. D) Mean glutamate levels for each task phase during the stress session are depicted. Error bars: ± 1 SEM. ^Paired t-test; p ≤ .10; *Paired t-test; p < .05.

Figure 5–

A) A cartoon illustration of a noradrenergic synapse during ‘normal’ (blue) and ‘stressed’ (red) conditions are depicted. Moderate levels of postsynaptic receptor stimulation are mediated primarily through the high-affinity α₂-adrenoceptor during ‘normal’ conditions. During acute stress (i.e., YOH dosing), the synapse is flooded with noradrenaline, which binds lower-affinity receptors, including α₁- and β₁-adrenoceptors. B) The theorized inverted ‘U’-relationship between noradrenaline levels and dlPFC function is depicted. YOH+HYD dosing increased noradrenaline levels which impaired 2-back response accuracy and disrupted dlPFC engagement/excitatory activity (glutamate modulation).