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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.

SUBMITTER: Woodcock EA

PROVIDER: S-EPMC6491044 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Woodcock Eric A EA Greenwald Mark K MK Khatib Dalal D Diwadkar Vaibhav A VA Stanley Jeffrey A JA

NeuroImage 20181117

Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (<sup>1</sup>H 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 lact ...[more]

PMID: 30458306

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Project description:ImportanceThe extent of dorsolateral prefrontal cortex (DLPFC) plasticity in Alzheimer disease (AD) and its association with working memory are not known.ObjectivesTo determine whether participants with AD had impaired DLPFC plasticity compared with healthy control participants, to compare working memory between participants with AD and controls, and to determine whether DLPFC plasticity was associated with working memory.Design, setting, and participantsThis cross-sectional study included 32 participants with AD who were 65 years or older and met diagnostic criteria for dementia due to probable AD with a score of at least 17 on the Mini-Mental State Examination and 16 age-matched control participants. Participants were recruited from a university teaching hospital from May 2013 to October 2016.Main outcomes and measuresPlasticity of the DLPFC measured as potentiation of cortical-evoked activity using paired associative stimulation (a combination of peripheral nerve electrical stimulation and transcranial magnetic stimulation) combined with electroencephalography. Working memory was assessed with the n-back task (1- and 2-back) and measured using the A' statistic.ResultsAmong the 32 participants with AD, 17 were women and 15 were men (mean [SD] age, 76.3 [6.3] years); among the 16 controls, 8 were men and 8 were women (mean [SD] age, 76.4 [5.1] years). Participants with AD had impaired DLPFC plasticity (mean [SD] potentiation, 1.18 [0.25]) compared with controls (mean [SD] potentiation, 1.40 [0.35]; F1,44 = 5.90; P = .02; between-group comparison, Cohen d = 0.77; P = .01). Participants with AD also had impaired performances on the 1-back condition (mean [SD] A' = 0.47 [0.30]) compared with controls (mean [SD] A' = 0.96 [0.01]; Cohen d = 1.86; P < .001), with similar findings for participants with AD on the 2-back condition (mean [SD] A' = 0.29 [0.2]) compared with controls (mean [SD], A' = 0.85 [0.18]; Cohen d = 2.83; P < .001). Plasticity of DLPFC was positively associated with working memory performance on the 1-back A' (parameter estimate B [SE] = 0.32 [0.13]; standardized β = 0.29; P = .02) and 2-back A' (B [SE] = 0.43 [0.15]; β = 0.39; P = .006) across both groups after controlling for age, education, and attention.Conclusions and relevanceThis study demonstrated impaired in vivo DLPFC plasticity in patients with AD. The findings support the use of DLPFC plasticity as a measure of DLPFC function and a potential treatment target to enhance DLPFC function and working memory in patients with AD.

Project description:Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F (1, 19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t (18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD. Clinical Trial Registration: Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

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

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

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