• Jessica Archibald, Erin L MacMillan, Alinda Enzler, Catherine R Jutzeler, Petra Schweinhardt, and KramerJohn L KJLKInternational Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada; Department of Experimental Medicine, University of British Columbia, Vancouver, Canada; School of Kinesiology, University of Bri.
• International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada; Department of Experimental Medicine, University of British Columbia, Vancouver, Canada. Electronic address: jessica.archibald@ubc.ca.
• Neuroimage. 2020 Jul 15; 215: 116794.

BackgroundThe role of the brain in processing pain has been extensively investigated using various functional imaging techniques coupled with well controlled noxious stimuli. Studies applying experimental pain have also used proton magnetic resonance spectroscopy (1H-MRS). The advantage of MRS compared to other techniques is the capacity to non-invasively examine metabolites involved in neurotransmission of pain, including glutamate, γ-aminobutyric acid (GABA), glutamate ​+ ​glutamine (Glx), and glutamine.ObjectiveTo systematically review MRS studies used in the context of studying experimental pain in healthy human participants.Data SourcesPubMed, Ovid Medline, and Embase databases were searched using pre-specified search terms.Eligibility CriteriaStudies investigating glutamate, GABA, Glx and/or glutamine in relation to experimental pain (e.g., heat) in healthy participants via MRS.Appraisal CriteriaEach study was evaluated with a modified quality criterion (used in previous imaging systematic reviews) as well as a risk of bias assessment.ResultsFrom 5275 studies, 14 met the selection criteria. Studies fell into two general categories, those examining changes in metabolites triggered by noxious stimulation or examining the relationship between sensitivity to pain and resting metabolite levels. In five (out of ten) studies, glutamate, Glx and/or glutamine increased significantly in response to experimental pain (compared to baseline) in three different brain areas. To date, there is no evidence to suggest Glx, glutamate or glutamine levels decrease, suggesting an overall effect in favour of increased excitation to pain. In addition to no changes, both increases and decreases were reported for levels of GABA+ (=GABA ​+ ​macromolecules). A positive correlation between pain sensitivity and resting glutamate and Glx levels were reported across three studies (out of three). Further research is needed to examine the relationship of GABA+ and pain sensitivity.LimitationsA major limitation of our review was a limited number of studies that used MRS to examine experimental pain. In light of this and major differences in study design, we did not attempt to aggregate results in a meta-analysis. As for the studies we reviewed, there was a limited number of brain areas were examined by studies included in our review. Moreover, the majority of studies included lacked an adequate control condition (i.e., non-noxious stimulation) or blinding, which represent a major source of potential bias.ConclusionMRS represents a promising tool to examine the brain in pain, functionally, and at rest with support for increased glutamate, glutamine and Glx levels in relation to pain.ImplicationsResting and functional MRS should be viewed as complementary to existing neuroimaging techniques, and serve to investigate the brain in pain. Systematic review registration number- CRD42018112917.Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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