Brain GABA and glutamate levels across pain conditions: A systematic literature review and metaanalysis of 1HMRS studies using the MRSQ quality assessment tool Abstract   Background  A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to painfree controls across different pain conditions. However, this has yet to be systematically investigated.    Aims  To establish whether GABA, glutamate, glutamine and Glx levels differ across pain conditions when compared to painfree controls.    Methods  Five databases were searched. Studies were included if they investigated: 1) A pain condition compared to control. 2) Reported GABA, glutamate, glutamine or glutamateglutamine level. 3) Used 1HMagnetic Resonance Spectroscopy (Prospero Project ID CRD42018092170). Data extracted included neurometabolite level, pain diagnosis, and spectroscopy parameters. Metaanalyses were conducted to establish the difference in neurometabolite level between participants with pain and painfree controls for different pain conditions. The MRSQ was developed from existing clinical consensus to allow for the assessment of quality in the included studies.    Results  Thirtyfive studies were included investigating combinations of migraine (nxe2x80xafxe2x80xaf11), musculoskeletal pain (nxe2x80xafxe2x80xaf8), chronic pain syndromes (nxe2x80xafxe2x80xaf9) and miscellaneous pain (nxe2x80xafxe2x80xaf10). Higher GABA levels were found in participants with migraine compared to controls (Hedgeu0027s G 0.499, 95%CI: 0.2 to 0.798). In contrast, GABA levels in musculoskeletal pain conditions (Hedgeu0027s G xe2x88x920.189, 95%CI: 0.530 to 0.153) and chronic pain syndromes (Hedgeu0027s G 0.077, 95%CI: 1.612 to 1.459) did not differ from controls. Results for other brain neurometabolites revealed significantly higher levels for glutamate in participants with migraine and Glx in chronic pain syndromes compared to controls.    Conclusion  These results support the theory that underlying neurometabolite levels may be unique in different pain conditions and therefore representative of biomarkers for specific pain conditions.

Models for nociception stimulation and memory effects in awake and aware healthy individuals Objective: This paper introduces a primer in the health care practice, namely a mathematical model and methodology for detecting and analysing nociceptor stimulation followed by related tissue memory effects. Methods: Noninvasive nociceptor stimulus protocol and prototype device for measuring bioimpedance is provided. Various time instants, sensor location, and stimulus train have been analysed. Results: The method and model indicate that nociceptor stimulation perceived as pain in awake healthy volunteers is noninvasively detected. The existence of a memory effect is proven from data. Sensor location had minimal effect on detection level, while daytoday variability was observed without being significant. Conclusion: Following the experimental study, the model enables a comprehensive management of chronic pain patients, and possibly other analgesia, or pain related regulatory loops. Significance: A device and methodology for noninvasive for detecting nociception stimulation have been developed. The proposed method and models have been validated on healthy volunteers.