Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.

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 pain-free 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 pain-free 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 glutamate/glutamine level. 3) Used 1H-Magnetic Resonance Spectroscopy (Prospero Project ID CRD42018092170). Data extracted included neurometabolite level, pain diagnosis, and spectroscopy parameters. Meta-analyses were conducted to establish the difference in neurometabolite level between participants with pain and pain-free controls for different pain conditions. The MRS-Q was developed from existing clinical consensus to allow for the assessment of quality in the included studies. RESULTS: Thirty-five studies were included investigating combinations of migraine (n = 11), musculoskeletal pain (n = 8), chronic pain syndromes (n = 9) and miscellaneous pain (n = 10). Higher GABA levels were found in participants with migraine compared to controls (Hedge's G 0.499, 95%CI: 0.2 to 0.798). In contrast, GABA levels in musculoskeletal pain conditions (Hedge's G -0.189, 95%CI: 0.530 to 0.153) and chronic pain syndromes (Hedge's 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.

Six-month clinical course and factors associated with non-improvement in migraine and non-migraine headaches.

Background Evidence on the medium-term clinical course of recurrent headaches is scarce. This study explored the six-month course and factors associated with non-improvement in migraine compared with tension-type headache and cervicogenic headache. Methods In this longitudinal cohort study, the six-month course of headaches was prospectively examined in participants (n = 37 with migraine; n = 42 with tension-type or cervicogenic headache). Participants underwent physical examination for cervical musculoskeletal impairments at baseline. Participants also completed questionnaires on pain, disability and other self-report measures at baseline and follow-up, and kept an electronic diary for 6 months. Course of headaches was examined using mixed within-between analyses of variance and Markov chain modeling. Multiple factors were evaluated as possible factors associated with non-improvement using regression analysis. Results Headache frequency, intensity, and activity interference in migraine and non-migraine headaches were generally stable over 6 months but showed month-to-month variations. Day-to-day variations were more volatile in the migraine than the non-migraine group, with the highest probability of transitioning from any headache state to no headache (probability = 0.82-0.85). The odds of non-improvement in disability was nearly six times higher with cervical joint dysfunction (odds ratio [95% CI] = 5.58 [1.14-27.42]). Conclusions Headache frequency, intensity, and activity interference change over 6 months, with day-to-day variation being more volatile in migraine than non-migraine headaches. Cervical joint dysfunction appears to be associated with non-improvement for disability in 6 months. These results may contribute to strategies for educating patients to help align their expectations with the nature of their headaches.

Definitions and participant characteristics of frequent recurrent headache types in clinical trials: A systematic review.

Background Clear definitions of study populations in clinical trials may facilitate application of evidence to clinical populations. This review aimed to explore definitions of study populations in clinical trials on migraine, tension-type headache, cluster headache, and cervicogenic headache. Methods We performed a systematic review of clinical trials investigating treatment efficacy for migraine, tension-type headache, cluster headache, and cervicogenic headache. We extracted data on diagnosis, inclusion criteria and baseline headache characteristics. Results Of the 229 studies reviewed, 205 studies (89.5%) defined their populations in adherence to the International Classification of Headache Disorders (ICHD) criteria. Some studies ( n = 127, 55.5%) specified diagnosing through interview, clinical examination and diary entry. The most commonly reported inclusion criteria were pain intensity for migraine and tension-type headache studies ( n = 123, 66.1% and n = 21, 67.7%, respectively), episode frequency ( n = 5, 71.4%) for cluster headache studies, and neck-related pain for cervicogenic headache studies ( n = 3, 60%). Few studies reported details on the extent to which diagnostic criteria were present at baseline. Conclusions ICHD is routinely used in defining populations in headache studies. Details of baseline headache characteristics were not as consistently reported.

Elevated levels of GABA+ in migraine detected using (1) H-MRS.

γ-Aminobutyric acid (GABA) has been implicated in several pain conditions, yet no study has systematically evaluated GABA levels in migraine using (1) H-MRS. The accurate detection, separation and quantification of GABA in individuals with migraine could elucidate the role of this neurotransmitter in migraine pathophysiology. Such information may eventually be useful in the diagnosis and development of more effective treatments for migraine. The aims of this study were therefore to compare the concentration of GABA+ in individuals with migraine with that in asymptomatic individuals, and to determine the diagnostic potential of GABA+ in the classification of those with or without migraine. In this case-control study, GABA+ levels in the brain were determined in 19 participants with migraine and 19 matched controls by (1) H-MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence. The diagnostic accuracy of GABA+ for the detection of migraine and the optimal cut-off value were determined by receiver operating characteristic analysis. GABA+ levels were significantly higher (p = 0.002) in those with migraine [median, 1.41 institutional units (IU); interquartile range, 1.31-1.50 IU] than in controls (median, 1.18 IU; interquartile range, 1.12-1.35 IU). The GABA+ concentration appears to have good accuracy for the classification of individuals with or without migraine [area under the curve (95% confidence interval), 0.837 (0.71-0.96); p < 0.001]. The optimal GABA+ cut-off value for migraine was 1.30 IU, with a sensitivity of 84.2%, specificity of 68.4% and positive likelihood ratio of +2.67. The outcomes of this study suggest altered GABA metabolism in migraine. These results add to the scarce evidence on the putative role of GABA in migraine and provide a basis to further explore the causal relationship between GABA+ and the pathophysiology of migraine. This study also demonstrates that GABA+ concentration has good diagnostic accuracy for migraine. These findings offer new research and practice directions for migraine diagnosis.

An Evaluation of Policies Promoting Physical Activity among Filipino Youth.

Government is key to promoting physical activity at the population level through policy. The government was one of the physical activity indicators graded for the 2022 Philippine Physical Activity Report Card based on ten physical activity-related policies. This study aimed to evaluate the scope of the policies and to update these policies. Philippine government databases were searched for policies using physical activity-related key terms. Policies found were evaluated using the Wales Active Healthy Kids scoring rubric. The overall grade was converted to a letter grade based on the Global Matrix 4.0 grading system. The authors analyzed the policies' scope and implications to practice and policy. Seven additional policies were found. Considering all 17 policies, the government indicator grade is now A- from the preliminary grade of B. The scope covers promoting physical activity mainly through sports participation and active transport among students, student-athletes, persons with disabilities, and the general population in school and community settings. The gap between government and overall physical activity (F) scores suggests the need for a comprehensive physical activity plan promoting various forms of physical activity and reducing sedentary behavior among all Filipino youth and across various settings. Crucial to achieving change is a well-coordinated, whole-of-systems approach to promoting active healthy lifestyles.

Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain.

Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. PERSPECTIVE: This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.

The Association Between Clinical Characteristics of Migraine and Brain GABA Levels: An Exploratory Study.

UNLABELLED: Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker. PERSPECTIVE: Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker.