Precision of metabolite-selective MRS measurements of glutamate, GABA and glutathione: A review of human brain studies.

Single-voxel proton magnetic resonance spectroscopy (SV 1 H-MRS) is an in vivo noninvasive imaging technique used to detect neurotransmitters and metabolites. It enables repeated measurements in living participants to build explanatory neurochemical models of psychiatric symptoms and testing of therapeutic approaches. Given the tight link among glutamate, gamma-amino butyric acid (GABA), glutathione and glutamine within the cellular machinery, MRS investigations of neurocognitive and psychiatric disorders must quantify a network of metabolites simultaneously to capture the pathophysiological states of interest. Metabolite-selective sequences typically provide improved metabolite isolation and spectral modelling simplification for a single metabolite at a time. Non-metabolite-selective sequences provide information on all detectable human brain metabolites, but feature many signal overlaps and require complicated spectral modelling. Although there are short-echo time (TE) MRS sequences that do not use spectral editing and are optimised to target either glutamate, GABA or glutathione, these approaches usually imply a precision tradeoff for the remaining two metabolites. Given the interest in assessing psychiatric and neurocognitive diseases that involve excitation-inhibition imbalances along with oxidative stress, there is a need to survey the literature on the quantification precision of current metabolite-selective MRS techniques. In this review, we locate and describe 17 studies that report on the quality of simultaneously acquired MRS metabolite data in the human brain. We note several factors that influence the data quality for single-shot acquisition of multiple metabolites of interest using metabolite-selective MRS: (1) internal in vivo references; (2) brain regions of interests; (3) field strength of scanner; and/or (4) optimised acquisition parameters. We also highlight the strengths and weaknesses of various SV spectroscopy techniques that were able to quantify in vivo glutamate, GABA and glutathione simultaneously. The insights from this review will assist in the development of new MRS pulse sequences for simultaneous, selective measurements of these metabolites and simplified spectral modelling.

Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study.

Seven Tesla magnetic resonance spectroscopy (7T MRS) offers a precise measurement of metabolic levels in the human brain via a non-invasive approach. Studying longitudinal changes in brain metabolites could help evaluate the characteristics of disease over time. This approach may also shed light on how the age of study participants and duration of illness may influence these metabolites. This study used 7T MRS to investigate longitudinal patterns of brain metabolites in young adulthood in both healthy controls and patients. A four-year longitudinal cohort with 38 patients with first episode psychosis (onset within 2 years) and 48 healthy controls was used to examine 10 brain metabolites in 5 brain regions associated with the pathophysiology of psychosis in a comprehensive manner. Both patients and controls were found to have significant longitudinal reductions in glutamate in the anterior cingulate cortex (ACC). Only patients were found to have a significant decrease over time in γ-aminobutyric acid, N-acetyl aspartate, myo-inositol, total choline, and total creatine in the ACC. Together we highlight the ACC with dynamic changes in several metabolites in early-stage psychosis, in contrast to the other 4 brain regions that also are known to play roles in psychosis. Meanwhile, glutathione was uniquely found to have a near zero annual percentage change in both patients and controls in all 5 brain regions during a four-year follow-up in young adulthood. Given that a reduction of the glutathione in the ACC has been reported as a feature of treatment-refractory psychosis, this observation further supports the potential of glutathione as a biomarker for this subset of patients with psychosis.

Central Oxidative Stress and Early Vocational Outcomes in First Episode Psychosis: A 7-Tesla Magnetic Resonance Spectroscopy Study of Glutathione.

BACKGROUND AND HYPOTHESIS: Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Evidence from preclinical, genetic, and biochemical studies suggest a role for high oxidative stress in poor functional outcomes among patients. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) enables investigating the relationship between central antioxidant tone and functional outcomes at the time of first-episode psychosis (FEP). We hypothesized that patients with higher central antioxidant tone at first presentation will have better functional outcomes in early stages of illness. STUDY DESIGN: We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimized the confounding effects of illness chronicity, long-term treatment exposure, and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. STUDY RESULTS: Patients who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in EET did not differ from healthy subjects in their GSH levels. CONCLUSION: Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.

Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione.

Patients with schizophrenia diverge in their clinical trajectories. Such diverge outcomes may result from the resilience provided by antioxidant response system centered on glutathione (GSH). Proton Magnetic Resonance Spectroscopy (1H-MRS) has enabled the precise in vivo measurement of intracortical GSH; but individual studies report highly variable results even when GSH levels are measured from the same brain region. This inconsistency could be due to the presence of distinct subgroups of schizophrenia with varying GSH-levels. At present, we do not know if schizophrenia increases the interindividual variability of intracortical GSH relative to matched healthy individuals. We reviewed all 1H-MRS GSH studies in schizophrenia focused on the Anterior Cingulate Cortex published until August 2021. We estimated the relative variability of ACC GSH levels in patients compared to control groups using the variability ratio (VR) and coefficient of variation ratio (CVR). The presence of schizophrenia significantly increases the variability of intracortical GSH in the ACC (logVR = 0.12; 95% CI: 0.03-0.21; log CVR = 0.15; 95% CI = 0.06-0.23). Insofar as increased within-group variability (heterogeneity) could result from the existence of subtypes, our results call for a careful examination of intracortical GSH distribution in schizophrenia to seek redox-deficient and redox-sufficient subgroups. An increase in GSH variability among patients also indicate that the within-group predictability of adaptive response to oxidative stress may be lower in schizophrenia. Uncovering the origins of this illness-related reduction in the redox system stability may provide novel treatment targets in schizophrenia.

Acute conceptual disorganization in untreated first-episode psychosis: a combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum.

Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Several lines of evidence implicate disrupted cognitive control, excitatory overdrive and oxidative stress relating to the anterior cingulate cortex as mechanisms of conceptual disorganization (CD). We examined 3 candidate mechanistic markers related to CD in firstepisode psychosis: glutamate excess, cortical antioxidant (glutathione) status and the integrity of the cingulum bundle that connects regions implicated in cognitive control. Methods: We used fractional anisotropy maps from 7 T diffusion-weighted imaging to investigate the bilateral cingulum based on a probabilistic white matter atlas. We compared high CD, low CD and healthy control groups and performed probabilistic fibre tracking from the identified clusters (regions of interest within the cingulum) to the rest of the brain. We quantified glutamate and glutathione using magnetic resonance spectroscopy (MRS) in the dorsal anterior cingulate cortex. Results: We found a significant fractional anisotropy reduction in a cluster in the left cingulum in the high CD group compared to the low CD group (Cohen's d = 1.39; p < 0.001) and controls (Cohen's d = 0.86; p = 0.009). Glutamate levels did not vary among groups, but glutathione levels were higher in the high CD group than in the low CD group. We also found higher glutathione related to lower fractional anisotropy in the cingulum cluster in the high CD group. Limitations: The MRS measures of glutamine were highly uncertain, and MRS was acquired from a single voxel only. Conclusion: Acute CD relates to indicators of oxidative stress, as well as reduced white matter integrity of the cingulum, but not to MRI-based glutamatergic excess. We propose that both oxidative imbalance and structural dysconnectivity underlie acute disorganization.

Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate.

Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response (F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment (F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis.

Glutathione and glutamate in schizophrenia: a 7T MRS study.

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Antioxidant defense in schizophrenia and bipolar disorder: A meta-analysis of MRS studies of anterior cingulate glutathione.

BACKGROUND: Glutathione [GSH] is a major intracellular antioxidant that disposes peroxides and protects neurons and glial cells from oxidative stress. In both schizophrenia and bipolar disorder, atypical levels of GSH have been demonstrated, particularly in the anterior cingulate cortex (ACC), though no consistent results have emerged due to limitations in sample size. Our objective was to evaluate if GSH levels in the ACC are abnormal in these 2 disorder, when compared to healthy controls. METHODS: We reviewed all 1H-MRS studies reporting GSH values for patients satisfying DSM or ICD based criteria for (1) the psychotic disorders - schizophrenia or schizoaffective disorder or (2) bipolar disorder in comparison to a healthy controls (HC) group in the Anterior Cingulate Cortex (ACC) published until June 2018. A random-effects model was used to calculate the pooled effect size. A meta-regression analysis of moderator variables was also undertaken. RESULTS: The literature search identified 18 studies with a total sample size of 581 controls, 578 patients with schizophrenia or bipolar disorder. There is a small but significant reduction in ACC GSH in patients with schizophrenia compared to HC (N = 13; RFX SMD =0.26; 95% CI [0.07 to 0.44]; p = 0.008; heterogeneity p = 0.11). There is a significant increase in the ACC GSH concentration in bipolar disorder compared to HC (N = 6; RFX SMD = -0.28, 95% CI [-0.09 to -0.47]; p = 0.003; heterogeneity p = 0.95). CONCLUSIONS: We report a small, but significant reduction in GSH concentration in the ACC in schizophrenia, and a similar sized increase in bipolar disorder. A notable limitation is the lack of sufficient data to examine the moderating effect of the symptom profile. Schizophrenia and bipolar disorder have notably different patterns of redox abnormalities in the ACC. Reduced ACC GSH may confer a schizophrenia-like clinical phenotype, while an excess favouring a bipolar disorder-like profile.

Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder.

Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-α, contributes to the neuroanatomical changes in MDD. In this cross-sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-α expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity.

Disparities in Access to Early Psychosis Intervention Services: Comparison of Service Users and Nonusers in Health Administrative Data.

OBJECTIVE: There is a dearth of information on people with first-episode psychosis who do not access specialized early psychosis intervention (EPI) services. We sought to estimate the proportion of incident cases of nonaffective psychosis that do not access these services and to examine factors associated with EPI admission. METHODS: Using health administrative data, we constructed a retrospective cohort of incident cases of nonaffective psychosis in the catchment area of the Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario, between 1997 and 2013. This cohort was linked to primary data from PEPP to identify EPI users. We used multivariate logistic regression to model sociodemographic and service factors associated with EPI admission. RESULTS: Over 50% of suspected cases of nonaffective psychosis did not have contact with EPI services for screening or admission. EPI users were significantly younger, more likely to be male (odds ratio [OR] 1.58; 95% confidence interval [CI] 1.24 to 2.01), and less likely to live in areas of socioeconomic deprivation (OR 0.51; 95% CI 0.36 to 0.73). EPI users also had higher odds of psychiatrist involvement at the index diagnosis (OR 7.35; 95% CI 5.43 to 10.00), had lower odds of receiving the index diagnosis in an outpatient setting (OR 0.50; 95% CI 0.38 to 0.65), and had lower odds of prior alcohol-related (OR 0.42; 95% CI 0.28 to 0.63) and substance-related (OR 0.68; 95% CI 0.50 to 0.93) disorders. CONCLUSIONS: We need a greater consideration of patients with first-episode psychosis who are not accessing EPI services. Our findings suggest that this group is sizable, and there may be sociodemographic and clinical disparities in access. Nonpsychiatric health professionals could be targeted with interventions aimed at increasing detection and referral rates.