scholarly journals Early Treatment Response in First Episode Psychosis: A 7-Tesla Magnetic Resonance Spectroscopic Study of Glutathione and Glutamate

2019 ◽  
Author(s):  
Kara Dempster ◽  
Peter Jeon ◽  
Michael MacKinley ◽  
Peter Williamson ◽  
Jean Théberge ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Treatment Response ◽  
Longitudinal Design ◽  
Anterior Cingulate ◽  
7 Tesla ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Inadequate Response ◽  
Dorsal Anterior Cingulate Cortex ◽  
Early Intervention In Psychosis

AbstractEarly 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 ultra-high field 7-Tesla 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-naïve (34.6% of the sample) or minimally medicated first episode patients with non-affective psychosis. 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= .017), while higher glutamate was associated with more severe functional impairment (F=5.33, P= .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 favourable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis.

scholarly journals Counteracting Effects of Glutathione on the Glutamate-Driven Excitation/Inhibition Imbalance in First-Episode Schizophrenia: A 7T MRS and Dynamic Causal Modeling Study

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 75
Author(s):  
Roberto Limongi ◽  
Peter Jeon ◽  
Jean Théberge ◽  
Lena Palaniyappan
Keyword(s):  
Magnetic Resonance ◽  
Inhibitory Activity ◽  
Blood Oxygenation ◽  
Causal Modeling ◽  
Anterior Cingulate ◽  
7 Tesla ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Dynamic Causal Modeling ◽  
First Episode Schizophrenia

Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is centered on N-Methyl-D-aspartate (NMDA) receptors. GSH levels increase during glutamate-mediated excitatory neuronal activity, which serves as a checkpoint to protect neurons from oxidative damage and reduce excitatory overdrive. We studied the possible influence of GSH on the glutamate-mediated dysconnectivity in 19 first-episode schizophrenia (FES) patients and 20 healthy control (HC) subjects. Using ultra-high field (7 Tesla) magnetic resonance spectroscopy (MRS) and resting state functional magnetic resonance imaging (fMRI), we measured GSH and GLU levels in the dorsal anterior cingulate cortex (dACC) and blood-oxygenation level-dependent activity in both the dACC and the anterior insula (AI). Using spectral dynamic causal modeling, we found that when compared to HCs, in FES patients inhibitory activity within the dACC decreased with GLU levels whereas inhibitory activity in both the dACC and AI increased with GSH levels. Our model explains how higher levels of GSH can reverse the downstream pathophysiological effects of a hyperglutamatergic state in FES. This provides an initial insight into the possible mechanistic effect of antioxidant system on the excitatory overdrive in the salience network (dACC-AI).

scholarly journals Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

2020 ◽  
Author(s):  
Min Wang ◽  
Peter B. Barker ◽  
Nicola Cascella ◽  
Jennifer M. Coughlin ◽  
Gerald Nestadt ◽  
...  
Keyword(s):  
Young Adulthood ◽  
Brain Regions ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
7 Tesla ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Invasive Approach ◽  
Longitudinal Changes ◽  
Episode Psychosis

AbstractObjective7 Tesla (T) longitudinal magnetic resonance spectroscopy (MRS) offers a precise measurment of metabolic levels in human brain via a non-invasive approach. Studying longitudinal changes in neurometabolites could help identify trait and state markers for diseases and understand inconsistent findings from different researchers due to differences in the age of study participants and duration of illness. This study is the first to report novel longitudinal patterns in young adulthood from both physiological and pathological viewpoints using 7T MRS.MethodsUtilizing a four-year longitudinal cohort with 38 first episode psychosis (FEP) patients (onset within 2 years) and 48 healthy controls (HC), the authors examined the annual percentage changes of 9 neurometabolites in 5 brain regions.ResultsBoth FEP patients and HC subjects were found to have significant longitudinal reductions in glutamate (Glu) in the anterior cingulate cortex (ACC). Only FEP patients were found to have a significant decrease over time in γ-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mI), and total choline (tCho: phosphocholine plus glycerophosphocholine) in the ACC. Uniquely, glutathione (GSH) was found to have a near zero annual percentage change in both FEP patients and HC subjects in all 5 brain regions over a four-year timespan in young adulthood.ConclusionsGSH could be a trait marker for diagnostic applications at least in young adulthood. Glu, GABA, NAA, mI, and tCho in the ACC are associated with the patient’s status and could be state markers for mechanistic studies of psychotic disorders, including those for progressive pathological changes and medication effects in young adulthood.

Reward disturbances in antipsychotic-naïve patients with first-episode psychosis and their association to glutamate levels

2021 ◽  
pp. 1-10
Author(s):  
Karen Tangmose ◽  
Egill Rostrup ◽  
Kirsten B Bojesen ◽  
Anne Sigvard ◽  
Kasper Jessen ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Parental Education ◽  
First Episode Psychosis ◽  
Outcome Evaluation ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Episode Psychosis ◽  
Motivational Salience ◽  
Monetary Incentive Delay

Abstract Background Aberrant anticipation of motivational salient events and processing of outcome evaluation in striatal and prefrontal regions have been suggested to underlie psychosis. Altered glutamate levels have likewise been linked to schizophrenia. Glutamatergic abnormalities may affect the processing of motivational salience and outcome evaluation. It remains unresolved, whether glutamatergic dysfunction is associated with the coding of motivational salience and outcome evaluation in antipsychotic-naïve patients with first-episode psychosis. Methods Fifty-one antipsychotic-naïve patients with first-episode psychosis (22 ± 5.2 years, female/male: 31/20) and 52 healthy controls (HC) matched on age, sex, and parental education underwent functional magnetic resonance imaging and magnetic resonance spectroscopy (3T) in one session. Brain responses to motivational salience and negative outcome evaluation (NOE) were examined using a monetary incentive delay task. Glutamate levels were estimated in the left thalamus and anterior cingulate cortex using LCModel. Results Patients displayed a positive signal change to NOE in the caudate (p = 0.001) and dorsolateral prefrontal cortex (DLPFC; p = 0.003) compared to HC. No group difference was observed in motivational salience or in levels of glutamate. There was a different association between NOE signal in the caudate and DLPFC and thalamic glutamate levels in patients and HC due to a negative correlation in patients (caudate: p = 0.004, DLPFC: p = 0.005) that was not seen in HC. Conclusions Our findings confirm prior findings of abnormal outcome evaluation as a part of the pathophysiology of schizophrenia. The results also suggest a possible link between thalamic glutamate and NOE signaling in patients with first-episode psychosis.

scholarly journals The trajectory of putative astroglial dysfunction in first episode schizophrenia: A longitudinal 7-Tesla MRS study

2021 ◽  
Author(s):  
Peter Jeon ◽  
Michael MacKinley ◽  
Jean Theberge ◽  
Lena Palaniyappan
Keyword(s):  
Anterior Cingulate ◽  
7 Tesla ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Early Stages ◽  
Metabolic Marker ◽  
Time Period ◽  
The Status ◽  
First Episode Schizophrenia

Abstract Astroglial pathology has been long suspected in schizophrenia. Myo-inositol, a metabolic marker particularly abundant in astroglia, is reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of first episode schizophrenia. We employed 7T magnetic resonance spectroscopy (1H-MRS) and quantified myo-inositol spectra at the dorsal ACC in 31 participants; 21 patients with schizophrenia with median lifetime antipsychotic exposure of less than 3 days, followed up after 6 months of treatment, and 10 healthy subjects scanned twice over the same time period. We studied the time by group interaction for myo-inositol after adjusting for gender and age. We report significant reduction in myo-inositol concentration in the ACC in schizophrenia at an early, untreated state of acute illness that improves over time. This trajectory indicates that dynamic astroglial changes are likely to operate in the early stages of schizophrenia. MRS myo-inositol may be a critical marker of amelioration of active psychosis in early stages of schizophrenia.

scholarly journals Neurometabolic abnormalities in schizophrenia and depression observed with magnetic resonance spectroscopy at 7 T

BJPsych Open ◽  
2017 ◽  
Vol 3 (1) ◽  
pp. 6-11 ◽  
Author(s):  
Reggie Taylor ◽  
Elizabeth A. Osuch ◽  
Betsy Schaefer ◽  
Nagalingam Rajakumar ◽  
Richard W. J. Neufeld ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Anterior Cingulate ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Healthy Controls ◽  
Pharmacological Interventions ◽  
Major Depressive ◽  
Schizophrenia Group ◽  
Tesla Scanner

BackgroundExamining neurometabolic abnormalities in critical brain areas in schizophrenia and major depressive disorder (MDD) may help guide future pharmacological interventions including glutamate-modulating treatments.AimsTo measure metabolite concentrations within the anterior cingulate cortex (ACC) and thalamus of people with schizophrenia and people with MDD.MethodsSpectra were acquired from 16 volunteers with schizophrenia, 17 with MDD and 18 healthy controls using magnetic resonance spectroscopy on a 7 Tesla scanner.ResultsIn the thalamus, there were lower glycine concentrations in the schizophrenia group relative to control (P=0.017) and MDD groups (P=0.012), and higher glutamine concentrations relative to healthy controls (P=0.009). In the thalamus and the ACC, the MDD group had lower myo-inositol concentrations than the control (P=0.014, P=0.009, respectively) and schizophrenia (P=0.004, P=0.002, respectively) groups.ConclusionThese results support the glutamatergic theory of schizophrenia and indicate a potential glycine deficiency in the thalamus. In addition, reduced myo-inositol concentrations in MDD suggest its involvement in the disorder.

scholarly journals Structural and functional imaging of the hippocampus in young people at familial risk of depression

2014 ◽  
Vol 44 (14) ◽  
pp. 2939-2948 ◽  
Author(s):  
Z. N. Mannie ◽  
N. Filippini ◽  
C. Williams ◽  
J. Near ◽  
C. E. Mackay ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Young People ◽  
Familial Risk ◽  
Memory Task ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Resonance Spectroscopy ◽  
Dorsal Anterior Cingulate Cortex ◽  
Parental History ◽  
History Of

BackgroundMajor depression is associated with abnormalities in the function and structure of the hippocampus. However, it is unclear whether these abnormalities might also be present in people ‘at risk’ of illness.MethodWe studied 62 young people (mean age 18.8 years) at familial risk of depression (FH+) but who had never been depressed themselves. Participants underwent magnetic resonance imaging to assess hippocampal structure and neural responses to a task designed to activate hippocampal memory networks. Magnetic resonance spectroscopy was used to measure levels of a combination of glutamine and glutamate (Glx) in the right hippocampus. A total of 59 matched controls with no history of mood disorder in a first-degree relative underwent the same investigations.ResultsHippocampal volume did not differ between FH+ participants and controls; however, relative to controls, during the memory task, FH+ participants showed increased activation in brain regions encompassing the insular cortices, putamen and pallidum as well as the dorsal anterior cingulate cortex (ACC). FH+ participants also had increased hippocampal levels of Glx.ConclusionsEuthymic individuals with a parental history of depression demonstrate increased activation of hippocampal-related neural networks during a memory task, particularly in brain regions involved in processing the salience of stimuli. Changes in the activity of the ACC replicate previous findings in FH+ participants using different psychological tasks; this suggests that task-related abnormalities in the ACC may be a marker of vulnerability to depression. Increased levels of Glx in the hippocampus might also represent a risk biomarker but follow-up studies will be required to test these various possibilities.

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

2020 ◽  
Author(s):  
Pan Yunzhi ◽  
Kara Dempster ◽  
Peter Jeon ◽  
Jean Théberge ◽  
Ali Khan ◽  
...  
Keyword(s):  
White Matter ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Cohen’S D ◽  
Episode Psychosis ◽  
Cohen's D

Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Based on the close association between cingulum and disorganized thinking, we examine three candidate mechanistic markers in relation to acute conceptual disorganization (CD) in first episode psychosis: glutamate excess; cortical antioxidant (glutathione) status and the integrity of the cingulum bundle. Methods: We used fractional anisotropy (FA) maps from 7T diffusion-weighted imaging to investigate bilateral cingulum based on a probabilistic white-matter atlas. We compared the high-CD, low-CD and healthy control groups and performed probabilistic fiber tracking from the identified clusters (ROI within cingulum) to the rest of the brain. We quantified glutamate and glutathione with magnetic-resonance-spectroscopy (MRS) in the dorsal anterior cingulate cortex.Results: There was a significant FA reduction (F=9.04; p=0.036) in a cluster in left cingulum in high-CD compared to low-CD (Cohen’s d=1.39; p=0.003) and controls (Cohen’s d=0.86; p=0.009). Glutamate levels did not vary among the groups, but glutathione levels were higher in high-CD compared to the low-CD group. Higher glutathione related to lower FA in the high-CD group in the cingulum cluster.Discussion: 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.Limitation: MRS measures of glutamine were highly uncertain and MRs was acquired from a single voxel only.

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