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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Jeon ◽  
Michael Mackinley ◽  
Jean Théberge ◽  
Lena Palaniyappan
Keyword(s):  
Acute Illness ◽  
Anterior Cingulate ◽  
7 Tesla ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Early Stages ◽  
Gender And Age ◽  
The Status ◽  
First Episode Schizophrenia

AbstractMyo-inositol is mainly found in astroglia and its levels has been shown to be 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 7 T 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 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 becomes insignificant over time, after instituting early intervention. 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 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 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 Progressive changes in glutamate concentration in early stages of schizophrenia: A longitudinal 7-Tesla MRS study

2020 ◽  
Author(s):  
Peter Jeon ◽  
Roberto Limongi ◽  
Sabrina Ford ◽  
Michael MacKinley ◽  
Kara Dempster ◽  
...  
Keyword(s):  
Anterior Cingulate ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Healthy Controls ◽  
Dorsal Anterior Cingulate Cortex ◽  
1H Mrs ◽  
Glutamate Concentration ◽  
Early Stages ◽  
Time Interaction ◽  
Cortical Maturation

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Healthy controls were also scanned at two time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, p = 0.03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, p = 0.50), and the group by time interaction was not significant (F(1,27) = 0.86, p = 0.36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/year increase, while healthy controls showed a 0.06 mM/year reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset glutamate loss in schizophrenia. Interestingly, it provides evidence in favour of a lack of progressive glutamate change in our schizophrenia sample indicating that the glutamatergic level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamatergic dynamics in schizophrenia.

scholarly journals Focal changes in brain energy and phospholipid metabolism in first-episode schizophrenia

2004 ◽  
Vol 184 (5) ◽  
pp. 409-415 ◽  
Author(s):  
J. Eric Jensen ◽  
Jodi Miller ◽  
Peter C. Williamson ◽  
Richard W J. Neufeld ◽  
Ravi S. Menon ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Imaging Techniques ◽  
High Energy ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Membrane Breakdown ◽  
First Episode Schizophrenia

BackgroundMembrane phospholipid and high-energy abnormalities measured with phosphorus magnetic resonance spectroscopy (31P-MRS) have been reported in patients with schizophrenia in several brain regions.AimsUsing improved imaging techniques, previously inaccessible brain regions were examined in patients with first-episode schizophrenia and healthy volunteers with 4.0 T 31P-MRS.MethodBrain spectra were collected in vivo from 15 patients with first-episode schizophrenia and 15 healthy volunteers from 15 cm3 effective voxels in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex and parieto-occipital cortex.ResultsPeople with first-episode schizophrenia showed increased levels of glycerophosphocholine in the anterior cingulate. Inorganic phosphate, phosphocreatine and adenosine triphosphate concentrations were also increased in the anterior cingulate in this group.ConclusionsThe increased phosphodiester and high-energy phosphate levels in the anterior cingulate of brains of people with first-episode schizophrenia may indicate neural overactivity in this region during the early stages of the illness, resulting in increased excitotoxic neural membrane breakdown.

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.

scholarly journals Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia

2011 ◽  
Vol 198 (6) ◽  
pp. 448-456 ◽  
Author(s):  
Naoko Aoyama ◽  
Jean Théberge ◽  
Dick J. Drost ◽  
Rahul Manchanda ◽  
Sandra Northcott ◽  
...  
Keyword(s):  
Social Functioning ◽  
Grey Matter ◽  
Rating Scale ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Brain Metabolite ◽  
Left Thalamus ◽  
Profile Rating ◽  
First Episode Schizophrenia

BackgroundThalamic glutamine loss and grey matter reduction suggest neurodegeneration in first-episode schizophrenia, but the duration is unknown.AimsTo observe glutamine and glutamate levels, grey matter volumes and social functioning in patients with schizophrenia followed to 80 months after diagnosis.MethodGrey matter volumes and proton magnetic resonance spectroscopy metabolites in left anterior cingulate and left thalamus were measured in 17 patients with schizophrenia before medication and 10 and 80 months after diagnosis. Social functioning was assessed with the Life Skills Profile Rating Scale (LSPRS) at 80 months.ResultsThe sum of thalamic glutamate and glutamine levels decreased over 80 months, and correlated inversely with the LSPRS. Thalamic glutamine and grey matter loss were significantly correlated in frontal, parietal, temporal and limbic regions.ConclusionsBrain metabolite loss is correlated with deteriorated social functioning and grey matter losses in schizophrenia, consistent with neurodegeneration.

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 Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis

2019 ◽  
Vol 50 (13) ◽  
pp. 2182-2193 ◽  
Author(s):  
Kirsten B. Bojesen ◽  
Bjørn H. Ebdrup ◽  
Kasper Jessen ◽  
Anne Sigvard ◽  
Karen Tangmose ◽  
...  
Keyword(s):  
Psychotic Disorders ◽  
Poor Response ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
First Episode ◽  
Antipsychotic Treatment ◽  
Resonance Spectroscopy ◽  
Reference Levels ◽  
Clinical Prognosis ◽  
Episode Psychosis

AbstractBackgroundPoor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).MethodsThirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.ResultsBefore treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.ConclusionGlutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

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