Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis: Relationship to Gray Matter Volume

TLDR: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder.

About: This article is published in Biological Psychiatry.The article was published on 2009-09-15 and is currently open access. It has received 224 citations till now. The article focuses on the topics: Psychosis & Glutamatergic.

Figures

Figure 2: significant correlations between thalamic glutamate and gray matter volume in ARMS subjects (n=26). Thalamic glutamate levels correlated directly with lower gray matter volume in left prefrontal cortex, insula, cingulate, superior temporal gyrus and temporal pole, as well as bilaterally in the cerebellum and lingual gyrus. They showed an inverse correlation with gray matter volume in dorsal anterior cingulate extending to the posterior cingulate gyrus.

Table 1: subject demographics

Table 2: clinical measures

Table 3: metabolite measures (mean(SD)) in anterior cingulate, left thalamus and left hippocampus (* p<0.05).

Figure 1: differences in gray matter volume between ARMS and controls (n=27). The ARMS group had significantly lower cortical gray matter volumes in orbitofrontal cortex bilaterally, extending into the adjacent ventral anterior cingulate cortex, but relatively more gray matter volume in left cerebellum and left occipital cortex

Frequently asked questions

Q1. What are the contributions in "Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume" ?

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Q2. What are the future works mentioned in the paper "Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume" ?

Future work will determine whether thalamic 

Q3. What is the main reason why NMDA receptor antagonists are used in schizophrenia?

Uncompetitive NMDA receptor antagonists such as phencyclidine (PCP) and ketamine consistently induce effects resembling the positive and negative symptoms of schizophrenia in humans. 

Q4. What is the effect of apoptosis on gray matter volume?

It has been suggested that increases in gray matter volume might occur in the very early stages of apoptosis (42), so it possible that this might be a relatively early effect of disinhibition of thalamocortical glutamatergic projections, with a reduction in cortical volume occurring at a later stage. 

Q5. Why was the GLM used in the first step?

Due to the small number of subjects with well-fitted Gln peaks, group differences in Gln levels were entered into the GLM in a subsequent step. 

Q6. What was the effect of the ANCOVA model on the CSF content of each ROI?

Between-group differences in gray matter volume, and correlations of gray matter volume difference with significant CSF-corrected metabolite differences were analysed by fitting an analysis of covariance (ANCOVA) model at each intracerebral voxel in standard space, covarying for total gray matter, using the BAMM package. 

Q7. What could be the effect of differences in tissue relaxation times?

Differences in tissue relaxation times between patients and controls, as previously reported in patients with schizophrenia (36), could lead to differences in estimation of water-scaled metabolite concentrations. 

Q8. What is the main reason for the NMDA receptor dysfunction in schizophrenia?

Neuroimaging studies in patients with schizophrenia have provided some evidence of NMDA receptor dysfunction, and of a disinhibition of Glu release. 

Q9. What is the reason for the difficulties in measuring Gln?

The reason for the difficulties in measuring Gln probably relate to the fact that this study was performed using a 3T scanner, whereas groups studying Gln as a separate peak have generally employed 4T scanners (9,10,12). 

Q10. How was the effect of drug use and of demographic differences between groups studied?

The effect of drug use and of demographic differences between groups on significantly different metabolite measures was studied using linear regression (stepwise). 

Q11. Why did the authors have to exclude a large number of Gln estimates?

The fact that the authors could only obtain reliable measures of Gln in anterior cingulate is likely to be a result of the better quality (lower linewidth) spectra obtained from this region. 

Q12. How many subjects were required to detect a 20% difference in anterior cingulate Glu?

The authors used G*Power statistical software (23), to calculate that 26 subjects in each group would be required to detect a 20% difference in anterior cingulate Glu + 

Q13. What is the correlation between thalamic Glu levels and gray matter volume?

Glu levels and reductions in gray matter volume the authors observed raises the possibility that changes in Glu function might contribute to the structural findings, possibly throughdisinhibition of thalamocortical pyramidal cells (17).