Abstract
Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia and bipolar-I disorders, mostly in single voxels. Though the critical nodes remain unknown, schizophrenia and bipolar-I involve brain networks with broad abnormalities. To provide insight on the biochemical differences that may underlie these networks, the combined glutamine and glutamate signal (Glx) and other metabolites were examined in patients in early psychosis with whole brain 1H-MRS imaging (1H-MRSI). Data were acquired in young schizophrenia subjects (N = 48), bipolar-I subjects (N = 21) and healthy controls (N = 51). Group contrasts for Glx, as well as for N-acetyl aspartate, choline, myo-inositol and creatine, from all voxels that met spectral quality criteria were analyzed in standardized brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05) analysis. Schizophrenia subjects had higher Glx in the right middle cingulate gyrus (19 voxels, CCLAV = 0.05) than bipolar-I subjects. Healthy controls had intermediate Glx values, though not significant. Schizophrenia subjects also had higher N-acetyl aspartate (three clusters, left occipital, left frontal, right frontal), choline (two clusters, left and right frontal) and myo-inositol (one cluster, left frontal) than bipolar-I, with healthy controls having intermediate values. These increases were likely accounted for by antipsychotic medication effects in the schizophrenia subgroup for N-acetyl aspartate and choline. Likewise, creatine was increased in two clusters in treated vs. antipsychotic-naïve schizophrenia, supporting a medication effect. Conversely, the increments in Glx in right cingulate were not driven by antipsychotic medication exposure. We conclude that increments in Glx in the cingulate may be critical to the pathophysiology of schizophrenia and are consistent with the NMDA hypo-function model. This model however may be more specific to schizophrenia than to psychosis in general. Postmortem and neuromodulation schizophrenia studies focusing on right cingulate, may provide critical mechanistic and therapeutic advancements, respectively.
Highlights
The N-methyl-D-aspartate receptor (NMDAR) hypo-function model of psychosis originated from pharmacological studies documenting the emergence of positive and negative symptoms as well as cognitive deficits in healthy volunteers exposed acutely to the NMDAR blocker ketamine (1)
Using 3D 1H-MRS imaging (1H-MRSI) with a short echo time (TE) and a voxel-wide approach, we recently reported reduced Glx in the left superior temporal gyrus (STG) in early schizophrenia vs. healthy control subjects as well as more widespread creatine increases in antipsychotic treated schizophrenia (15)
Total-Creatine Because we previously detected higher t-Cr in treated Sz relative to healthy controls (HC) in three clusters (15) but not in antipsychotic-naïve Sz vs. HCs, we examined in our largest patient sample (i.e., Sz) the effect of antipsychotic medication
Summary
The N-methyl-D-aspartate receptor (NMDAR) hypo-function model of psychosis originated from pharmacological studies documenting the emergence of positive and negative symptoms as well as cognitive deficits in healthy volunteers exposed acutely to the NMDAR blocker ketamine (1). Acute systemic NMDAR blockers in the awake rat lead to an increase in frontal extracellular glutamate (1) Consistent with these findings, a single ketamine infusion in healthy controls (HC) results in an increase in the combined glutamate and glutamine signal (Glx) (2) in medial frontal cortex, as measured with proton magnetic resonance spectroscopy (1H-MRS). This paradoxical increase in glutamate release with NMDAR blockers has been postulated to result from higher sensitivity of NMDAR receptors in GABAergic interneurons than in pyramidal neurons, leading to disinhibition of pyramidal neurons (1). None of these three studies found glutamatergic differences between the two clinical groups
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