Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study

Juan R Bustillo, Joel Upston, Elizabeth Grace Mayer, Thomas Jones, Andrew A Maudsley, Charles Gasparovic, Mauricio Tohen, Rhoshel Lenroot, Juan R Bustillo, Joel Upston, Elizabeth Grace Mayer, Thomas Jones, Andrew A Maudsley, Charles Gasparovic, Mauricio Tohen, Rhoshel Lenroot

Abstract

Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain 1H-MRS, in early schizophrenia. Three dimensional 1H-MRS was acquired in young schizophrenia subjects (N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N-acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV's > 0.05). However, creatine was higher in antipsychotic-treated vs HC's in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.

Figures

Fig. 1. Summary of data processing steps…
Fig. 1. Summary of data processing steps (two rightmost columns, include software used), with corresponding descriptions (to the left) and representative illustrations.
NAA is N-acetyl-aspartate, Glx is glutamate plus glutamine, t-Cr is creatine plus phosphocreatine and t-Cho is choline, glycerol-phospho-choline, plus phos-phocholine.
Fig. 2. Reduced glutamine plus glutamate (Glx)…
Fig. 2. Reduced glutamine plus glutamate (Glx) in schizophrenia.
Row a Reduced Glx (shown in red) in schizophrenia (SP) compared to healthy controls (HC) in one 16 voxel cluster (CCLAV = 0.04), mainly in the left superior temporal gyrus-STG and the middle temporal gyrus (MTG; see x, y, z, the MNI-based, cluster-center coordinates). Row b 10/16 voxels (shown in purple) have reduced Glx (p ≤ 0.001, at the voxel-level) in antipsychotic-naïve schizophrenia vs, healthy controls. Blue voxels also have reduced Glx but are not part of the original significant cluster, which is shown in red and purple. Row c 8/16 voxels (shown in purple) have reduced Glx (p ≤ 0.001) in antipsychotic-treated schizophrenia vs, healthy controls. Blue voxels also have reduced Glx but are not part of the original significant cluster, which is shown in red and purple.
Fig. 3. Increased creatine plus phosphocreatine (t-Cr)…
Fig. 3. Increased creatine plus phosphocreatine (t-Cr) in schizophrenia.
Row a Increased t-Cr in SP compared to HC in two clusters (shown in orange): one involved 32 voxels (CCLAV = 0.02) mainly in the left STG, inferior parietal lobule (IPL) and insula. The second cluster involved 18 voxels (CCLAV = 0.04) mainly in the left middle temporal and angular gyri. Row b 32/32 voxels (shown in purple) in the first cluster and 14/18 voxels (shown in purple) in the second cluster have reduced t-Cr (p ≤ 0.001, at the voxel-level) in antipsychotic-treated schizophrenia vs, healthy controls. Blue voxels also have increased t-Cr but are not part of the original significant clusters, which are shown in orange and purple. Row c 1/32 voxels (shown in purple) in the first cluster and 6/18 voxels (shown in purple) in the second cluster have reduced t-Cr (p ≤ 0.001, at the voxel-level) in antipsychotic-naive schizophrenia vs, healthy controls. Blue voxels also have increased t-Cr but are not part of the original significant clusters, which are shown in orange and purple.
Fig. 4. Abnormalities in total choline (t-Cho),…
Fig. 4. Abnormalities in total choline (t-Cho), N-acetylaspartate (NAA) and myo-inositol (MINO) in schizophrenia.
Row a Increased t-Cho (shown in pink) in antipsychotic-treated SP vs HC in one cluster (18 voxels, CCLAV = 0.04) in mainly the left middle frontal gyrus. Row b Reduced NAA (shown in green) in antipsychotic-naive SP vs HC in one cluster (19 voxels, CCLAV = 0.05) in mainly right medial, superior frontal gyri and middle frontal white matter. Row c Reduced myo-inositol (shown in light blue) in antipsychotic-naive SP vs HC in one cluster (34 voxels, CCLAV = 0.02) in mainly the left cerebellum.

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