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Original Investigation |

Increased Hippocampal Glutamate and Volumetric Deficits in Unmedicated Patients With Schizophrenia

Nina V. Kraguljac, MD1; David M. White, MPH, MPA1; Meredith A. Reid, MS1; Adrienne C. Lahti, MD1
[+] Author Affiliations
1Departments of Psychiatry and Behavioral Neurobiology and Biomedical Engineering, University of Alabama at Birmingham
JAMA Psychiatry. 2013;70(12):1294-1302. doi:10.1001/jamapsychiatry.2013.2437.
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Importance  Alterations in glutamatergic neurotransmission have been postulated to be a key pathophysiologic mechanism in schizophrenia.

Objective  To evaluate hippocampal volumetric measures and neurometabolites in unmedicated patients with schizophrenia and the correlations between these markers. Our a priori hypothesis was that glutamate levels would negatively correlate with hippocampal volume in schizophrenia.

Design, Setting, and Participants  Combined 3-T structural magnetic resonance imaging and single-voxel proton magnetic resonance spectroscopy study at the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, of 27 unmedicated patients with schizophrenia and 27 healthy controls.

Main Outcomes and Measures  Hippocampal volumetric measures and neurometabolites, and the correlations between volumetric measurements and neurometabolites.

Results  Hippocampal volumetric deficits, increased ratios of hippocampal glutamate and glutamine to creatine (Glx/Cr), and a loss of correlation between hippocampal N-acetylaspartate (NAA)/Cr and Glx/Cr in patients with schizophrenia were found. Significant correlations between hippocampal volumetric measures and Glx/Cr were also found in patients with schizophrenia but not healthy controls.

Conclusions and Relevance  Our findings support the theory that alterations in hippocampal glutamate levels potentially account for structural deficits in the hippocampus observed in schizophrenia neuroimaging studies.

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Figures

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Figure 1.
Spectra and Voxel Placement in the Left Hippocampus From Proton Magnetic Resonance Spectroscopy (1H-MRS)

Examples of 1H-MRS voxel placement in the left hippocampus (2.7 × 1.5 × 1 cm) are shown on the right; the images are displayed per radiological convention (ie, the right side of the image is the participant's left side). On the left side are 2 examples of an 1H-MRS spectrum. The black line is a spectrum (640 averages) obtained from the left hippocampus voxel, and the red line is an overlay of the spectral fit. Cho indicates choline; Cr, creatine; Glx, glutamate and glutamine; and NAA, N-acetylaspartate.

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Figure 2.
Hippocampal Volumetric Changes and Neurometabolite Alterations, and the Correlations Between Hippocampal Voxel-Based Morphometry (VBM) Measures and Neurometabolites

A, Hippocampal volumetric deficits in patients with schizophrenia are compared with those from healthy controls. One significant cluster was found using a small-volume correction for the left hippocampus. The single cluster shown is located in the dentate gyrus extending posterolaterally to the cornu ammonis and parahippocampal gyrus, with maximum intensity peak (t = 4.47; familywise error [FWE]–corrected P = .03; cluster extent [ie, number of voxels] kE = 46; Montreal Neurological Institute [MNI] coordinates: x = −18, y = −30, z = −9). The data were corrected for multiple comparisons using FWE-corrected P < .05. The cluster was overlaid on the MRIcron ch2bet template. B, A negative correlation is seen between the glutamate and glutamine to creatine ratio (Glx/Cr) and the left hippocampal VBM measure in patients with schizophrenia. Two significant clusters were found using a small-volume correction for the left hippocampus. The first cluster (top row) had a maximum intensity peak located in the dentate gyrus (t = 4.81; FWE-corrected P = .02; kE = 110; MNI coordinates: x = −26, y = −32, z = −4). The second cluster (bottom row) had a maximum intensity peak located in the cornu ammonis (t = 4.96; FWE-corrected P = .04; kE = 110; MNI coordinates: x = −36, y = −15, z = −16). The 2 clusters do not overlap. The data were corrected for multiple comparisons using FEW-corrected P < .05. Clusters were overlaid on the MRIcron ch2bet template. C, Scatterplot for the relationship between Glx/Cr and volumetric beta weight extractions from 1-sample t tests of VBM in patients with schizophrenia, controlling for age, smoking status (packs per day), and total intracranial volume (r = −0.35). The numbers adjacent to the slices indicate x, y, and z coordinates in MNI convention for sagittal, coronal, and axial slices, respectively. The color bar indicates the t values.

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Figure 3.
Glx/Cr in the Left Hippocampus of Patients With Schizophrenia and Healthy Controls

The horizontal lines represent the mean value. Cr indicates creatine; Glx, glutamate and glutamine.

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Figure 4.
Partial Correlations Between Glx/Cr and NAA/Cr in the Left Hippocampus

For each group, the solid line represents the linear regression fit across all participants, and the dashed lines represent the 95% confidence bands for the regression line. Data were controlled for age, smoking status (packs per day), and voxel gray and white matter content (healthy controls: r = 0.39, P = .04; patients with schizophrenia: r = −0.19, P = .21). Cr indicates creatine; Glx, glutamate and glutamine; and NAA, N-acetylaspartate.

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