0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

First Page Preview

View Large
First page PDF preview

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 6

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Related Multimedia

Author Interview

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
brightcove.createExperiences();