Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging

Abstract

Background: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia.

Methods: We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC).

Results: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr.

Conclusions: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Figure 1

(A) Example of magnetic resonance spectroscopy (MRS) voxel placement in the left hippocampus. Image is displayed in radiological convention (right side of image is subject’s left side). (B) Spectra obtained from one healthy control scanned on 5 consecutive days to assess reproducibility of MRS data. Cho, choline; Cr, creatine; Glx, glutamate + glutamine; NAA, N-acetylaspartate; ppm, parts per million.

Figure 2

Association between the metabolites NAA/Cr and Glx/Cr both measured in the left hippocampus of healthy controls (HC, n = 28) and participants with schizophrenia (SZ, n = 28). The HC group showed a positive correlation (r = 0.450, p = .019) that was not seen in the SZ group (r = 0.010, p = .959) (Z = 1.68, p = .093). The healthy control group’s positive correlation did not survive multiple comparison testing. Solid lines are linear regressions and dashed lines are 95% confidence intervals.

Figure 3

Whole-brain between-group difference (healthy control participants > participants with schizophrenia) during the encode task and retrieve task. For encode, the single cluster shown is located at the inferior frontal gyrus (MNI coordinate: x = -39, y = 19, z = -9). For retrieve, the top slices show a cluster located at the anterior cingulate (MNI coordinates: x = 2, y= 39, and z = 3). The bottom slices show a cluster in the left superior temporal gyrus (MNI coordinates: x = -45, y= -53, and z = 18). Multiple comparisons corrected by using a cluster level false discovery rate (FDR) of .05. Activation overlaid on the SPM8 single-subject T1 template. Left, sagittal slices; right axial slices. Numbers below slices indicate x and z coordinates in MNI convention. Color bar indicates t values.

Figure 4

Association between blood oxygen level-dependent (BOLD) acquired in the left inferior frontal gyrus and a behavioral index of discriminability, Pr (see methods). BOLD mean percent signal change was acquired during the encode task. A significant negative correlation was found for the SZ group (r = -0.386, p = .042) but not the HC (r = 0.163, p = .408). These two correlations were significantly different (Z = -2.02; p = .043). Solid lines are linear regressions and dashed lines are 95% confidence intervals.

Figure 5

Association between blood oxygen level-dependent (BOLD) mean percent signal change during the retrieve task and the MRS metabolite Glx/Cr. The BOLD measurement was collected in the left inferior frontal gyrus and the MRS measurement was measured in the left hippocampus. HC showed a significant positive correlation (r = 0.489, p = .008) that was not present in SZ group (r = 0.139, p = .480). These two correlations are not significantly different (Z = 1.4, p = .162). Solid lines are linear regressions and dashed lines are 95% confidence intervals.