Impact of glutamate levels on neuronal response and cognitive abilities in schizophrenia

Abstract

Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy ((1)H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI-(1)H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia.

Keywords: 1H-MRS; Anterior cingulate cortex; BOLD; Cognitive control; Combined fMRI–MRS; Connectivity; Glutamate; Inferior parietal lobe.

Fig. 1

Voxel placements for the ¹H-MRS in the bilateral dorsal anterior cingulate cortex.

Fig. S1

Representative ¹H-MRS spectra from the four glutamate-groups. Spectra were acquired by LCModel from four individuals representing the four groups. The absorption peak from which glutamate is measured is marked by an asterisk (*). SZ, schizophrenia patients; HC, healthy controls; rsGlu, resting-state glutamate.

Fig. S2

Overall fMRI BOLD response from the auditory cognitive control task. Showing the results for the schizophrenia patients (SZ) and healthy controls (HC) separately, together with the combined BOLD response over the two groups (P < .001, extent threshold k = 50 voxels). See Falkenberg et al. (2011) and Westerhausen et al. (2010) for a more detailed discussion of the above regions and the dichotic listening task in healthy individuals.

Fig. S3

Group difference in fMRI BOLD response. The red cluster shows the region where schizophrenia patients (SZ) show higher BOLD response during high demands for cognitive control compared to healthy controls (HC; P < .001, extent threshold k = 50 voxels). The blue cluster indicates the region influenced by glutamate levels (see also Fig. 2). LE, left ear; RE, right ear; FR, forced-right attention condition; FL, forced-left condition; “+” indicates the ear with louder (by 18 dB) sound intensity.

Fig. 2

Results from the combined fMRI–¹H-MRS analysis, showing the regions where right ACC resting-state glutamate (rsGlu) differentially moderates the BOLD response in the cognitive control task (P < .001, extent threshold k = 50 voxels). Schizophrenia patients (SZ) and healthy controls (HC) display a positive and negative correlation, respectively, between BOLD response and right rsGlu. IPL, inferior parietal lobe; L, left; R, right.

Fig. 3

Task performance for the four glutamate-groups. Effect sizes (?²) are shown for the four groups' degree of sound intensity dependency (i.e., the effect size of the IID × ear interaction) and the capability for attentional modulation (i.e., the effect size of the ATT × ear interaction) of the auditory cognitive control task. IID, interaural intensity difference; ATT, attention instruction.