Association of cortical glutamate and working memory activation in patients with schizophrenia: a multimodal 1H-MRS and fMRI study

Abstract Background Cognitive deficits like working memory impairment are core features of schizophrenia. One candidate marker for the integrity of synaptic neurotransmission necessary for cognitive processes is glutamate. It is frequently postulated that antipsychotic medication possibly alters functional mechanisms in the living brain. We tested in vivo for group differences in activation of the dorsolateral prefrontal cortex (dLPFC) during working memory (WM) performance and the association with glutamate concentration in dLPFC depending on medication status. Methods 90 subjects (35 controls, 36 medicated and 19 unmedicated patients) contributed magnetic resonance spectroscopy data (1H-MRS). We estimated glutamate in left dLPFC. Subjects performed an n-back WM task (2-back vs. 0-back) during functional magnetic resonance imaging and local activation in left dLPFC was measured. For analysis of association with medication status, we calculated linear regression models including an interaction effect with group. Results Medicated and unmedicated patients with schizophrenia showed impaired performance. We found significantly reduced WM activation in left dLPFC in medicated patients and a trendwise reduction in unmedicated patients as compared to controls. We found no group difference in local glutamate concentration. However, we found differential effects of medication status on the association between local glutamate concentration and WM activation in left dLPFC, with a positive association in unmedicated patients but not in medicated patients. Conclusion We provide evidence that WM dependent activation is associated with glutamate concentration in unmedicated schizophrenia patients. Our finding points to putative allostatic changes which affect the functioning of the brain and might be altered through medication.