Schizophrenia (SCZ) is characterized by deficits across multiple cognitive domains presumed to be associated with altered glutamate (Glu) related neuroplasticity in the dorsolateral prefrontal cortex (dlPFC) and the hippocampus. However, how Glu deficits, are related to cognition in SCZ, and whether the relationship between Glu and cognition is different in patients compared to controls has not been systematically addressed. To address these questions, here we acquired proton magnetic resonance spectroscopy (¹H MRS) from the dlPFC and hippocampus at 3T in 44 SCZ and 39 age-and sex-matched adult controls. The ¹H MRS data were acquired under behavioral constraint (passive viewing of a visual stimulus) reducing signal heterogeneity that results from processes like mind wandering. In parallel, a comprehensive cognitive assessment battery (working memory, episodic memory, and processing speed) was acquired in all subjects. We investigate inter-group differences in neurochemistry and mediation/moderation effects between glutamate-cognition relationships using structural equation modelling (SEM). SCZ were characterized by lower Glu and myo-Inositol levels from the hippocampus (p=.0044 and p=.023), with non-significant reductions in the dlPFC. Patients showed significantly poorer performance across all three cognitive domains (p<.0032). Finally, while SEM analyses demonstrated no relationship between SCZ-related hippocampal deficits and cognition, a moderation analyses revealed inter-group differences in the degree of association between right dlPFC Glu levels and processing speed. Glu and myo-Inositol deficits from the hippocampus in SCZ are consistent with the evidence of a reduced neuropil density related to the glutamatergic system. More notably, the SEM analyses indicate that hippocampal Glu deficits in SCZ were not driven by poorer cognitive ability. In SCZ, altered neurochemistry of the hippocampus acquired in a passive state does not appear to predict altered cognition. We suggest that task-based ¹H functional MRS is a more meaningful framework for investigation relationships between neurochemistry and cognition in SCZ.

Schizophrenia (SCZ) is characterized by deficits across multiple cognitive domains presumed to be associated with altered glutamate (Glu) related neuroplasticity in the dorsolateral prefrontal cortex (dlPFC) and the hippocampus. However, how Glu deficits, are related to cognition in SCZ, and whether the relationship between Glu and cognition is different in patients compared to controls has not been systematically addressed. To address these questions, here we acquired proton magnetic resonance spectroscopy (¹H MRS) from the dlPFC and hippocampus at 3T in 44 SCZ and 39 age- and sex-matched adult controls. The ¹H MRS data were acquired under behavioral constraint (passive viewing of a visual stimulus) reducing signal heterogeneity that results from processes like mind wandering. In parallel, a comprehensive cognitive assessment battery (working memory, episodic memory, and processing speed) was acquired in all subjects. We investigate inter-group differences in neurochemistry and mediation/moderation effects between glutamate–cognition relationships using structural equation modelling (SEM). SCZ were characterized by lower Glu and myo-Inositol levels from the hippocampus (p=.0044 and p=.023), with non-significant reductions in the dlPFC. Patients showed significantly poorer performance across all three cognitive domains (p<.0032). Finally, while SEM analyses demonstrated no relationship between SCZ-related hippocampal deficits and cognition, a moderation analyses revealed inter-group differences in the degree of association between right dlPFC Glu levels and processing speed. Glu and myo-Inositol deficits from the hippocampus in SCZ are consistent with the evidence of a reduced neuropil density related to the glutamatergic system. More notably, the SEM analyses indicate that hippocampal Glu deficits in SCZ were not driven by poorer cognitive ability. In SCZ, altered neurochemistry of the hippocampus acquired in a passive state does not appear to predict altered cognition. We suggest that task-based ¹H functional MRS is a more meaningful framework for investigation relationships between neurochemistry and cognition in SCZ.