Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Smucny, Jason; Carter, Cameron S.; Maddock, Richard J.

doi:10.1016/j.biopsych.2021.06.008

“…Consistent with several (including recent 7 Tesla) ¹H MRS studies [25,[48][49][50][51], basal Glu levels from the dlPFC were not significantly different between SCZ and HC. However, basal Glu and myo-Inositol levels from the hippocampus were significantly lower in SCZ.…”

Section: Implication Of Glu and Myo-inositol In Sczsupporting

confidence: 85%

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modeling

Stanley

¹

,

Daugherty

²

,

Gorey³

et al. 2022

Preprint

0

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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.

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“…In schizophrenia, although the exact nature of glutamate dysfunction in schizophrenia is yet to be clarified, meta- and mega-analyses of MRS data demonstrate a glutamatergic deficit state, at least in the prefrontal cortex [ 66 , 128 , 129 ]. Emerging observations implicate antipsychotics in progressive glutamate reduction in schizophrenia [ 128 ] but evidence in this regard is still inconclusive (see [ 84 , 129 ]). Interestingly, lower GSH levels co-occur with reduced glutamate in the chronic stage [ 65 , 68 ], especially in ultra-treatment-resistant patients [ 71 ].…”

Section: Glutathione—glutamate Relationshipmentioning

confidence: 99%

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Palaniyappan

¹

,

Park

²

,

Jeon

³

et al. 2021

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Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia.

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“…In schizophrenia, while the exact nature of glutamate dysfunction in schizophrenia is yet to be clarified, meta-and mega-analyses of MRS data demonstrate a glutamatergic deficit state, at least in the prefrontal cortex [66,130,131]. Emerging observations implicate antipsychotics in progressive glutamate reduction in schizophrenia [130] but evidence in this regard is still inconclusive (see [84] and [131]). Interestingly, lower GSH levels cooccur with reduced glutamate in the chronic stage [65,68], especially in ultra-treatmentresistant patients [71].…”

Section: Glutathione -Glutamate Relationshipmentioning

confidence: 99%

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Palaniyappan¹,

Park²,

Jeon³

et al. 2021

Preprint

View full text Add to dashboard Cite

Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia.

show abstract

Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Cited by 31 publications

References 81 publications

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modeling

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modeling

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

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