In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia

Parsa Ravanfar^{1

2}, Warda T Syeda³, Mahesh Jayaram⁴, R Jarrett Rushmore^{5

6

7}, Bradford Moffat⁸, Alexander P Lin^{5

9}, Amanda E Lyall^{5

10

11}, Antonia H Merritt³, Negin Yaghmaie^{8

12}, Liliana Laskaris³, Sandra Luza^{3

13}, Carlos M Opazo¹³, Benny Liberg¹⁴, M Mallar Chakravarty^{15

16

17}, Gabriel A Devenyi^{15

16}, Patricia Desmond¹⁸, Vanessa L Cropley³, Nikos Makris^{5

6}, Martha E Shenton⁵, Ashley I Bush¹³, Dennis Velakoulis^{3

19}, Christos Pantelis^{20

21}

Affiliations

¹ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia. sravanfar@student.unimelb.edu.au.
² Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. sravanfar@student.unimelb.edu.au.
³ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
⁴ Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Australia.
⁵ Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Center for Morphometric Analysis (CMA), Massachusetts General Hospital, Charlestown, MA, USA.
⁷ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
⁸ Melbourne Brain Centre Imaging Unit, Department of Radiology, University of Melbourne, Parkville, VIC, Australia.
⁹ Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Biomedical Engineering, The University of Melbourne, Parkville, VIC, Australia.
¹³ Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, and The University of Melbourne, Parkville, VIC, Australia.
¹⁴ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Cerebral Imaging Center, Douglas Research Centre, Montreal, QC, Canada.
¹⁶ Department of Psychiatry, McGill University, Montreal, QC, Canada.
¹⁷ Department of Biomedical Engineering, McGill University, Montreal, QC, Canada.
¹⁸ Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
¹⁹ Neuropsychiatry, The Royal Melbourne Hospital, Parkville, VIC, Australia.
²⁰ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia. cpant@unimelb.edu.au.
²¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. cpant@unimelb.edu.au.

PMID: 36289238
PMCID: PMC9605948
DOI: 10.1038/s41537-022-00293-1

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia

Parsa Ravanfar et al. Schizophrenia (Heidelb). 2022.

. 2022 Oct 26;8(1):86.

doi: 10.1038/s41537-022-00293-1.

Authors

Affiliations

¹ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia. sravanfar@student.unimelb.edu.au.
² Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. sravanfar@student.unimelb.edu.au.
³ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
⁴ Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Australia.
⁵ Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Center for Morphometric Analysis (CMA), Massachusetts General Hospital, Charlestown, MA, USA.
⁷ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
⁸ Melbourne Brain Centre Imaging Unit, Department of Radiology, University of Melbourne, Parkville, VIC, Australia.
⁹ Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Biomedical Engineering, The University of Melbourne, Parkville, VIC, Australia.
¹³ Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, and The University of Melbourne, Parkville, VIC, Australia.
¹⁴ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Cerebral Imaging Center, Douglas Research Centre, Montreal, QC, Canada.
¹⁶ Department of Psychiatry, McGill University, Montreal, QC, Canada.
¹⁷ Department of Biomedical Engineering, McGill University, Montreal, QC, Canada.
¹⁸ Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
¹⁹ Neuropsychiatry, The Royal Melbourne Hospital, Parkville, VIC, Australia.
²⁰ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia. cpant@unimelb.edu.au.
²¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. cpant@unimelb.edu.au.

PMID: 36289238
PMCID: PMC9605948
DOI: 10.1038/s41537-022-00293-1

Abstract

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T₁ imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

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Conflict of interest statement

A.I.B. is a shareholder in Alterity Ltd, Cogstate Ltd and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd. He has received speaker fees from Biogen Ltd. C.P. has received honoraria for talks at educational meetings and has served on an advisory board for Lundbeck, Australia Pty Ltd. A.P.L. is a co-founder of BrainSpec and paid consultant for Agios Pharmaceuticals, Biomarin Pharmaceuticals, and Moncton MRI.

Figures

**Fig. 1. Between-group comparison of regional QSM and MRS metabolites.**
a a representative QSM image from our dataset. Regions with higher magnetic susceptibility (higher levels of iron) appear brighter. b Tukey’s boxplots overlaid on dot plots of ROI-based comparison of mean susceptibility values between healthy controls (blue circles) and individuals with schizophrenia (red triangles). Black dots represent the mean values in each group. High signal intensity in the SN and GP indicates high iron content in these regions in both groups. c a representative MRS spectrum from our dataset (d). Tukey’s boxplots overlaid on dot plots demonstrating the between-group comparison of neurometabolites in the daCC. Blue circles represent healthy controls and red triangles represent individuals with schizophrenia. Black dots indicate mean values in each group. SN substantia nigra, GP globus pallidus, NAc nucleus accumbens. Cr creatine, PCr phosphocreatine, GSH glutathione, ppb parts per billion.

**Fig. 2. Correlation network plots for regional QSM and MRS measures in schizophrenia and control groups.**
a correlation network of QSM in the main regions of cortico-subcortical networks in the control (left) and schizophrenia group (right) – (b). correlation network of neurometabolites in the caCC and QSM in the regions related to the caCC in the control (left) and schizophrenia group (right). Only the correlations with Pearson coefficients higher than 0.4 are shown. caCC caudal anterior cingulate cortex, conc. concentration, Cr creatine, GABA gamma-aminobutyric acid, Glu glutamate, GP globus pallidus, GSH glutathione, Lac lactate, lOFC lateral orbitofrontal cortex, mOFC medial orbitofrontal cortex, NAA N-acetyl-aspartate, NAAG N-acetyl-aspartyl-glutamate, NAc nucleus accumbens, PCr phosphocreatine, raCC rostral anterior cingulate cortex, rmFC rostral middle frontal cortex, SN substantia nigra.

**Fig. 3. Correlation between mean QSM value and volume/thickness in ROIs within schizophrenia and control groups.**
a correlation between mean QSM and volume or thickness within each ROI in the control (left) and schizophrenia group (right). The middle column shows the difference of z scores after r to z transformation in the regions where the correlation between QSM and volume where significantly different between groups. (z difference) = (z schizophrenia) - (z control) (b). bar plot showing the correlation between QSM and volume/thickness in ROIs. Numbers indicate correlation coefficients and significant between-group differences are marked by asterisks. caCC caudal anterior cingulate cortex, GP globus pallidus, lOFC lateral orbitofrontal cortex, lh left hemisphere, mOFC medial orbitofrontal cortex, NAc nucleus accumbens, raCC rostral anterior cingulate cortex, rh right hemisphere, rmFC rostral middle frontal cortex, SN substantia nigra.

**Fig. 4. Neuroanatomical representation of MRS acquisition voxel and the ROIs comprising CSTC circuits.**
a location of the MRS acquisition voxel in the caCC (b). CSTC pathways that involve the limbic striatum (right) and associative striatum (left), top: medial view, bottom: superior view.

See this image and copyright information in PMC

References

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In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia

Affiliations

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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