Multicenter Study

. 2019 May 1:191:537-548.

doi: 10.1016/j.neuroimage.2019.02.059. Epub 2019 Mar 3.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

Mark Mikkelsen¹, Daniel L Rimbault², Peter B Barker³, Pallab K Bhattacharyya⁴, Maiken K Brix⁵, Pieter F Buur⁶, Kim M Cecil⁷, Kimberly L Chan⁸, David Y-T Chen⁹, Alexander R Craven¹⁰, Koen Cuypers¹¹, Michael Dacko¹², Niall W Duncan¹³, Ulrike Dydak¹⁴, David A Edmondson¹⁴, Gabriele Ende¹⁵, Lars Ersland¹⁶, Megan A Forbes¹⁷, Fei Gao¹⁸, Ian Greenhouse¹⁹, Ashley D Harris²⁰, Naying He²¹, Stefanie Heba²², Nigel Hoggard²³, Tun-Wei Hsu²⁴, Jacobus F A Jansen²⁵, Alayar Kangarlu²⁶, Thomas Lange¹², R Marc Lebel²⁷, Yan Li²¹, Chien-Yuan E Lin²⁸, Jy-Kang Liou²⁴, Jiing-Feng Lirng²⁴, Feng Liu²⁹, Joanna R Long³⁰, Ruoyun Ma³¹, Celine Maes³², Marta Moreno-Ortega³³, Scott O Murray³⁴, Sean Noah³⁵, Ralph Noeske³⁶, Michael D Noseworthy³⁷, Georg Oeltzschner³, Eric C Porges¹⁷, James J Prisciandaro³⁸, Nicolaas A J Puts³, Timothy P L Roberts³⁹, Markus Sack¹⁵, Napapon Sailasuta⁴⁰, Muhammad G Saleh³, Michael-Paul Schallmo⁴¹, Nicholas Simard⁴², Diederick Stoffers⁶, Stephan P Swinnen⁴³, Martin Tegenthoff²², Peter Truong⁴⁴, Guangbin Wang¹⁸, Iain D Wilkinson²³, Hans-Jörg Wittsack⁴⁵, Adam J Woods¹⁷, Hongmin Xu²¹, Fuhua Yan²¹, Chencheng Zhang⁴⁶, Vadim Zipunnikov⁴⁷, Helge J Zöllner⁴⁸, Richard A E Edden³

Affiliations

¹ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address: mmikkel5@jhmi.edu.
² Division of Biomedical Engineering, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
³ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA.
⁴ Imaging Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Radiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁶ Spinoza Centre for Neuroimaging, Amsterdam, the Netherlands.
⁷ Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁸ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Radiology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan.
¹⁰ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; NORMENT - Norwegian Center for Mental Disorders Research, University of Bergen, Bergen, Norway.
¹¹ Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium; REVAL Rehabilitation Research Center, Hasselt University, Diepenbeek, Belgium.
¹² Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
¹³ Brain and Consciousness Research Centre, Taipei Medical University, Taipei, Taiwan.
¹⁴ School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Department of Neuroimaging, Central Institute of Mental Health, Mannheim, Germany.
¹⁶ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; NORMENT - Norwegian Center for Mental Disorders Research, University of Bergen, Bergen, Norway; Department of Clinical Engineering, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA; Center for Cognitive Aging and Memory, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
¹⁸ Shandong Medical Imaging Research Institute, Shandong University, Jinan, China.
¹⁹ Department of Human Physiology, University of Oregon, Eugene, OR, USA.
²⁰ Department of Radiology, University of Calgary, Calgary, AB, Canada.
²¹ Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²² Department of Neurology, BG University Hospital Bergmannsheil, Bochum, Germany.
²³ Academic Unit of Radiology, University of Sheffield, Sheffield, UK.
²⁴ Department of Radiology, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan.
²⁵ Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands.
²⁶ Department of Psychiatry, Columbia University, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.
²⁷ GE Healthcare, Calgary, AB, Canada.
²⁸ GE Healthcare, Taipei, Taiwan.
²⁹ New York State Psychiatric Institute, New York, NY, USA.
³⁰ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA; National High Magnetic Field Laboratory, Gainesville, FL, USA.
³¹ School of Health Sciences, Purdue University, West Lafayette, IN, USA; Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
³² Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium.
³³ Department of Psychiatry, Columbia University, New York, NY, USA.
³⁴ Department of Psychology, University of Washington, Seattle, WA, USA.
³⁵ Center for Mind and Brain, University of California, Davis, Davis, CA, USA.
³⁶ GE Healthcare, Berlin, Germany.
³⁷ Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON, Canada.
³⁸ Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
³⁹ Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴⁰ Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴¹ Department of Psychology, University of Washington, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
⁴² School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada.
⁴³ Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium; Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.
⁴⁴ Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁴⁵ Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
⁴⁶ Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴⁸ Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany; Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

PMID: 30840905
PMCID: PMC6818968
DOI: 10.1016/j.neuroimage.2019.02.059

Multicenter Study

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

Mark Mikkelsen et al. Neuroimage. 2019.

. 2019 May 1:191:537-548.

doi: 10.1016/j.neuroimage.2019.02.059. Epub 2019 Mar 3.

Authors

Affiliations

¹ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address: mmikkel5@jhmi.edu.
² Division of Biomedical Engineering, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
³ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA.
⁴ Imaging Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Radiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁶ Spinoza Centre for Neuroimaging, Amsterdam, the Netherlands.
⁷ Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁸ Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Radiology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan.
¹⁰ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; NORMENT - Norwegian Center for Mental Disorders Research, University of Bergen, Bergen, Norway.
¹¹ Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium; REVAL Rehabilitation Research Center, Hasselt University, Diepenbeek, Belgium.
¹² Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
¹³ Brain and Consciousness Research Centre, Taipei Medical University, Taipei, Taiwan.
¹⁴ School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Department of Neuroimaging, Central Institute of Mental Health, Mannheim, Germany.
¹⁶ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; NORMENT - Norwegian Center for Mental Disorders Research, University of Bergen, Bergen, Norway; Department of Clinical Engineering, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA; Center for Cognitive Aging and Memory, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
¹⁸ Shandong Medical Imaging Research Institute, Shandong University, Jinan, China.
¹⁹ Department of Human Physiology, University of Oregon, Eugene, OR, USA.
²⁰ Department of Radiology, University of Calgary, Calgary, AB, Canada.
²¹ Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²² Department of Neurology, BG University Hospital Bergmannsheil, Bochum, Germany.
²³ Academic Unit of Radiology, University of Sheffield, Sheffield, UK.
²⁴ Department of Radiology, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan.
²⁵ Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands.
²⁶ Department of Psychiatry, Columbia University, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.
²⁷ GE Healthcare, Calgary, AB, Canada.
²⁸ GE Healthcare, Taipei, Taiwan.
²⁹ New York State Psychiatric Institute, New York, NY, USA.
³⁰ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA; National High Magnetic Field Laboratory, Gainesville, FL, USA.
³¹ School of Health Sciences, Purdue University, West Lafayette, IN, USA; Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA.
³² Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium.
³³ Department of Psychiatry, Columbia University, New York, NY, USA.
³⁴ Department of Psychology, University of Washington, Seattle, WA, USA.
³⁵ Center for Mind and Brain, University of California, Davis, Davis, CA, USA.
³⁶ GE Healthcare, Berlin, Germany.
³⁷ Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON, Canada.
³⁸ Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
³⁹ Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴⁰ Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴¹ Department of Psychology, University of Washington, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
⁴² School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada.
⁴³ Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium; Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.
⁴⁴ Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁴⁵ Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
⁴⁶ Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴⁸ Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany; Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

PMID: 30840905
PMCID: PMC6818968
DOI: 10.1016/j.neuroimage.2019.02.059

Abstract

Accurate and reliable quantification of brain metabolites measured in vivo using ¹H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T₁-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Keywords: Editing; GABA; MEGA-PRESS; MRS; Quantification; Tissue correction.

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Figures

**Fig. 1.**
(A) Representative MRS voxel placement on a T₁-weighted structural image and probabilistic partial volume voxel maps following tissue segmentation for one participant. Corresponding tissue fractions of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) are shown. (B) Vendor-mean GABA-edited difference spectra acquired by GABA+ and MM-suppressed GABA editing. The gray patches represent ±1 standard deviation. The associated sample sizes are shown in parentheses.

**Fig. 2.**
(A) Water-referenced GABA+ and (B) MM-suppressed GABA measurements fully corrected for partial volume effects, displayed by site and by vendor. The boxes shaded with lighter colors represent ±1 standard deviation and the darker boxes represent the 95% confidence interval. The solid white lines denote the mean, while the dashed white lines denote the median. Sites are colored by vendor (GE sites in green, Philips sites in orange, Siemens sites in blue).

**Fig. 3.**
Gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) voxel tissue fractions, displayed by site and by vendor. GM = gray fill; WM = white fill; CSF = black fill. The red lines denote the mean. Sites are colored by vendor (GE sites with a green background, Philips sites with an orange background, Siemens sites with a blue background).

**Fig. 4.**
Quality metrics and water-referenced Cr measurements (from the TE = 68 ms data), displayed by site and by vendor. (A) water fit error; (B) water linewidth; (C) Cr measurements fully corrected for partial volume effects. The boxes shaded with lighter colors represent ±1 standard deviation and the darker boxes represent the 95% confidence interval. The solid white lines denote the mean, while the dashed white lines denote the median. Sites are colored by vendor (GE sites in green, Philips sites in orange, Siemens sites in blue).

**Fig. 5.**
Scatterplots illustrating the relationship between (A) water-referenced GABA+ measurements and GABA+/Cr ratios and (B) water-referenced MM-suppressed GABA measurements and MM-suppressed GABA/Cr ratios. Individual measurements are color-coded by vendor (GE in green, Philips in orange, Siemens in blue). The black regression line shows the relationship between GABA+/Cr and water-referenced GABA+ over the entire dataset. Additional color-coded regression lines are shown for each site. R² values (i.e., the effect sizes) are also displayed.

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Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

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Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

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