Current Practice and New Developments in the Use of In Vivo Magnetic Resonance Spectroscopy for the Assessment of Key Metabolites Implicated in the Pathophysiology of Schizophrenia

Abstract

Through the four years spent on this PhD project, I'm very grateful to have had so many wonderful people around me as supervisors, co-authors, co-workers, colleagues, friends and family. Two people I can never thank enough are my supervisor Renate Grüner, and cosupervisor Kenneth Hugdahl. During my Master's thesis project, where she was also my main supervisor, I remember apologising to Renate for spending an inordinate amount of time trying to find an answer to a rather trivial question, to which she simply said "Don't apologise for wanting to find answers to your questions, this is what makes you a good scientist" and I have not forgotten this. My thanks and my gratitude to Renate for her continued assistance and encouragement. Kenneth Hugdahl, in addition to making this PhD project possible, and sending us around the world to soak our sponge-like brains in knowledge, has also been a great inspiration. Clarke's first law states "When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong." Listening to Kenneth, one feels as if anything is possible, they need only figure out how it needs to be done. Clarke's third law states that "Any sufficiently advanced technology is indistinguishable from magic," by extension, Alex Craven is nothing short of a magician. Alex is the "sine qua non" of this project, and his invaluable work is greatly appreciated. Massive thanks and gratitude go to everyone that helped in the planning, organisation, data collection and analysis involved with the three articles presented here, namely

Extrinsic and default mode networks in psychiatric conditions: Relationship to excitatory-inhibitory transmitter balance and early trauma

“…Regarding inhibitory neurotransmission, a recent meta-analysis of 1 H-MRS studies investigating GABA levels across psychiatric conditions (Schur, et al 2016) report reduced GABA levels in symptomatic depressed patients and in patients with schizophrenia relative to healthy controls. These findings provide further support for E/I neurotransmitter imbalance in MDD and schizophrenia, supported by more recent studies which all report aberrant metabolite levels in schizophrenia and psychosis (Dwyer, et al 2018;Jelen, et al 2018;Psomiades, et al 2018;Reid, et al 2019;Kim, et al 2018;Singh, et al 2018). However, currently there is no evidence for differences in GABA levels between healthy controls and patients with bipolar or anxiety disorders (Schur, et al 2016 concentrations have also been shown to predict local activation during a word memory task, an association that appears to be absent in a CHR cohort ).…”

Age and Sex Influences Gamma-aminobutyric Acid Concentrations in the Developing Brain of Very Premature Infants

“…GABA concentrations in the developing brain are inherently low (1-2 µmol/g) 19,28,29 and its spectroscopic signals are overlapped by more dominant metabolites in the standard 1 H-MRS spectra 15 . To enhance spectral resolution, animal studies have utilized ultra-high strength magnetic field (7-9 T) scanners 30,31 , while adult human studies on 3 T scanners have used alternative techniques including short-echo time and/or spectral editing techniques like MEGA-PRESS 14,[32][33][34] . Additional challenges in the preterm population including smaller brain volumes limiting voxel size, motion artifacts on non-sedated research scans, and dependence on intensive care during the early postnatal period have further limited in vivo www.nature.com/scientificreports www.nature.com/scientificreports/ investigation during this crucial phase of brain development.…”

“…Proton magnetic resonance spectroscopy ( 1 H-MRS) enables non-invasive measurement of the in vivo concentrations of neurometabolites like N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr); which have been associated with neurodevelopmental outcomes 13 . GABA and glutamate signals in the standard 1 H-MRS spectrum on conventional 1.5 Tesla MRI are overlapped by other dominant metabolites, which necessitate using higher field strength MR scanners, shorter echo-times or spectral editing techniques to improve their signal resolution 14,15 . Studies using the spectral J-difference editing technique, MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS) have reported lower regional GABA and glutamate concentrations in older subjects with disorders like epilepsy, autism, attention-deficit disorder 14,16 , known to affect a high proportion of prematurely born surviving adults 3 .…”

“…GABA and glutamate signals in the standard 1 H-MRS spectrum on conventional 1.5 Tesla MRI are overlapped by other dominant metabolites, which necessitate using higher field strength MR scanners, shorter echo-times or spectral editing techniques to improve their signal resolution 14,15 . Studies using the spectral J-difference editing technique, MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS) have reported lower regional GABA and glutamate concentrations in older subjects with disorders like epilepsy, autism, attention-deficit disorder 14,16 , known to affect a high proportion of prematurely born surviving adults 3 . While interpreting these results, it should be noted that measurements by MEGA-PRESS have contributions from other co-edited metabolites; e.g macromolecules with GABA (represented as GABA+) and glutamine with glutamate (represented as Glx) 14,15 .…”

“…Studies using the spectral J-difference editing technique, MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS) have reported lower regional GABA and glutamate concentrations in older subjects with disorders like epilepsy, autism, attention-deficit disorder 14,16 , known to affect a high proportion of prematurely born surviving adults 3 . While interpreting these results, it should be noted that measurements by MEGA-PRESS have contributions from other co-edited metabolites; e.g macromolecules with GABA (represented as GABA+) and glutamine with glutamate (represented as Glx) 14,15 . However, in vivo assessment of GABA in the developing human preterm brain has been limited by motion artifacts on non-sedated neonatal scans, the small brain volumes limiting the size of the 1 H-MRS voxel, the limited availability of high magnetic field strength MRI scanners for this population and additional challenges associated with intensive care support during early postnatal life.…”