Assessment of intra- and inter-regional interrelations between GABA+, Glx and BOLD during pain perception in the human brain – A combined 1H fMRS and fMRI study

Cleve, Marianne; Gussew, Alexander; Wagner, Gerd; Bär, Karl‐Jürgen; Reichenbach, Jürgen R.

doi:10.1016/j.neuroscience.2017.09.037

Cited by 24 publications

(21 citation statements)

References 51 publications

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“…functional MRS (fMRS), involves the acquisition and analysis of spectra in such a way that dynamic changes in metabolite levels may be measured in relation to a stimulus, task or change in state. In what is widely considered the first fMRS experiment, Prichard et al (1991) investigated a mismatch between increased blood flow and glucose uptake with oxygen consumption in the visual cortex in response to visual stimulation (Fox, Raichle, Mintun, & Dence, 1988 (Bednařík et al, 2015;Lin, Stephenson, Xin, Napolitano, & Morris, 2012;Mangia et al, 2007;Mekle et al, 2017;Schaller, Mekle, Xin, Kunz, & Gruetter, 2013), changes in glutamate in the anterior cingulate cortex (ACC) and insula in response to pain (Cleve, Gussew, Wagner, Bär, & Reichenbach, 2017;Gussew et al, 2010;Gutzeit et al, 2011;Mullins, Rowland, Jung, & Sibbitt, 2005) as well as dynamic changes in GABA in the sensorimotor cortex in response to learning (Floyer-Lea, Wylezinska, Kincses, & Matthews, 2006) and in the dorsolateral prefrontal cortex (DLPFC) under a working memory task (Michels et al, 2012).…”

Section: Functional Mrsmentioning

confidence: 99%

“…Despite the strengths of functional MRS, one of its limitations is that it may not measure neural activity directly. While it is possible to perform an experimental paradigm using fMRI and fMRS separately (Cleve et al, 2017), attempts have been made to measure both activity and metabolism simultaneously using a combination of fMRI and fMRS. Another approach to combining BOLD-fMRI and MRS takes advantage of the BOLD-effect on the lineshape of MR-Spectra.…”

Section: Combining Fmri and Mrsmentioning

confidence: 99%

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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

Dwyer

Hugdahl

Specht

et al. 2019

CTMC

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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

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Section: Functional Mrsmentioning

confidence: 99%

Section: Combining Fmri and Mrsmentioning

confidence: 99%

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

Dwyer

Hugdahl

Specht

et al. 2019

CTMC

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“…Glutamate reuptake in glia accounts for ~50% of energy expenditure in the brain [ 17 ], so that changes in glutamate/glutamine cycling and energy expenditure are highly correlated [ 18 – 21 ]. The increased energy expenditure, in turn, leads to an increase in local cerebral blood flow that can be detected using BOLD imaging [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

Kantrowitz

Grinband

Goff

et al. 2020

Neuropsychopharmacol.

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Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

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“…Ultrahigh field 1 H-MRS will likely improve the spectral quality, while requiring shorter scan times, compared to clinical field strengths, such as 1.5T and 3T (Mekle et al, 2009;Pradhan et al, 2015;Terpstra et al, 2016). This may open up the opportunity to study pharmacokinetic effects in multiple brain regions and/or include other modalities that complement the investigations in multimodal study designs (Mangia et al, 2009;Cleve et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy

et al. 2020

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Glutamate detection in pons and thalamus using proton magnetic resonance spectroscopy (1 H-MRS) after an intervention is of interest for studying various brain disorders. However, 1 H-MRS in these brain regions is challenging and time-consuming, especially in longitudinal study designs. 1 H-MRS of more cortical structures at the ultrahigh magnetic field strength of 7T yields an improved spectral output, including separation of the glutamate signal from the glutamine signal, in a shorter and more feasible scan time, as compared to conventional clinical field strengths. For this purpose, we compared the feasibility of 1 H-MRS at 3T and 7T in pons and thalamus by applying a longitudinal study design of repeated measures on same day and three separate days at both field strength in five healthy participants. Total 1 H-MRS acquisition time was reduced by a factor 3.75 for pons and by a factor 3 for thalamus at 7T as compared to 3T. We found higher spectral signal-to-noise ratio (SNR) (p < 0.001), lower linewidth (p = 0.001) and lower Cramér-Rao lower bounds (CRLB) (p < 0.001) for the combined glutamate and glutamine signal (Glx) in thalamus at 7T as compared to 3T. In pons, CRLB of Glx and SNR were lower at 7T (p = 0.002 and p = 0.006), with no differences in linewidth compared to 3T. Mean within-subject variability of Glx concentration estimates was lower at 7T compared to 3T for both pons and thalamus. At 7T, it was possible to assess glutamate and γ-aminobutyric acid (GABA) simultaneously in pons and thalamus. In conclusion, 1 H-MRS at 7T resulted in improved spectral quality while allowing shorter scan times than at 3T as well as estimation of the pure glutamate signal in pons and thalamus. This opens up the opportunity for multimodal study designs and multiregional subcortical 1 H-MRS research. Glutamate and GABA measurement at 7T in pons and thalamus is advantageous for future investigations of excitatory-inhibitory mechanisms in brain disorders.

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Assessment of intra- and inter-regional interrelations between GABA+, Glx and BOLD during pain perception in the human brain – A combined 1H fMRS and fMRI study

Cited by 24 publications

References 51 publications

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

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

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy

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