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PurposeThis study aimed to characterize blood oxygen level-dependent (BOLD) effects in proton magnetic resonance (1H-MR) spectra obtained during optogenetic activation of the rat forelimb cortex to correct and estimate the accurate changes in metabolite concentration.MethodsFor a more comprehensive understanding of BOLD effects detected with functional magnetic resonance spectroscopy (fMRS) and to optimize the correction method, a 1 Hz line-narrowing effect was simulated. Then, proton functional magnetic resonance spectroscopy (1H-fMRS) data acquired using stimulated echo acquisition mode (STEAM) at 9.4T in rats (n = 8) upon optogenetic stimulation of the primary somatosensory cortex were utilized. The data were analyzed using MATLAB routines and LCModel. Uncorrected and corrected 1H-MR spectra from the simulated and in vivo data were quantified and compared. BOLD-corrected difference spectra were also calculated and analyzed. Additionally, the effects of stimulated and non-stimulated water on the quantification of metabolite concentration swere investigated.ResultsSignificant mean increases in water and N-acetylaspartate (NAA) peak heights (+1.1% and +4.5%, respectively) were found to be accompanied by decreased linewidths (−0.5 Hz and −2.8%) upon optogenetic stimulation. These estimates were used for further defining an accurate line-broadening (lb) factor. The usage of a non-data-driven lb introduced false-positive errors in the metabolite concentration change estimates, thereby altering the specificity of the findings. The water and metabolite BOLD contributions were separated using different water scalings within LCModel.ConclusionThe linewidth-matching procedure using a precise lb factor remains the most effective approach for accurately quantifying small (±0.3 μmol/g) metabolic changes in 1H-fMRS studies. A simple and preliminary compartmentation of BOLD effects was proposed, but it will require validation.

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies. [ABSTRACT FROM AUTHOR]

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies.

The glutamate system is implicated in the pathophysiology of schizophrenia and mood disorders. Using functional magnetic resonance spectroscopy (1H-fMRS), it is possible to monitor glutamate dynamically in activated brain areas and may give a closer estimate of glutamatergic neurotransmission than standard magnetic resonance spectroscopy. 14 patients with schizophrenia, 15 patients with bipolar disorder II (BPII) and 14 healthy volunteers underwent a 15 min N-back task in a 48s block design during 1H-fMRS acquisition. Data from the first, second and third 16s group of 8 spectra for each block were analysed to measure levels of glutamate and Glx (glutamate + glutamine), scaled to total creatine (TCr), across averaged 0-back and 2-back conditions. A 6 × 3 repeated-measures analysis of variance (rmANOVA) demonstrated a significant main effect of time for Glx/TCr (P = 0.022). There was a significant increase in Glu/TCr (P = 0.004) and Glx/TCr (P < 0.001) between the final spectra of the 0-back and first spectra of the 2-back condition in the healthy control group only. 2 × 2 rmANOVA revealed a significant time by group interaction for Glx/TCr (P = 0.019) across the 0-back condition, with levels reducing in healthy controls and increasing in the schizophrenia group. While healthy volunteers showed significant increases in glutamatergic measures between task conditions, the lack of such a response in patients with schizophrenia and BPII may reflect deficits in glutamatergic neurotransmission. Abnormal increases during periods of relatively low executive load, without the same dynamic modulation as healthy volunteers with increasing task difficulty, further suggests underlying abnormalities of glutamatergic neurotransmission in schizophrenia. [ABSTRACT FROM AUTHOR]

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo . Functional magnetic resonance spectroscopy ( 1 H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1 H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION ( p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1 H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies., Competing Interests: JS: In the last 3 years, he has been PI or sub-investigator on studies sponsored by Takeda, Janssen and Lundbeck Plc. He has attended an Investigators' meeting run by Allergan Plc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jelen, Lythgoe, Jackson, Howard, Stone and Egerton.)