Periodic Reporting for period 4 - SYNAPLAST MR (Imaging synaptic plasticity by ultra-high field magnetic resonance spectroscopy in health and psychiatric disease)
Reporting period: 2021-01-01 to 2021-12-31
A large number of psychiatric disorders including major and bipolar depression (MDD / BD) lack objective criteria for primary diagnosis, early differential diagnosis with regard to subtypes in treatment response and disease progression or effective therapy monitoring. Hence, the search for relevant biomarkers is of high importance. This projects aim was the development of novel methodology for highly spatially and temporally resolved imaging of disease effects on neurotransmission, cell membrane dynamics and brain energy metabolism in psychiatric disorders and the acute and chronic impact of related pharmacological treatment in the human brain. To that, the advantages of a unique 9.4 T whole body human magnetic resonance imaging (MRI) system for magnetic resonance spectroscopic imaging (MRSI) of the human brain was exploited. The combination of complementary enabling ultra-high field MRI technology including radiofrequency coils, parallel transmission, high order B0 shimming, radiofrequency pulse and sequences, image reconstruction and data analysis approaches ensured very high data quality. Next to obtaining novel image contrasts based on steady state metabolite concentrations at high spatial resolution in the entire human brain, the ultimate goal of the proposed research was to enable temporally resolved metabolic imaging in order to investigate metabolic turnover rates, adaptation of neurotransmission and brain metabolism to environmental stimuli as well as the impact of pharmacological intervention. Finally, the novel spatially and temporally resolved metabolic imaging technology should be used to investigate patients with major depressive disorder to reveal novel biomarkers relevant for diagnostics and patient stratification.
Highly spatially resolved whole-brain metabolite imaging by proton and phosphporous MRSI at 9.4T in humans:
A fast whole brain 1H MRSI scan protocol has been developed. First, a 1H head radiofrequency transceiver coil array with whole brain coverage and maximum sensitivity in central brain has been developed. Second different 1H MRSI acceleration and reconstruction methods have been evaluated and it was found that using neural networks to reconstruct under-sampled metabolic imaging data yields superior lipid aliasing artefact control and sensitivity. Third to increase coverage and data quality novel static magnetic B0 methodology as well as parallel transmission technology was implemented. The optimized scan protocol yielded very high-resolution metabolite images of an extended neurochemical profile in large parts of the human brain at 9.4T showing anatomical detail including visualization of gyri and concentration differences between white matter and grey matter. A comprehensive data analysis pipeline was developed to ensure accurate and precise quantitative metabolite maps in mmol/kg units. Quantitative metabolic brain imaging of the tissue concentrations of 12 brain metabolites were demonstrated. Furthermore a metabolic brain atlas is currently created.
A dual-tune 31P/1H RF coil with whole-brain coverage and high signal-to-noise was developed. A fast whole-brain sensitivity optimized 31P MRSI scan protocol with a 3D weighted k-space acquisition scheme and nOe sensitivity enhancement was implemented. A comprehensive data analysis pipeline including low rank filtering was developed to derive accurate and precise quantitative metabolite images. Quantitative whole brain imaging of the tissue concentrations of 4 brain metabolites and the intracellular pH was demonstrated and brain region specific quantification of additional 12 detectable brain metabolites.
Proton and phosphorous metabolic imaging pilot data in patients with major depression versus healthy volunteers has been acquired and is currently analyzed.
Functional single voxel 1H and 31P magnetic resonance spectroscopy at 9.4T:
Single shot (STEAM) and multi shot (ISIS) single volume 31P MRS sequences were implemented and optimized for human brain application at 9.4T. In addition a metabolite cycled non-water suppressed single voxel semi-LASER 1H MRS sequence was further developed with respect to gradient spoiling and phase cycling to yield artefact free spectra. It enables simultaneous detection of the water BOLD effect as used in functional brain imaging and metabolite concentration changes. Functional spectroscopy experiments under visual stimulation have been performed using the respective scan protocols. Next to glutamate and lactate concentration changes, also changes of intracellular pH as well as in the phosphocreatine buffer system have been observed.
13C and 2H MRSI to measure metabolic turnover rates at 9.4T:
The optimized 1H MRS and MRSI scan protocols have been utilized for imaging the uptake of 13C labelled glucose in the human brain over time after oral intake as well as the incorporation of 13C labels into downstream metabolic products glutamate and glutamine. In addition, a 2H / 1H dual tune radiofrequency coil was developed and a whole-brain 2H MRSI sequence was implemented. In vivo human trials after oral uptake of deuterated glucose have been performed and the deuterium label incorporation into water, glucose, glutamate and lactate has been observed in the human brain. Respective data analysis and metabolic modelling pipelines have been implemented. Imaging of glycolytic and TCA cycle rates in the human brain has been achieved by 2H MRSI at high spatial resolution in the human brain. Quantitative data analysis and metabolic modelling demonstrated that rates can be determined with high regional specificity and resolution.
Combination of PET and MRS to investigate neurotransmission in human brain at 3T:
We implemented a single voxel 2D J-resolved semi-LASER sequence at 3T that allows for detection of 18 brain metabolites at 3T and adopted the previously developed ProFit spectral fitting software for quantitative analysis. The sequence was used for consecutive PET and MRS readouts immediately after pharmacological intervention with Ketamine in 20 healthy volunteers and in 20 patients with major depression. First results indicate changes in glutamate and choline concentrations as well as the expression level of the metabotropic glutamate receptor type 5 (mGluR5) under and after acute Ketamine infusion. In addition, correlations between glutamate and choline, glutamate and mGluR5 and choline and mGluR5 were observed after Ketamine infusion.
A fast whole brain 1H MRSI scan protocol has been developed. First, a 1H head radiofrequency transceiver coil array with whole brain coverage and maximum sensitivity in central brain has been developed. Second different 1H MRSI acceleration and reconstruction methods have been evaluated and it was found that using neural networks to reconstruct under-sampled metabolic imaging data yields superior lipid aliasing artefact control and sensitivity. Third to increase coverage and data quality novel static magnetic B0 methodology as well as parallel transmission technology was implemented. The optimized scan protocol yielded very high-resolution metabolite images of an extended neurochemical profile in large parts of the human brain at 9.4T showing anatomical detail including visualization of gyri and concentration differences between white matter and grey matter. A comprehensive data analysis pipeline was developed to ensure accurate and precise quantitative metabolite maps in mmol/kg units. Quantitative metabolic brain imaging of the tissue concentrations of 12 brain metabolites were demonstrated. Furthermore a metabolic brain atlas is currently created.
A dual-tune 31P/1H RF coil with whole-brain coverage and high signal-to-noise was developed. A fast whole-brain sensitivity optimized 31P MRSI scan protocol with a 3D weighted k-space acquisition scheme and nOe sensitivity enhancement was implemented. A comprehensive data analysis pipeline including low rank filtering was developed to derive accurate and precise quantitative metabolite images. Quantitative whole brain imaging of the tissue concentrations of 4 brain metabolites and the intracellular pH was demonstrated and brain region specific quantification of additional 12 detectable brain metabolites.
Proton and phosphorous metabolic imaging pilot data in patients with major depression versus healthy volunteers has been acquired and is currently analyzed.
Functional single voxel 1H and 31P magnetic resonance spectroscopy at 9.4T:
Single shot (STEAM) and multi shot (ISIS) single volume 31P MRS sequences were implemented and optimized for human brain application at 9.4T. In addition a metabolite cycled non-water suppressed single voxel semi-LASER 1H MRS sequence was further developed with respect to gradient spoiling and phase cycling to yield artefact free spectra. It enables simultaneous detection of the water BOLD effect as used in functional brain imaging and metabolite concentration changes. Functional spectroscopy experiments under visual stimulation have been performed using the respective scan protocols. Next to glutamate and lactate concentration changes, also changes of intracellular pH as well as in the phosphocreatine buffer system have been observed.
13C and 2H MRSI to measure metabolic turnover rates at 9.4T:
The optimized 1H MRS and MRSI scan protocols have been utilized for imaging the uptake of 13C labelled glucose in the human brain over time after oral intake as well as the incorporation of 13C labels into downstream metabolic products glutamate and glutamine. In addition, a 2H / 1H dual tune radiofrequency coil was developed and a whole-brain 2H MRSI sequence was implemented. In vivo human trials after oral uptake of deuterated glucose have been performed and the deuterium label incorporation into water, glucose, glutamate and lactate has been observed in the human brain. Respective data analysis and metabolic modelling pipelines have been implemented. Imaging of glycolytic and TCA cycle rates in the human brain has been achieved by 2H MRSI at high spatial resolution in the human brain. Quantitative data analysis and metabolic modelling demonstrated that rates can be determined with high regional specificity and resolution.
Combination of PET and MRS to investigate neurotransmission in human brain at 3T:
We implemented a single voxel 2D J-resolved semi-LASER sequence at 3T that allows for detection of 18 brain metabolites at 3T and adopted the previously developed ProFit spectral fitting software for quantitative analysis. The sequence was used for consecutive PET and MRS readouts immediately after pharmacological intervention with Ketamine in 20 healthy volunteers and in 20 patients with major depression. First results indicate changes in glutamate and choline concentrations as well as the expression level of the metabotropic glutamate receptor type 5 (mGluR5) under and after acute Ketamine infusion. In addition, correlations between glutamate and choline, glutamate and mGluR5 and choline and mGluR5 were observed after Ketamine infusion.
Quantitative metabolite imaging of the concentrations of 16 human brain metabolites and brain pH has been achieved with anatomical detail in the human brain for the first time using 1H and 31P MRSI.
Quantitative imaging of glycolytic, TCA cycling and neurotransmitter turnover rates has been enabled in the human brain by 1H and 2H MRSI after oral uptake of 13C or 2H labelled glucose.
The observation of changes of the phosphocreatine buffer system, which stabilizes brain ATP concentrations, and brain pH have been observed for the first time in the human brain by functional 1H MRS under visual stimulation.
The combination of PET and MRS indicate adaptations of glutamatergic neurotransmission after Ketamine infusion and altered membrane turnover presumably related to alterations in neurotransmitter vesicle fusion and / or receptor trafficking.
Quantitative imaging of glycolytic, TCA cycling and neurotransmitter turnover rates has been enabled in the human brain by 1H and 2H MRSI after oral uptake of 13C or 2H labelled glucose.
The observation of changes of the phosphocreatine buffer system, which stabilizes brain ATP concentrations, and brain pH have been observed for the first time in the human brain by functional 1H MRS under visual stimulation.
The combination of PET and MRS indicate adaptations of glutamatergic neurotransmission after Ketamine infusion and altered membrane turnover presumably related to alterations in neurotransmitter vesicle fusion and / or receptor trafficking.