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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SYNAPLAST MR (Imaging synaptic plasticity by ultra-high field magnetic resonance spectroscopy in health and psychiatric disease)

Teaser

Summary

A large number of psychiatric disorders (major and bipolar depression (MDD / BD), schizophrenia, obsessive-compulsive disorder (OCD), addiction, anxiety, attention deficit hyperactivity syndrome (ADHS), posttraumatic stress disorder (PTSD), autism) 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 project aims at the development of novel methodology for highly spatially and temporally resolved imaging of disease effects on neurotransmission, membrane processes related to synaptic plasticity 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 1H, 31P and 13C magnetic resonance spectroscopic imaging shall be exploited. Highly innovative enabling MRI technology including parallel transmission, very high order B0 shimming, a real time field stabilization and motion correction approach along with the principles of advanced encoding and non-Fourier image reconstruction shall ensure high data quality. Next to obtaining 20 novel image contrasts based on steady state metabolite concentrations, the ultimate goal of the proposed research is to enable functional spectroscopic imaging in the entire human brain in order to investigate adaptation of neurotransmission and brain metabolism to environmental stimuli as well as the impact of acute pharmacological intervention. Finally, the spatially and temporally resolved metabolic imaging technology shall be used for investigation of patients with major depressive disorder to reveal novel biomarkers relevant for diagnostics and patient stratification.

Work performed

Highly spatially resolved whole-brain metabolite mapping by 1H MRSI at 9.4T
Different 1H MRSI acceleration and reconstruction methods including SENSE, GRAPPA and compressed sensing have been evaluated. The focus was on lipid aliasing artefact control and signal-to-noise optimization. The calibration of B0 shim systems and the impact of optimization algorithms have been investigated in detail. Two different static and dynamic B0 shimming methods - a very high order shim insert versus a multi-coil shim setup - were implemented and compared. The optimized scan protocol included a novel RF coil design optimized for maximized SNR in the center of the brain, slice wise dynamic higher order B0 shimming and neural-network based parallel imaging (GRAPPA) reconstruction. High-resolution mapping of an extended neurochemical profile in the entire human brain at 9.4T has been achieved for the first time. Metabolite maps derived from 1H MRSI demonstrate anatomical detail including visualization of gyri and concentration differences between white matter and grey matter for up to 12 metabolites including glutamate, GABA and glutathione at resolutions of 1.5 - 3 mm in-plane resolution.

Highly spatially resolved whole-brain metabolite mapping by 31P MRSI at 9.4T
A dual-tune 31P / 1H radiofrequency coil was constructed. Safety evaluation and approval for human use of this RF coil was finalized. 31P 3D MRSI data acquisition methods for whole-brain application at 9.4T have been developed. To that, a 3D weighted k-space acquisition scheme and NOE enhancement was implemented and the respective radiofrequency pulses have been optimized. Low-rank filtering, compressed sensing, GRAPPA and over discrete SENSE have been implemented for acceleration and SNR improvement. The current scan protocol yields high quality whole-brain metabolite distribution maps of PCr, ATP, free phosphate as well as phosphomonoesters and phosphodiesters at a 9 mm in-plane and 15 mm through-plane spatial resolution. In addition mapping of the pH is possible. Distinction of tissue types such as of white matter, grey matter, cerebrospinal fluid and skeletal muscle is possible which demonstrates the good anatomical precision.

Highly temporally resolved single voxel 1H and 31P magnetic resonance spectroscopy at 9.4T
1H single voxel MRS methodology was implemented to detect functional changes of glutamate and GABA under visual stimulation using single voxel 1H MRS in the visual cortex at 9.4T in the human brain. The utilized metabolite cycled non-water suppressed semiLASER sequence enables simultaneous observation of the BOLD effect on the water resonance as detected by functional brain MRI and revealed correlations between metabolite concentration changes and BOLD effect as well between BOLD effect of water and BOLD effect of metabolite peaks.
The implementation of 31P single voxel MRS methodology for human brain application at 9.4T is about to be finalized. Three distinct sequences (ISIS, SPECIAL, semiLASER) were implemented and optimized with respect to radiofrequency pulses (adiabatic), gradient spoiling and phase cycling schemes. A spatial resolution of 3 x 3 x 3 cm is achieved and different pH could be measured in extracellular versus intracellular space. The ISIS sequence has the best signal-to-noise ratio, while SPECIAL seems the best compromise between signal-to-noise and robustness against subject motion. Both protocols will be tested for functional trials and measurement of metabolic turnover rates.

PET-MRS at 3T and 7T
We implemented inner-volume saturated 2D J-resolved single voxel 1H PRESS at 3T that allows for detection of 18 brain metabolites and adopted existing 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. The respective data acquisition in 20 patients with major depression is ongoing. The healthy volunteers w

Final results

1) Whole brain spatially resolved mapping of a large number of steady state metabolites concentration (project A) shall be achieved for the first time. This corresponds to the introduction of a large number of novel diagnostic imaging contrasts. It has to be pronounced that we aim at 10-12 contrasts for 1H MRSI and another 7 contrasts for 31P MRSI. So altogether up to 20 novel image contrasts shall become available for imaging of psychiatric and neurological disorders, which in its own is a highly desirable research goal.

2) Disturbed information processing is characteristic for psychiatric disorders with prominent examples being altered emotion processing in major depressive disorder or psychotic episodes and hallucinations in schizophrenia. Hence, not only steady state metabolic readouts may serve as potential diagnostic biomarkers, but also measures that reflect the ability to adopt neurotransmission and brain metabolism to environmental stimuli (projects B, C). Therefore, monitoring of synaptic plasticity by the herein proposed time resolved single voxel MRS and metabolic imaging methods is of high relevance and holds the potential to gain novel insight into the disease mechanisms and to reveal novel diagnostic and predictive biomarkers for patient stratification. Temporally and spatially resolved metabolic brain imaging is also expected to largely improve treatment response monitoring including dose dependent effects and pharmacodynamics. This in turn might enable personalized treatment of psychiatric disorders with regard to the type, dose and administration interval of pharmacological treatment. To be able to monitor acute and chronic effects of pharmacological treatment is also of outermost importance in the drug development process.

3) Psychiatric disorders with major depressive disorder being the most important one cause 40% of unemployability cases and related disability benefits in the EU. Hence, herein major depressive disorder has been chosen for pilot trials using the novel imaging technology, which are expected to reveal novel insight in to the disease mechanism as well as biomarkers that may exploited for diagnostics and patient stratification in future. Once established and validated novel metabolic imaging methodology will be applicable to other psychiatric and neurological disorders and larger clinical trials including different subgroups of patients at a later stage.

4) Finally, the proposed functional metabolic brain imaging methodology may also prove beneficial to neuroscience in general in order to gain better understanding of basic brain physiology or to gain a better understanding about other imaging contrasts.