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Neuronal MRI: Harnessing chemical exchange between N-Acetylaspartate and water for functional imaging of neural activity

Periodic Reporting for period 1 - Neuronal MRI (Neuronal MRI: Harnessing chemical exchange between N-Acetylaspartate and water for functional imaging of neural activity)

Reporting period: 2017-05-01 to 2019-04-30

"• ""Neuronal fMRI"" will measure brain function in a much more accurate and specific fashion as compared to conventional methods. Undoubtedly the brain remains the most intriguing organ in the human body, and it's study requires techniques that can provide a fine and detailed look inside its function, in a non-invasive way, so that its mechanisms can be followed up along time by measuring as many times as needed without any harm. Since it’s composed by billions of neurons interacting in functional networks, we would need a global view of the whole brain, not only the microscopic detail of a synapse in a specific localization. And magnetic resonance provides not only a static view of the whole brain but also measurements about brain function and its dynamics non invasively. Besides the mentioned traditional advantages of MRI, being non invasive, versatile and measuring the whole brain at once, this new technique proposed here will provide measurements of brain function tightly linked to the neuronal activity (as opposed to the conventional method BOLD, which relies on the vascular tree response), thus taking MRI to the level of detail of optics while avoiding the light diffusivity in the tissue.
• If we, as a society, would like to alleviate the mortality or improve the life conditions of patients of neurodegenerative diseases, cerebrovascular accidents or brain cancer amongst many others, we need to start by understanding how the healthy brain works in order to have a baseline reference. In addition, deeper knowledge about the brain function will open up new possibilities for brain-computer interfaces and a wide range of technological developments.
• Therefore, our aims are to obtain more accurate and better localized signals of brain function through magnetic resonance, and to scan at accelerated sampling rates since the events we are targeting happen at the scale of tenths of milisenconds. To validate the methodology we will study the auditory pathway, which has very complex dynamics and also presents a very special spatial pattern, where different frequency stimuli are processed in adjacent brain layers (tonotopy)."
Objective 1: we developed and evaluated diffusion functional magnetic resonance sequences, showing that the diffusion signal present very different dynamics as the conventional BOLD contrast imaging, and have an earlier onset at some specific cortex layers. As the next step we tried to implement an NAA specific dfMRI sequence, although irradiation of NAA through different types of pulses and timings didn’t provide significant magnetization transfer in the water peak. The diffusion fMRI results were yearly presented in the International Society for Magnetic Resonance in Medicine annual conferences and apre being prepared for a journal.

Objective 2: in parallel we starting developing an accelerated sequence that could be merged with the NAA specific dfMRI, which we successfully implemented for a single slice experiment and tested in phantoms. Next stages include debugging the sequence to achieve whole brain coverage -multislice- and evaluating which reconstruction algorithm better suits these type of signals. These results were yearly presented in the International Society for Magnetic Resonance in Medicine annual conferences.

Objective 3: since the development of the methodology was progressing slowly, we also started in parallel to prepare for the final evaluation, by finishing an ongoing study of the auditory system in mice with the conventional acquisition methods, in order to establish a reference for our new methodology. The BOLD signal was detected accross the auditory pathway, and its properties were evaluated both by coherence analysis and standard analysis. This work was presented as well in the International Society for Magnetic Resonance in Medicine annual conference and was published in Neuroimage journal (G. Blazquez Freches*, C. Chavarrias*, and N. Shemesh, “BOLD-fMRI in the mouse auditory pathway,” NeuroImage, vol. 165, 2018, *both authors contributed equally to the work).

Remaining work consists of merging the dfmri with the accelerated sequences, and comparing invivo against the conventional BOLD results.
We expect to provide a novel methodology to explore and study brain function, which would be of wide use in many disciplines such as basic neuroscience, neurology, oncology, stroke, or computational neuroscience. Such a tool allowing full brain longitudinal studies non invasively would provide information at the detail close to microscopy or electrophysiology without any brain implantation, which makes it directly translational, applicable in human research and on the clinic. The fact that we could potentially obtain the same type of information directly in humans means that all the preclinical stages can be minimized, with the subsequent economical impact on the research and health systems, plus the animal welfare considerations.
Objective 1: dfMRI signal shows faster dynamics, closer to neuronal timing
Objective 1: NAA specific signla could not be obtained
Objective 3: Conventional BOLD exploration of the auditory mouse system
Objective 2: Acceleration was implemented in single slice, tested in phantoms