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Sensing activity-induced cell swellings and ensuing neurotransmitter releases for in-vivo functional imaging sans hemodynamics

Periodic Reporting for period 3 - DIRECT-fMRI (Sensing activity-induced cell swellings and ensuing neurotransmitter releases for in-vivo functional imaging sans hemodynamics)

Reporting period: 2019-03-01 to 2020-08-31

DIRECT-fMRI aims to (1) develop novel means for mapping neural activity in the brain without relying on blood oxygenation level dynamics, which is the current state-of-the-art; and (2) to demonstrate the methods’ applicability in rodents behaving in the scanner, thus bridging Cognitive and Systems Neuroscience approaches. In particular, the project’s main goals were:
Research Objective 1 (Mapping neural activity via sensing cell swellings upon activity, termed µfMRI, which relies on diffusion to measure perturbations to the underlying microstructure):
Research Objective 2 (Probing the nature of elicited activity via detection of neurotransmitter release):
Research Objective 3 (DIRECT-fMRI network mapping in optogenetically-stimulated behaving mice):
DIRECT-fMRI will thus benefit society by providing means for detecting and understanding neural activity in subjects with disrupted vasculature; in addition, it provides crucial basic knowledge on the neurophysiology of brain activity, and the development of rodent behavior in the magnet is revolutionary in terms of understanding the neural correlates of behavior.
The project is midway and progressing full speed. In particular, the following have been achieved

- Most of the required pulse sequences have been implemented and validated
- The setup for imaging living slices has been developed, built and tested, optogenetic stimulation has been achieved.
- The same system was modified to work on the cryocoil for enhanced sensitivity.
- Intrinsic optical microscopy was established to validate the slice work.
- Microscopic fMRI (µfMRI) scans were performed in-vivo and revealed increased spatial specificity compared to their BOLD counterparts.
- µfMRI experiments with ultrafast resolution revealed fast components (<200 ms) in the signal, suggesting neural origins
- Validations of µfMRI were performed using hypercapnia and cerebral blood volume contrasts
- Functional Magnetic Resonance Spectroscopy (fMRS) for detecting GABA and Glu were executed in-vivo in the mouse, for the first time, and showed significant activation time courses.
- fMRS experiments are now being performed for elucidating the nature of the underlying activity.
- Behavioral fMRI (e.g. scanning awake and behaving rodents) has been achieved and this part is now being written for publication.
- µfMRI experiments were performed in the organotypic slices setup with, so far, inconclusive results. Further experiments are being conducted to elucidate the findings.
DIRECT-fMRI has already exceeded the state-of-the-art by showing that (i) layer-specific connectivity can be inferred from dfMRI; (2) fast time scales of neural activity can be measured; (3) changes in Glu / GABA can be measured in the mouse; (4) behavior fMRI is possible.

At the next stages we will be exploiting these methodological developments to try and advance the state-of-the-art in terms of understanding the discovered phenomena