Periodic Reporting for period 4 - DIRECT-fMRI (Sensing activity-induced cell swellings and ensuing neurotransmitter releases for in-vivo functional imaging sans hemodynamics)
Berichtszeitraum: 2020-09-01 bis 2021-08-31
Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag ‘active’ brain regions. Nevertheless, until now fMRI only detected neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity were not fully known. DIRECT-fMRI aimed to develop and apply novel MR methodologies for directly mapping neural activity and gaining insights into its nature, without relying on hemodynamics or neurovascular couplings, thereby generating novel means for studying global circuitry in vivo.
The objectives of the project were 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.
Along this project, we were able to establish the “µFMRI” methodology, as foretold, using diffusion weighted signals and, through orthogonal validation (such as optical microscopy in living brain slices), to show that it arises from swelling of cells and not only from vascular responses. We successfully established functional magnetic resonance spectroscopy in mice and tested the method in-vivo, to probe the dynamics of the neurotransmitters involved. Finally we managed to apply these methods to awake-behaving mice and, in the latest phase and continuation of the project, we used them to interrogate the visual system modulations upon restricted sensorial input. As unforeseen side projects, we have also developed deeper understanding of the diffusion weighted MR signals in tissues, and successfully applied some of these novel concepts to study stroke; we are currently applying them to Alzheimer and Parkison’s animal models in subsequent projects.
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 objectives of the project were 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.
Along this project, we were able to establish the “µFMRI” methodology, as foretold, using diffusion weighted signals and, through orthogonal validation (such as optical microscopy in living brain slices), to show that it arises from swelling of cells and not only from vascular responses. We successfully established functional magnetic resonance spectroscopy in mice and tested the method in-vivo, to probe the dynamics of the neurotransmitters involved. Finally we managed to apply these methods to awake-behaving mice and, in the latest phase and continuation of the project, we used them to interrogate the visual system modulations upon restricted sensorial input. As unforeseen side projects, we have also developed deeper understanding of the diffusion weighted MR signals in tissues, and successfully applied some of these novel concepts to study stroke; we are currently applying them to Alzheimer and Parkison’s animal models in subsequent projects.
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.
After the project completion, we are proud to list the following achievements:
- Most of the required imaging methods have been implemented and validated
- Microscopic fMRI (µfMRI) scans were performed in-vivo and revealed increased spatial specificity compared to their BOLD conventional counterparts.
- µfMRI experiments with ultrafast resolution revealed fast components (<200 ms) in the signal, suggesting neural origins instead of only vascular.
- Validations of µfMRI were performed using hypercapnia and cerebral blood volume contrasts, as well as with optical microscopy.
- 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.
- Behavioral fMRI (e.g. scanning awake and behaving rodents) has been achieved and will be further optimized and applied to study the different brain pathways.
- The visual system was interrogated in rodents to discover how some of its different regions interact between them and to study the perception of continuity.
(ongoing)
- ufMRI assists in investigating brain-wide aberrations in neurodegenerative diseases and stroked subjects.
- Most of the required imaging methods have been implemented and validated
- Microscopic fMRI (µfMRI) scans were performed in-vivo and revealed increased spatial specificity compared to their BOLD conventional counterparts.
- µfMRI experiments with ultrafast resolution revealed fast components (<200 ms) in the signal, suggesting neural origins instead of only vascular.
- Validations of µfMRI were performed using hypercapnia and cerebral blood volume contrasts, as well as with optical microscopy.
- 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.
- Behavioral fMRI (e.g. scanning awake and behaving rodents) has been achieved and will be further optimized and applied to study the different brain pathways.
- The visual system was interrogated in rodents to discover how some of its different regions interact between them and to study the perception of continuity.
(ongoing)
- ufMRI assists in investigating brain-wide aberrations in neurodegenerative diseases and stroked subjects.
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; (4) these methods are game-changers when applied to the pathological brain -stroke, neurodegenerative diseases-.