The Center for Neuroscience Imaging Research (CNIR) in the Institute of Basic Science (IBS), Suwon, Korea, is developing new neuroimaging approaches to explore biophysics, physiology, and biology, and to use novel tools for conducting animal and human brain research.
As CNIR director and leader of the CNIR, which has over 100 staff members and 10 principal investigators, Dr. Seong-Gi Kim hopes to go beyond simply understanding neurological processes; his goal is to plunge deeper into underlying causalities.
He is motivated to comprehend the reasons that underlie specific neural responses as well as the factors that influence them. This curiosity surrounding the complex mechanisms and relationships underpinning brain functionality has been the key force fuelling his work at the helm of magnetic resonance imaging (MRI) research, with a heavy emphasis on its clinical application.
“My background is in human functional MRI (fMRI), and I want to understand the contributing factors to the fMRI signal,” Dr. Kim says. “I’m looking to find how we can utilize fMRI to solve questions that have never been addressed before. We want to move beyond correlation to determine causality. For example, if you use fMRI and see an active area, what’s driving that specific activity? We’re developing tools to understand that.”
fMRI is a non-invasive approach that assesses fluctuations in blood flow associated with neural activity. Ultra-high field (UHF) MRI increases fMRI sensitivity, allowing more precise and localized mapping of neurological activity in response to particular stimuli or tasks. This capability aids researchers in their study of brain functionality and in investigating the neural networks that underlie different cognitive processes.
Utilizing state-of-the-art technology from Bruker BioSpin, Dr. Kim and his team are at the forefront of UHF MRI with the principal goal of developing novel approaches to assess both brain physiology and functionality.
Measuring brain physiology and function
MRI is among the world’s most formidable and dynamic neuroimaging instruments for the noninvasively measuring brain structure, physiology, and functionality with high spatial and temporal resolution. The CNIR’s Functional Neurovascular Mapping Team designs high-resolution MRI and optical imaging methods for identifying neural or hemodynamic responses to external stimuli (such as optogenetic and electric), and for mapping functional activities in both animals and humans.
Two key methods are utilized: macro- and meso-scale functional imaging with UHF MRI and wide-field optics, alongside microscale mapping with multi-photon microscopy in health and disease.
“We want to provide tools for neuroscientists to enhance their research dramatically,” Dr. Kim says. “Our goal is to provide information they’ve never seen before. By giving them the big picture, we can help scientists pinpoint the information they are looking for in detail, so they can find what is most likely to be the underlying mechanism or the source of the neuropathology and decide on the next steps.”
The research team includes the Advanced MR Neuroimaging and Neurovascular Coupling units. With access to ultrahigh magnetic fields (7 Tesla MRI for humans, and 9.4 Tesla and 15.2 Tesla MRIs for animals), the Advanced MR Neuroimaging team is focused on developing ultrahigh resolution fMRI, layer-specific fMRI, and dynamic blood oxygenation level-dependent (BOLD) MRI with hypoxic/hypercapnia challenge in both animals and humans.
These fMRI approaches are used in tandem with cell-type-specific optogenetic, chemogenetic, or electric modulations for identifying neural circuits in both healthy and diseased animals. For instance, Dr. Kim and colleagues utilize fMRI with optogenetic neural manipulation to enable brain-wide mapping of effective functional networks. This research includes mouse optogenetic functional magnetic resonance imaging (opto-fMRI). 1,2
In associated research, the Neurovascular Coupling team utilizes cellular resolution optical imaging approaches to explore the relationship among neurons, glial cells, and the vascular system to develop new therapeutics for neurological conditions like Alzheimer’s disease, epilepsy, and brain cancer.
In such neurological diseases, immune cell interactions introduced from the periphery and innate glial cells inside the brain can have a crucial role in the development of pathologies. Although Dr. Kim began his career in human research, his more recent work has focused on preclinical animal studies to understand more about the effect causality recorded in human studies.
By researching disease progression alongside treatment effects in animal models, new lessons can be learned about potential treatment targets for translation to human clinical trials. Dr. Kim believes that uncovering the underlying causes of disease is a key part of medical research and healthcare.
This research has profound effects for developing effective therapeutics, preventive strategies, and public health initiatives, that can improve patient outcomes and lead to a healthier population.
“I wanted to go back to basics, in a way, to understand what was going on,” Dr. Kim explains. “The degree of manipulation in human observational studies is low, so I went back to animal studies to answer questions about why we were seeing certain things. That’s where fMRI really benefits this work, as you can silence one part of the animal’s brain or activate another to see what changes to determine the causality of observations.”
Overcoming hurdles in preclinical animal studies
MRI enables investigators to gain detailed and high-resolution images of the brain’s anatomical structures in small animals like rodents. This approach makes possible the precise visualization of different brain areas alongside their connectivity, improving understanding of neural circuits and brain organization.
Yet, attaining high spatial resolution in rodent imaging can be technically challenging, and necessitate specialized hardware and pulse sequences. To reduce movement throughout the imaging process, rodents are typically anesthetized, which can impact brain functionality and potentially affect study outcomes. While rodent models are a common feature of neuroscience studies, findings from rodents do not always translate over to humans due to interspecies differences.
Image Credit: Bruker BioSpin - NMR, EPR and Imaging
Dr. Kim and colleagues utilize UHF MRI to overcome these issues by increasing the sensitivity of multiple imaging approaches, including fMRI and molecular imaging, which enables researchers to explore brain activity and specific molecular processes with increased precision.
Elevated field strengths can lead to higher sensitivity, which is critical for high-resolution imaging. UHF MRI also enables chemical exchange-sensitive MRI or spectroscopy investigations, enabling investigators to assess concentrations of certain neurochemicals in the brain, which can deliver critical insights into neurological conditions and brain functionality alike.
To attain versatile manipulation of neural excitation across the mouse cortex, Dr. Kim and his team integrated spatiotemporal programmable optogenetic stimuli produced by a digital micromirror device into an MRI scanner using an optical fiber bundle.
Brain-wide effective connectivity of atlas-based cortical areas is typically congruent with anatomically-defined axonal tracing data, but is impacted by the kinds of anesthetics that selectively act on certain connections.
The use of fMRI alongside flexible optogenetics provides a gateway for investigating dynamic changes in functional brain states within the same animal, via high-throughput brain-wide effective connectivity mapping.3
“While there are still species differences, using UHF MRI in rodent studies may yield more relevant findings compared to lower field strengths, bridging the gap between preclinical and clinical research,” Dr. Kim explains. “UHF MRI studies in animal models can provide valuable insights into basic brain function, which can guide human neuroimaging studies and advance our understanding of human brain networks and cognition.”
Detecting potential therapeutic targets
The lessons learned from Dr. Kim’s UHF MRI research may also be translated into clinical settings, especially for identifying potential therapeutic targets for drug development and personalized treatment approaches.
Preclinical research with UHF MRI can examine the efficacy of potential therapeutic interventions before entering human clinical trials, which can help optimize treatment protocols and identify therapeutics that have a stronger chance of efficacy in humans.
The approach can also detect specific biomarkers linked to disease progression and treatment response, which could be helpful for diagnosing early-stage neurological conditions and monitoring disease progression in clinical settings.
“These tools are useful for basic research, but they also need to be easy enough to be useful for humans in a clinical setting,” Dr. Kim says. “Identifying the root causes of a disease allows for the development of targeted and more effective treatments. Treating the cause rather than just managing symptoms can lead to better outcomes and potentially even cure the disease.”
Their fMRI research includes the usage of BOLD contrast to map brain activation in both humans and animals. Non-invasive mapping of cerebral perfusion is additionally important for understanding neurovascular and neurodegenerative conditions. Yet, perfusion MRI approaches are not easy to implement for whole-brain research in mice due to their small size.
This non-invasive, repeatable, simple hypoxia BOLD-MRI method is capable of perfusion mapping in rodents. It additionally has potential for clinical application, including in fields of cognitive neuroscience, psychology, and clinical research to improve understanding of brain diseases, cognitive processes, and the neural mechanisms underpinning multiple functions.4
“BOLD imaging has revolutionized the study of brain function because it allows researchers to non-invasively investigate brain activity in vivo,” Dr. Kim explains. “When a specific brain area becomes active, there is an increase in the demand for oxygen and nutrients to support the increased neural activity. In response, blood flow to that area is increased to meet this demand. However, the increase in blood flow occurs at a higher rate than the increase in oxygen consumption.”
“As a result, the ratio of oxygenated to deoxygenated hemoglobin in the blood changes, leading to an increase in the concentration of oxygenated hemoglobin. The MRI scanner detects these changes in blood oxygenation levels by measuring the magnetic properties of hemoglobin. It has been used in a wide range of animal studies and is well established in humans, but the specificity and sensitivity greatly benefit from ultra-high magnetic fields.”
World-class MRI technology
During his long career in fMRI, Dr Kim has worked with tools from multiple vendors. His recent interest in the Bruker UHF BioSpec tools was triggered by the company’s reputation and its production of the highest-quality commercially available preclinical MRI tools.
These tools provide unmatched signal-to-noise ratio (SNR) for in-vivo imaging and make innovative research possible, whether for addressing fundamental questions or treating diseases. Alongside increased sensitivity, Dr. Kim’s reasons for using Bruker’s UHF tools also include higher magnetic susceptibility and elevated spectral dispersion, which facilitate his team’s novel research.
“When I moved to Korea, I bought the BioSpec 9.4 Tesla instrument as a default, because that’s what I’d used for a long time,” he says. “But sensitivity is very important in fMRI research, which is why I decided to order the BioSpec 15.2 Tesla. When you go to a higher field, you also need to improve your experimental technique, and it’s had a significant impact on our research and what we’re planning. Plus, the Bruker instruments work well with multiple lines of our research, so that was part of the decision-making process.”
More than the technical abilities, however, it was Bruker’s support that freed up Dr. Kim’s time and energy to concentrate on these new research areas.
“When I became a Bruker user, the support was so good, I didn’t need to waste my time changing the set up and fixing issues. Now I can concentrate on science. It’s a big plus.”
A world-leading center for brain research
The merging of UHF MRI with other state-of-the-art neuroscience approaches holds great promise for increasing understanding of the brain and its diseases, paving the way for better clinical diagnostics and therapeutics in the future.
In an upcoming project, Dr. Kim and colleagues are expanding their research to carry out more sensitive molecular imaging to quantify concentrations of certain neurochemicals in the brain. This research has implications for researching neurotransmitter imbalances and metabolic changes in neurological conditions.
Even with his center’s strong track record, Dr. Kim remains dedicated to helping build a future focused on solving novel questions and exploring new approaches for examining brain physiology and functionality.
“From an international perspective, my goal is to bring our center to the next level,” he says. “I want our center to become a global pioneer in the field. We want to have an impact on scientific research that will pave the way for future generations of discovery.”
References and further reading
- Shim, H.-J. et al. (2022). Protocol for mouse optogenetic fMRI at ultrahigh magnetic fields, STAR Protocols, 3(4), p. 101846. https://doi.org/10.1016/j.xpro.2022.101846.
- Jung, W.B. et al. (2022). Dissection of brain-wide resting-state and functional somatosensory circuits by fMRI with optogenetic silencing, Proceedings of the National Academy of Sciences, 119(4). https://doi.org/10.1073/pnas.2113313119.
- Kim, S. et al. (2023). Whole-brain mapping of effective connectivity by fMRI with cortex-wide patterned optogenetics, Neuron, 111(11), pp. 1732-1747.e6. https://doi.org/10.1016/j.neuron.2023.03.002.
- Lee, D. et al. (2022). Whole-brain perfusion mapping in mice by dynamic BOLD MRI with transient hypoxia, Journal of Cerebral Blood Flow & Metabolism, 42(12), pp. 2270–2286. https://doi.org/10.1177/0271678x221117008.
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