Brain
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KAIST Unveils New Possibilities for Treating Intractable Brain Tumors
< Photo 1. (From left) Professor Heung Kyu Lee, KAIST Department of Biological Sciences, and Dr. Keun Bon Ku >
Immunotherapy, which enhances the immune system's T cell response to eliminate cancer cells, has emerged as a key approach in cancer treatment. However, in the case of glioblastoma, an aggressive and treatment-resistant brain tumor, numerous clinical trials have failed to confirm their efficacy. Korean researchers have recently analyzed the mechanisms that cause T cell exhaustion, which is characterized by a loss of function or a weakened response following prolonged exposure to antigens in such intractable cancers, identifying key control factors in T cell activation and clarifying the mechanisms that enhance therapeutic effectiveness.
KAIST (represented by President Kwang Hyung Lee) announced on the 6th of November that Professor Heung Kyu Lee’s team from the Department of Biological Sciences, in collaboration with the Korea Research Institute of Chemical Technology (represented by President Young Kuk Lee), has confirmed improved survival rates in a glioblastoma mouse model. By removing the inhibitory Fc gamma receptor (FcγRIIB), the research team was able to restore the responsiveness of cytotoxic T cells to immune checkpoint inhibitors, leading to enhanced anticancer activity.
The research team examined the effect of FcγRIIB, an inhibitory receptor recently found in cytotoxic T cells, on tumor-infiltrating T cells and the therapeutic effectiveness of the anti-PD-1 immune checkpoint inhibitor.
< Figure 1. Study results on improved survival rate due to increased antitumor activity of anti-PD-1 treatment in inhibitory Fc gamma receptor(Fcgr2b) ablation mice with murine glioblastoma. >
Their findings showed that deleting FcγRIIB induced the increase of tumor antigen-specific memory T cells, which helps to suppress exhaustion, enhances stem-like qualities, and reactivates T cell-mediated antitumor immunity, particularly in response to anti-PD-1 treatment. Furthermore, FcγRIIB deletion led to an increase in antigen-specific memory T cells that maintained continuous infiltration into the tumor tissue.
This study presents a new therapeutic target for tumors unresponsive to immune checkpoint inhibitors and demonstrates that combining FcγRIIB inhibition with anti-PD-1 treatment can produce synergistic effects, potentially improving therapeutic outcomes for tumors like glioblastoma, which typically show resistance to anti-PD-1 therapy.
< Figure 2. Overview of the study on the enhanced response to anti-PD-1 therapy for glioblastoma brain tumors upon deletion of the inhibitory Fc gamma receptor (FcγRIIB) in tumor microenvironment. When the inhibitory Fc gamma receptor (FcγRIIB) of cytotoxic T cells is deleted, an increase in tumor-specific memory T cells (Ttsms) was observed. In addition, this T cell subset is identified as originating from the tumor-draining lymph nodes(TdLNs) and leads to persistent infiltration into the tumor tissue. Anti-PD-1 therapy leads to an increased anti-tumor immune response via Ttsms, which is confirmed by increased tumor cell toxicity and increased cell division and decreased cell de-migration indices. Ultimately, the increased cytotoxic T cell immune response leads to an increase in the survival rate of glioblastoma. >
Professor Heung Kyu Lee explained, "This study offers a way to overcome clinical failures in treating brain tumors with immune checkpoint therapy and opens possibilities for broader applications to other intractable cancers. It also highlights the potential of utilizing cytotoxic T cells for tumor cell therapy."
The study, led by Dr. Keun Bon Ku of KAIST (currently a senior researcher at the Korea Research Institute of Chemical Technology's Center for Infectious Disease Diagnosis and Prevention), along with Chae Won Kim, Yumin Kim, Byeong Hoon Kang, Jeongwoo La, In Kang, Won Hyung Park, Stephen Ahn, and Sung Ki Lee, was published online on October 26 in the Journal for ImmunoTherapy of Cancer, an international journal in tumor immunology and therapy from the Society for Immunotherapy of Cancer. (Paper title: “Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma,” http://dx.doi.org/10.1136/jitc-2024-009449).
This research received support from the National Research Foundation of Korea, the Bio & Medical Technology Development Program, and the Samsung Science & Technology Foundation.
2024.11.15 View 283 -
A KAIST research team identifies a cause of mental diseases induced by childhood abuse
Childhood neglect and/or abuse can induce extreme stress that significantly changes neural networks and functions during growth. This can lead to mental illnesses, including depression and schizophrenia, but the exact mechanism and means to control it were yet to be discovered.
On August 1, a KAIST research team led by Professor Won-Suk Chung from the Department of Biological Sciences announced the identification of excessive synapse removal mediated by astrocytes as the cause of mental diseases induced by childhood abuse trauma. Their research was published in Immunity, a top international journal in the field of immunology.
The research team discovered that the excessive astrocyte-mediated removal of excitatory synapses in the brain in response to stress hormones is a cause of mental diseases induced by childhood neglect and abuse. Clinical data have previously shown that high levels of stress can lead to various mental diseases, but the exact mechanism has been unknown. The results of this research therefore are expected to be widely applied to the prevention and treatment of such diseases.
The research team clinically screened an FDA-approved drug to uncover the mechanism that regulates the phagocytotic role of astrocytes, in which they capture external substances and eliminate them. As a result, the team found that synthetic glucocorticoids, namely stress hormones, enhanced astrocyte-mediated phagocytosis to an abnormal level. Glucocorticoids play essential roles in processes that maintain life, such as carbohydrate metabolism and anti-inflammation, but are also secreted in response to external stimuli such as stress, allowing the body to respond appropriately. However, excessive and long-term exposure to glucocorticoids caused by chronic stress can lead to various mental diseases including depression, cognitive disorders, and anxiety.
< Figure 1. Results of screening for compounds that increase astrocyte phagocytosis
(A) Discovered that synthetic glucocorticoid (stress hormone) increases the phagocytosis of astrocytes through screening of FDA-approved clinical compounds. (B-C) When treated with stress hormones, the phagocytosis of astrocytes is greatly increased, but this phenomenon is strongly suppressed by the GR antagonist (Mifepristone). CORT: corticosterone (stress hormone), Eplerenone: mineralocorticoid receptor (MR) antagonist, Mifepristone: glucocorticoid receptor (GR) antagonist >
To understand the changes in astrocyte functions caused by childhood stress, the research team used mice models with early social deprivation, and discovered that stress hormones bind to the glucocorticoid receptors (GRs) of astrocytes. This significantly increased the expression of Mer tyrosine kinase (MERK), which plays an essential role in astrocyte phagocytosis. Surprisingly, out of the various neurons in the cerebral cortex, astrocytes would eliminate only the excitatory synapses of specific neurons. The team found that this builds abnormal neural networks, which can lead to complex behavioral abnormalities such as social deficiencies and depression in adulthood.
The team also observed that microglia, which also play an important role in cerebral immunity, did not contribute to synapse removal in the mice models with early social deprivation. This confirms that the response to stress hormones during childhood is specifically astrocyte-mediated.
To find out whether these results are also applicable in humans, the research team used a brain organoid grown from human-induced pluripotent stem cells to observe human responses to stress hormones. The team observed that the stress hormones induced astrocyte GRs and phagocyte activation in the human brain organoid as well, and confirmed that the astrocytes subsequently eliminated excessive amounts of excitatory synapses. By showing that mice and humans both showed the same synapse control mechanism in response to stress, the team suggested that this discovery is applicable to mental disorders in humans.
< Figure 2. A schematic diagram of the study published in Immunity. Excessive stress hormone secretion in childhood increases the expression of the MERTK phagocytic receptor through the glucocorticoid receptor (GR) of astrocytes, resulting in excessive elimination of excitatory synapses. Excessive synaptic elimination by astrocytes during brain development causes permanent damage to brain circuits, resulting in abnormal neural activity in the adult brain and psychiatric behaviors such as depression and anti-social tendencies. >
Prof. Won-Suk Chung said, “Until now, we did not know the exact mechanism for how childhood stress caused brain diseases. This research was the first to show that the excessive phagocytosis of astrocytes could be an important cause of such diseases.” He added, “In the future, controlling the immune response of astrocytes will be used as a fundamental target for understanding and treating brain diseases.”
This research, written by co-first authors Youkyeong Byun (Ph.D. candidate) and Nam-Shik Kim (post-doctoral associate) from the KAIST Department of Biological Sciences, was published in the internationally renowned journal Immunity, a sister magazine of Cell and one of the best journal in the field of immunology, on July 31 under the title "Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis."
This work was supported by a National Research Foundation of Korea grant, the Korea Health Industry Development Institute (KHIDI), and the Korea Dementia Research Center (KDRC).
2023.08.04 View 4430 -
The cause of disability in aged brain meningeal membranes identified
Due to the increase in average age, studies on changes in the brain following general aging process without serious brain diseases have also become an issue that requires in-depth studies. Regarding aging research, as aging progresses, ‘sugar’ accumulates in the body, and the accumulated sugar becomes a causative agent for various diseases such as aging-related inflammation and vascular disease. In the end, “surplus” sugar molecules attach to various proteins in the body and interfere with their functions.
KAIST (President Kwang Hyung Lee), a joint research team of Professor Pilnam Kim and Professor Yong Jeong of the Department of Bio and Brain Engineering, revealed on the 15th that it was confirmed that the function of being the “front line of defense” for the cerebrocortex of the brain meninges, the layers of membranes that surrounds the brain, is hindered when 'sugar' begins to build up on them as aging progresses.
Professor Kim's research team confirmed excessive accumulation of sugar molecules in the meninges of the elderly and also confirmed that sugar accumulation occurs mouse models in accordance with certain age levels. The meninges are thin membranes that surround the brain and exist at the boundary between the cerebrospinal fluid and the cortex and play an important role in protecting the brain. In this study, it was revealed that the dysfunction of these brain membranes caused by aging is induced by 'excess' sugar in the brain. In particular, as the meningeal membrane becomes thinner and stickier due to aging, a new paradigm has been provided for the discovery of the principle of the decrease in material exchange between the cerebrospinal fluid and the cerebral cortex.
This research was conducted by the Ph.D. candidate Hyo Min Kim and Dr. Shinheun Kim as the co-first authors to be published online on February 28th in the international journal, Aging Cell. (Paper Title: Glycation-mediated tissue-level remodeling of brain meningeal membrane by aging)
The meninges, which are in direct contact with the cerebrospinal fluid, are mainly composed of collagen, an extracellular matrix (ECM) protein, and are composed of fibroblasts, which are cells that produce this protein. The cells that come in contact with collagen proteins that are attached with sugar have a low collagen production function, while the meningeal membrane continuously thins and collapses as the expression of collagen degrading enzymes increases.
Studies on the relationship between excess sugar molecules accumulation in the brain due to continued sugar intake and the degeneration of neurons and brain diseases have been continuously conducted. However, this study was the first to identify meningeal degeneration and dysfunction caused by glucose accumulation with the focus on the meninges itself, and the results are expected to present new ideas for research into approach towards discoveries of new treatments for brain disease.
Researcher Hyomin Kim, the first author, introduced the research results as “an interesting study that identified changes in the barriers of the brain due to aging through a convergent approach, starting from the human brain and utilizing an animal model with a biomimetic meningeal model”.
Professor Pilnam Kim's research team is conducting research and development to remove sugar that accumulated throughout the human body, including the meninges. Advanced glycation end products, which are waste products formed when proteins and sugars meet in the human body, are partially removed by macrophages. However, glycated products bound to extracellular matrix proteins such as collagen are difficult to remove naturally. Through the KAIST-Ceragem Research Center, this research team is developing a healthcare medical device to remove 'sugar residue' in the body.
This study was carried out with the National Research Foundation of Korea's collective research support.
Figure 1. Schematic diagram of proposed mechanism showing aging‐related ECM remodeling through meningeal fibroblasts on the brain leptomeninges. Meningeal fibroblasts in the young brain showed dynamic COL1A1 synthetic and COL1‐interactive function on the collagen membrane. They showed ITGB1‐mediated adhesion on the COL1‐composed leptomeningeal membrane and induction of COL1A1 synthesis for maintaining the collagen membrane. With aging, meningeal fibroblasts showed depletion of COL1A1 synthetic function and altered cell–matrix interaction.
Figure 2. Representative rat meningeal images observed in the study. Compared to young rats, it was confirmed that type 1 collagen (COL1) decreased along with the accumulation of glycated end products (AGE) in the brain membrane of aged rats, and the activity of integrin beta 1 (ITGB1), a representative receptor corresponding to cell-collagen interaction. Instead, it was observed that the activity of discoidin domain receptor 2 (DDR2), one of the tyrosine kinases, increased.
Figure 3. Substance flux through the brain membrane decreases with aging. It was confirmed that the degree of adsorption of fluorescent substances contained in cerebrospinal fluid (CSF) to the brain membrane increased and the degree of entry into the periphery of the cerebral blood vessels decreased in the aged rats. In this study, only the influx into the brain was confirmed during the entry and exit of substances, but the degree of outflow will also be confirmed through future studies.
2023.03.15 View 4607 -
Professor Jae-Woong Jeong Receives Hyonwoo KAIST Academic Award
Professor Jae-Woong Jeong from the School of Electrical Engineering was selected for the Hyonwoo KAIST Academic Award, funded by the HyonWoo Cultural Foundation (Chairman Soo-il Kwak, honorary professor at Seoul National University Business School).
The Hyonwoo KAIST Academic Award, presented for the first time in 2021, is an award newly founded by the donations of Chairman Soo-il Kwak of the HyonWoo Cultural Foundation, who aims to reward excellent KAIST scholars who have made outstanding academic achievements.
Every year, through the strict evaluations of the selection committee of the HyonWoo Cultural Foundation and the faculty reward recommendation board, KAIST will choose one faculty member that may represent the school with their excellent academic achievement, and reward them with a plaque and 100 million won.
Professor Jae-Woong Jeong, the winner of this year’s award, developed the first IoT-based wireless remote brain neural network control system to overcome brain diseases, and has been leading the field. The research was published in 2021 in Nature Biomedical Engineering, one of world’s best scientific journals, and has been recognized as a novel technology that suggested a new vision for the automation of brain research and disease treatment. This study, led by Professor Jeong’s research team, was part of the KAIST College of Engineering Global Initiative Interdisciplinary Research Project, and was jointly studied by Washington University School of Medicine through an international research collaboration. The technology was introduced more than 60 times through both domestic and international media, including Medical Xpress, MBC News, and Maeil Business News.
Professor Jeong has also developed a wirelessly chargeable soft machine for brain transplants, and the results were published in Nature Communications. He thereby opened a new paradigm for implantable semi-permanent devices for transplants, and is making unprecedented research achievements.
2022.06.13 View 5569 -
Decoding Brain Signals to Control a Robotic Arm
Advanced brain-machine interface system successfully interprets arm movement directions from neural signals in the brain
Researchers have developed a mind-reading system for decoding neural signals from the brain during arm movement. The method, described in the journal Applied Soft Computing, can be used by a person to control a robotic arm through a brain-machine interface (BMI).
A BMI is a device that translates nerve signals into commands to control a machine, such as a computer or a robotic limb. There are two main techniques for monitoring neural signals in BMIs: electroencephalography (EEG) and electrocorticography (ECoG).
The EEG exhibits signals from electrodes on the surface of the scalp and is widely employed because it is non-invasive, relatively cheap, safe and easy to use. However, the EEG has low spatial resolution and detects irrelevant neural signals, which makes it difficult to interpret the intentions of individuals from the EEG.
On the other hand, the ECoG is an invasive method that involves placing electrodes directly on the surface of the cerebral cortex below the scalp. Compared with the EEG, the ECoG can monitor neural signals with much higher spatial resolution and less background noise. However, this technique has several drawbacks.
“The ECoG is primarily used to find potential sources of epileptic seizures, meaning the electrodes are placed in different locations for different patients and may not be in the optimal regions of the brain for detecting sensory and movement signals,” explained Professor Jaeseung Jeong, a brain scientist at KAIST. “This inconsistency makes it difficult to decode brain signals to predict movements.”
To overcome these problems, Professor Jeong’s team developed a new method for decoding ECoG neural signals during arm movement. The system is based on a machine-learning system for analysing and predicting neural signals called an ‘echo-state network’ and a mathematical probability model called the Gaussian distribution.
In the study, the researchers recorded ECoG signals from four individuals with epilepsy while they were performing a reach-and-grasp task. Because the ECoG electrodes were placed according to the potential sources of each patient’s epileptic seizures, only 22% to 44% of the electrodes were located in the regions of the brain responsible for controlling movement.
During the movement task, the participants were given visual cues, either by placing a real tennis ball in front of them, or via a virtual reality headset showing a clip of a human arm reaching forward in first-person view. They were asked to reach forward, grasp an object, then return their hand and release the object, while wearing motion sensors on their wrists and fingers. In a second task, they were instructed to imagine reaching forward without moving their arms.
The researchers monitored the signals from the ECoG electrodes during real and imaginary arm movements, and tested whether the new system could predict the direction of this movement from the neural signals. They found that the novel decoder successfully classified arm movements in 24 directions in three-dimensional space, both in the real and virtual tasks, and that the results were at least five times more accurate than chance. They also used a computer simulation to show that the novel ECoG decoder could control the movements of a robotic arm.
Overall, the results suggest that the new machine learning-based BCI system successfully used ECoG signals to interpret the direction of the intended movements. The next steps will be to improve the accuracy and efficiency of the decoder. In the future, it could be used in a real-time BMI device to help people with movement or sensory impairments.
This research was supported by the KAIST Global Singularity Research Program of 2021, Brain Research Program of the National Research Foundation of Korea funded by the Ministry of Science, ICT, and Future Planning, and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education.
-PublicationHoon-Hee Kim, Jaeseung Jeong, “An electrocorticographic decoder for arm movement for brain-machine interface using an echo state network and Gaussian readout,” Applied SoftComputing online December 31, 2021 (doi.org/10.1016/j.asoc.2021.108393)
-ProfileProfessor Jaeseung JeongDepartment of Bio and Brain EngineeringCollege of EngineeringKAIST
2022.03.18 View 9221 -
Scientists Develop Wireless Networks that Allow Brain Circuits to Be Controlled Remotely through the Internet
Wireless implantable devices and IoT could manipulate the brains of animals from anywhere around the world due to their minimalistic hardware, low setup cost, ease of use, and customizable versatility
A new study shows that researchers can remotely control the brain circuits of numerous animals simultaneously and independently through the internet. The scientists believe this newly developed technology can speed up brain research and various neuroscience studies to uncover basic brain functions as well as the underpinnings of various neuropsychiatric and neurological disorders.
A multidisciplinary team of researchers at KAIST, Washington University in St. Louis, and the University of Colorado, Boulder, created a wireless ecosystem with its own wireless implantable devices and Internet of Things (IoT) infrastructure to enable high-throughput neuroscience experiments over the internet. This innovative technology could enable scientists to manipulate the brains of animals from anywhere around the world. The study was published in the journal Nature Biomedical Engineering on November 25
“This novel technology is highly versatile and adaptive. It can remotely control numerous neural implants and laboratory tools in real-time or in a scheduled way without direct human interactions,” said Professor Jae-Woong Jeong of the School of Electrical Engineering at KAIST and a senior author of the study. “These wireless neural devices and equipment integrated with IoT technology have enormous potential for science and medicine.”
The wireless ecosystem only requires a mini-computer that can be purchased for under $45, which connects to the internet and communicates with wireless multifunctional brain probes or other types of conventional laboratory equipment using IoT control modules. By optimally integrating the versatility and modular construction of both unique IoT hardware and software within a single ecosystem, this wireless technology offers new applications that have not been demonstrated before by a single standalone technology. This includes, but is not limited to minimalistic hardware, global remote access, selective and scheduled experiments, customizable automation, and high-throughput scalability.
“As long as researchers have internet access, they are able to trigger, customize, stop, validate, and store the outcomes of large experiments at any time and from anywhere in the world. They can remotely perform large-scale neuroscience experiments in animals deployed in multiple countries,” said one of the lead authors, Dr. Raza Qazi, a researcher with KAIST and the University of Colorado, Boulder. “The low cost of this system allows it to be easily adopted and can further fuel innovation across many laboratories,” Dr. Qazi added.
One of the significant advantages of this IoT neurotechnology is its ability to be mass deployed across the globe due to its minimalistic hardware, low setup cost, ease of use, and customizable versatility. Scientists across the world can quickly implement this technology within their existing laboratories with minimal budget concerns to achieve globally remote access, scalable experimental automation, or both, thus potentially reducing the time needed to unravel various neuroscientific challenges such as those associated with intractable neurological conditions.
Another senior author on the study, Professor Jordan McCall from the Department of Anesthesiology and Center for Clinical Pharmacology at Washington University in St. Louis, said this technology has the potential to change how basic neuroscience studies are performed. “One of the biggest limitations when trying to understand how the mammalian brain works is that we have to study these functions in unnatural conditions. This technology brings us one step closer to performing important studies without direct human interaction with the study subjects.”
The ability to remotely schedule experiments moves toward automating these types of experiments. Dr. Kyle Parker, an instructor at Washington University in St. Louis and another lead author on the study added, “This experimental automation can potentially help us reduce the number of animals used in biomedical research by reducing the variability introduced by various experimenters. This is especially important given our moral imperative to seek research designs that enable this reduction.”
The researchers believe this wireless technology may open new opportunities for many applications including brain research, pharmaceuticals, and telemedicine to treat diseases in the brain and other organs remotely. This remote automation technology could become even more valuable when many labs need to shut down, such as during the height of the COVID-19 pandemic.
This work was supported by grants from the KAIST Global Singularity Research Program, the National Research Foundation of Korea, the United States National Institute of Health, and Oak Ridge Associated Universities.
-PublicationRaza Qazi, Kyle Parker, Choong Yeon Kim, Jordan McCall, Jae-Woong Jeong et al. “Scalable and modular wireless-network infrastructure for large-scale behavioral neuroscience,” Nature Biomedical Engineering, November 25 2021 (doi.org/10.1038/s41551-021-00814-w)
-ProfileProfessor Jae-Woong JeongBio-Integrated Electronics and Systems LabSchool of Electrical EngineeringKAIST
2021.11.29 View 11856 -
Two Researchers Designated as SUHF Fellows
Professor Taeyun Ku from the Graduate School of Medical Science and Engineering and Professor Hanseul Yang from the Department of Biological Sciences were nominated as 2021 fellows of the Suh Kyungbae Foundation (SUHF).
SUHF selected three young promising scientists from 53 researchers who are less than five years into their careers. A panel of judges comprised of scholars from home and abroad made the final selection based on the candidates’ innovativeness and power to influence. Professor You-Bong Hyun from Seoul National University also won the fellowship.
Professor Ku’s main topic is opto-connectomics. He will study ways to visualize the complex brain network using innovative technology that transforms neurons into optical elements.
Professor Yang will research the possibility of helping patients recover from skin diseases or injuries without scars by studying spiny mouse genes.
SUHF was established by Amorepacific Group Chairman Suh Kyungbae in 2016 with 300 billion KRW of his private funds. Under the vision of ‘contributing to humanity by supporting innovative discoveries of bioscience researchers,’ the foundation supports promising Korean scientists who pioneer new fields of research in biological sciences.
From 2017 to this year, SUHF has selected 20 promising scientists in the field of biological sciences. Selected scientists are provided with up to KRW 500 million each year for five years. The foundation has provided a total of KRW 48.5 billion in research funds to date.
2021.09.15 View 6454 -
A Mechanism Underlying Most Common Cause of Epileptic Seizures Revealed
An interdisciplinary study shows that neurons carrying somatic mutations in MTOR can lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons
During fetal development, cells should migrate to the outer edge of the brain to form critical connections for information transfer and regulation in the body. When even a few cells fail to move to the correct location, the neurons become disorganized and this results in focal cortical dysplasia. This condition is the most common cause of seizures that cannot be controlled with medication in children and the second most common cause in adults.
Now, an interdisciplinary team studying neurogenetics, neural networks, and neurophysiology at KAIST has revealed how dysfunctions in even a small percentage of cells can cause disorder across the entire brain. They published their results on June 28 in Annals of Neurology.
The work builds on a previous finding, also by a KAIST scientists, who found that focal cortical dysplasia was caused by mutations in the cells involved in mTOR, a pathway that regulates signaling between neurons in the brain.
“Only 1 to 2% of neurons carrying mutations in the mTOR signaling pathway that regulates cell signaling in the brain have been found to include seizures in animal models of focal cortical dysplasia,” said Professor Jong-Woo Sohn from the Department of Biological Sciences. “The main challenge of this study was to explain how nearby non-mutated neurons are hyperexcitable.”
Initially, the researchers hypothesized that the mutated cells affected the number of excitatory and inhibitory synapses in all neurons, mutated or not. These neural gates can trigger or halt activity, respectively, in other neurons. Seizures are a result of extreme activity, called hyperexcitability. If the mutated cells upend the balance and result in more excitatory cells, the researchers thought, it made sense that the cells would be more susceptible to hyperexcitability and, as a result, seizures.
“Contrary to our expectations, the synaptic input balance was not changed in either the mutated or non-mutated neurons,” said Professor Jeong Ho Lee from the Graduate School of Medical Science and Engineering. “We turned our attention to a protein overproduced by mutated neurons.”
The protein is adenosine kinase, which lowers the concentration of adenosine. This naturally occurring compound is an anticonvulsant and works to relax vessels. In mice engineered to have focal cortical dysplasia, the researchers injected adenosine to replace the levels lowered by the protein. It worked and the neurons became less excitable.
“We demonstrated that augmentation of adenosine signaling could attenuate the excitability of non-mutated neurons,” said Professor Se-Bum Paik from the Department of Bio and Brain Engineering.
The effect on the non-mutated neurons was the surprising part, according to Paik. “The seizure-triggering hyperexcitability originated not in the mutation-carrying neurons, but instead in the nearby non-mutated neurons,” he said.
The mutated neurons excreted more adenosine kinase, reducing the adenosine levels in the local environment of all the cells. With less adenosine, the non-mutated neurons became hyperexcitable, leading to seizures.
“While we need further investigate into the relationship between the concentration of adenosine and the increased excitation of nearby neurons, our results support the medical use of drugs to activate adenosine signaling as a possible treatment pathway for focal cortical dysplasia,” Professor Lee said.
The Suh Kyungbae Foundation, the Korea Health Technology Research and Development Project, the Ministry of Health & Welfare, and the National Research Foundation in Korea funded this work.
-Publication:Koh, H.Y., Jang, J., Ju, S.H., Kim, R., Cho, G.-B., Kim, D.S., Sohn, J.-W., Paik, S.-B. and Lee, J.H. (2021), ‘Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia’ Annals of Neurology, 90: 285 299. (https://doi.org/10.1002/ana.26149)
-ProfileProfessor Jeong Ho Lee Translational Neurogenetics Labhttps://tnl.kaist.ac.kr/ Graduate School of Medical Science and Engineering KAIST
Professor Se-Bum Paik Visual System and Neural Network Laboratory http://vs.kaist.ac.kr/ Department of Bio and Brain EngineeringKAIST
Professor Jong-Woo Sohn Laboratory for Neurophysiology, https://sites.google.com/site/sohnlab2014/home Department of Biological SciencesKAIST
Dr. Hyun Yong Koh Translational Neurogenetics LabGraduate School of Medical Science and EngineeringKAIST
Dr. Jaeson Jang Ph.D.Visual System and Neural Network LaboratoryDepartment of Bio and Brain Engineering KAIST
Sang Hyeon Ju M.D.Laboratory for NeurophysiologyDepartment of Biological SciencesKAIST
2021.08.26 View 10334 -
Hydrogel-Based Flexible Brain-Machine Interface
The interface is easy to insert into the body when dry, but behaves ‘stealthily’ inside the brain when wet
Professor Seongjun Park’s research team and collaborators revealed a newly developed hydrogel-based flexible brain-machine interface. To study the structure of the brain or to identify and treat neurological diseases, it is crucial to develop an interface that can stimulate the brain and detect its signals in real time. However, existing neural interfaces are mechanically and chemically different from real brain tissue. This causes foreign body response and forms an insulating layer (glial scar) around the interface, which shortens its lifespan.
To solve this problem, the research team developed a ‘brain-mimicking interface’ by inserting a custom-made multifunctional fiber bundle into the hydrogel body. The device is composed not only of an optical fiber that controls specific nerve cells with light in order to perform optogenetic procedures, but it also has an electrode bundle to read brain signals and a microfluidic channel to deliver drugs to the brain.
The interface is easy to insert into the body when dry, as hydrogels become solid. But once in the body, the hydrogel will quickly absorb body fluids and resemble the properties of its surrounding tissues, thereby minimizing foreign body response.
The research team applied the device on animal models, and showed that it was possible to detect neural signals for up to six months, which is far beyond what had been previously recorded. It was also possible to conduct long-term optogenetic and behavioral experiments on freely moving mice with a significant reduction in foreign body responses such as glial and immunological activation compared to existing devices.
“This research is significant in that it was the first to utilize a hydrogel as part of a multifunctional neural interface probe, which increased its lifespan dramatically,” said Professor Park. “With our discovery, we look forward to advancements in research on neurological disorders like Alzheimer’s or Parkinson’s disease that require long-term observation.”
The research was published in Nature Communications on June 8, 2021. (Title: Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity) The study was conducted jointly with an MIT research team composed of Professor Polina Anikeeva, Professor Xuanhe Zhao, and Dr. Hyunwoo Yook.
This research was supported by the National Research Foundation (NRF) grant for emerging research, Korea Medical Device Development Fund, KK-JRC Smart Project, KAIST Global Initiative Program, and Post-AI Project.
-PublicationPark, S., Yuk, H., Zhao, R. et al. Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity. Nat Commun 12, 3435 (2021). https://doi.org/10.1038/s41467-021-23802-9
-ProfileProfessor Seongjun ParkBio and Neural Interfaces LaboratoryDepartment of Bio and Brain EngineeringKAIST
2021.07.13 View 9319 -
Prof. Sang Wan Lee Selected for 2021 IBM Academic Award
Professor Sang Wan Lee from the Department of Bio and Brain Engineering was selected as the recipient of the 2021 IBM Global University Program Academic Award. The award recognizes individual faculty members whose emerging science and technology contains significant interest for universities and IBM.
Professor Lee, whose research focuses on artificial intelligence and computational neuroscience, won the award for his research proposal titled A Neuroscience-Inspired Approach for Metacognitive Reinforcement Learning. IBM provides a gift of $40,000 to the recipient’s institution in recognition of the selection of the project but not as a contract for services.
Professor Lee’s project aims to exploit the unique characteristics of human reinforcement learning. Specifically, he plans to examines the hypothesis that metacognition, a human’s ability to estimate their uncertainty level, serves to guide sample-efficient and near-optimal exploration, making it possible to achieve an optimal balance between model-based and model-free reinforcement learning.
He was also selected as the winner of the Google Research Award in 2016 and has been working with DeepMind and University College London to conduct basic research on decision-making brain science to establish a theory on frontal lobe meta-enhance learning.
"We plan to conduct joint research for utilizing brain-based artificial intelligence technology and frontal lobe meta-enhanced learning technology modeling in collaboration with an international research team including IBM, DeepMind, MIT, and Oxford,” Professor Lee said.
2021.06.25 View 9222 -
What Guides Habitual Seeking Behavior Explained
A new role of the ventral striatum explains habitual seeking behavior
Researchers have been investigating how the brain controls habitual seeking behaviors such as addiction. A recent study by Professor Sue-Hyun Lee from the Department of Bio and Brain Engineering revealed that a long-term value memory maintained in the ventral striatum in the brain is a neural basis of our habitual seeking behavior. This research was conducted in collaboration with the research team lead by Professor Hyoung F. Kim from Seoul National University. Given that addictive behavior is deemed a habitual one, this research provides new insights for developing therapeutic interventions for addiction.
Habitual seeking behavior involves strong stimulus responses, mostly rapid and automatic ones. The ventral striatum in the brain has been thought to be important for value learning and addictive behaviors. However, it was unclear if the ventral striatum processes and retains long-term memories that guide habitual seeking.
Professor Lee’s team reported a new role of the human ventral striatum where long-term memory of high-valued objects are retained as a single representation and may be used to evaluate visual stimuli automatically to guide habitual behavior.
“Our findings propose a role of the ventral striatum as a director that guides habitual behavior with the script of value information written in the past,” said Professor Lee.
The research team investigated whether learned values were retained in the ventral striatum while the subjects passively viewed previously learned objects in the absence of any immediate outcome. Neural responses in the ventral striatum during the incidental perception of learned objects were examined using fMRI and single-unit recording.
The study found significant value discrimination responses in the ventral striatum after learning and a retention period of several days. Moreover, the similarity of neural representations for good objects increased after learning, an outcome positively correlated with the habitual seeking response for good objects.
“These findings suggest that the ventral striatum plays a role in automatic evaluations of objects based on the neural representation of positive values retained since learning, to guide habitual seeking behaviors,” explained Professor Lee.
“We will fully investigate the function of different parts of the entire basal ganglia including the ventral striatum. We also expect that this understanding may lead to the development of better treatment for mental illnesses related to habitual behaviors or addiction problems.”
This study, supported by the National Research Foundation of Korea, was reported at Nature Communications (https://doi.org/10.1038/s41467-021-22335-5.)
-ProfileProfessor Sue-Hyun LeeDepartment of Bio and Brain EngineeringMemory and Cognition Laboratoryhttp://memory.kaist.ac.kr/lecture
KAIST
2021.06.03 View 8107 -
Wirelessly Rechargeable Soft Brain Implant Controls Brain Cells
Researchers have invented a smartphone-controlled soft brain implant that can be recharged wirelessly from outside the body. It enables long-term neural circuit manipulation without the need for periodic disruptive surgeries to replace the battery of the implant. Scientists believe this technology can help uncover and treat psychiatric disorders and neurodegenerative diseases such as addiction, depression, and Parkinson’s.
A group of KAIST researchers and collaborators have engineered a tiny brain implant that can be wirelessly recharged from outside the body to control brain circuits for long periods of time without battery replacement. The device is constructed of ultra-soft and bio-compliant polymers to help provide long-term compatibility with tissue. Geared with micrometer-sized LEDs (equivalent to the size of a grain of salt) mounted on ultrathin probes (the thickness of a human hair), it can wirelessly manipulate target neurons in the deep brain using light.
This study, led by Professor Jae-Woong Jeong, is a step forward from the wireless head-mounted implant neural device he developed in 2019. That previous version could indefinitely deliver multiple drugs and light stimulation treatment wirelessly by using a smartphone. For more, Manipulating Brain Cells by Smartphone.
For the new upgraded version, the research team came up with a fully implantable, soft optoelectronic system that can be remotely and selectively controlled by a smartphone. This research was published on January 22, 2021 in Nature Communications.
The new wireless charging technology addresses the limitations of current brain implants. Wireless implantable device technologies have recently become popular as alternatives to conventional tethered implants, because they help minimize stress and inflammation in freely-moving animals during brain studies, which in turn enhance the lifetime of the devices. However, such devices require either intermittent surgeries to replace discharged batteries, or special and bulky wireless power setups, which limit experimental options as well as the scalability of animal experiments.
“This powerful device eliminates the need for additional painful surgeries to replace an exhausted battery in the implant, allowing seamless chronic neuromodulation,” said Professor Jeong. “We believe that the same basic technology can be applied to various types of implants, including deep brain stimulators, and cardiac and gastric pacemakers, to reduce the burden on patients for long-term use within the body.”
To enable wireless battery charging and controls, researchers developed a tiny circuit that integrates a wireless energy harvester with a coil antenna and a Bluetooth low-energy chip. An alternating magnetic field can harmlessly penetrate through tissue, and generate electricity inside the device to charge the battery. Then the battery-powered Bluetooth implant delivers programmable patterns of light to brain cells using an “easy-to-use” smartphone app for real-time brain control.
“This device can be operated anywhere and anytime to manipulate neural circuits, which makes it a highly versatile tool for investigating brain functions,” said lead author Choong Yeon Kim, a researcher at KAIST.
Neuroscientists successfully tested these implants in rats and demonstrated their ability to suppress cocaine-induced behaviour after the rats were injected with cocaine. This was achieved by precise light stimulation of relevant target neurons in their brains using the smartphone-controlled LEDs. Furthermore, the battery in the implants could be repeatedly recharged while the rats were behaving freely, thus minimizing any physical interruption to the experiments.
“Wireless battery re-charging makes experimental procedures much less complicated,” said the co-lead author Min Jeong Ku, a researcher at Yonsei University’s College of Medicine.
“The fact that we can control a specific behaviour of animals, by delivering light stimulation into the brain just with a simple manipulation of smartphone app, watching freely moving animals nearby, is very interesting and stimulates a lot of imagination,” said Jeong-Hoon Kim, a professor of physiology at Yonsei University’s College of Medicine. “This technology will facilitate various avenues of brain research.”
The researchers believe this brain implant technology may lead to new opportunities for brain research and therapeutic intervention to treat diseases in the brain and other organs.
This work was supported by grants from the National Research Foundation of Korea and the KAIST Global Singularity Research Program.
-Profile
Professor Jae-Woong Jeong
https://www.jeongresearch.org/
School of Electrical Engineering
KAIST
2021.01.26 View 23281