Tag Archives: mini-brains

In vitro biological neural networks (BNNs): review paper

The race to merge the biological with machines continues apace as this press release makes clear, From a March 9, 2023 Beijing Institute of Technology Press Co. press release on EurekAlert, Note: A link has been removed,

A review paper by scientists at the Beijing Institute of Technology summarized recent efforts and future potentials in the use of in vitro biological neural networks (BNNs) for the realization of biological intelligence, with a focus on those related to robot intelligence.

The review paper, published on Jan. 10 in the journal Cyborg and Bionic Systems, provided an overview of 1) the underpinnings of intelligence presented in in vitro BNNs, such as memory and learning; 2) how these BNNs can be embodied with robots through bidirectional connection, forming so-called BNN-based neuro-robotic systems; 3) preliminary intelligent behaviors achieved by these neuro-robotic systems; and 4) current trends and future challenges in the research area of BNN-based neuro-robotic systems.

“our human brain is a complex biological neural network (BNN) composed of billions of neurons, which gives rise to our consciousness and intelligence. However, studying the brain as a whole is extremely challenging due to its intricate nature. By culturing a part of the neurons from the brain in a Petri dish, simpler BNNs, such as mini-brains, can be formed, allowing for easier observation and investigation of the network. These mini-brains may provide valuable insights into the enigmatic origins of consciousness and intelligence.” explained study author Zhiqiang Yu, an assistant researcher at the Beijing Institute of Technology.

“Interestingly, mini-brains are not only structurally similar to human brains, but they can also learn and memorize information in a similar way.” said Yu. In particular, these in vitro BNNs share the same basic structure as in vivo BNNs, where neurons are connected through synapses, and they exhibit short-term memory through fading and hidden memory processes. Additionally, these mini-brains can perform supervised learning and be trained to respond to specific stimuli signals. Recently, researchers have demonstrated that in vitro BNNs can even accomplish unsupervised learning tasks, such as separating mixed signals. “This fascinating ability may have something to do with the famous free energy principle. That is, these BNNs have a tendency to minimize their uncertainty about the outer world,” said Yu.

These abilities of in vitro BNNs are quite intriguing. However, only having such a ‘mini-brain’ on your hand is not enough for the rise of consciousness and intelligence. Our brain relies on our body to perceive, comprehend, and adapt to the outside world, and similarly, these mini-brains require a body to interact with their environment. A robot is an ideal candidate for this purpose, leading to a burgeoning interdisciplinary field at the intersection of neuroscience and robotics: BNN-based neuro-robotic systems.

“A stable bidirectional connection is a prerequisite for these systems.” said study authors, “In this review, we summarize the mainstream means of constructing such a bidirectional connection, which can be broadly classified into two categories based on the direction of connection: from robots to BNNs and from BNNs to robots.” The former involves transmitting sensor signals from the robot to BNNs, utilizing electrical, optical, and chemical stimulation methods, while the latter records the neural activities of BNNs and decode these activities into commands to control the robot, using extracellular, calcium, and intracellular recording techniques.

“Embodied by robots, in vitro BNNs exhibit a wide range of fascinating intelligent behaviors,” according to Yu. “These behaviors include supervised and unsupervised learning, memorization, mobile object tracking, active obstacle avoidance, and even learning to play games such as ‘Pong’.”

The intelligent behaviors displayed by these BNN-based neuro-robotic systems can be divided into two categories based on their dependence on either computing capacity or network plasticity, as explained by Yu. “In computing capacity-dependent behaviors, learning is unnecessary, and the BNN is regarded as an information processor that generates specific neural activities in response to stimuli. However, for the latter, learning is a crucial process, as the BNN adapts to stimuli and these changes are integral to the behaviors or tasks performed by the robot,” added Yu.

To facilitate easy comparison of the recording and stimulation techniques, encoding and decoding rules, training policies, and robot tasks, representative studies from these two categories have been compiled into two tables. Additionally, to provide readers with a historical overview of BNN-based neuro-robotic systems, several noteworthy studies have been selected and arranged chronologically.

The study authors also discussed current trends and main challenges in the field. According to Yu, “Four challenges are keen to be addressed and are being intensely investigated. How to fabricate BNNs in 3D, thereby making in vitro BNNs close to their in vivo counterparts, is the most urgent one of them”

Perhaps the most challenging aspect is how to train these robot-embodied BNNs. The study authors noted that BNNs are composed only of neurons and lack the participation of various neuromodulators, which makes it difficult to transplant various animal training methods to BNNs. Additionally, BNNs have their own limitations. While a monkey can be trained to ride a bicycle, it is much more challenging to accomplish tasks that require higher-level thought processes, such as playing Go.

“The mystery of how consciousness and intelligence emerge from the network of cells in our brains still eludes neuroscientists” said Yu. However, with the development of embodying in vitro BNNs with robots, we may observe more intelligent behaviors in them and bring people closer to the truth behind the mystery.

I think that ‘in vitro biological neural networks (BNNs) or mini-brains’ can also be called brain organoids, which seems to be the more popular term in some circles.

Here’s a link to and a citation for the paper,

An Overview of In Vitro Biological Neural Networks for Robot Intelligence by Zhe Chen, Qian Liang, Zihou Wei, Xie Chen, Qing Shi, Zhiqiang Yu, and Tao Sun. Cyborg and Bionic Systems 10 Jan 2023 Vol 4 Article ID: 0001 DOI: 10.34133/cbsystems.0001

This paper is open access.

Cortical spheroids (like mini-brains) could unlock (larger) brain’s mysteries

A March 19, 2021 Northwestern University news release on EurekAlert announces the creation of a device designed to monitor brain organoids (for anyone unfamiliar with brain organoids there’s more information after the news),

A team of scientists, led by researchers at Northwestern University, Shirley Ryan AbilityLab and the University of Illinois at Chicago (UIC), has developed novel technology promising to increase understanding of how brains develop, and offer answers on repairing brains in the wake of neurotrauma and neurodegenerative diseases.

Their research is the first to combine the most sophisticated 3-D bioelectronic systems with highly advanced 3-D human neural cultures. The goal is to enable precise studies of how human brain circuits develop and repair themselves in vitro. The study is the cover story for the March 19 [March 17, 2021 according to the citation] issue of Science Advances.

The cortical spheroids used in the study, akin to “mini-brains,” were derived from human-induced pluripotent stem cells. Leveraging a 3-D neural interface system that the team developed, scientists were able to create a “mini laboratory in a dish” specifically tailored to study the mini-brains and collect different types of data simultaneously. Scientists incorporated electrodes to record electrical activity. They added tiny heating elements to either keep the brain cultures warm or, in some cases, intentionally overheated the cultures to stress them. They also incorporated tiny probes — such as oxygen sensors and small LED lights — to perform optogenetic experiments. For instance, they introduced genes into the cells that allowed them to control the neural activity using different-colored light pulses.

This platform then enabled scientists to perform complex studies of human tissue without directly involving humans or performing invasive testing. In theory, any person could donate a limited number of their cells (e.g., blood sample, skin biopsy). Scientists can then reprogram these cells to produce a tiny brain spheroid that shares the person’s genetic identity. The authors believe that, by combining this technology with a personalized medicine approach using human stem cell-derived brain cultures, they will be able to glean insights faster and generate better, novel interventions.

“The advances spurred by this research will offer a new frontier in the way we study and understand the brain,” said Shirley Ryan AbilityLab’s Dr. Colin Franz, co-lead author on the paper who led the testing of the cortical spheroids. “Now that the 3-D platform has been developed and validated, we will be able to perform more targeted studies on our patients recovering from neurological injury or battling a neurodegenerative disease.”

Yoonseok Park, postdoctoral fellow at Northwestern University and co-lead author, added, “This is just the beginning of an entirely new class of miniaturized, 3-D bioelectronic systems that we can construct to expand the capacity of the regenerative medicine field. For example, our next generation of device will support the formation of even more complex neural circuits from brain to muscle, and increasingly dynamic tissues like a beating heart.”

Current electrode arrays for tissue cultures are 2-D, flat and unable to match the complex structural designs found throughout nature, such as those found in the human brain. Moreover, even when a system is 3-D, it is extremely challenging to incorporate more than one type of material into a small 3-D structure. With this advance, however, an entire class of 3-D bioelectronics devices has been tailored for the field of regenerative medicine.

“Now, with our small, soft 3-D electronics, the capacity to build devices that mimic the complex biological shapes found in the human body is finally possible, providing a much more holistic understanding of a culture,” said Northwestern’s John Rogers, who led the technology development using technology similar to that found in phones and computers. “We no longer have to compromise function to achieve the optimal form for interfacing with our biology.”

As a next step, scientists will use the devices to better understand neurological disease, test drugs and therapies that have clinical potential, and compare different patient-derived cell models. This understanding will then enable a better grasp of individual differences that may account for the wide variation of outcomes seen in neurological rehabilitation.

“As scientists, our goal is to make laboratory research as clinically relevant as possible,” said Kristen Cotton, research assistant in Dr. Franz’s lab. “This 3-D platform opens the door to new experiments, discovery and scientific advances in regenerative neurorehabilitation medicine that have never been possible.”

Caption: Three dimensional multifunctional neural interfaces for cortical spheroids and engineered assembloids Credit: Northwestern University

As for what brain ogranoids might be, Carl Zimmer in an Aug. 29, 2019 article for the New York Times provides an explanation,

Organoids Are Not Brains. How Are They Making Brain Waves?

Two hundred and fifty miles over Alysson Muotri’s head, a thousand tiny spheres of brain cells were sailing through space.

The clusters, called brain organoids, had been grown a few weeks earlier in the biologist’s lab here at the University of California, San Diego. He and his colleagues altered human skin cells into stem cells, then coaxed them to develop as brain cells do in an embryo.

The organoids grew into balls about the size of a pinhead, each containing hundreds of thousands of cells in a variety of types, each type producing the same chemicals and electrical signals as those cells do in our own brains.

In July, NASA packed the organoids aboard a rocket and sent them to the International Space Station to see how they develop in zero gravity.

Now the organoids were stowed inside a metal box, fed by bags of nutritious broth. “I think they are replicating like crazy at this stage, and so we’re going to have bigger organoids,” Dr. Muotri said in a recent interview in his office overlooking the Pacific.

What, exactly, are they growing into? That’s a question that has scientists and philosophers alike scratching their heads.

On Thursday, Dr. Muotri and his colleagues reported that they  have recorded simple brain waves in these organoids. In mature human brains, such waves are produced by widespread networks of neurons firing in synchrony. Particular wave patterns are linked to particular forms of brain activity, like retrieving memories and dreaming.

As the organoids mature, the researchers also found, the waves change in ways that resemble the changes in the developing brains of premature babies.

“It’s pretty amazing,” said Giorgia Quadrato, a neurobiologist at the University of Southern California who was not involved in the new study. “No one really knew if that was possible.”

But Dr. Quadrato stressed it was important not to read too much into the parallels. What she, Dr. Muotri and other brain organoid experts build are clusters of replicating brain cells, not actual brains.

If you have the time, I recommend reading Zimmer’s article in its entirety. Perhaps not coincidentally, Zimmer has an excerpt titled “Lab-Grown Brain Organoids Aren’t Alive. But They’re Not Not Alive, Either.” published in Slate.com,

From Life’s Edge: The Search For What It Means To Be Alive by Carl Zimmer, published by Dutton, an imprint of Penguin Publishing Group, a division of Penguin Random House, LLC. Copyright © 2021 by Carl Zimmer.

Cleber Trujillo led me to a windowless room banked with refrigerators, incubators, and microscopes. He extended his blue-gloved hands to either side and nearly touched the walls. “This is where we spend half our day,” he said.

In that room Trujillo and a team of graduate students raised a special kind of life. He opened an incubator and picked out a clear plastic box. Raising it above his head, he had me look up at it through its base. Inside the box were six circular wells, each the width of a cookie and filled with what looked like watered-down grape juice. In each well 100 pale globes floated, each the size of a housefly head.

Getting back to the research about monitoring brain organoids, here’s a link to and a citation for the paper about cortical spheroids,

Three-dimensional, multifunctional neural interfaces for cortical spheroids and engineered assembloids by Yoonseok Park, Colin K. Franz, Hanjun Ryu, Haiwen Luan, Kristen Y. Cotton, Jong Uk Kim, Ted S. Chung, Shiwei Zhao, Abraham Vazquez-Guardado, Da Som Yang, Kan Li, Raudel Avila, Jack K. Phillips, Maria J. Quezada, Hokyung Jang, Sung Soo Kwak, Sang Min Won, Kyeongha Kwon, Hyoyoung Jeong, Amay J. Bandodkar, Mengdi Han, Hangbo Zhao, Gabrielle R. Osher, Heling Wang, KunHyuck Lee, Yihui Zhang, Yonggang Huang, John D. Finan and John A. Rogers. Science Advances 17 Mar 2021: Vol. 7, no. 12, eabf9153 DOI: 10.1126/sciadv.abf9153

This paper appears to be open access.

According to a March 22, 2021 posting on the Shirley Riley AbilityLab website, the paper is featured on the front cover of Science Advances (vol. 7 no. 12).