Tag Archives: Quentin Barraud

Reversing lower limb paralysis

This regenerative treatment is at a very early stage, which means the Swiss researchers have tried it on mice as you can see in the following video (runtime: 2 mins. 15 secs.). Towards the end of the video, researcher Grégoire Courtine cautions there are many hurdles before this could be used in humans, if ever,

A September 22, 2023 Ecole Polytechnique Fédérale de Lausanne (EPFL) press release (also on EurekAlert but published September 21, 2023) by Emmanuel Barraud, describes the work in more detail,

When the spinal cords of mice and humans are partially damaged, the initial paralysis is followed by the extensive, spontaneous recovery of motor function. However, after a complete spinal cord injury, this natural repair of the spinal cord doesn’t occur and there is no recovery. Meaningful recovery after severe injuries requires strategies that promote the regeneration of nerve fibers, but the requisite conditions for these strategies to successfully restore motor function have remained elusive.

“Five years ago, we demonstrated that nerve fibers can be regenerated across anatomically complete spinal cord injuries,” says Mark Anderson, a senior author of the study. “But we also realized this wasn’t enough to restore motor function, as the new fibers failed to connect to the right places on the other side of the lesion.” Anderson is the director of Central Nervous System Regeneration at .NeuroRestore and a scientist at the Wyss Center for Bio and Neuroengineering.

Working in tandem with peers at UCLA [University of California at Los Angeles] and Harvard Medical School, the scientists used state-of-the-art equipment at EPFL’s Campus Biotech facilities in Geneva to run in-depth analyses and identity which type of neuron is involved in natural spinal-cord repair after partial spinal cord injury. “Our observations using single-cell nuclear RNA sequencing not only exposed the specific axons that must regenerate, but also revealed that these axons must reconnect to their natural targets to restore motor function,” says Jordan Squair, the study’s first author. The team’s findings appear in the 22 September 2023 issue of Science.

Towards a combination of approaches

Their discovery informed the design of a multipronged gene therapy. The scientists activated growth programs in the identified neurons in mice to regenerate their nerve fibers, upregulated specific proteins to support the neurons’ growth through the lesion core, and administered guidance molecules to attract the regenerating nerve fibers to their natural targets below the injury. “We were inspired by nature when we designed a therapeutic strategy that replicates the spinal-cord repair mechanisms occurring spontaneously after partial injuries,” says Squair.

Mice with anatomically complete spinal cord injuries regained the ability to walk, exhibiting gait patterns that resembled those quantified in mice that resumed walking naturally after partial injuries. This observation revealed a previously unknown condition for regenerative therapies to be successful in restoring motor function after neurotrauma. “We expect that our gene therapy will act synergistically with our other procedures involving electrical stimulation of the spinal cord,” says Grégoire Courtine, a senior author of the study who also heads .NeuroRestore together with Jocelyne Bloch. “We believe a complete solution for treating spinal cord injury will require both approaches – gene therapy to regrow relevant nerve fibers, and spinal stimulation to maximize the ability of both these fibers and the spinal cord below the injury to produce movement.”

While many obstacles must still be overcome before this gene therapy can be applied in humans, the scientists have taken the first steps towards developing the technology necessary to achieve this feat in the years to come.

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

Recovery of walking after paralysis by regenerating characterized neurons to their natural target region by Jordan W. Squair, Marco Milano, Alexandra de Coucy, Matthieu Gautier, Michael A. Skinnider, Nicholas D. James, Newton Cho, Anna Lasne, Claudia Kathe,Thomas H. Hutson, Steven Ceto, Laetitia Baud, Katia Galan, Viviana Aureli, Achilleas Laskaratos, Quentin Barraud, Timothy J. Deming, Richie E. Kohman, Bernard L. Schneider, Zhigang He, Jocelyne Bloch, Michael V. Sofroniew, Gregoire Courtine, and Mark A. Anderson. Science 21 Sep 2023 Vol 381, Issue 6664 pp. 1338-1345 DOI: 10.1126/science.adi641

This paper is behind a paywall.

This March 25, 2015 posting, “Spinal cords, brains, implants, and remote control,” features some research from EPFL researchers whose names you might recognize from this posting’s research paper.

Mentioned in the press release, the Swiss research centre website for NeuroRestore is here.

Spinal cords, brains, implants, and remote control

I have two items about implants and brains and an item about being able to exert remote control of the brain, all of which hint at a cyborg future for at least a few of us.

e-Dura, the spinal column, and the brain

The first item concerns some research, at the École Polytechnique de Lausanne (EPFL) which features flexible electronics. From a March 24, 2015 article by Ben Schiller for Fast Company (Note: Links have been removed),

Researchers at the Swiss Federal Institute of Technology, in Lausanne, have developed the e-Dura—a tiny skinlike device that attaches directly to damaged spinal cords. By sending out small electrical pulses, it stimulates the cord as if it were receiving signals from the brain, thus allowing movement.

“The purpose of the neuro-prosthesis is to excite the neurons that are on the spinal cord below the site of the injury and activate them, just like if they were receiving information from the brain,” says Stéphanie Lacour, a professor at the institute.

A January 8, 2015 (?) EPFL press release provides more information about the research,

EPFL scientists have managed to get rats walking on their own again using a combination of electrical and chemical stimulation. But applying this method to humans would require multifunctional implants that could be installed for long periods of time on the spinal cord without causing any tissue damage. This is precisely what the teams of professors Stéphanie Lacour and Grégoire Courtine have developed. Their e-Dura implant is designed specifically for implantation on the surface of the brain or spinal cord. The small device closely imitates the mechanical properties of living tissue, and can simultaneously deliver electric impulses and pharmacological substances. The risks of rejection and/or damage to the spinal cord have been drastically reduced. An article about the implant will appear in early January [2015] in Science Magazine.

So-called “surface implants” have reached a roadblock; they cannot be applied long term to the spinal cord or brain, beneath the nervous system’s protective envelope, otherwise known as the “dura mater,” because when nerve tissues move or stretch, they rub against these rigid devices. After a while, this repeated friction causes inflammation, scar tissue buildup, and rejection.

Here’s what the implant looks like,

Courtesy: EPFL

Courtesy: EPFL

The press release describes how the implant is placed (Note: A link has been removed),

Flexible and stretchy, the implant developed at EPFL is placed beneath the dura mater, directly onto the spinal cord. Its elasticity and its potential for deformation are almost identical to the living tissue surrounding it. This reduces friction and inflammation to a minimum. When implanted into rats, the e-Dura prototype caused neither damage nor rejection, even after two months. More rigid traditional implants would have caused significant nerve tissue damage during this period of time.

The researchers tested the device prototype by applying their rehabilitation protocol — which combines electrical and chemical stimulation – to paralyzed rats. Not only did the implant prove its biocompatibility, but it also did its job perfectly, allowing the rats to regain the ability to walk on their own again after a few weeks of training.

“Our e-Dura implant can remain for a long period of time on the spinal cord or the cortex, precisely because it has the same mechanical properties as the dura mater itself. This opens up new therapeutic possibilities for patients suffering from neurological trauma or disorders, particularly individuals who have become paralyzed following spinal cord injury,” explains Lacour, co-author of the paper, and holder of EPFL’s Bertarelli Chair in Neuroprosthetic Technology.

The press release goes on to describe the engineering achievements,

Developing the e-Dura implant was quite a feat of engineering. As flexible and stretchable as living tissue, it nonetheless includes electronic elements that stimulate the spinal cord at the point of injury. The silicon substrate is covered with cracked gold electric conducting tracks that can be pulled and stretched. The electrodes are made of an innovative composite of silicon and platinum microbeads. They can be deformed in any direction, while still ensuring optimal electrical conductivity. Finally, a fluidic microchannel enables the delivery of pharmacological substances – neurotransmitters in this case – that will reanimate the nerve cells beneath the injured tissue.

The implant can also be used to monitor electrical impulses from the brain in real time. When they did this, the scientists were able to extract with precision the animal’s motor intention before it was translated into movement.

“It’s the first neuronal surface implant designed from the start for long-term application. In order to build it, we had to combine expertise from a considerable number of areas,” explains Courtine, co-author and holder of EPFL’s IRP Chair in Spinal Cord Repair. “These include materials science, electronics, neuroscience, medicine, and algorithm programming. I don’t think there are many places in the world where one finds the level of interdisciplinary cooperation that exists in our Center for Neuroprosthetics.”

For the time being, the e-Dura implant has been primarily tested in cases of spinal cord injury in paralyzed rats. But the potential for applying these surface implants is huge – for example in epilepsy, Parkinson’s disease and pain management. The scientists are planning to move towards clinical trials in humans, and to develop their prototype in preparation for commercialization.

EPFL has provided a video of researcher Stéphanie Lacour describing e-Dura and expressing hopes for its commercialization,

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

Electronic dura mater for long-term multimodal neural interfaces by Ivan R. Minev, Pavel Musienko, Arthur Hirsch, Quentin Barraud, Nikolaus Wenger, Eduardo Martin Moraud, Jérôme Gandar, Marco Capogrosso, Tomislav Milekovic, Léonie Asboth, Rafael Fajardo Torres, Nicolas Vachicouras, Qihan Liu, Natalia Pavlova, Simone Duis, Alexandre Larmagnac, Janos Vörös, Silvestro Micera, Zhigang Suo, Grégoire Courtine, Stéphanie P. Lacour. Science 9 January 2015: Vol. 347 no. 6218 pp. 159-163 DOI: 10.1126/science.1260318

This paper is behind a paywall.

Carbon nanotube fibres could connect to the brain

Researchers at Rice University (Texas, US) are excited about the possibilities that carbon nanotube fibres offer in the field of implantable electronics for the brain. From a March 25, 2015 news item on Nanowerk,

Carbon nanotube fibers invented at Rice University may provide the best way to communicate directly with the brain.

The fibers have proven superior to metal electrodes for deep brain stimulation and to read signals from a neuronal network. Because they provide a two-way connection, they show promise for treating patients with neurological disorders while monitoring the real-time response of neural circuits in areas that control movement, mood and bodily functions.

New experiments at Rice demonstrated the biocompatible fibers are ideal candidates for small, safe electrodes that interact with the brain’s neuronal system, according to the researchers. They could replace much larger electrodes currently used in devices for deep brain stimulation therapies in Parkinson’s disease patients.

They may also advance technologies to restore sensory or motor functions and brain-machine interfaces as well as deep brain stimulation therapies for other neurological disorders, including dystonia and depression, the researchers wrote.

A March 25, 2015 Rice University news release (also on EurekAlert*), which originated the news item, provides more details,

The fibers created by the Rice lab of chemist and chemical engineer Matteo Pasquali consist of bundles of long nanotubes originally intended for aerospace applications where strength, weight and conductivity are paramount.

The individual nanotubes measure only a few nanometers across, but when millions are bundled in a process called wet spinning, they become thread-like fibers about a quarter the width of a human hair.

“We developed these fibers as high-strength, high-conductivity materials,” Pasquali said. “Yet, once we had them in our hand, we realized that they had an unexpected property: They are really soft, much like a thread of silk. Their unique combination of strength, conductivity and softness makes them ideal for interfacing with the electrical function of the human body.”

The simultaneous arrival in 2012 of Caleb Kemere, a Rice assistant professor who brought expertise in animal models of Parkinson’s disease, and lead author Flavia Vitale, a research scientist in Pasquali’s lab with degrees in chemical and biomedical engineering, prompted the investigation.

“The brain is basically the consistency of pudding and doesn’t interact well with stiff metal electrodes,” Kemere said. “The dream is to have electrodes with the same consistency, and that’s why we’re really excited about these flexible carbon nanotube fibers and their long-term biocompatibility.”

Weeks-long tests on cells and then in rats with Parkinson’s symptoms proved the fibers are stable and as efficient as commercial platinum electrodes at only a fraction of the size. The soft fibers caused little inflammation, which helped maintain strong electrical connections to neurons by preventing the body’s defenses from scarring and encapsulating the site of the injury.

The highly conductive carbon nanotube fibers also show much more favorable impedance – the quality of the electrical connection — than state-of-the-art metal electrodes, making for better contact at lower voltages over long periods, Kemere said.

The working end of the fiber is the exposed tip, which is about the width of a neuron. The rest is encased with a three-micron layer of a flexible, biocompatible polymer with excellent insulating properties.

The challenge is in placing the tips. “That’s really just a matter of having a brain atlas, and during the experiment adjusting the electrodes very delicately and putting them into the right place,” said Kemere, whose lab studies ways to connect signal-processing systems and the brain’s memory and cognitive centers.

Doctors who implant deep brain stimulation devices start with a recording probe able to “listen” to neurons that emit characteristic signals depending on their functions, Kemere said. Once a surgeon finds the right spot, the probe is removed and the stimulating electrode gently inserted. Rice carbon nanotube fibers that send and receive signals would simplify implantation, Vitale said.

The fibers could lead to self-regulating therapeutic devices for Parkinson’s and other patients. Current devices include an implant that sends electrical signals to the brain to calm the tremors that afflict Parkinson’s patients.

“But our technology enables the ability to record while stimulating,” Vitale said. “Current electrodes can only stimulate tissue. They’re too big to detect any spiking activity, so basically the clinical devices send continuous pulses regardless of the response of the brain.”

Kemere foresees a closed-loop system that can read neuronal signals and adapt stimulation therapy in real time. He anticipates building a device with many electrodes that can be addressed individually to gain fine control over stimulation and monitoring from a small, implantable device.

“Interestingly, conductivity is not the most important electrical property of the nanotube fibers,” Pasquali said. “These fibers are intrinsically porous and extremely stable, which are both great advantages over metal electrodes for sensing electrochemical signals and maintaining performance over long periods of time.”

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

Neural Stimulation and Recording with Bidirectional, Soft Carbon Nanotube Fiber Microelectrodes by Flavia Vitale, Samantha R. Summerson, Behnaam Aazhang, Caleb Kemere, and Matteo Pasquali. ACS Nano, Just Accepted Manuscript DOI: 10.1021/acsnano.5b01060 Publication Date (Web): March 24, 2015

Copyright © 2015 American Chemical Society

The paper is open access provided you register on the website.

Remote control for stimulation of the brain

Mo Costandi, neuroscientist and freelance science writer, has written a March 24, 2015 post for the Guardian science blog network focusing on neuronal remote control,

Two teams of scientists have developed new ways of stimulating neurons with nanoparticles, allowing them to activate brain cells remotely using light or magnetic fields. The new methods are quicker and far less invasive than other hi-tech methods available, so could be more suitable for potential new treatments for human diseases.

Researchers have various methods for manipulating brain cell activity, arguably the most powerful being optogenetics, which enables them to switch specific brain cells on or off with unprecedented precision, and simultaneously record their behaviour, using pulses of light.

This is very useful for probing neural circuits and behaviour, but involves first creating genetically engineered mice with light-sensitive neurons, and then inserting the optical fibres that deliver light into the brain, so there are major technical and ethical barriers to its use in humans.

Nanomedicine could get around this. Francisco Bezanilla of the University of Chicago and his colleagues knew that gold nanoparticles can absorb light and convert it into heat, and several years ago they discovered that infrared light can make neurons fire nervous impulses by heating up their cell membranes.

Polina Anikeeva’s team at the Massachusetts Institute of Technology adopted a slightly different approach, using spherical iron oxide particles that give off heat when exposed to an alternating magnetic field.

Although still in the experimental stages, research like this may eventually allow for wireless and minimally invasive deep brain stimulation of the human brain. Bezanilla’s group aim to apply their method to develop treatments for macular degeneration and other conditions that kill off light-sensitive cells in the retina. This would involve injecting nanoparticles into the eye so that they bind to other retinal cells, allowing natural light to excite them into firing impulses to the optic nerve.

Costandi’s article is intended for an audience that either understands the science or can deal with the uncertainty of not understanding absolutely everything. Provided you fall into either of those categories, the article is well written and it provides links and citations to the papers for both research teams being featured.

Taken together, the research at EPFL, Rice University, University of Chicago, and Massachusetts Institute of Technology provides a clue as to how much money and intellectual power is being directed at the brain.

* EurekAlert link added on March 26, 2015.