From Rats to Humans: Project NEUWalk Closer to Clinical Trials

EPFL scientists have discovered how to control the limbs of a completely paralyzed rat in real time to help it walk again. Their results are published today in Science Translational Medicine.

Building on earlier work in rats, this new breakthrough is part of a more general therapy that could one day be implemented in rehabilitation programs for people with spinal cord injury, currently being developed in a European project called NEUWalk. Clinical trials could start as early as next summer using the new Gait Platform, built with the support of the Valais canton and the SUVA, and now assembled at the CHUV (Lausanne University Hospital).

How it works

The human body needs electricity to function. The electrical output of the human brain, for instance, is about 30 watts. When the circuitry of the nervous system is damaged, the transmission of electrical signals is impaired, often leading to devastating neurological disorders like paralysis.

Electrical stimulation of the nervous system is known to help relieve these neurological disorders at many levels. Deep brain stimulation is used to treat tremors related to Parkinson’s disease, for example. Electrical signals can be engineered to stimulate nerves to restore a sense of touch in the missing limb of amputees. And electrical stimulation of the spinal cord can restore movement control in spinal cord injury.

But can electrical signals be engineered to help a paraplegic walk naturally? The answer is yes, for rats at least.

“We have complete control of the rat’s hind legs,” says EPFL neuroscientist Grégoire Courtine. “The rat has no voluntary control of its limbs, but the severed spinal cord can be reactivated and stimulated to perform natural walking. We can control in real-time how the rat moves forward and how high it lifts its legs.”

The scientists studied rats whose spinal cords were completely severed in the middle-back, so signals from the brain were unable to reach the lower spinal cord. That’s where flexible electrodes were surgically implanted. Sending electric current through the electrodes stimulated the spinal cord.

They realized that there was a direct relationship between how high the rat lifted its limbs and the frequency of the electrical stimulation. Based on this and careful monitoring of the rat’s walking patterns – its gait – the researchers specially designed the electrical stimulation to adapt the rat’s stride in anticipation of upcoming obstacles, like barriers or stairs.

“Simple scientific discoveries about how the nervous system works can be exploited to develop more effective neuroprosthetic technologies,” says co-author and neuroengineer Silvestro Micera. “We believe that this technology could one day significantly improve the quality of life of people confronted with neurological disorders.”

Taking this idea a step further, Courtine and Micera together with colleagues from EPFL’s Center for Neuroprosthetics are also exploring the possibility of decoding signals directly from the brain about leg movement and using this information to stimulate the spinal cord.

Towards clinical trials using the Gait Platform at the CHUV

The electrical stimulation reported in this study will be tested in patients with incomplete spinal cord injury in a clinical study that may start as early as next summer, using a new Gait Platform that brings together innovative monitoring and rehabilitation technology.

Designed by Courtine’s team, the Gait Platform consists of custom-made equipment like a treadmill and an overground support system, as well as 14 infrared cameras that detect reflective markers on the patient’s body and two video cameras, all of which generate extensive amounts of information about leg and body movement. This information can be fully synchronized for complete monitoring and fine-tuning of the equipment in order to achieve intelligent assistance and adaptive electrical spinal cord stimulation of the patient.

The Gait Platform is housed in a 100 square meter room provided by the CHUV. The hospital already has a rehabilitation center dedicated to translational research, notably for orthopedic and neurological pathologies.

“The Gait Platform is not a rehabilitation center,” says Courtine. “It is a research laboratory where we will be able to study and develop new therapies using very specialized technology in close collaboration with medical experts here at the CHUV, like physiotherapists and doctors.”

New research: teaching the brain to reduce pain

People can be conditioned to feel less pain when they hear a neutral sound, new research from the University of Luxembourg has found. This lends weight to the idea that we can learn to use mind-over-matter to beat pain. The scientific article was published recently in the online journal “PLOS One”.

Scientists have known for many years that on-going pain in one part of the body is reduced when a new pain is inflicted to another part of the body. This pain blocking is a physiological reaction by the nervous system to help the body deal with a potentially more relevant novel threat.

To explore this “pain inhibits pain” phenomenon, painful electric pulses were first administered to a subject’s foot (first pain) and the resulting pain intensity was then measured. Then the subject was asked to put their hand in a bucket of ice water (novel stimulus causing pain reduction), and as they did so, a telephone ringtone sounded in headphones. After this procedure had been repeated several times, it was observed that the pain felt from the electrical stimulation was reduced simply when the ring tone sounded.

The brain had been conditioned to the ringtone being a signal to trigger the body’s physical pain blocking mechanism. The people being tested not only felt significantly less pain, but there were also fewer objective signs of pain, such as activity in the muscles used in the facial expression of pain (frowning). In total, 32 people were tested.

“We have shown that just as the physiological reaction of saliva secretion was provoked in Pavlov’s dogs by the ringing of a bell, an analogous effect occurs regarding the ability to mask pain in humans,” said Fernand Anton, Professor of Biological Psychology at the University of Luxembourg. “Conversely, similar learning effects may be involved in the enhancement and maintenance of pain in some patients,” added Raymonde Scheuren, lead researcher in this study.

Optogenetics as good as electrical stimulation

Neuroscientists are eagerly, but not always successfully, looking for proof that optogenetics – a celebrated technique that uses pulses of visible light to genetically alter brain cells to be excited or silenced – can be as successful in complex and large brains as it has been in rodent models.

A new study in the journal Current Biology may be the most definitive demonstration yet that the technique can work in nonhuman primates as well as, or even a little better than, the tried-and-true method of perturbing brain circuits with small bursts of electrical current. Brown University researchers directly compared the two techniques to test how well they could influence the visual decision-making behavior of two primates.

“For most of my colleagues in neuroscience to say ‘I’ll be able to incorporate [optogenetics] into my daily work with nonhuman primates,’ you have to get beyond ‘It does seem to sort of work’,” said study senior author David Sheinberg, professor of neuroscience professor affiliated with the Brown Institute for Brain Science. “In our comparison, one of the nice things is that in some ways we found quite analogous effects between electrical and optical [stimulation] but in the optical case it seemed more focused.”

Ultimately if it consistently proves safe and effective in the large, complex brains of primates, optogenetics could eventually be used in humans where it could provide a variety of potential diagnostic and therapeutic benefits.

Evidence in sight

With that in mind, Sheinberg, lead author Ji Dai and second author Daniel Brooks designed their experiments to determine whether and how much optical or electrical stimulation in a particular area of the brain called the lateral intraparietal area (LIP) would affect each subject’s decision making when presented with a choice between a target and a similar-looking, distracting character.

“This is an area of the brain involved in registering the location of salient objects in the visual world,” said Sheinberg who added that the experimental task was more cognitively sophisticated than those tested in optogenetics experiments in nonhuman primates before.

The main task for the subjects was to fixate on a central point in middle of the screen and then to look toward the letter “T” when it appeared around the edge of the screen. In some trials, they had to decide quickly between the T and a similar looking “+” or “†” character presented on opposite ends of the screen. They were rewarded if they glanced toward the T.

Before beginning those trials, the researchers had carefully placed a very thin combination sensor of an optical fiber and an electrode amid a small population of cells in the LIP of each subject. Then they mapped where on the screen an object should be in order for them to detect a response in those cells. They called that area the receptive field. With this information, they could then look to see what difference either optical or electrical stimulation of those cells would have on the subject’s inclination to look when the T or the distracting character appeared at various locations in visual space.

They found that stimulating with either method increased both subjects’ accuracy in choosing the target when it appeared in their receptive field. They also found the primates became less accurate when the distracting character appeared in their receptive field. Generally accuracy was unchanged when neither character was in the receptive field.

In other words, the stimulation of a particular group of LIP cells significantly biased the subjects to look at objects that appeared in the receptive field associated with those cells. Either stimulation method could therefore make the subjects more accurate or effectively distract them from making the right choice.

The magnitude of the difference made by either stimulation method compared to no stimulation were small, but statistically significant. When the T was in the receptive field, one research subject became 10 percentage points more accurate (80 percent vs. 70 percent) when optically stimulated and eight points more accurate when electrically stimulated. The subject was five points less accurate (73 percent vs. 78 percent) with optical stimulation and six percentage points less accurate with electrical stimulation when the distracting character was in the receptive field.

The other subject showed similar differences. In all, the two primates made thousands of choices over scores of sessions between the T and the distracting character with either kind of stimulation or none. Compared head-to-head in a statistical analysis, electrical and optical stimulation showed essentially similar effects in biasing the decisions.

Optical advantages

Although the two methods performed at parity on the main measure of accuracy, the optogenetic method had a couple of advantages, Sheinberg said.

Electrical stimulation appeared to be less precise in the cells it reached, a possibility suggested by a reduction in electrically stimulated subjects’ reaction time when the T appeared outside the receptive field. Optogenetic stimulation, Sheinberg said, did not produce such unintended effects.

Electrical stimulation also makes simultaneous electrical recording very difficult, Sheinberg said. That makes it hard to understand what neurons do when they are stimulated. Optogenetics, he said, allows for easier simultaneous electrical recording of neural activity.

Sheinberg said he is encouraged about using optogenetics to investigate even more sophisticated questions of cognition.

“Our goal is to be able to now expand this and use it again as a daily tool to probe circuits in more complicated paradigms,” Sheinberg said.

He plans a new study in which his group will look at memory of visual cues in the LIP.

Beauty and the Brain: Electrical Stimulation of the Brain Makes You Perceive Faces as More Attractive

The researchers, led by scientists at the California Institute of Technology (Caltech), have used a well-known, noninvasive technique to electrically stimulate a specific region deep inside the brain previously thought to be inaccessible. The stimulation, the scientists say, caused volunteers to judge faces as more attractive than before their brains were stimulated.

Being able to effect such behavioral changes means that this electrical stimulation tool could be used to noninvasively manipulate deep regions of the brain—and, therefore, that it could serve as a new approach to study and treat a variety of deep-brain neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia, the researchers say.

"This is very exciting because the primary means of inducing these kinds of deep-brain changes to date has been by administering drug treatments," says Vikram Chib, a postdoctoral scholar who led the study, which is being published in the June 11 issue of the journal Translational Psychiatry. “But the problem with drugs is that they’re not location-specific—they act on the entire brain.” Thus, drugs may carry unwanted side effects or, occasionally, won’t work for certain patients—who then may need invasive treatments involving the implantation of electrodes into the brain.

So Chib and his colleagues turned to a technique called transcranial direct-current stimulation (tDCS), which, Chib notes, is cheap, simple, and safe. In this method, an anode and a cathode are placed at two different locations on the scalp. A weak electrical current—which can be powered by a nine-volt battery—runs from the cathode, through the brain, and to the anode. The electrical current is a mere 2 milliamps—10,000 times less than the 20 amps typically available from wall sockets. “All you feel is a little bit of tingling, and some people don’t even feel that,” he says.

"There have been many studies employing tDCS to affect behavior or change local neural activity," says Shinsuke Shimojo, the Gertrude Baltimore Professor of Experimental Psychology and a coauthor of the paper. For example, the technique has been used to treat depression and to help stroke patients rehabilitate their motor skills. "However, to our knowledge, virtually none of the previous studies actually examined and correlated both behavior and neural activity," he says. These studies also targeted the surface areas of the brain—not much more than a centimeter deep—which were thought to be the physical limit of how far tDCS could reach, Chib adds.

The researchers hypothesized that they could exploit known neural connections and use tDCS to stimulate deeper regions of the brain. In particular, they wanted to access the ventral midbrain—the center of the brain’s reward-processing network, and about as deep as you can go. It is thought to be the source of dopamine, a chemical whose deficiency has been linked to many neuropsychiatric disorders.

The ventral midbrain is part of a neural circuit that includes the dorsolateral prefrontal cortex (DLPFC), which is located just above the temples, and the ventromedial prefrontal cortex (VMPFC), which is behind the forehead. Decreasing activity in the DLPFC boosts activity in the VMPFC, which in turn bumps up activity in the ventral midbrain. To manipulate the ventral midbrain, therefore, the researchers decided to try using tDCS to deactivate the DLPFC and activate the VMPFC.

To test their hypothesis, the researchers asked volunteers to judge the attractiveness of groups of faces both before and after the volunteers’ brains had been stimulated with tDCS. Judging facial attractiveness is one of the simplest, most primal tasks that can activate the brain’s reward network, and difficulty in evaluating faces and recognizing facial emotions is a common symptom of neuropsychiatric disorders. The study participants rated the faces while inside a functional magnetic resonance imaging (fMRI) scanner, which allowed the researchers to evaluate any changes in brain activity caused by the stimulation.

A total of 99 volunteers participated in the tDCS experiment and were divided into six stimulation groups. In the main stimulation group, composed of 19 subjects, the DLPFC was deactivated and the VMPFC activated with a stimulation configuration that the researchers theorized would ultimately activate the ventral midbrain. The other groups were used to test different stimulation configurations. For example, in one group, the placement of the cathode and anode were switched so that the DLPFC was activated and the VMPFC was deactivated—the opposite of the main group. Another was a “sham” group, in which the electrodes were placed on volunteers’ heads, but no current was run.

Those in the main group rated the faces presented after stimulation as more attractive than those they saw before stimulation. There were no differences in the ratings from the control groups. This change in ratings in the main group suggests that tDCS is indeed able to activate the ventral midbrain, and that the resulting changes in brain activity in this deep-brain region are associated with changes in the evaluation of attractiveness.

In addition, the fMRI scans revealed that tDCS strengthened the correlation between VMPFC activity and ventral midbrain activity. In other words, stimulation appeared to enhance the neural connectivity between the two brain areas. And for those who showed the strongest connectivity, tDCS led to the biggest change in attractiveness ratings. Taken together, the researchers say these results show that tDCS is causing those shifts in perception by manipulating the ventral midbrain via the DLPFC and VMPFC.

"The fact that we haven’t had a way to noninvasively manipulate a functional circuit in the brain has been a fundamental bottleneck in human behavioral neuroscience," Shimojo says. This new work, he adds, represents a big first step in removing that bottleneck.

Using tDCS to study and treat neuropsychiatric disorders hinges on the assumption that the technique directly influences dopamine production in the ventral midbrain, Chib explains. But because fMRI can’t directly measure dopamine, this study was unable to make that determination. The next step, then, is to use methods that can—such as positron emission tomography (PET) scans.

More work also needs to be done to see how tDCS may be used for treating disorders and to precisely determine the duration of the stimulation effects—as a rule of thumb, the influence of tDCS lasts for twice the exposure time, Chib says. Future studies will also be needed to see what other behaviors this tDCS method can influence. Ultimately, clinical tests will be needed for medical applications.

Loyola surgeon using electrical stimulation to speed recovery in Bell’s palsy patients

A Loyola University Medical Center surgeon is using electrical stimulation as part of an advanced surgical technique to treat Bell’s palsy. Bell’s palsy is a condition that causes paralysis on one side of a patient’s face.

During surgery, Dr. John Leonetti stimulates the patient’s damaged facial nerve with an electric current, helping to jump-start the nerve in an effort to restore improved facial movement more quickly.

Leonetti said some patients who have received electrical stimulation have seen muscle movement return to their face after one or two months — rather than the four-to-six months it typically takes for movement to return following surgery.

A virus triggered Bell’s palsy in Audrey Rex, 15, of Lemont, Ill. Her right eye could not close and her smile was lopsided, making her feel self-conscious. She had to drink from a straw, and eating was frustrating - she would accidently bite her bottom lip when it got stuck on her teeth.

She was treated with steroids, but after six weeks, there were no improvements. So Audrey’s mother did further research and made an appointment with Leonetti, and he recommended surgery with electrical stimulation, followed by physical therapy. Today, Audrey’s appearance has returned to normal, and she has regained nearly all of the facial muscle movements she had lost.

“I feel very blessed that we were referred to Dr. Leonetti,” said Deborah Rex, Audrey’s mother.

Bell’s palsy is classified as an idiopathic disorder, meaning its cause is not definitely known. However, most physicians believe Bell’s palsy is caused by a viral-induced swelling of the facial nerve within its bony covering. Symptoms include paralysis on one side of the face; inability to close one eye; drooling; dryness of the eye; impaired taste; and a complete inability to express emotion on one side of the face. 

Bell’s palsy occurs when the nerve that controls muscles on one side of the face becomes swollen, inflamed or compressed. The nerve runs through a narrow, bony canal called the Fallopian canal. Following a viral infection, the nerve swells inside the canal, restricting the flow of blood and oxygen to nerve cells.

Most cases can be successfully treated with oral steroids, and 85 percent of patients experience good recovery within a month. But if symptoms persist for longer than a month, the patient may need surgery, Leonetti said. If surgery is delayed for longer than three months, the nerve damage from Bell’s palsy can be permanent. Thus, the optimal window for surgery is between one and three months after onset of symptoms.

The surgery is called microscopic decompression of the facial nerve. The surgeon removes the bony covering of the facial nerve, then slits open the outer covering of the nerve. This gives the nerve room to swell. In addition to this standard procedure, Leonetti uses an electric stimulator to send a current through the nerve. This jump starts the nerve to speed its recovery.

Decompression of the facial nerve is an established technique for treating Bell’s palsy, and electric stimulation is an established technique used in other surgeries involving the nerve. “We are combining two standard treatments to create an exceptional treatment,” Leonetti said.

Following surgery, Audrey worked with Loyola physical therapist Lisa Burkman, who used a mirror and biofeedback to teach Audrey individualized exercises of her mouth, eye, forehead, cheek and chin. Leonetti said Audrey’s case illustrates that the road back from Bell’s palsy is a multidisciplinary effort that involves the surgeon, physical therapist and patient.

Lower Extremity Functional Electrical Stimulation Cycling Promotes Physical & Neurological Recovery In Chronic Spinal Cord Injury

A new study by Kennedy Krieger Institute’s International Center for Spinal Cord Injury (Epub ahead of print) finds that long-term lower extremity functional electrical stimulation (FES) cycling, as part of a rehabilitation regimen, is associated with substantial improvements in individuals with chronic spinal cord injury (SCI). Improvements include neurological and functional gains, as well as enhanced physical health demonstrated by decreased fat, increased muscle mass and improved lipid profile. Prior to this study’s publication in the Journal of Spinal Cord Medicine, the benefits of activity-based restorative therapy (ABRT) programs, such as FES cycling, were largely anecdotal despite publicity in conjunction with the recovery of actor and activist Christopher Reeve.

In FES, small electrical pulses are applied to paralyzed muscles to stimulate movement. In the case of FES cycling, FES pulses prompt the legs of an individual with SCI to “cycle” on an adapted stationary recumbent bicycle. The repetitive activity offers cardiovascular exercise similar to that which an able-bodied individual achieves through walking, but this new research shows that the results go far beyond basic health benefits.

“Exercise has not been commonly advocated for individuals with paralysis because of the assumption that it is of little benefit and it is challenging to exercise limbs that an individual cannot voluntarily move,” said John W. McDonald, M.D., Ph.D., senior study author and director of the International Center for Spinal Cord Injury at the Kennedy Krieger Institute. “However, we found that FES cycling is a practical form of exercise that provides substantial benefits, including improved physical integrity, enhanced neurological and functional performance, increased muscle size and strength, reduced muscle spasticity and improved quality of life.”

Brain-to-brain interface allows transmission of tactile and motor information between rats

Researchers have electronically linked the brains of pairs of rats for the first time, enabling them to communicate directly to solve simple behavioral puzzles. A further test of this work successfully linked the brains of two animals thousands of miles apart—one in Durham, N.C., and one in Natal, Brazil.

The results of these projects suggest the future potential for linking multiple brains to form what the research team is calling an “organic computer,” which could allow sharing of motor and sensory information among groups of animals. The study was published Feb. 28, 2013, in the journal Scientific Reports.

"Our previous studies with brain-machine interfaces had convinced us that the rat brain was much more plastic than we had previously thought," said Miguel Nicolelis, M.D., PhD, lead author of the publication and professor of neurobiology at Duke University School of Medicine. "In those experiments, the rat brain was able to adapt easily to accept input from devices outside the body and even learn how to process invisible infrared light generated by an artificial sensor. So, the question we asked was, ‘if the brain could assimilate signals from artificial sensors, could it also assimilate information input from sensors from a different body?’"

To test this hypothesis, the researchers first trained pairs of rats to solve a simple problem: to press the correct lever when an indicator light above the lever switched on, which rewarded the rats with a sip of water. They next connected the two animals’ brains via arrays of microelectrodes inserted into the area of the cortex that processes motor information.

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Groundbreaking treatment that enabled paralysed animals to walk again will be tested on humans within months

Scientists behind groundbreaking research that enabled rats with severed spines to run again after two weeks have outlined their plans for human trials.

The technology brings fresh hope to sufferers of spinal cord injuries, and the team say they hope the first humans could be implanted with the technology within months.

Using a cocktail of drugs and electrical impulses, researchers hope to begin testing the project to ‘regrow’ nerves linking the spinal cord to the brain in five patients in a Swiss clinic.

Last June in the journal Science, Grégoire Courtine, of the École Polytechnique Fédérale de Lausanne (EPFL), reported that rats in his lab are not only voluntarily initiating a walking gait, but they were sprinting, climbing up stairs, and avoiding obstacles after a couple of weeks of neurorehabilitation with a combination of a robotic harness and electrical and chemical stimulation.

At the 2013 Annual Meeting of the American Association for the Advancement of Science (AAAS) in Boston, Courtine revealed the next step for the research.

He has since repeated the study in rats with bruised spines, which more closely resembles human trauma patients, and after a few weeks they could walk with no assistance.

He now believes that the technique could help people who have been immobile for up to two years.

Although full human trials are still a few years off, he plans to attempt electrical stimulation on five patients who have limited leg movement in the coming months.

‘We know that spinal cord stimulation is safe, we know that training is good, so we want to start the first trial in people who can move their legs but cannot walk independently.

'So we will implant five patients, we have a new technology which allows us to stimulate the spinal cord of humans just like we do in the rats.’

Once they have refined the technique, they hope to fully rehabilitate patients with moderately damaged spines, while others would regain some movement.

‘We already have preliminary data from the rats with these clinically relevant lesions is that a number of them would recover at the end of the training and could walk without any help. It depends on the severity of the damage,’ he said.

‘But if you talk to the patient and you tell them at least you could use it at home to cook, to watch TV and have normal activity, they say their life would be so different. So it is less ambitious, but we are talking about improving the quality of life, allowing people to stand and take a few steps at home with a walker.’

Fighting disease deep inside the brain

Some 90,000 patients per year are treated for Parkinson’s disease, a number that is expected to rise by 25 percent annually. Deep Brain Stimulation (DBS), which consists of electrically stimulating the central or peripheral nervous system, is currently standard practice for treating Parkinson’s, but it can involve long, expensive surgeries with dramatic side effects. Miniature, ultra-flexible electrodes developed in Switzerland, however, could be the answer to more successful treatment for this and a host of other health issues.

Today, Professor Philippe Renaud of the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland reports on soft arrays of miniature electrodes developed in his Microsystems Laboratory that open new possibilities for more accurate and local DBS. At the 2013 Annual Meeting of the American Association for the Advancement of Science (AAAS) in Boston, in a symposium called “Engineering the Nervous System: Solutions to Restore Sight, Hearing, and Mobility,” he announces the start of clinical trials and early, yet promising results in patients, and describes new developments in ultra-flexible electronics that can conform to the contours of the brainstem—in the brain itself—for treating other disorders.

At AAAS, Renaud outlines the technology behind these novel electronic interfaces with the nervous system, the associated challenges, and their immense potential to enhance DBS and treat disease, even how ultra flexible electronics could lead to the auditory implants of the future and the restoration of hearing. “Although Deep Brain Stimulation has been used for the past two decades, we see little progress in its clinical outcomes,” Renaud says. “Microelectrodes have the potential to open new therapeutic routes, with more efficiency and fewer side effects through a much better and finer control of electrical activation zones.” The preliminary clinical trials related to this research are being done in conjunction with EPFL spin-off company Aleva Neurotherapeutics, the first company in the world to introduce microelectrodes in Deep Brain Stimulation leading to more precise directional stimulation.