Non-invasive neuromodulation approaches can prevent invasive surgery in Parkinson's patients

From optogenetics to sonogenetics to magnetognetics, scientists around the world are investigating new techniques to treat Parkinson's disease without the need for invasive surgery.

There is still no treatment that can reverse the effects of Parkinson's disease, a condition estimated to affect 10 million people worldwide. As life expectancy increases, the number of people suffering from this disease is set to rise in the future, making the need for effective treatment a priority.

Doctors prescribe oral medication to alleviate the main symptoms and, for a few patients, use deep brain stimulation. The electrodes stimulate the affected areas and relieve the reactions induced by the disease such as tremor or rigidity.

However, this technique presents significant challenges because surgeons have to drill a hole in the skull to implant the electrodes.But what if we could control the neurons without the need of this invasive and expensive procedure?

This is the question some scientists asked themselves a few decades ago, opening the doors to what are known as non-invasive neuromodulation techniques. Although manipulating neurons without touching them was regarded as science fiction, this method gained a lot of popularity, and several groups of researchers worldwide jumped onto investigating it for a wide variety of conditions, including Parkinson's disease.

In 2004, one of those techniques, named optogenetics,was described for the first time, revolutionising the field of neuroscience. It consists of genetically modifying the brain cells to express proteins sensitive to light, meaning that aneuron's activity can be controlled using light pulses. Until last year, this procedure was still considered invasive, as getting the pulses of light inside the brain to control cells required implants.

However, this changed last October when a group of researchers from Stanford University reported having successfully developed an implant-free version of the technique, making deep brain optogenetics without surgery possible in mice.

Following the principles of optogenetics, a new technique called sonogeneticswas proposed in 2015.

We discovered a new set of proteins, which are not normally expressed in the cells that we are trying to control. And the special thing about these proteins is that they are sensitive to ultrasound. By delivering these proteins to the affected cells, they become responsive to ultrasound," he says. "You don't need any surgery, you stick your transducer on the skull, and you deliver theultrasound to control the cells."

Sreekanth Chalasani, Associate Professor, Salk Institute for Biological Studies, US

Chalasani first described sonogenetics. Besides the fact that surgery is not needed, one of the main advantages of this technique is its safety, as Chalasani points out. "Ultrasound is sound waves with frequencies higher than what humans can hear.

It is safe, non-invasive, and we have a lot of experience with it. For decades, we've been using ultrasound to image babies, and to relieve pain," he explains. Moreover, ultrasound goes through skin and bone. Because of this, "the transducer that produces the ultrasound can be outside of the body and still target structures that are deep in the brain, as is required to alleviate symptoms of Parkinson's disease," adds Chalasani.

Although a lot has been accomplished since 2015, some questions remain unsolved. On the one hand,scientists need to find a reliable way to introduce light- and ultrasound-sensitive proteins to the human body. "At the moment, we don't have a way of delivering genes to a specific targets in the human brain," says Chalasani.

"We need a way to express a protein just in the desired cells, and not anywhere else." On the other hand,the technology of the transducer also has to be further developed. "We want something that is tiny, but that produces enough energy to go through the skull without heating the brain," Chalasani explains. "We're developing a new class of transducer that does not cause any heating and, at the same time, produces enough energy to control the cells".

Other than using light and ultrasound, scientists also discovered they could use magnets to control the cells' behaviour. They named this approachmagnetogenetics. The EU FET open project Magneuron, which started in 2016, sought to use the technique to advance cell replacement therapy one step further.

The principle is simple: to replace damaged neurons in the brain with healthy new ones created in the laboratory. But the therapy faces a significant challenge given the complexity of the human brain.

"In brain regeneration, we have a problem when it comes to the central nervous system. You place the neurons in the brain and they don't know where to go after transplantation. Also, the connectivity between neurons is not restored," explains Rolf Heumann, head of the group molecular neurochemistry at the University Ruhr Bochum, in Germany, and one of the participants in the Magneuron project.

To overcome this challenge, the interdisciplinary consortium had the idea to preload neurons in the laboratory with magnetic nanoparticles so that, once implanted in the brain, scientists would be able to control the direction in which the neurons grow by using magnets.

One of the main differences regarding the two techniques explained before is that, in this case, the patients' neurons don't need to be genetically modified. "With the methods we use, we try to avoid genetic manipulation," Heumann explains. "We use nanoparticles that have proteins responsible for directing the growth of the neuron attached to them. Those proteins are made in bacteria, purified and attached to the nanoparticles. Therefore, it's not a primary genetic method on the patient," Heumann points out.

The researchers achieved various milestones. "We described how to handle the pure nanoparticles and bind the proteins to them. Also, we found a way to get the nanoparticles into living cells and manipulate them once inside," explains Fabian Raudzus, an assistant professor at Kyoto University, in Japan, who also worked on the project.

One of the most significant achievements was to find a way to load the nanoparticles into a lot of cells at the same time. "The idea is that we apply some pressure to the cells so that we are able to push a higher quantity of nanoparticles into them," says doctor Sebastian Neumann, from the University Ruhr Bochum, in Germany, and another participant in the Magneuron project. "And this would be an important approach for the future when it comes to the treatment of patients".

Although the project ended in 2019, some of the members continue to work in this field, focusing mainly on finding a stable magnetic gradient to control the nanoparticles, assessing the effects of the nanoparticles in the long term, and moving from in vitro studies in cells to organoids.

Scientists are still far from testing optogenetics, sonogenetics and magnetogenetics in the clinics, but the neuromodulation approaches are fuelling high hopes: they promise not only to avoid invasive surgery, but also reactivate the damaged neurons and reverse the effects of many neurodegenerative disorders.

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