A next-generation neural probe for diagnosing and treating epilepsy
In focal epilepsy, a seizure begins in a specific part of the brain. Depending on which brain area is affected, the symptoms can vary from involuntary muscle spasms to flashing lights, or even sudden feelings of terror.
But diagnosing focal epilepsy is far from simple, because a variety of neurological disorders share similar symptoms. And for patients who have received a diagnosis, removal of the affected area of the brain might be the only remaining treatment option if medications fail to control the condition. Yet pinpointing the precise focal point of the seizures is no easy task.
Probing the brain
Narrowing down the location involves inserting several needle-like stereo-electroencephalography (SEEG) probes into the patient’s brain. “What you have are metal cylinders made of platinum-iridium, around 0.8 millimeters in diameter, and then you arrange them in pearl-chain fashion,” says Patrick Ruther, an engineer at the University of Freiburg in Germany1. “You implant up to 15 of these roughly five- to six-centimeter-long tools into one hemisphere to detect the epileptic focus, and potentially surgically remove that part of the brain to help these patients.”
Each probe has a series of electrodes, which detect tiny voltage changes as neurons fire nearby. But Ruther says that whereas typical SEEG probes might only have around a dozen electrodes, the probe being developed by his team can fit around a hundred. “In principle it would allow us to have a much more precise image of what is going on in the brain,” he says. “The idea was to have a device with many, many small electrodes that would allow the neuroscientist not only to analyse the epilepsy of that specific patient, but also to gain more insight into what is going on in case of this neurological disorder.”
In principle it would allow us to have a much more precise image of what is going on in the brain.
The key innovation
Typical SEEG probes have a bundle of wires in their interior, each connecting to a different cylindrical electrode. But because the diameter of the probe has to be small to ensure minimal damage to the patient’s brain when inserted, there is a limit to the number of wires that can fit into the interior.
Ruther and his co-workers dispensed with the interior wires of the standard SEEG probes, replacing them with thin metal tracks sandwiched in a dual layer polyimide substrate. This allowed them to integrate the tracks into the circumference of the cylindrical probe, leaving its interior hollow. This innovation means that many more electrodes can be fitted onto each probe, thus potentially increasing the accuracy of epilepsy diagnosis. Ruther also suggests that integrating electronics2 into the hollow probe cylinder lowers the number of interconnecting wires and increases the device’s reliability. Furthermore, he thinks the interior of the probe could potentially be utilised for other purposes3: “You could do optogenetic stimulation in the brain by integrating miniaturized light sources into the probe.”
Route to the clinic
Ruther and his Freiburg colleagues, along with scientists at the University of Parma in Italy, began the initial development on the probes around eight years ago, demonstrating simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites4. Most recently, in January 2021, the team showed that the probes could be safely implanted into the brain of a monkey (Macaca mulatta) for several weeks5, with minimal damage to the animal’s brain tissue. The authors concluded that the probes should be suitable for human trials.
“The next goal should be a first in human experiment,” says Ruther, “but to fulfil that, we have to apply for new funding.” Assuming that funding is forthcoming, he thinks the probes could be approved for use in the clinic within five to ten years.
Challenges along the way
Ruther says that the trickiest part of development was rolling the 10 µm thick polymeric substrates with electrodes and metal tracks into a cylinder to become the probe. “We had to turn the 2D substrates from microsystems engineering into 3D devices,” he says. Creating a functional, stable device that is just 0.8 mm in diameter was a formidable challenge: “It is easier to construct neural probes on a computer than manually handling these small components in real life.”
Ruther’s key advice for other innovators is to be patient – and to chase after goals that are realistic. “Know your technology, know what can be accomplished with the technology you use. Be open to new ideas, but also do not promise more than what is feasible.” He thinks it’s important to adopt realistic timeframes, because developing a new device can take a very long time. “I think you have to be careful with false expectations, in what kind of information you transmit, in particular in the case of clinical devices,” he says.
The fun part
For Ruther, aside from scientific and technical challenges the best aspect of the process – of his work in general – is the opportunity to collaborate with researchers from different disciplines. “That’s what I love,” he says. “I'm in a really unique situation, because I'm allowed to work with neuroscientists, with cardiologists, with otologists, with people who are very deep in their medical topic, and having discussions about what is needed for these specific disciplines, what has to be improved.”
“When we start with our project partners, we have to learn a common language. This implies breaking down complex technical processes for non-engineer to understand, and vice versa. It takes some time finding this common language, and then using that for the benefit of the entire project. I learnt a lot about various medical professions, and I hope I could transmit the technical aspects from our side – and bringing that together, that's the fun part.”
Interview with Patrick Ruther, February 2021.
Schwaerzle, M. et al. High-resolution Neural Depth Probe with Integrated 460 nm Light Emitting Diode for Optogenetic Applications. In Dig. Tech. Papers IEEE Transducers Conf. 2015 (Anchorage, Alaska, USA, June 21-25, 2015) pp. 1774–1777.
Pothof, F. et al. Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites. J Neural Eng. 2016; 13, 046006.
Gerbella, M. et al. Histological assessment of a chronically implanted cylindrically-shaped, polymer-based neural probe in the monkey. J Neural Eng. 2021; doi: 10.1088/1741-2552/abdd11.