By Deborah Borfitz

May 21, 2024 | In the not-too-distant future, disorders of the brain could be treated with the same precision as heart disease and cancer. The means will be a therapeutic brain-computer interface (BCI) the size of a small blueberry for people suffering from treatment-resistant depression that uses a similar type of implant technology as Elon Musk’s Neuralink for helping paralyzed people speak, according to Jacob Robinson, Ph.D., an engineer at Rice University. 

Two years ago, Robinson founded Motif Neurotech to commercialize the tiny implantable neuromodulation device and began talking to the U.S. Food and Drug Administration (FDA) about how best to proceed toward clinical trials. The startup also set up a community advisory board to gain patient input on design of both the product and clinical studies, he says. 

More than 100 people have already signed up to be notified of future clinical trials on the Motif Neurotech website, Robinson reports, although it is not expected to begin enrollment for another couple of years. “There is so much silent suffering.” 

The clinical need is profound and the condition life-threatening. “About a third of people who suffer from major depressive disorder fail to respond to two or more medications and things can become quite desperate,” he says. “We lose over half a million people to suicide every year, and depression is a biological disorder for which there should be biological solutions.” 

Power of DOT

For years now, doctors have been using brain-stimulating devices in severely depressed people who don’t benefit from medication and talk therapy, but with limited success, says Robinson. This is in part because the transcranial magnetic stimulation devices currently approved by the FDA involve six weeks of once-daily sessions and the benefits accrue for an average of only about 11 months. 

Robinson likens the odyssey of patients with treatment-resistant depression to individuals with kidney disease who need dialysis to stay alive but at the price of being tethered to the clinic. For people often having a hard time simply getting out of bed in the morning, “they fall off because it becomes too hard.”  

This motivated work in his lab to miniaturize a brain stimulator that could be implanted directly and inconspicuously into the bottom of the skull, a device called a digitally programmable over-brain therapeutic, or DOT. As described in an article recently published in Science Advances (DOI: 10.1126/sciadv.adn0858), DOT has sufficient energy to activate human cortical tissue through the dura, the protective membrane covering the brain, yet still implantable through a standard, roughly 14-millimeter hole commonly made in the skull during neurosurgical procedures.  

The device has no implanted batteries and instead wirelessly delivers power to generate stimulation currents using an external transmitter. It was tested temporarily in a human patient to activate the motor cortex, resulting in hand movement. 

This showed that DOT, despite its size, could efficiently activate a brain network on par with clinical-grade brain stimulation devices being prescribed by psychiatrists today that are reimbursed by insurance companies, Robinson says. The hand movement indicated an entire neural circuit was being engaged with electrical stimulation—something impossible to do with over-the-counter, battery-powered mood enhancement devices sold by Amazon as a treatment for depression and anxiety.   

DOT is sealed in a glass package and was found to interface with the brain stably for a 30-day duration study in pigs. Some animals had a natural inflammatory reaction to the foreign body within the first two weeks and then stabilized, explains Robinson, which is a biological response akin to that seen with implanted cardiac devices and spinal cord stimulators. While a good sign, the finding will be confirmed in a longer preclinical safety study, he adds. 

The real possibility here is that the same treatment now available to patients only via a big machine in the doctor’s office will eventually be a therapeutic they literally take with them, says Robinson. With a minor procedure that he likens to skin surgery, DOT could be chronically implanted in about 30 minutes on an outpatient basis.   

Venture Support

Motif Neurotech was one of the first Rice-invented technologies that translated into a venture-backed company thanks to the efforts of the Rice Biotech Launch Pad, says Robinson. “The launchpad is developing the programming and policies that will facilitate this transfer and, hopefully, make stories like Motif more common.” 

Commercialization was the only way to get the “extreme miniaturization” wireless power technology through the expensive and time-consuming FDA approval process and into real-world use to benefit patients, he says. Some of the first versions of the device were created with funding from the Defense Advanced Research Projects Agency, and those prototypes subsequently helped Motif raise a little over $20 million from venture capitalists (e.g., Arboretum Ventures, re.Mind Capital, Dolby Family Ventures, and KdT Ventures) to fund further research and development work. 

Other neurotech companies are emerging to probe the potential of BCIs to treat neurological disorders, most notably the device under development by Musk’s brain-implant company Neuralink. One of the first investors in Motif was on the founding team of Neuralink, its former president and CEO Max Hodak has also invested, Robinson notes.  

Neuralink is intent on building a BCI to help people with paralysis communicate, but “for every person with a spinal cord injury there are 10 people suffering from treatment-resistant depression and those people are suffering just as much, it is just not visible,” Robinson adds. The Neuralink implant is also meant to fit into the skull with thin threads reaching into brain tissue, which is more invasive than what is under development by Motif. The Motif device is thus less likely to cause tissue damage, bleeding, and infection.  

From a technology standpoint, the main advancement that DOT represents is the ability for magnetic power transfer— like the technology used to wirelessly power earbuds for iPhones—to work well for much smaller devices because the energy is transferred based on the strength rather than the area of the magnetic field, Robinson explains. To keep the stimulator charged, users would need only wear a special cap for about 20 minutes a day. 

The device is also compatible with surgical tooling neurosurgeons routinely use today to remove the skull. “The [surgical] procedure is done about 200,000 times a year for other applications and so there is already a workforce that, in principle, knows how to do the procedure to implant this device,” he says. That means “relatively no new training for neurosurgeons in order to deploy it, and that was a big unlock for us.” 

Patient-Inspired Design

Based on conversations Motif Neurotech has had with the FDA, the initial phase 1 clinical trial will enroll several patients and be an open label study where everyone gets the therapy, Robinson says. Randomized clinical trials would inevitably follow where the sham control would involve a “delayed start” of the actual therapy by two or three weeks. A strong placebo effect is not expected, considering that participants will be patients who have already failed multiple other interventions, he adds. 

Creation of the community advisory board—including those who have found help through clinical trials for medical implantable devices or received electroconvulsive therapy for relief of severe symptoms—is designed to help the company make decisions with the end user in mind and keep patients engaged during the wait for trials to begin, Robinson says. “We are leaning on them to help advise us on the most meaningful way to give patients hope but in line with [the] reality... that we are working just as hard and as fast as we can to get [to study start].” 

Critically, advisory board members will also have input on the design of the trial and usability of the DOT product from the patient experience perspective. “There are so many choices that we have to make in terms of usability, for example if patients want to use it at night when they’re sleeping or during the day when they’re brushing their teeth,” he says. Another key question is how they’d prefer to engage with the device through an associated, smartphone-based app.  

The longer-term vision of the company is to create networks of implants for adaptive personalized therapies based on a person’s “brain signature,” says Robinson. The activity in everybody’s brain is slightly different and scientists believe that certain patterns correspond to different types of brain disorders, which would help doctors figure out the best mental health therapy for individual patients.  

Robinson says he wants people who suffer from difficult-to-treat mental health conditions to know researchers are working on creating more treatment options, and to share the news about Motif’s forthcoming trials among fellow patients and their families. He also hopes clinicians and engineers appreciated the importance of developing science-based therapeutic options “not just for the communication-disabled but also for the millions of people who suffer from difficult-to-treat depression.” 

One vision for the future is that “mental health looks a lot like interventional cardiology today,” he says. That means a trip to the doctor’s office for a diagnosis followed, as appropriate, by the prescribing of medicine or a device. “It is a biological problem that should have no more shame and stigma than breaking your ankle. “